WO2000063165A1 - Mmp inhibitor - Google Patents

Mmp inhibitor Download PDF

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Publication number
WO2000063165A1
WO2000063165A1 PCT/JP2000/002508 JP0002508W WO0063165A1 WO 2000063165 A1 WO2000063165 A1 WO 2000063165A1 JP 0002508 W JP0002508 W JP 0002508W WO 0063165 A1 WO0063165 A1 WO 0063165A1
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WIPO (PCT)
Prior art keywords
compound
group
membered
heterocyclic
salt
Prior art date
Application number
PCT/JP2000/002508
Other languages
French (fr)
Inventor
Masahiro Neya
Hitoshi Yamazaki
Kentaro Sato
Noriko Yoshida
Yoshimasa Imamura
Hiroyuki Setoi
Original Assignee
Fujisawa Pharmaceutical 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.)
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Publication date
Application filed by Fujisawa Pharmaceutical Co., Ltd. filed Critical Fujisawa Pharmaceutical Co., Ltd.
Priority to EP00917336A priority Critical patent/EP1171422A1/en
Priority to JP2000612261A priority patent/JP2002542228A/en
Publication of WO2000063165A1 publication Critical patent/WO2000063165A1/en

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    • 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
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/70—Sulfur atoms
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    • A61P19/00—Drugs for skeletal disorders
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    • 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
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    • 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]
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    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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    • C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
    • C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
    • C07C259/06—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms
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    • 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
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    • 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
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    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no 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
    • C07D211/56—Nitrogen atoms
    • C07D211/58—Nitrogen atoms attached in position 4
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    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/92—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with a hetero atom directly attached to the ring nitrogen atom
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    • 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
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/68—One oxygen atom attached in position 4
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    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or 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
    • C07D307/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no 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
    • C07D309/10—Oxygen atoms
    • C07D309/12—Oxygen atoms only hydrogen atoms and one oxygen atom directly attached to ring carbon atoms, e.g. tetrahydropyranyl ethers
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    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no 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
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    • 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
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    • 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
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    • 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
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    • C07C2601/14—The ring being saturated

Definitions

  • the present invention relates to new compounds and pharmaceutically acceptable salts thereof.
  • MMP matrix metalloproteinases
  • TNF tumor necrosis factor
  • piperazine compounds to be useful as metalloproteinase inhibitors, or the like are known (WO 97/20824, etc.).
  • One object of the present invention is to provide new and useful compounds and pharmaceutically acceptable salts thereof, and to provide a process for preparing said new compound and salts thereof, which have pharmacological activities such as MMP- or TNF -inhibitory activity and the like.
  • Another object of the present invention is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising, as an active ingredient, said compound or a pharmaceutically acceptable salt thereof.
  • a further object of the present invention is to provide use of said compounds and pharmaceutically acceptable salts thereof as medicaments for prophylactic and therapeutic treatment of MMP- or TNF -mediated diseases.
  • a still further object of the present invention is to provide a method for using the same for the treatment and/ or the prevention of MMP- or TNF -mediated diseases in mammals, especially humans.
  • the compounds of the present invention have inhibitory activity on MMP or the production of TNF , and are useful for the treatment and/or prevention of diseases such as stroke, arthritis, cancer, tissue ulceration, decubitus ulcer, restenosis, periodontal disease, epidermolysis buUosa, scleritis, psoriasis and other diseases characterized by matrix metalloproteinase activity, as well as AIDS, sepsis, septic shock and other diseases caused by the production of TNF ⁇ .
  • diseases such as stroke, arthritis, cancer, tissue ulceration, decubitus ulcer, restenosis, periodontal disease, epidermolysis buUosa, scleritis, psoriasis and other diseases characterized by matrix metalloproteinase activity, as well as AIDS, sepsis, septic shock and other diseases caused by the production of TNF ⁇ .
  • Matrix-degrading metallo- proteases such as gelatinase (MMP-2, MMP-9), stromelysin (MMP-3) and collagenase (MMP-1, MMP-8, MMP-13), are involved in tissue matrix degradation and have been implicated in many pathological conditions involving abnormal connective tissue and basement membrane matrix metabolism, such as arthritis (e.g., O-feoarthritis and rheumatoid arthritis), cerebral disease (e.g., stroke, etc.), tissue ulceration (e.g. , corneal, epidermal and gastric ulcerations), abnormal wound healing, periodontal disease, bone disease (e.g., Paget's disease and osteoporosis), tumor metastasis or invasion and HrV-infection.
  • MMP-2, MMP-9 gelatinase
  • MMP-3 stromelysin
  • MMP-1, MMP-8, MMP-13 collagenase
  • TNF is the prime mediator of the inflammatory response seen in sepsis and septic shock.
  • R 1 is halogen, nitro, lower alkoxy, optionally substituted aryloxy, arylthio, aroyl, heterocyclic-oxy, optionally substituted aryl or optionally substituted heterocyclic group;
  • R 2 is hydrogen or halogen
  • R 3 is hydrogen or lower alkyl
  • R 4 and R 5 are independently hydrogen, lower alkyl, or lower cycloalkyl, or R 4 and R 5 are combined together to form lower alkylene, which is optionally interrupted by oxygen, sulfur, sulfinyl, sulfonyl or optionally mono-substituted nitrogen; R 6 is hydroxy or protected hydroxy;
  • X is aryl or heterocyclic group
  • Y is carbonyl or sulfonyl
  • Z is lower alkylene; and a pharmaceutically acceptable salt thereof.
  • the object compounds of the present invention can be prepared by the following processes.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X, Y and Z are as defined above, R 61 is protected hydroxy, R 7 is imino-protective group, R 8 is protected carboxy, L is a leaving group, m and n are independently an integer of 1 to 5, provided that 2- ⁇ m+n ⁇ 6.
  • the starting compounds (Tf), (HI) and (TV) can be prepared according to the following Preparations or by a conventional method.
  • Suitable pharmaceutically acceptable salts of the object compounds may be conventional non-toxic salts and include an add addition salt such as an organic add salt (e.g., acetate, trifluoroacetate, maleate, tartrate, fumarate, methanesulfonate, benzenesulfonate, formate, toluenesulfonate, etc.), an inorganic add salt (e.g., hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, etc.), or a salt with a base such as an amino add (e.g., arginine, aspartic add, glutamic add, etc.), an alkali metal salt (e.g., sodium salt, potassium salt, etc.), an alkaline earth metal salt (e.g., caldum salt, magnesium salt, etc.), an ammonium salt, an organic base salt (e.g., trimethylamine salt, triethylamine salt, pyridine salt
  • the object compounds and pharmaceutically acceptable salts thereof may indude solvates such as endosure compounds (e.g., hydrate, etc.).
  • Suitable "aryl” in the term “aryl”, “optionally substituted aryl”, “optionally substituted aryloxy” and “arylthio” indudes an aryl having 6 to 10 carbon atoms, such as phenyl, tolyl, xylyl, cumenyl, mesiryl, naphthyl and the like, preferably phenyl and naphthyl for R 1 , and phenyl for X.
  • substituents for substituted aryl are halogen, cyano, nitro, amino, acylamino, lower alkylamino, carbamoyl, hydroxy, lower alkoxy, C 6 -C 10 aryloxy, lower alkyl, C 5 -C 10 aryl, heterocyclic-oxy and the like, preferably heterocyclic-oxy (e.g., pyridyloxy, etc.).
  • substituents for substituted aryloxy are the same as ones defined above with regard to "substituted aryl", preferably halogen, lower alkyl and cyano.
  • heterocyclic group in the term “heterocyclic group”, “optionally substituted heterocyclic group” and 'heterocyclic-oxy group” means saturated or unsaturated, 3- to 8-membered monocyclic or polycyclic heterocyclic group containing at least one hetero atom such as oxygen atom, sulfur atom, nitrogen atom and the like.
  • heterocyclic groups are:
  • pyrrolyl pyrrolinyl, imidazolyl, pyrazolyl, pyridyl and its N-oxide, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (e.g., 4H-l,2,4-triazolyl, lH-l,2,3-triazolyl, 2H-l,2,3-triazolyl, etc.), tetrazolyl (e.g., lH-tetrazolyl, 2H- tetrazolyl, etc.), dihydrotriazinyl (e.g., 4,5-dihydro-l,2,4-triazinyl, 2,5-dihydro- 1,2,4-triazinyl, etc.), and the like;
  • -unsaturated condensed preferably bicyclic, 7- to 13-membered, preferably 9- or 10-membered, heterocyclic group containing 1 to 5 nitrogen atoms, for example, indolyl, isoindolyl, mdolizinyl, benz midazolyl, quinolyl, iso-quinolyl, indazolyl, benzotriazolyl, tetrazolopyridyl, tetrazolopyridazinyl (e.g., tetrazolo[l,5- b]pyridazinyl, etc.), d ytirotriazolopyridazinyl, and the like;
  • oxazolyl e.g., 1,2,4-oxadiazolyl, 1,3,4- oxadiazolyl, 1,2,5-oxadiazolyl, etc.
  • oxadiazolyl e.g., 1,2,4-oxadiazolyl, 1,3,4- oxadiazolyl, 1,2,5-oxadiazolyl, etc.
  • -unsaturated condensed preferably bicyclic, 7- to 13-membered, preferably 9- or 10-membered, heterocyclic group containing 1 or 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, benzoxazolyl, benzoxadiazolyl, and the like;
  • thiazolyl 1,2-thiazolyl, thiazolinyl, thiadiazolyl (e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,2,3-thiadiazolyl, etc.), and the like;
  • -unsaturated condensed preferably bicyclic, 7- to 13-membered, preferably 9- or 10-membered, heterocyclic group containing 1 or 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, berjzothiazolyl, ben ⁇ thiadiazolyl, and the like;
  • More preferable heterocyclic groups may be unsaturated 5- or 6-membered heteromonocyclic group containing 1 to 4 nitrogen atoms (e.g. pyridyl, etc.), unsaturated 5- or 6-membered heteromonocyclic group containing 1 or 2 sulfur atoms (e.g., thienyl, etc.), unsaturated 5- or 6-membered heteromonocyclic group containing 1 or 2 oxygen atoms (e.g., furyl, etc.), and the most preferable examples are pyridyloxy for R 1 and pyridyl, thienyl and furyl for X.
  • nitrogen atoms e.g. pyridyl, etc.
  • unsaturated 5- or 6-membered heteromonocyclic group containing 1 or 2 sulfur atoms e.g., thienyl, etc.
  • unsaturated 5- or 6-membered heteromonocyclic group containing 1 or 2 oxygen atoms e.g., furyl
  • heterocyclic groups may have one or more substituents.
  • substituents for substituted heterocyclic group are the same as those for optionally substituted aryl or optionally substituted aryloxy.
  • Suitable “aroyl” may include C 6 -C 10 aroyl (e.g., benzoyl, toluoyl, xyloyl, etc.), preferably benzoyl for R 1 .
  • Suitable 'lower alkyl is a straight or branched alkyl having 1 to 6 carbon atoms, and exemplified by methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert- butyl, pentyl, hexyl and the like, preferably methyl for R 1 , and methyl and ethyl for R 4 and/or R 5 .
  • Suitable 'lower alkoxy is a straight or branched alkenyl having 1 to 6 carbon atoms, and exemplified by methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, tert-pentyloxy, hexyloxy and the like, preferably methoxy for R 1 .
  • Suitable "protected hydroxy” includes hydroxy protected by a conventional protective group, for example, tetrahydropyranyloxy, substituted lower alkoxy such as lower alkoxy(lower)alkoxy (e.g., methoxymethoxy), lower alkoxy(-Ower)alkoxy(lower)alkoxy (e.g., methoxyethoxymethoxy) and substituted or unsubstituted C 6 -C 10 aryl(lower)alkoxy (e.g., benzyloxy, nitrobenzyloxy); acyloxy such as lower alkanoyloxy (e.g., acetoxy, propionyloxy, pivaloyloxy), C 6 -C 10 aroyloxy (e.g., benzoyloxy, fluorenecarbonyloxy), lower alkoxycarbonyloxy (e.g., methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, is
  • lower is intended to mean 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, unless otherwise indicated.
  • Suitable "halogen” includes fluorine, bromine, chlorine and iodine.
  • Suitable 'lower cydoalkyl is a cydoalkyl having 3 to 7 carbon atoms, and exemplified by cyclopropyl, cyclobutyl, cydopentyl and cydohexyl, preferably cydohexyl for R 4 and/ or R 5 .
  • Suitable 'lower alkylene is exemplified by methylene, ethylene, tri-methylene, tetra-methylene, penta-methylene and hexa-methylene, preferably, tri-methylene. tetia-methylene and penta-methylene for R 4 and R 5 , methylene and methylmethylene for Z.
  • Suitable substituent of "optionally mono-substituted nitrogen” is exemplified by C 6 -C 10 ar(lower)alkoxycarbonyl, lower alkylsulfonyl, C 6 -C 10 arylsulfonyl, C 5 -C 10 aroyl, mono- or di(lower)alkylcarbamoyl, lower cycloalkylcarbonyl, and the like.
  • Suitable R 4 R 5 is exemplified as follows.
  • acyla ino Suitable acyl moiety of "acyla ino" indudes acyl such as aliphatic acyl, aromatic acyl, heterocyclic acyl and aliphatic acyl substituted by aromatic or heterocyclic group(s) derived from carboxylic, carbonic, sulfonic and carbamic adds.
  • alkanoyl such as lower alkanoyl (e.g. , formyl, acetyl, propionyl, butylyl, isobutylyl, valeryl, isovaleryl, pivaloyl, hexanoyl, etc.)
  • alkylsulfonyl such as lower alkylsulfonyl (e.g., mesyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, pentylsulfonyl, hexylsulfonyl, etc.)
  • carbamoyl N- alkylcarbamoyl (e.g., methylcarbamoyl, ethylcar
  • the aromatic acyl may indude C 5 -C 10 aroyl (e.g., benzoyl, toluoyl, xyloyl, etc.), N-(C 6 -C 10 )arylcarbamoyl (e.g., N-phenylcarbamoyl, N-tolylcarbamoyl, N- naphthylcarbamoyl, etc.), C 6 -C 10 arenesulfonyl (e.g., benzenesulfonyl, tosyl, etc.), and the like.
  • C 5 -C 10 aroyl e.g., benzoyl, toluoyl, xyloyl, etc.
  • N-(C 6 -C 10 )arylcarbamoyl e.g., N-phenylcarbamoyl, N-tolylcarbamoyl, N- naphthyl
  • the heterocyclic acyl may indude heterocyclic-carbonyl (e.g., furoyl, thenoyl, nicotinoyl, isonicotinoyl, thiazolylcarbonyl, thiadiazolylcarbonyl, tetrazolylcarbonyl, etc.), and the like.
  • heterocyclic-carbonyl e.g., furoyl, thenoyl, nicotinoyl, isonicotinoyl, thiazolylcarbonyl, thiadiazolylcarbonyl, tetrazolylcarbonyl, etc.
  • the aliphatic acyl substituted by aromatic group(s) may indude aralkanoyl such as phenyl(lower)alkanoyl (e.g., phenylacetyl, phenylpropionyl, phenylhexanoyl, etc.), aralkoxycarbonyl such as phenyl(lower) alkoxycarbonyl (e.g., benzyloxycarbonyl, phenethyloxycarbonyl, etc.), aryloxyalkanoyl such as phenoxy(lower)alkanoyl (e.g., phenoxyacetyl, phenoxypropionyl, etc.), and the like.
  • aralkanoyl such as phenyl(lower)alkanoyl (e.g., phenylacetyl, phenylpropionyl, phenylhexanoyl, etc.), aralkoxycarbonyl such
  • the aliphatic acyl substituted by heterocydc group(s) may include heterocyclic-alkanoyl such as heterocyclic-(lower)alkanoyl (e.g., thienylacetyl, imidazolylacetyl, furylacetyl, tetrazolylacetyl, thiadiazolylpropionyl, etc.), and the like.
  • heterocyclic-alkanoyl such as heterocyclic-(lower)alkanoyl (e.g., thienylacetyl, imidazolylacetyl, furylacetyl, tetrazolylacetyl, thiadiazolylpropionyl, etc.), and the like.
  • lower alkyl moiety of "lower alkylamino" is the same as lower alkyl defined above.
  • Suitable compounds having the formula (I) are: compound (I) wherein
  • R 1 is halogen, nitro, lower alkoxy, C 6 -C 10 aryloxy optionally substituted by at least one group selected from the group consisting of halogen, cyano, nitro, amino, acylamin, lower alkylamino, carbamoyl, hydroxy, lower alkoxy, C 6 -C 10 aryloxy, lower alkyl, C 6 -C 10 aryl and heterocyclic-oxy, C 6 -C 10 arylthio, C 6 -C 10 aroyl, heterocyclic-oxy, C 6 -C 10 aryl optionally substituted by at least one group selected from the group consisting of halogen, cyano, nitro, amino, acylamino, lower alkylamino, carbamoyl, hydroxy, lower alkoxy, C 6 -C 10 aryloxy, lower alkyl, C 6 -C 10 aryl and heterocyclic-oxy, or heterocyclic group optionally substituted by at least one group selected from
  • R 4 and R 5 are independently hydrogen, lower alkyl, or lower cydoalkyl, or R 4 and R 5 are combined together to form lower alkylene, which is optionally interrupted by oxygen, sulfur, sulfinyl, sulfonyl or imino, wherein the imino is optionally mono- substituted by a group of C 6 -C 10 ar(lower)alkoxycarbonyl, lower alkylsulfonyl, C 6 - C 10 arylsulfonyl, C 6 -C 10 aroyl, mono(lower)alkylcarbamoyl, di(lower)alkylcarbamoyl or lower cydoalkylcarbonyl;
  • R 6 is hydroxy, tetrahydropyranyloxy or C 6 -C 10 aryl(lower)alkoxy
  • X is C 6 -C 10 aryl or heterocyclic group, said heterocyclic group being unsaturated 3- to 8-membered, heteromonocyclic group containing 1 to 4 nitrogen atoms, saturated 3- to 8-membered, heteromonocyclic group containing 1 to 4 nitrogen atoms, unsaturated bicyclic 7- to 13-membered, heterocyclic group containing 1 to 5 nitrogen atoms, unsaturated 3- to 8-membered, heteromonocyclic group containing 1 or 2 oxygen atoms and 1 to 3 nitrogen atoms, saturated 3- to 8-membered, heteromonocyclic group containing 1 or 2 oxygen atoms and 1 to 3 nitrogen atoms, unsaturated bicyclic 7- to 13-membered, heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, unsaturated 3- to 8-membered, heteromonocyclic group containing 1 or 2 sulfur atoms and 1 to 3 nitrogen atoms, saturated 3- to 8-membered,
  • R 1 is halogen; nitro; lower alkoxy; C 6 -C 10 aryloxy optionally substituted by at least one group selected from the group consisting of halogen, cyano, nitro, amino, acylamino, lower alkylamino, carbamoyl, hydroxy, lower alkoxy, C 6 -C 10 aryloxy, lower alkyl, C 6 -C 10 aryl and heterocyclic-oxy, said heterocyclic group being unsaturated 5- or 6-membered, heteromonocyclic group containing 1 to 4 nitrogen atoms; C 5 -C 10 arylthio; C 5 -C 10 aroyl; heterocyclic- ⁇ xy, said heterocyclic group being unsaturated 5- or 6-membered, heteromonocyclic group containing 1 to 4 nitrogen atoms; C 5 -C 10 aryl optionally substituted by at least one group selected from the group consisting of halogen, cyano, nitro, amino, acylamino, lower al
  • heterocyclic group being unsaturated 5- or
  • heterocyclic group 6-membered, heteromonocyclic group containing 1 to 4 nitrogen atoms; or heterocyclic group, said heterocyclic group being unsaturated 5- or 6-membered, heteromonocyclic group containing 1 to 4 nitrogen atoms, which is also optionally substituted by at least one group selected from the group consisting of halogen, cyano, nitro, amino, acylamino, lower alkylamino, carbamoyl, hydroxy, lower alkoxy, C 6 -C 10 aryloxy, lower alkyl, C 6 -C 10 aryl and heterocyclic-oxy, said heterocyclic group being unsaturated 5- or 6-membered, heteromonocyclic group containing 1 to 4 nitrogen atoms;
  • R 4 and R 5 are independently hydrogen, lower alkyl, or lower cydoalkyl, or R 4 and R 5 are combined together to form lower alkylene, which is optionally interrupted by oxygen, sulfur, sulfinyl, sulfonyl, imino, C 6 -C 10 ar(lower)alkoxyc ⁇ rbonylirr ⁇ ino, lower alkylsulfonyljmino, C 6 -C 10 arylsulfonylirriino, C 6 -C 10 aroylimino, mono(lower)alkylcarbamoylimino, di(lower)alkylcarban oylirx ⁇ ino or lower
  • X is C 6 -C 10 aryl or heterocyclic group, said heterocyclic group being unsaturated 5- or 6-membered, heteromonocyclic group containing 1 to 4 nitrogen atoms, unsaturated 5- or 6-membered, heteromonocyclic group containing 1 or 2 sulfur atoms, or unsaturated 5- or 6-membered, heteromonocyclic group containing 1 or 2 oxygen atoms, compound (I) wherein
  • R 1 is halogen; nitro; lower alkoxy; phenoxy or naphthyloxy, each of which is optionally substituted by at least one group selected from the group consisting of halogen, cyano and lower alkyl; phenylthio; benzoly; pyridyloxy; phenyl optionally substituted by halogen; or pyridyl,
  • R 4 and R 5 are independently hydrogen, lower alkyl, or lower cydoalkyl, or R 4 and R 5 are combined together to form lower alkylene, which is optionally interrupted by oxygen, sulfur, sulfinyl, sulfonyl, imino, phenyl(lower)alkoxyc ⁇ rbonylirnino, lower al ylsuffonylimino, phenylsuffony]imino, benzoylimino, mono(lower)a]kylcarbarnoylimino, di(lower)alkylcarbamoylimino or lower cycloalkylcarbonylimino,
  • R 6 is hydroxy, tetrahydropyranyloxy or phenyl(lower)alkoxy
  • X is phenyl, pyridyl, thienyl or furyl and compound (I) wherein
  • R 1 is halogen; nitro; lower alkoxy; phenoxy, naphthyloxy, halophenoxy, cyanophenoxy, lower alkylphenoxy, phenylthio; benzoyl; pyridyloxy; halophenyl; or pyridyl;
  • R 4 and R 5 are combined together to form a group of the formula selected from the group consisting of the following formulas:
  • R 6 is hydroxy
  • X is a group selerted from the group consisting of
  • the compound (1-2) or a salt thereof can be prepared by hydrolysis or reduction of the compound (1-1) or a salt thereof.
  • Suitable method of this elimination reaction indudes conventional ones such as hydrolysis, reduction and the like.
  • the hydrolysis is preferably carried out in the presence of a base or an add induding Lewis add.
  • Suitable base indudes an inorganic base and an organic base such as an alkali metal (e.g., sodium, potassium, etc.), an alkaline earth metal (e.g., magnesium, caldum, etc.), the hydroxide or carbonate or hydrogencarbonate thereof, trialkylamine (e.g., trimetriylamine, triethylamine, etc.), picoline, 1,5- diazabicydo[4.3.0]non-5-one, and the like.
  • alkali metal e.g., sodium, potassium, etc.
  • an alkaline earth metal e.g., magnesium, caldum, etc.
  • trialkylamine e.g., trimetriylamine, triethylamine, etc.
  • picoline 1,5- diazabicydo[4.3.0]non-5-one, and the like.
