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WO2001023363A1 - Derives de sulfonamide - Google Patents

Derives de sulfonamide Download PDF

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Publication number
WO2001023363A1
WO2001023363A1 PCT/JP2000/006798 JP0006798W WO0123363A1 WO 2001023363 A1 WO2001023363 A1 WO 2001023363A1 JP 0006798 W JP0006798 W JP 0006798W WO 0123363 A1 WO0123363 A1 WO 0123363A1
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Prior art keywords
group
ethyl
methyl
dione
multiplet
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English (en)
Japanese (ja)
Inventor
Tomio Kimura
Kazuhiko Tamaki
Shoujiro Miyazaki
Shinichi Kurakata
Kosaku Fujiwara
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Sankyo Co Ltd
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Sankyo Co Ltd
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Priority to AU74503/00A priority Critical patent/AU7450300A/en
Publication of WO2001023363A1 publication Critical patent/WO2001023363A1/fr
Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/52—Two oxygen atoms
    • C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to a novel sulfonamide derivative having an excellent inhibitory effect on matrix metalloproteinase-13 and an inhibitory activity on aggrecanase, and a pharmaceutical composition containing the same.
  • Non-steroidal anti-inflammatory drugs have been used to treat osteoarthritis and rheumatoid arthritis.
  • NSAIDs Non-steroidal anti-inflammatory drugs
  • Such treatment is a symptomatic treatment, and there is no drug that can be used for causal treatment to suppress the progress of these diseases.
  • MMP matrix metalloproteinase
  • collagenase-13 is an enzyme localized in joints and has strong degrading activity against type II collagen, one of the major components of joint cartilage.
  • aggrecanase another major component of joint cartilage, aggrein.
  • aggrecanase an enzyme that cleaves aggrecan in the highly distinctive sequence GLu373-A1a374.
  • MMP-13 is highly expressed in several cancer tissues including breast cancer tissues. It has been strongly pointed out that it may play an important role in metastasis (JMP Freije et al., Journal of Biological Chemistry, Vol. 269, 16766-1677 3, 1994). Has less side effects and is useful as an inhibitor of metastasis, invasion and growth of various cancer cells.
  • the present inventors have conducted intensive studies on the synthesis and pharmacological action of compounds that strongly inhibit both MMP-13 and aglycanase. As a result, a novel sulfonamide derivative has potent MMP-13 inhibitory activity. And aglycanase inhibitory activity And completed the present invention ⁇
  • the present invention is a.
  • R 1 represents a hydroxyl group, a hydroxyamino group or a protected hydroxyamino group
  • R 2 is a group having the following formula (II) or (III)
  • X 1 is an oxygen atom, a group having the formula —COO—, a group having the formula —CO S—, a carbonyl group, a group having the general formula —S (0) ra —, a general formula—N (R 7 )
  • a group having the general formula — a group having one CON (R 7 ), a group having one C (R 8 ) (R 9 ) or one COC (R 8 ) (R 9 ) having the general formula represents a group,
  • X 2 represents an oxygen atom, a sulfur atom, a group having the general formula 1 N (R 7 ) 1 or a group having the general formula 1 C (R 8 ) (R 9 )
  • X 3 is an oxygen atom, a carbonyl group, a group having the general formula —S (0) m —, A group having (R 7 ) — or a group having the general formula C (R 8 ) (R 9 ) —
  • X 4 represents a nitrogen atom or a group having the general formula —CR 5 —,
  • R 5 and R 6 are the same or different and are each a hydrogen atom, a lower alkyl group, a carboxy group, an arbitrary group selected from the substituent group and y, or an arbitrary group selected from the substituent group ⁇ and y
  • R 5 and R 6 represents a lower alkyl, lower alkoxy, lower alkylthio, lower alkylsulfinyl or lower alkylsulfonyl group substituted with a group of the formula: or R 5 and R 6 together with the carbon atom to which they are attached
  • an alicyclic hydrocarbon group a substituent group / Alicyclic heterocyclic group, aryl group substituted with any group selected from? And y, substituent group ⁇ , aryl group substituted with any group selected from /? And y, heteroaryl Group or substituent group ⁇ , /? And y
  • substituent group ⁇ aryl group substituted with any group selected from /? And y, heteroaryl Group or substituent group ⁇ , /? And y
  • To an optionally substituted group that is-option Teroari Ichiru groups may form a,
  • R 7 represents a protecting group for a hydrogen atom, a lower alkyl group or an imido group
  • R 8 and R 9 are the same or different and each represent a hydrogen atom or a lower alkyl group, and R 8 and R 9 are taken together with the carbon atom to which they are attached to form an alicyclic carbon
  • a hydrogen group, an alicyclic hydrocarbon group, an alicyclic heterocyclic group, or an alicyclic heterocyclic group substituted with an arbitrary group selected from the substituent group ⁇ , /? And y May form an alicyclic heterocyclic group substituted with any group,
  • n 01 or 2. Represents a group having
  • A represents a lower alkylene group (an oxygen atom, which may be interrupted by a group having the general formula —S (0) m — or a group having the general formula N (R 10 ) —); , Showing the same meaning as above,
  • R 3 and R 1Q are the same or different and are a hydrogen atom, a lower alkyl group, a substituent group, and a lower alkyl group, a cycloalkyl group, a substituent group ⁇ , and y substituted with any group selected from y
  • L is an arylene group, an arylene group, a heteroarylene group or a substituent group substituted with an arbitrary group selected from a substituent group ⁇ , and y.
  • M represents an oxygen atom or a sulfur atom
  • R 4 is substituted with an arbitrary group selected from a lower alkyl group, a substituent group and 7; a lower alkyl group, an aryl group, and an arbitrary group selected from a substituent group ff , /? And y.
  • a substituted aryl group, a heteroaryl group or a group of substituents ", / 3 and y represents a heteroaryl group substituted with an arbitrary group.
  • Halogen atom lower alkoxy group, lower alkylthio group, halogeno lower alkoxy group, halogeno lower alkylthio group, nitro group, and cyano group.
  • halogen atom lower alkoxy group, lower alkylthio group, halogeno lower alkoxy group, halogeno lower alkylthio group, nitro group, and cyano group.
  • R 1 is a hydroxyamino group, a pharmacologically acceptable salt thereof, or an ester or other derivative
  • R 2 is a group having the formula (II)
  • X 1 is a group having the general formula —N (R 7 ) — or a group having one general formula CON (R 7 ), Pharmacologically acceptable salts, or esters or other derivatives,
  • R 2 is a group having the formula (III), a group having the formula X 2 5 ′, and a group having the general formula N (R 7 ) 1, a pharmaceutically acceptable salt thereof, or an ester thereof or the like Induction body,
  • X 3 has the general formula one C (R 8) (R 9 ) -?
  • a group having a, X 4 force, a is of compound nitrogen atom, a pharmacologically acceptable salt or ester or other Derivatives of
  • X 3 is an oxygen atom, a carbonyl group, a group having the general formula S (0) m —, a group having the general formula —N (R 7 ) or a group having the general formula C (R 8 ) (R 9 A compound wherein X 4 is a group having the general formula —CR 5 —, a pharmacologically acceptable salt or ester or other derivative thereof,
  • R 5 and R 6 are the same or different and each is a hydrogen atom, a lower alkyl group, a carboxy group, an arbitrary group selected from the substituent groups ⁇ and a, or a substituent group ⁇ and 7
  • substituted group ⁇ and any group selected from y include a halogen atom, a lower aliphatic acyl group, an amino group, a mono-lower alkylamino group, a di (low A compound which is an amino group, a cyano group, a nitro group, an aryl group or a heteroaryl group, a pharmacologically acceptable salt thereof, or an ester or other derivative thereof;
  • substituted group ⁇ and any group selected from a are halogen atom, lower aliphatic acyl group, cyano group, nitro group, aryl group and hetero group.
  • substituted group ⁇ and any group selected from a are halogen atom, lower aliphatic acyl group, cyano group, nitro group, aryl group and hetero group.
  • a compound in which A is an alkylene group having 1 to 4 carbon atoms (which may be interrupted by an oxygen atom or —S (0) m —), a pharmaceutically acceptable salt thereof, or an ester thereof. Young or other derivatives,
  • A is an uninterrupted alkylene group having 1 to 4 carbon atoms, a pharmacologically acceptable salt thereof, or an ester or other derivative thereof;
  • A is methylene, ethylene or trimethylene, a pharmacologically acceptable salt or ester or other derivative thereof,
  • R 3 and R 1 are the same or different and each are a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a substituent group selected from the group consisting of An alkyl group having 1 to 4 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, an alkenyl group having 2 to 4 carbon atoms, a substituent group ⁇ and a carbon number substituted with any group selected from y
  • R 3 is methyl, ethyl, propyl, cyclopropyl, aryl, 2-butenyl, prono. Lugyl, 2-butynyl, benzyl, 2-phenylethyl, 3-phenylpropyl, 3- (4-chlorophenyl) propyl, 3-phenylpropargyl or 3- (4-chlorophenyl) propargyl, its pharmacologically acceptable salts, esters or other derivatives,
  • (21) a compound which is p-phenylene, a pharmacologically acceptable salt thereof, or an ester or other derivative thereof;
  • R 4 is an alkyl group having 1 to 4 carbon atoms, an alkyl group having 1 to 4 carbon atoms, an aryl group, a substituent group substituted with a group selected from the substituent groups ⁇ and y ⁇
  • R 4 force 5 ', 1 to 4 alkyl groups having a carbon number, substituted having 1 to 4 alkyl group having a carbon halogen atom, Ariru group, halogen, lower alkyl, lower alkoxy Moshiku is Shiano A compound which is an aryl group, a heteroaryl group or a heteroaryl group substituted with a halogen, a lower alkyl, a lower alkoxy or a cyano group, a pharmacologically acceptable salt thereof, or an ester or other derivative thereof;
  • R 4 is methyl, ethyl, propyl, butyl, trifluoromethyl, phenyl, 3-fluorophenyl, 4-fluorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3-methylphenyl, 4 —Methylphenyl, 3-Methoxyphenyl, 4-Methoxyphenyl, 3-Cyanophenyl, 4-Cyanophenyl, 2,4-Difluorophenyl, 2,4-Dichlorophenyl, 3,4-Difluorophenyl, 3, Compounds that are 4-dichlorophenyl, 3-pyridyl, 4-pyridyl, 2-phenyl or 3-phenyl, their pharmacologically acceptable salts, or esters or other derivatives;
  • R 8 and R 9 force 5 ' each represents a hydrogen atom or compound is lower alk kill group, a pharmacologically acceptable salt or ester or other derivative thereof,
  • a medicament containing as an active ingredient the compound according to any one of the above (1) to (29), a pharmacologically acceptable salt thereof, or an ester or other derivative thereof [
  • a method for producing a medicament for example, a medicament for preventing or treating arthritis (preferably osteoarthritis) and a medicament for suppressing metastasis, invasion or growth of cancer] 1) use of the compound according to any one of the above (29), a pharmaceutically acceptable salt thereof, or an ester or other derivative thereof as an active ingredient;
  • a pharmacologically effective amount of the compound described in any one of the above (1) to (29), a pharmacologically acceptable salt thereof, or an ester or other derivative thereof, is added to a warm-blooded animal.
