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WO2007105650A1 - Derive 4-hydroxyisoleucine et son procede de production - Google Patents

Derive 4-hydroxyisoleucine et son procede de production Download PDF

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Publication number
WO2007105650A1
WO2007105650A1 PCT/JP2007/054716 JP2007054716W WO2007105650A1 WO 2007105650 A1 WO2007105650 A1 WO 2007105650A1 JP 2007054716 W JP2007054716 W JP 2007054716W WO 2007105650 A1 WO2007105650 A1 WO 2007105650A1
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group
substituent
alkyl group
heterocyclic
hydrogen atom
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English (en)
Japanese (ja)
Inventor
Satoshi Katayama
Munetaka Tokumasu
Atsushi Konishi
Misato Noguchi
Noriko Kawasaki
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Ajinomoto Co Inc
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Ajinomoto Co Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/0202—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-X-X-C(=0)-, X being an optionally substituted carbon atom or a heteroatom, e.g. beta-amino acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/04—1,3-Oxazines; Hydrogenated 1,3-oxazines
    • C07D265/06—1,3-Oxazines; Hydrogenated 1,3-oxazines not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06139—Dipeptides with the first amino acid being heterocyclic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0802—Tripeptides with the first amino acid being neutral
    • C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
    • C07K5/0808—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to a 4-hydroxyisoleucine derivative and a method for producing the derivative.
  • HIL 4-Hydroxyisoleucine
  • This 4-hydroxyisoleucine has a blood glucose level-dependent insulin secretion promoting activity (Non-patent Document 2, Patent Document 1), an insulin sensitivity enhancing action (Non-patent Document 3, Patent Document 2), Have been reported to promote glycogen production (Non-patent Document 4, Patent Document 3), and protect skin and scalp (Patent Document 4). Drugs, health food materials and cosmetics to which these effects are applied Useful as a material.
  • Patent Document 1 EP587476
  • Patent Document 2 WO200lZ015689
  • Patent Document 3 WO2005Z039626
  • Patent Document 4 WO2004Z087091, US2005 / 019357
  • Patent Document 5 WO2005Z012334, WO2005 / 012542
  • Non-patent literature l Phytochemistry, vol.12, 1707, 1973
  • Non-Patent Document 2 Diabetes, Vol. 47, Issue 2 206-210, 1988
  • Non Patent Literature 3 American Journal of Pnysiology Endocrinology ana Metabolism, Vol.2 87, E463-E471, 2004
  • Non-Patent Document 4 Amino Acids, vol.28, 71, 2005
  • Non-Patent Document 5 European Journal of Pharmacology, vol.390, 339, 2000
  • Non-Patent Document 6 Liebigs Annalen der Chemie, vol.9, 803, 1987
  • a structural feature of 4-hydroxyisoleucine is that it has a methyl group and a hydroxyl group in the side chain in a unique configuration, and this point is greatly different from other amino acids.
  • This characteristic side chain structure is thought to contribute to the expression of a unique physiological activity.
  • this characteristic structure has the disadvantage that the hydroxyl group and carboxylic acid in the molecule easily form lactone and lose its physiological activity, as shown in the following scheme.
  • the ratatatoni occurs under acidic conditions and is particularly prominent especially in the stomach (Non-patent Document 5). Similar structural changes are also expected in cosmetics and foods that are mixed with acidic substances.
  • an object of the present invention is to provide a stable derivative of 4-hydroxyisoleucine, and also to provide a method for producing a powerful derivative.
  • the present inventors have focused on the amides of carboxylic acids and studied the synthesis of various amide derivatives as a method for preventing exogeneization while maintaining the hydroxyl group of the side chain. did.
  • the C-terminal carboxylic acid of 4-hydroxyisoleucine is used as an amido compound, the ratatoni in the molecule is not obtained even if the N-terminal amino group is protected with a normal protecting group and then condensed with the amine compound. It progressed quickly and it was found that the desired amide derivative could not be obtained.
  • the present inventors have focused on a method of protecting the hydroxyl group and amino group of 4-hydroxyisoleucine with aminal and then protecting the N-terminal with a general protecting group and then subjecting it to a condensation reaction.
  • Amino-4-hydroxy mono (4-hydroxyphenol) 3 Methyl butanoic acid and other special ⁇ -positioned hydroxyl group
  • a method for protecting the hydroxyl group and amino group in amino acid with amino acid is known (non-patent Reference 6), there was no knowledge about whether the powerful method could be applied to 4-hydroxyisoleucine.
  • the present inventors reacted 4-hydroxyisoleucine with formaldehyde or ⁇ -trobenzaldehyde to form an aminal form of a hydroxyl group and an amino group, and then, if necessary, an amino group protecting group.
  • an amide compound by condensing an N-terminal protected compound and an amine compound such as an amino acid, that is, by appropriately protecting the hydroxyl group and the N-terminal amino group in this way, Found that it would be possible.
  • Thereafter, by deprotecting the N-terminal protecting group and aminal it was possible to obtain a derivative in which the C-terminal carboxylic acid of 4-hydroxyisoleucine was amidated.
  • Q 1 and Q 2 each independently have a hydrogen atom, an alkyl group that may have a substituent, an aryl group that may have a substituent, or a substituent.
