WO2004060892A1 - Composes heterocycliques contenant n condense et leur utilisation medicale - Google Patents

Composes heterocycliques contenant n condense et leur utilisation medicale Download PDF

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Publication number
WO2004060892A1
WO2004060892A1 PCT/JP2003/017067 JP0317067W WO2004060892A1 WO 2004060892 A1 WO2004060892 A1 WO 2004060892A1 JP 0317067 W JP0317067 W JP 0317067W WO 2004060892 A1 WO2004060892 A1 WO 2004060892A1
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Prior art keywords
oxo
pyridine
group
hexahydro
pyrazo
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PCT/JP2003/017067
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English (en)
Japanese (ja)
Inventor
Makoto Shiozaki
Akira Suma
Katsutaka Yasue
Atsushi Sakai
Takafumi Matsuo
Masahiro Tanaka
Yuichi Shinozaki
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Japan Tobacco Inc.
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Priority to AU2003292724A priority Critical patent/AU2003292724A1/en
Publication of WO2004060892A1 publication Critical patent/WO2004060892A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a novel condensed N-containing heterocyclic compound, and more particularly, to a condensed N-containing heterocyclic compound having Aggrecanase-damaging activity or MMP-13 inhibitory activity or a medicament thereof.
  • the present invention relates to a pharmaceutically acceptable salt, a pharmaceutical composition containing the salt and a pharmaceutical use thereof.
  • Aggrecan is the major proteoglycin in cartilage, and its degradation by its proteases is a chronic joint! It is one of the early signs of joint disease involving articular cartilage destruction such as osteoarthritis and osteoarthritis. This degradation process, which leads to cartilage destruction, begins with the loss of aggrecan on the cartilage surface, followed by the degradation of type I collagen fibers.
  • the enzymes involved in the degradation of this aggrecan include MMPS (Matrix metalloproteinases), which cleaves A sn 341-P he 342, and aglycanase, which cleaves Glu 373-A la 374. Are both sold, and both are metalloproteases that have sub- ⁇ mainly in the catalytic activity.
  • AD AMT S Disintegrin and Metaloproteinase with Tnrombosponain. Motifs.
  • AD AMT S has been identified from 1 to 13
  • AD AMT S 4,5 correspond to aggrecanases 1 and 12.
  • MMPs were thought to be the center of cartilage destruction, but studies have shown that aggrecanase fragments found in joints of patients with osteoarthritis (OA) are markedly cleaved by aggrecanase. Aggrecanase is reported to be an important malignant factor in pathological conditions.
  • Conservative therapies include weight loss to reduce risk factors, exercise therapy, physical therapy, pharmacotherapy (administration of anti-inflammatory drugs), and heat.
  • pharmacotherapy administration of anti-inflammatory drugs
  • heat In the course of these therapies, it is common practice to inject hyaluronic acid into the joints to smooth the joints.
  • conservative treatment such as pharmacotherapy or physical therapy, does not help, surgical treatment will be required.
  • the joints are highly deformed, If the pain is severe, joint arthroplasty, such as implantation of a prosthetic joint, will eventually be performed. The prosthesis only lasts for about 15 to 20 years, after which the patient's quality of life (QOL) deteriorates.
  • QOL quality of life
  • the compound of the present invention has improved absorptivity and has strong agglase inhibitory activity. In addition, it has no inhibitory effect on MMP-1 but also has an inhibitory effect on aggrecanase as well as a selective inhibitory effect on other MMPs involved in joint destruction such as MMP-13, causing side effects. It is expected that the progression of arthropathy will be suppressed without performing.
  • gliomas express aggrecanase
  • aggrecanase is involved in tumor cell metastasis and tissue invasion, similar to MMPs.
  • the compounds of the present invention which have both aggrecanase and MMP inhibitory effects, are expected to be more effective anticancer agents.
  • MMPs control the breakdown of bone matrix and play an important role in bone resorption.
  • lung structure rupture and remodeling Proteases play an important role in the process, and MMP, whose constituent is extracellular matrix (ECM), is thought to be an important factor. Therefore, it is considered that the compound of the present invention which also has an inhibitory action can be applied to bone resorption diseases and lung diseases involving MMP.
  • Japanese Patent Application Laid-Open No. 2002-284686 discloses a sulfonamide derivative having an MMP-13 inhibitory action and an aggrecanase inhibitory action.
  • the publication does not disclose any compound having a structure such as the compound of the present invention, nor does it mention any suggestion thereof.
  • Japanese Patent Application Laid-Open No. 2001-111506 discloses a general formula
  • R 1 and R 2 are independently selected from the group consisting of hydrogen, hydroxy, and methyl, and at least one of R 1 and R 2 is methyl
  • R 3 and R 4 are independently selected from the group consisting of hydrogen, hydroxy, and methyl; or R 3 and R 4 are combined to form a functional reporter group.
  • R 5 and R 6 are independently selected from the group consisting of hydrogen, halogen, cyano, methyl, and diethyl; provided that, when X is carbon, both R 7 and R 8 are hydrogen in, 1, R ⁇ R and R 4 at least one ⁇ ⁇ is hydroxy; X is case of R 5 is para one cog port carbon, at least one hydrogen of R 6, R ⁇ and R 4 None; when X is nitrogen, R 8 is absent and R 7 is hydrogen or a formula:
  • Ar 2 represents a 6-membered aromatic ring which may include 1 to 2 nitrogen atoms
  • D 1 represents one (CH 2 ) n-(n Is an integer of 1 to 3), an oxygen atom, a sulfur atom, one S (O) one, — S (O) 2 — or one NR 4 —
  • R 4 is a hydrogen atom, a C i -C 8 alkyl group or C , Represents a C 8 acyl group
  • D 2 represents one (CH) one or a nitrogen atom
  • R 2 and R 3 represent a hydrogen atom, a hydroxyl group, an alkyl group or the like
  • R 1 represents hydrogen It represents an atom or a methyl group
  • W is one S 0 2 - represents like
  • X is one substituted base may be benzene ring or an oxygen atom, a sulfur atom 1 Kowaka Sig contains 1-2 nitrogen atoms Which represents a 5- or 6-member
  • the publication does not disclose a compound having a structure such as the present compound, and does not disclose any suggestion thereof.
  • the compounds disclosed in the publication are used as inhibitors of solubilizing enzymes of heparin-binding epidermal growth factor-like growth factor. It is useful, and of course, there is no disclosure suggesting its usefulness as an aglicanase inhibitor, and no description suggesting this is found.
  • An object of the present invention is to prevent or treat rheumatoid arthritis, having an excellent inhibitory effect on aggrecanase or MMP-13, and preventing or treating osteoarthritis.
  • An object of the present invention is to provide a compound useful as an agent for preventing or treating the above diseases.
  • Another object of the present invention is to provide an aggrecanase inhibitor, an MMP-13 inhibitor, an agent for preventing or treating osteoarthritis, and an agent for preventing or treating rheumatoid arthritis.
  • the present inventors have conducted intensive studies to achieve the above object, and consequently found that the condensed N-containing heterocyclic compound represented by the following general formula (1) has an excellent inhibitory effect on aggrecanase or MMP-13 inhibition.
  • the present invention has been found to be effective as an aggrecanase inhibitor or an MMP-13 inhibitor, a prophylactic or therapeutic agent for osteoarthritis and a prophylactic or therapeutic agent for rheumatoid arthritis, and completed the present invention. . .
  • the present invention relates to the following compounds [1] to [38] and pharmaceutical uses thereof. That is, the present invention is as follows.
  • X is a single bond, an alkylene group, C 2 - 6 alkenyl - alkylene group, C 2 - 6 alkynylene group, — O—, one N (R 22 ) one, one S (O) r— , one CO—, -CON (R 22 ) —, one N (R 22 ) CO—, -SOgN (R 22 ) —, one N (R 22 ) S0 2 —, one N (R 22 ) CON (R 23 ) —, one N (R 22 ) S0 2 N (R 23 ) —, one OCON (R 22 ) one or — N (R 22 ) COO—
  • R 22 and R 23 are the same or different, a hydrogen atom, C _ 6 alkyl group, optionally substituted C 3 - 14 hydrocarbon ring group, optionally substituted fused be C 6 _ 14 hydrocarbons permanent ring A group, an optionally substituted heterocyclic group or an optionally substituted fused heterocyclic group,
  • r represents 0 or an integer of 1 to 2
  • a 1 is an optionally substituted C 3 _ 14 hydrocarbon ring group, an optionally substituted fused C 6 _ 14 hydrocarbon group, an optionally substituted Which represents a fused ring group).
  • R s and R 4 are each independently a hydrogen atom, an alkyl group, an alkoxy group, an amino group, an amino-de-group, optionally substituted C s - 14 hydrocarbon ring group, a condensed C 6 optionally substituted — 14 hydrocarbon ring group, optionally substituted heterocyclic group or optionally substituted condensed heterocyclic group, or! ⁇
  • R 5 is a carbonyl group or a carbon atom to which R 3 and R 4 are bonded to form a C 3 _ 7 cycloalkyl group or a heterocyclic group.
  • R 8 and R 9 are each independently:
  • (2) represents a C- 6 alkyl group
  • R 12 may be taken together with the carbon atom to which it is attached to form a carbonyl group.
  • C may be a C ⁇ hydrocarbon ring d_ 6 alkyl
  • R 26 and R 27 are each independently
  • (7) represents a fused heterocyclic group which may be substituted
  • R 28 and R 29 are each independently
  • (11) represents an optionally substituted fused heterocyclic monoalkyl group
  • R 8 , R 9 , R 10 , R U , R 12 , R 13 and R 17 are as defined above, R 6 represents a hydrogen atom or a CM alkyl group;
  • R 7 is (1) —OR 14 group (wherein R 14 represents a hydrogen atom or an alkyl group),
  • R 15 and R 16 each independently represent a hydrogen atom or a C 6 alkyl group.
  • A is 6 alkylene group, C 2 - 6 Aruke - alkylene group or a C 2 - shows a 6 Arukyuren group; ring B,
  • n 0, 1, 2, or 3
  • R 1 and R 2 are each independently
  • R 3 ⁇ Pi R 4 are each independently, if force represents a hydrogen atom or a C 1 ⁇ alkyl group>, C 3 become carbon atoms and over ⁇ R 3 and R 4 are bonded - 7 cycloalkyl Or when forming a heterocyclic group, R 5 is taken together with
  • R 8 and R 9 are each independently:
  • Or '(2) C -! 6 represents an alkyl group, or Yuireiconnection such together with the carbon atoms to carbo - may form a group,
  • R 12 is
  • R 13 is
  • (6) d_ shows a 6 alkoxy group) to form
  • R 6 represents a hydrogen atom or an alkyl group
  • R 1 and R 2 are each independently
  • (9) may be substituted 6:14 Ariru Cw alkoxy group.
  • R 3 and R 4 each independently represent a hydrogen atom or an alkyl group
  • R 5 is taken together with R 6
  • R 8 and R 9 are each independently:
  • R 1Q and R 11 are each independently
  • a reporter may also be formed.
  • R 12 is
  • R 6 represents a hydrogen atom or an alkyl group
  • R 21 represents a hydrogen atom
  • R 5 is joined with R 6
  • R 8 has the same meaning as in the above [1].
  • R 12 and R 17 have the same meanings as in the above [1]), or a fused N-containing heterocyclic compound or a prodrug thereof or a pharmaceutical thereof as described in the above [1] or C2] Acceptable salts.
  • R 8 and R 9 are as defined above [1].
  • R 7 is —OR 14 group (where R ′′ is as defined in the above [1]) or hydroxyamino group, [1] to [7]. Or a prodrug thereof, or a pharmaceutically acceptable salt thereof.
  • R 1 is — (CH 2 ) P -X- (CH 2 ) q — A 1 (where each symbol is as defined in the above [1]), and R 2 is a hydrogen atom A fused N-containing heterocyclic compound or a prodrug thereof according to any one of the above [1] to [10], or Their pharmaceutically acceptable salts.
  • An aggrecanase inhibitor comprising, as an active ingredient, the fused N-containing heterocyclic compound according to any one of the above [1] to [15], or a prodrug thereof, or a pharmaceutically acceptable salt thereof. Agent.
  • a method for treating osteoarthritis comprising, as an active ingredient, the fused N-containing heterocyclized compound according to any one of the above [1] to [15], a prodrug thereof, or a pharmaceutically acceptable salt thereof.