  • a method for inhibiting MMP-13 and aggrecanase is added to a warm-blooded animal.
  • arthritis preferably osteoarthritis
  • metastasis invasion or proliferation of cancer. Also aim.
  • I In the above general formula (I),
  • protecting group of the “protected hydroxyamino group” in the definition of R 1 , for example, formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl Le, Vivaloyl, Isonorelyl, Octanoyl, Nonanoyl, Decanoyl, 3-Metynonanoyl, 8-Methylnonanoyl, 3-Ethylocanoyl, 3,7-Dimethyloktanoyl, Pendecanol, Dodecanoyl, Tridecanol, Tridecanol, Tridecanol , Hexadecanoyl, 1-methylpentadecanoyl, 14-methylpentadecanoyl, 13,13-dimethyltetradecanoyl, heptadecanol, 15—methylhexadecanoyl, octadecanoyl, 1-methylhepta
  • “Aliphatic acyl” such as lower alkoxyalkylcarbonyl group such as acetyl, unsaturated alkylcarbonyl group such as acryloyl, propioloyl, methacryloyl, crotonyl, isocrotonyl, (E) -2-methyl-2-butenyl, etc.
  • acyl group preferably an aliphatic acyl group having 1 to 6 carbon atoms
  • benzoyl "arylcarbonyl group such as mono-naphthyl, /?-Naphthyl, 2-bromobenzoyl, 4-chloro Halogenated arylcarbonyl groups such as benzoyl, lower alkylated arylcarbonyl groups such as 2,4,6-trimethylbenzoyl, 4-toluoyl, and lower alkoxylation groups such as 4-anisole Arylylcarbonyl such as arylcarbonyl, 4-nitrobenzoyl and 2-nitrobenzoyl
  • aromatic acyl group such as a lower alkoxycarbonylated arylcarbonyl group such as a 2- (methoxycarbonyl) benzoyl group or an arylated arylcarbonyl group such as 4-phenylbenzoyl group; Lower alkoxycarbonyl groups such as methoxycarbonyl, ethoxy
  • a lower alkoxymethyl group such as 1-methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl, tert-butoxymethyl; a lower alkoxylated lower alkoxymethyl group such as 2-methoxyethoxymethyl; 2 , 2,
  • Alkoxymethyl group such as halogeno-lower alkoxymethyl such as 2-triethoxymethyl and bis (2-cycloethoxy) methyl; 1-ethoxyxetyl, 1 —
  • (Substituted ethyl groups) such as lower alkoxylated ethyl groups such as (isopropoxy) ethyl and halogenated ethyl groups such as 2,2,2-trichloroethyl; benzyl, ⁇ -naphthylmethyl, /?-Naphthylmethyl, diphenylmethyl A-naphthyldiphenylmethyl, 9-lower alkyl group substituted with 1 to 3 aryl groups such as anthrylmethyl, 4-methylbenzyl, 2,4,6-trimethyl Benzyl, 3,4,5-trimethylbenzyl, 4-methoxybenzyl, 4-methoxyphenyldiphenylmethyl, 2-nitrobenzyl, 4-nitrobenzyl, 4-chlorobenzyl, 4-bromobenzyl, 4-cyanobenzyl 1 to 3 in which the aryl ring is substituted with a lower alkyl, lower alkoxy, nitro, halogen
  • One or two lower alkoxy or two-ports such as benzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, 412-port benzyloxycarbonyl
  • An arylalkyl ring which may be substituted with an aryl group And preferably a “tetrahydrobiranyl or tetrahydrothiopyranyl group”; a “tetrahydrofuranyl or tetrahydrothiofuranyl group”; a “silyl group” and an “aralkyl group”; more preferably, benzyl, tert- Butyldimethylsilyl, tetrahydropyran-12-yl and tetrahydrofuran-12-yl.
  • the “lower alkyl” of the “alkylthio group” is, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl Tert-butyl, pentyl, 2-pentyl, 3-pentyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, hexyl, 2- Hexyl, 3-hexyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1,1,2 Represents a straight-chain or branched-chain alkyl group having 1 to 6 carbon atoms such as trimethylpropy
  • the “lower alkylthio group” of the “group” and the “lower alkylthio” of the “halogeno lower alkylthio group” represent a group in which a sulfur atom is bonded to the above “lower alkyl group”, and preferably have 1 to 4 carbon atoms. And more preferably, methylthio, ethylthio, propylthio, isopropylthio and butylthio, and particularly preferably methylthio, ethylthio and propylthio.
  • lower alkylsulfinyl of “substituent group. And lower alkylsulfinyl substituted with any group selected from y” in the definition of R 5 and R 6 above
  • the “lower alkylsulfinyl group” of the “lower alkylsulfinyl group” refers to a group in which the above-mentioned “lower alkyl group” has a sulfinyl (1 S ⁇ 1) force 5 ′ bond, and preferably has 1 to 4 carbon atoms.
  • methylsulfinyl ethylsulfinyl, propylsulfinyl, isopropylpropylsulfinyl and butylsulfinyl, and particularly preferably methylsulfinyl, ethylsulfinyl And propylsulfinyl.
  • R 5 and the "lower alkylsulfonyl group" of the “lower alkylsulfonyl group substituted with any group selected from substituent group monument and 7" in the definition of R 6 are the “lower alkyl group” Represents a group having a sulfonyl (-S 0 2 —) bonded thereto, preferably a linear or branched alkylsulfonyl group having 1 to 4 carbon atoms, more preferably methylsulfonyl, ethylsulfonyl Propylsulfonyl, isopropylsulfonyl and butylsulfonyl, particularly preferably methylsulfonyl, ethylsulfonyl and propylsulfonyl.
  • the “halogeno lower alkylthio group” in the definition of the “substituent group y” are the above “lower alkyl” Represents a group in which one or more hydrogen atoms of the group have been substituted with the following halogen atom, and is preferably a halogeno lower alkyl group having 1 to 4 carbon atoms, more preferably Trifluoromethyl, trichloromethyl, difluoromethyl, dichloromethyl, dibromomethyl, fluoromethyl, 2,2,2-trichloroethyl, 2,2,2-trifluoroethyl, 2-bromoethyl, 2-chloroethyl, 2-fluoroethyl And 2,2-dibromoethyl, particularly preferably trifluoromethyl, trichloromethyl, di
  • halogeno lower alkylthio group in the above definition of the substituent group refers to a group in which the above “halogeno lower alkyl group” is bonded to a sulfur atom, and particularly preferably, difluoromethylthio, trifluoro Methylthio and 2,2,2-trifluoroethylthio.
  • the “mono-lower alkylamino group” in the definition of the above “substituent group ⁇ ” refers to a group in which one hydrogen atom of one NH 2 group is substituted with the above “lower alkyl group”.
  • Cycloalkyl group and “substituent group ⁇ , /? And y in the definition of R 3 and R io "Cycloalkyl group” of "cycloalkyl group substituted with any group selected from” and "cycloalkyl group” in the definition of [substituent group]] are cycloalkyl groups having 3 to 7 carbon atoms. And examples thereof include cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
  • alkenyl group and alkenyl group” in “substituent group ⁇ and an alkenyl group substituted with an arbitrary group selected from a” are straight-chain or 2 to 10 carbon atoms.
  • an ⁇ alkynyl group '' and an ⁇ alkynyl group '' in the ⁇ alkynyl group substituted with an arbitrary group selected from the group of substituents ⁇ and y '' are straight-chain or 2 to 10 carbon atoms.
  • Aryl group in the definition of R 4 and “Aryl group” in “Substituent group ⁇ , Aryl group substituted with any group selected from ⁇ and ⁇ ”; “Aryl group” in the definition of R 5 and R 6 “Aryl group” and “aryl group substituted with an arbitrary group selected from /, '/?' And ⁇ ” and “aryl” in the definition of [substituent group ⁇ ] —Aryl group ”,“ Aryl group ”of“ Aryl group substituted with an arbitrary group selected from the group consisting of
  • Aryl refers to an aromatic hydrocarbon group having 6 to 10 carbon atoms, such as phenyl and naphthyl. Preferred are phenyl and naphthyl, and particularly preferred is phenyl.
  • the “aryl group” may be condensed with a cycloalkyl group having 3 to 10 carbon atoms, and examples of such a ring include indanyl.
  • y Is a monovalent group of a 5- to 7-membered aromatic heterocyclic ring containing 1 to 3 sulfur atoms, oxygen atoms or nitrogen atoms, and is, for example, furyl, chenyl, pyrrolyl, azepinyl, pyrazolyl, imidazolyl, oxazolyl And groups such as isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-oxoxadiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazuryl.
  • it is a monovalent group of a 5- to 6-membered aromatic heterocycle containing 1 to 2 sulfur atoms, oxygen atoms or Z and nitrogen atoms, and more preferably chenyl, imidazolyl, pyridyl and birazinyl. is there.
  • heteroaryl group may be condensed with another cyclic group, and examples of such a group include indolyl, benzofuryl, benzothenyl, isoquinolyl, and quinolyl. .
  • the "lower alkoxy group” of the "halogeno lower alkoxy group” refers to a group in which an oxygen atom is bonded to the "lower alkyl group", and is preferably a linear or branched alkoxy group having 1 to 4 carbon atoms. Yes, more preferably, methoxy, ethoxy, propoxy, isopropoxy and butoxy, particularly preferably methoxy, ethoxy and propoxy.
  • halogeno lower alkoxy group in the definition of the above “substituent group” refers to a group in which the “halogeno lower alkyl group” is bonded to an oxygen atom, and is particularly preferably -difluoromethoxy, trifluoromethoxy or 2 , 2, 2-trifluoretoxy.