  • Suitable add indudes an organic add (e.g., formic add, acetic add, propionic add, trichloroacetic add, tiifiuoroacetic add, etc.), and an inorganic add (e.g., hydrochloric add, hydrobromic add, sulfuric add, hydrogen chloride, hydrogen bromide, etc.).
  • organic add e.g., formic add, acetic add, propionic add, trichloroacetic add, tiifiuoroacetic add, etc.
  • an inorganic add e.g., hydrochloric add, hydrobromic add, sulfuric add, hydrogen chloride, hydrogen bromide, etc.
  • Lewis add such as trihaloacetic add (e.g., trichloroacetic add, tiifiuoroacetic add, etc.) and the like is preferably carried out in the presence of cation trapping agent (e.g. , anisole, phenol, etc.). This reaction is usually carried out without solvent
  • the reaction may be carried out in a conventional solvent such as water, alcohol (e.g., methanol, ethanol, isopropyl alcohol, etc.), tetrahydrofuran, dioxane, toluene, methylene chloride, ethylene dichloride, chloroform, N,N- dimethylformamide and N,N-dimethylacetamide, a mixture thereof, or any other organic solvents which do not adversely affect the reaction.
  • a conventional solvent such as water, alcohol (e.g., methanol, ethanol, isopropyl alcohol, etc.), tetrahydrofuran, dioxane, toluene, methylene chloride, ethylene dichloride, chloroform, N,N- dimethylformamide and N,N-dimethylacetamide, a mixture thereof, or any other organic solvents which do not adversely affect the reaction.
  • the reaction temperature is not critical and the reaction is usually carried out under cooling to warming.
  • the reduction is carried out in a conventional manner, including chemical reduction and catalytic reduction.
  • Suitable reducing reagents to be used in chemical reduction are a hydride (e.g., hydrogen iodide, hydrogen sulfide, lithium aluminum hydride, sodium borohydride, sodium cyanoborohydride, etc.), or a combination of a metal (e.g., tin, zinc, iron, etc.) or a metallic compound (e.g., diromium chloride, chromium acetate, etc.) and an organic add or an inorganic add (e.g., formic add, acetic add, propionic add, trifluoroacetic add, p-toluenesulfonic add, hydrochloric add, hydrobromic add, etc.).
  • a hydride e.g., hydrogen iodide, hydrogen sulfide, lithium aluminum hydride, sodium borohydride, sodium cyanoborohydride, etc.
  • a metal e.g., tin, zinc, iron, etc.
  • Suitable catalyst to be used in catalytic reduction is conventional one such as platinum catalyst (e.g., platinum plate, spongy platinum, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.), palladium catalyst (e.g., spongy palladium, palladium black, palladium oxide, palladium on carbon, colloidal palladium, palladium on barium sulfate, palladium on barium carbonate, etc.), nickel catalyst (e.g., reduced nickel, nickel oxide, Raney nickel, etc.), cobalt catalyst (e.g., reduced cobalt, Raney cobalt, etc.), iron catalyst (e.g., reduced iron, Raney iron, Ullman iron, etc.), and the like.
  • platinum catalyst e.g., platinum plate, spongy platinum, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.
  • palladium catalyst e.g., spongy palladium, palladium black, palladium oxide, palladium on carbon
  • the reduction is usually carried out in a conventional solvent such as water, alcohol (e.g., methanol, ethanol, isopropyl alcohol, etc.), tetrahydrofuran, dioxane, toluene, methylene chloride, ethylene dichloride, chloroform, N,N- dirneu ylformamide, N,N-dirnethylacetamide and cyclohexane, a mixture thereof, or any other organic solvents which do not adversely affect the reaction.
  • a conventional solvent such as water, alcohol (e.g., methanol, ethanol, isopropyl alcohol, etc.), tetrahydrofuran, dioxane, toluene, methylene chloride, ethylene dichloride, chloroform, N,N- dirneu ylformamide, N,N-dirnethylacetamide and cyclohexane, a mixture thereof, or any other organic solvents which do not adversely affect the reaction.
  • alcohol
  • the compound (I) or a salt thereof can be prepared by reacting the compound (II) or its reactive derivative at the carboxyl group, or a salt thereof, with the compound: H 2 N-R 6 or its reactive derivative at the amino group, or a salt thereof.
  • Suitable salts of the compound (IT) and the compound: H 2 N-R 6 may be the same as those exemplified for the compound (I).
  • the reaction is usually carried out in a conventional solvent such as water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dirnethyl-formamide, pyridine and dichloromethane, a mixture thereof, or any other organic solvents which do not adversely affect the reaction.
  • a conventional solvent such as water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dirnethyl-formamide, pyridine and dichloromethane, a mixture thereof, or any other organic solvents which do not adversely affect the reaction.
  • This reaction can be carried out in the presence of an organic or inorganic base such as alkali metal (e.g., lithium, sodium, potassium, etc.), alkaline earth metal (e.g., caldum, etc.), alkali metal hydride (e.g., sodium hydride, etc.), alkaline earth metal hydride (e.g., caldum hydride, etc.), alkali metal hydroxide (e.g., sodium hydroxide, potassium hydroxide, etc.) , alkali metal carbonate (e.g.
  • alkali metal e.g., lithium, sodium, potassium, etc.
  • alkaline earth metal e.g., caldum, etc.
  • alkali metal hydride e.g., sodium hydride, etc.
  • alkaline earth metal hydride e.g., caldum hydride, etc.
  • alkali metal hydroxide e.g., sodium hydroxide, potassium hydroxide, etc.
  • alkali metal bicarbonate e.g., sodium bicarbonate, potassium bicarbonate, etc.
  • alkali metal alkoxide e.g., sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.
  • alkali metal alkanoic add e.g., sodium acetate, etc.
  • trialkylamine e.g., triethylamine, etc.
  • pyridine compound e.g., pyridine, lutidine, picoline, 4-dimeu ylaminopyridine, etc.
  • quinoline lithium diisopropylamide, and the like.
  • Suitable reactive derivative at the amino group of the compound: H 2 N-R 6 may indude Schiffs base type irnino or its tautomeric enamine type isomer formed by the reaction of the compound: HjN-R 6 with a carbonyl compound such as aldehyde, ketone or the like; a silyl derivative formed by the reaction of the compound: ⁇ tjN-R 6 with a silyl compound such as bis(trirnethylsilyl)acetamide, mono(rrimethylsilyl)acetamide, bis(trimethylsilyl)urea or the like; a derivative formed by the reaction of the compound: H 2 N-R 6 with phosphorus trichloride or phosgene, and the like.
  • Suitable reactive derivative at the carboxy group of the compound (II) may indude an add halide, an add anhydride, an activated amide, an activated ester, and the like.
  • Suitable examples of the reactive derivative may be an add chloride; an add azide; a mixed add anhydride with add such as substituted phosphoric add (e.g., dialkylphosphoric add, phenylphosphoric add, diphenylphosphoric add, dibenzylphosphoric add, halogenated phosphoric add, etc.), dialkylphosphorous add, sulfurous add, thiosulfuric add, su furic add, sulfonic add (e.g., methanesulfonic add, etc.), aliphatic carboxylic add (e.g., acetic add, propionic add, butyric add, isobutyric add, pivalic add, pentanoic add, isopentanoic add, 2-ethylbutyric add, trichlor
  • the reaction is preferably carried out in the presence of a conventional condensing agent such as N, N'-cficydohexylcarbodiimide; N-cydohexyl-N'- morpholmoethylcarbodiimide; N-cyclohexyl-N-(4-di- ethylaminocydohexyl)- c ⁇ rbodiimide; N,N'-cfiethylcarbodiimide; N,N'-di- isopropylcarbodiimide; N-ethyl- N'-(3-cl-methylam opropyl)-carbodiimide; N,N'-c ⁇ rbonylbis-(2-methylimidazole) ; pentamethyleneketene-N-cydohexylimine; diphenylketene-N-cyclohexylimine; ethoxyacetylene; 1 -alk
  • reaction temperature is not critical, and the reaction is usually carried out under cooling.
  • the compound (I) or a salt thereof can be prepared by reacting the compound (HI) or a salt thereof with the compound: R X -X(R 2 )-Y-L or a salt thereof.
  • Suitable salts of the compound (HI) and the compound: R'-X ⁇ J-Y-L may be the same as those exemplified with respect to the compound
  • the reaction is usually carried out in a conventional solvent such as water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine and dichloromethane, a mixture thereof, or any other organic solvents which do not adversely affect the reaction.
  • a conventional solvent such as water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine and dichloromethane, a mixture thereof, or any other organic solvents which do not adversely affect the reaction.
  • This reaction can be carried out in the presence of an organic or inorganic base such as alkali metal (e.g., lithium, sodium, potassium, etc.), alkaline earth metal (e.g., caldum, etc.), alkali metal hydride (e.g., sodium hydride, etc.), alkaline earth metal hydride (e.g., caldum hydride, etc.), alkali metal hydroxide (e.g., sodium hydroxide, potassium hydroxide, etc.), alkali metal carbonate (e.g., sodium carbonate, potassium carbonate, etc.), alkali metal bicarbonate (e.g., sodium bicarbonate, potassium bicarbonate, etc.), alkali metal alkoxide (e.g., sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.), alkali metal alkanoic add (e.g., sodium acetate, etc.), trialkylamine (e.g., triethylamine, etc
  • the reaction temperature is not critical, and the reaction is usually carried out under cooling to heating.
  • Suitable salts of the compound: R 7 -L may be the same as those exemplified for the compound (I).
  • the compound (1-3) or a salt thereof can be prepared by reacting the compound (TV) or a salt thereof with the compound: H 2 N-OH or a salt thereof.
  • Suitable salts of the compound: H 2 N-OH may be the same as those exemplified for the compound (I).
  • the compound (1-3) or a salt thereof can be prepared by elirninating the hydroxy protective group of the compound (1-4) or a salt thereof.
  • the reaction of this process can be carried out in a manner similar to that in Process 1.
  • the compounds obtained can be isolated and purified by a conventional method such as pulverization, re ⁇ ystallization, column chromatography, repredpitation and the like.
  • the object compounds can be transformed into their salts in a conventional manner.
  • object compounds may include one or more stereoisomers due to asymmetric carbon atoms, and all of such isomers and mixtures thereof are included within the scope of this invention.
  • Collagenases initiate the degradation of collagen in vertebrates and, in addition to their normal function in the metabolism of connective tissue and wound healing, they have been implicated to be involved in a number of pathological conditions such as joint destruction in rheumatoid arthritis, periodontal disease, corneal ulceration, tumor metastasis, osteoarthritis, decubitus restenosis after percutaneous tiansluminal coronary angiopsty, osteoporosis, proriasis, chronic active heatitis, autoimmune keratitis, and the like, and therefore the compounds of the present invention are useful for treating and/or preventing such pathological conditions.
  • pathological conditions such as joint destruction in rheumatoid arthritis, periodontal disease, corneal ulceration, tumor metastasis, osteoarthritis, decubitus restenosis after percutaneous tiansluminal coronary angiopsty, osteoporosis, proriasis, chronic active heatitis, autoimmune keratitis, and the like
  • Test Method 1 Inhibitory activity of human MMP- 1
  • Human collagenase was prepared from the culture medium of human skin fibroblast stimulated with interleukin- 1 ⁇ ( 1 ng/ml) .
  • Latent collagenase was activated by incubation with tryspin (200 ⁇ g/ml) at 37°C for 60 minutes and the reaction was stopped by adding soybean tiypsin inhibitor (800 ⁇ g/ml).
  • Collagenase activity was determined using FITC-labeled calf skin type I collagen.
  • FITC-collagen (2.5 mg/ml) was incubated at 37°C for 120 minutes with the activated collagenase and test compound in 50 mM Tris buffer (containing 5 mM CaC ., 200 mM NaCl and 0.02% NaN 3 , pH 7.5). After stopping the enzyme reaction by adding the equal volume of 70% ethanol-200 mM Tris buffer (pH 9.5), the reaction mixture was centrifuged, and collagenase activity was estimated by measuring the fluorescence intensity of supernatant at 495 nm (exdtation) and
  • test compounds against human MMP-8 were assayed by using commercial kit (Chondrex, USA) contained recombinant human pro-MMP-8 and FITC-labeled telopeptide-free soluble bovine type I collagen as a substrate.
  • Recombinant human pro-MMP-8 was activated by a sequential incubation with mercury compound and proteinase at 35°C for 1 hour. Reaction mixture containing the activated MMP-8, substrate and test compounds were incubated at 35°C for 2 hours.
  • test compounds against human MMP-9 were measured by using commercial kits (Yagai, Japan). Gelatinolytic activity was determined by monitoring the degradation of FITC-labeled bovine type IV collagen after incubation for 4 hours at 42°C. The amount of degraded collagen was estimated by measuring the fluorescence intensity at 495 nm (exdtation) and 520 nm (emission). Test Method 4: Inhibitory activity of human MMP- 13
  • the inhibitory potential of test compounds against human MMP- 13 were assayed by using commercial kit (Chondrex, USA) contained truncated form of human recombinant MMP- 13 and fluorogenic peptide substrate.
  • Activity of human MMP- 13 was determined by monitoring the degradation of fluorogenic peptide substrate after incubation for 1 hour at 35°C and estimated by measuring the fluorescence intensity of degraded peptide substrate at 495 nm (exdtation) and 520 nm (emission).
  • the compounds and pharmaceutically acceptable salts thereof of the present invention can be used in the form of a pharmaceutical preparation containing, as an active ingredient, one of said compounds in admixture with a pharmaceutically acceptable carrier such as an organic or inorganic solid or liquid exdpient suitable for oral, parenteral or external administration.
  • a pharmaceutically acceptable carrier such as an organic or inorganic solid or liquid exdpient suitable for oral, parenteral or external administration.
  • the pharmaceutical preparations may be capsules, tablets, dragees, granules, solutions, suspensions, emulsions, sublingual tablets, suppositories, ointments, and the like. If desired, there may be induded, in these preparations, auxiliary substances, stabilizing agents, wetting agents, emulsifying agents, buffers and other commonly used additives.
  • a daily dose of 0.01 - 100 mg of the active ingredient per kg weight of a human being in the case of intravenous administration, a daily dose of 0.01 - 100 mg of the active ingredient per kg weight of a human being, and in the case of intramuscular administration, a daily dose of 0.05 - 100 mg of the same per kg weight of a human being, or in the case of oral administration, a daily dose of 0.1 - 100 mg of the same per kg weight of a human being, is generally given for the treatment of MMP or TNF mediated diseases.
  • the inhibitory potential of test compounds against human MMP- 13 were assayed by using commercial kit (Chondrex, USA) contained truncated form of human recombinant MMP- 13 and fluorogenic peptide substrate.
  • Activity of human MMP- 13 was determined by monitoring the degradation of fluorogenic peptide substrate after incubation for 1 hour at 35°C and estimated by measuring the fluorescence intensity of degraded peptide substrate at 495 nm (exdtation) and 520 nm (emission).
  • Hycfroxylamine 2-chlorotrityl resin (1.46 g) was swelled in N, N-dimethyl- formamide (10 ml) for 20 minutes.
  • a solution of 2-[l-(9-fluorenylmethoxy- c ⁇ rbonylamino)cyclohexyl]acetic add (2.1 g), O-(7-azabenzotriazol-l-yl)-(l,l,3,3- tetiarnethyluronium hexafluorophosphate (2.1 g) and N,N-d ⁇ sopropylethylamine (1.43 g) in N,N-dirnethylformamide (10 ml) was added to this suspension and shaken for 24 hours.
  • N-[2-[l-(9-I uorenyln ethoxycarbonylarru ⁇ o)cydohexyl]acetyl]- hycfroxylamine 2-chlorotrityl resin (2.92 g) was swelled in N, N-cfrmethylformamide ( 10 ml) for 20 minutes. To a solution of 20% piperidine in N,N-dimethyl- formamide (20 ml) was added the resin and shaken for 24 hours.
  • N-(2-Tetrahydropyranyloxy)-2-[4-benzyloxycarbonylaminotetrahydropyran- 4-yl]acetamide was obtained in the similar manner as in Preparation 1-3.
  • N-(2-Tetrahydropyranyloxy)-2-[ 1 -benzyloxycarbonyl-4-(9-fluorenylmethoxy- c ⁇ rbonylammo)piperidin-4-yl]acetamide (27.5 g) was dissloved in 20% piperidine in DMF (250 ml) at room temperature. After stirring at the same temperature for 1 hour, the solution was concentrated in vacuo. The residue was purified by SiO 2 column chromatography (CHCl 3 -2% MeOH in CHCLJ to give N-(2-tetrahydro- pyranyloxy)-2-(4-ammo-l-benzyloxyc ⁇ bonylpipe (15.6 g) as an oil.
  • N-(2-Tetiahydropyranyloxy)-2-benzyloxycarbonylarn opropionamide was obtained as a solid from 2-benzyloxycarbonylaminopropionic add (5.0 g) in the similar manner as in Preparation 1-3.
  • N-(2-Tetiahycfropyranyloxy)-2-arninopropionamide was obtained as an oil from N-(2-tet ⁇ ahydropyranyloxy)-2-benzyloxycarbonylarj inopropionamide in the similar manner as in Preparation 1-4.
  • N-(2-Tetiahycfropyranyloxy)-3-benzyloxyc ⁇ rbonylammo-3-cydohexyl- propionamide was obtained from 3-benzyloxyc ⁇ rbonylamino-3-cydohexyl- propionic add in the similar manner as in Preparation 1-3.
  • N-(2-Tetiahydropyranyloxy)-3-arnmo-3-cydohexylpropionamide was obtained from N-(2-tetiahydropyranyloxy)-3-benzyloxycarbonylamino-3- cyclohexylpropionamide in the similar manner as in Preparation 1-4.
  • NMR (DMSO-cLJ ⁇ 0.74-1.76(17H, m), 1.82-2.20(2H, m), 2.71-2.86(1H, m), 3.42-3.57(lH, m), 3.84-4.02(lH, m), 4.74-4.86(lH, m)
  • N-Benzyloxy-2-( 1 -(t-butoxycarbonylammo)cyclobutyl)acetamide was obtained in the similar manner as in Preparation 1-3.
  • N-(2-Tetrahydropyranyloxy)-2-[4-(4-phenoxybenzenesulfonyl- amino)piperidin-4-yl]acetarnide was obtained in the similar manner as in Preparation 1-4.
  • N-(2-Ttetiahycfropyranyloxy)-2-[l-(N-methyl-N-(4-phenoxybenzene- suffonyl)arrrino)cydohexyl]acetamide (250 mg) was obtained from 2-[l-(N-methyl- N-(4-phenoxybenzensuffonyl)amino)cyclohexyl]acetic add(210 mg) in the similar manner as in Preparation 2-4 as an amorphous powder.
  • N-(2-Tetiahydropyranyloxy)-2-[4-(4-phenoxybenzenesuffonyl-amino)- 1 - benzyloxycarbonylpiperidin-4-yl]acetamide was obtained in the similar manner as in Preparation 1-3.
  • N-Hy ⁇ froxy-2-[l- ⁇ 4-(4-bromophenoxy)benzenesuifonylamino ⁇ - cyclohexyl]acetamide (35 mg) was obtained as a white amorphous in the similar manner as in Example 17.
  • N-Hycfroxy-2-[l-(2-phenoxypyridin-5-ylsuffonylam o)cydohexyl]acetamide was obtained as a yellow oil in the similar manner as in Example 17.
  • N-[2- ⁇ l-(4-phenoxybenzoylamino)cydohexyl ⁇ acetyl]hydroxylamine 2-chlorotrityl resin was filtered and washed with N,N-dirnethylformamide, methanol and dichloromethane each three times. The resin was suspended in a 5% trifluoroacetic add in dichloromethane for 1 hour. After draining the resin, it was washed with a 5% trifluoroacetic add in dichloromethane and dichloromethane several times. The filtrate was concentrated in vacuo to give N- hycfroxy-2- ⁇ l-(4-phenoxybenzoylamino)cyclohexyl ⁇ acetamide as a white amorphous (84 mg).
  • N-Hy ⁇ iroxy-2-[l-(4-phenyltltiobenzoylamino)cydohexyl]acetan ⁇ ide was obtained in the similar manner as in Example 24.
  • N-Hycfroxy-2-[l- ⁇ 4-(pyridin-4-yloxy)benzoylammo ⁇ cyclohexyl]acetarnide (46 mg) was obtained as a yellow oil in the similar manner as in Example 24.
  • N-Hycfroxy-2-[l- ⁇ 4-(4-fluorophenoxy)benzoylammo ⁇ cydohexyl]a ⁇ tamide (38 mg) was obtained as a yellow oil in the similar manner as in Example 24.
  • N-Hycfroxy-3-(4-phenoxybenzenesuffonylamino)propionamide was obtained from N-(2-tetrahydropyranyloxy)-3-aminopropionamide as a powder in the similar manner as in Example 38 as mentioned below.
  • N-Hydroxy-3-(4-phenoxybenzenesuffonyla ⁇ mo)-3-cyclohexyl-propiffnide was obtained from N-(2-tetrahy ⁇ j-opyranyloxy)-3-amino-3-cydohexylpropion- amide in the similar manner as in Example 38.
  • N-(2-Tetrahydropyranyloxy)-2-[4-(4-phenoxybenzenesuffonyl)-amino- 1 - methansuffonylpiperidin-4-yl]acetamide was obtained in the similar manner as in Preparation 2-2.
  • N-(2-Tetiahycfropyranyloxy)-2-[l-(N,N-dirnethylcarbamoyl)-4-(4-phenoxy- benzenesuffonylan u o)piperid- ⁇ -4-yl]acetamide 160 mg was obtained from N-(2- tetiahydropyranyloxy)-2-[4-(4-phenoxybenzene-sulfonylarn-no)piperidm yljacetamide (140 mg) as a yellow oil in the similar manner as in Example 36.
  • N-Hycfroxy-2- ⁇ l-cyclopropylcarbonyl-4-(4-phenoxybenzenesuffonylamino)- piperidin-4-yl ⁇ acetamide (10 mg) was obtained from N-(2-tetrahydropyranyloxy)- 2- ⁇ 4-(4-phenoxybenzenesuffonylan ⁇ ino)piperidm-4-yl ⁇ acetamide (100 mg) in the similar manner as in Example 38.
  • the obteined oil was purified by preparative thin layer chromatography with 10% methanol in chloroform and triturated with diisopropyl ether to give N-hydroxy-2-[4-(4-phenoxyben ⁇ nesuffonylamino)- tetrahycfrotmopyran-4-yl]acetarrride (16 mg) as a powder.
  • N-Hydroxy-2-[4-(4-phenoxybenzenes ⁇ ffonylarr ⁇ acetamide was obtained in the similar manner as in Example 43.
  • N-Hycfroxy-2- ⁇ 4-(4-phenoxybenzoylammo)tetiahydropyran-4-yl ⁇ -ac ⁇ tamide (0.40 g) was obtained in the similar manner as in Example 43.
  • N-Hydroxy-2-[ 1 , 1 -cfioxo-4-(4-phenoxybenzenesuffonylamino)tetrahydro- thiopyran-4-yl]acetamide was obtained in the similar manner as in Example 43.
  • N-Hydroxy-2-[4-(4-phenoxybenzenesuffonylamino)- 1 -methansulfonyl- piperidin-4-yl]acetamide was obtained in the similar manner as in Example 43.
  • N-Hydroxy-2- ⁇ l-(N-t-butylcarbamoyl)-4-(4-phenoxybenzene- suffonylaminojpiperidin ⁇ -yljacetamide (14.7 mg) was obtained in the similar manner as in Example 43.
  • N-Hydroxy-2- [ 1 -benzyloxycarbonyl-4-(5-(4-fluorophenyl)thiophen-2-yl- carbonylaminojpiperidm ⁇ -yljacetamide (55 mg) was obtained as a white amorphous in the similar manner as in Example 43.