  • Prophylactic or therapeutic drugs comprising, as an active ingredient, the fused N-containing heterocyclized compound according to any one of the above [1] to [15], a prodrug thereof, or a pharmaceutically acceptable salt thereof.
  • [20] A method for treating rheumatoid arthritis, comprising as an active ingredient the condensed N-containing heterocyclic compound according to any one of the above [1] to [15], a prodrug thereof, or a pharmaceutically acceptable salt thereof.
  • Prophylactic or therapeutic agents comprising as an active ingredient the condensed N-containing heterocyclic compound according to any one of the above [1] to [15], a prodrug thereof, or a pharmaceutically acceptable salt thereof.
  • a prophylactic or therapeutic agent for osteoarthritis comprising as an active ingredient a compound having an aggrecanase inhibitory activity or a prodrug thereof, or a pharmaceutically acceptable salt thereof.
  • a prophylactic or therapeutic agent for osteoarthritis comprising as an active ingredient a compound having an MMP-13 inhibitory activity or a prodrug thereof, or a pharmaceutically acceptable salt thereof.
  • a prophylactic or therapeutic agent for chronic rheumatoid arthritis comprising as an active ingredient a compound having an aggrecanase inhibitory activity or a prodrug thereof, or a pharmaceutically acceptable salt thereof.
  • An agent for preventing or treating rheumatoid arthritis comprising as an active ingredient a compound having an MMP-13 inhibitory activity or a prodrug thereof, or a pharmaceutically acceptable salt thereof. : '
  • a method comprising administering the fused N-containing heterocyclic compound according to any one of the above [1] to [15], a prodrug thereof, or a pharmaceutically acceptable salt thereof to a mammal.
  • a method for preventing or treating osteoarthritis which comprises administering a compound having an aggrecanase inhibitory activity, a prodrug thereof, or a pharmaceutically acceptable salt thereof to a mammal.
  • a method for preventing or treating osteoarthritis which comprises administering a compound having an MP-13 inhibitory action, a prodrug thereof, or a pharmaceutically acceptable salt thereof to a mammal.
  • a method for preventing or treating rheumatoid arthritis which comprises administering a compound having an aglicanase inhibitory activity, a prodrug thereof, or a pharmaceutically acceptable salt thereof to a mammal.
  • administering comprising administering the compound to a mammal.
  • single bond means a direct connection.
  • (CH 2) p - (CH 2) q - means that it is a 1.
  • halogen atom is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, and is preferably a fluorine atom or a chlorine atom.
  • R ⁇ R 2 is a fluorine atom.
  • alkyl group refers to a linear or branched alkyl group having 1 to 10 carbon atoms. Represents specifically, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, 1 —Ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, ⁇ ⁇ "ethylbutyl, heptyl, octyl, Examples thereof include a nor group and a decyl group.
  • R 9 is preferably a methyl group, a butyl group, a tert-butyl group, a pentyl group, a hexyl group, or a heptyl group.
  • Alkyl group means a linear or branched alkyl group having 1 to ⁇ carbon atoms, and specifically, a methyle group, a butyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group Group, tert-butynole group, pentyl group, isopentyl group, neopentyl group, tert-pentyl group, 1-ethylpropyl group, hexyl group and the like. It is preferably a straight-chain or branched-chain alkyl group having 1 to 0.4 carbon atoms.
  • R] RR 3 , RR 6 , 10 R ", R 12 , R 13 , R 14 , R 1S , R 16 are preferably a methyl group, and R 8 is preferably a methyl group, a butyl group; 17 is preferably a methyl group or an ethyl group.
  • halo C M alkyl group is a group in which the above-defined “dialkyl group” is substituted with the above-defined “halogen atom”, specifically, a fluoromethyl group, a difluoromethyl group, and a trifluoromethyl group.
  • halogen atom specifically, a fluoromethyl group, a difluoromethyl group, and a trifluoromethyl group. Examples include a methyl group, a bromomethyl group, a chloromethyl group, a 1,2-dichloromethyl group, a 2,2-dichloromethyl group, a 2,2,2-trifluoroethyl group, a pentafluoroethyl group, and the like.
  • the alkyl moiety is a halo C1 ⁇ alkyl group, which is a linear or branched alkyl group having 1 to 4 carbon atoms, more preferably a trifluoromethyl group or a pentafluoroethyl group. .
  • alkylene group represents a linear or branched alkylene group having 1 to 6 carbon atoms, and examples thereof include a methylene group, an ethylene group, a trimethylene group, a tetramethylene group, a pentamethylene group, and a hexamethylene group. It is preferably a straight-chain or branched-chain alkylene group having 1 to 4 carbon atoms, particularly preferably a methylene group or a styrene group. 7
  • A is preferably an ethylene group.
  • the - "C 2 6 alkenylene group", the “. 6 alkylene group” of the “C 2 _ 6 alkylene group” any linear ⁇ having a double bond in position of the partial skill chain number of 2 to 6 carbon atoms Alke is a diene group.
  • the position and number of the double bond are not particularly limited. Specific examples include an ethylene group, a probene group, a pterene group, a pentylene group, and a hexylene group. It is preferably a climbing or branched-chain alkenylene group having 4 to 4 carbon atoms, and particularly preferably an ethenylene group.
  • A it is preferably ethenylene block.
  • the "C 2 - - 6 alkylene group”, the above! It is a straight-chain or branched-chain alkynylene group having 2 to 6 carbon atoms having a triple bond at any position of the “C 2 -6 alkylene group” of the “ ⁇ alkylene group”.
  • the position and number of triple bonds are not particularly limited. It is preferably a straight-chain or branched-chain alkylene group having 2 to 4 carbon atoms, and particularly preferably an ethylene-group.
  • A is preferably an ethynylene group.
  • Die 6 alkoxy group ” refers to a linear or branched alkoxy group having 1 to 6 carbon atoms, specifically, methoxy, ethoxy, propoxy, isopropoxy, butoxy, butoxy, tert. — Butoxy group, pliers / reoquine group, hexyloxy group and the like.
  • the straight chain X having 1 to 4 carbon atoms is a branched chain alkoxy group.
  • RR 2 is main butoxy group, a butoxy group, good Mashiku in R 13 is methoxy.
  • halo CM alkoxy group is a group in which the above-defined “0, -6 alkoxy group” is substituted with the above-defined “halogen atom”, specifically, a fluoromethoxy group, a difluoromethoxy group, a trifluoro group.
  • halogen atom specifically, a fluoromethoxy group, a difluoromethoxy group, a trifluoro group.
  • the alkoxy moiety is a haloalkoxy group having 1 to 4 carbon atoms, which is a linear or branched a / recoxy group.
  • rc ⁇ 6 alkoxy 6 alkyl group means "C w alkyl group” as defined above. It is substituted with the above defined "C ⁇ 6 alkoxy group”. Specifically, methoxymethyl, ethoxymethyl, propoxymethyl, butoxymethyl, sec-butoxymethyl, tert-butoxymethyl, methoxytyl, ethoxytyl Tert-butoxyl, tert-butoxyethyl, methoxypropyl, ethoxypropyl, propoxypropyl, butoxypropyl, sec-butoxypropyl, and tert-butoxypropyl.
  • the direct linking moiety having 1 to 4 carbon atoms is a C w alkoxy C, _ 4 alkyl group which is a branched alkyl group.
  • the "C 3 _ 14 hydrocarbon ring group” is a cyclic saturated or unsaturated hydrocarbon group of 3 to 1 4 carbon atoms, for example, Ji 6 _ 14 Ariru groups, C 3 - 7 cycloalkyl groups, C 3 _ 10 Kuroarukeniru group.
  • C 6 _14 aryl group refers to an aromatic hydrocarbon group having 6 to 14 carbon atoms, specifically, a phenyl group, a nabutyl group, a biphenyl group (eg, 2-biphenyl) -Ryl group, 3-biphenylyl group, 4-biphenyl group), anthryl group and the like. Preferred are a phenyl group, a naphthyl group and a biphenyl group, and more preferred are a phenyl group.
  • R 1 , R 2 , R 8 and R 12 are preferably a phenyl group
  • R 9 is preferably a phenyl group or a naphthyl group
  • ring B is preferably a phenyl group or a biphenyl group. is there.
  • C 3 _ 7 cycloalkyl group a cycloalkyl group having 3 to 7 carbon atoms, specifically cyclopropyl group, Shikuropuchiru group, a cyclopentyl group, by key sill Moto ⁇ Pi consequent opening heptyl cycloheteroalkyl is there.
  • Preferred are cycloalkyl groups having 5 to 7 carbon atoms, and particularly preferred are cyclohexyl groups.
  • R 8 , R 12 and A 1 are preferably a cyclohexyl group, and R 9 is preferably a cyclopropynole group, a cyclopentinole group, a cyclopentynole group or a cyclohexynole group.
  • Cycloalkenyl group is a cycloalkenyl group having 3 to 10 carbon atoms, specifically, 2-cyclopentene-11-yl, 3-cyclopentene-11-yl, and 2-cyclopentene.
  • Hexene 1-yl, 3-cyclohexene 1-yl and the like Can be Preferred are cycloalkenyl groups having 5 to 7 carbon atoms, particularly preferred are 2-cyclohexene-1-yl and 3-cyclohexene-11-yl.
  • C 3 - 14 hydrocarbon ring - Okishi group walking, the defined as “hydrocarbon ring” portion - a Kamizu Yasushi ⁇ Okishi group having "C 3 14 hydrocarbon ring group", for example, C 6 — 14 aryloxy group, C 3 — 7- cycloalkyl: oxy group and. And a cycloalkenyl group.
  • the - "c 6 14 Ariruokishi group” is a Ariruokishi group having "c 6 _ 14 Ariru group” defined as the "Ariru” moiety, specifically a phenoxy group, naphthyl Chiruokishi group, Bifue - Riruokishi group ( For example, 2-biphenyloxy group, 3-biphenyloxy group, 4-biphenyloxy group), anthroxy group and the like.
  • Preferred are a phenoxy group and a biphenyloxy group, and more preferred is a phenoxy group.
  • RR 2 it is preferably a phenoxy group.
  • the - "C 6 14 Ariru 6 alkyl group”, the defined as “Ariru” portion - the “C 6 14 Ariru group” is a Ararukiru group having an alkyl group as defined above as “alkyl” moiety ", specifically Specific examples include a benzyl group, a phenethyl group, a 3-phenylpropyl group, and the like.
  • 6 _ 14 Ariru CH alkyl group And particularly preferably a benzyl group or a phenethyl group.
  • R 8 and R 9 are preferably a benzyl group and a phenethyl group, and R 12 is preferably a benzyl group.
  • Te Ariru alkoxy ⁇ J, Te Ariru part of the definition of "C 6 _ 14 Ariru group” is a Ararukiruokishi group having "alkoxycarbonyl group defined above as alkoxy J moiety", specifically Targets include a benzyloxy group, a phenethyloxy group, and a 3-phenylpropyloxy group.
  • Preferably Flip 6 - 14 are Ariru CH alkoxy group, 'particularly Ru preferably base Njiruokishi groups der.
  • a benzyloxy group is preferred. .
  • C 3 - a cycloalkyl C M ⁇ alkyl group more preferably C S - a 7 cycloalkyl CH group, preferably especially Ho, a cyclohexylmethyl group cyclohexylene.
  • R 9 is preferably a cyclohexylmethyl group.
  • “Fused C 6 _ 14 hydrocarbon ring group” means a saturated or unsaturated C 6 _ 14 hydrocarbon ring as defined above, wherein the C 3 _ 14 hydrocarbon rings are fused together (partially unsaturated and completely unsaturated). (Including saturation).
  • Preferable is a condensed ring of a furyl group and another ring, for example, an indul group, a fluoro group, a 9-oxo-fluoro group and the like.
  • R 9 is preferably an indanyl group, and ring B is preferably fluorenyl.
  • "Fused C 6 _ 14 hydrocarbon ring one Okishi group” walk, "fused C 6 before Symbol defined as f fused hydrocarbon ring” moiety.
  • “Fused C 6 _ 14 hydrocarbon ring-alkyl group” means “fused C e _ 14 carbon: main ring” as defined above as a “fused hydrocarbon ring” moiety, It is a condensed hydrocarbon ring alkyl group having a “C w alkyl group” as defined above as a part.