  • hydrocarbon group is a saturated hydrocarbon ring group having 3 to 7 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cycloprobenyl, cyclobutenyl, cyclopentenyl, cyclo A partially unsaturated hydrocarbon ring group having 3 to 7 carbon atoms such as hexenyl and cycloheptenyl; preferably a saturated hydrocarbon ring group having 5 to 6 carbon atoms and a partially unsaturated hydrocarbon group; And more preferably a partially unsaturated hydrocarbon ring group having 5 to 6 carbon atoms.
  • alicyclic heterocyclic group in the above refers to a 5- to 7-membered saturated heterocyclic group containing 1 to 3 sulfur atoms, oxygen atoms or Z and nitrogen atoms or a partially unsaturated heterocyclic group, Represents a 5- to 6-membered saturated heterocyclic group or a partially unsaturated heterocyclic group containing one or two sulfur atoms, oxygen atoms, and nitrogen atoms, and such a group is, for example, dithiolane Diyl, dioxane-diyl, pyrrolidine-diyl, etc., and preferably pyrrolidine-diyl. It is.
  • protecting group for imido group in the definition of R 7 refers to a protecting group that can be removed by a chemical method such as hydrogenolysis, hydrolysis, electrolysis, or photolysis.
  • lower alkoxy lower alkyl groups such as lower alkoxymethyl groups (for example, methoxymethyl and ethoxymethyl) in which the above “lower 0 alkoxy group” is bonded to a methyl group; and benzyloxymethyl Aralkyloxy lower alkyl groups such as ralquiloxymethyl group; tetrahydrofuran group such as tetrahydrofuran-12-yl; tetrahydropyran group such as tetrahydropropylan-2-yl; 2- ( 2— [tri (lower alkyl) silyl] ethoxy lower alkyl groups such as ethoxymethyl); the above “aliphatic acyl” groups; and
  • the "aromatic acyl group” Preferably, they are a tetrahydrofuran
  • the “lower alkylene group” in the definition of A includes, for example, methylene, ethylene, trimethylene, propylene, tetramethylene, 1,1-dimethylethylene, 1,1-dimethyltrimethylene, and 1,1-dimethyltetramethylene.
  • a linear or branched alkylene group having 1 to 6 carbon atoms preferably a linear or branched alkylene group having 1 to 4 carbon atoms, more preferably 1 to 6 carbon atoms.
  • Four straight-chain alkylenes, particularly preferred are methylene, ethylene and trimethylene.
  • an oxygen atom, a lower alkylene group interrupted by a group having the general formula 1 S (0) n — or a group having the general formula 1 N (R 10 ) — means an oxygen atom, a general alkyl group represented by the general formula 1 A group having S (0) n — or a group having the general formula —N (R 10 ) —in which the above “lower alkylene group” is interrupted, and such a group is preferably CH 2 OCH 2 —, CH 2 S CH 2 —, CH 2 NHCH 2 —, CH 2 N (CH 3 ) CH 2 —, CH 2 0 CH 2 CH 2 —, CH 2 SCH 2 CH 2 —, One CH 2 NHCH 2 CH 2 —,-CH 2 N (CH 3 ) CH 2 CH 2- , one CH 2 S 0 CH 2 CH 2- , one CH 2 S 0 2 CH 2 CH 2 — Can be.
  • arylene group of "arylene group” and “arylene group substituted with an arbitrary group selected from substituent groups ⁇ , /? And y” It represents a divalent group of an aromatic hydrocarbon group having 6 to 10 carbon atoms, such as phenylene and naphthylene, and is preferably phenylene, and particularly preferably p-phenylene.
  • arylene group may be condensed with a cycloalkyl group having 3 to 10 carbon atoms. Examples of such a group include an indane-1,4,7-diyl group.
  • L "heteroarylene group” of “heteroarylene group” and “heteroarylene group substituted with a substituent group ⁇ any group selected from /, and y" means sulfur.
  • it is a 5- to 6-membered aromatic heterocyclic ring containing 1 to 2 sulfur atoms, oxygen atoms and 1 or 2 nitrogen atoms, and more preferably, cherenylene, imidazolylene, pyridylene and pyrazinylene. Particularly preferred is Chenylene.
  • heteroarylene group may be condensed with another cyclic group, and examples of such a group include indole-14,7-diyl, benzothiophene-14 , 7—Jill.
  • Halogen atom in "halogeno lower alkyl group” in the definition of [substituent group /?]
  • halogen atom and “halogeno lower alkylthio” in “halogen atom” and “halogeno lower alkoxy group” in the definition of substituent group
  • the “halogen atom” of the group includes a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, and is preferably a fluorine atom, a chlorine atom and a bromine atom.
  • lower aliphatic acyl group in the definition of the substituent group means formyl or a group in which the above-mentioned "lower alkyl group” is bonded to a carbonyl group, and is preferably a straight chain having 1 to 4 carbon atoms.
  • the “aryloxy group” in the “aryloxy group” and the “aryloxy group substituted with an arbitrary group selected from the substituent groups /? And y” in the definition of [substituent group] is the above “aryl group” Represents a group bonded to an oxygen atom.
  • arylthio group of the “arylthio group” and the “arylthio group substituted with any group selected from the substituent groups /? And 7 ” in the definition of [Substituent group ⁇ ]
  • aryl group represents a group bonded to a sulfur atom.
  • Heteroaryloxy group in the definition of [substituent group ⁇ ] and "heteroaryloxy group” of “heteroaryloxy group substituted with any group selected from substituent group and 7" Represents a group in which the above “heteroaryl group” is bonded to an oxygen atom.
  • heteroarylthio group of the "heteroarylthio group” and the “heteroarylthio group substituted with any group selected from the substituent groups /? And y" in the definition of [substituent group]
  • the above “heteroaryl group” represents a group bonded to a sulfur atom.
  • “Pharmacologically acceptable salt thereof” means that the compound (I) of the present invention is reacted with an acid when it has a basic group such as an amino group.
  • the salt can be converted into a salt by reacting with a base.
  • the salt based on a basic group is preferably a hydrohalide such as hydrofluoride, hydrochloride, hydrobromide, hydroiodide, nitrate, perchlorate, sulfuric acid Inorganic salts such as salts and phosphates; lower alkanesulfonates such as methanesulfonate, trifluoromethansulfonate, ethanesulfonate, benzenesulfonate and p-toluenesulfonate; Organic salts such as arylsulfonate, acetate, malate, fumarate, succinate, citrate, ascorbate, tartrate, oxalate, maleate and the like; and Examples thereof include amino acid salts such as sine salt, lysine salt, arginine salt, ordinine salt, glutamate, and aspartate.
  • hydrohalide such as hydrofluoride, hydrochloride, hydrobromide, hydroiodide, nitrate
  • the salt based on an acidic group is preferably an alkali metal salt such as a sodium salt, a potassium salt, or a lithium salt, an alkaline earth metal salt such as a calcium salt or a magnesium salt, or aluminum.
  • Metal salts such as salts and iron salts; inorganic salts such as ammonium salts, tert-octylamine salts, dibenzylamine salts, morpholine salts, glucosamine salts, phenylglycine alkyl ester salts, ethylenediamine salts, and N-methylglucamine.
  • Aminic salts such as organic salts such as roxymethyl) aminomethanate; and amino acid salts such as glycine, lysine, arginine, ordinine, glutamate, and aspartate.
  • the compound (I) of the present invention absorbs water by leaving it in the air or by recrystallization to form adsorbed water or form a hydrate. In some cases, such salts are also included in the present invention.
  • the compound (I) of the present invention may absorb some other solvent and form a solvate, and such salts are also included in the present invention.
  • esters means that the compound (I) of the present invention can be converted into an ester, which means an ester thereof.
  • ester examples include a "ester of a hydroxyl group” and an "ester of a hydroxyl group”.
  • General protecting group refers to a protecting group that can be cleaved by chemical methods such as hydrogenolysis, hydrolysis, electrolysis, and photolysis.
  • the “general protecting group” for the “ester of a hydroxyl group preferably, the “aliphatic acyl group”; the “aromatic acyl group”; the “alkoxycarbonyl group”; and the “tetrahydroviranyl” Or a tetrahydrothiofuranyl group "; the above” tetrahydrofurofranyl or tetrahydrothiofuranyl group "; the above” silyl certain I “; the above” alkoxymethyl ".
  • protecting group that can be cleaved in vivo by a biological method such as hydrolysis as the “ester of a hydroxyl group”, preferably, formyloxymethyl, acetoxmethyl, dimethylaminoacetoxymethyl, propionyl Oxymethyl, butyryloxymethyl, pinoloyloxymethyl, norrelyloxymethyl, isonorelyloxymethyl, hexanoyloxymethyl, 1-formyloxetyl, 1-acetoxethyl, 1-propionyloxethyl, 1—butyryloxexetil, 1—pivaloyloxetil, 1 reryloxexetil, 1—isorelyloxexetil, 1 xanoyloxyxetil, 1—formyloxypropyl, 1—acetoxyp mouth pill, 1 one propionyloxypropyl, 1—butyryloxypropyl, 1 Pivaloyloxypropyl, 1-valeryloxypropyl,
  • the “general protecting group” for the “ester of a carboxy group” preferably, the above “lower alkyl group”; the above “alkenyl group”; the above “alkynyl group”; the above “halogeno lower alkyl group” Hydroxy “lower alkyl groups” such as 2-hydroxyl, 2,3-dihydroxypropyl, 3-hydroxypropyl, 3,4-dihydroxybutyl, 4-hydroxybutyl; “fats” such as acetylmethyl Group ";” lower alkyl group "; the above-mentioned” aralkyl group "; and the above-mentioned” silyl group ".
  • Protective group that can be cleaved in vivo by a biological method such as hydrolysis '' means that it is cleaved in the human body by a biological method such as hydrolysis to produce a free acid or a salt thereof.
  • “Other derivatives” means the above compound (I) when the compound (I) has a hydroxyl group, an amino group, a carboxy group, an imino group, an amide group, an imido group and / or a sulfonamide group.
  • Derivatives other than “esters” and the following “pharmacologically acceptable salts” can be used. Examples of such a derivative include an ether derivative in the case of a hydroxyl group, an amide derivative in the case of an amino group or a carboxy group, and an amide derivative of an imino group, an amide group, an imido group or a sulfonamide group.
  • a derivative in which those nitrogen atoms have been modified with a group described as a protecting group according to the above-mentioned “ester of a hydroxyl group” can be mentioned.
  • the compound (I) of the present invention has an asymmetric center in the molecule, and there are stereoisomers each having R-coordination and S-coordination. Both are included in the present invention.