  • N-Hycfroxy-3-(4-phenoxybenzenesuffonylamino)-3-ethylvaleramide was obtained in the similar manner as in Example 43.
  • N-benzyloxy-3-(4-phenoxybenzoylam o)-3-ethylvaleramide 69 mg
  • palladium on carbon 10 mg
  • the catalyst was removed by filtration and the solvent was removed under reduced pressure.
  • the crude product was purified with silica gel column chromatography (eluent: 1% methanol in chloroform) to give N-hydr ⁇ xy-3-(4-phenoxybenzoy]arr ⁇ ino)-3-ethylvaleramide.
  • N-Hycfroxy-2-(l-(4-phenoxybenzenesuffonylamino)cydobutyl)a ⁇ tamide was obtained in the similar manner as in Example 61.

Abstract

The compound of the present invention is useful as a medicament for prophylactic and therapeutic treatment of MMP- or TNF α-mediated diseases.

Description

DESCRIPTION MMPINHΓBΓTOR
Technical Field
The present invention relates to new compounds and pharmaceutically acceptable salts thereof.
More particularly, it relates to new compounds and pharmaceutically acceptable salts thereof which are useful as inhibitors of matrix metalloproteinases (hereinafter to be referred to as MMP) or the production of tumor necrosis factor (hereinafter to be referred to as TNF ), to pharmaceutical compositions comprising the same, to use of the same as medicaments, and to methods for using the same therapeutically in the treatment and/ or the prevention of MMP- or TNF -mediated diseases.
Background Art
Some piperazine compounds to be useful as metalloproteinase inhibitors, or the like are known (WO 97/20824, etc.).
Disclosure of the Invention
One object of the present invention is to provide new and useful compounds and pharmaceutically acceptable salts thereof, and to provide a process for preparing said new compound and salts thereof, which have pharmacological activities such as MMP- or TNF -inhibitory activity and the like.
Another object of the present invention is to provide a pharmaceutical composition comprising, as an active ingredient, said compound or a pharmaceutically acceptable salt thereof.
A further object of the present invention is to provide use of said compounds and pharmaceutically acceptable salts thereof as medicaments for prophylactic and therapeutic treatment of MMP- or TNF -mediated diseases.
A still further object of the present invention is to provide a method for using the same for the treatment and/ or the prevention of MMP- or TNF -mediated diseases in mammals, especially humans.
The compounds of the present invention have inhibitory activity on MMP or the production of TNF , and are useful for the treatment and/or prevention of diseases such as stroke, arthritis, cancer, tissue ulceration, decubitus ulcer, restenosis, periodontal disease, epidermolysis buUosa, scleritis, psoriasis and other diseases characterized by matrix metalloproteinase activity, as well as AIDS, sepsis, septic shock and other diseases caused by the production of TNFα .
There are a number of structurally related metalloproteases which effect the breakdown of structural proteins. Matrix-degrading metallo- proteases, such as gelatinase (MMP-2, MMP-9), stromelysin (MMP-3) and collagenase (MMP-1, MMP-8, MMP-13), are involved in tissue matrix degradation and have been implicated in many pathological conditions involving abnormal connective tissue and basement membrane matrix metabolism, such as arthritis (e.g., O-feoarthritis and rheumatoid arthritis), cerebral disease (e.g., stroke, etc.), tissue ulceration (e.g. , corneal, epidermal and gastric ulcerations), abnormal wound healing, periodontal disease, bone disease (e.g., Paget's disease and osteoporosis), tumor metastasis or invasion and HrV-infection.
A tumor necrosis factor is recognized to be involved in many infections and autoimmune diseases. Furthermore, it has been shown that TNF is the prime mediator of the inflammatory response seen in sepsis and septic shock.
The object compounds of the present invention are novel and can be represented by the following formula (I):
Figure imgf000004_0001
R2 R3 wherein
R1 is halogen, nitro, lower alkoxy, optionally substituted aryloxy, arylthio, aroyl, heterocyclic-oxy, optionally substituted aryl or optionally substituted heterocyclic group;
R2 is hydrogen or halogen;
R3 is hydrogen or lower alkyl;
R4 and R5 are independently hydrogen, lower alkyl, or lower cycloalkyl, or R4 and R5 are combined together to form lower alkylene, which is optionally interrupted by oxygen, sulfur, sulfinyl, sulfonyl or optionally mono-substituted nitrogen; R6 is hydroxy or protected hydroxy;
X is aryl or heterocyclic group;
Y is carbonyl or sulfonyl; and
Z is lower alkylene; and a pharmaceutically acceptable salt thereof.
The object compounds of the present invention can be prepared by the following processes.
Process 1
N
Figure imgf000005_0001
(M)
Figure imgf000005_0002
(l-2) Pro
Figure imgf000006_0001
(II)
R'
R£ RJ
Figure imgf000006_0002
R' R
Process 3
Figure imgf000006_0003
(110
R'
R
Figure imgf000006_0004
R' R' Process 4
H N
(CH2)m (CH2)n
M ^^ ft
N Z-CONH-R6
(1-2)
R'-L or
lower alkyl isocyanate
R7
I N
(CH2)m (CH2)n
N Z-CONH-R6
Rc (1-1 )
Pro
Figure imgf000007_0001
(IV)
R' R
Figure imgf000008_0001
ONHOH
(1-3)
Process 6
Figure imgf000008_0002
(M)
R Rύ
R=
R1 X
Figure imgf000008_0003
Z-CONHOH
(1-3)
In the above formulas (1-1), (1-2), (1-3), (1-4), (U), (HI) and (TV), R1, R2, R3, R4, R5, R6, X, Y and Z are as defined above, R61 is protected hydroxy, R7 is imino-protective group, R8 is protected carboxy, L is a leaving group, m and n are independently an integer of 1 to 5, provided that 2-≥m+n≤6.
The starting compounds (Tf), (HI) and (TV) can be prepared according to the following Preparations or by a conventional method.
Suitable pharmaceutically acceptable salts of the object compounds may be conventional non-toxic salts and include an add addition salt such as an organic add salt (e.g., acetate, trifluoroacetate, maleate, tartrate, fumarate, methanesulfonate, benzenesulfonate, formate, toluenesulfonate, etc.), an inorganic add salt (e.g., hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, etc.), or a salt with a base such as an amino add (e.g., arginine, aspartic add, glutamic add, etc.), an alkali metal salt (e.g., sodium salt, potassium salt, etc.), an alkaline earth metal salt (e.g., caldum salt, magnesium salt, etc.), an ammonium salt, an organic base salt (e.g., trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N,N'-dibenzyl-ethylenediamine salt, etc.), or the like.
The object compounds and pharmaceutically acceptable salts thereof may indude solvates such as endosure compounds (e.g., hydrate, etc.).
Suitable examples and illustrations of the various definitions, which the present invention indudes within its scope and which are shown in the above and subsequent descriptions of the present specification, are as follows.
Suitable "aryl" in the term "aryl", "optionally substituted aryl", "optionally substituted aryloxy" and "arylthio" indudes an aryl having 6 to 10 carbon atoms, such as phenyl, tolyl, xylyl, cumenyl, mesiryl, naphthyl and the like, preferably phenyl and naphthyl for R1 , and phenyl for X. Examples of the substituents for substituted aryl are halogen, cyano, nitro, amino, acylamino, lower alkylamino, carbamoyl, hydroxy, lower alkoxy, C6-C10 aryloxy, lower alkyl, C5-C10 aryl, heterocyclic-oxy and the like, preferably heterocyclic-oxy (e.g., pyridyloxy, etc.). Examples of the substituents for substituted aryloxy are the same as ones defined above with regard to "substituted aryl", preferably halogen, lower alkyl and cyano.
Suitable "heterocyclic group" in the term "heterocyclic group", "optionally substituted heterocyclic group" and 'heterocyclic-oxy group" means saturated or unsaturated, 3- to 8-membered monocyclic or polycyclic heterocyclic group containing at least one hetero atom such as oxygen atom, sulfur atom, nitrogen atom and the like.
Preferable heterocyclic groups are:
-unsaturated 3- to 8-membered, preferably 5- or 6-membered, heteromonocyclic group containing 1 to 4 nitrogen atoms, for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl and its N-oxide, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (e.g., 4H-l,2,4-triazolyl, lH-l,2,3-triazolyl, 2H-l,2,3-triazolyl, etc.), tetrazolyl (e.g., lH-tetrazolyl, 2H- tetrazolyl, etc.), dihydrotriazinyl (e.g., 4,5-dihydro-l,2,4-triazinyl, 2,5-dihydro- 1,2,4-triazinyl, etc.), and the like;
-saturated 3- to 8-membered, preferably 5- or 6-membered, heteromonocyclic group containing 1 to 4 nitrogen atoms, for example, azetidinyl, pyrrolidinyl, irnidazolidinyl, piperidinyl, piperidino, pyrazolidinyl, piperazinyl, and the like;
-unsaturated condensed, preferably bicyclic, 7- to 13-membered, preferably 9- or 10-membered, heterocyclic group containing 1 to 5 nitrogen atoms, for example, indolyl, isoindolyl, mdolizinyl, benz midazolyl, quinolyl, iso-quinolyl, indazolyl, benzotriazolyl, tetrazolopyridyl, tetrazolopyridazinyl (e.g., tetrazolo[l,5- b]pyridazinyl, etc.), d ytirotriazolopyridazinyl, and the like;
-unsaturated 3- to 8-membered, preferably 5- or 6-membered, heteromonocyclic group containing 1 or 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl, 1,3,4- oxadiazolyl, 1,2,5-oxadiazolyl, etc.), and the like;
-saturated 3- to 8-membered, preferably 5- or 6-membered, heteromonocyclic group containing 1 or 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, morpholinyl, morpholino, and the like;
-unsaturated condensed, preferably bicyclic, 7- to 13-membered, preferably 9- or 10-membered, heterocyclic group containing 1 or 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, benzoxazolyl, benzoxadiazolyl, and the like;
-unsaturated 3- to 8-membered, preferably 5- or 6-membered, heteromonocyclic group containing 1 or 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl, 1,2-thiazolyl, thiazolinyl, thiadiazolyl (e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,2,3-thiadiazolyl, etc.), and the like;
-saturated 3- to 8-membered, preferably 5- or 6-membered, heteromonocyclic group containing 1 or 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolidinyl, and the like;
-unsaturated 3- to 8-membered, preferably 5- or 6-membered, heteromonocyclic group containing 1 or 2 sulfur atoms, for example, thienyl, and the like; -unsaturated 3- to 8-membered, preferably 5- or 6-membered, heteromonocyclic group containing 1 or 2 oxygen atoms, for example, furyl, and the like;
-saturated 3- to 8-membered, preferably 5- or 6-membered, heteromonocyclic group containing oxygen atom, for example, oxolanyl, and the like;
-unsaturated condensed, preferably bicyclic, 7- to 13-membered, preferably 9- or 10-membered, heterocyclic group containing 1 or 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, berjzothiazolyl, ben∞thiadiazolyl, and the like;
-unsaturated condensed 7- to 13-membered, preferably 9- or 10-membered, heterocyclic group containing 1 or 2 oxygen atoms, for example, benzodihydrofuranyl, benzodioxolenyl, and the like.
More preferable heterocyclic groups may be unsaturated 5- or 6-membered heteromonocyclic group containing 1 to 4 nitrogen atoms ( e.g. pyridyl, etc.), unsaturated 5- or 6-membered heteromonocyclic group containing 1 or 2 sulfur atoms (e.g., thienyl, etc.), unsaturated 5- or 6-membered heteromonocyclic group containing 1 or 2 oxygen atoms (e.g., furyl, etc.), and the most preferable examples are pyridyloxy for R1 and pyridyl, thienyl and furyl for X.
These heterocyclic groups may have one or more substituents. Examples of the substituents for substituted heterocyclic group are the same as those for optionally substituted aryl or optionally substituted aryloxy.
Suitable "aroyl" may include C6-C10 aroyl (e.g., benzoyl, toluoyl, xyloyl, etc.), preferably benzoyl for R1.
Suitable 'lower alkyl" is a straight or branched alkyl having 1 to 6 carbon atoms, and exemplified by methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert- butyl, pentyl, hexyl and the like, preferably methyl for R1, and methyl and ethyl for R4 and/or R5.
Suitable 'lower alkoxy" is a straight or branched alkenyl having 1 to 6 carbon atoms, and exemplified by methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, tert-pentyloxy, hexyloxy and the like, preferably methoxy for R1.
Suitable "protected hydroxy" includes hydroxy protected by a conventional protective group, for example, tetrahydropyranyloxy, substituted lower alkoxy such as lower alkoxy(lower)alkoxy (e.g., methoxymethoxy), lower alkoxy(-Ower)alkoxy(lower)alkoxy (e.g., methoxyethoxymethoxy) and substituted or unsubstituted C6-C10 aryl(lower)alkoxy (e.g., benzyloxy, nitrobenzyloxy); acyloxy such as lower alkanoyloxy (e.g., acetoxy, propionyloxy, pivaloyloxy), C6-C10 aroyloxy (e.g., benzoyloxy, fluorenecarbonyloxy), lower alkoxycarbonyloxy (e.g., methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, isopropoxycarbonyloxy, butoxycarbonyloxy, isobutoxycarbonyloxy, tert- butoxycarbonyloxy, pentyloxycarbonyloxy, hexyloxycarbonyloxy), substituted or unsubstituted C6-C10 aryl(lower)alkoxycarbonyloxy (e.g., benzyloxycarbonyloxy, bromobenzyloxycarbonyloxy), C6-C10 arenesulfonyloxy (e.g., benzenesulfonyloxy, tosyloxy) and alkanesulfonyloxy (e.g., methanesulfonyloxy, ethanesulfonyloxy); tri(lower)alkylsilyloxy (e.g., trimethylsilyloxy); tetrahydropyranyloxy; and the like, preferably, tetrahydropyranyloxy and C6-C10 aryl(lower) alkoxy, and most preferably
Figure imgf000012_0001
The term 'lower" is intended to mean 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, unless otherwise indicated.
Suitable "halogen" includes fluorine, bromine, chlorine and iodine.
Suitable 'lower cydoalkyl" is a cydoalkyl having 3 to 7 carbon atoms, and exemplified by cyclopropyl, cyclobutyl, cydopentyl and cydohexyl, preferably cydohexyl for R4 and/ or R5.
Suitable 'lower alkylene" is exemplified by methylene, ethylene, tri-methylene, tetra-methylene, penta-methylene and hexa-methylene, preferably, tri-methylene. tetia-methylene and penta-methylene for R4 and R5, methylene and methylmethylene for Z.
Suitable substituent of "optionally mono-substituted nitrogen" is exemplified by C6-C10 ar(lower)alkoxycarbonyl, lower alkylsulfonyl, C6-C10 arylsulfonyl, C5-C10 aroyl, mono- or di(lower)alkylcarbamoyl, lower cycloalkylcarbonyl, and the like. Suitable R4 R5 is exemplified as follows.
Figure imgf000013_0001
Figure imgf000013_0002
Figure imgf000013_0003
-CONH-tBu - CONHEt
Figure imgf000013_0004
Suitable acyl moiety of "acyla ino" indudes acyl such as aliphatic acyl, aromatic acyl, heterocyclic acyl and aliphatic acyl substituted by aromatic or heterocyclic group(s) derived from carboxylic, carbonic, sulfonic and carbamic adds.
The aliphatic acyl indudes saturated or unsaturated, acyclic or cyclic ones, for example, alkanoyl such as lower alkanoyl (e.g. , formyl, acetyl, propionyl, butylyl, isobutylyl, valeryl, isovaleryl, pivaloyl, hexanoyl, etc.), alkylsulfonyl such as lower alkylsulfonyl (e.g., mesyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, pentylsulfonyl, hexylsulfonyl, etc.), carbamoyl, N- alkylcarbamoyl (e.g., methylcarbamoyl, ethylcarbamoyl, etc.), alkoxycarbonyl such as lower alkoxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, etc.), alkenyloxycarbonyl such as lower alkenyloxycarbonyl (e.g., vinyloxycarbonyl, allyloxycarbonyl, etc.), alkenoyl such as lower alkenoyl (e.g., acryloyl, methacryloyl, crotonoyl, etc.), cycloalkanecarbonyl such as cydo(lower)alkanecarbonyl (e.g., cydopropanecarbonyl, cyclopentanecarbonyl, cydohexanecarbonyl, etc.), and the like.
The aromatic acyl may indude C5-C10 aroyl (e.g., benzoyl, toluoyl, xyloyl, etc.), N-(C6-C10)arylcarbamoyl (e.g., N-phenylcarbamoyl, N-tolylcarbamoyl, N- naphthylcarbamoyl, etc.), C6-C10 arenesulfonyl (e.g., benzenesulfonyl, tosyl, etc.), and the like.
The heterocyclic acyl may indude heterocyclic-carbonyl (e.g., furoyl, thenoyl, nicotinoyl, isonicotinoyl, thiazolylcarbonyl, thiadiazolylcarbonyl, tetrazolylcarbonyl, etc.), and the like.
The aliphatic acyl substituted by aromatic group(s) may indude aralkanoyl such as phenyl(lower)alkanoyl (e.g., phenylacetyl, phenylpropionyl, phenylhexanoyl, etc.), aralkoxycarbonyl such as phenyl(lower) alkoxycarbonyl (e.g., benzyloxycarbonyl, phenethyloxycarbonyl, etc.), aryloxyalkanoyl such as phenoxy(lower)alkanoyl (e.g., phenoxyacetyl, phenoxypropionyl, etc.), and the like.
The aliphatic acyl substituted by heterocydc group(s) may include heterocyclic-alkanoyl such as heterocyclic-(lower)alkanoyl (e.g., thienylacetyl, imidazolylacetyl, furylacetyl, tetrazolylacetyl, thiadiazolylpropionyl, etc.), and the like.
Suitable lower alkyl moiety of "lower alkylamino" is the same as lower alkyl defined above.
Suitable compounds having the formula (I) are: compound (I) wherein
R1 is halogen, nitro, lower alkoxy, C6-C10 aryloxy optionally substituted by at least one group selected from the group consisting of halogen, cyano, nitro, amino, acylamin, lower alkylamino, carbamoyl, hydroxy, lower alkoxy, C6-C10 aryloxy, lower alkyl, C6-C10 aryl and heterocyclic-oxy, C6-C10 arylthio, C6-C10 aroyl, heterocyclic-oxy, C6-C10 aryl optionally substituted by at least one group selected from the group consisting of halogen, cyano, nitro, amino, acylamino, lower alkylamino, carbamoyl, hydroxy, lower alkoxy, C6-C10 aryloxy, lower alkyl, C6-C10 aryl and heterocyclic-oxy, or heterocyclic group optionally substituted by at least one group selected from the group consisting of halogen, cyano, nitro, amino, acylamino, lower alkylamino, carbamoyl, hydroxy, lower alkoxy, C6-C10 aryloxy, lower alkyl, C6-C10 aryl and heterocyclic-oxy;
R4 and R5 are independently hydrogen, lower alkyl, or lower cydoalkyl, or R4 and R5 are combined together to form lower alkylene, which is optionally interrupted by oxygen, sulfur, sulfinyl, sulfonyl or imino, wherein the imino is optionally mono- substituted by a group of C6-C10 ar(lower)alkoxycarbonyl, lower alkylsulfonyl, C6- C10 arylsulfonyl, C6-C10 aroyl, mono(lower)alkylcarbamoyl, di(lower)alkylcarbamoyl or lower cydoalkylcarbonyl;
R6 is hydroxy, tetrahydropyranyloxy or C6-C10 aryl(lower)alkoxy; and
X is C6-C10 aryl or heterocyclic group, said heterocyclic group being unsaturated 3- to 8-membered, heteromonocyclic group containing 1 to 4 nitrogen atoms, saturated 3- to 8-membered, heteromonocyclic group containing 1 to 4 nitrogen atoms, unsaturated bicyclic 7- to 13-membered, heterocyclic group containing 1 to 5 nitrogen atoms, unsaturated 3- to 8-membered, heteromonocyclic group containing 1 or 2 oxygen atoms and 1 to 3 nitrogen atoms, saturated 3- to 8-membered, heteromonocyclic group containing 1 or 2 oxygen atoms and 1 to 3 nitrogen atoms, unsaturated bicyclic 7- to 13-membered, heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, unsaturated 3- to 8-membered, heteromonocyclic group containing 1 or 2 sulfur atoms and 1 to 3 nitrogen atoms, saturated 3- to 8-membered, heteromonocyclic group containing 1 or 2 sulfur atoms and 1 to 3 nitrogen atoms, unsaturated 3- to 8-membered, heteromonocyclic group containing 1 or 2 sulfur atoms, unsaturated 3- to 8-membered, heteromonocyclic group containing 1 or 2 oxygen atoms, saturated 3- to 8-membered, heteromonocyclic group containing oxygen atom, unsaturated bicyclic 7- to 13-membered, heterocyclic group containing 1 or 2 sulfur atoms and 1 to 3 nitrogen atoms, or unsaturated bicyclic 7- to 13-membered, heterocyclic group containing 1 or 2 oxygen atoms, compound (I) wherein
R1 is halogen; nitro; lower alkoxy; C6-C10 aryloxy optionally substituted by at least one group selected from the group consisting of halogen, cyano, nitro, amino, acylamino, lower alkylamino, carbamoyl, hydroxy, lower alkoxy, C6-C10 aryloxy, lower alkyl, C6-C10 aryl and heterocyclic-oxy, said heterocyclic group being unsaturated 5- or 6-membered, heteromonocyclic group containing 1 to 4 nitrogen atoms; C5-C10 arylthio; C5-C10 aroyl; heterocyclic-αxy, said heterocyclic group being unsaturated 5- or 6-membered, heteromonocyclic group containing 1 to 4 nitrogen atoms; C5-C10 aryl optionally substituted by at least one group selected from the group consisting of halogen, cyano, nitro, amino, acylamino, lower alkylamino, carbamoyl, hydroxy, lower alkoxy, C6-C10 aryloxy, lower alkyl,
C6-C10 aryl and heterocyclic-oxy, said heterocyclic group being unsaturated 5- or
6-membered, heteromonocyclic group containing 1 to 4 nitrogen atoms; or heterocyclic group, said heterocyclic group being unsaturated 5- or 6-membered, heteromonocyclic group containing 1 to 4 nitrogen atoms, which is also optionally substituted by at least one group selected from the group consisting of halogen, cyano, nitro, amino, acylamino, lower alkylamino, carbamoyl, hydroxy, lower alkoxy, C6-C10 aryloxy, lower alkyl, C6-C10 aryl and heterocyclic-oxy, said heterocyclic group being unsaturated 5- or 6-membered, heteromonocyclic group containing 1 to 4 nitrogen atoms;
R4 and R5 are independently hydrogen, lower alkyl, or lower cydoalkyl, or R4 and R5 are combined together to form lower alkylene, which is optionally interrupted by oxygen, sulfur, sulfinyl, sulfonyl, imino, C6-C10 ar(lower)alkoxyc^rbonylirrιino, lower alkylsulfonyljmino, C6-C10 arylsulfonylirriino, C6-C10 aroylimino, mono(lower)alkylcarbamoylimino, di(lower)alkylcarban oylirxιino or lower
(^doalkylcarbonylimino, and
X is C6-C10 aryl or heterocyclic group, said heterocyclic group being unsaturated 5- or 6-membered, heteromonocyclic group containing 1 to 4 nitrogen atoms, unsaturated 5- or 6-membered, heteromonocyclic group containing 1 or 2 sulfur atoms, or unsaturated 5- or 6-membered, heteromonocyclic group containing 1 or 2 oxygen atoms, compound (I) wherein
R1 is halogen; nitro; lower alkoxy; phenoxy or naphthyloxy, each of which is optionally substituted by at least one group selected from the group consisting of halogen, cyano and lower alkyl; phenylthio; benzoly; pyridyloxy; phenyl optionally substituted by halogen; or pyridyl,
R4 and R5 are independently hydrogen, lower alkyl, or lower cydoalkyl, or R4 and R5 are combined together to form lower alkylene, which is optionally interrupted by oxygen, sulfur, sulfinyl, sulfonyl, imino, phenyl(lower)alkoxyc^rbonylirnino, lower al ylsuffonylimino, phenylsuffony]imino, benzoylimino, mono(lower)a]kylcarbarnoylimino, di(lower)alkylcarbamoylimino or lower cycloalkylcarbonylimino,
R6 is hydroxy, tetrahydropyranyloxy or phenyl(lower)alkoxy, and
X is phenyl, pyridyl, thienyl or furyl and compound (I) wherein
R1 is halogen; nitro; lower alkoxy; phenoxy, naphthyloxy, halophenoxy, cyanophenoxy, lower alkylphenoxy, phenylthio; benzoyl; pyridyloxy; halophenyl; or pyridyl;
R4 and R5 are combined together to form a group of the formula selected from the group consisting of the following formulas:
Figure imgf000018_0001
Figure imgf000018_0002
Figure imgf000018_0003
-CONH-tBu - CONHEt
Figure imgf000018_0004
R6 is hydroxy, and
X is a group selerted from the group consisting of
Figure imgf000018_0005
The processes for preparing the object compounds are explained in detail in the following. Process 1
The compound (1-2) or a salt thereof can be prepared by hydrolysis or reduction of the compound (1-1) or a salt thereof.