  • heterocyclic group refers to a saturated or unsaturated (partially partially containing, in addition to carbon atoms, at least one, preferably one heteroatom selected from a nitrogen atom, an oxygen atom and a sulfur atom. (Including unsaturated and fully unsaturated) monocyclic 5- to 7-membered heterocyclic rings.
  • “Saturated monocyclic heterocyclic group J includes pyrrolidyl group (eg, pyrrolidine-12-yl group, etc.), 2-oxo-1-pyrrolidinyl group, tetrahydrofuryl group (eg, tetrahydrofuran-1-yl 3 ⁇ 4 Etc.), tetrahydrochel group (eg, tetrahydrothiophene-2-yl group, etc.), imidazolidyl group (eg, imidazolidine-11-yl group, etc.), 2-oxo-imidazolidyl group, virazolizide -Nore group (eg, pyrazolidine-1-yl group, etc.), 1,3-dioxolar group, 1,3-oxathiolael group, oxazolidiel group (eg, oxazolidin-2-yl group, etc.), 2 —Oxooxazolidinyl group, thiazolidinyl group
  • a tetrahydropyrael group is used.
  • the unsaturated monocyclic heterocyclic group J includes a pyrrolyl group (eg, pyrroyl-l-yl group, etc.), a 1,5-dihydro-12-oxopyrrolyl group, a furyl group (eg, furan- 2-yl group, etc., chel group (eg, thiophene-2-yl group, etc.), imidazolyl group (eg, imidazole-1-yl group, etc.), 1,2-dihydro-2- Oxomidazolyl group, 1,3-dihydro-12-oxoimidazolyl group, pyrazolyl group (eg, pyrazole-11-yl group, etc.), oxazolyl group (eg, oxazole-2-yl group, etc.), 2-oxo Oxazolyl group, isoxazolyl group (eg, isoxazolyl 3-yl group, etc.), thiazolyl group (eg, thiazol
  • R ⁇ R 2 and R 9 a pyr group is preferable; and in Ring B, a phenyl group is preferable.
  • the “heterocyclic oxy group” is a “heterocyclic oxy group having the“ heterocyclic group ”as defined above as a heterocyclic moiety, specifically, a furyloxy group (eg, a furan-2-yloxy group, etc.), Chenyloxy group (eg, thiophene 1-2-yloxy group, etc.), pyrrolyloxy group (eg, pyrrole-11-yloxy group, etc.), oxazolyloxy group (eg, oxazolyl-2-yloxy group, etc.), isoxazolylo Xy group (eg, isooxazole-13-yloxy group, etc.), thiazolyloxy group (eg, thiazole-2-yloxy group, etc.), isothiazolyloxy group (eg, isothiazol-13-yloxy group, etc.), imidazolyloxy Xy group (eg, imidazole-11-yl
  • R 1 and R 2 are preferably a pyrinyl-4-yloxy group.
  • hetero ring one d_ 6 alkyl group as ⁇ heterocyclic "moieties:.. ⁇ has a" heterocyclic group "of his own definition,” alkyl "portion and to” Ji alkyl of said ⁇ A heterocyclic alkyl group having a “group”.
  • fused heterocyclic group refers to a saturated or unsaturated group containing at least one, preferably 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur atoms in addition to carbon atoms.
  • indolyl isoindolyl, 2,3-dihydroindolyl, 2,3-dihydroisoindolyl, 1,3-dihydro-2-oxoisoindolyl, 2,3-dihydro-indolyl 1-oxoisoindolyl, 1,3-dihydro-1,3-dioxoisoindolyl, benzimidazolyl, indazolyl, 4,5,6,7-tetrahydroindazolyl, benzotria Zolyl group, benzothiazolyl group, benzisothiazolyl group, 4,5,6,7-tetrahydrobenzoisothiazolyl group, 2-oxobenzothiazolyl group, benzothiophenol group, dibenzothiophenyl group, 4, 5, 6, 7-tetrahydrobenzothiophenol, benzofuranyl, dibenzofuranyl, isobenzo
  • a 1 is preferably a 1,3-benzodioxolyl group.
  • condensed heterocyclic monoalkyl group means "condensed heterocyclic ring j having a" condensed heterocyclic group "as defined above, and" alkyl “as a” CB alkyl group "as defined above. Is a fused heterocyclic alkyl group having
  • the “condensed hetero ring—C M alkoxy group” has the “condensed hetero ring group” as defined above as the “condensed hetero ring” portion, and the “c alkoxy group” as defined above as the “alkoxy” portion. Having a fused heterocyclic alkoxy group. For example, a 1,3-benzodioxolylmethoxy group and the like can be mentioned.
  • the “ring group” (including a group containing them as a part) may be substituted with 1 to 5 (preferably 1 to 3) substituents selected from the following groups. 2003/017067
  • halogen atom as the substituent of the group which may be substituted includes the “halogen atom” as defined above, and is preferably a fluorine atom or a chlorine atom.
  • the above alkyl group is a substituent of the group which may be substituted.
  • straight-chain or branched-chain alkyl groups specifically, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group and tert-butyl group. Represents a methyl group, an isopropyl group and a tert-butyl group.
  • the ⁇ halo CH alkyl group '' which is a substituent of the group which may be substituted is a haloalkyl group in which a linear or branched alkyl group having 1 to 4 carbon atoms is substituted with a ⁇ halogen atom '' as defined above, Specifically, fluoromethyl, difluoromethy / re, Trifluoromethyl group, bromomethyl group, chloromethyl group, 1,2-dichloroethyl group, 2,2-dichloroethyl group, 2,2,2-trifluoromethyl group, pentafluoroethyl, etc. are preferably used.
  • the ⁇ C w alkoxy group '' which is a substituent of the group which may be substituted is a straight-chain or branched-chain alkoxy group having 1 to 4 carbon atoms, specifically, methoxy group, ethoxy group, propoxy group.
  • alkylamino group which is a substituent of the group which may be substituted is an amino group mono-substituted by a linear or branched alkyl group having 1 to 6 carbon atoms, specifically, a methylamino group , Ethylamino, propylamino, butylamino, isoptylamino, sec-butylamino /, tert-butylamino, pentylamino, isopentylamino, neopentylamino, tert-pentylamino, 1-ethyl Examples thereof include a propylamino group and a hexylamino group, and an alkylamino group is preferable.
  • the “di (C w) alkynoleamino group” which is a substituent of the group which may be substituted is an amino group disubstituted with a linear or branched alkyl group having 1 to 6 carbon atoms, Specific examples include a dimethylamino group, a dimethylamino group, a dipropylamino group, a dibutylamino group, a dipentylamino group, a dihexylamino group, and the like, and preferably a di (C- 4 ) alkylamino group.
  • C 2 - - 7 alkoxy force Lupo Le group Ri Karuponiru groups der substituted with straight or branched chain alkoxy group having 1 to 6 carbon atoms Specifically, methoxycarbyl group, ethoxycarbol group, propoxycarbol group, isopropoxycarbol group, butoxycarbyl group, isoptoxycarbonyl group, tert-butoxycarboyl group, .
  • R 1 is preferably one is a hydroxyl group, a halogen atom (e.g., bromine atom), one 6 alkyl group (e.g., methyl group), e alkoxy group (e.g., main butoxy. Butoxy Group) or — (CH 2 ) P —X— (CH 2 ) Q —A 1 (wherein each symbol is as defined above), and the other is a hydrogen atom or a halogen atom (preferably a fluorine atom). And more preferably one is one (CH A ) P to X— (CH 2 ) Q —A 1 and the other is a hydrogen atom.
  • a halogen atom e.g., bromine atom
  • one 6 alkyl group e.g., methyl group
  • e alkoxy group e.g., main butoxy. Butoxy Group
  • — (CH 2 ) P —X— (CH 2 ) Q —A 1 wherein each symbol is as defined above
  • X is preferably a single bond or 1 O—.
  • C 3 _ 7 cycloalkyl group e.g., cyclohexyl group.
  • halogen atom eg, chlorine atom, fluorine atom
  • alkyl groups eg, methyl, ethyl, isopropyl
  • Ariruokishi group e.g., phenoxy group
  • Heterocyclic oxy group that may be substituted eg, tomb of zeridyloxy
  • halogen atoms eg, chlorine atoms, fluorine atoms
  • haloalkyl groups eg, trifluoromethyl
  • the number of substituents is preferably 1 to 3.
  • (1) may be substituted with at least one halogen atom 0 6 - 14 Ariru group (Hue - / Les, 4 one black port Hue - Z les etc.);
  • aryloxy group for example, phenoxy, 2-chlorophenoxy, 4-chlorophenoxy, 2-phenylenophenoxy, 4-fluorophenoxy, 2,3-dichlorophenoxy 2,5— Dichlorophenoxy, 3,5-dichlorophenoxy, 3,4-dichloromouth phenoxy, 3,5-difluorophenoxy, 4-fluoro-2-methylphenoxy, 2-methinolephenoxy, 3-methyl ⁇ "Phenoxy, 4-methylphenoxy, 2-ethyl ⁇ / lephenoxy, 2,3-dimethylphenoxy, 3,5-dimethylphenoxy, 3-isopropyl- 15-methylphenoxy, 2-methoxyphenoxy, 4-methan Toxiphenoxy, 3-Methoxy 5-Methylphenoxy, 2-Trifluor Oral
  • Ariru alkyl group e.g., benzyl, Fuenechi Le etc.>;
  • halogen atom Shiano group, - A key group, halo C _ 4 alkyl Moto ⁇ Pi CH ⁇ alkoxy may be substituted with 1 to 3 m substituents ho selected from the group consisting of group C 6 _
  • C 6 - 14 Ariruokishi alkyl group e.g., Fuenokishime ethyl group, etc.
  • an optionally substituted heterocyclic oxy group eg, pyridine-1-yloxy and the like
  • a condensed heterocyclic alkoxy group which may be substituted with at least one halogen atom (eg, 6-chlorobenzo [1,3] dioxol-15-ylmethoxy, etc.);
  • R 3 and R 4 are each preferably a hydrogen atom or an alkyl group (e.g., methylation) are either, connexion C 3 _ 7 cycloalkyl group (e.g. a together with the carbon atoms to which they are attached cyclo propyl group, Forms a cyclobutyl group, a cyclohexyl group) or a heterocyclic group (eg, a tetrahydrovinyl group). More preferably, each is a hydrogen atom.
  • the group formed by R 5 together with R 6 is preferably
  • R 8 , R, R 12 and R ′′ are as defined above.
  • Group 3 ⁇ Pi 1 4 forms together with R 5 is preferably
  • R 6 is preferably a hydrogen atom.
  • R 7 is preferably a hydroxyl group or a hydroxyamino group.
  • R 8 is preferably a hydrogen atom or an alkyl group (eg, a methyl group, a butyl group), and more preferably a hydrogen atom.
  • R 9 is preferably
  • Alkyl groups eg, methyl, butyl, tert-butyl, pentyl, hexyl, heptyl
  • C 3 - 7 cycloalkyl e.g., cyclopropyl, Shikuropu ethyl group, cyclopentyl grave, cyclohexyl group
  • C 3 - 7 cycloalkyl e.g., cyclopropyl, Shikuropu ethyl group, cyclopentyl grave, cyclohexyl group
  • C 3 _ cycloalkylalkyl group eg, cyclohexylmethyl group
  • halogen atoms eg, chlorine atoms, fluorine atoms
  • C- 4 alkyl group eg, methyl group, ethyl group, tert-butyl group
  • halo CH alkyl group eg, U-fluoromethyl group
  • the number of substituents is preferably 1 to 3.