  • Pr Ph -63 GH GH (GH NHOH p r Ph H-64 ⁇ u_i32 2 NHOH p r Ph H-65, H ⁇ NHOH p r Ph H-66 CH OCH NHOH p r Ph H-67 t H ⁇ , ⁇ NHOH Pr Ph H-68 CH NHCH NHOH Pr Ph H-69 CH, NHOH i-Pr Ph H-70 2 NHOH i-Pr Ph H-71 NHOH i-Pr Ph H-72 (CH NHOH i-Pr Ph H-73 CH 9 NHOH IH «— H ( ⁇ H Ph H-74 NHOH H ⁇ —, HH Ph H-75 3 NHOH, HHH o Ph H-76 (CH_2 NHOH I.
  • T-Bu indicates t-butyl
  • C-Hx represents cyclohexyl
  • Ph represents phenyl
  • C-Pn represents cyclopentyl
  • Pr represents propyl
  • C-Pr represents cyclopropyl
  • THF tetrahydrofuran-1-yl
  • THP refers to tetrahydropyran-12-yl.
  • position 1 to “position 23” respectively represent the following groups.
  • Place 22 In the above table, compounds in which R 1 in the general formula (I) is a hydroxyamino group are shown, but the present invention relates to the corresponding hydroxy derivative [R in the general formula (I). Compounds wherein 1 is a hydroxyl group] are also included as specific examples.
  • Exemplified Compound Nos. 4-1 1 to 415 Exemplified Compound Nos. 417 to 412, Exemplified Compound Nos. 425 to 418, Exemplified Compound Nos. 411 to 414 , Exemplified Compound Nos. 417-410, Exemplified Compound Nos. 416-9-176, Exemplified Compound Nos. 418-419, Exemplified Compound Nos. 4-1108, Exemplified Compound No. 4-112 1 to 4-124, Exemplified Compound No. 4-136 to 4-1400, Exemplified Compound No. 4-1 153 to 4-1 56, Exemplified Compound No.
  • Exemplified Compound No. 4-1 18 1-4-190 Exemplified Compound No. 4-1 193-4-210 and Exemplified Compound No. 4-1 21 2 to 4 1 2 3 0 compounds
  • Exemplified compound numbers 5-1 to 5-5 Exemplified compound numbers 5-7 to 5-12
  • Exemplified compound numbers 5-25 to 5-28 Exemplified compound numbers 5-4 1 to 5-4 4 4
  • Exemplified compound numbers 5-57 to 5-60 Exemplified compound numbers 5-69 to 5-76
  • Exemplified compound numbers 5-89 to 5-92 Exemplified compound numbers 5-10 5 to 5-1 08, Exemplified Compound No.
  • Exemplified compound number 10-1 to 10-3 Exemplified compound number 10-5 to 10-9 Exemplified compound number 10-11, Exemplified compound number 10-13 to 10-15, Exemplified Compound No. 10--17, Exemplified Compound No. 10- 19 to 10-23, Exemplified Compound No. 10-25, Exemplified Compound No. 10-27 to 10-29, Exemplified Compound No. 10—3 1 Exemplified compound number 10—33, Exemplified compound number 10—37, Exemplified compound number 10—39, Exemplified compound number 10—41, Exemplified compound number 10—4 4 And compounds of exemplary compound numbers 10 to 46,
  • More preferred compounds include
  • Exemplified Compound No. 2-10 Exemplified Compound No. 2-26, Exemplified Compound No. 2-42, Exemplified Compound No. 2-58, Exemplified Compound No. 2-70, Exemplified Compound No. 2-74, Exemplified Compound number 2-90, Exemplified compound number 2-106, Exemplified compound number 2-181, Exemplified compound number 2-18 2, Exemplified compound number 2-18 5, Exemplified compound number 2-19 8 and Exemplified Compound No. 2-1 9 9,
  • Exemplified Compound No. 5-10 Exemplified Compound No. 5-26, Exemplified Compound No. 5-42, Exemplified Compound No. 5-58, Exemplified Compound No. 5-7, Exemplified Compound No. 5-74, Exemplified Compound No. 5—90, Exemplified Compound No. 5—106, Exemplified Compound No. 5—181, Exemplified Compound No. 5—182, Exemplified Compound No. 5—185, Exemplified Compound No. 5—19 8 and Exemplified Compound No. 5-19,
  • Exemplified compound number 6-10 Exemplified compound number 6-26, Exemplified compound number 6-42, Exemplified compound number 6-58, Exemplified compound number 6-70, Exemplified compound number 6-74, Exemplified Compound number 6-90, Exemplified compound number 6-106, Exemplified compound number 6-181, Exemplified compound number 6-182, Exemplified compound number 6-185, Exemplified compound number 6-19 8 and Exemplified Compound No. 6-1 9 9,
  • Exemplified compound number 7-10 Exemplified compound number 7-26, Exemplified compound number 7-42, Exemplified compound number 7-58, Exemplified compound number 7-70, Exemplified compound number 7-74, Exemplified Compound No. 7-90, Exemplified Compound No. 7-106, Exemplified Compound No. 7-181, Exemplified Compound No. 7-182, Exemplified Compound No. 7-185, Exemplified Compound No. 7-19 8, and Exemplified Compound No. 7-1 9 9,
  • Exemplified compound number 8-10 Exemplified compound number 8-26, Exemplified compound number 8-42, Exemplified compound number 8-58, Exemplified compound number 8-70, Exemplified compound number 8-74, Exemplified Compound No. 8—90, Exemplified Compound No. 8—106, Exemplified Compound No. 8—181, Exemplified Compound No. 8—182, Exemplified Compound No. 8—185, Exemplified Compound No. 8—19 8 and Exemplified Compound No. 8-19, Exemplified Compound No. 9-1, Exemplified Compound No. 9-1 17 to 9-120, Exemplified Compound No. 9-45 and Exemplified Compound No. 9-1 46, and
  • Exemplified compound number 10-1 Exemplified compound number 10-5, Exemplified compound number 10-7 Exemplified compound number 10-13, Exemplified compound number 10-17, Exemplified compound number 10-19 Compounds of Exemplified Compound No. 10-21 and Exemplified Compound No. 10-27 can be mentioned.
  • the most preferred compounds include
  • the compound having the general formula (I) of the present invention can be produced according to the following methods (I) to (D).
  • Method A is a method for producing compound (Ia), compound (Ib), compound (Ic) and compound (Id) of the present invention.
  • Step 1 R -ML— S0 2 -Q (V)
  • R 2 , R 4 , A, L and M are as defined above,
  • R 3 a represents a group other than a hydrogen atom in the definition of R 3,
  • R 11 represents a protecting group for a carboxy group
  • Y represents a hydroxyl group or a leaving group
  • Q represents the “halogen atom” (preferably a bromine atom or a chlorine atom, most preferably a chlorine atom).
  • protecting group for carboxy group in the definition of R 11 means hydrogenolysis, hydrolysis, 408 represents a protecting group that can be removed by a chemical method such as gasolysis or photolysis, and includes the same groups as the “general protecting group” according to the “ester of a carboxy group”.
  • Y usually indicates a group leaving as a nucleophilic residue, and such a group includes, for example, a halogen atom such as chlorine, bromine and iodine; and trichloromethyloxy.
  • Trihalogenomethyloxy groups lower alkenyl sulfonyloxy groups such as methanesulfonyloxy and ethanesulfonyloxy; trifluoromethoxymethanesulfonyloxy and pentafluoroethanesulfonyloxy
  • halogeno lower alkyl sulfonyloxy groups and arylsulfonyloxy groups such as benzenesulfonyloxy, p-toluenesulfonyloxy, and p-nitrobenzenesulfonyloxy.
  • they are a halogen atom and a lower alkane sulfonyloxy group.
  • Step 1 is a process for producing a compound (VI) by reacting the amino group of the compound (IV) with a sulfonyl halide compound (V), in a solvent, in the presence or absence of a base. Done.
  • the solvent used is not particularly limited as long as it does not hinder the reaction and dissolves the starting materials to some extent, but is preferably a halogenated compound such as dichloromethane, chloroform, carbon tetrachloride or dichloroethane.
  • Hydrocarbons such as getyl ether, diisopropyl ether, tetrahydrofuran, and dioxane; non-protonic polarities such as N, N-dimethylformamide, N, N-dimethylacetamide, and dimethylsulfoxide Solvents; nitriles such as acetonitrile; esters such as methyl acetate and ethyl acetate; aromatic hydrocarbons such as benzene, toluene and xylene; or aliphatic hydrocarbons such as pentane, hexane and heptane Can be mentioned.
  • ethers such as getyl ether, diisopropyl ether, tetrahydrofuran, and dioxane
  • non-protonic polarities such as N, N-dimethylformamide, N, N-dimethylacetamide, and dimethylsulfoxide Solvents
  • nitriles such as ace
  • Usable bases include those usually used in amidation reactions.
  • alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide
  • alkali metal hydrides such as sodium hydride, lithium hydride
  • hydrogenation Alkali metal hydroxides
  • alkali metal carbonates such as sodium carbonate and lium carbonate or triethylamine, triptylamine, pyridine, picoline, 1,8-diazabicyclo [ 5.4.0] — 7—Examples of amines such as ndene.
  • the reaction time is from 120 to 150 ° C, preferably from 0 ° C to 100 ° C.
  • the reaction time varies depending mainly on the reaction temperature, the starting materials used, the solvent and the like, but is usually from 10 minutes to 48 hours, preferably from 30 minutes to 12 hours.
  • Step 2 removes the R 11 group of the compound (VI) and, if desired, removes the protecting group, if the R 2 group is protected, to give the compound (la) of the present invention. It is the process of manufacturing.
  • the removal of the R 11 group depends on its type, but is generally carried out by a method well known in the art as follows. .
  • R 11 group is a lower alkyl group or an aryl group, it can be removed by treating with an acid or a base.
  • the acid examples include hydrochloric acid, sulfuric acid, phosphoric acid, and hydrobromic acid.
  • the base is not particularly limited as long as it does not affect the other parts of the compound, but is preferably sodium carbonate, Alkaline metal carbonates such as potassium carbonate, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, or concentrated ammonia-methanol solution are used.
  • isomerization may occur in hydrolysis with a base.
  • the solvent used is not particularly limited as long as it does not inhibit the reaction, and is not limited to water or an alcohol such as methanol, ethanol, n-propanol, or tetrahydrofuran. Like dioxane A mixed solvent of a solvent and water is preferred.
  • reaction temperature and reaction time vary depending on the starting material, the solvent, the reagents used, and the like, and are not particularly limited. However, in order to suppress a side reaction, the reaction is usually performed at 0 ° C to 150 ° C and 1 Run for 0 hours.