Suitable method of this elimination reaction indudes conventional ones such as hydrolysis, reduction and the like.
The hydrolysis is preferably carried out in the presence of a base or an add induding Lewis add.
Suitable base indudes an inorganic base and an organic base such as an alkali metal (e.g., sodium, potassium, etc.), an alkaline earth metal (e.g., magnesium, caldum, etc.), the hydroxide or carbonate or hydrogencarbonate thereof, trialkylamine (e.g., trimetriylamine, triethylamine, etc.), picoline, 1,5- diazabicydo[4.3.0]non-5-one, and the like.
Suitable add indudes an organic add (e.g., formic add, acetic add, propionic add, trichloroacetic add, tiifiuoroacetic add, etc.), and an inorganic add (e.g., hydrochloric add, hydrobromic add, sulfuric add, hydrogen chloride, hydrogen bromide, etc.).
The elimination using Lewis add such as trihaloacetic add (e.g., trichloroacetic add, tiifiuoroacetic add, etc.) and the like is preferably carried out in the presence of cation trapping agent (e.g. , anisole, phenol, etc.). This reaction is usually carried out without solvent
Alternatively, the reaction may be carried out in a conventional solvent such as water, alcohol (e.g., methanol, ethanol, isopropyl alcohol, etc.), tetrahydrofuran, dioxane, toluene, methylene chloride, ethylene dichloride, chloroform, N,N- dimethylformamide and N,N-dimethylacetamide, a mixture thereof, or any other organic solvents which do not adversely affect the reaction.
The reaction temperature is not critical and the reaction is usually carried out under cooling to warming.
The reduction is carried out in a conventional manner, including chemical reduction and catalytic reduction.
Suitable reducing reagents to be used in chemical reduction are a hydride (e.g., hydrogen iodide, hydrogen sulfide, lithium aluminum hydride, sodium borohydride, sodium cyanoborohydride, etc.), or a combination of a metal (e.g., tin, zinc, iron, etc.) or a metallic compound (e.g., diromium chloride, chromium acetate, etc.) and an organic add or an inorganic add (e.g., formic add, acetic add, propionic add, trifluoroacetic add, p-toluenesulfonic add, hydrochloric add, hydrobromic add, etc.).
Suitable catalyst to be used in catalytic reduction is conventional one such as platinum catalyst (e.g., platinum plate, spongy platinum, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.), palladium catalyst (e.g., spongy palladium, palladium black, palladium oxide, palladium on carbon, colloidal palladium, palladium on barium sulfate, palladium on barium carbonate, etc.), nickel catalyst (e.g., reduced nickel, nickel oxide, Raney nickel, etc.), cobalt catalyst (e.g., reduced cobalt, Raney cobalt, etc.), iron catalyst (e.g., reduced iron, Raney iron, Ullman iron, etc.), and the like.
The reduction is usually carried out in a conventional solvent such as water, alcohol (e.g., methanol, ethanol, isopropyl alcohol, etc.), tetrahydrofuran, dioxane, toluene, methylene chloride, ethylene dichloride, chloroform, N,N- dirneu ylformamide, N,N-dirnethylacetamide and cyclohexane, a mixture thereof, or any other organic solvents which do not adversely affect the reaction.
When the above-mentioned adds to be used in chemical reduction are liquid, they can also be used as a solvent.
The reaction temperature of this reduction is not critical and the reaction is usually carried out under cooling to wanning. Process 2
The compound (I) or a salt thereof can be prepared by reacting the compound (II) or its reactive derivative at the carboxyl group, or a salt thereof, with the compound: H2N-R6 or its reactive derivative at the amino group, or a salt thereof.
Suitable salts of the compound (IT) and the compound: H2N-R6 may be the same as those exemplified for the compound (I).
The reaction is usually carried out in a conventional solvent such as water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dirnethyl-formamide, pyridine and dichloromethane, a mixture thereof, or any other organic solvents which do not adversely affect the reaction.
This reaction can be carried out in the presence of an organic or inorganic base such as alkali metal (e.g., lithium, sodium, potassium, etc.), alkaline earth metal (e.g., caldum, etc.), alkali metal hydride (e.g., sodium hydride, etc.), alkaline earth metal hydride (e.g., caldum hydride, etc.), alkali metal hydroxide (e.g., sodium hydroxide, potassium hydroxide, etc.) , alkali metal carbonate (e.g. , sodium carbonate, potassium carbonate, etc.), alkali metal bicarbonate (e.g., sodium bicarbonate, potassium bicarbonate, etc.), alkali metal alkoxide (e.g., sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.), alkali metal alkanoic add (e.g., sodium acetate, etc.), trialkylamine (e.g., triethylamine, etc.), pyridine compound (e.g., pyridine, lutidine, picoline, 4-dimeu ylaminopyridine, etc.), quinoline, lithium diisopropylamide, and the like.
Suitable reactive derivative at the amino group of the compound: H2N-R6 may indude Schiffs base type irnino or its tautomeric enamine type isomer formed by the reaction of the compound: HjN-R6 with a carbonyl compound such as aldehyde, ketone or the like; a silyl derivative formed by the reaction of the compound: ϊtjN-R6 with a silyl compound such as bis(trirnethylsilyl)acetamide, mono(rrimethylsilyl)acetamide, bis(trimethylsilyl)urea or the like; a derivative formed by the reaction of the compound: H2N-R6 with phosphorus trichloride or phosgene, and the like.
Suitable reactive derivative at the carboxy group of the compound (II) may indude an add halide, an add anhydride, an activated amide, an activated ester, and the like. Suitable examples of the reactive derivative may be an add chloride; an add azide; a mixed add anhydride with add such as substituted phosphoric add (e.g., dialkylphosphoric add, phenylphosphoric add, diphenylphosphoric add, dibenzylphosphoric add, halogenated phosphoric add, etc.), dialkylphosphorous add, sulfurous add, thiosulfuric add, su furic add, sulfonic add (e.g., methanesulfonic add, etc.), aliphatic carboxylic add (e.g., acetic add, propionic add, butyric add, isobutyric add, pivalic add, pentanoic add, isopentanoic add, 2-ethylbutyric add, trichloroacetic add, etc.) or aromatic carboxylic add (e.g., benzoic add, etc.); a symmetrical add anhydride; an activated amide with imidazole, 4-substituted imidazole, dimethylpyrazole, triazole or tetrazole; or an activated ester (e.g., cyanomethyl ester, methoxymethyl ester, dimethyliminomethyl
Figure imgf000021_0001
ester, vinyl ester, propargyl ester, p- nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, mesylphenyl ester, phenyl azophenyl ester, phenyl thioester, p-nitrophenyl thioester, p-cresyl thioester, carboxymethyl thioester, pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolyl thioester, etc.), or an ester with a N-hydroxy compound (e.g., N,N-dimethy ydroxylarnine, l-hydroxy-2- (lH)pyridone, N-hycfroxysuccinimide, N-hydroxyphtlialimide, 1-hydroxy-lH- benzotriazole, etc.), and the like. These reactive derivatives can be optionally selected from them according to the kind of the compound (H) to be used.
The reaction is preferably carried out in the presence of a conventional condensing agent such as N, N'-cficydohexylcarbodiimide; N-cydohexyl-N'- morpholmoethylcarbodiimide; N-cyclohexyl-N-(4-di- ethylaminocydohexyl)- c^rbodiimide; N,N'-cfiethylcarbodiimide; N,N'-di- isopropylcarbodiimide; N-ethyl- N'-(3-cl-methylam opropyl)-carbodiimide; N,N'-c^rbonylbis-(2-methylimidazole) ; pentamethyleneketene-N-cydohexylimine; diphenylketene-N-cyclohexylimine; ethoxyacetylene; 1 -alkoxy- 1-chloroethylene; trialkyl phosphite; ethyl polyphosphate; isopropyl polyphosphate; phosphorus oxychloride (phosphoryl chloride); phosphorus trichloride; diphenyl phosphorylazide; thionyl chloride; oxalyl chloride; lower alkyl haloformate (e.g., ethyl chloroformate, isopropyl chloroformate); triphenylphosphine; 2-ethyl-7-hydroxybenz- isoxazolium salt; 2- ethyl-5-(m-sulfophenyl)isoxazolium hydroxide intramolecular salt; l-(p- chlorobenzenesulfonyloxy)-6-chloro-lH- benzotiiazole; l-hydroxybenzotriazole; or so-called Vilsmeier reagent prepared by the reaction of N,N-dimethylforamide with thionyl chloride, phosgene, trichloromethyl chloroformate, phosphorus oxychloride or oxalyl chloride.
The reaction temperature is not critical, and the reaction is usually carried out under cooling. Process 3
The compound (I) or a salt thereof can be prepared by reacting the compound (HI) or a salt thereof with the compound: RX-X(R2)-Y-L or a salt thereof.
Suitable salts of the compound (HI) and the compound: R'-X^J-Y-L may be the same as those exemplified with respect to the compound
(I).
The reaction is usually carried out in a conventional solvent such as water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine and dichloromethane, a mixture thereof, or any other organic solvents which do not adversely affect the reaction.
This reaction can be carried out in the presence of an organic or inorganic base such as alkali metal (e.g., lithium, sodium, potassium, etc.), alkaline earth metal (e.g., caldum, etc.), alkali metal hydride (e.g., sodium hydride, etc.), alkaline earth metal hydride (e.g., caldum hydride, etc.), alkali metal hydroxide (e.g., sodium hydroxide, potassium hydroxide, etc.), alkali metal carbonate (e.g., sodium carbonate, potassium carbonate, etc.), alkali metal bicarbonate (e.g., sodium bicarbonate, potassium bicarbonate, etc.), alkali metal alkoxide (e.g., sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.), alkali metal alkanoic add (e.g., sodium acetate, etc.), trialkylamine (e.g., triethylamine, etc.), pyridine compound (e.g., pyridine, lutidine, picoline, 4-dimethylaminopyridine, etc.), quinoline, lithium diisopropylamide, and the like.
The reaction temperature is not critical, and the reaction is usually carried out under cooling to heating. Process 4
The compound (I- 1) or a salt thereof can be prepared by reacting the compound (1-2) or a salt thereof with the compound: R7-L or lower alkyl isocyanate such as t-butyl-N=C=O, or a salt thereof.
Suitable salts of the compound: R7-L may be the same as those exemplified for the compound (I).
The reaction of this process can be carried out in a manner similar to that in Process 3. Process 5
The compound (1-3) or a salt thereof can be prepared by reacting the compound (TV) or a salt thereof with the compound: H2N-OH or a salt thereof.
Suitable salts of the compound: H2N-OH may be the same as those exemplified for the compound (I).
The reaction of this process can be carried out in a manner similar to that in Process 2. Process 6
The compound (1-3) or a salt thereof can be prepared by elirninating the hydroxy protective group of the compound (1-4) or a salt thereof. The reaction of this process can be carried out in a manner similar to that in Process 1.
The compounds obtained can be isolated and purified by a conventional method such as pulverization, reαystallization, column chromatography, repredpitation and the like.
The object compounds can be transformed into their salts in a conventional manner.
It is to be noted that the object compounds may include one or more stereoisomers due to asymmetric carbon atoms, and all of such isomers and mixtures thereof are included within the scope of this invention.
Collagenases initiate the degradation of collagen in vertebrates and, in addition to their normal function in the metabolism of connective tissue and wound healing, they have been implicated to be involved in a number of pathological conditions such as joint destruction in rheumatoid arthritis, periodontal disease, corneal ulceration, tumor metastasis, osteoarthritis, decubitus restenosis after percutaneous tiansluminal coronary angiopsty, osteoporosis, proriasis, chronic active heatitis, autoimmune keratitis, and the like, and therefore the compounds of the present invention are useful for treating and/or preventing such pathological conditions.
Inhibitory activity of MMP can be assayed by a conventional test method as mentioned below. Test methods: Test Method 1: Inhibitory activity of human MMP- 1
Human collagenase was prepared from the culture medium of human skin fibroblast stimulated with interleukin- 1 β ( 1 ng/ml) . Latent collagenase was activated by incubation with tryspin (200 μg/ml) at 37°C for 60 minutes and the reaction was stopped by adding soybean tiypsin inhibitor (800μg/ml). Collagenase activity was determined using FITC-labeled calf skin type I collagen. FITC-collagen (2.5 mg/ml) was incubated at 37°C for 120 minutes with the activated collagenase and test compound in 50 mM Tris buffer (containing 5 mM CaC ., 200 mM NaCl and 0.02% NaN3, pH 7.5). After stopping the enzyme reaction by adding the equal volume of 70% ethanol-200 mM Tris buffer (pH 9.5), the reaction mixture was centrifuged, and collagenase activity was estimated by measuring the fluorescence intensity of supernatant at 495 nm (exdtation) and
520 nm (emission).
Test Method 2:
Inhibitory activity of human MMP-8
The inhibitory activity of test compounds against human MMP-8 were assayed by using commercial kit (Chondrex, USA) contained recombinant human pro-MMP-8 and FITC-labeled telopeptide-free soluble bovine type I collagen as a substrate. Recombinant human pro-MMP-8 was activated by a sequential incubation with mercury compound and proteinase at 35°C for 1 hour. Reaction mixture containing the activated MMP-8, substrate and test compounds were incubated at 35°C for 2 hours. After stopping the enzyme reaction by adding the stop solution (o-phenathroline), the reaction mixture was centrifuged and MMP-8 activity was estimated by measuring the fluorescence intensity of supernatant at 490 nm (exdtation) and 520 nm (emission). Test Method 3: Inhibitory activity of human MMP-9
The inhibitory activity of test compounds against human MMP-9 were measured by using commercial kits (Yagai, Japan). Gelatinolytic activity was determined by monitoring the degradation of FITC-labeled bovine type IV collagen after incubation for 4 hours at 42°C. The amount of degraded collagen was estimated by measuring the fluorescence intensity at 495 nm (exdtation) and 520 nm (emission). Test Method 4: Inhibitory activity of human MMP- 13
The inhibitory potential of test compounds against human MMP- 13 were assayed by using commercial kit (Chondrex, USA) contained truncated form of human recombinant MMP- 13 and fluorogenic peptide substrate. Activity of human MMP- 13 was determined by monitoring the degradation of fluorogenic peptide substrate after incubation for 1 hour at 35°C and estimated by measuring the fluorescence intensity of degraded peptide substrate at 495 nm (exdtation) and 520 nm (emission).
For therapeutic purposes, the compounds and pharmaceutically acceptable salts thereof of the present invention can be used in the form of a pharmaceutical preparation containing, as an active ingredient, one of said compounds in admixture with a pharmaceutically acceptable carrier such as an organic or inorganic solid or liquid exdpient suitable for oral, parenteral or external administration. The pharmaceutical preparations may be capsules, tablets, dragees, granules, solutions, suspensions, emulsions, sublingual tablets, suppositories, ointments, and the like. If desired, there may be induded, in these preparations, auxiliary substances, stabilizing agents, wetting agents, emulsifying agents, buffers and other commonly used additives.
While the dose of the compound will vary depending upon the age and condition of patient and the like, in the case of intravenous administration, a daily dose of 0.01 - 100 mg of the active ingredient per kg weight of a human being, and in the case of intramuscular administration, a daily dose of 0.05 - 100 mg of the same per kg weight of a human being, or in the case of oral administration, a daily dose of 0.1 - 100 mg of the same per kg weight of a human being, is generally given for the treatment of MMP or TNF mediated diseases.
In order to illustrate the usefulness of the object compound, the pharmacological test data of a representative compound of the compound are shown in the following. Inhibitory activity of human MMP- 13 1. Test method
The inhibitory potential of test compounds against human MMP- 13 were assayed by using commercial kit (Chondrex, USA) contained truncated form of human recombinant MMP- 13 and fluorogenic peptide substrate. Activity of human MMP- 13 was determined by monitoring the degradation of fluorogenic peptide substrate after incubation for 1 hour at 35°C and estimated by measuring the fluorescence intensity of degraded peptide substrate at 495 nm (exdtation) and 520 nm (emission).
2. Test Compound
Compound of Example 43
3. Test Result
Figure imgf000027_0001
Moreover, other abbreviations used in this specification are, for example, as follows.
HOBT: N-Hydroxybenzotriazole
WSCD: N-Ethyl-N'-(3-dimemylaminopropyl)carbodiimide
Bzl: Benzyl
Z: Benzyloxycarbonyl
DMF: Dimethyfformamide
The following examples are given for the purpose of iUustrating the present invention in detail. Preparation 1-1
A mixture of cydohexanone (60.0 g), malonic add (63.6 g) and sodium acetate (94.2 g) in 95% aqueous ethanol (1 L) was refluxed for 6 days. After cooling to ambient temperature, the resultant mixture was stirred for 6 hours on an ice bath until a solid was formed. The separated solid was collected and washed with ethanol (100 ml) to give 2-(l-aminocyclohexyl)acetic add (38.3 g). NMR p2O) δ =1.14-1.69(10H, m), 2.38(2H, s) Mass ESI (-): 156(M-1) Preparation 1-2
To a solution of 2-(l-aminocydohexyl)acetic add (2.0 g) in IN NaOH (25.4 ml) and dioxane (20 ml) was added Z-Cl (2.17 g) at room temperature. After being stirred for 5 hours, the solution was evaporated in vacuo to remove dioxane. The solution was addified by 6N HCl and extracted with AcOEt (60 m 1 ) . The solution was washed with brine, dried over MgS04 and concentrated in vacuo to give 2-(l- (benzyloxycarbonylamino)cyclohexyl)acetic add (1.80 g) as an oil. NMR (CDCy δ =1.18-1.68(8H, m), 1.96-2.20(2H, m), 2.83(2H, s), 4.84(1H, brs), 5.08(2H, s), 732(5H, s) Mass (ESI-): 290(M-H) Preparation 1-3
To a solution of 2-(l-(benzyloxycarbonylamino)cyclohexyl)acetic add (1.5 g), O-(2-tetiahydropyranyl)hycfroxylarnine (663 mg) and HOBT (765 mg) in DMF (20 ml) was added WSCD • HCl ( 1.09 g) at room temperature. After being stirred overnight, the solution was concentrated in vacuo. The residue was dissolved in
AcOEt (50 ml) and the solution was washed with 5% aq. dtric add solution, sat.
NaHCO3 solution and brine, and dried over MgSO4. The solution was concentrated in vacuo to give N-(2-tetrahydropyranyloxy)-2-(l-(benzyloxy- carbonylam o)cyclohexyl)acetarnide (1.83 g) as an amorphous powder.
NMR (CDCLJ δ = 1.20-1.91(14H, m), 1.95-2.15(2H, m), 2.60(2H, s), 3.52-3.63(lH, m), 3.80-3.94(lH, m), 4.87(1H, s), 4.90(1H, s), 5.02(1H, d, J=10.5Hz), 5.10(1H, d,
J=10.5Hz), 7.35(5H, s), 8.59(1H, s)
Mass (ESI+): 391(M+H)
Preparation 1-4
A solution of N-(2-tetiahydropyranyloxy)-2-(l-(benzyloxycarbonylamino)- cydohexyl)acetamide (1.8 g) in MeOH (50 ml) was catalytically reduced with 20% palladium hydroxide on carbon (300 mg) under 3 atmospheric pressure of hydrogen for 1 hour. The catalyst was removed by filteration and the filterate was concentrated in vacuo to give N-(2-tetrahydropyranyloxy)-2-(l-aminocyclohexyl)- acetamide (1.18 g) as an oil.
NMR (DMSO-cLJ δ =1.14-1.75(15H, m), 1.95-2.32(3H, m), 3.48-3.59(lH, m), 3.83-3.97(lH, m), 4.34-4.53(2H, m), 5.00-5.10(1H, m) Mass (ESI+): 257(M+H) Preparation 2-1
To a solution of thionyl chloride (9.84 g) in MeOH (150 ml) was added 2-(l- aminocyclohexyl)acetic add ( 10 g) on an ice-bath. After the mixture was refluxed overnight, it was concentrated in vacuo. The residue was triturated with ether to give methyl 2-(l-aminocydohexyl)acetate (12.2 g) as a solid. NMR (DMSO-cLJ δ =1.21-1.52(4H, m), 1.55-1.80(6H, m), 2.77(2H, s), 3.65(3H, s) Mass (ESI+): 172(M+H) Preparation 2-2
To a solution of methyl 2-(l-aminocydohexyl)acetate (500 mg) and N,N- diisopropylethylamine (685 mg) in CHC13 (1O ml) was added 4-phenoxybenzene- sulfonyl chloride (712 mg) in CHC13 (5 ml) at room temperature. After st-jτring overnight at the same temperature, the reaction mixure was concentrated in vacuo. The residue was dissolved in AcOEt (30 ml) and the solution was washed with 0.5N HCl, sat. NaHCO3 aq, and brine, dried over MgSO4 and concentrated in vacuo. The residue was crystalized from AcOEt and hexane to give methyl 2-[ 1-
(4-phenoxybenzenesuffonylamino)cydohexyl]acetate (693 mg).
NMR (DMSO-cLJ δ =1.85-2.02(2H, m), 1.25-1.57(8H, m), 2.60(2H, s), 3.63(3H, s),
5.29(1H, s), 7.01(2H, d, J=8Hz), 7.06(2H, d, J=8Hz), 7.22(1H, t, J=8Hz), 7.41(2H, t,
J=8Hz), 7.83(2H, d, J=8Hz)
Mass (ESI-): 402(M-H)
Preparation 2-3
To a solution of methyl 2-[l-(4-phenoxybenzenesuffonylamino)cydohexyl]- acetate (600 mg) and 60% NaH (65.5 mg) in DMF (10 ml) was added methyl iodide (253 mg) at room temperature. After stirring for 5 hours at the same temperature, the reaction mixture was concentrated in vacuo. The residue was dissolved in AcOEt (30 ml) and the solution was washed with 0.5N HCl, sat. NaHCO3 aq, and brine, dried over MgS04 and concentrated in vacuo to give methyl 2-[l-N-methyl- N-(4-phenoxyben2enesuffonylamino)cydohexyl]acetate (580 mg). NMR (CDC1J δ =1.30-1.56(6H, m), 1.94-2.12(4H, m), 2.88(3H, s), 2.94(2H, s), 3.66(3H, s), 7.01(2H, d, J=8Hz), 7.06(2H, d, J=8Hz), 7.21(1H, t, J=8Hz), 7.40(2H, t, J=8Hz), 7.80(2H, d, J=8Hz) Mass (ESI+): 418(M+H) Preparation 2-4
To a solution of methyl 2-[l-N-methyl-N-(4-phenoxybenzenesuffonylamino)- cydohexyljacetate (550 mg) in MeOH (10 ml) was added IN NaOH aqueous solution (10 ml) at room temperature. After being stirred overnight, the mixture was concentrated in vacuo to remove MeOH. The residual solution was addified by IN HCl and extracted with AcOEt (30 ml). The solution was washed with brine, dried over MgS04 and concentrated in vacuo. The residue was purified by SiO2 column (eluent CHCLJ to give 2-[l-N-methyl-N-(4-henoxybenzenesulfonyl- arnino)cydohexyl]acetic add (220 mg) as an oil.