  • a compound having a heterocyclic group or a substituent which may be optionally represented by a cycloalkyl group hereinafter also referred to as compound (A)
  • compound (IV) Reacted with general formula (IV)
  • n, m, o, p and 1 each independently represent 0 or 1 (provided that n + m and o + p are not 0);
  • R 3a , R 3b , R 3c , R 3d , R 4a , R 4b , R 4c and R 4d each independently have a hydrogen atom, an alkyl group which may have a substituent, or a substituent.
  • R 5 represents a hydrogen atom, an alkyl group which may have a substituent, an alkyl group which may have a substituent, an alkyl group which may have a substituent, or a substituent.
  • R 6 represents a hydrogen atom, an alkyl group which may have a substituent, an alkyl group which may have a substituent, an alkyl group which may have a substituent, or a substituent.
  • a cycloalkyl group optionally having an aryl group, optionally having an aralkyl group, having a substituent! /, Or a heterocyclic group Or having a substituent and having a substituent which can be bonded to one of the forces selected to represent a heterocyclic alkyl group, or R 4a , R 4b , R 4c and R 4d. May also form a heterocycle;
  • Y may have a protecting group, may be a hydroxyl group or a protecting group, and may be an amino group.
  • group (Via) Group (hereinafter also referred to as group (Via)), or general formula (Vlb)
  • ring A represents a heterocyclic ring which may have a substituent.
  • group (Vlb) A compound represented by the general formula (VII), characterized by reacting a compound represented by the following formula (VII) or a salt thereof:
  • a method for producing a compound represented by the formula (wherein each symbol is as defined above) (hereinafter also referred to as compound (VII)) or a salt thereof.
  • an active ester compound (hereinafter also referred to as active ester compound (VIII)) is obtained.
  • active ester compound (VIII) is obtained.
  • [5] A method for producing a compound ( ⁇ ) or a salt thereof, comprising the method according to [1], [2] and [4] above.
  • a method for producing a compound ( ⁇ ) or a salt thereof comprising the method according to [1], [3] and [4] above.
  • Q 1 and Q 2 each independently have a hydrogen atom, an alkyl group which may have a substituent, a substituent, or an aryl group or a substituent.
  • Q 1 is a hydrogen atom
  • Q 2 is a p-trophenyl group, a cyclohexyl group, a phenol group, a 4-pyridyl group, a 4-chlorophenol group, a 4-methoxyphenol group, 4 Methylphenol group, 4 trifluoromethylphenyl group, 4 fluorophenyl group, 4 cyanol group [2] to [6] above, wherein 2 is a closed mouth group, 2 -trophenyl group, 3 -trophenyl group, 2 chael group or 2 furyl group, and PG is a hydrogen atom
  • the manufacturing method in any one of.
  • Q 1 and Q 2 each independently have a hydrogen atom, an alkyl group that may have a substituent, an aryl group that may have a substituent, or a substituent.
  • PG represents a hydrogen atom or an amino group protecting group
  • X ′ represents a hydroxyl group, an active ester residue, a group (Via) or a group (VIb). Or a salt thereof (hereinafter, also referred to as compound (IV ′)).
  • Q 1 and Q 2 each independently have a hydrogen atom, an alkyl group which may have a substituent, a substituent, or an aryl group or a substituent.
  • Q 2 is a hydrogen atom
  • PG is a hydrogen atom, t-butoxycarbonyl group or benzyloxycarbonyl group
  • X ′ is a hydroxyl group, an active ester residue, or Gly ⁇ Ala ⁇ Val, Leu ⁇ lie ⁇ Met ⁇ Phe ⁇ Tyr ⁇ Trp ⁇ His ⁇ Lys ⁇ Arg ⁇ Ser ⁇ ⁇ ⁇ ⁇ Thr ⁇ Asp ⁇ Amino acid residue selected from Glu, Asn, Gln, Cys and Pro (carboxylic acid is protected) May be. Or the salt thereof according to [12] above.
  • Q 1 is a hydrogen atom
  • Q 2 is a p-trophenyl group, a cyclohexyl group, a phenol group, a 4-pyridyl group, a 4-chlorophenol group, a 4-methoxyphenol group, 4 Methylphenyl group, 4-trifluoromethylphenyl group, 4-fluorophenyl group, 4-cyanophenyl group, 2-chlorophenol group, 2-trifluorophenyl group, 3-trifluorophenyl group, 2 Chayl group or 2-Furyl group
  • PG is hydrogen atom, X 'is hydroxyl group, Gly, Ala, Val, Leu ⁇ lie ⁇ Met ⁇ Phe ⁇ Tyr ⁇ Trp ⁇ His ⁇ Lys ⁇ Arg ⁇ Ser ⁇ Thr ⁇ Asp ⁇ Glu ⁇ Asn, Gln, Cys and Pro
  • PG is hydrogen atom
  • the present invention also provides the following [1 '] to [9'].
  • R 1 and R 2 are each independently a hydrogen atom, an alkyl group which may have a substituent, an alkyl group which may have a substituent, or a substituent.
  • R 3a , R 3b , R 3c , R 3d , R 4a , R 4b , R 4c and R 4d each independently have a hydrogen atom, an alkyl group which may have a substituent, or a substituent.