  • C- 10 alkyl group eg, methyl, butyl, tert-butyl, 3-pentyl, 2
  • halogen atom C i-4 alkyl group, halo CH alkyl optionally substituted with a group and 1 or 2 substituents selected from the group consisting of alkoxy ⁇ 6 _ 14 Ariru group (eg, Fueyu / Les , 2-Funore Lofenore, 3-Funole Lofenore, 4-Fenole Lofenore, 3-Black Fennole, 4-Black Feninole, 2,5-Dicloth Fenore, 3, 5-Dichlorophenol, 2-chlorophenol, 3-chlorophenol, 25-difluorophenyl, 2-methylphenyl, 3-methylphenol, 2-ethylphenyl, 4-tert-butylphenol 2,5-Dimethynolephenyl, 3,5-Dimethylphenol, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 5-fluoro-2-met
  • (4) may be expired substituted C 3 - 7 cycloalkyl tomb (e.g., cyclopropyl, Shikuropuchi Le, cyclohexyl and the like cyclopentyl, cyclohexylene);
  • C 3 - 7 cycloalkyl tomb e.g., cyclopropyl, Shikuropuchi Le, cyclohexyl and the like cyclopentyl, cyclohexylene
  • C 3 _ 7 cycloalkyl group e.g., cyclopropyl base cyclohexyl methyl and the like
  • a heterocyclic group which may be substituted with at least one halogen atom (eg, pyridin-1-yl, 3-cyclopyridine-12: -yl, etc.);
  • Condensed heterocyclic groups which may be substituted (eg, quinolin-12-yl, etc.).
  • R 1 () and R 11 preferably forms a connexion Karuboeru groups together with the carbon atom bonded.
  • R 12 is preferably optionally substituted 0 6 - is a 6 alkyl group (e.g., benzyl group) - 14 Ariru group (e.g., Hue - Le group), which may be substitution C 6 - 14 Ariru.
  • 6 alkyl group e.g., benzyl group
  • Ariru group e.g., Hue - Le group
  • R 13 is preferably an alkyl group (eg, a methyl group) or an alkoxy group (eg, a methoxy group).
  • R 14 is preferably a hydrogen atom.
  • R 15 and R 16 are each preferably a hydrogen atom.
  • R 17 is preferably an alkyl group (eg, methyl, ethyl, etc.).
  • R 21 is preferably a hydrogen atom.
  • A is preferably C - a 6 alkylene group (e.g., ethylene group)!.
  • Ring B is preferably a C 6 - 14 Ariru group (e.g., Hue - Le group), condensed C 6 - 14 hydrocarbons ⁇ (eg, Furuoreniru group) or a Hajime Tamaki (e.g., thienyl group ).
  • the substitution position is preferably the 3-position and the 4-position, particularly preferably the 4-position.
  • the substitution position is preferably the 7-position.
  • the substitution position is preferably the 5-position.
  • n is preferably 0 or 2, and more preferably 0.
  • the “pharmaceutically acceptable salt” may be any salt as long as it forms a nontoxic salt with the compound represented by the above general formula (1), for example, hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid Or inorganic acids such as oxalic acid, malonic acid, citric acid, fumaric acid, lactic acid, lingoic acid, succinic acid, tartaric acid, acetic acid, trifluoroacetic acid, gluconic acid, ascorbic acid, methylsulfonic acid, benzylsulfonic acid, etc.
  • hydrochloric acid sulfuric acid, phosphoric acid, hydrobromic acid
  • inorganic acids such as oxalic acid, malonic acid, citric acid, fumaric acid, lactic acid, lingoic acid, succinic acid, tartaric acid, acetic acid, trifluoroacetic acid, gluconic acid, ascorbic acid, methylsulfonic acid, benzylsulf
  • inorganic bases such as sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, ammonium hydroxide, etc .; or methylamine, getylamine, triethylamine, triethanolamine, ethylenediamine, tris (Hydroxymethyl) methylamine, guanidine, choline, cinchonine, N-methyl-D-glucamine, etc.
  • Machine base; or lysine, histidine, arginine can be obtained by Rukoto reacted with amino acids such Aranin.
  • a hydrate or a hydrate and a solvate of each compound are also included.
  • prodrugs and metabolites of the compound represented by the general formula (1) are also included.
  • prodrug refers to a derivative of a drug molecule that is chemically modified and has no physiological activity per se, but has a reconstituted effect on the original drug molecule in the body after administration.
  • the “prodrug” in the present invention has a group that can be chemically or metabolically degraded, and is a pharmaceutically active condensation by hydrolysis or solvolysis, or by decomposition under physiological conditions. It is a derivative of the N-containing heterocyclic compound (1).
  • -CO- alkyl For example, relative to the hydroxyl group of the compound, -CO- alkyl, - C 0 2 - alkyl, - CO NH- alkyl Le, -CO- Arukeniru, -C 0 2 - Arukeyuru, - CO NH- Aruke - le, - CO —Aryl, —C 0 2 —Aryl, —CONH—Aryl, —CO—Heterocycle—C 0 2 —Heterocycle, —CO NH—Heterocycle (the alkyl, alkaryl, aryl, Heterocycle halogen atom, an alkyl group, a hydroxyl group, an alkoxy group, a carboxy group, ⁇ amino group, amino acid residue, mono P0 3 H 2, one SO s H, One OP0 3 H 2, substituted Broken one OS0 3 H, etc.
  • H 2 H 2 , saccharides (eg, glucose), or other substituted prodrugs, etc .;
  • —CO—alkyl For the amino group of the compound, —CO—alkyl, one co 2 —alkyl, one CO—alkenyl, —co 2 —alkenyl, —CO ⁇ —aryl, —CO—aryl, one CO—heterocycle, — co 2 - heterocycle (wherein alkyl, alkenyl, Ariru, heterocycle, halogen atom, an alkyl group, a hydroxyl group, an alkoxy group, a carboxy group, amino group, amino acid residue, mono P0 3 H 2, one S0 3 H, one .
  • the OP0 3 H 2 may be substituted by one OS0 3 H, etc.) and one CO- polyethylene glycol residue, mono co 2 - Poryechi glycol residue, mono CO- polyethylene glycol monoalkyl ether residue, -C0 2 - polyethylene glycol monoalkyl ether residue, mono P0 3 H 2, sugars (such as glucose), or other known polymers such as a prodrug those they replaced; or
  • an alkoxy group, Ariruokishi group (said an alkoxy group, Ariruokishi group is a halogen atom, an alkyl group, a hydroxyl group, an alkoxy group, a carboxy group, an amino group, an amino acid residue, mono P0 3 H 2, one S0 3 H, one OP0 3 H 2, -. OS0 may be substituted with 3 H and the like) or polyethylene glycol residue, polyethylene Chi glycol monoalkyl ether groups, sugars (such as glucose), or for the other prodrugs Examples include those substituted by known polymers and the like.
  • prodrugs can be produced by a means known per se used in the art, for example, esterification, acylation, alkoxycarbonylation and the like.
  • a pharmaceutically acceptable carrier excipient, diluent, bulking agent, disintegrant, stabilizer, preservative, buffer, emulsifier, fragrance, Coloring agents, sweeteners, thickeners, flavoring agents, solubilizers, and other additives, specifically, water, vegetable oils, alcohols such as ethanol or benzyl alcohol, and polyethylene
  • carbohydrates such as lenglycol, glycerol triacetate, gelatin, lactose, starch, etc., magnesium stearate, talc, lanolin, petrolatum, etc.
  • Eye drops liquids, capsules, lozenges, aerosols, elixirs, suspensions, emulsions, syrups, etc., to be administered systemically or locally, orally
  • the dose of the compound of the present invention varies depending on the age, body weight, and symptoms: the disease to be treated, the administration method, and the like. However, it is generally within the range of 1 mg to 10 mg of Omg per day per adult. One to several doses are administered.
  • the compound (1) of the present invention is an ataricanase inhibitor, 3 ⁇ 4!?-13 (5 harmful agent, a preventive or therapeutic agent for osteoarthritis (OA), a preventive or therapeutic agent for rheumatoid arthritis (RA), Aglicanase or MMP for joint damage, reactive arthritis, cancer, asthma, allergic reaction, chronic emphysema, pulmonary fibrosis, acute respiratory distress syndrome (ARDS), lung infection, interstitial pneumonia, bone resorption disease, etc.
  • prevention includes, for example, both preventing recurrence of the disease and prevention of the occurrence of the disease.
  • the compound (1) of the present invention can be co-administered to a mammal together with another therapeutic agent for osteoarthritis for the purpose of preventing or treating osteoarthritis.
  • the compound (1) of the present invention can be co-administered to a mammal together with another therapeutic agent for rheumatoid arthritis for the purpose of preventing or treating rheumatoid arthritis.
  • the compound of the present invention may be administered simultaneously with other drugs for treating osteoarthritis or other drugs for treating rheumatoid arthritis (hereinafter referred to as concomitant drugs), or may be administered at intervals of time. Good.
  • concomitant drugs drugs for treating osteoarthritis or other drugs for treating rheumatoid arthritis
  • it can be administered as a pharmaceutical composition containing the compound of the present invention and a concomitant drug.
  • the pharmaceutical composition containing the compound of the present invention and the pharmaceutical composition containing the concomitant drug may be separately administered.
  • the route of administration of each pharmaceutical composition may be the same or different.
  • the compounds of the invention When administered in combination, the compounds of the invention may range from lmg to 100 mg at a time.
  • the dosage may be administered once to several times a day, or may be administered in a smaller dosage.
  • Concomitant medications may be administered at normal dosages where they can be used for the prevention or treatment of osteoarthritis, or for the prevention or treatment of chronic rheumatoid arthritis, or at lower doses. r is also good.
  • a compound having an inhibitory activity on adalicanase or an inhibitory activity on MMP-13 such as the compound (1) of the present invention or a prodrug thereof, or a pharmaceutically acceptable salt thereof, may be used for osteoarthritis, rheumatoid arthritis, etc.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound (1) and a pharmaceutically acceptable carrier, and the g drug composition, which can be used for the prevention or treatment of osteoarthritis or rheumatoid arthritis.
  • a commercial package containing a description of the pharmaceutical composition stating that it should be used.
  • the functional group other than the site may be protected beforehand as necessary, and may be deprotected at an appropriate stage.
  • reaction may be carried out by a usual method, and the isolation and purification may be carried out by appropriately selecting or combining conventional methods such as crystallization, recrystallization, column chromatography, and preparative HPLC. Just do it.
  • This production process is a process for preparing a compound of the following cases become R s and R 6 Gar cord (1).
  • Examples of the base used in the reaction include alkali metal hydrides such as sodium hydride and potassium hydride; alkali metal alkoxides such as potassium tert-butoxide; alkali metal amides such as lithium diisopropylamide; sodium carbonate potassium carbonate Alkali metal carbonates such as sodium hydrogen carbonate, potassium hydrogen carbonate, etc .; Alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, hydroxylating lime; Alkali metal carboxylate such as sodium acetate, acetic acid rim; phosphoric acid Alkali metal phosphates such as sodium potassium phosphate; organic bases such as triethylamine, pyridine and N-methylmorpholine; and sodium methoxide is preferred.
  • alkali metal hydrides such as sodium hydride and potassium hydride
  • alkali metal alkoxides such as potassium tert-butoxide
  • alkali metal amides such as lithium diisopropylamide
  • solvent examples include ether solvents such as getyl ether, tetrahydrofuran (THF), dioxane, 1,2-dimethoxyethane, and diglyme; hydrocarbon solvents such as benzene, toluene, hexane, and xylene; and dichloromethane.
  • ether solvents such as getyl ether, tetrahydrofuran (THF), dioxane, 1,2-dimethoxyethane, and diglyme
  • hydrocarbon solvents such as benzene, toluene, hexane, and xylene
  • dichloromethane examples of the solvent include ether solvents such as getyl ether, tetrahydrofuran (THF), dioxane, 1,2-dimethoxyethane, and diglyme
  • hydrocarbon solvents such as benzene, toluene, hexane, and xylene
  • dichloromethane
  • Halogen-based solvents such as chloromethane, carbon form, carbon tetrachloride, and 1,2-dichloroethane; alcohol-based solvents such as methanol, ethanol, ethanol, tert-butanol, etc .; ethyl acetate, acetic acid Estenole solvents such as methyl and butyl acetate; polar solvents such as acetone N, N-dimethylformamide and water; these can be used alone or in combination.
  • a preferred solvent in this reaction is methanol.
  • the reaction temperature is usually in at O e C to 6 0, preferably room temperature.
  • the reaction time is generally 1 hour to 48 hours, preferably 2 hours to 24 hours.
  • the compound represented by the general formula (4) By reacting the compound represented by the general formula (4) in a solvent in the presence of a reducing agent, the compound represented by the formula (5) can be obtained.