NMR(CDCLJ δ =1.27-1.72(6H, m), 1.98-2.12(4H, m), 2.89(3H, s), 3.02(2H, s), 7.01(2H, d, J=8Hz), 7.07(2H, d, J=8Hz), 7.21(1H, t, J=8Hz), 7.41(2H, d, J=8Hz), 7.80(2H, d, J=8Hz) Mass (ESI-): 402(M-H) Preparation 3-1
To a solution of 2-(l-aminocydohexyl)acetic add (3.5 g) and (4.21 g) in water (60 ml) was added a solution of 9-fluorenylmethyl sucdnirnidyl carbonate (6.71 g) in dioxane (100 ml) at room temperature. After being stirred for 5 hours, the solution was evaporated in vacuo to remove dioxane. The residue was addified by 3N HCl and extracted with AcOEt ( 100 ml X 2) . The combined organic layer was washed with brine, dried over MgSO4 and concentrated. The residue was triturated with Et,O (100 ml) and hexane (100 ml) to give 2-[l-(9- fluorenylrnethLθxycarbonylarruno)cydohexyl]acetic add (6.6 g) as a solid. NMR (DMSO-cLJ δ =1.04-1.62(8H, m), 1.95-2.22(2H, m), 2.57(2H, s), 4.03- 4.33(3H, m), 7.04(1H, s), 7.22-7.53(4H, m), 7.73(2H, d, J=8Hz), 7.87(2H, d, J=8Hz) Mass (ESI-): 378(M-H) Preparation 3-2
Figure imgf000030_0001
Hycfroxylamine 2-chlorotrityl resin (1.46 g) was swelled in N, N-dimethyl- formamide (10 ml) for 20 minutes. A solution of 2-[l-(9-fluorenylmethoxy- c^rbonylamino)cyclohexyl]acetic add (2.1 g), O-(7-azabenzotriazol-l-yl)-(l,l,3,3- tetiarnethyluronium hexafluorophosphate (2.1 g) and N,N-dήsopropylethylamine (1.43 g) in N,N-dirnethylformamide (10 ml) was added to this suspension and shaken for 24 hours. N-[2-[l-(9-πuorenylrnethoxycarbonylarrιino)cyclohexyl]- acetyl]hydroxylamine 2-chlorotrityl resin was filtered and washed with N, N- dimethyfformamide, methanol and dichloromethane each three times. Preparation 3-3
Figure imgf000030_0002
Figure imgf000031_0001
N-[2-[l-(9-I uorenyln ethoxycarbonylarruΩo)cydohexyl]acetyl]- hycfroxylamine 2-chlorotrityl resin (2.92 g) was swelled in N, N-cfrmethylformamide ( 10 ml) for 20 minutes. To a solution of 20% piperidine in N,N-dimethyl- formamide (20 ml) was added the resin and shaken for 24 hours. N-[2-[l- Am ocyclohe^l]acetyl]hycfroxylamine 2-chlorotrityl resin was filtered and washed with N,N-crimethyffoπnamide, methanol and dichloromethane each three times. Preparation 4-1
To a solution of malonic add (1.0 g) and ammonium acetate (1.48 g) in EtOH (40 ml) was added tetrahydropyran-4-one ( 1.01 g) at room temperature. After the reaction solution was stirred at 90°C for 2 days, it was cooled to room temperature. The resulting predpitate was collected by filteration to give 2-(4-amino- tetrahydropyran-4-yl)acetic add (450 mg).
NMR (D2O) δ =1.73(4H, brs), 2.51(2H, s), 3.51-3.58(2H, m), 3.69-3.76(2H, m) Mass (ESI-): 158(M-H) Preparation 4-2
2-[4-(Ben2yloxycarbonylamino)tetrahydropyran-4-yl]acetic add was obtained in the similar manner as in Preparation 1-2.
NMR (CDCLJ δ =1.62-1.88(2H, m), 2.08-2.24(2H, m), 2.85(2H, s), 3.47-3.78(4H, m), 4.97(1H, brs), 5.08(2H, s), 7.35(5H, s) Mass (ESI-): 292(M-H) Preparation 4-3
N-(2-Tetrahydropyranyloxy)-2-[4-benzyloxycarbonylaminotetrahydropyran- 4-yl]acetamide was obtained in the similar manner as in Preparation 1-3. NMR (DMSO-cLJ δ =1.42-1.73(8H, m), 1.98-2.15(2H, m), 2.39(2H, dd, J=7, 15Hz), 3.40-3.64(6H, m), 3.84-3.96(lH, m), 4.81(1H, s), 5.00(2H, s), 7.15(1H, s), 7.36(5H, s)
Mass (ESI-): 391(M-H) Preparation 4-4
N-(2-Tetrahydropyranyloxy)-2-(4-arrrinotetiahydropyran-4-yl)-acetarm obtained in the similar manner as in Preparation 1-4.
NMR (CDCLJ δ =1.30-1.95(10H, m), 2.35(2H, s), 3.54-3.82(6H, m), 3.88-4.04(lH, m), 4.88-5.07(lH, m) Mass (ESI+): 259(M+H) Preparation 5-1
Methyl 2-(4-aminotetrahydropyran-4-yl)acetate hydrochloride (6.18 g) was obtained from 2-(4-aminotetrahydropyran-4-yl)acetic add (5 g) in the similar manner as in Preparation 2- 1 as a solid.
NMR p2O) δ =3.77-3.71(2H, m), 3.61-3.53(5H, m), 2.87(2H, s), 1.80(4H, br.s) ESI(+): 174(M+H) Preparation 5-2
To a solution of methyl 2-(4-aminotetrahydropyran-4-yl)acetate hydrochloride (1.0 g), 4-phenoxybenzoic add (1.48 g) and l-hydroxybenzotriazole (858 mg) in N,N-dimeu yfformarnide (20 ml) was added l-(3-dimethyl- aminopropyl)-3-ethylcarbodiimide (980 mg) at room temperature. After stirring for 13 hours, the mixture was concentrated in vacuo. The residue was dissolved in AcOEt (100 ml), the solution was washed with IN HCl, sat. NaHCO3 aq. and brine, dried over MgSO4 and was concentrated in vacuo to give methyl 2-{4-(4- phenoxybenzoylamino)tetrahydropyran-4-yl}acetate (1.0 g) as an amorphous. NMR (CDCLJ δ =1.78-1.88(2H, m), 2.41-2.46(2H, m), 3.00(2H, s), 3.63(3H, s), 3.68-3.83(4H, m), 6.08(1H, s), 6.99-7.06(4H, m), 7.17(1H, dd, J=7, 7Hz), 7.27- 7.41(2H, dd, J=8, 8Hz), 7.73(2H, d, J=9Hz) ESI(-): 368(M-H) Preparation 5-3
2-{4-(4-Phenoxybenzoylammo)tetiahydropyran-4-yl}acetic add (1.0 g) was obtained from methyl 2-{4-(4-phenoxyben2»ylamino)tetiahydropyran-4-yϊ}acetate (1.0 g) in the similar manner as in Preparation 2-4.
NMR PMSO-DJ δ = 1.62-1.71(2H, m), 2.33-2.38(2H, m), 2.81(2H, s), 3.53- 3.67(4H, m), 7.02-7.08(4H, m), 7.20(1H, dd, J=7, 7Hz), 7.41-7.46(2H, dd, J=8, 8Hz), 7.75(2H, d, J=9Hz) ESI(-): 354(M-H) Preparation 6-1
2-(4-Aminotetiahycfrothiopyran-4-yl)acetic add was obtained in the similar manner as in Preparation 1.
NMR (D2O) δ =1.77-1.90(2H, m), 1.95-2.05(2H, m), 2.42(2H, s), 2.49-2.60 (2H, m), 2.61-2.24(2H, m) Mass ESI(+): 176(M+1) Preparation 6-2
Methyl 2-(4-ammotetiahydrothiopyran-4-yl)acetate hydrodiloride was obtained in the similar manner as in Preparation 2- 1.
NMR (DMSO-cLJ δ =1.91-2.10(4H, m), 2.62-2.70(4H, m), 2.73(2H, s), 3.15(3H, s), 8.35(3H, brs., exchangeable) Mass ESI(+): 190(M+1) Preparation 6-3
Methyl 2-[4-(4-phenoxybenzenesuffonylarrrmo)tetiahydrothiopyran-4- yl]acetate was obtained in the similar manner as in Example 8 as mentioned below.
NMR (CDCLJ δ =1.75(2H, t, J=12Hz), 2.87(4H, d, J=12Hz), 2.55(2H, s), 2.84(2H, t, J=12Hz), 3.64(3H, s), 5.25(1H, s), 7.04(2H, d, J=8Hz), 7.06(2H, d, J=8Hz), 7.23(1H, t, J=8Hz), 7.42(2H, t, J=8Hz), 7.84(2H, d, J=8Hz) Mass ESI(-): 420(M-1) Preparation 6-4
To a solution of methyl 2-[4-(4-phenoxybenzenesuffonylamino)- tetrahydrothiopyran-4-yl]acetate (150 mg) in tetrahydrofuran (2 ml) was added a solution of sodium periodate (76 mg) in water (1 ml) on an ice bath. After been removed the ice bath, the mixture was stirred for 2 days at ambient temperature. The resultant rnixture was extracted with ethyl acetate. The separated organic layer was washed with water and brine, dried over sodium sulfate and evaporated in vacuo. The obtained residue was purified by column chromatography with 1- 5% methanol in chloroform stepwise gradient to give methyl 2-[l-oxo-4-(4- phenoxybenzenesuffonylarmno)tetrahycfr^ (166 mg) as an amorphous solid.
NMR (CDCLJ δ =2.14-2.31(4H, m), 2.34(2H, s), 2.77(2H, d, J=14Hz), 2.90(2H, td, J=4.5, 14Hz), 3.57(3H, s), 5.52(1H, s), 7.04(2H, d, J=8Hz), 7.07(2H, d, J=8Hz), 7.24(1H, t, J=8Hz), 7.44(2H, t, J=8Hz), 7.80(2H, d, J=8Hz) Mass ESI(-): 436(M-1) Preparation 7-1
Methyl 2-[l , l-dioxo-4-(4-phenoxybenzenesuffonylamino)tetrahydro- thiopyran-4-yl]acetate was obtained in the similar manner as in Preparation 6-4. NMR (CDCIJ δ = 2.08(2H, t, J=13.5Hz), 2.44(2H, s), 2.64(2H, d, J=13.5Hz), 2.84(2H, d, J=13.5Hz), 3.43(3H, t, J=13.5Hz), 3.60(3H, s), 5.50(1H, s), 7.05(2H, d, J=8Hz), 7.80(2H, d, J=8Hz), 7.25(1H, t, J=8Hz), 7.45(2H, t, J=8Hz), 7.81(2H, d, J=8Hz)
Mass ESI(-): 452(M-1) Preparation 7-2
2-[l , l-Dioxo-4-(4-phenoxybenzenesuffonylamijιo)tetiahycfro-thiopyran-4- yl]acetic add was obtained in the similar manner as in Preparation 2-4. NMR (DMSO-cLJ δ =2.03-2.54(6H, m), 2.86-3.05(4H, m), 7.13(4H, d, J=8Hz), 7.25(1H, t, J=8Hz), 7.46(2H, t, J=8Hz), 7.78(1H, s), 7.85(2H, d, J=8Hz), 8.86(1H, s) Mass ESI(-): 438(M-l) Preparation 8-1
To a solution of malonic add (1.0 g) and ammonium acetate (1.48 g) in EtOH (50 ml) was added l-benzyloxycarbonyl-4-piperidone (2.24 g) at room temperature. After the reaction solution was stirred at 90°C overnight, the reaction mixture was concentrated in vacuo. The residue was dissolved in 0.5N hydrochloric add (200 ml) and the solution was washed with ether (200 ml) . The aqueous solution was applied to a column of Diaion HP-20 (50 ml) eluting with MeOH (100 ml). After the eluent was concentrated in vacuo, the residue was triturated with ether to give 2-(4-amino-l-benzyloxycarbonylpiperidin-4-yl)acetic add (1.70 g) as an amorphous powder.
NMR (DMSO-cLJ δ =1.54-1.65(4H, m), 2.20(2H, s), 3.26-3.42(2H, m), 3.45-
3.60(2H, m), 5.08(2H, s), 7.35(5H, s)
Mass (ESI-): 291(M-H)
Preparation 8-2
To a solution of 2-(4-arrrmo-l-ber-zyloxycarbonylpiperidin-4-yl)acetic add (1.50 g) in IN NaOH (7.7 ml) was added a solution of di-tert-butyl dicarbonate (1.68 g) in dioxane (10 ml) at room temperature. After stirring at 40°C for 6 hours, the mixture was concentrated in vacuo to remove dioxane. The residual solution was addified with 3N HCl to adjust to pH 2 and extracted with AcOEt (50 ml ). The solution was washed with brine, dried over MgSO4 and concentrated in vacuo to give 2-[4-(tert-butoxycarbonylarnmo)-l-bc add (1.48 g) as an amorphous powder.
NMR (CDC1J δ =1.48(9H, s), 1.50-1.78(2H, m), 2.07-2.32(2H, m), 2.70(2H, brs), 3.03-3.28(2H, m), 3.78-4.02(2H, m), 5.10(2H, s), 7.34(5H, s) Mass (ESI-): 391(M-H) Preparation 8-3
To a solution of 2-[4-(tert-butoxyrarbonylamino)-l-benzyloxycarbonyl- piperidin-4-yl]acetic add (1.40 g) and ethyl iodide (668 mg) in DMF (10 ml) was added potassium carbonate (296 mg) at room temperature. After stirring for 4 hours, the reaction solution was concentrated in vacuo. The residue was dissolved in AcOEt (50 ml) and the solution was washed with IM hydrochloric add solution, saturated sodium bicarbonate solution and brine, and dried over MgSO4. The solution was concentrated in vacuo to give ethyl 2-[4-(tert-butoxycarbonyl- am.no)-l-ben2yloxycarbonylpiperidin-4-yl]acetate (1.52 g) as a powder. NMR (CDC1J δ =1.25(3H, t, J=7Hz), 1.44(9H, s), 1.48-1.72(2H, m), 2.10-2.31(2H, m), 2.74(2H, s), 3.04-3.30(2H, m), 3.75-3.99(2H, m), 4.12(2H, q, J=7Hz), 4.51(1H, s), 5.12(2H, s), 7.34(5H, s) Mass (ESI+): 421(M+H) Preparation 8-4
To a solution of ethyl 2-[4-(tert-butoxycarbonylarnmo)-l-benzyloxycarbonyl- piperidin-4-yl]acetate (1.48 g) in AcOEt (10 ml) was added 4N hydrogenchloride in AcOEt (20 ml) at room temperature. After stirring for 1 hour, the reaction solution was concentrated in vacuo. The residue was triturated with ether to give ethyl 2-[4-amino-l-ben2yloxycarbonylpiperidin-4-yl]acetate hydrochloride (1.36 g) as a solid.
NMR (DMSO-cLJ δ =1.22(3H, t, J=7Hz), 1.70-1.90(4H, m), 2.86(2H, s), 3.30-
3.48(2H, m), 3.58-3.76(2H, m), 4.13(2H, q, J=7Hz), 5.08(2H, s), 7.34(5H, s),
8.40(2H, brs)
Mass (ESI+): 321(M+H)
Preparation 8-5
Ethyl 2-[4-(4-phenoxybenzenesuffonylamino)- 1-benzyloxycarbonyl- piperidin-4-yl]acetate was obtained in the similar manner as in Example 8 as mentioned below.
NMR (CDC1J δ =1.23(3H, t, J=7Hz), 1.35-1.53(2H, m), 2.06-2.17(2H, m), 2.48(2H, s), 3.05-3.32(2H, m), 3.62-3.82(2H, m), 4.08(2H, q, J=7Hz), 5.10(2H, s), 5.40(1H, s), 7.02(2H, d, J=8Hz), 7.08(2H, d, J=8Hz), 7.22(1H, t, J=8Hz), 7.33(5H, s), 7.42(2H, t, J=8Hz), 7.81(2H, d, J=8Hz) Mass (ESI-): 551(M-H) Preparation 8-6
2-[4-(4-Phenoxybenzenesuffonylammo)-l-benzyloxycarbonyl-piperidin-4- yl]acetic add (800 mg) was obtained in the same manner as in Preparation 2-4 as an amorphous state.
NMR (CDCLJ δ =1.42-1.60(2H, m), 2.03-2.18(2H, m), 2.65(2H, s), 2.92-3.20(2H, m), 3.62-3.80(2H, m), 5.09(2H, s), 5.58(1H, s), 7.02(2H, d, J=8Hz), 7.06(2H, d, J=8Hz), 7.22(1H, t, J=8Hz), 7.32(5H, s), 7.49(2H, t, J=8Hz), 7.82(2H, d, J=8Hz) Mass (ESI-): 523(M-H) Preparation 9-1
2- [ 1 -Benzyloxycarbonyl-4-(9-fluorenylmethoxycarbonylamino)piperidin-4- yl]acetic add was obtained as an oil from 2-[4-amino-l-benzyloxycarbonyl- piperidin-4-yl]acetic add in the sirriilar manner as in Preparation 3-1. NMR (DMSO-cLJ δ =1.38-1.63(2H, m), 2.06-2.26(2H, m), 2.62(2H, s), 2.90- 3.17(2H, m), 3.62-3.80(2H, m), 4.15-4.32(3H, m), 5.07(2H, s), 7.26-7.48(9H, m), 7.73(2H, d, J=7Hz), 7.88(2H, d, J=7Hz) Mass (ESI-): 513(M-H) Preparation 9-2 N-(2-Tetrahydropyranyloxy)-2-[ 1 -benzyloxcarbonyl-4-(9-fluorenylmethoxy- carbonylarriino)pipericlin-4-yl]acetamide was obtained as a powder from 2-[l- benzyloxycarbonyl-4-(9-fluorenylrnethoxycarbonylarrιino)pipericto in the similar manner as in Preparation 1-3.
NMR (DMSO-cLJ δ =1.40-1.72(8H, m), 2.08-2.25(2H, m), 2.28-2.49(2H, m), 2.88-3.13(2H, m), 3.36-3.48(2H, m), 3.64-3.78(2H, m), 3.82-3.94(lH, m), 4.78(1H, s), 5.07(2H, s), 7.18-7.48(10H, m), 7.73(2H, d, J=7Hz), 7.89(2H, d, J=7Hz) Mass (ESI+): 614(M+H) Preparation 9-3
N-(2-Tetrahydropyranyloxy)-2-[ 1 -benzyloxycarbonyl-4-(9-fluorenylmethoxy- c^rbonylammo)piperidin-4-yl]acetamide (27.5 g) was dissloved in 20% piperidine in DMF (250 ml) at room temperature. After stirring at the same temperature for 1 hour, the solution was concentrated in vacuo. The residue was purified by SiO2 column chromatography (CHCl3-2% MeOH in CHCLJ to give N-(2-tetrahydro- pyranyloxy)-2-(4-ammo-l-benzyloxyc^bonylpipe (15.6 g) as an oil.
NMR (DMSO-cLJ δ =1.22-1.75(10H, mJ=Hz), 2.07(2H, s), 3.35-3.65(6H, m), 3.84- 3.96(1H, m), 4.82(1H, s), 5.06(2H, s), 7.27-7.42(5H, m) Mass (ESI-): 390(M-H) Preparation 10-1
N-(2-Tetiahydropyranyloxy)-2-benzyloxycarbonylarn opropionamide was obtained as a solid from 2-benzyloxycarbonylaminopropionic add (5.0 g) in the similar manner as in Preparation 1-3.
NMR (DMSO-cLJ δ =1.42-1.72(6H, m), 2.17(2H, t, J=7Hz), 3.15-3.26(2H, m), 3.45-3.54(lH, m), 3.85-3.95(lH, m), 4.81(1H, s), 5.00(2H, s), 7.25-7.40(5H, m) Mass (ESI-): 321(M-H) Preparation 10-2
N-(2-Tetiahycfropyranyloxy)-2-arninopropionamide was obtained as an oil from N-(2-tetτahydropyranyloxy)-2-benzyloxycarbonylarj inopropionamide in the similar manner as in Preparation 1-4.
NMR (DMSO-cLJ δ =1.20-1.72(6H, m), 2.05-2.30(2H, m), 2.65-2.86(2H, m), 3.32- 3.81(2H, m), 4.56-4.82(lH, m) Mass (ESI+): 189(M+H) Preparation 11-1
3-Benzyloxycarbonylamino-3-cydohexylpropionic add was obtained from 3- amino-3-cyclohexylpropionic add in the similar manner as in Preparation 1-2. NMR (DMSO-dJ δ =0.88-1.43(6H, m), 1.53-1.75(5H, m), 2.18-2.46(2H, m), 3.65- 3.79(1H, m), 5.00(2H, s), 7.17(1H, d, J=9Hz), 7.26-7.40(5H, m) Mass (ESI-): 304(M-H) Preparation 11-2
N-(2-Tetiahycfropyranyloxy)-3-benzyloxyc^rbonylammo-3-cydohexyl- propionamide was obtained from 3-benzyloxyc^rbonylamino-3-cydohexyl- propionic add in the similar manner as in Preparation 1-3. NMR (DMSO-cLJ δ =0.82-1.74(17H, m), 2.00-2.26(2H, m), 3.40-3.53(lH, m), 3.67-3.80(lH, m), 3.84-3.95(lH, m), 4.72-4.81(lH, m), 5.00(2H, s),6.98-7.07(lH, m), 7.26-7.40(5H, m) Mass (ESI-): 403(M-H) Preparation 11-3
N-(2-Tetiahydropyranyloxy)-3-arnmo-3-cydohexylpropionamide was obtained from N-(2-tetiahydropyranyloxy)-3-benzyloxycarbonylamino-3- cyclohexylpropionamide in the similar manner as in Preparation 1-4. NMR (DMSO-cLJ δ =0.74-1.76(17H, m), 1.82-2.20(2H, m), 2.71-2.86(1H, m), 3.42-3.57(lH, m), 3.84-4.02(lH, m), 4.74-4.86(lH, m) Mass (ESI-): 269(M-H) Preparation 12-1
To a solution of 2-ethyl-l-butene (1.82 g) in Et-0 (8 ml) was added N- chlorosulfonyl isocyanate (3 g) at 0°C and the mixture was stirred for 5 hours at room temperature. The mixture was poured into water (10 ml) and organic layer was separated. To this ether solution was added an aqueous sodium sulfite solution (9.35 g in 30 ml of water) and the solution was stirred for 1 hour at room temperature. The organic layer was separated, and the aqueous layer was extracted with ether twice. The ether layer was gathered and washed with brine, dried over magnesium sulfate. Solvent was removed under reduced pressure to give 4,4-diethyl-2-azetidinone as a colorless oil.