  • a good carboxyl group, having a substituent, or a strong rubamoyl group or having a substituent may be a sulfamoyl group;
  • R 5 represents a hydrogen atom, an alkyl group which may have a substituent, an alkyl group which may have a substituent, an alkyl group which may have a substituent, or a substituent.
  • a cycloalkyl group optionally having an aryl group, optionally having an aralkyl group, having a substituent! /, Or a heterocyclic group Or having a substituent and having a substituent that is bonded to one of the forces selected to represent a heterocyclic alkyl group, or R 3a , R 3b , R 3e and R 3d May also form a heterocycle;
  • R 6 represents a hydrogen atom, an alkyl group which may have a substituent, an alkyl group which may have a substituent, an alkyl group which may have a substituent, or a substituent.
  • a cycloalkyl group optionally having an aryl group, optionally having an aralkyl group, having a substituent! /, Or a heterocyclic group Or having a substituent and having a substituent which can be bonded to one of the forces selected to represent a heterocyclic alkyl group, or R 4a , R 4b , R 4c and R 4d. May also form a heterocycle;
  • Y may have a protecting group, may be a hydroxyl group or a protecting group, and may be an amino group.
  • a salt thereof hereinafter also referred to as compound (I)).
  • ring A represents an optionally substituted heterocyclic ring
  • compound ( ⁇ ) an optionally substituted heterocyclic ring
  • [6 ′] A pharmaceutical composition comprising the compound or salt thereof according to any one of [] to [5 ′] above.
  • [8 ′] A food composition comprising the compound or salt thereof according to any one of [] to [5 ′] above.
  • the 4-hydroxyisoleucine derivative of the present invention has a characteristic side chain structure possessed by 4-hydroxyisoleucine and is thought to maintain its unique physiological activity and physical properties or to exhibit a novel effect.
  • the C-terminal carboxylic acid is stabilized by amidation, and its action and durability are considered to be improved.
  • the 4-hydroxysoleucine derivative of the present invention is a peptide with glycine or the like, even if the amide bond is hydrolyzed in vivo or on the surface of the living body, the action of the generated HIL can be expected, and the other degradation can be expected.
  • An advantage is that glycine, which is a product, is a highly safe amino acid.
  • the 4-hydroxyisoleucine derivative of the present invention can be stabilized by modifying the C-terminal carboxylic acid, so that it can be stabilized and used for various uses such as pharmaceuticals and foods. Can be used.
  • alkyl group means a linear or branched alkyl group having 1 to LO, preferably 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, propyl, isobutyl, sec butyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, 2-ethylbutyl, heptyl, octyl, nonyl, decyl, etc., preferably methyl, ethyl, propyl, isopropyl, butyl, sec butyl, isobutyl Or t-butyl.
  • alkenyl group means a linear or branched alkenyl group having 2 to 10 carbon atoms, preferably 2 to 6 carbon atoms, such as ethyl, 1-probe, Aryl, 1-methyl-2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenol, 1-hexenol, 2-hexenol, 1-heptenol, 2 —Hepte-Nole, 1-Otatur, 2-Otatur, 1-None, 2-Nonel, 1-Desele, 2-Deser, etc. Probe, 1-methyl-2-propenyl, 1-butenyl, 2-butenyl or 3-butenyl.
  • alkynyl group means a straight-chain or branched alkyl group having 2 to 10 carbon atoms, preferably 2 to 6 carbon atoms, such as etul, 1-probule, 2-propy- 1-methyl-2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentininole, 2-pentyninore, 1-hexyninole, 2-hexyninole, 1-heptinol, 2-heptul, 1-octyl -L-, 2-octyl, 1-no-l, 2-non-l, 1-decyl, 2-decyl, etc., preferably etlur, 1-probule, 2-propyl 1-methyl-2-propynyl, 1-butynyl, 2-butynyl or 3-butynyl.
  • cycloalkyl group means a cycloalkyl group having 3 to 10 carbon atoms, preferably 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclyl. Examples thereof include oral hexyl and cycloheptyl, and cyclohexyl and cyclopentyl are preferable.
  • aryl group refers to an aryl group having 6 to 14 carbon atoms, preferably 6 to 10 carbon atoms, such as a phenol, 11 or 2-naphthyl, biphenyl and the like. Preferably, it is a file.
  • aralkyl group means an aralkyl group formed by substituting the above-defined “aryl group” at any position of the above-defined “alkyl group”.
  • benzyl 1- or 2 pheethyl, 1—, 2 or 3 propylpropyl, 1 or 2—naphthylmethyl, 1 or 2— (1 naphthyl) ethyl, 1 or 2— (2 naphthyl) ethyl , 2-ethyl-1-phenylbutyl, benzhydryl, trityl and the like, preferably benzyl.
  • heterocyclic group means, for example, a 5- to 10-membered aromatic heterocyclic group containing 1 to 4 heteroatoms selected from oxygen atoms, sulfur atoms and nitrogen atomic energy in addition to carbon atoms. Or a non-aromatic heterocyclic ring and its condensed ring group are mentioned.