  • the solvent for example, Jechirue - Te, tetrahydrofuran (THF), Jiokisan, 1, 2 - dimethoxy ethane:, ⁇ E ether solvents such as glyme; benzene, toluene, hexane, hydrocarbons present containing solvents such as xylene Halogen-based solvents such as dichloromethane, chloroform, carbon tetrachloride, and 1,2-dichloroethane; alcohol-based solvents such as methanol, ethanol, isopropyl alcohol, and tert-butanol; N, N-dimethylformamide; Examples thereof include polar solvents such as dimethyl sulfoxide and water, and these can be used alone or in combination.
  • the preferred solvent in this reaction is water.
  • Examples of the reducing agent used in the reaction include sodium borohydride, lithium borohydride, lithium aluminum hydride, and the like.
  • a preferable reducing agent in this reaction is sodium borohydride.
  • the reaction temperature is usually from 30 ° C. to 50, preferably from 0 ° C. to room temperature.
  • the reaction time is usually 30 minutes to 24 hours, preferably 3 hours to 12 hours.
  • the solvent examples include ether solvents such as diethyl ether, tetrahydrofura (THF), dioxane, 1,2-dimethyloxetane, and diglyme; hydrocarbon solvents such as benzene, toluene, hexane, and xylene; dichloromethane, and chloroform.
  • Halogen solvents such as mouth form, carbon tetrachloride and 1,2-dichloroethane
  • alcohols such as methanol, ethanol, isopropyl alcohol and tert-butanol
  • Polar solvents such as acetone, N, N-dimethylformamide, dimethylsulfoxide, water and the like, and these can be used alone or in combination.
  • Preferred solvents in this reaction are tetrahi, drofuran.
  • the reaction temperature is usually from 130 ° C to 100 ⁇ , preferably from 0 to room temperature.
  • the reaction time is generally 1 hour to 24 hours, preferably 2 hours to 14 hours.
  • Solvents include, for example, ether solvents such as jeti-earth, tetrahydrofuran (THF), dioxane, 1,2-dimethoxy " ⁇ ene, and diglyzine; benzene, toluene, hexane, xylene and the like.
  • ether solvents such as jeti-earth, tetrahydrofuran (THF), dioxane, 1,2-dimethoxy " ⁇ ene, and diglyzine
  • benzene toluene, hexane, xylene and the like.
  • Hydrocarbon-based solvents such as dichloromethane, chloroform, carbon tetrachloride, and 1,2-dichloroethane; ester-based solvents such as ethyl acetate, methyl acetate, and butyl acetate; acetone, N, Examples thereof include polar solvents such as N-dimethylformamide and the like, which can be used alone or in combination
  • the preferred solvent in this reaction is dichloromethane.
  • the reaction temperature is usually 0 to 100 ° C, preferably room temperature.
  • the reaction time is generally 1 hour to 24 hours, preferably 2 hours to 12 hours.
  • the same target compound (8) can be obtained also by using methyldaryoxalate in place of 2-hydroxy-12-methoxyacetic acid.
  • the compound represented by (10) can be obtained.
  • the solvent examples include ether solvents such as getyl ether, tetrahydrofuran (THF), dioxane, 1,2-dimethoxyethane, and diglyme; hydrocarbon solvents such as benzene, toluene, hexane, and xylene; dichloromethane, Halogen solvents such as chloroform, carbon tetrachloride, and 1,2-dichloroethane; ester solvents such as ethyl acetate, methyl acetate, and butyl acetate; acetone, N, N-dimethyl Examples thereof include polar solvents such as formamide and dimethyl sulfoxide, and these can be used alone or in combination.
  • the preferred solvent in this reaction is dichloromethane or no solvent.
  • the reaction temperature is usually from 0 ° C to 100 ° C, preferably from room temperature to 40 ° C.
  • the reaction time is generally 1 hour to 2.0 hours, preferably 2 hours to 10 hours.
  • the base used in the reaction includes, for example, sodium metal hydroxide, metal hydride such as hydrogen hydride; alkali metal alkoxide such as potassium tert-butoxide; alkali metal amide such as lithium diisopropylamide; Alkali metal carbonates such as sodium, carbon dioxide, sodium bicarbonate and hydrogen carbonate; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; alkali metal carboxylate such as sodium acetate and acetate lime Alkali metal phosphates such as sodium phosphate and potassium phosphate; and organic bases such as triethylamine, pyridine and N-methylmorpholine. N-methylmorpholine is preferred.
  • Lewis acid examples include boron trifluoride, aluminum chloride, titanium tetrachloride and the like.
  • Solvents include, for example, edel solvents such as getyl ether, tetrahydrofuran (THF), dioxane, 1,2-dimethoxetane and diglyme; hydrocarbon solvents such as benzene, toluene, hexane and xylene; dichloromethane, chloroform Halogen solvents such as oral form, carbon tetrachloride, and 1,2-dichloroethane; ester solvents such as ethyl acetate, methyl acetate, and butyl acetate; polar solvents such as acetone and N, N-dimethylformamide; These can be used alone or in combination.
  • a preferred solvent in this reaction is tetrahydrofuran.
  • the reaction temperature is usually 0 ° C. to 60 ° C., preferably room temperature.
  • reaction time is generally 1 hour to 24 hours, preferably 2 hours to 10 hours.
  • the compound represented by the general formula (1.2) can be obtained by reacting the compound represented by the general formula (11) with a mesylation reagent in a solvent in the presence of a base.
  • Examples of the base used in the reaction include hydrogen hydride metal such as sodium hydride and hydrogen hydride; potassium te :; r: metal alkoxide such as r-t-poxide; lithium diisopropyl TMI; Alkali metal amides; sodium carbonate Alkali metal carbonates such as potassium carbonate, sodium bicarbonate, sodium bicarbonate; alkali metal carboxylate such as sodium acetate and potassium acetate; sodium phosphate, phosphoric acid such as potassium phosphate Metal salts; organic bases such as triethylamine, diisopropylethylamine, pyridine, N-methylmorpholine and the like, preferably diisopropylethylamine.
  • the solvent examples include ether solvents such as getyl ether, tetrahydrofuran (THF), dioxane, 1,2-dimethoxyethane, and diglyme; hydrocarbon solvents such as benzene, toluene, hexane, and xylene; and dichloromethane.
  • ether solvents such as getyl ether, tetrahydrofuran (THF), dioxane, 1,2-dimethoxyethane, and diglyme
  • hydrocarbon solvents such as benzene, toluene, hexane, and xylene
  • dichloromethane halogen-based solvents such as chloroform, carbon tetrachloride, and 1,2-dichloroethane
  • ester-based solvents such as ethyl acetate, methyl acetate, and butyl acetate
  • polar solvents such as acetone and N, N-dimethylformamide.
  • mesylation reagent used in the reaction examples include methanesulfonyl chloride, methanesulfonic anhydride and the like, and preferred is methanesulfonyl chloride. .
  • the reaction temperature is usually in at 0 ° C to 6 0, preferably room temperature ⁇
  • the reaction time is generally 1 hour to 24 hours, preferably 2 hours to 10 hours ( Steps 1-8).
  • the compound represented by the general formula (13) can be obtained by reacting the compound represented by the general formula (12) in a solvent in the presence of a base.
  • Examples of the base used in the reaction include alkali metal hydrides such as sodium hydride and hydrogenation hydride; alkali metal alkoxides such as potassium tert-butoxide.
  • Alkali metal amides such as lithium disopropyl amide
  • alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, and potassium hydrogen carbonate
  • carboxyl acids such as sodium acetate and acetic acid rim
  • Alkali metal phosphates such as sodium phosphate and potassium phosphate
  • tritylamine and diisoprophyl Organic bases such as leutylamine, lysine, N-methylmorpholine and the like are mentioned, and cesium carbonate is preferred.
  • the solvent examples include ether solvents such as gelate, tetrahydrofuran (THF), dioxane, 1,2-dimethoxytan and diglyme; hydrocarbon solvents such as benzene, toluene, hexane and xylene; dichloromethane, Halogen solvents such as chromatoform, carbon tetrachloride, and 1,2-dichloro: loethane; ester solvents such as ethyl acetate, methyl acetate, and butyl acetate; polar solvents such as acetone, N, N-dimethylformamide These can be used alone or in combination.
  • a preferred solvent in this reaction is dioxane.
  • the reaction temperature is usually 0 ° C. to 60 ° C., preferably room temperature.
  • the reaction time is usually 2 hours to 48 hours, preferably 10 hours to 24 hours.
  • the compound represented by the general formula (14) can be obtained by reacting the compound represented by the general formula (13) in a solvent in the presence of a base.
  • Examples of the base used in the reaction include alkali metal hydrides such as sodium hydride and hydrogenation hydride; alkali metal alkoxides such as potassium tert-butoxide; alkali metal amides such as lithium diisopropylamide; sodium carbonate; potassium carbonate; Alkali metal carbonates such as cesium carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; and sodium hydroxide is preferable.
  • alkali metal hydrides such as sodium hydride and hydrogenation hydride
  • alkali metal alkoxides such as potassium tert-butoxide
  • alkali metal amides such as lithium diisopropylamide
  • sodium carbonate potassium carbonate
  • Alkali metal carbonates such as cesium carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate
  • alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide
  • the solvent examples include ether solvents such as getyl ether, tetrahydrofuran (THF), dioxane, 1,2-dimethoxyethane and diglyme; hydrocarbon solvents such as benzene, toluene, hexane and xylene; dichloromethane, Black Halogen solvents such as mouth form, carbon tetrachloride and 1,2-dichloroethane; alcohol solvents such as methanol, ethanol, isopropyl alcohol and tert-butanol; polar solvents such as water are used. Can be used together.
  • Preferred solvents in this reaction are tedrahi, drofuran (THF), and methanol.
  • the reaction temperature is generally 0 to 60, preferably room temperature.
  • the reaction time is generally 1 hour to 24 hours, preferably 2 hours to 12 hours.
  • an alkylating reagent represented by the general formula (15) in a solvent in the presence of a base, a compound represented by the general formula (16) is obtained. be able to.
  • the solvent examples include ether solvents such as getyl-ter, tetrahydrofuran (THF), dioxane, 1,2-dimethoxyethane, and diglyme; hydrocarbon solvents such as benzene, toluene, hexane, and xylene; dichloromethane, Halogen solvents such as chloroform, carbon tetrachloride and 1,2-dichloroethane; ester solvents such as ethyl acetate, methyl acetate and butyl acetate; polar solvents such as acetone and N, N-dimethylformamide These can be used alone or in combination.
  • a preferred solvent in this reaction is N, N-dimethylformamide.
  • Bases include, for example, sodium hydride, alkali metal alkoxides such as potassium tert-butoxide, alkali metal amides such as lithium diisopropylamide; sodium carbonate, carbonated lithium, etc. And alkali metal carbonates such as cesium carbonate, sodium hydrogencarbonate and potassium hydrogencarbonate; and alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide, with potassium carbonate being preferred.
  • the reaction temperature is usually 0 ° C. to 60, preferably room temperature.
  • the reaction time is generally 1 hour to 24 hours, preferably 2 hours to 10 hours.
  • Examples of the base used in the reaction include alkali metal hydrides such as sodium hydride and potassium hydride; alkali metal alkoxides such as potassium tert-butoxide; alkali metal amides such as lithium diisopropylamide; sodium carbonate, carbon dioxide lime; Alkali metal carbonates such as cesium carbonate, sodium hydrogen carbonate, hydrogen carbonate and the like; and alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide, and the like, with sodium hydroxide being preferred.
  • alkali metal hydrides such as sodium hydride and potassium hydride
  • alkali metal alkoxides such as potassium tert-butoxide
  • alkali metal amides such as lithium diisopropylamide
  • sodium carbonate, carbon dioxide lime Alkali metal carbonates such as cesium carbonate, sodium hydrogen carbonate, hydrogen carbonate and the like
  • alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide
  • Solvents include, for example, ether solvents such as getyl ether, tedrahydrofuran (THF), dioxane, 1,2-dimethoxane, and dig] dimethyl; benzene, toluene, hexane, xylene, and the like. Hydrocarbon solvents; dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloro; halogen solvents such as mouth ethane; alcohol solvents such as methanol, ethanol, isopropyl alcohol, tert-butanol; water, etc. And these can be used alone or in combination. Preferred solvents in this reaction are tetrahydrofuran (THF) and methanol.
  • the reaction temperature is usually 0. C to 60 ° C, preferably room temperature.
  • the reaction time is generally 1 hour to 24 hours, preferably 2 hours to 12 hours.