NMR (DMSO-cLJ δ = 0.93(t, 6H, J=8Hz), 1.70(q, 4H, J=8Hz), 2.64(d, 2H, J=2Hz), 6.14(br, 1H) MS (ES+)= 128.2 Preparation 12-2
To a suspension of sodium hydride (60% oil dispersion, 69 mg) in N,N- dimethyfformamide (DMF, 5 ml) was added 4,4-cfiethyl-2-azetidinone (200 mg) at 0°C, and the mixture was stirred for 30 minutes. Then a solution of 4-phenoxy- benzenesulfonyl chloride (465 mg) in DMF (3 ml) was slowly added at 0°C, and the mixture was stirred for 1 hour at room temperature. The reaction was quenched with 5% aqueous dtric add solution. The organic layer was separated, washed with water (X 2) and brine, and dried over magnesium sulfate. The solvent was evaporated. The oily residue was purified with silica gel column chromatography (eluent: chlorofoιm)to give l-(4-phenoxy-benzenesulfonyl)-4,4-diethyl-2- azetidinone as a slightly yellow oil.
NMR (CDC1J δ =0.94(t, 6H, J=7Hz), 1.96(q, 4H, J=7Hz), 2.76 (s, 2H), 7.03- 7.09(m, 2H), 7.20-7.26(m, 1H), 7.38-7.45(m, 2H), 7.97(d, 2H, J=9Hz) Preparation 12-3
To a solution of l-(4-phenoxyben2εnesuffonyl)-4,4-diethyl-2-a2«tidinone (290 mg) in methanol (5 ml) was added IN aqueous sodium hydroxide solution (1.2 ml) at room temperature and the mixture was stirred for 5 hours at 50°C. The reaction mixture was cooled to room temperature and addified with IN hydrochloric add (ca. pH=3). This solution was extracted with ethyl acetate (10 ml X 2). The organic layer was combined and washed with water, brine, and dried over magnesium sulfate. The solvent was evaporated. This residue was purified with silica gel column chromatography (eluent: hexane-ethyl acetate 1:1) to give 3-(4-phenoxybenzenesuffonylamino)-3-ethylvaleric add as a colorless oil. NMR (DMSO-cLJ δ = 0.66(t, 6H, J=8Hz) , 1.53(q, 2H, J=8Hz) , 1.64(q, 2H, J=8Hz) , 2.36(s, 2H), 7.05-7.13(m, 4H), 7.24(dd, 1H, J=9Hz, 9Hz), 7.46(dd, 2H, J=9Hz, 9Hz), 7.80(d, 2H, J=9Hz) MS (ES-): 376 Preparation 13-1 t-Butoxycarbonyl dicarbonate (3.43 g) and 4-chmethylaminopyricline (96 mg) were added to a solution of 4,4-diethyl-2-azetidinone (1 g) in acetonitrile (20 ml) at 0°C, and the mixture was stirred overnight Then, ethyl acetate (25 ml) was added, and the mixture was washed with IN hydrochloric add, a saturated solution of sodium bicarbonate and brine. The organic layer was dried over magnesium sulfate, and the solvent was removed in vacuo. Products were purified by silica gel column chromatography to give l-(t-butoxycarbonyl)-4,4-cfiethyl-2-azeticiinone as a colorless solid.
NMR (CDCIJ δ =0.95(t, 6H, J=l lHz), 1.52(s, 9H), 1.89(q, 4H, J=l lHz), 2.72 (s,
2H)
Preparation 13-2
To a solution of l-(t-butoxycarbonyl)-4,4-cfiethyl-2-azetidinone (300 mg) in methanol (7 ml) was added IN sodium hydroxide solution (4 ml) at 0°C and the mixture was stirred for 5 hours at room temperature. The mixture was evaporated to remove methanol. The residue was addified with IN hydrochloric add (ca. pH=3) and extracted with ethyl acetate (X 2). The organic layer was gathered, washed with brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure to give 3-(t-butoxycarbonylamino)-3-ethylvaleric pentanoic add.
NMR pMSO-dJ δ = 0.74(t, 6H, J=8Hz), 1.37(s, 9H), 1.64(q, 4H, J=8Hz), 2.49(s, 2H), 6.23(bs, 1H) Preparation 13-3
A mixture of 3-(t-butoxycarbonylamino)-3-ethylvaleric add (315 mg), O- benzylhycfroxylarriine hydrochloride (307 mg), WSCD (239 mg) and 1- hydroxybenzotiiazole (208 mg) in DMF (5 ml) was sttirred at room temperature. After 5 hours, the solvent was evaporated and the residue was partitioned with water (10 ml) and ethyl acetate (10 ml). The organic layer was combined and washed with 5% aqueous dtric acid solution, saturated NaHCO3 aq, and brine, and then dried over MgSO4. The solvent was removed under reduced pressure. The crude product was purified with silica gel column chromatography to give N- ber.2yloxy-3-(t-butoxycarbonylamino)-3-ethylvaleramide.
NMR pMSO-cLJ δ = 0.84(t, 6H, J=8Hz), 1.40(s, 9H), 1.67(q, 4H, J=8Hz), 2.49(s, 2H), 4.89(s, 2H), 7.33-7.42(m, 5H) MS (ES-): 349 Preparation 13-4
N-Benzyloxy-3-amino-3-ethylvaleramide hydrochloride was obtained in the similar manner as in Preparation 8-4. NMR (DMSO-cLJ δ =0.83(t, 6H, J=8Hz), 1.56(q, 4H, J=8Hz), 2.28(s, 2H), 3.38(br, 3H(variable)), 4.84(s, 2H), 7.34-7.44(m, 5H) MS (ES+): 251 Preparation 14-1
3,4,4-Trirnethyl-2-azeticiinone was obtained in the similar manner as in Preparation 12-2.
NMR (DMSO-cLJ δ =1.19(d, 3H, J=7Hz), 1.31(s, 3H), 1.42(s, 3H), 1.78(s, 1H), 2.89(q, 1H, J=7Hz) Preparation 14-2 l-(4-Phenoxybenzenesuffonyl)-3,4,4-triιnethyl-2-azetidinone was obtained in the similar manner as in Preparation 12-2.
NMR PMSO-dJ δ =1.17(d, 3H, J=7Hz), 1.47(s, 3H), 1.62(s, 3H), 2.98(q, 1H, J=7Hz), 7.02-7. ll(m, 4H), 7.24(dd, 1H, J=9Hz, 9Hz), 7.43(dd, 2H, J=9Hz, 9Hz), 7.97(d, 2H, J=9Hz) Preparation 14-3
2,3-Dimethyl-3-(4-phenoxybenzenesuffonylarn^ add was obtained in the similar manner as in Preparation 12-3.
NMR (DMSO-cLJ δ =1.21(d, 3H, J=7Hz), 1.27(s, 3H), 1.29(s, 3H), 2.66(q, 1H, J=7Hz), 5.81(s, 1H), 6.99-7.09(m, 4H), 7.22(dd, 1H, J=9Hz, 9Hz), 7.41(dd, 2H, J=9Hz, 9Hz), 7.83(d, 2H, J=9Hz) Preparation 15-1
2-(l-(t-Butoxycarbonylamino)cydobutyl)acetic add was obtained in the similar manner as in Preparation 13-2.
NMR (CDCIJ δ =1.45(s, 9H), 1.77-2.02(m, 2H), 2.1 l-2.31(m, 4H), 2.70-3.03(m, 2H), 5.12(br, 1H) MS (ES-): 228(M-1) Preparation 15-2
N-Benzyloxy-2-( 1 -(t-butoxycarbonylammo)cyclobutyl)acetamide was obtained in the similar manner as in Preparation 1-3.
NMR (CDCIJ δ =1.41(s, 6H), 1.44(s, 3H), 1.75-2.00(m, 2H), 2.10-2.33(m, 4H), 2.65(s, 4/3H), 2.86(s, 2/3H), 4.90(s, 4/3H), 5.04(s, 2/3H), 7.38(s, 5H), 8.33(bs, 1H) MS (ES-): 333(M-1) Preparation 15-3
N-Benzyloxy-2-(l-ammocyclobutyl)acetamide was obtained in the similar manner as in Preparation 13-2.
NMR (CDCIJ δ =1.65-1.87(m, 4H), 1.95-2.08(m, 2H), 2.46(s, 2H), 4.92(s, 2H), 7.29-7.43(m, 5H) MS (ES+)=234(M+1) Example 1
N-(2-Tetrahydropyranyloxy)-2-[4-(4-phenoxybenzenesulfonyl- amino)piperidin-4-yl]acetarnide was obtained in the similar manner as in Preparation 1-4.
NMR (DMSO-dJ δ = 1.32-1.90(10H, m), 2.18-2.34(2H, m), 2.47-2.60(2H, m), 3.20-3.54(3H, m), 3.84-3.98(lH, m), 4.80(1H, s), 7.04-7.18(4H, m), 7.20-7.30(1H, m), 7.40-7.52(2H, m), 7.78-7.88(2H, m) Mass (ESI+): 490(M+H) Example 2
N-(2-Ttetiahycfropyranyloxy)-2-[l-(N-methyl-N-(4-phenoxybenzene- suffonyl)arrrino)cydohexyl]acetamide (250 mg) was obtained from 2-[l-(N-methyl- N-(4-phenoxybenzensuffonyl)amino)cyclohexyl]acetic add(210 mg) in the similar manner as in Preparation 2-4 as an amorphous powder.
NMR (CDCIJ 5 = 1.28-2.20(16H, m), 2.70-2.90(2H, m), 2.84(3H, s), 3.59-3.70(lH, m), 3.92-4.06(lH, m), 5.03(1H, s), 7.03(2H, d, J=8Hz), 7.08(2H, d, J=8Hz), 7.22(1H, t, J=8Hz), 7.41(2H, t, J=8Hz), 7.70(2H, d, J=8Hz), 9.13(1H, s) Mass (ESI+): 503(M+H) Example 3
N-(2-Tefrahy(fropyranyloxy)-2-{4-(4-phenoxybenzoylamino)- tetiahycfropyran-4-yl}acetamide (1.0 g) was obtained from 2-{4-(4- phenoxybenzoylamino)tetrahydropyran-4-yl}acetic add (1.0 g) in the similar manner as in Preparation 1-3.
NMR (CDCIJ c = 1.60-1.78(8H, m), 2.32-2.40(2H, m), 2.78-2.88(2H, m), 3.41- 3.47(1H, m), 3.67-3.86(4H, m), 6.07(1H, br.s), 6.99-7.07(4H, m), 7.18(1H, dd, J=7, 7Hz), 7.37-7.41(2H, dd, J=8, 8Hz), 7.72 (2H, d, 9Hz) ESI(-): 453(M-H) Example 4 N-Tetrahydropyranyloxy-2-[l , l-dioxo-4-(4-phenoxybenzene- suffonylanι o)tetiahydrothiopyran-4-yl]acetamide was obtained in the similar manner as in Preparation 1-3.
NMR (CDCIJ d =1.49-1.89(6H, m), 2.00-2.21(2H, m), 2.33-2.50(2H, m), 2.52- 2.90(4H, m), 3.10-3.30(2H, m), 3.55-3.68(lH, m), 3.80-4.01(lH, m), 4.65(0.5H, s), 4.95(0.5H, s), 5.70(0.5H, s), 6.05(0.5H, s), 7.05(2H, d, J=8Hz), 7.09(2H, d, J=8Hz), 7.25(1H, m), 7.44(2H, t, J=8Hz), 7.80-7.90(2H, m), 8.02(0.5H, s), 8.68(0.5H, s) Mass ESI(-): 537(M-1) Example 5
N-(2-Tetiahydropyranyloxy)-2-[4-(4-phenoxybenzenesuffonyl-amino)- 1 - benzyloxycarbonylpiperidin-4-yl]acetamide was obtained in the similar manner as in Preparation 1-3.
NMR (CDCIJ <5 =1.38-2.10(10H, m), 2.33-2.65(2H, m), 2.84-3.26(2H, m), 3.52- 3.78(3H, m), 3.92-4.06(lH, m), 5.02(1H, s), 5.08(2H, s), 5.22(1H, s), 7.02(2H, d, J=8Hz), 7.08(2H, d, J=8Hz), 7.24(1H, t, J=8Hz), 7.32(5H, s), 7.83(2H, d, J=8Hz), 8.82(1H, s)
Mass (ESI-): 622(M-H) Example 6
N-(2-Tetiahycfropyranyloxy)-3-(4-phenoxybenzenesuffonylamino)-3- ethylvaler amide was obtained in the similar manner as in Preparation 1-3. NMR (DMSO-dJ 6 =0.70(t, 3H, J=8Hz), 0.75(t, 3H, J=8Hz), 1.50-1.94(m, 10H), 2.46(dd, 2H, J=7Hz, 16Hz), 3.60-3.70(m, 1H), 4.01(t, 1H, J=10Hz), 5.04(s, 0.5H), 5.18(s, 0.5H), 7.01(d, 2H, J=9Hz), 7.06(d, 2H, J=9Hz), 7.17-7.24(m, 1H), 7.38(dd, 2H, J=9Hz, 9Hz), 7.85(d, 2H, J=9Hz), 8.97(s, 1H) MS (ES+)=477 Example 7
N-(2-Tetiahycfropyranyloxy)-2,3-ciimethyl-3-(4-phenoxybenzene- suffonylarrιino)butyramide was obtained in the similar manner as in Preparation 1-3.
NMR (CDC1J d = 1.13-1.31(m, 9H), 1.52-1.93(m, 6H), 2.31(q, 0.5H, J=7Hz), 2.44(q, 0.5H, J=7Hz), 3.63(bs, 1H), 3.67(bs, 1H), 3.90-4.09(m, 1H), 4.99(s, 1H), 5.77(s, 0.5H), 5.93(s, 0.5H), 6.97-7.09(m, 4H), 7.22(dd, 1H, J=9Hz, 9Hz), 7.39(dd, 2H, J=9Hz, 9Hz), 7.83(d, 2H, J=9Hz), 8.66(s, 0.5H), 8.68(s, 0.5H)(diastereomeric mixture) MS (ES-)=461 Example 8
To a solution of N-(2-tetiahycfropyranyloxy)-2-(l-am-nocydohexyl)acetamide (200 mg) in pyridine (8 ml) was added 4-phenoxybenzenesulfonyl chloride (314 mg) in CHC13 (4 ml) at room temperature. After being stirred for 4 hours, the solution was concentrated in vacuo. The residue was dissolved in AcOEt (20 ml) and the solution was washed with a 5% aqueous dtric add solution, sat NaHCO3 solution and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by SiO2 column chromatography (eluent: 1% MeOH in CHCIJ to give N-(2-tetiahycfropyranyloxy)-2-[l-(4-phenoxybenzenesuffonylarrιino)cyclohexyl]- acetamide (120 mg) as an amorphous powder.
NMR (CDCIJ <5 = 1.18-1.95(16H, m), 2.50(1H, d, J=14Hz), 2.53(1H, d, J=14Hz), 3.60-3.70(lH, m), 3.96-4.09(lH, m), 4.98(1H, s), 5.06(1H, s), 7.03(2H, d, J=8Hz), 7.07(2H, d, J=8Hz), 7.22(1H, t, J=8Hz), 7.41(2H, t, J=8Hz), 7.85(2H, d, J=8Hz), 8.95(1H, s)
Mass (ESI-): 487(M-H) Example 9
N-(2-Tefrahycfropyranyloxy)-2-[l-(5-(4-fluorophenyl)t ophen-2-ylsulfonyl- arruno)cyclohexyl]acetamide (213 mg) was obtained as an amorphous powder in the similar manner as in Example 8.
NMR (CDCIJ δ = 1.22-2.05(16H, m), 2.50(1H, d, J=14Hz), 2.62(1H, d, J=14Hz), 3.51-3.70(1H, m), 3.92^.08(1H, m), 5.03(1H, s), 5.24(1H, s), 7.03-7.21(3H, m), 7.48-7.65(3H, m), 8.80(1H, s) Mass (ESI-): 495(M-H) Example 10
N-(2-Tetrahydroρyranyloxy)-2-[ 1 -(4-(4-fluorophenoxy) benzenesulfonyl- amino)cyclohexyl]acetamide was obtained in the similar manner as in Example 8. NMR (CDCIJ ά = 1.24-1.97(16H, m), 2.50(1H, d, J=14Hz), 2.60(1H, d, J=14Hz), 3.95-4.10(1H, m), 5.01(1H, s), 5.04(1H, s), 6.90-7.17(6H, m), 7.28-7.40(lH, m), 7.85(2H, d, J=8Hz), 8.93(1H, s) Mass (ESI-): 505(M-H) Example 11 N-(2-Tetiahydropyranyloxy)-2-[l-(4-methoxybenzensuffonylamino)- cydohexyl]acetamide was obtained as an amorphous powder in the similar manner as in Example 8.
NMR (CDCIJ ά = 1.12-2.00(16H, m), 2.42-2.66(2H, m), 3.53(1H, m), 3.87(1H, s), 3.96-4.12(lH, m), 4.90(1H, s), 5.06(1H, s), 6.96(2H, d, J=8Hz), 7.84(2H, d, J=8Hz), 8.98(1H, s)
Mass (ESI-): 425(M-H) Example 12
N-(2-Tetiahycfropyranyloxy)-2-[4-(4-phenoxybenzensuffonylamino)- tetrahydropyran-4-yl]acetamide was obtained in the similar manner as in Example 8.
NMR (CDCIJ δ = 1.46-2.02(10H, m), 2.55(2H, dd, J=10, 12Hz), 3.30-3.74(6H, m), 3.95-4.10(1H, m), 5.20(1H, s), 7.02(2H, d, J=8Hz), 7.07(2H, d, J=8Hz), 7.22(1H, t, J=8Hz), 7.40(2H, t, J=8Hz), 7.84(2H, d, J=8Hz), 8.82(1H, s) Mass (ESI-): 489(M-H) Example 13
To a solution of N-(2-tetiahycfropyranyloxy)-2-(4-amino-l-benzyl- oxyc^rbonylpiperidin-4-yl)acetamide (150 mg) in N,N-climethylformamide (3 ml) was added 1-hycfroxybenztriazole (38 mg) and l-(3-cr-methyl-aminopropyl)-3- ethylcarbodiimide (54 mg) at ambient temperature and the reaction mixture was stirred at ambient temperature for 24 hours. The mixture was poured into water and was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogencarbonate and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The crude product was purified by column chromatography on silica gel 60 (10 g) using 1% methanol-chloroform to give N-(2-tetiahycfropyranyloxy)-2-[l-benzyloxycarbony-4-(4-phenoxybenzoyl- amino)piperid -4-yl]acetamide as a white amorphous (80 mg). NMR (CDCIJ δ = 1.60(br, 2H), 1.67-1.85(m, 6H), 2.42(br d, J=15Hz, 2H), 2.77(dd, J=12.5, 12.5Hz, 2H), 3.24(br t, J=12.5Hz, 2H), 3.41-3.48(br, 1H), 3.75-3.91(br, 4H), 4.82(s, 1H), 5.13(s, 2H), 6.06(s, 1H), 6.98-7.04(m, 4H), 7.29-7.39(m, 7H), 7.70(d, J=8.0Hz, 2H), 8.50(s, 1H) MASS (ESI): 586.6 (M-H) Example 14 N-(2-Tetrahydropyranyloxy)-2- [ 1 -benzyloxycarbonyl-4-(5-(4-fluorophenyl) - tMophen-2-ylcarbonylamino)piperidin-4-yl]acetarnide (100 mg) was obtained as a white amorphous from N-(2-tetrahydropyranyl-oxy)-2-(4-amino-l-benzyloxy- carbonylpiperid -4-yl)acetamide (100 mg) was obtained in the similar manner as in Example 13.
NMR (DMSO-dJ δ =1.46(br s, 2H), 1.60(br, 6H), 2.40-2.44(m, 2H), 2.53-2.62(m, 2H), 3.15(br, 2H), 3.35-3.43(m, IH), 3.71-3.76(m, 2H), 3.82-3.90(m, IH), 4.76(s, IH), 5.08(s, 2H), 7.25-7.36(m, 6H), 7.51(d, J=3.0Hz, IH), 7.72-7.77(m, 2H), 7.84(s, 1 H), 7.88(d, J=3.0Hz, IH) MASS (ESI): 594.3 (M-H) Example 15
N-I3enzyloxy-3-(4-phenoxybenzoylanιino)-3-ethylvaleramide was obtained in the similar manner as in Example 13.
NMR PMSO-dJ <5=0.88(t, 6H, J=8Hz), 1.87(q, 2H, J=8Hz), 1.91(q, 2H, J=8Hz), 2.54(s, 2H), 4.84(s, 2H), 6.73(bs, IH), 6.95-7.08(m, 4H), 7.17(dd, IH, J=9Hz, 9Hz), 7.27-7.41(m, 7H), 7.71(d, 2H, J=9Hz), 8.62(bs, IH) MS (ES-)=445 Example 16
N-Benzyloxy-2-(l-(4-phenoxybenzenesuffonylam o)cyclobutyl)-acetamide was obtained in the similar manner as in Example 8.
NMR (CDCIJ =1.52-2.44(m, 6H), 2.60(s, 2H), 4.77(br, IH), 4.92(s, IH), 5.50(s, IH), 6.89-7.49(m, 12H), 7.80(d, 2H, J=8Hz), 8.71(bs, IH) MS (ES-): 465(M-1) Example 17
Figure imgf000046_0001
Figure imgf000047_0001
To a solution of 4-(4-methylphenoxy)benzenesulfonyl chloride (124 mg) and N,N-dώsopropylethylamine (57 mg) in dichloromethane (1 ml) was added the N- [2-(l-arrιinc)cyclohexyl)acetyl]hycfroxylamine 2-chlorotrityl resin (100 mg) and shaken for 24 hours, the resin was filtered and washed successively with 20% piperidine in N,N-dimethyffomιamide, N,N-dimethyfformamide, methanol and dichloromethane each three times. N-[2-[l-{4-(4-Methylphenoxy)benzene- suffonylarnmo}cydohexy]acetyl]hycirOxylarrrine 2-chlorotrityl resin was suspended in a 5% trifluoroacetic add in dichloromethane for 1 hour. After draining the resin, it was washed successively with a 5% trifluoroacetic add in dichloromethane and dichloromethane several times. The filtrate was concentrated in vacuo to give N-hydroxy-2-[l-{4-(4-methylphenoxy)benzene- suffonylamino}cydohexyl]ace1amide as a yellow oil (44 mg).
NMR pMSO-dJ <5 =1.15-1.29(m, 6H), 1.45-1.52(m, 2H), 1.77-1.82(m, 2H), 2.19(s, 2H), 2.32(s, 3H), 7.00-7.06(m, 4H), 7.26(d, J=8.0Hz, 2H), 7.35(s, IH), 7.80(d, J=8.0Hz, 2H) MASS (ESI): 417.2 (M-H) Example 18
N-Hycfroxy-2-[l-(4-phenylthiobenzenesuIfonylamino)cydohexyl]a∞tamide (40 mg) was obtained as a white amorphous in the similar manner as in Example 17.