  • the aromatic heterocyclic group or its condensed ring group includes 2—, 3 chaels, 2—, or ⁇ or 3 frinoles, 1 or 2; or ⁇ or 3 pyrrolinoles, 1; 2—4, 1 or 5 or 5 Imida Linole, 2 or 4 or 5 or 5—Aged Kilinole, 2—, 4 or 5—Cheer: / Linole, 1—, 3—, 4, Or 5-pyrazolyl, 3-, 41, or 5-isoxazolyl, 3-, 41, or 5-isothiazolyl, 1, 2, 4 triazole, 1-, 3-, 4, or 5-yl, 1, 2, 3 Triazol 1 1, 2— or 4 yl, 1H—Tetrazol 1 1 or 5 il, 2 ⁇ —Tetrazo, 1 nore 2—, or ⁇ or 5—inore, 2—, 3 —, ⁇ or 4 pyridinole, 2—, 4 1, or ⁇ or 5 pyrimidyl, 1—,
  • Non-aromatic heterocyclic groups or condensed ring groups thereof include 2— or 3 dihydrochel, 2—, or 3 dihydrofurinole, 1, 1, 2—, or 3 pyrrolininore, 1 1 ⁇ 2 ⁇ ⁇ 4 1 ⁇ 5—Imida / Lininore, 2—, 4 or ⁇ 5—Old Kisah / Lininore, 2—, 4 or ⁇ 5—Chia: / Li Ninore, 1—, 3—, 4 or ⁇ 5 Villa: / Lininore, 3—, 4 or Mt.
  • heterocyclic group is preferably pyridyl, chael, furyl, 4 imidazolyl or 3 indolyl.
  • heterocyclic alkyl group is a heterogeneous group formed by substituting the above-defined “heterocyclic group” at any position of the above-defined “alkyl group”.
  • examples thereof include a cyclic alkyl group, preferably 4-imidazolylmethyl or 3-indolylmethyl.
  • a "heterocycle” formed by R 5 combining with one selected from R 3a , R 3b , R 3c and R 3d , R 6 Is formed by combining with one selected from R 4a , R 4b , R 4e and R 4d , and the “heterocycle” in ring A is not only a nitrogen atom, but also a nitrogen atom, oxygen Atoms and sulfur Nuclear power may also be selected 1 to 4 heteroatoms may contain 1 to 4 heteroatoms, e.g. pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine, homopiperidine , Homopiperazine, oxazine and the like, and pyrrolidine is preferable.
  • “having a substituent may be” means “having a substituent at an unsubstituted or substitutable position”.
  • substituent group A The following substituents are exemplified as the following substituents (hereinafter referred to as substituent group A).
  • Alkyl group (as defined above, eg, methyl, ethyl, propyl, isopropyl, etc., but not a substituent of an alkyl group, an alkenyl group or an alkyl group),
  • alkenyl groups (as defined above, eg, etul, 1-probe, aryl, etc., but not substituted for alkyl groups or alkenyl groups),
  • Alkyl group (same as above, eg, Etul, 1-Probule, 2-Propyl, etc., but it is not a substituent of alkyl group or alkyl group),
  • Halogen atom eg, fluorine atom, chlorine atom, bromine atom, iodine atom
  • a cycloalkyl group (as defined above, eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.),
  • aryl group (as defined above, eg, phenyl, etc., but not a substituent of an alkyl group)
  • Heterocyclic group (as defined above, eg, pyridyl etc., but not a substituent of an alkyl group),
  • haloalkyl group preferably having 1 to 10 carbon atoms, such as trifluoromethyl
  • alkoxy group preferably having 1 to 10 carbon atoms, such as methoxy, ethoxy, etc.
  • 10 haloalkoxy groups preferably having 1 to 10 carbon atoms, eg, trifluoromethoxy, etc.
  • 11 aryloxy groups the aryl ring moiety is as defined above, eg, phenoxy, etc.
  • heterocyclic oxy group heterocyclic moiety is as defined above, eg, pyridyloxy, etc.
  • 13 aralkyloxy group aralkyl moiety is as defined above, eg, benzyloxy, etc.
  • 14 cycloalkylalkyl group cycloalkyl moiety is as defined above E.g., cyclopropylmethyl
  • heterocyclic alkoxy group (the heterocyclic moiety is as defined above, eg, pyridylmethoxy, etc.), 17 alkylthio group (preferably having 1 to 10 carbon atoms, eg, methylthio, etc.),
  • heterocyclic thio group (the heterocyclic moiety is as defined above, eg, pyridylthio, etc.),
  • acyl groups preferably 1 to 7 carbon atoms, eg, formyl, acetyl, benzoyl, etc.
  • monoalkylamino groups preferably 1 to carbon atoms: L0, eg, methylaminoethylamino, etc.
  • dialkylamino groups (preferably having 2 to 20 carbon atoms, such as dimethylamino-containing ketylamino N--methyl-N-ethylamino),
  • alkylsulfonyl groups preferably having 1 to 10 carbon atoms, eg, methanesulfonyl etc.
  • 31 force rubamoyl groups preferably having 1 to 10 carbon atoms, eg, methanesulfonyl etc.