  • the compound obtained in this reaction can be used in the next reaction without isolation.
  • Examples of the base used in the reaction include alkali metal carbonates such as sodium carbonate, potassium carbonate, sodium carbonate, sodium hydrogen carbonate, and sodium hydrogen carbonate; alkali metal carboxylate such as sodium acetate and potassium acetate; sodium phosphate; Metal phosphate metal such as potassium phosphate; organic bases such as triethylamine, diisopropylethylamine, pyridine, and N-methylmorpholine; and N-methylmorpholine is preferable.
  • alkali metal carbonates such as sodium carbonate, potassium carbonate, sodium carbonate, sodium hydrogen carbonate, and sodium hydrogen carbonate
  • alkali metal carboxylate such as sodium acetate and potassium acetate
  • sodium phosphate Metal phosphate metal such as potassium phosphate
  • organic bases such as triethylamine, diisopropylethylamine, pyridine, and N-methylmorpholine
  • N-methylmorpholine is preferable.
  • the solvent examples include ether solvents such as getyl ether, tetrahydrofuran (THF), dioxane, 1,2-dimethoxyethane, and diglyme; hydrocarbon solvents such as benzene, toluene, hexane, and xylene; dichloromethane, Halogen-based solvents such as chloroform, carbon tetrachloride, 1,2-dichloro, and mouth; esters such as ethyl acetate, methyl acetate, and butyl acetate; certain solvents; acetone, N, N-dimethylformamide; and acetonitrile, etc. Polar solvents and the like can be mentioned, and these can be used alone or in combination.
  • a preferred solvent in this reaction is tetrahydrofuran.
  • the condensing agent may be a condensing agent used in an ordinary peptide condensation method (for example, an acid chloride method, a mixed acid anhydride method, etc.), and among them, a combination of ethyl ethyl carbonate and N-methylmorpholine is preferable.
  • an ordinary peptide condensation method for example, an acid chloride method, a mixed acid anhydride method, etc.
  • a combination of ethyl ethyl carbonate and N-methylmorpholine is preferable.
  • hydroxyamine derivative used for the reaction examples include O- (trimethylsilyl) hydroxylamine.
  • the reaction temperature is usually 0 T to 100 ° C, preferably room temperature to 60.
  • the reaction time is usually from 1 hour to 24 hours, preferably from 2 hours to 2 hours.
  • RR 2 , R 8 , RA, B, and n are as defined above, and X is a halogen atom.
  • the compound represented by the general formula (19) can be obtained by reacting the compound represented by the general formula (18) with an acrylic acid derivative in a solvent in the presence of a base.
  • the base used in the reaction include alkali metal hydrides such as sodium hydride and hydrogenation hydride; alkali metal alkoxides such as potassium tert-butoxide; alkali metal amides such as lithium diisopropylamide; sodium carbonate potassium carbonate; Alkali metal carbonates such as sodium hydrogen and potassium hydrogen carbonate; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; alkali metal carboxylate such as sodium acetate and potassium acetate; sodium phosphate and potassium phosphate
  • Organic bases such as alkali metal phosphate; triethylamine, pyridine, N-methylmorpholine and the like are preferred, and preferably triethylamine.
  • the solvent examples include ether solvents such as getyl ether, tetrahydro 7 lan (THF), dioxane, 1,2-dimethoxyethane, and diglyme; hydrocarbon solvents such as benzene, toluene, hexane, and xylene; Halogen solvents such as dichloromethane, chloroform, carbon tetrachloride, and 1,2-dichloroethane; alcohol solvents such as methanol, ethanol, isopropyl alcohol, and tert-butanol; ester solvents such as ethyl acetate, methyl acetate, and butyl acetate Solvent: acetone. ⁇ , ⁇ ⁇ ⁇ ⁇ -dimethylformamide; polar solvents such as water, etc., which can be used alone or in combination. Preferred solvents in this reaction are methanol and ⁇ , ⁇ -dimethylformamide.
  • acrylic acid derivative used for the reaction examples include methyl acrylate.
  • the reaction temperature is usually from 130 ° C. to 100 ° C., preferably from 0 ° to room temperature.
  • the reaction time is usually 1 hour to 48 hours, preferably 2 hours to 24 hours. .
  • Compound (19) can be used in the next reaction without isolation.
  • the solvent examples include ether solvents such as getyl-tere, tetrahydrofuran (THF), dioxane, 1,2-dimethyloxetane and diglyme; hydrocarbon solvents such as benzene, toluene, hexane and xylene; dichloromethane, Halogen solvents such as chloroform, carbon tetrachloride, and 1,2-dichlorotan; alcohol solvents such as methanol, ethanol, isopropyl alcohol, and tert-butanol; ethyl acetate, methyl acetate, and butyl acetate And other polar solvents such as acetone, N, N-dimethylformamide, dimethylsulfoxide and water. These solvents can be used alone or in combination.
  • a preferred solvent in this reaction is a mixed solvent of dioxane and water.
  • Examples of the base used in the reaction include alkali metal carbonates such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, and potassium hydrogen carbonate; and alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, and hydroxylated lime.
  • Metal salts of carboxylic acids such as sodium acetate and potassium acetate; alkali metal phosphates such as sodium phosphate and potassium phosphate; and organic bases such as triethylamine, pyridine and N-methylmorpholine.
  • the reaction temperature is usually from 130 ° C to 60 ° C, preferably from 0 ° C to room temperature.
  • the reaction time is generally 5 minutes to 60 hours, preferably 10 hours to 50 hours.
  • the compound represented by the general formula (21) can be obtained by reacting the compound represented by the general formula (20) in a solvent in the presence of a base. In this reaction, the following positional isomers are obtained.
  • solvent used in the reaction examples include: diethyl ether, tetrahydrofuran
  • Ether solvents such as (THF), dioxane, 1,2-metho-shetan and diglyme; hydrocarbon solvents such as benzene, toluene, hexane and xylene; dichloromethane, chloroform, tetrachloride; ,: Halogen solvents such as 2-dichloroethane; alcohol solvents such as methanol, ethanol, isopropyl alcohol and tert-butanol; polar solvents such as N, N-dimethylformamide, dimethylsulfoxide and the like. Or they can be used in combination.
  • Preferred solvents in this reaction are tetrahydrofuran and methanol.
  • the base examples include alkali metal hydrides such as sodium hydride and lithium hydride; alkali metal alkoxides such as potassium tert-butoxide; alkali metal amides such as lithium diisopropylamide; sodium carbonate; Alkali metal carbonates such as sodium bicarbonate and hydrogen bicarbonate; Alkali metal carboxylate such as sodium acetate and acetate lithium; Alkali metal phosphates such as sodium phosphate and potassium phosphate; Triethylamine; Organic bases such as pyridine and m-methylmorpholine are exemplified, and sodium methoxide is preferred.
  • alkali metal hydrides such as sodium hydride and lithium hydride
  • alkali metal alkoxides such as potassium tert-butoxide
  • alkali metal amides such as lithium diisopropylamide
  • sodium carbonate Alkali metal carbonates such as sodium bicarbonate and hydrogen bicarbonate
  • Alkali metal carboxylate such as sodium
  • the reaction temperature is usually from 130 ° C. to 100 ° C., preferably from 0 ° C. to 60 ° C.
  • the reaction time is generally 1 hour to 24 hours, preferably 2 hours to 12 hours, step 2-4
  • a compound represented by the general formula (23) By reacting the compound represented by the general formula (21) with a hydrazine compound represented by the general formula (22) in a solvent, a compound represented by the general formula (23) can be obtained.
  • the solvent examples include ether solvents such as getyl ether, tetrahydrofuran (THF), dioxane, 1,2-dimethoxyethane and diglyme; hydrocarbon solvents such as benzene, toluene, hexane and xylene; dichloromethane, Halogen solvents such as chloroform, carbon tetrachloride, and 1,2-dichloroethane; methanol
  • ether solvents such as getyl ether, tetrahydrofuran (THF), dioxane, 1,2-dimethoxyethane and diglyme
  • hydrocarbon solvents such as benzene, toluene, hexane and xylene
  • dichloromethane Halogen solvents such as chloroform, carbon tetrachloride, and 1,2-dichloroethane
  • methanol examples include phenolic solvents such as phenol, ethanol, isopropyl alcohol, ter
  • the reaction temperature is usually from 80 ° C. to 150, preferably from 100 ⁇ to 120.
  • the reaction time is generally from 10 hours to 48 hours, preferably from 12 hours to 24 hours.
  • the compound .. (22) obtained in this reaction can be used in the next reaction without isolation.
  • the compound represented by the general formula (24) can be obtained by reacting the compound represented by the general formula (23) with a carboxylic acid activator or an acid erosion medium in a solvent.
  • the solvent examples include ether solvents such as getyl ether, tetrahydrofuran (THF), dioxane, 1,2-dimethoxyethane and diglyme; hydrocarbon solvents such as benzene, toluene, hexane and xylene; dichloromethane, Halogen solvents such as chloroform, carbon tetrachloride, and 1,2-dichloroethane; alcohol solvents such as methanol, ethanol, isopropyl alcohol, and tert-butanol; esters such as ethyl acetate, methyl acetate, and butyl acetate And the like. These can be used alone or in combination.
  • a preferred solvent in this reaction is methanol.
  • carboxylic acid activator examples include thiol chloride.
  • Examples of the acid catalyst include sulfuric acid and p-toluenesulfonic acid.
  • the reaction temperature is usually from 80 ° C to 150 ° C, preferably from 100 ° C to 120 ° C.
  • the reaction time is generally from 10 hours to 48 hours, preferably from 12 hours to 24 hours.
  • the compound (24) obtained in this reaction can be used in the next reaction without isolation. Can be.
  • bases used in the reaction include: ⁇ , alkali metal hydrides such as sodium hydride and potassium hydride; alkali metal alkoxides such as potassium hydride and the like; sodium carbonate, sodium carbonate, sodium hydrogen carbonate, hydrogen carbonate and the like.
  • Alkali metal carbonates such as sodium chloride; sodium carboxylate metals such as sodium acetate and potassium acetate; aluminum phosphate metals such as sodium phosphate and potassium phosphate; triethylamine, pyridine, N-methylmorpholine And the like. Preferred is triethylamine.
  • the solvent examples include ether solvents such as getyl ether, tetrahydrofuran (THF), dioxane, 1,2-dimethoxyethane, and diglyme; hydrocarbon solvents such as benzene, toluene, hexane, and xylene; dichloromethane, Halogen-based solvents such as chloroform, carbon tetrachloride, and 1,2-dichloroethane; alcohol-based solvents such as methanol, ethanol, isopropyl alcohol, and tert-butanol; ester-based solvents such as ethyl acetate, methyl acetate, and butyl acetate Bright solvents; acetone N, N-dimethylformamide; dimethylsulfoxide; polar solvents such as water, etc., which can be used alone or in combination.
  • a preferred solvent in this reaction is a mixed solvent of dioxane and water.
  • the reaction temperature is usually from 130 ° C to 60 ° C, preferably from 0 ° C to room temperature.
  • the reaction time is generally 1 hour to 36 hours, preferably 2 hours to 24 hours ⁇ Step 2-7
  • the compound represented by the general formula (27) is obtained by reacting the compound represented by the general formula (25) with a compound represented by the general formula (26) in a solvent in the presence of a base.
  • the solvent examples include ether solvents such as getyl ether, tetrahydrofuran (THF), dioxane, 1,2-dimethoxyethane, and diglyme; Hydrocarbon solvents such as toluene, toluene, hexane, and xylene; halogen solvents such as dichloromethane, chloroform, carbon tetrachloride, and 1,2-dichloroethane; polyester solvents such as ethyl acetate, dimethyl, and butyl acetate. Polar solvents such as acetone, N.N-dimethylformamide, water and the like, and these can be used alone or in combination.
  • ether solvents such as getyl ether, tetrahydrofuran (THF), dioxane, 1,2-dimethoxyethane, and diglyme
  • Hydrocarbon solvents such as toluene, toluene, hexane, and xylene
  • the preferred solvent in this reaction is N, N-dimethylformamide.
  • the base for example, hydrogen: alkali metal hydrides such as tri, kum, potassium hydroxide and the like; alkali metal alkoxides such as potassium tert-butoxyne; alkali metals such as lithium methylene isopropylamide; Amides; alkali metal carbonates such as sodium carbonate, carbonic acid carbonate, cesium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate; and alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like. Preferably, it is potassium carbonate.