  • R n groups in the case of Jiariru substituted methyl group such as Jifue two Rumechiru is usually in a solvent, is removed Ri by the treatment with an acid.
  • the solvent used is preferably an aromatic hydrocarbon such as anisol, and the acid used is a fluorinated organic acid such as trifluoroacetic acid.
  • the reaction temperature and the reaction time vary depending on the starting material, the solvent, the acid used and the like, but are usually at room temperature for 30 minutes to 10 hours.
  • R 11 group is an aralkyl group or a halogeno lower alkyl group, it is usually removed by reduction in a solvent.
  • the reduction method when the protecting group for the carboxy group is a halogeno lower alkyl group, a method by chemical reduction such as zinc-acetic acid is preferable, and when the protecting group for the carboxy group is an aralkyl group, palladium carbon or water is used. It is carried out by a method of catalytic reduction using a catalyst such as palladium oxide or platinum, or a method of chemical reduction using an alkali metal sulfide such as potassium sulfide or sodium sulfide.
  • the solvent to be used is not particularly limited as long as it does not participate in this reaction, but includes alcohols such as methanol and ethanol; ethers such as tetrahydrofuran and dioxane; fatty acids such as acetic acid; A mixed solvent of a solvent and water is preferred.
  • reaction temperature and reaction time vary depending on the starting material, solvent, reduction method and the like, but are usually 0 to around room temperature, for 5 minutes to 12 hours.
  • R 11 group is an alkoxymethyl group, it is usually removed by treating with an acid in a solvent.
  • the acid to be used is not particularly limited as long as it is usually used as Brenstead acid, but is preferably an inorganic acid such as hydrochloric acid or sulfuric acid or an organic acid such as acetic acid or p-toluenesulfonic acid. It is.
  • the solvent to be used is not particularly limited as long as it does not participate in the reaction, but alcohols such as methanol and ethanol; ethers such as tetrahydrofuran and dioxane, and organic solvents such as these. A mixed solvent with water is preferred.
  • reaction temperature and the reaction time are different depending on the starting material, the solvent and the kind of the acid to be used, etc.
  • the reaction is carried out at Ot: to 100 ° C for 10 minutes to 18 hours.
  • performed Ri by the ammonia treatment may be amino-de reduction.
  • the carboxylic acid produced above is dissolved in a mixed solvent of water and an organic solvent immiscible with water such as ethyl acetate according to a conventional method, and the solution is mixed with an aqueous solution of sodium hydrogencarbonate or aqueous solution of carbonated lime.
  • An alkali metal carbonate or bicarbonate aqueous solution is added at 0 ° C. to room temperature, the pH is adjusted to around pH 7, and the deposited precipitate is filtered to produce an alkyl metal salt.
  • the salt thus produced or the above carboxylic acid is mixed with a solvent (preferably, ethers such as tetrahydrofuran or N, N-dimethylformamide, dimethylsulfoxide, hexamethylphosphonate).
  • a solvent preferably, ethers such as tetrahydrofuran or N, N-dimethylformamide, dimethylsulfoxide, hexamethylphosphonate.
  • polar solvents such as triamide and triethyl phosphate
  • two equivalents of a base preferably an organic base such as triethylamine, dicyclohexylamine, sodium hydride
  • hydrogenated alkali metal salts or alkali metal carbonates or bicarbonates such as sodium bicarbonate, sodium carbonate, and potassium carbonate
  • Aliphatic acyloxymethyl halides such as mid, 1-methoxycarbonyloxyl-shrink, 1-ethoxy 1-Lower alkoxycarbonyloxyshetyl halides such as cycarbonyloxyshetyl iodide, phthalidyl halides or (2-oxo-5-methyl-1,3-dioxolen-14-yl) methyl halide
  • alkoxycarbonyloxyshetyl halides such as cycarbonyloxyshetyl iodide, phthalidyl halides or (2-oxo-5-methyl-1,3-dioxolen-14-yl) methyl halide
  • reaction temperature and the reaction time vary depending on the types of the starting material, the solvent and the reaction reagent, but are usually from 0 to 100, for 30 minutes to 10 hours.
  • the desired step, removal of the protecting group when the R 2 group is protected is of the type By different forces s, it is performed in the following manner generally by methods well known in the art.
  • the protecting group is a silyl group
  • it is usually removed by treatment with a compound that produces a fluorine anion, such as tetrabutylammonium fluoride.
  • the reaction solvent is not particularly limited as long as it does not inhibit the reaction, but ethers such as tetrahydrofuran and dioxane are preferable.
  • the reaction temperature and reaction time are not particularly limited, but the reaction is usually performed at room temperature for 10 minutes to 18 hours.
  • the protecting group is an aliphatic acyl group, an aromatic acyl group or an alkoxycarbonyl group, it can be removed by treating with an acid or a base in the presence of an aqueous solvent.
  • the acid used is not particularly limited as long as it does not inhibit the reaction, as long as it is generally used as an acid.
  • inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, and hydrobromic acid are used.
  • Acids, organic acids such as trifluoroacetic acid or Lewis acids such as B-bromocatecholborane are used (more preferably Lewis acids, most preferably B-bromocatecholborane).
  • the base used is not particularly limited as long as it does not affect the other parts of the compound.
  • the base is a metal alkoxide such as sodium methoxide, or sodium carbonate.
  • Alkali metal carbonates such as potassium carbonate, lithium carbonate, alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide or ammonia water, concentrated ammonia-methanol Ammonia is used. It should be noted that isomerization may occur in hydrolysis with a base.
  • the solvent to be used is not particularly limited as long as it is used in a usual hydrolysis reaction.
  • Water alcohols such as methanol, ethanol, n-propanol, tetrahydrofuran;
  • Organic solvents such as ethers such as dioxane and the like, or mixed solvents of water and the above-mentioned organic solvents are suitable.
  • reaction temperature and reaction time vary depending on the starting material, solvent and acid or base used, and are not particularly limited.However, in order to suppress a side reaction, the reaction is usually performed at 0 to 150 ° C. For 1 to 10 hours.
  • the protecting group is an aralkyl group or an aralkyloxycarbonyl group
  • it is usually contacted with a reducing agent in a solvent (preferably, catalytic reduction at room temperature under a catalyst).
  • a solvent preferably, catalytic reduction at room temperature under a catalyst.
  • the removal method or the removal method using an oxidizing agent is preferable.
  • the solvent used in the removal by catalytic reduction is not particularly limited as long as it does not participate in the reaction, but alcohols such as methanol, ethanol, and isopropanol, and solvents such as getyl ether, tetrahydrofuran, and dioxane.
  • Acetates, aromatic hydrocarbons such as toluene, benzene, xylene, aliphatic hydrocarbons such as hexane and cyclohexane, esters such as ethyl acetate and propyl acetate, and acetic acid Fatty acids or mixed solvents of these organic solvents and water are preferred.
  • the catalyst to be used is not particularly limited as long as it is usually used in a catalytic reduction reaction.
  • the catalyst is palladium carbon, palladium hydroxide, nickel nickel, platinum oxide, platinum black, rhodium monoxide.
  • Aluminum oxide, triphenylphosphine rhodium monochloride and palladium barium monosulfate are used.
  • the pressure is not particularly limited, it is usually set at 1013.25 hPa to 10132.5 hPa.
  • reaction temperature and the reaction time vary depending on the type of the starting material, the solvent and the catalyst, and the like, but are generally performed at Ot: to 100 t for 5 minutes to 24 hours.
  • the solvent used in the removal by oxidation is not particularly limited as long as it does not participate in the reaction, but is preferably a water-containing organic solvent.
  • organic solvents include ketones such as acetone, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, nitriles such as acetonitrile, getyl ether, Ethers such as tetrahydrofuran and dioxane, amides such as N, N-dimethylformamide, N, N-dimethylacetamide, hexamethylphosphoriotriamide, and dimethylsulfoxide Sulfoxides.
  • ketones such as acetone
  • halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride
  • nitriles such as acetonitrile
  • getyl ether Ethers such as tetrahydrofuran and dioxane
  • amides such as N, N-dimethylformamide, N, N-dimethylacetamide, hexamethylphosphoriotriamide, and dimethylsulfoxide
  • the oxidizing agent used is not particularly limited as long as it is a compound used for oxidation, Preferably, potassium persulfate, sodium persulfate, ammonium cerium nitrate (CAN;), 2,3-dichloro-5,6-dicyanor p-benzoquinone (DDQ) are used.
  • potassium persulfate, sodium persulfate, ammonium cerium nitrate (CAN;), 2,3-dichloro-5,6-dicyanor p-benzoquinone (DDQ) are used.
  • reaction temperature and the reaction time vary depending on the starting material, the solvent, the type of the catalyst, and the like, but are usually carried out at 0 ° C to 150 ° C for 10 minutes to 24 hours.
  • the removal reaction is generally performed in the same manner as in the case of the above-described removal reaction in the case where the protecting group for the amino group is the above-mentioned aliphatic acyl group, aromatic acyl group or alkoxycarbonyl group. It is achieved by treating with a base.
  • the removal method using palladium and triphenylphosphine or nickel tetracarbonyl is particularly simple and can be carried out with few side reactions.
  • Step 3 is obtained by reacting the compound (la) of the present invention or a reactive derivative thereof with hydroxyamine in a solvent, and optionally, when the R 2 group is protected, In this step, the protecting group is removed in accordance with the desired step of tep 2 to produce the compound (lb) of the present invention.
  • the solvent used is not particularly limited as long as it does not hinder the reaction and dissolves the starting material to some extent, but is preferably a halogenated hydrocarbon such as dichloromethane, chloroform, carbon tetrachloride, and dichloroethane.
  • Ethers such as getyl ether, diisopropyl ether, tetrahydrofuran, dioxane; methanol, ethanol, propanol, isoprono.
  • Alcohols such as ethanol, butanol, s-butanol, isobutanol, and t-butanol; N, N-dimethylformamide, N, N-dimethylacetamide, and dimethylsulfoxide.
  • Nonprotonic polar solvents such as; nitriles such as acetonitril; methyl acetate and ethyl acetate Esters; water or a mixed solvent thereof;
  • the reaction is carried out at a temperature of from 120 ° C. to 150 ° C., preferably from 0 to 100 ° C.
  • the reaction time varies depending on the starting material, reaction temperature, solvent and type of reaction reagent, but is usually from 10 minutes to 48 hours, and preferably from 30 minutes to 12 hours.
  • examples of the reactive derivative include acid halides, mixed acid anhydrides, and active esters.