  • Dialkyl-powered rubermoyl group (preferably having 3 to 20 carbon atoms, such as dimethylcarbamoyl, jetylcarbamoyl, N-methyl-Nethylcarbamoyl, etc.),
  • monoalkylsulfamoyl groups (preferably having 1 to 10 carbon atoms, eg, methylsulfamoyl, ethylsulfamoyl, etc.),
  • Dialkylsulfamoyl groups (preferably having 2 to 20 carbon atoms, such as dimethylsulfamoyl, jetylsulfamoyl, N-methyl-Nethylsulfamoyl, etc.),
  • Alkoxycarbon groups (preferably having 2 to 10 carbon atoms, such as methoxycarbol and ethoxycarbol),
  • an acyloxy group (preferably having a carbon number of 1 to 10.
  • acyloxy group preferably having a carbon number of 1 to 10.
  • Alkylsulfo-lumino groups (preferably having 1 to 10 carbon atoms, such as methylsulfo-amino-ethylsulfo-ramino),
  • arylsulfo-lumino group (the aryl moiety is as defined above, eg, phenol sulfo-amino),
  • a guanidino group substituted with an alkyl group preferably having 2 to 10 carbon atoms, for example, 3 methylguanidino, etc.
  • the "protecting group” of “having a protecting group! / May be a hydroxyl group” in Y etc. and “the carboxylic acid may be protected” in Xaa etc. is a carboxyl group known per se
  • the protecting group for the group can be used without particular limitation.
  • Examples of the protective group for the carboxyl group that can be used include:
  • alkyl ester preferably having 1 to 10 carbon atoms, eg, methyl ester, ethyl ester, t-butyl ester, etc.
  • aryl ester preferably having 6 to 10 carbon atoms, such as phenyl ester
  • aralkyl ester e.g., preferred 7 to 14 carbon atoms, such as benzyl ester
  • alkylamides preferably having 1 to 10 carbon atoms, such as methylamide, ethylamide, dimethylamide, etc.
  • arylamide preferably 6 to 10 carbon atoms, such as furamide
  • aralkylamide (preferably 7 to 14 carbon atoms, such as benzylamide)
  • amino group optionally having a protecting group in Y, etc.
  • Amino group may be protected” in compound ( ⁇ ), compound (III), etc.
  • PG in PG
  • protecting group a known protecting group for an amino group can be used without particular limitation.
  • Examples of a powerful amino-protecting group include:
  • alkyl preferably having 1 to 10 carbon atoms, such as methyl, ethyl, etc.
  • Asil preferably, 1 to 10 carbon atoms, eg, acetyl (Ac), benzoyl (Bz), etc.
  • Alkoxycarbol preferably having 1 to 10 carbon atoms, such as methoxycarbol, ethoxycarbol, t-butoxycarbol (Boc), etc.
  • aryloxy balls eg, phenoxy balls
  • aralkyloxycarbol eg, benzyloxycarbol (Z), 9 fluoromethoxycarbole (Fmoc), etc.
  • aralkyl preferably 7-20 carbon atoms, such as benzyl (Bn), triphenylmethyl, etc.
  • protecting groups for amino groups described in Protective uroups in Organic Syntnesis 3rd edition, Wiley, John & Sons, Incorporated (1999) can be used.
  • the "active ester residue" in E means a group that can be easily removed by a nucleophilic attack by a nucleophile, such as succinimidoxy (OSu), 1-benzotriazolyl.
  • a nucleophile such as succinimidoxy (OSu), 1-benzotriazolyl.
  • examples include ruoxy, 4-nitrophenoxy, pentafluorophenoxy, N-hydroxy-15-norbornene 2,3 dicarboxylic acid imidooxy, and succinimideoxy is preferable.
  • HIL 4-hydroxyisoleucine
  • cHIL Compound represented by general formula (IVa)
  • Trp Tryptophan
  • the 4-hydroxyisoleucine derivative of the present invention is represented as, for example, H-HIL-Xaa-OH, the left side is the N-terminus, the right side is the C-terminus, and the N-terminus and C-terminus are protected respectively. It means that.
  • Boc-HIL-Xaa-OtBu when it is protected with N-terminal carboxycarbol or C-terminal force butyl, it is expressed as Boc-HIL-Xaa-OtBu, and is protected with N-terminal force tert-butoxycarbonyl.
  • the C-terminal is activated with succinimidoxy, it is expressed as Boc-HIL-Xaa-OSu.
  • the compound of the present invention may be in the form of a salt. Where the compound of the present invention can be in the form of a salt, a pharmaceutically acceptable salt is preferred.
  • Examples of such pharmaceutically acceptable salts include ammonium salts, salts with alkali metals such as sodium and potassium, and calcium for compounds having an acidic group such as a carboxyl group. , Salts with alkaline earth metals such as magnesium, aluminum salts, zinc salts, salts with organic amines such as morpholine, pyrrolidine, piperidine, piperazine, dicyclohexylamine, arginine And salts with basic amino acids such as lysine.
  • salts with inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, hydrobromic acid, acetic acid, citrate, benzoic acid, maleic acid, fumaric acid, tartaric acid , Succinic acid, tannic acid, butyric acid, hybenzic acid, pamoic acid, enanthic acid, decanoic acid, teocric acid, salicylic acid, lactic acid, oxalic acid, mandelic acid, salt with organic carboxylic acid such as malic acid, methanesulfonic acid And salts with organic sulfonic acids such as benzenesulfonic acid and p-toluenesulfonic acid.
  • inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, hydrobromic acid, acetic acid, citrate, benzoic acid, maleic acid, fumaric acid, tartaric acid , Su
  • the compound of the present invention and a necessary acid or base are mixed in an appropriate amount ratio in a solvent or a dispersant, or cation exchange or anion is performed depending on the state of other salts. It can also be obtained by exchanging ions.
  • the compounds of the present invention also include solvates thereof such as hydrates and alcohol adducts.
  • the compounds of the present invention include optical isomers, stereoisomers, positional isomers, tautomers, rotamers, and mixtures thereof in any ratio. It is. Each of these can be obtained as a single product by a synthesis method and a separation method known per se.
  • an optical isomer can be obtained by using an optically active synthetic intermediate, or by optical resolution of a synthetic intermediate or a final racemate in accordance with a conventional method.
  • the compounds of the present invention can also be converted into prodrugs.
  • the prodrug in the present invention refers to a compound that is converted in the body to produce the compound of the present invention.
  • the active substance contains a carboxyl group
  • examples thereof include esters and amides thereof, or groups that can be converted into a carboxyl group by oxidation metabolism, such as a hydroxymethyl group.
  • the active main body contains an amino group, its amide, carbamate and the like can be mentioned.
  • the active main body contains a hydroxyl group, its ester, carbonate, carbamate and the like can be mentioned.
  • the compound of the present invention may be bound to an amino acid or a saccharide.
  • R 1 and R 2 are preferably a hydrogen atom or a lower alkyl group having 1 to 6 carbon atoms.
  • n, m, o, p, and 1 an embodiment in which 1 is 0, n force and m is 1 is preferable.
  • R 3a , R 3 R 4a and R 4c are preferably hydrogen atoms.
  • R 3b , R 3d , R 4b and R 4d include a hydrogen atom, a methyl group, an isopropyl group, an isobutyl group, a sec butyl group, a 2-methylthioethyl group, a phenylmethyl group, a 4-hydroxyphenylmethyl group, a 3- Indolylmethyl group, 4-imidazolylmethyl group, 4 aminobutyl group, 3-gua-dinopropyl group, hydroxymethyl group, 1-hydroxyethyl group, carboxymethyl group, 2-carboxyethyl group, rubamoylmethyl group, 2 —Strengthening Various amino acid side chains selected from groups such as a group and a mercaptomethyl group are preferred.
  • R 5 and are preferably hydrogen atoms.
  • Y is preferably a hydroxyl group.
  • R 5 is combined with one of R 3a , R 3b , R 3c and R 3d forces to form a heterocycle
  • R 6 is R 4a , R 4b , R 4e and R 4d forces.
  • a pyrrolidine ring is preferred as the heterocycle, in which a heterocycle is preferably formed by bonding to one.
  • the 4-hydroxyisoleucine derivative represented by the general formula (I) is preferably a compound represented by the general formula (IV) which is a peptide derivative.
  • Xaa is preferably Gly, Ile, Met, Phe, Trp, Thr, Lys or Pro from the viewpoint of hypoglycemic activity. From the viewpoint of stability, Pro is particularly preferable.
  • the N-terminus and C-terminus are protected, and the embodiment is preferred.
  • the compound of the present invention also contains a compound represented by the general formula (III).
  • Ring A is preferably pyrrolidine.
  • Examples of the substituent that ring A may have include an alkyl group having 1 to 6 carbon atoms, an alkyl group having 2 to 6 carbon atoms, an alkyl group having 2 to 6 carbon atoms, a hydroxyl group, a carboxyl group, Among the amino groups that may have the substituent group A, a carboxyl group is preferable.
  • Q 1 and Q 2 are hydrogen atoms
  • PG is a tert butoxycarbonyl group or a benzyloxycarbonyl group, or
  • Q 1 is a hydrogen atom
  • Q 2 is a phenyl group, a 4-methylphenol group, a 4-chlorophenol group, a 2-chlorophenol group, a 4-fluorophenol group, a 4-methoxyphenol group , 2 Cyanphenol group, 4-Trophenyl group, 3-Trophenyl group, 2-Trophenyl group, 4-Trifluoromethylphenyl group, 4-Pyridyl group, 2-Chell Preferred is an embodiment in which PG is a hydrogen atom, a 2-furyl group or a cycloalkyl group (preferably a cyclohexyl group) (more preferably a phenyl group or a p-type 2-phenyl group).
  • HIL 4-hydroxyisoleucine
  • 2S, 3 R, 4S 4-hydroxyisoleucine
  • (2R, 3R, 4S) 4-hydroxyisoleucine
  • (2 S, 3S, 4R) 4-hydroxyisoleucine
  • (2R, 3S, 4R) 4-hydroxyisolocine
  • isine 4-Hydroxyisoleucine
  • general formulas (1), ( ⁇ ), ( ⁇ ) and (III) the three-dimensional structure of the HIL corresponding part is As shown in the 2S, 3R, 4S body is preferred! / ,.
  • the steric structures of the general formulas (IV), (V), (VII) and (VIII) preferably have the steric configuration represented by the following formula.