  • the reaction temperature is usually 0 ° C. to 60 ° C., preferably room temperature.
  • reaction time is generally 1 hour to 24 hours, preferably 2 hours to 10 hours.
  • the compound represented by the general formula (28) can be obtained by reacting the compound represented by the general formula (27) in a solvent in the presence of an acid.
  • the solvent examples include ether solvents such as getyl ether, tetrahydrofuran (THF), dioxane, 1,2-dimethoxetane and diglyme; hydrocarbon solvents such as benzene, toluene, hexane and xylene; dichloromethane, chloroform Halogen-based solvents such as form, carbon tetrachloride, and 1,2-dichloroethane; ester-based solvents such as ethyl acetate, methyl acetate, and butyl acetate; polar solvents such as acetone and N, N-dimethylformamide These can be used alone or in combination.
  • a preferred solvent in this reaction is dioxane.
  • Examples of the acid used in the reaction include inorganic acids such as hydrochloric acid, sulfuric acid, and nitric acid; and organic acids such as trifluoroacetic acid, trichloroacetic acid, acetic acid, methanesulfonic acid, and p-toluenesulfonic acid, and hydrochloric acid is preferable.
  • inorganic acids such as hydrochloric acid, sulfuric acid, and nitric acid
  • organic acids such as trifluoroacetic acid, trichloroacetic acid, acetic acid, methanesulfonic acid, and p-toluenesulfonic acid, and hydrochloric acid is preferable.
  • the reaction temperature is usually from 130 ° C. to 60 ° C., preferably from O 2 to room humidity.
  • the reaction time is generally 1 hour to 24 hours, preferably 2 hours to 12 hours.
  • the obtained compound (28) can be used in the next reaction without isolation.
  • the compound represented by the general formula (30) is obtained by reacting the compound represented by the general formula (2S) with the chemical corrosion represented by the general formula (29) in a solvent in the presence of a base to obtain the compound represented by the general formula (30) Can be.
  • Examples of the base used in the reaction include alkali metal hydrides such as sodium hydride and potassium hydride; sodium metal hydride, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, sodium borohydride and the like; Sodium, acetic acid, carboxylic acid such as lime; metal phosphate, such as sodium phosphate and potassium phosphate; organic bases, such as triethylamine, diisopropylethylamine, pyridine and N-methylmorpholine O, preferably with triethylamine
  • the solvent examples include ether solvents such as getyl ether, tetrahydrofuran (THF), dioxane, 1,2-dimethyloxetane, and diglyme; hydrocarbon solvents such as benzene, toluene, hexane, and xylene; dichloromethane, Halogen solvents such as chloroform, carbon tetrachloride and 1,2-dichloroethane; ester solvents such as ethyl acetate, methyl acetate and butyl acetate; polar solvents such as acetone and N, N-dimethylformamide These can be used alone or in combination.
  • a preferred solvent in this reaction is N, N-dimethylformamide.
  • Reaction temperature is usually -30. C to 60 ⁇ , preferably O to room temperature.
  • reaction time is usually 2 hours to 24 hours, preferably 4 hours to 12 hours.
  • the compound represented by the general formula (30) By reacting the compound represented by the general formula (30) in a solvent in the presence of a base, the compound represented by the general formula (31) can be obtained.
  • Examples of the base used for the reaction include alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like, and preferably lithium hydroxide.
  • the solvent examples include getyl ether, tetrahydrofuran (THF), Ether solvents such as dioxane, 1,2-dimethoxyethane and diglyme; hydrocarbon solvents such as benzene, toluene, hexane and xylene; dichloromethane, chloroform, 4: Hazardous charcoal, 1,2 zita P Halogen solvents such as octane, etc .; alcohol solvents such as methanol, ethanol, isopropyl alcohol, tert-butanol, etc .; polar solvents such as acetone, etc .: These may be used alone or in combination. Can be. Preferred solvents in this reaction are methanol and tetrahydrofuran.
  • the reaction temperature is usually 0 ° C. to 60 ° C., preferably room temperature.
  • the reaction time is generally 1 hour to 24 hours, preferably 2 hours to 12 hours.
  • the compound obtained in this reaction (3.3.1) can be used in the next reaction without separation.
  • Examples of the base used in the reaction include alkali metal hydrides such as sodium hydride and potassium hydride; alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, and potassium hydrogen carbonate; Alkali metal hydroxides such as lithium, sodium hydroxide, and hydroxylated aluminum; alkali metal carboxylate such as sodium acetate and potassium acetate; aluminum phosphate metal such as sodium phosphate and potassium phosphate Organic bases such as triethylamine, diisopropylethylamine, pyridine, N-methylmorpholine and the like, and preferably N-methylmorpholine.
  • alkali metal hydrides such as sodium hydride and potassium hydride
  • alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, and potassium hydrogen carbonate
  • Alkali metal hydroxides such as lithium, sodium hydroxide, and hydroxylated aluminum
  • alkali metal carboxylate such as sodium
  • the solvent examples include ether solvents such as getyl ether, tetrahydrofuran (THF), dioxane, 1,2-dimethyloxetane, and diglyme; hydrocarbon solvents such as benzene, toluene, hexane, and xylene; dichloromethane, and chloroform.
  • Halogen solvents such as form, carbon tetrachloride and 1,2-dichloroethane
  • ester solvents such as ethyl acetate, methyl acetate and butyl acetate
  • polar solvents such as acetone, N, N-dimethylformamide
  • a preferred solvent in this reaction is N, N-dimethylformamide.
  • the condensing agent may be any condensing agent used in a usual peptide condensation method (for example, an acid chloride method, a mixed acid anhydride method, etc.), and among them, 1-hydroxybenzotriazole-hydrate and 1- ( Combination with 3- (dimethylamino) propyl) -1-ethylcarbodiimide hydrochloride is preferred.
  • the reaction temperature is usually from 130 ° C. to 60 ° C., preferably 0. (: To room temperature.
  • the reaction time is generally 1 hour to 24 hours, preferably 2 hours to 12 hours, step 2-1 2
  • the solvent examples include ether solvents such as getyl ether, tetrahydrofuran (THF), dioxane, 1,2-dimethoxyethane, and diglyme; hydrocarbon solvents such as benzene, toluene, hexane, and xylene; and dichloromethane.
  • ether solvents such as getyl ether, tetrahydrofuran (THF), dioxane, 1,2-dimethoxyethane, and diglyme
  • hydrocarbon solvents such as benzene, toluene, hexane, and xylene
  • dichloromethane halogen-based solvents such as methane, chloroform, carbon tetrachloride and 1,2-dichloroethane
  • alcohol-based solvents such as methanol, ethanol, isopropylaryl, tert-butanol
  • polar solvents such as acetone N, N-dimethylformamide
  • Examples of the acid used in the reaction include inorganic acids such as hydrochloric acid, sulfuric acid, and nitric acid; and organic acids such as trifluoroacetic acid, trichloroacetic acid, acetic acid, methanesulfonic acid, and p-toluenesulfonic acid. Hydrochloric acid.
  • the reaction temperature is usually from 130 ° C to 6.0 ° C, preferably 0 ° C. C to room temperature.
  • the reaction time is usually 1 hour to 2 4.
  • H Konomashigu is 2 hours to 12 hours, Manufacturing Method 3]
  • This production method is the production method of compound (1) in the case where R and R 6 are taken together to form the following formula.
  • Process 3-1 is the production method of compound (1) in the case where R and R 6 are taken together to form the following formula.
  • a compound represented by the general formula (36) is subjected to a reductive amination reaction with a compound represented by the general formula (35) in a solvent; Can be obtained.
  • solvent used in the reaction examples include ether solvents such as getyl ether, tetrahydrofuran (THF), dioxane, 1,2-dimethoxyethane, and diglyme; hydrocarbon solvents such as benzene, toluene, hexane, and xylene; Halogen-based solvents such as dichloromethane, methane, chloroform, carbon tetrachloride, and 1,2-dichloroethane.
  • ether solvents such as getyl ether, tetrahydrofuran (THF), dioxane, 1,2-dimethoxyethane, and diglyme
  • hydrocarbon solvents such as benzene, toluene, hexane, and xylene
  • Halogen-based solvents such as dichloromethane, methane, chloroform, carbon tetrachloride, and 1,2-dichloroethane.
  • Examples of the reducing agent used in the reaction include sodium triacetoxyborohydride, sodium borohydride, lithium borohydride, aluminum hydride, and the like.
  • a preferred reducing agent in this reaction is hydrogenation It is sodium triacetoxyborohydride.
  • the reaction temperature is usually from 30 ° C to 50, preferably from 0 ° to room temperature.
  • the reaction time is generally 30 minutes to 24 hours, preferably 3 hours to 12 hours.
  • the compound represented by the general formula (37) can be obtained from the compound represented by the general formula (36) in the same manner as in Step 2-2 of Production Method 2.
  • the compound represented by the general formula (38) can be obtained by reacting the compound represented by the general formula (37) in a solvent in the presence of a base.
  • R 3 and R 4 is a hydrogen atom, The isomer is obtained.
  • Solvents used in the reaction include, for example, dityl ether, tetrahydrofuran
  • THF dioxane
  • 1,2-dimethoxy dioxane, 1,2-dimethoxy
  • ether solvents such as ⁇ -tan and diglyme
  • hydrogen peroxide solvents such as benzene, toluene, hexane, and xylene
  • an alcohol-based solvent such as methanol, ethanol, isopropyl alcohol, and tert-butanol
  • polar solvent such as N, N-dimethylformamide, dimethylsulfoxide, and water.
  • a preferred solvent in this reaction is tetrahydrofuran.
  • the base examples include alkali metal hydrides such as sodium hydride and hydrogenation hydride; alkali metal alkoxides such as potassium tert-butoxide and lithium hexamethyldisilazide; alkali metal amides such as lithium diisopropylamide And the like, and preferred is lithium hexamethyldisilazide.
  • alkali metal hydrides such as sodium hydride and hydrogenation hydride
  • alkali metal alkoxides such as potassium tert-butoxide and lithium hexamethyldisilazide
  • alkali metal amides such as lithium diisopropylamide And the like, and preferred is lithium hexamethyldisilazide.
  • the reaction temperature is usually from 100 ° C. to 60 ° C., preferably from 180 ° C. to room temperature.
  • the reaction time is generally 2 hours to 24 hours, preferably 2 hours to 12 hours.
  • the compound represented by the general formula (40) is obtained by reacting the compound represented by the general formula (38) with the compound represented by the general formula (39) in a solvent in the presence of a base.
  • the solvent examples include ether solvents such as getyl ether, tetrahydrofuran (THF), dioxane, 1,2-dimethoxyethane, and diglyme; hydrocarbon solvents such as benzene, toluene, hexane, and xylene; dichloromethane; Halogen solvents such as chloroform, carbon tetrachloride, and 1,2-dichloroethane; ester solvents such as ethyl acetate, methyl acetate, and butyl acetate; acetone, N, N-dimethyl Examples thereof include polar solvents such as formamide and water, which can be used alone or in combination. A preferred solvent in this reaction is tetrahydrofuran.
  • ether solvents such as getyl ether, tetrahydrofuran (THF), dioxane, 1,2-dimethoxyethane, and diglyme
  • hydrocarbon solvents such as benzene, tol
  • the Shiohaka for example, hydrogenation Nadoriu arm, hydrogenated force Liu;.
  • Alkali excess genus such as lithium diisopropylamide; al force Li metal Al Kishido such as potassium tert- butoxide; hydrogenated Al force Li metal arm parable ⁇ Mid;
  • alkali metal carbonates such as sodium carbonate, sodium carbonate, sodium bicarbonate and potassium bicarbonate; carboxylic acids such as sodium acetate and sodium acetate: lithium metal; sodium phosphate, potassium phosphate And organic bases such as triethylamine, pyridine and N-methylmorpholine, and preferably sodium hydride.
  • the reaction temperature is usually from ⁇ 30 to 60 ° C., preferably from 110 ° C. to room temperature.
  • the reaction time is usually from 1 hour to 2 hours, preferably from 2 hours to 15 hours.
  • the solvent examples include ether solvents such as getyl ether, tetrahydrophenyl (THF), dioxane, 1,2-dimethoxyethane, and diglyme; and hydrocarbon solvents such as benzene, toluene, hexane, and xylene.