NMR (DMSO-d <5 =l.l l-1.26(m, 6H), 1.41-1.48(m, 2H), 1.73-1.78(m, 2H), 2.17(s, 2H), 7.28(d, J=8.0Hz, 2H), 7.42-7.46(m, 6H), 7.74(d, J=8.0Hz, 2H), 8.79(s, IH) MASS (ESI) : 421.0 (M-H) Example 19
N-Hy<froxy-2-[l-{4-(4-bromophenoxy)benzenesuifonylamino}- cyclohexyl]acetamide (35 mg) was obtained as a white amorphous in the similar manner as in Example 17. NMR PMSO-dJ S =1.76-1.93(m, 6H), 2.11(br, 2H), 2.38-2.43(m, 2H), 2.82(s, 2H), 7.78-7.75(m, 4H), 8.02(s, IH), 8.25(d, J=8.0Hz, 2H), 8.46(d, J=8.0Hz, 2H), 9.44(s,
IH)
MASS (ESI): 483 (M-H)
Example 20
N-Hycfroxy-2-[l-(2-phenoxypyridin-5-ylsuffonylam o)cydohexyl]acetamide was obtained as a yellow oil in the similar manner as in Example 17. NMR pMSO-dJ <5=1.23-1.37(m, 6H), 1.47-1.55(m, 2H), 1.78-1.84(m, 2H), 2.21(s, 2H), 7.20(br d, J=8.0Hz, 2H), 7.27(dd, J=8.0, 8.0Hz, IH), 7.46(dd, J=8.0, 8.0Hz, 2H), 7.53(br s, IH), 8.22(br d, J=8.0Hz, 2H), 8.54(br, IH), 8.80(br, IH) MASS (ESI): 404.2 (M-H) Example 21
N-Hydroxy-2 - [ 1 -{4-(4-cyanophenoxy)benzenesuffonylamino}- cydohexyl]acetamide (78 mg) was obtained as a white amorphous in the similar manner as in Example 17.
NMR pMSO-dJ d=1.29(br, 6H), 1.46-1.54(m, 2H), 1.78-1.85(m, 2H), 2.21(s, 2H), 7.23-7.29(m, 4H), 7.77-7.80(m, 4H), 10.44(s, IH). MASS (ESI): 428.1 (M-H) Example 22
N-Hycfroxy-2-[l-(3-fluoro-4-phenoxybenzenesuffonylamino)cydohexyl]- acetamide (45 mg) was obtained as a white amorphous in the similar manner as in Example 17.
NMR pMSO-dJ δ = 1.15-1.32(m, 6H), 1.48-1.56(m, 2H), 1.81-1.86(m, 2H), 2.20(s, 2H), 7.10(d, J=7.0Hz, 2H), 7.10-7.16(m, 2H), 7.42-7.49(m, 3H), 7.65(d, J=8.0Hz, IH), 7.82(d, J=8.0Hz, IH), 8.80(s, IH) MASS (ESI): 421.1 (M-H) Example 23
N-Hycfroxy-2-[l-{4-(naphthalen-2-yloxy)benzenesuffonylamino}- cydohexyl]acetamide (31 mg) was obtained as a white amorphous in the similar manner as in Example 17.
NMR pMSO-dJ δ = 1.17-1.31(m, 6H), 1.46-1.54(m, 2H), 1.80-1.86(m, 2H), 2.21(s, 2H), 7.18(d, J=7.0Hz, 2H), 7.30-7.37(m, 2H), 7.46-7.57(m, 3H), 7.83-7.87(m, 3H), 7.95(d, J=7.0Hz, IH), 8.03(d, J=7.0Hz, IH), 8.81(s, IH), 10.44(s, IH) MASS (ESI): 453.1 (M-H) Example 24
Figure imgf000049_0001
To a solution of 4-phenoxybenzoic add (189 mg) in N,N-dimethyl-formamide (3 ml) were added l-hydroxybenzotriazole (119 mg) and 1,3- dnsopropylcarbo<iiimide (111 mg) at ambient temperature and the mixture was stirred at ambient temperature for 30 minutes. To the solution was added N-[2- (l-ammocydohexyl)acetyl]hycfroxylamine 2-chlorotrityl resin (200 mg) and shaken for 24 hours. N-[2-{l-(4-phenoxybenzoylamino)cydohexyl}acetyl]hydroxylamine 2-chlorotrityl resin was filtered and washed with N,N-dirnethylformamide, methanol and dichloromethane each three times. The resin was suspended in a 5% trifluoroacetic add in dichloromethane for 1 hour. After draining the resin, it was washed with a 5% trifluoroacetic add in dichloromethane and dichloromethane several times. The filtrate was concentrated in vacuo to give N- hycfroxy-2-{l-(4-phenoxybenzoylamino)cyclohexyl}acetamide as a white amorphous (84 mg).
NMR PMSO-dJ r5=1.23-1.26(m, 2H), 1.46(br, 8H), 2.35-2.39(m, 2H), 7.02- 7.08(m, 3H), 7.19(dd, J=7.0, 7.0Hz, IH), 7.42(dd, J=7.0, 7.0Hz, 2H), 7.73(s, IH), 7.82(d, J=7.0Hz, 2H), 8.71(s, IH) MASS (ESI): 367.2 (M-H) Example 25
N-Hy<iroxy-2-[l-(4-phenyltltiobenzoylamino)cydohexyl]acetanιide was obtained in the similar manner as in Example 24.
NMR (CDCIJ <5 = 1.15-2.20(m, 10H), 2.48(d, 2H, J=10Hz), 7.28(d, 2H, J=9Hz), 7.33-7.90(m, 7H), 10.41(bs, IH) MS (ES-): 383 (M-H) Example 26
N-Hycfroxy-2-{l-(4-benzoylbenzoylamino)cydohexyl}acetamide (40 mg) was obtained as a yellow oil in the similar manner as in Example 24. NMR PMSO-dJ δ =1.17-1.63(m, 10H), 2.36(s, 2H), 7.58(dd, J=8.0, 8.0Hz, IH), 7.68-7.95(m, 8H) MASS (ESI): 379.2 (M-H) Example 27
N-Hydroxy-2-[ 1 -{5-(4-c^orophenyl)furan-2-ylcarbonylamino}- cyclohexyljacetamide (40 mg) was obtained as a white amorphous in the similar manner as in Example 24.
NMR (DMSO-dJ <5=1.36-1.48(m, 10H), 2.35-2.42(m, 2H), 7.15-7.16(m, 2H), 7.54(d, J=7.5Hz, 2H), 7.9 l(d, J=7.5Hz, 2H), 7.98(s, IH) MASS (ESI): 375.2 (M-H) Example 28
N-Hy(froxy-2-{l-(4-mtrober-zoylamino)cyclohexyl} acetamide (39 mg) was obtained as a white amorphous in the similar manner as in Example 24. NMR PMSO-dJ <5=1.23-1.48(m, 10H), 2.36(br s, 2H), 7.86(br, IH), 7.99(d, J=7.5Hz, 2H), 8.29(d, J=7.5Hz, 2H), 10.41(br s, IH) MASS (ESI): 320.1 (M-H) Example 29
N-Hycfroxy-2-[l-{4-(pyridin-4-yloxy)benzoylammo}cyclohexyl]acetarnide (46 mg) was obtained as a yellow oil in the similar manner as in Example 24. NMR PMSO-dJ <5=1.22-1.48(m, 10H), 2.50(br, 2H), 7.36-7.39(m, 4H), 7.88(br s, 2H), 7.97(d, J=7.5Hz, 2H), 8.71(d, J=5.0Hz, 2H), 10.45(s, IH) MASS (ESI): 368.2 (M-H) Example 30
N-Hydroxy-2-[l-(4-bromobenzoylarnmo)cyclohexyl]acetamide (36 mg) was obtained as a yellow oil in the similar manner as in Example 24. NMR (DMSO-dJ 5=1.22(br s, 2H), 1.46(br, 8H), 2.35(br, 2H), 7.65(d, J=7.5Hz, 2H), 7.72(d, J=7.5Hz, 2H), 7.85(br s, IH) MASS (ESI): 355.23 (M+H) Example 31
N-Hycfroxy-2-[l-{4-(4-fluorophenoxy)benzoylammo}cydohexyl]a∞tamide (38 mg) was obtained as a yellow oil in the similar manner as in Example 24. NMR (DMSO-dJ S=1.23(br s, 2H), 1.46(br, 8H), 2.35-2.47(m, 2H), 7.02(d, J=7.5Hz, 2H), 7.10-7.26(m, 2H), 7.71-7.83(m, 4H), 10.43(s, IH) MASS (ESI): 387.2 (M+H) Example 32
N-Hycfroxy-3-(4-phenoxybenzenesuffonylamino)propionamide was obtained from N-(2-tetrahydropyranyloxy)-3-aminopropionamide as a powder in the similar manner as in Example 38 as mentioned below.
NMR PMSO-dJ S=2.14(2H, t, J=7Hz), 2.92(2H, dd, J=7, 8Hz), 7.12(2H, d, J=8Hz), 7.18(2H, d, J=8Hz), 7.26(1H, t, J=8Hz), 7.47(2H, t, J=8Hz), 7.62(1H, t, J=8Hz), 7.78(2H, d, J=8Hz), 8.77(1H, s) Mass (ESI-): 335(M-H) Example 33
N-Hydroxy-3-(4-phenoxybenzenesuffonylaπιmo)-3-cyclohexyl-propionarnide was obtained from N-(2-tetrahyαj-opyranyloxy)-3-amino-3-cydohexylpropion- amide in the similar manner as in Example 38.
NMR (CDCIJ 5=0.57-1.77(1 IH, m), 2.19-2.46(2H, m), 3.42-3.59(lH, m), 6.02- 6.18(1H, m), 6.90-7.11(4H, m), 7.21(1H, t, J=8Hz), 7.38(2H, t, J=8Hz), 7.82(2H, t, J=8Hz), 9.23(1H, s) Mass (ESI-): 417(M-H) Example 34
N-(2-Tetrahydropyranyloxy)-2-[4-(4-phenoxybenzenesuffonyl)-amino- 1 - methansuffonylpiperidin-4-yl]acetamide was obtained in the similar manner as in Preparation 2-2. NMR (CDCIJ d=1.45-1.82(8H, m), 1.98-2.08(2H, m), 2.29(2H, s), 2.64-2.78(2H, m), 2.75(3H, s), 3.12-3.22(2H, m), 3.45-3.53(lH, m), 3.85-3.96(lH, m), 4.81(1H, s), 7.12(4H, d, J=8Hz), 7.26(1H, t, J=8Hz), 7.47(2H, t, J=8Hz), 7.54(1H, s), 7.85(2H, d, J=8Hz), 8.32(1H, s) Mass (ESI-): 566(M-H) Example 35
To a solution of N-(2-tetrahydropyranyloxy)-2-{4-(4-phenoxy- benzenesuffonylarrιino)piperidin-4-yl}acetamide (100 mg) in CHC13 (2.0 ml) were added Et3N (20.7 mg) and t-butyl isocyanate (24.3 mg) at room temperature. After being stirred for 10 hours, the solution was concentrated in vacuo. The residue was dissolved in AcOEt and the solution was washed with 1% aqueous dtric add solution, sat. NaHCO3 solution and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent: CHCIJ to give N-(2-tetrahydropyranyloxy)-2-{l-(N-t- butylcarbamoyl)-4-(4-phenoxybenzenesuffonylam (100 mg) as an amorphous.
NMR (CDCIJ δ = 1.26-2.04(19H, m), 2.43-2.57(2H, m), 2.95-3.29 (6H, m), 4.02(1H, dd, J= ), 7.01-7.09(4H, m), 7.24(1H, dd, J=7, 7Hz), 7.42(2H, dd, J=8, 8Hz), 7.85(2H, d, J=9Hz) ESI(-): 587(M-H) Example 36
To a solution of N-(2-tetrahydropyranyloxy)-2-[4-(4-phenoxy- benzenesuffonylan ino)pipericlin-4-yl]acetamide (150 mg) in 1,2-dichloromethane (4 ml) were added triethylamine (37 mg) and acetylchloride (52 mg) at 0°C and the mixture was stirred at ambient temperature for 24 hours. The reaction mixture was poured into water and was extracted with ethyl acetate. The organic layer was washed with 10% aqueous dtric add solution and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to give N-(2- tetiahydropyranyloxy)-2-[l-benzoyl-4-(4-phenoxyben2enesulfonyl- aιnmo)piperidin-4-yl]acetamide as a white amorphous (135 mg). NMR (CDCIJ <5=1.60(br, 8H), 1.77-1.83(m, 2H), 2.05(s, 2H), 3.43-3.64(m, 2H), 4.00(br, 2H), 5.00(s, IH), 5.29(s, IH), 6.00(s, IH), 7.00-7.09(m, 4H), 7.30-7.44(m, 8H), 7.80-7.88(m, 2H), 8.82(s, IH) MASS (ESI): 592.5 (M-H) Example 37
N-(2-Tetiahycfropyranyloxy)-2-[l-(N,N-dirnethylcarbamoyl)-4-(4-phenoxy- benzenesuffonylan u o)piperid-ιι-4-yl]acetamide (160 mg) was obtained from N-(2- tetiahydropyranyloxy)-2-[4-(4-phenoxybenzene-sulfonylarn-no)piperidm yljacetamide (140 mg) as a yellow oil in the similar manner as in Example 36. NMR (CDCIJ δ = 1.61-1.85(m, 8H), 1.92-1.99(m, 2H), 2.42-2.55(m, 3H), 2.77(s, 6H), 2.85-3.00(m, 2H), 3.18-3.27(m, 2H), 3.60-3.66(m, IH), 3.96-4.04(m, IH), 7.00-7.08(m, 5H), 7.41(dd, J=7.0, 7.0Hz, 2H), 7.83(d, J=7.0Hz, 2H), 8.92(s, IH) MASS (ESI): 559.4 (M-H) Example 38
To a solution of N-(2-tetrahydropyranyloxy)-2-{4-(4-phenoxybenzene- suffonylammo)piperi(im-4-yl}acetamide (100 mg) in CHC13(2.0 ml) were added Et3N (24.8 mg) and benzenesulfonyl chloride (54.1 mg) at room temperature. After being stirred for 10 hours, the solution was concentrated in vacuo. The residue was dissolved in AcOEt, the solution was washed with 1% aqueous dtric add solution and brine, dried over MgS04 and concentrated in vacuo.
To a solution of this residue in MeOH (2 ml) was added a 10% HCl in MeOH ( 1 ml) at room temperature. After being stirred for 1 hour, the solution was concentrated in vacuo. The residue was purified by silica gel column chromatography (10% MeOH in CHCIJ to give N-hydrαxy-2- {1-benzenesulfonyl- 4-(4-phenoxybenzenesuffonylarnino)piperidine-4-yl}acetamide (10 mg) as a power. NMR (CDCIJ 5 = 1.55-1.65(4H, m), 2.25-2.39(2H, m), 2.49(2H, br.s), 3.10-3.20(2H, m), 6.86(2H, d, J=8Hz), 7.13(2H, d, J=8Hz), 7.28(1H, dd, J=7, 7Hz), 7.40-7.55(9H, m)
ESI(-): 544(M-H) Example 39
N-Hycfroxy-2-{l-cyclopropylcarbonyl-4-(4-phenoxybenzenesuffonylamino)- piperidin-4-yl}acetamide (10 mg) was obtained from N-(2-tetrahydropyranyloxy)- 2-{4-(4-phenoxybenzenesuffonylanιino)piperidm-4-yl}acetamide (100 mg) in the similar manner as in Example 38.
NMR (CDCIJ δ =0.69-0.71(2H, m), 0.89-0.91(2H, m), 1.59-1.79(5H, m), 2.2(1H, br.s), 2.52(1H, br.s), 2.65-2.71(2H, m), 3.70-3.82(2H, m), 6.37(1H, br.s), 6.99- 7.09(4H, m), 7.21(1H, dd, J=7, 7Hz), 7.42(2H, dd, J=8, 8Hz), 7.83(2H, d, J=9Hz) ESI(-): 472(M-H) Example 40
To a solution of N-(2-tetrahydropyranyloxy)-2-{4-(4-phenoxybenzene- suffonylamino)piperidin-4-yl}acetarnide (100 mg) in CHC13 (2.0 ml) was added Et3N (20.7 mg) and ethyl isocyanate ( 17.4 mg) at room temperature. After being stirred for 10 hours, the solution was concentrated in vacuo. The residue was dissolved in AcOEt and the solution was washed with 1% aqueous dtric add solution and brine, dried over MgSO4 and concentrated in vacuo.
To a solution of this residue in MeOH (2 ml) was added a 10% HCl in MeOH ( 1 ml) at room temperature. After being stirred for 1 hour, the solution was concentrated in vacuo. The residue was purified by silica gel column chromatography (10% MeOH in CHCIJ to give N-hydroxy-2- {l-(N-ethyl- carbamoyl)-4-(4-phenoxybenzenesuffonylarrun^ (13.6 mg) as a power.
NMR (CDCIJ δ =1.07(3H, dd, J=7.5, 7.5Hz), 1.55-1.65(4H, m), 2.59(2H, br.s), 2.86-2.94(2H, m), 3.16-3.20(2H, m), 3.32-3.37(2H, m), 6.96-7.07(4H, m), 7.21(1H, dd, J=7, 7Hz), 7.40(2H, dd, J=8, 8Hz), 7.81(2H, d, J=9Hz) ESI(-): 472(M-H) Example 41
A solution of hydroxylamine in methanol (1.7 M, 1.1 ml) prepared as described in Fieser and Fieser, Vol 1, p 478) was added to a solution of methyl 2- [4-(4-phenoxybenzenesuffonylammo)tetiahyc^ (100 mg) at ambient temperature. After stirring for 5 hours, the mixture was addified with IN hydrochloric add and concentrated. The residue was extrarted with ethyl acetate. The separated organic phase was washed with brine, dried over sodium sulfate and evaporated in vacuo. The obteined oil was purified by preparative thin layer chromatography with 10% methanol in chloroform and triturated with diisopropyl ether to give N-hydroxy-2-[4-(4-phenoxyben∞nesuffonylamino)- tetrahycfrotmopyran-4-yl]acetarrride (16 mg) as a powder.
NMR (DMSO-dJ ά =1.84(2H, t, J=12Hz), 2.05-2.23(4H, m), 2.76-2.91(2H, m), 2.63(2H, t, J=12Hz), 7.12(4H, d, J=8Hz), 7.25(1H, t, J=8Hz), 7.40-7.53(3H, m), 7.85(2H, d, J=8Hz), 8.85(1H, s) Mass ESI(-): 421(M-l) Example 42
N-Hydroxy-2- [ 1 -oxo-4-(4-phenoxybenzenesuffonylamino)tetrahydro- thiopyran-4-yl]acetamide was obtained in the similar manner as in Example 41. NMR (DMSO-dJ δ =1.89-2.40(5H, m), 2.40-2.70(lH, m), 2.90-3.05(4H, m), 7.14(4H, d, J=8Hz), 7.25(1H, t, J=8Hz), 7.47(2H, t, J=8Hz), 7.77(1H, s), 7.85(2H, d, J=8Hz), 8.86(1H, s) Mass ESI(-): 437(M-1) Example 43
To a solution of N-(2-tetrahydropyranyloxy)-2-[l-(4-phenoxybenzene- suffonylarnino)cyclohexyl]acetamide (120 mg) in MeOH (4 ml) was added 10% HCl in MeOH (1 ml) at room temperature. After being stirred for 30 minutes, the solution was concentrated in vacuo. The residue was purified by SiO2 column chromatography (eluent: 1% MeOH in CHCIJ to give N-hydroxy-2-[l-(4-phenoxy- benzenesuffonylamino)cydohexyl]acetamide (80 mg) as an amotphous powder. NMR (CDCIJ <5=0.98-1.96(10H, m), 2.56(2H, s), 6.14(1H, s), 7.00(2H, d, J=8Hz), 7.05(2H, d, J=8Hz), 7.22(1H, t, J=8Hz), 7.40(2H, d, J=8Hz), 7.85(2H, d, J=8Hz), 8.98(1H, s)
Mass (ESI+): 405(M+H) Example44
N-Hydroxy-2-[ 1 -(5-(4-fluorophenyl)t ophen-2-ylsuffonylamino)cyclohexyl] - acetamide (68 mg) was obtained as an amotphous powder in the similar manner as in Example 43.
NMR (CDC13 DMSO-dJ ά=1.15-2.05(10H, m), 2.58(2H, s), 6.17(1H, s), 7.00- 7.19(3H, m), 7.47-7.63(3H, m), 8.80(1H, s) Mass (ESI-): 391(M+H) Example 45
N-Hycfroxy-2-[l-(4-(4-fluorophenoxy)benzenesuffonylarrιino)cydohexyπ acetamide was obtained in the similar manner as in Example 43. NMR (CDCIJ 5 =1.16-1.42(6H, m), 1.48-1.90(4H, m), 2.56(2H, s), 6.00(1H, s), 6.89-7.18(6H, m), 7.84(2H, d, J=8Hz), 8.86(1H, brs) Mass (ESI-): 421(M-H) Example 46
N-Hydroxy-2-[l-(4-methoxybenzensulfony (120 mg) was obtained as an amorphous powder in the similar manner as in Example
43.
NMR (CDCIJ δ = 1.02-1.68(8H, m), 1.65-1.90(2H, m), 2.17(2H, s), 3.82(3H, s),
7.08(2H, d, J=8Hz), 7.28(1H, s), 7.76(2H, d, J=8Hz), 8.82(1H, s), 10.4(1H, s)
Mass (ESI-): 341 (M-H)
Example 47
N-Hycfroxy-2-[l-N-met±ιyl-N-(4-phenoxybenzenesuffonylamino)cydohexyl]- acetamide (160 mg) was obtained as an amorphous powder in the similar manner as in Example 43.
NMR (CDCIJ <5 = 1.30-1.64(6H, m), 1.96-2.14(4H, m), 2.78(3H, s), 2.82(2H, s), 7.03(2H, d, J=8Hz), 7.07(2H, d, J=8Hz), 7.23(1H, t, J=8Hz), 7.42(2H, t, J=8Hz), 7.79(2H, d, J=8Hz), 9.28(1H, s) Mass (ESI+): 419(M+H) Example 48
N-Hydroxy-2-[4-(4-phenoxybenzenesιιffonylarr^ acetamide was obtained in the similar manner as in Example 43. NMR pMSO-dJ 5 =1.60-1.95(4H, m), 2.25(2H, s), 3.20-3.55(4H, m), 7.10(2H, d, J=8Hz), 7.14(2H, d, J=8Hz), 7.25(1H, t, J=8Hz), 7.48(2H, t, J=8Hz), 7.54(1H, s), 7.83(2H, d, J=8Hz), 10.4(1H, s) Mass (ESI-): 405(M-H) Example 49
N-Hycfroxy-2-{4-(4-phenoxybenzoylammo)tetiahydropyran-4-yl}-ac^tamide (0.40 g) was obtained in the similar manner as in Example 43. NMR (DMSO-dJ δ=1.61-1.71(2H, m), 2.36-2.40(2H, m), 2.54(2H, s), 3.55- 3.65(4H, m), 7.02-7.08(4H, m), 7.20(1H, dd, J=7, 7Hz), 7.43(2H, dd, J=8, 8Hz), 7.85(2H, d, J=9Hz), 8.69(1H, s) ESI(-): 369(M-H) Example 50
N-Hydroxy-2-[ 1 , 1 -cfioxo-4-(4-phenoxybenzenesuffonylamino)tetrahydro- thiopyran-4-yl]acetamide was obtained in the similar manner as in Example 43. NMR pMSO-dJ δ =2.14-2.40(6H, m), 2.90-3.06(4H, m), 7.15(4H, d, J=8Hz), 7.25(1H, t, J=8Hz), 7.46(2H, t, J=8Hz), 7.79(1H, s), 7.86(2H, d, J=8Hz) 8.87(1H, s) Mass ESI(-): 453(M-1) Example 51
N-Hy(froxy-2-[4-(4-phenoxybenzenesuffonylamino)-l-benzyloxycarbonyl- piperidm-4-yl]acetamide was obtained in the similar manner as in Example 43. NMR (CDCIJ <5 =1.46-1.72(2H, m), 1.89-2.17(2H, m), 2.40-3.06(4H, m), 3.44- 3.67(2H, m), 5.04(2H, s), 6.28(1H, s), 6.97(2H, d, J=8Hz), 7.05(2H, d, J=8Hz), 7.15-7.47(8H, m), 7.80(2H, d, J=8Hz), 8.98(1H, s) Mass (ESI-): 538(M-H) Example 52
N-Hycfroxy-2-[4-(4-phenoxyphenylsuffonylammo)piperid.n-4-yl]acetamide hydrochloride was obtained in the similar manner as in Example 43. NMR (CDC13 DMSO-dJ δ =1.78-2.28(6H, m), 2.67-2.90(2H, m), 2.95-3.12(2H, m), 7.12(2H, d, J=8Hz), 7.14(2H, d, J=8Hz), 7.28(1H, t, J=8Hz), 7.47(2H, t, J=8Hz), 7.85(2H, d, J=8Hz), 8.48-8.64(lH, m), 8.88-9.00(lH, m) Mass (ESI+) : 406(M+H) Example 53
N-Hydroxy-2-[4-(4-phenoxybenzenesuffonylamino)- 1 -methansulfonyl- piperidin-4-yl]acetamide was obtained in the similar manner as in Example 43. NMR (DMSO-dJ δ=1.70-1.85(2H, m), 1.96-2.08(2H, m), 2.24(2H, s), 2.65- 2.80(2H, m), 2.76(3H, s), 3.12-3.24(2H, m), 7.12(4H, d, J=8Hz), 7.26(1H, t, J=8Hz), 7.47(2H, t, J=8Hz), 7.58(1H, s), 7.84(2H, d, J=8Hz) Mass (ESI-): 482(M-H) Example 54
N-Hydroxy-2-{l-(N-t-butylcarbamoyl)-4-(4-phenoxybenzene- suffonylaminojpiperidin^-yljacetamide (14.7 mg) was obtained in the similar manner as in Example 43.