  • the compound of the present invention has an excellent inhibitory effect on blood glucose elevation for humans and other mammals such as mice, horses, dogs, mice, rats and the like.
  • a pharmaceutical composition mixed with a pharmaceutically acceptable carrier as it is or according to a method known per se it can be used orally or parenterally (for example, intravenous, subcutaneous, intramuscular, suppository, enema) , Ointments, patches, sublingual, eye drops, inhalation routes).
  • the dose to be used for the above purpose is determined by the intended therapeutic effect, administration method, treatment period, age, body weight, etc.
  • the content of the compound of the present invention in the pharmaceutical composition is about 0.01% to 100% by weight of the whole composition.
  • a pharmaceutically acceptable carrier in the pharmaceutical composition of the present invention examples include various conventional organic or inorganic carrier materials, such as excipients, lubricants, binders, disintegrants, water-soluble polymers, basic inorganic salts in solid preparations; solvents, dissolution aids in liquid preparations, Suspending agents, tonicity agents, buffers, soothing agents and the like can be mentioned.
  • additives such as ordinary preservatives, antioxidants, coloring agents, sweeteners, sour agents, foaming agents, and fragrances can be used as necessary.
  • Examples of the dosage form of such a pharmaceutical composition include tablets, powders, pills, granules, capsules, suppositories, solutions, dragees, depots, syrups, suspensions, and emulsions. , Lozenges, sublinguals, patches, buccal disintegrants (tablets), inhalants, enemas, ointments, adhesives, tapes, ophthalmic preparations And can be produced according to conventional methods.
  • the pharmaceutical composition of the present invention can be produced by a method commonly used in the field of pharmaceutical technology, such as the method described in the Japanese Pharmacopoeia. The specific production method of the preparation is described in detail below.
  • an excipient and, if necessary, a binder, a disintegrant, a lubricant, a coloring agent, a flavoring agent and the like are added, followed by a conventional method.
  • a binder e.g., a polyethylene glycol dimethacrylate copolymer, a polyethylene glycol dimethacrylate copolymer, a polypropylene glycol dimethacrylate copolymer, a sulfate, a steaglycerin, glycerin, glycerin, glycerin, glycerin, glycerin, glycerin, glycerin, glycerin, a glycerin, glycerin, a glycerin, a glycerin, a glycerin, a glycerin, a sulfate, a sulfate, a stearate, glycerin,
  • excipients include lactose, corn starch, sucrose, butter sugar, sorbit, crystalline cellulose, etc.
  • binders include polybutyl alcohol, polyvinyl ether, ethyl cellulose, methinorescenellose, gum arabic, Tragacanth, gelatin, shellac, hydroxypropylcellulose, hydroxypropyl starch, polyvinylpyrrolidone, etc.
  • disintegrants include starch, agar, gelatin powder, crystalline cellulose, calcium carbonate, sodium bicarbonate, calcium citrate, dextran, pectin, etc.
  • lubricants for example, magnesium stearate, talc, polyethylene glycol, silica, hydrogenated vegetable oil, etc. are permitted to be added to pharmaceuticals as colorants.
  • a flavoring agent cocoa Powders, potatoes, buckwheat brains, aromatic acids, hearth oil, dragon brains, cinnamon powders, etc. are used.
  • these tablets or granules may be coated with sugar, gelatin or other appropriate coatings.
  • a pH adjuster, a buffer, a stabilizer, a preservative, etc. are added as necessary, and a subcutaneous, intramuscular or intravenous injection is prepared by a conventional method.
  • the compound of the present invention can be used as a preventive / therapeutic agent for diabetes, but it is used in combination with other commonly used therapeutic agents for diabetes and the prevention of diabetic complications' therapeutic agents.
  • the drugs used in combination with the compound of the present invention are mixed to form one agent, each is formulated separately, or each is formulated separately in one container.
  • the combined preparation (set, kit, knock) may be used.
  • the form of administration when used in combination is not particularly limited. For example, (1) administration as a single preparation, (2) simultaneous administration of different preparations in the same route of administration, (3) same preparation of different preparations Examples include administration with a time difference in the administration route, (4) simultaneous administration of different preparations in different administration routes, and (5) administration of the different preparations in different administration routes with a time difference.
  • insulin preparations include sputum, lente, ultralente, and insulin that can be absorbed through the lungs.
  • Insulin derivatives refer to proteins or peptides derived from insulin capsules that retain insulin action, such as the spout mouth, B10Asp, glargine, etc.
  • An insulin-like agent is a substance other than an insulin derivative that exerts a hypoglycemic effect by exerting insulin physiological actions such as promoting glucose uptake into cells without depending on insulin to some extent. Examples include insulin receptor kinase stimulants (eg, L-783281, TER-17411, CLX-0901, KRX-613) and nonadium.
  • An insulin secretagogue refers to an agent that exerts a hypoglycemic effect by acting on spleen ⁇ -cells and increasing the secretion of insulin into the blood, such as a sulfonylurea agent (eg, tolptamide, Chlorpropamide, tolazamide, acetohexamide, daliclazide, glimepiride, glipizide, dalibenclamide (glyburide), etc., meglitides (eg, nateglinide, repaglinide, mitiglinide, etc.), sulfo-lurea agents ⁇ -sensitive potassium channel inhibitors (such as BTS-67-582).