  • the acid halide is obtained by reacting the compound (la) with a halogenating agent such as thioyl chloride and oxalyl chloride, and the mixed acid anhydride is converted into the compound (Ia) and By reacting with an acid halide such as methyl or ethyl ethyl carbonate, the active ester is converted into a compound (Ia) in the presence of the above condensing agent, for example, N-hydroxysuccinic acid imide, All are produced by reaction with a hydroxy compound such as N-hydroxyphthalic acid imide, using reaction conditions commonly used in ordinary organic synthetic chemistry.
  • a halogenating agent such as thioyl chloride and oxalyl chloride
  • 0-benzylhydroxylamine, 0- (tert-butyldimethylsilyl) hydroxylamine, ⁇ -1 (tetrahydropyran-12-yl) hydroxylamine, 0— (tetrahydrolamine) are used instead of hydroxylamine.
  • a protected hydroxyamide is prepared using a protected hydroxylamine, such as drofuran-2-yl) hydroxylamine, which is deprotected by the method described below to give compound (Ib). Can be manufactured.
  • the removal of the protecting group depends on its type, but is generally carried out as follows by a method well known in the art.
  • a compound that produces fluorine ion such as tetrabutylammonium fluoride, hydrofluoric acid, hydrofluoric acid-pyridine, or potassium fluoride is usually used.
  • an organic acid such as acetic acid, methanesulfonic acid, paratoluenesulfonic acid, trifluoroacetic acid, trifluoromethansulfonic acid or an inorganic acid such as hydrochloric acid.
  • the reaction may be accelerated by adding an organic acid such as formic acid, acetic acid, or propionic acid.
  • the solvent used is not particularly limited as long as it does not hinder the reaction and dissolves the starting material to some extent.
  • it is preferably dimethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, or dimethoxetane.
  • Ethers such as diethylene glycol dimethyl ether; nitriles such as acetonitrile and isobutyronitrile; water; organic acids such as acetic acid; and mixed solvents thereof.
  • the reaction temperature and reaction time are not particularly limited, but the reaction is usually carried out at 0 ° C. to 100 ° C. (preferably at 10 ° C. to 30 ° C.) for 1 hour to 24 hours.
  • the protecting group for the hydroxyl group is an aralkyl group or an aralkyloxycarbonyl group
  • it is usually contacted with a reducing agent in a solvent (preferably, catalytic reduction at room temperature under contact).
  • a solvent preferably, catalytic reduction at room temperature under contact.
  • the removal method or the removal method using an oxidizing agent is preferable.
  • the solvent used in the removal by catalytic reduction is not particularly limited as long as it does not participate in the reaction, but alcohols such as methanol, ethanol, and isopropanol, getyl ether, and tetrahydrofuran , Ethers such as dioxane, aromatic hydrocarbons such as toluene, benzene, xylene, aliphatic hydrocarbons such as hexane and cyclohexane, and ethers such as ethyl acetate and propyl acetate.
  • Amides such as amides, formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, hexamethyl phosphorotriamide, formic acid, acetic acid And water, or a mixed solvent thereof, is more preferable.
  • Alcohols, fatty acids, and alcohols are more preferable.
  • the catalyst to be used is not particularly limited as long as it is usually used in a catalytic reduction reaction, but is preferably palladium carbon, palladium black, Raney nickel, platinum oxide, platinum black, or rhodium.
  • Aluminum oxide, trifenylphosphine rhodium monochloride, and barium palladium monosulfate are used.
  • the pressure is set at a force f which is not particularly limited, and is usually from 10 13 .25 hPa to 10 132.5 hPa.
  • the reaction temperature and reaction time vary depending on the starting material, solvent, type of catalyst, etc., but are usually 0 to 10 (TC (preferably at 20 ° C. to 70), 5 minutes to 5 minutes. 48 hours (preferably 1 hour to 24 hours).
  • the solvent used in the removal by oxidation is not particularly limited as long as it does not participate in the reaction, but is preferably a water-containing organic solvent.
  • Suitable examples of such an organic solvent include ketones such as acetone, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, and acetonitrile.
  • ketones such as acetone, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, and acetonitrile.
  • Nitrites ethers such as dimethyl ether, tetrahydrofuran, and dioxane; amides such as dimethylformamide, dimethylacetamide, hexamethylphospho-mouth triamide; and dimethylsulfoxide Sulfoxides.
  • the oxidizing agent to be used is not particularly limited as long as it is a compound used for the oxidation.
  • potassium persulfate, sodium persulfate, ammonium cerium nitrate (CAN), 2, 3 —Dichloro-1,6-dicyano-p-benzoquinone (DDQ) is used.
  • reaction temperature and the reaction time vary depending on the starting material, the solvent, the type of the catalyst, and the like, but are usually 0 to 150, and the reaction is carried out for 10 minutes to 24 hours.
  • an alkali metal such as lithium metal or sodium metal in liquid ammonia or alcohol such as methanol or ethanol at a temperature of 178 to -20 ° C. Can be removed.
  • alkylsilyl halide such as aluminum chloride sodium or sodium trimethylsilyl iodide in a solvent.
  • the solvent used is not particularly limited as long as it does not participate in the reaction, but is preferably a nitrile such as acetonitrile, or a halogenated carbon such as dichloromethane or chloroform. Hydrogens or a mixed solvent thereof is used.
  • reaction temperature and reaction time vary depending on the starting material, solvent and the like, but are usually carried out at 0 ° C to 50 ° C for 5 minutes to 3 days.
  • reaction substrate has a sulfur atom
  • aluminum chloride monoiodide is used.
  • a trim is used.
  • the protecting group for the hydroxyl group is an aliphatic acyl group, an aromatic acyl group or an alkoxycarbonyl group, it is removed by treating with a base in a solvent.
  • the base used is not particularly limited as long as it does not affect the other parts of the compound, but is preferably a metal alkoxide such as sodium methoxide; sodium carbonate, potassium carbonate.
  • Alkali metal carbonates such as lithium carbonate;
  • Alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide or aqueous ammonia, concentrated ammonia-methanol Ammonia is used.
  • the solvent to be used is not particularly limited as long as it is used in a usual hydrolysis reaction.
  • Water alcohols such as methanol, ethanol, and n-propanol;
  • Organic solvents such as ethers such as drofuran and dioxane, or mixed solvents of water and the above-mentioned organic solvents are preferred.
  • reaction temperature and reaction time vary depending on the starting material, solvent and base used, and are not particularly limited.However, in order to suppress a side reaction, the reaction is usually performed at 0 ° C to 150 ° C. It will take 10 hours.
  • the protecting group for the hydroxyl group is an alkoxymethyl group, a tetrahydrobiranyl group, a tetrahydrothiopyranyl group, a tetrahydrofuranyl group, a tetrahydrothiofuranyl group, or a substituted ethyl group, it is usually treated with an acid in a solvent. Removed by the protecting group for the hydroxyl group.
  • the acid used is not particularly limited as long as it is usually used as Brenstead acid or Lewis acid, and is preferably hydrogen chloride; an inorganic acid such as hydrochloric acid, sulfuric acid, or nitric acid; or Brenstead acids such as acetic acid, trifluoroacetic acid, methanesulfonic acid, organic acids such as p-toluenesulfonic acid, etc .: Lewis acids such as boron trifluoride, but strongly acidic cations such as Dowex 50W Zeon exchange resins can also be used.
  • the solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but is preferably a fat such as hexane, heptane, lignin, or petroleum ether.
  • Aromatic hydrocarbons aromatic carbons such as benzene, toluene and xylene Hydrocarbons; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, cyclobenzene, and dichlorobenzene; esters such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate, and getyl carbonate Ethers such as getyl-ter, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; methanol, ethanol, n-propanol, isopropanol,
  • reaction temperature and reaction time vary depending on the starting material, solvent and type of acid used * concentration, etc., but are usually from ⁇ 10 to 100 ° C. (preferably ⁇ 5 to 5 ° C. 0 V) for 5 minutes to 48 hours (preferably 30 minutes to 10 hours).
  • the removal reaction is usually carried out in the same manner as in the removal reaction when the protecting group for the hydroxyl group is the above-mentioned aliphatic acyl group, aromatic acyl group or alkoxycarbonyl group. It is achieved by treating with a base.
  • aryloxycarbonyl in particular, palladium and triphenylphosphine, or bis (methyldiphenylphosphine) (1,5-cyclohexyl) iridium (I) .hexafluorophosphine
  • the method of removal using a catalyst is simple and can be carried out with few side reactions.
  • S tep 4 is a nitrogen atom of the sulfonamide head portion of compound (VI), is reacted with a compound R 3 a- Y, and modified with R 3 a group, compound c (1 is a step for preparing a (VIII)
  • the Mitsunobu reaction (DLHughes, Org. React., ⁇ , 335 (1992)) is applied.
  • the reagent used in the Mitsunobu reaction is not particularly limited as long as it can be used in the Mitsunobu reaction.
  • getyl azodicarboxylate, diisopropyl An azo compound such as a di-lower alkyl azodicarboxylate such as azodicarboxylate or an azodicarbonyl such as 1,1 '-(azodicarbonyl) dipiperidine and triphenyl phosphine.
  • phosphines such as tri-lower alkylphosphines such as tri-n-butylphosphine, and more preferably di-lower alkylazodicarboxy.
  • force 5 is not particularly limited as long as it dissolves a starting substance to a certain extent ', preferably, benzene, toluene, aromatic hydrocarbons such as xylene Halogenated hydrocarbons such as dichloromethane, black form, carbon tetrachloride, carbon tetrachloride, dichloroethane, chlorobenzene, dichlorobenzene; esters such as ethyl ethyl formate, ethyl ethyl acetate, propyl acetate, butyl acetate, and getyl carbonate; Ethers such as mono-ter, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxetane, and diethylene glycol dimethyl ether; nitriles such as acetate nitrile and isobutyronitrile; formamide, N, N-dimethylformamide, N
  • the reaction is carried out at a temperature of from 120 ° C. to 150 ° C., preferably from 0 to 100: 1.
  • the reaction time varies depending on the reaction temperature, the starting compound, the reaction reagent or the type of the solvent used, but is usually from 10 minutes to 3 days, preferably from 30 minutes to 12 hours. .
  • the solvent used is not particularly limited as long as it does not hinder the reaction and dissolves the starting material to some extent, but is preferably methanol, ethanol, propanol, or methanol.
  • Alcohols such as sopropanol; ethers such as getyl ether, disopropyl ether, tetrahydrofuran, and dioxane; non-esters such as N, N-dimethylformamide, N, N-dimethylacetamide, dimethylsulfoxide Protonic polar solvents; nitriles such as acetonitrile; esters such as methyl acetate and ethyl acetate; aromatic hydrocarbons such as benzene, toluene and xylene or fats such as pentane, hexane and heptane Group hydrocarbons.