  • Halogen solvents such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, etc .
  • Alcohol solvents such as methanol, ethanol, isopropyl alcohol, tei: t-butanol; N, N-dimethylformamide, etc. And these can be used alone or in combination.
  • a preferred solvent in this reaction is ethanol.
  • the reaction temperature is usually from 130 to 60 ° C, preferably from 0 ° C to room temperature.
  • the reaction time is generally 1 hour to 24 hours, preferably 2 hours to 12 hours.
  • the compound represented by the general formula (41) By reacting the compound represented by the general formula (41) in a solvent in the presence of a base, the compound represented by the general formula (42) can be obtained.
  • the solvent include ether solvents such as getyl ether, tetrahydrofuran (THF), dioxane, 1,2-dimethoxyethane and diglyme; hydrocarbon solvents such as benzene, toluene, hexane and xylene; dichloromethane, Halogen-based solvents such as chloroform, carbon tetrachloride, and 1,2-dichloro-13ethane; alcohol-based solvents such as methanol, ethanol, isopropyl alcohol tert-butanol, and 2-methoxyethanol:] S (A polar solvent such as dimethylformamide and the like can be used, and these can be used alone or in combination. A preferred solvent in this reaction is 2-methoxyethanol).
  • the base examples include alkali metal hydrides such as sodium hydride and potassium hydride; alkali metal alkoxides such as potassium tert-butoxide; alkali metal amides such as lithium dimethylisopropylamide; sodium carbonate; Alkali metal carbonates such as lime, sodium bicarbonate, hydrogen carbonate, etc .; Alkali metal carboxylate, such as sodium acetate, acetate lime; Alkaline metal phosphate, such as sodium phosphate, potassium phosphate Organic bases such as triethylamine, pyridine, N-methylmorpholine and the like, preferably sodium hydride.
  • the reaction temperature is usually from 130 ° C to 200 ° C. C, preferably between ⁇ 10 ° C. and 150 ° C.
  • the reaction time is generally 2 hr to 48 hr, preferably 6 hr to 24 hr ⁇ Step 3-7
  • the compound represented by the general formula (43) can also be obtained by reacting the compound represented by the general formula (42) in a solvent in the presence of an acid.
  • the solvent examples include ether solvents such as getyl ether, tetrahydrofuran (THF), dioxane, 1,2-dimethoxyethane, and diglyme; hydrocarbon solvents such as benzene, toluene, hexane, and xylene; dichloromethane, Halogen solvents such as chloroform, carbon tetraoxide, and 1,2-dichloroethane; alcohol solvents such as methanol, ethanol, isopropyl alcohol, tert-butanol, and 2-methoxyethanol; N, N-dimethylformamide And the like, and these can be used alone or in combination. Preferred in this reaction A new solvent is methanol.
  • ether solvents such as getyl ether, tetrahydrofuran (THF), dioxane, 1,2-dimethoxyethane, and diglyme
  • hydrocarbon solvents such as benzene, toluene, hexane
  • Examples of the acid used in the reaction include inorganic acids such as hydrochloric acid, sulfuric acid, and nitric acid; and organic acids such as tributanol, acetic acid, trichloroacetic acid, acetic acid, medansulfonic acid, ⁇ > -toluenesulfonic acid, and thiol chloride.
  • inorganic acids such as hydrochloric acid, sulfuric acid, and nitric acid
  • organic acids such as tributanol, acetic acid, trichloroacetic acid, acetic acid, medansulfonic acid, ⁇ > -toluenesulfonic acid, and thiol chloride.
  • the sign is thiol chloride.
  • the reaction temperature is usually from ⁇ 20 ° C. to 60, preferably from 0 ° C. to room temperature.
  • the reaction time is usually from 6 hours to 48 hours, preferably from 12 hours to 24 hours.
  • Examples of the base used in the reaction include alkali metal hydrides such as sodium hydride and potassium hydride; alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, and potassium hydrogen carbonate; sodium acetate, acetic acid Alkali metal carboxylate such as lime; alkali metal phosphate such as sodium phosphate and potassium phosphate; organic base such as triethylamine, diisopropylethylamine, pyridine N-methylmorpholine, and preferably pyridine. is there.
  • alkali metal hydrides such as sodium hydride and potassium hydride
  • alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, and potassium hydrogen carbonate
  • sodium acetate acetic acid
  • Alkali metal carboxylate such as lime
  • alkali metal phosphate such as sodium phosphate and potassium phosphate
  • organic base such as triethylamine, diisopropy
  • the solvent examples include ether solvents such as getyl ether, tetrahydrofuran (THF), dioxane, 1,2-dimethoxyethane, and diglyme; hydrocarbon solvents such as benzene, toluene, hexane, and xylene; dichloromethane, Halogen solvents such as chloroform, carbon tetrachloride, and 1,2-dichloroethane; polar solvents such as N, N-dimethylformamide; and pyridine, which can be used alone or in combination.
  • a preferred solvent in this reaction is pyridine.
  • the reaction temperature is usually from 130 ° C to 60 ° C. C, preferably from 0 ° C to room temperature.
  • the reaction time is generally from 6 hours to 72 hours, preferably from 12 hours to 48 hours.
  • the base used for the reaction includes, for example, alkali hydroxides such as lithium hydroxide, sodium hydroxide, and hydroxide hydroxide, and is preferably sodium hydroxide.
  • the solvent examples include ether solvents such as dimethyl ether, tetrahydrofuran (THF), dioxane, 1,2-dimethoxy ⁇ : ⁇ tan, and diglyme; hydrocarbon solvents such as benzene, toluene, hexane, and xylene; dichloromethane, Halogen solvents such as chloroform, carbon tetrachloride and 1,2-dichloromethane; phenolic solvents such as methanol, ethanol, isopropyl and tert-butanol; and polar solvents such as acetone. These can be used alone or in combination. Preferred solvents in this reaction are methanol and tetrahydrofuran.
  • ether solvents such as dimethyl ether, tetrahydrofuran (THF), dioxane, 1,2-dimethoxy ⁇ : ⁇ tan, and diglyme
  • hydrocarbon solvents such as benzene, toluene
  • the reaction temperature is usually from 0 ⁇ to 60, preferably room temperature.
  • the reaction time is usually 1 hour to 24 hours, preferably 2 hours to 12 hours.
  • the compound (1-c) obtained by this reaction can be subjected to a general optical resolution method to give an optically active compound as one of the target compounds.
  • optically active amine used in the reaction examples include phenethylamine, kyun, cudine, cinchonine, cinchon-gin or an optically active amino acid derived from an amino acid.
  • Preferred optically active amines are Kyun, Keyzin, Cinchonine and Cinchonidine.
  • Examples of the base used in the reaction include alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, and hydrogen carbonate; alkali metal carboxylate such as sodium acetate and potassium acetate; sodium phosphate; Rin Alkali metal phosphates such as potassium acid; organic bases such as triethylamine, diisopropylethylamine, pyridine and N-methylmorpholine; and N-methylmorpholine is preferable.
  • alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, and hydrogen carbonate
  • alkali metal carboxylate such as sodium acetate and potassium acetate
  • sodium phosphate Rin Alkali metal phosphates such as potassium acid
  • organic bases such as triethylamine, diisopropylethylamine, pyridine and N-methylmorpholine
  • N-methylmorpholine is preferable.
  • the solvent examples include ether solvents such as getyl ether, tetrahydrofuran (THF), dioxane, 1,2-dimethoxyethane, and diglyme; benzene, toluene, hexane, and xenium; Halogen solvents such as dichloromethane, chloroform, carbon tetrachloride, and 1,2-dichloroethane; ester solvents such as ethyl acetate, methyl acetate, and butyl acetate; ester solvents; acetone, N, N-dimethylformamide Acetonitrile, etc., which can be used alone or in combination.
  • a preferred solvent in this reaction is N, N-dimethylformamide or tetrahydrofuran.
  • the condensing agent may be a condensing agent used in a usual peptide condensation method (for example, an acid chloride method, a mixed acid anhydride method, etc.), and among them, ethyl ethyl carbonate and N-methylmorpholine or oxalyl chloride and N- Combinations with methylmorpholine are preferred.
  • a usual peptide condensation method for example, an acid chloride method, a mixed acid anhydride method, etc.
  • ethyl ethyl carbonate and N-methylmorpholine or oxalyl chloride and N- Combinations with methylmorpholine are preferred.
  • the hydroxyamine derivative used for the reaction include O- (trimethylsilyl) hydroxylamine.
  • the reaction temperature is usually 0. C to 100, preferably room temperature to 60.
  • the reaction time is generally 1 hour to 24 hours, preferably 2 hours to 12 hours.
  • the production method described in the present specification is an example of the production method of the compound of the present invention, and a compound other than the above-described compound is produced by combining conventional methods known in the field of synthetic organic chemistry. be able to.
  • Example 11 Methyl ( ⁇ [4-(. 5-Dicguchi-T3phenoxy) phenyl] sulfonyl ⁇ amino) (hydroxy) acetate (0.97 g, 2. To 3mmo 1), add thionyl chloride (3mL, 3v / V) solution and add 40-45. The mixture was stirred at C for 2 hours. After removing the solvent, toluene (10 mL, 10 v / w) was added, the solvent was removed, and the residue was dried under reduced pressure. The crude product of the title compound (0.98 g of a white solid) obtained was directly used in the next reaction.
  • 0- (trimethylsilyl) hydroxylamine (0.25 g, 2.3 mmo 1) was added, and the mixture was stirred for 10 minutes. (0.2 mL, 1 v / w) and stirred at room temperature for 30 minutes.After removing the solvent, water (ImL) was added, extracted twice with ethyl acetate (1 OmL), and the organic layer was extracted with water (5 mL). After removing the solvent, the resulting crude product was subjected to thin-layer silica gel chromatography.
  • Example J 1 the compounds of Example J 1: —2 to Cold Example 1-168 were obtained.

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Abstract

L'invention concerne un composé possédant un effet inhibiteur de l'aggrécanase ou de MMp-13 et utilisé comme médicament pour traiter la polyarthrite rhumatoïde, l'arthrite rhumatoïde, etc., et plus spécifiquement, un composé hétérocyclique contenant N condensé représenté par la formule (1), son promédicament ou un sel de celui-ci pharmaceutiquement acceptable. Dans la formule (1), R1 et R2 représentent chacun hydrogène, etc.; R3 et R4 représentent chacun hydrogène, etc.; R5 représente, conjointement avec R6, R3 ou R4, un groupe représenté par l'une quelconque des formules (A), (B), (C) ou (D) dans lesquelles, R8, R9, R10, R11, R12, R13 et R17 représentent chacun hydrogène, etc.; R7 représente hydrogène, etc.; R21 représente hydrogène, etc.; A représente alcylène, etc.; le noyau B représente aryle, etc.; m est égal à 1, etc.; et n est égal à 0, etc.
PCT/JP2003/017067 2002-12-27 2003-12-26 Composes heterocycliques contenant n condense et leur utilisation medicale WO2004060892A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007064914A2 (fr) * 2005-12-01 2007-06-07 Elan Pharmaceuticals, Inc. 5-(arylsulfonyl)-pyrazolopiperidines

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2000500145A (ja) * 1995-11-13 2000-01-11 ヘキスト・アクチエンゲゼルシヤフト 環式および複素環式のＮ−置換α−イミノヒドロキサム酸およびカルボン酸

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2000500145A (ja) * 1995-11-13 2000-01-11 ヘキスト・アクチエンゲゼルシヤフト 環式および複素環式のＮ−置換α−イミノヒドロキサム酸およびカルボン酸

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007064914A2 (fr) * 2005-12-01 2007-06-07 Elan Pharmaceuticals, Inc. 5-(arylsulfonyl)-pyrazolopiperidines
WO2007064914A3 (fr) * 2005-12-01 2007-12-27 Elan Pharm Inc 5-(arylsulfonyl)-pyrazolopiperidines
US7732609B2 (en) 2005-12-01 2010-06-08 Elan Pharmaceuticals, Inc. 5-(arylsulfonyl)-pyrazolopiperidines
EA014906B1 (ru) * 2005-12-01 2011-02-28 Элан Фармасьютикалз, Инк. 5-(арилсульфонил)пиразолопиперидины

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