NMR (CDCIJ δ=1.26-1.72(13H, m), 2.80-2.97(2H, m), 3.06-3.18(2H, m), 3.29- 3.43(2H, m), 6.96-7.07(4H, m), 7.21(1H, dd, J=7, 7Hz), 7.41(2H, dd, J=8, 8Hz), 7.79(2H, d, J=9Hz) ESI(-): 503(M-H) Example 55
N-Hydroxy-2-[ 1 -benzoyl-4-(4-phenoxyben2enesuffonylarn o)piperidin-4- yljacetamide (65 mg) was obtained as white crystals in the similar manner as in Example 43. NMR (DMSO-dJ <5 =1.63-1.71(m, 2H), 1.83-1.97(m, 2H), 2.26(s, 2H), 2.88(br, 2H), 3.03(br, 2H), 7.10 (d, J=8.0Hz, 3H), 7.22-7.30(m, 3H), 7.40-7.48(m, 5H), 7.62(s, IH), 7.84(d, J=8.0Hz, 2H), 8.80(s, IH), 10.43(s, IH) MASS (ESI): 508.3 (M-H) Example 56
N-Hy(froxy-2-[l-(N,N-ojmethylcarbamoyl)-4-(4-phenoxybenzenesulfonyl- arrιino)piperid -4-yl]acetamide (75 mg) was obtained as a white powder in the similar manner as in Example 43.
NMR pMSO-dJ δ =1.62(t, J=9.0Hz, 2H), 1.87(br d, J=9.0Hz, 2H), 2.23(s, 2H), 2.66(s, 6H), 2.75(t, J=9.0Hz, 2H), 3.11(br d, J=9.0Hz, 3H), 7.11(d, J=8.0Hz, 3H), 7.24(dd, J=7.0, 7.0Hz, IH), 7.42-7.51(m, 3H), 7.83(d, J=8.0Hz, 2H), 8.80(s, IH) MASS (ESI): 475.3 (M-H) Example 57
N-Hycfroxy-2-[l-benzyloxycarbonyl-4-(4-phenoxybenzoylamino)piperidin-4- yljacetamide (40 mg) was obtained as a white amorphous in the similar manner as in Example 43.
NMR (DMSO-dJ c5=1.53-1.63(m, 2H), 2.42(br, 2H), 2.51(s, 2H), 3.07-3.20(br, 2H), 3.69-3.74(m, 2H), 5.07(s, 2H), 6.98-7.09(m, 4H), 7.30-7.46(m, 7H), 7.83- 7.86(m, 2H), 8.70(s, IH) MASS (ESI): 502.4 (M-H) Example 58
N-Hydroxy-2- [ 1 -benzyloxycarbonyl-4-(5-(4-fluorophenyl)thiophen-2-yl- carbonylaminojpiperidm^-yljacetamide (55 mg) was obtained as a white amorphous in the similar manner as in Example 43.
NMR PMSO-dJ <5 =1.56-1.65(m, 2H), 2.40-2.46(m, 2H), 2.53(s, 2H), 3.15(br, 2H), 3.70-3.76(m, 2H), 5.08(s, 2H), 7.26-7.36(m, 5H), 7.51(d, J=3.0Hz, IH), 7.72- 7.77(m, 2H), 7.89(m, 2H), 8.72(s, IH), 10.43(s, IH) MASS (ESI): 510.2 (M-H) Example 59
N-Hycfroxy-3-(4-phenoxybenzenesuffonylamino)-3-ethylvaleramide was obtained in the similar manner as in Example 43.
NMR (DMSO-dJ δ = 0.69(t, 6H, J=8Hz), 1.46-1.70(m, 4H), 2.15(s, 2H), 7.05- 7.14(m, 4H), 7.24(dd, IH, J=9Hz, 9Hz), 7.46(dd, 2H, J=9Hz, 9Hz), 7.81(d, 2H, J=9Hz)
MS (ES-): 391
Example 60
N-Hycfroxy-2,3-cLimethyl-3-(4-phenoxybenzen^ was obtained in the similar manner as in Example 43.
NMR (CDCIJ δ =0.98(d, 3H, J=7Hz), 1.08(s, 3H), 1.20(s, 3H), 2.25(q, IH), 7.06- 7.15(m, 4H), 7.25(dd, IH, J=9Hz, 9Hz), 7.47(dd, 2H, J=9Hz, 9Hz), 7.81(d, 2H, J=9Hz), 8.86(s, IH) MS (ES-): 377 Example 61
To a solution of N-benzyloxy-3-(4-phenoxybenzoylam o)-3-ethylvaleramide (69 mg) was added palladium on carbon (10 mg) and shaken vigorously under hydrogen atmosphere (3 arm.). After 3 hours, the catalyst was removed by filtration and the solvent was removed under reduced pressure. The crude product was purified with silica gel column chromatography (eluent: 1% methanol in chloroform) to give N-hydrαxy-3-(4-phenoxybenzoy]arrιino)-3-ethylvaleramide. NMR (DMSO-dJ δ =0.69(t, 6H, J=8Hz), 1.46-1.70(m, 4H), 2.15 (s, 2H), 7.05- 7.14(m, 4H), 7.24(dd, IH, J=9Hz, 9Hz), 7.46(dd, 2H, J=9Hz, 9Hz), 7.81(d, 2H, J=9Hz) MS (ES-): 445 Example 62
N-Hycfroxy-2-(l-(4-phenoxybenzenesuffonylamino)cydobutyl)a∞tamide was obtained in the similar manner as in Example 61.
NMR pMSO-dJ δ =1.48-1.65(m, 2H), 1.90-2.04(m, 2H), 2.06-2.20(m, 2H), 2.35(s, 2H), 7.10(d, 2H, J=8Hz), 7.14(d, 2H, J=8Hz), 7.25(t, IH, J=8Hz), 7.47(t, 2H, J=8Hz), 7.75(s, IH), 7.83(d, 2H, J=8Hz), 8.83(s, IH), 10.43(s, IH) MS (ES-): 375(M-1)

Claims

1. A compound of the formula (I) :
Figure imgf000060_0001
wherein
R1 is halogen, nitro, lower alkoxy, optionally substituted aryloxy, arylthio, aroyl, heterocyclic-oxy, optionally substituted aryl or optionally substituted heterocyclic group;
R2 is hydrogen or halogen;
R3 is hydrogen or lower alkyl;
R4 and R5 are independently hydrogen, lower alkyl, or lower cydoalkyl, or R4 and R5 are combined together to form lower alkylene, which is optionally interrupted by oxygen, sulfur, sulfinyl, sulfonyl or optionally mono-substituted nitrogen;
R6 is hydroxy or proterted hydroxy;
X is aryl or heterocyclic group;
Y is carbonyl or sulfonyl; and
Z is lower alkylene; or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1, wherein
R1 is halogen, nitro, lower alkoxy, C6-C10 aryloxy optionally substituted by at least one group selected from the group consisting of halogen, cyano, nitro, amino, acylamin, lower alkylamino, carbamoyl, hydroxy, lower alkoxy, C6-C10 aryloxy, lower alkyl, C6-C10 aryl and heterocyclic-oxy, C6-C10 arylthio, C6-C10 aroyl, heterocyclic-oxy, C6-C10 aryl optionally substituted by at least one group selected from the group consisting of halogen, cyano, nitro, amino, acylamino, lower alkylamino, carbamoyl, hydroxy, lower alkoxy, C6-C10 aryloxy, lower alkyl, C6-C10 aryl and heterocyclic-oxy, or heterocyclic group optionally substituted by at least one group selected from the group consisting of halogen, cyano, nitro, amino, acylamino, lower alkylamino, carbamoyl, hydroxy, lower alkoxy, C6-C10 aryloxy, lower alkyl, C6-C10 aryl and heterocyclic-oxy;
R4 and R5 are independently hydrogen, lower alkyl, or lower cydoalkyl, or R4 and R5 are combined together to form lower alkylene, which is optionally interrupted by oxygen, sulfur, sulfinyl, sulfonyl or imino, wherein the imino is optionally mono- substituted by a group of C6-C10 ar (lower) alkoxycarbonyl, lower alkylsulfonyl, C6~ C10 arylsulfonyl, C6-C10 aroyl, mono(lower)alkylcarbamoyl, di(lower)alkylcarbamoyl or lower cydoalkylcarbonyl;
R6 is hydroxy, tetrahydropyranyloxy or C6-C10 aryl(lower) alkoxy; and
X is C6-C10 aryl or heterocyclic group, said heterocyclic group being unsaturated 3- to 8-membered, heteromonocyclic group containing 1 to 4 nitrogen atoms, saturated 3- to 8-membered, heteromonocyclic group containing 1 to 4 nitrogen atoms, unsaturated bicyclic 7- to 13-membered, heterocyclic group containing 1 to 5 nitrogen atoms, unsaturated 3- to 8-membered, heteromonocyclic group containing 1 or 2 oxygen atoms and 1 to 3 nitrogen atoms, saturated 3- to 8-membered, heteromonocyclic group containing 1 or 2 oxygen atoms and 1 to 3 nitrogen atoms, unsaturated bicyclic 7- to 13-membered, heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, unsaturated 3- to 8-membered, heteromonocyclic group containing 1 or 2 sulfur atoms and 1 to 3 nitrogen atoms, saturated 3- to 8-membered, heteromonocyclicrgroup containing 1 or 2 sulfur atoms and 1 to 3 nitrogen atoms, unsaturated 3- to 8-membered, heteromonocyclic group containing 1 or 2 sulfur atoms, unsaturated 3- to 8-membered, heteromonocyclic group containing 1 or 2 oxygen atoms, saturated 3- to 8-membered, heteromonocyclic group containing oxygen atom, unsaturated bicyclic 7- to 13-membered, heterocyclic group containing 1 or 2 sulfur atoms and 1 to 3 nitrogen atoms, or unsaturated bicyclic 7- to 13-membered, heterocyclic group containing 1 or 2 oxygen atoms.
3. The compound of claim 2, wherein
R1 is halogen; nitro; lower alkoxy; C6-C10 aryloxy optionally substituted by at least one group selected from the group consisting of halogen, cyano, nitro, amino, acylamino, lower alkylamino, carbamoyl, hydroxy, lower alkoxy, C5-C10 aryloxy, lower alkyl, C6-C10 aryl and heterocyclic-oxy, said heterocyclic group being unsaturated 5- or 6-membered, heteromonocyclic group containing 1 to 4 nitrogen atoms; C5-C10 arylthio; C6-C10 aroyl; heterocyclic-oxy, said heterocyclic group being unsaturated 5- or 6-membered, heteromonocyclic group containing 1 to 4 nitrogen atoms; C5-C10 aryl optionally substituted by at least one group selected from the group consisting of halogen, cyano, nitro, amino, acylamino, lower alkylamino, carbamoyl, hydroxy, lower alkoxy, C6-C10 aryloxy, lower alkyl, C6-C10 aryl and heterocyclic-oxy, said heterocyclic group being unsaturated 5- or 6-membered, heteromonocyclic group containing 1 to 4 nitrogen atoms; or heterocyclic group, said heterocyclic group being unsaturated 5- or 6-membered, heteromonocyclic group containing 1 to 4 nitrogen atoms, which is also optionally substituted by at least one group selected from the group consisting of halogen, cyano, nitro, amino, acylamino, lower alkylamino, carbamoyl, hydroxy, lower alkoxy, C6-C10 aryloxy, lower alkyl, C5-C10 aryl and heterocyclic-oxy, said heterocyclic group being unsaturated 5- or 6-membered, heteromonocyclic group containing 1 to 4 nitrogen atoms;
R4 and R5 are independently hydrogen, lower alkyl, or lower cydoalkyl, or R4 and R5 are combined together to form lower alkylene, which is optionally interrupted by oxygen, sulfur, sulfinyl, sulfonyl, imino, C6-C10 ar(lower)alkoxycarbonylimino, lower alkylsuffonylimino, C6-C10 arylsuffonylimino, C6-C10 aroylimino, monoflowerjalkylcarbamoylimino, cfi(lower)a]kylcarbamoylirnino or lower cydoalkylcarbonylirnino, and X is C6-C10 aryl or heterocyclic group, said heterocyclic group being unsaturated 5- or 6-membered, heteromonocyclic group containing 1 to 4 nitrogen atoms, unsaturated 5- or 6-membered, heteromonocyclic group containing 1 or 2 sulfur atoms, or unsaturated 5- or 6-membered, heteromonocyclic group containing 1 or 2 oxygen atoms.
4. The compound of claim 3, wherein
R1 is halogen; nitro; lower alkoxy; phenoxy or naphthyloxy, each of which is optionally substituted by at least one group selected from the group consisting of halogen, cyano and lower alkyl; phenylthio; benzoly; pyridyloxy; phenyl optionally substituted by halogen; or pyridyl,
R4 and R5 are independently hydrogen, lower alkyl, or lower cydoalkyl, or R4 and R5 are combined together to form lower alkylene, which is optionally interrupted by oxygen, sulfur, sulfinyl, sulfonyl, imino, phenyl(lower)alkoxycarbonylimino, lower alkylsuffonylimino, phenylsuffonylimino, ben2»y-imino, mono(lower)all^lcarbamoylimino, cfi(lower)alkylcarbarnoylimino or lower cydoalkylcarbonylimino,
R6 is hydroxy, tetrahydropyranyloxy or phenyl(lower)alkoxy, and
X is phenyl, pyridyl, thienyl ro furyl.
5. The compound of claim 4, wherein
R1 is halogen; nitro; lower alkoxy; phenoxy, naphthyloxy, halophenoxy, cyanophenoxy, lower alkylphenoxy, phenylthio; benzoyl; pyridyloxy; halophenyl; or pyridyl;
R4 and R5 are combined together to form a group of the formula selected from the group consisting of the following formulas:
Figure imgf000064_0001
Figure imgf000064_0002
Figure imgf000064_0003
-CONH-tBu - CONHEt
Figure imgf000064_0004
R6 is hydroxy, and
X is a group selected from the group consisting of
Figure imgf000064_0005
6. A process for the preparation of the compound of claim 1 or salt thereof, which comprises,
(1) removing the imino-protective group of a compound of the formula (I-l) R'
Figure imgf000065_0001
Rz R^ (1-1)
wherein
R1 is halogen, nitro, lower alkoxy, optionally substituted aryloxy, arylthio, aroyl, heterocyclic-oxy, optionally substituted aryl or optionally substituted heterocyclic group;
R2 is hydrogen or halogen;
R3 is hydrogen or lower alkyl;
R6 is hydroxy or protected hydroxy;
X is aryl or heterocyclic group;
Y is carbonyl or sulfonyl; z is lower alkylene;
R7 is imino-protective group; and m and n are independently an integer of 1 to 5, provided that 2-=m+n≤-6; or a salt thereof, to give a compound of formula (1-2):
H N
(CH2)m (CH2)n
Figure imgf000065_0002
R' R (1-2) wherein each symbol is as defined above or a salt thereof; (2) reacting a compound of the formula (H):
R< R^
X Y N Z-COOH
(II)
wherein R4 and R5 are independently hydrogen, lower alkyl, or lower cydoalkyl, or R4 and R5 are combined together to form lower alkylene, which is optionally interrupted by oxygen, sulfur, sulfinyl, sulfonyl or optionally mono-substituted nitrogen, and other symbols are each as defined above, or its reactive derivative at the carboxy group, or a salt thereof, with a compound: tysr-R6 wherein R6is as defined above, or its reactive derivative at the amino group, or a salt thereof to give the compound of the formula (I); (3) reacting a compound (HI):
Figure imgf000066_0001
(III)
Rc
wherein each symbol is as defined above, or a salt thereof with a compound
R -X(R2)-Y-L wherein L is a leaving group and other symbols are each as defined above, or a salt thereof to give the compound of the formula (I); (4) reacting a compound of the formula (1-2): H N
Figure imgf000067_0001
(1-2)
R^ RJ
wherein each symbol is as defined above, or a salt thereof with a compound:
R7-L wherein each symbol is as defined above, or a salt thereof, to give a compound of the formula (I-l):
R'
I N
(CH2)m (CH2)n
R1 X N Z-CONH-R6
R< (1-1)
wherein each symbol is as defined above, or a salt thereof; (5) reacting a compound of the formula (TV):
Figure imgf000067_0002
(IV)
RJ wherein R8 is a protected carboxy and other symbols are each as defined above, or a salt thereof, with a compound:
L^N-OH or a salt thereof; to give a compound of the formula (1-3):
Figure imgf000068_0001
N Z-CONHOH
(1-3)
wherein each symbol is as defined above, or a salt thereof; or
(6) elirninating the hydroxy-protective group of a compound of the formula (1-4):
Figure imgf000068_0002
(M)
R wherein R61 is a protected hydroxy, and other symbols are each as defined above, or a salt thereof, to give a compound of the formula (1-3):
R R5
R1 X Y Z-CONHOH
(1-3)
R< wherein each symbol is as defined above, or a salt thereof.
7. A pharmaceutical composition which comprises the compound of Claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceuticaUy acceptable carrier or exdpient
8. Use of the compound of Claim 1 or a pharmaceutically acceptable salt thereof as a medicament
9. Use of the compound of Claim 1 or a pharmaceutically acceptable salt thereof as an inhibitor of matrix metalloproteinases (MMP) or tumor necrosis factor (TNF ).
10. Use of the compound of Claim 1 or a pharmaceutically acceptable salt thereof for manufacturing a medicament for treating and/ or preventing MMP- or TNF a -mediated diseases.
11. A method for treating and/or preventing MMP- or TNF a -mediated diseases which comprises adir-inistering the compound of Claim 1 or a pharmaceutically acceptable salt thereof to a human being or an animal.
PCT/JP2000/002508 1999-04-19 2000-04-17 Mmp inhibitor WO2000063165A1 (en)

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US6495565B2 (en) 2000-03-17 2002-12-17 Bristol-Myers Squibb Pharma Company β-amino acid derivatives as inhibitors of matrix metalloproteases and TNF-α
WO2003022842A1 (en) * 2001-09-07 2003-03-20 Fujisawa Pharmaceutical Co., Ltd. Thiophenylthiopyrane dioxides as mmp or tnf-alpha inhibitors
US6743807B2 (en) 2000-03-17 2004-06-01 Bristol-Myers Squibb Pharma Company Cyclic β-amino acid derivatives as inhibitors of matrix metalloproteases and TNF-α
WO2005092844A1 (en) * 2004-03-22 2005-10-06 Southern Research Institute Nonpeptide inhibitors of matrix metalloproteinases
WO2008045671A1 (en) * 2006-10-06 2008-04-17 Janssen Pharmaceutica, N.V. Matrix metalloprotease inhibitors
JP2009051845A (en) * 2000-09-29 2009-03-12 Topotarget Uk Ltd Carbamic acid compound comprising sulfonamide linkage as hdac inhibitor
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US6743807B2 (en) 2000-03-17 2004-06-01 Bristol-Myers Squibb Pharma Company Cyclic β-amino acid derivatives as inhibitors of matrix metalloproteases and TNF-α
US6984648B2 (en) 2000-03-17 2006-01-10 Bristol-Myers Squibb Pharma Company Cyclic β-amino acid derivatives as inhibitors of matrix metalloproteases and TNF-α
JP2009051845A (en) * 2000-09-29 2009-03-12 Topotarget Uk Ltd Carbamic acid compound comprising sulfonamide linkage as hdac inhibitor
EP1233018A3 (en) * 2001-02-14 2002-09-04 Warner-Lambert Company Tricyclic biphenyl sulfonamide matrix metalloproteinase inhibitors
US6555535B2 (en) 2001-02-14 2003-04-29 Warner-Lambert Company Tricyclic biphenyl sulfonamide matrix metalloproteinase inhibitors
EP1233018A2 (en) * 2001-02-14 2002-08-21 Warner-Lambert Company Tricyclic biphenyl sulfonamide matrix metalloproteinase inhibitors
WO2003022842A1 (en) * 2001-09-07 2003-03-20 Fujisawa Pharmaceutical Co., Ltd. Thiophenylthiopyrane dioxides as mmp or tnf-alpha inhibitors
US7504537B2 (en) 2001-12-27 2009-03-17 Dainippon Sumitomo Pharma Co., Ltd. Hydroxamic acid derivative and MMP inhibitor containing the same as active ingredient
US8129406B2 (en) 2004-03-22 2012-03-06 Southern Research Institute Nonpeptide inhibitors of matrix metalloproteinases
WO2005092844A1 (en) * 2004-03-22 2005-10-06 Southern Research Institute Nonpeptide inhibitors of matrix metalloproteinases
WO2008045671A1 (en) * 2006-10-06 2008-04-17 Janssen Pharmaceutica, N.V. Matrix metalloprotease inhibitors
US8927549B2 (en) 2008-11-21 2015-01-06 High Point Pharmaceuticals, Llc Adamantyl benzamide derivatives
WO2011149213A2 (en) * 2010-05-25 2011-12-01 주식회사 이큐스앤자루 Novel derivative having inhibitory activity against 11β-hsd1, preparation method thereof, and pharmaceutical composition containing same as active ingredient
WO2011149213A3 (en) * 2010-05-25 2012-03-29 주식회사 이큐스앤자루 Novel derivative having inhibitory activity against 11β-hsd1, preparation method thereof, and pharmaceutical composition containing same as active ingredient
KR101377419B1 (en) 2010-05-25 2014-03-26 안국약품 주식회사 Novel derivatives inhibiting activity of 11beta-HSD1 (11β-Hydroxysteroid dehydrogenase type 1) enzyme, preparation method thereof and pharmaceutical composition containing the same as an active ingredient
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CN105829316B (en) * 2013-12-19 2019-01-08 默克专利股份公司 Tetrahydro-tetrazolo [1,5-a] pyrazine as ROR gamma inhibitors
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