  • the base to be used is not particularly limited as long as it can be usually used as a base, but is preferably an alkali such as sodium methoxide, sodium ethoxide, or potassium t-butoxide.
  • Metal carbonates or amines such as triethylamine, tributylamine, pyridine, picolin, 1,8-diazabicyclo [5.4.0] — 7-indene. it can.
  • Step 5 removes the R 11 group of the compound (VIII) in the same manner as Step 2, and optionally removes the desired step of Step 2 when the group R 2 is protected.
  • This is a step of producing the compound (Ic) of the present invention by removing the protecting group according to the following.
  • Step 6 is obtained by reacting the compound (Ic) of the present invention with hydroxyamine in a solvent in the same manner as in Step 3; if desired, when the R 2 group is protected, ,
  • Method B is a method for producing compound (IV), which is a starting material in the above Kakuha method. ' C00R “Step 7 i 00R “ Step 8 COOR "
  • R 2 , R u , A and Y are as defined above,
  • R 12 represents a protecting group for an amino group.
  • protecting group for an amino group indicates a protecting group that can be removed by a chemical method such as hydrogenolysis, hydrolysis, electrolysis, or photolysis.
  • aliphatic acyl group the “aromatic acyl group”, the “alkoxycarbonyl group”, the “alkenyloxycarbonyl group”, the “aralkyloxycarbonyl group”, the “silyl” Group '' and the above-mentioned ⁇ aralkyl group '', preferably, the above-mentioned ⁇ alkoxycarbonyl group '', the above-mentioned ⁇ alkenyloxycarbonyl group '' or the above-mentioned ⁇ aralkyloxycarbonyl group ''.
  • Step 7 is a step of reacting the compound (IX) with the compound (X) to produce the compound (XI), and is performed in the same manner as in Step D4.
  • Step 8 is a step of producing the compound (IV) by removing the R 12 group of the compound (XI) according to the desired step of Step 2.
  • the R 11 group may be removed in some cases.
  • the carboxy group can be protected again by the following method.
  • aliphatic hydrocarbons such as hexane and heptane
  • Aromatic hydrocarbons such as benzene, toluene, xylene
  • dichloromethane Halogenated hydrocarbons such as form, carbon tetrachloride, dichloroethane, cyclobenzene, dichlorobenzene
  • ethers such as getyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxetane, diethylene glycol dimethyl ether
  • Ketones such as acetone, methylethylketone, methylisobutylketone, isofolone, and hexahexanone
  • nitriles or formamides such as acetonitrile, isobutyronitrile Amides such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, N
  • the base to be used is not particularly limited as long as it is used as a base in a usual reaction, and preferably, sodium carbonate or potassium carbonate is used.
  • Alkali metal carbonates such as lithium carbonate, lithium bicarbonate; Alkali metal bicarbonates such as sodium hydrogen carbonate, potassium hydrogen carbonate, lithium bicarbonate; lithium hydride, sodium hydride, hydrogenation Alkali metal hydrides such as potassium; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, barium hydroxide and lithium hydroxide; sodium fluoride, fluoridation power Inorganic bases such as alkali metal fluorides such as lium; sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, potassium t Alkali metal alkoxides, such as butoxide and lithium methoxide; Alkali metals, such as methyl mercaptan natrium and ethyl mercaptan
  • the resulting carboxylic acid derivative and a compound having the general formula R 11 —OH (wherein R 11 has the same meaning as described above) in a solvent in the presence or absence of a base are as follows: A method of reacting with a condensing agent.
  • Carbodimids such as 1,3-dicyclohexylcarbodiimide, 1,3-diisopropylcarbodiimid, 1-ethyl-3- (3dimethylaminopropyl) carbodiimid, etc .; the above-mentioned carbodimids and the following bases
  • a combination of the above carbodiimides and N-hydroxy compounds such as N-hydroxysuccinimide, 1-hydroxybenzotriazole, N-hydroxy-15-norbornene-1,2,3-dicarboximide;
  • Phosphinic chlorides such as N, N, monobis (2-oxo-3-oxazolidinyl) phosphinic chloride
  • aromatic diazolyl 1,1,1-bis (6 benzobenzotriazolyl) oxalate, 1,1,1-bis (6-trifluoromethylbenzotriazolyl) oxalate Naxozarates;
  • N-Ethyl-5-phenylisoxazolymous 3'-N-lower alkyl-5-arylisoxazolymous 3'-sulfonates such as sulfonates; (sulfonates; ( 9) diheteroaryl diselenides such as di-2-pyridyl diselenide; (10) arylsulfonyl triazolides such as p nitrobenzenesulfonyl triazolide;
  • 1,1'-imidazoles such as one-year-old quinaryldiimidazole and N, N'carbonyldiimidazole;
  • Phosphates such as phenyl dichlorophosphate and polyphosphate esters
  • halogenosulfonyl isocyanates such as chlorosulfonyl isocyanate
  • halogenosilanes such as trimethylsilyl chloride and triethylsilyl chloride
  • N, N, ⁇ ', N'- ⁇ , —, ⁇ ', N'-tetra-lower alkylhalogenoformamide media chlorides such as tetramethylcloformformamide media chloride;
  • Preferable are carbodiimides and a combination of phosphines and azodicarboxylic acid esters or azodicarboxyamides.
  • Solvents used should not hinder the reaction and dissolve the starting materials to some extent
  • aliphatic hydrocarbons such as hexane and heptane
  • aromatic hydrocarbons such as benzene ', toluene, and xylene
  • esters such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate, and getyl carbonate; getyl ether, diisopropyl ether, and tetrahydrofuran
  • Ethers such as dioxane, dimethoxetane, diethylene glycol dimethyl ether
  • nitriles or formamide such as acetonitrile, isobutyronitrile or formamide
  • the base to be used is not particularly limited as long as it is used as a base in a usual reaction, but is preferably N-methylmorpholine, triethylamine, tributylamine, diisopropylethylamine. , Dicyclohexylamine, N-methylpiperidine, pyridine, 4-pyrrolidinopyridine, picolin, 4- (N, N-dimethylamino) pyridine, 2,6-di (t-butyl) -14-methylpyridine, Organic bases such as quinoline, N, N-dimethylaniline and N, N-getylaniline can be mentioned.
  • 4- (N, N-dimethylamino) pyridine and 4-pyrrolidinopyridine can be used in combination with other bases in a catalytic amount, and in order to make the reaction proceed effectively, molecular sieves are used.
  • Dehydrating agents such as benzyltriethylammonium chloride; quaternary ammonium salts such as tetrabutylammonium chloride; crown ethers such as dibenzo-18-crown-16;
  • An acid scavenger such as dihydro 2H-pyrido [1,2-a] pyrimidin-2-one can also be added.
  • the reaction temperature is between ⁇ 20 and 100 ° C., with a force of 5 ′, preferably between 0 ° C. and 50 ° C.
  • the reaction time varies depending mainly on the reaction temperature, the starting compound, the reaction reagent or the type of the solvent used, but is usually from 10 minutes to 3 days, preferably from 30 minutes to 1 day. is there.
  • the protecting group is a lower alkyl group, it is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent in the solvent, but is preferably the same alcohol as the reagent; hexane, Aliphatic hydrocarbons such as heptane; Aromatic hydrocarbons such as benzene, toluene, and xylene; Halogenated carbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, cyclobenzene, and dichlorobenzene Hydrogens; ethers such as ethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; acetone, methylethyl ketone, methyl isobutyl ketone, isophorone, cyclohexane Ketones such as hexanone; acetonit
  • Method C is a method for separately producing the compounds of the present invention (Ic) and (Id). -A- -A,
  • R 2, R 3 a, R 4, R u, A, L, M, Q and Y are as defined above.
  • Step 9, Step 10, Step 13, Step 14, Step 15 and Step 16 are Step 1, Step 4, Step 4 (1), Step 4, respectively. This is performed in the same manner as (2), Step 2 and Step 3.
  • Step 11 hydrolyzes the lactone compound (XIV) to form a carboxy group and a hydroxyl group, and then reacts the generated carboxy group with the halide compound (XV), This is a step of producing an ester derivative (XVI).
  • the hydrolysis reaction in the first stage is achieved by a method commonly used in synthetic organic chemistry, but a method in which the lactone compound (XIV) is treated with a base in a solvent is preferable.
  • the base used is not particularly limited as long as it does not affect the other parts of the compound, but is preferably a metal alkoxide such as sodium methoxide; sodium carbonate, potassium carbonate, or the like.
  • Alkali metal carbonates such as lithium carbonate; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide or aqueous ammonia, concentrated ammonia-methanol Ammonia is used.
  • the solvent to be used is not particularly limited as long as it is used in a usual hydrolysis reaction.
  • Water alcohols such as methanol, ethanol, n-propanol, tetrahydrofuran and dioxane;
  • Organic solvents such as ethers or mixed solvents of water and the above-mentioned organic solvents are preferred.
  • reaction temperature and reaction time vary depending on the starting material, solvent and base used, and are not particularly limited.However, in order to suppress a side reaction, the reaction is usually performed at 0 ° C to 150 ° C for 1 hour. It will be conducted for 10 hours.
  • the latter carboxy group protection reaction can be carried out in the same manner as the carboxy group protection reaction described in Step 8 and is preferably carried out according to Method 1> as described in Step 8 .
  • Step 12 is a step of converting the hydroxyl group of the compound (XVI) to a halogen atom to produce a conjugated compound (XVII).
  • DAST dimethylethylsulfur Chlorination reaction with carbon tetrachloride; hydrobromic acid, thionyl bromide, phosphorus tribromide, thionyl chloride, phosphorus pentachloride, phosphorus oxychloride, trifenylphosphine , Trifluorophosphine Z, bromination reaction with carbon tetrabromide; or hydroiodic acid, iodination reaction with phosphorus triiodide, WJ Middleton et al. (J. Org. Chem., 4Q, p. 574) 1975)).
  • Method D is a method for producing compounds (Ie) and (If) in which A in the compound of the present invention is a methylene group.
  • R 2, R 3 a, R 4, L, M, Q and Y represents the same meanings as defined above,
  • R 13 represents a protecting group for a hydroxyl group.
  • hydroxyl protecting group in the definition of R 13, said the show an "ester to such or that the general protecting group for a hydroxyl group", preferably, the a "silyl group", more preferably, before
  • tri-lower alkylsilyl group is particularly preferable, and trimethylsilyl, triethylsilyl, isopropyldimethylsilyl or t-butyldimethylsilyl is particularly preferable.
  • Step 17 is a step of reacting the amino group of serinol (XIX) with the sulfonyl halide compound (V) to produce the compound (XX), and is carried out in the same manner as in Step 1.
  • S tep 1 8 may be prepared by reacting a compound (XX) a nitrogen atom with a compound of the sulfonamide head portion of (VII), the nitrogen atom is compounds modified with R 3 a group (XX I) in the process you produce Yes, performed in the same way as Step 4.
  • anti- ⁇ method examples include a method described in Protective Groups in Organic Synthesis (John Wiley & Sons, New York 1991) as a method for synthesizing silyl ethers. By reacting with silyl halide compounds.
  • Step 20 is a step of producing the compound (XXIV) by reacting the compound (XXIII) with the compound (X), and is performed in the same manner as in Step 4 (1).
  • S tep 2 1 removes the hydroxyl protecting group R 13 of compound (XX IV), a step of producing the compound (XXV), in S te P 3, using the protected human Doroki Shiruami down
  • the reaction is carried out in the same manner as in the step of deprotection, for example, the method described in detail in Protective Groups in Organic Synthesis (John Wiley & Sons, New York 1991) as a method for decomposing silyl ethers Done by
  • Step 22 is a process for producing an aldehyde compound (XXVI) by oxidizing a hydroxyl group of the compound (XXV). For example, a hydroxyl group such as chromic acid, manganese dioxide, and dimethyl sulfoxide is converted to an aldehyde compound.
  • a hydroxyl group such as chromic acid, manganese dioxide, and dimethyl sulfoxide is converted to an aldehyde compound.
  • Step 23 is a step of producing the carboxy group by oxidizing the aldehyde compound (XXVI) to produce the compound (Ie) of the present invention.
  • Examples of the step include permanganic acids, chromic acid, and peroxide.
  • T. Kageyama, Y. Ueno and M. Okawara Synthesis, Oxidants, Oxidants, Oxygens, Halogens, Hypohalous Acids, Halogenous Acids, Halogenic Acids, and Nitric Acids 815 (1983)
  • CD. Hurd, JWGarrett and ENOsborne J. Am. Chem. Soc ", 1082 (1933)).
  • Step 24 is a step of reacting the compound (Ie) of the present invention with hydroxyamine to produce the hydroxyamide compound (If) of the present invention, and is carried out in the same manner as in Step 3.
  • Compound (IV), compound (V), compound (VII), compound (IX), compound (X), compound (XII), compound (XV), compound (XIX), Compound (XXII) is a compound known per se or can be easily produced from a known compound according to a known method. After completion of each of the above reactions, the target compound is collected from the reaction mixture according to a conventional method.
  • reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration, and then an immiscible organic solvent such as water and ethyl acetate is added.
  • an immiscible organic solvent such as water and ethyl acetate is added.
  • the organic layer containing the target compound is separated, dried over anhydrous magnesium sulfate or the like, and then the solvent is distilled off.
  • the obtained target compound can be used in a conventional manner, for example, recrystallization, reprecipitation, or a method usually used for separation and purification of organic compounds, for example, silica gel, alumina, magnesium gel, and a gel-based fluorinated gel.
  • Adsorption column chromatography using a carrier such as Jill; Sephadex LH-20 (Pharmacia), Amberlite X AD-11 (Rohm & And Haas), Diaion HP-2 0 (Mitsubishi Chemical Corporation Using a synthetic adsorbent, such as partition column chromatography using a carrier such as, or ion-exchange chromatography, or normal-phase and reverse-phase column chromatography using silica gel or alkylated silica gel. (Preferably high performance liquid chromatography), and separation and purification can be performed by eluting with an appropriate eluent.
  • a carrier such as Jill; Sephadex LH-20 (Pharmacia), Amberlite X AD-11 (Rohm & And Haas), Diaion HP-2 0 (Mitsubishi Chemical Corporation
  • a synthetic adsorbent such as partition column chromatography using a carrier such as, or ion-exchange chromatography, or normal-phase and reverse-phase column
  • the compound of the present invention having the general formula (I), a pharmacologically acceptable salt thereof, or an ester or other derivative thereof has excellent MMP-13 inhibitory activity and aggrecanase inhibitory activity.
  • a prophylactic or therapeutic agent for arthritis such as osteoarthritis and rheumatoid arthritis, or a drug for suppressing the growth, metastasis or invasion of cancer such as breast cancer and colorectal cancer).
  • Examples of the dosage form include oral administration using tablets, capsules, granules, powders, syrups, and the like, and parenteral administration using injections or suppositories.
  • compositions are manufactured in a known manner using additives such as excipients, lubricants, binders, disintegrants, stabilizers, flavoring agents, diluents and the like.
  • the excipients include, for example, sugar derivatives such as lactose, sucrose, glucose, mannite, and sorbit; corn starch, and starch.
  • Starch derivatives such as starch, dextrin and carboxymethyl starch; crystalline cell mouth, low-substituted hydroxypropylcellulose, hydroxypropylmethylcell mouth, carboxymethylcellulose, carboxymethylcellulose calcium, Cellulose derivatives such as internally crosslinked carboxymethylcellulose sodium; organic excipients such as gum arabic; dextran; pullulan; and silicates such as light silicic anhydride, synthetic aluminum silicate, magnesium metasilicate. Derivatives; phosphates such as calcium phosphate; carbonates such as calcium carbonate; sulfates such as calcium sulfate; and inorganic excipients.
  • Lubricants include, for example, metal stearate salts such as stearate, calcium stearate, and magnesium stearate; talc; colloid silica; waxes such as bigum, gay moth; boric acid : Adipic acid; sulfates such as sodium sulfate; Glycol; Fumaric acid; Sodium benzoate; DL—Mouth isine; Sodium fatty acid salt; Lauryl sulfate such as sodium lauryl sulfate and magnesium lauryl sulfate; Silicic anhydride, Silicic acid hydrate Such silicic acids; and the above-mentioned starch derivatives.
  • binder examples include polyvinylpyrrolidone, macrogol, and compounds similar to the above-mentioned excipients.
  • disintegrant examples include compounds similar to the above-mentioned excipients and chemically modified starch and celluloses such as croscarmellose sodium, carboxymethyl starch sodium and crosslinked polybulpyridone. You can't.
  • the stabilizer examples include parabenzoic acid esters such as methylparaben and propylparaben; alcohols such as chlorobutanol, benzyl alcohol and phenylethyl alcohol; benzalkonium chloride; phenols such as phenol and cresol. And sorbic acid.
  • the flavoring agent examples include, for example, commonly used sweeteners, sour agents, flavors and the like.
  • the amount of the compound having the general formula (I) of the present invention, a pharmaceutically acceptable salt thereof, or an ester or other derivative thereof varies depending on symptoms, age, administration method, and the like.
  • 0.1 mg (preferably 1 mg) per day, 300 mg (preferably 300 mg) per day It is desirable to administer the drug in several divided doses according to the symptoms.
  • the lower limit is 0.1 mg (preferably 0.1 mg) and the upper limit is 300 mg (preferably 30 mg) per day for adults. Is preferably administered once or divided into several doses depending on the symptoms.
  • the reaction solution was concentrated under reduced pressure, and the residue was basified with an aqueous 10% carbonated aqueous solution, and extracted with ethyl acetate.
  • the organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 1.67 g of the desilylated product as a colorless oil.
  • This was dissolved in 15 ml of tetrahydrofuran, 7.5 ml of 1N aqueous sodium hydroxide solution was added, the mixture was stirred at room temperature for 30 minutes, and 7.5 ml of 1N hydrochloric acid was added for neutralization. Extracted with ethyl acetate.
  • the organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 1.55 g of the title compound as a white amorphous solid (yield 98%).

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Abstract

La présente invention concerne des composés de formule générale (I), présentant des activités inhibitrices de la métalloprotéase 13 matricielle et de l'aggrécanase. Dans (I), R1 représente OH ou NHOH; R2 représente un groupe de formule générale (II) ou (III); A représente un alkylène pouvant être interrompu par une liaison éther ou une liaison similaire; R3 représente hydrogène, alkyle ou un élément similaire; L représente un (hétéro)arylène éventuellement substitué; M représente oxygène ou soufre; et R4 représente alkyle, (hétéro)aryle ou un élément similaire, éventuellement substitué.
PCT/JP2000/006798 1999-09-29 2000-09-29 Derives de sulfonamide Ceased WO2001023363A1 (fr)

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US6890915B2 (en) * 2001-05-25 2005-05-10 Bristol-Myers Squibb Pharma Company Hydantoins and related heterocycles as inhibitors of matrix metalloproteinases and/or TNF-α converting enzyme (TACE)
US8106064B2 (en) 2006-07-24 2012-01-31 Korea Research Institute Of Chemical Technology Pyrimidine-2,4-dione HIV reverse transcriptase inhibitors
US8119800B2 (en) 2007-12-21 2012-02-21 Korea Research Institute Of Chemical Technology Processes for preparing HIV reverse transcriptase inhibitors
US8334295B2 (en) 2007-06-29 2012-12-18 Korea Research Institute Of Chemical Technology Pyrimidine derivatives as HIV reverse transcriptase inhibitors
US8354421B2 (en) 2007-06-29 2013-01-15 Korea Research Insitute Of Chemical Technology HIV reverse transcriptase inhibitors
CN106928454A (zh) * 2015-12-30 2017-07-07 北京大学 聚氨基酸化合物

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WO1999006340A2 (fr) * 1997-07-31 1999-02-11 The Procter & Gamble Company Inhibiteurs de metalloprotease acycliques
WO1999042443A1 (fr) * 1998-02-04 1999-08-26 Novartis Ag Derives d'acide sulfonylamino inhibant des metalloproteases de degradation de matrice
WO1999051572A1 (fr) * 1998-04-03 1999-10-14 Sankyo Company, Limited Derives de sulfonamide

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WO1997027174A1 (fr) * 1996-01-23 1997-07-31 Shionogi & Co., Ltd. Derives d'acides amines sulfones et inhibiteurs de metalloproteinases contenant ces derives
WO1999006340A2 (fr) * 1997-07-31 1999-02-11 The Procter & Gamble Company Inhibiteurs de metalloprotease acycliques
WO1999042443A1 (fr) * 1998-02-04 1999-08-26 Novartis Ag Derives d'acide sulfonylamino inhibant des metalloproteases de degradation de matrice
WO1999051572A1 (fr) * 1998-04-03 1999-10-14 Sankyo Company, Limited Derives de sulfonamide

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