  • a sulfonylurea agent eg, tolptamide, Chlorpropamide, tolazamide, acetohexamide, daliclazide, glimepiride, glipizide, dalibenclamide (glyburide), etc.
  • meglitides
  • An insulin resistance ameliorating agent refers to an agent that exerts a hypoglycemic effect by enhancing the action of insulin in the target yarn and tissue of insulin, for example, peroxisome proliferator activity is received.
  • Body (PPAR) ⁇ -agonist eg, thiazolidinedione compounds such as pioglitazone, rosiglitazone, troglitazone, ciglitazone, or non-thiazolidinedione compounds such as GI-262570, GW-1929, JTT-501, ⁇ -440
  • ⁇ y AR y antagonist eg bisphenol A diglycidyl ether ⁇ LG-100641
  • PPAR ⁇ agonist fibrates such as clofibrate, bezafibrate, clinofibrate or non-fibrate compounds
  • PPAR a / y agonist eg K RP-297
  • retinoid X receptor agonist eg LG- 100268
  • Biguanide refers to an agent that exhibits a hypoglycemic effect by inhibiting gluconeogenesis in the liver, promoting anaerobic glycolysis in the tissue, or improving insulin resistance in the periphery.
  • gluconeogenesis inhibitors include those that exert a hypoglycemic effect by inhibiting gluconeogenesis, such as glucagon secretion inhibitors (such as M & B 39890A), glucago, etc.
  • Receptor receptor antagonists for example, CP-99711, NNC-92-1687, L-168049, BAY27-9955, etc.
  • glucose-6-phosphatase inhibitors and the like.
  • a sugar absorption inhibitor refers to a substance that exerts a hypoglycemic action by inhibiting enzyme digestion in the digestive tract of carbohydrates contained in food and inhibiting or delaying absorption of sugar into the body.
  • examples include ⁇ -darcosidase inhibitors (eg, carbolose, voglibose, miglitol, etc.), ⁇ -amylase inhibitors (eg, AZM-127, etc.), and the like.
  • Renal glucose reabsorption inhibitors refer to those that exert a hypoglycemic effect by inhibiting the reabsorption of sugars in renal tubules, such as sodium-dependent glucose transporter inhibitors (for example, ⁇ -1095, Phlorizin and the like).
  • ⁇ 3 -adrenergic receptor agonists are used to stimulate obesity and hyperinsulinemia by stimulating ⁇ 3 -adrenergic receptors in adipocytes, increasing fatty acid acid and consuming energy. This refers to those that exhibit an improving action, such as CL-316243 and ⁇ -677.
  • Examples of glucagon-like peptide-1 (7-37) analogs include exendin-4, ⁇ -2211 and the like, and examples of glucagon-like peptide-1 receptor agonists include, for example, A ZM-134 Examples of the dipeptidyl peptidase IV inhibitor include NVP-DPP-728.
  • Glucagon-like peptide-1 analog, glucagon-like peptide-1 receptor agonist, dipeptidylpeptidase IV inhibitor and glucagon-like peptide-1 mimics or enhances the action of glucagon-like peptide-1 in cells By doing this, it means a substance that exerts an action to improve diabetes.
  • aldose reductase inhibitors which are preferable for the treatment of diabetic complications, they are observed in tissues that develop glycouric complications. This refers to a substance that lowers intracellular sorbitol accumulated excessively by inhibiting aldose reductase. Examples thereof include enolrestat, tolrestat, fidarestat, and generestat.
  • the production of terminal glycosylation products inhibits the generation of terminal glycation products that are enhanced by the persistence of the hyperglycemic state in the diabetic state.
  • the therapeutic agents for diabetic complications of the present invention are also included in this category, but when used in combination with the therapeutic agents for the prevention of diabetic complications of the present invention, For example, NNC-39-00 28, OPB-9195, etc.
  • glycogen synthase kinase-3 inhibitor examples include SB-216763 and CHIR-98014, and examples of the glycogen phosphorylase inhibitor include CP-91149.
  • Antihyperlipidemic drugs include, for example, hydroxymethyldartalylcoenzyme A reductase inhibitors (for example, pravastatin, sympastatin, flupastatin, atorvastatin, etc.), fibrates (for example, clofib) Lato, bezafibrate, symfibrate, etc.) and bile acid excretion promoters.
  • hydroxymethyldartalylcoenzyme A reductase inhibitors for example, pravastatin, sympastatin, flupastatin, atorvastatin, etc.
  • fibrates for example, clofib Lato, bezafibrate, symfibrate, etc.
  • bile acid excretion promoters for example, bile acid excretion promoters.
  • appetite suppressant examples include sibutramine and mazindol
  • lipase inhibitor examples include orlistat.
  • antihypertensive agents include angiotensin converting enzyme inhibitors (for example, captopril, alaceptril, etc.), angiotensin II receptor antagonists (for example, candesartan cilexetil, valsartan, etc.), calcium antagonists (for example, sil-dipine) , Amlodipine, dicardipine, etc.), diuretics (eg, trichlormethiazide, spironolataton), sympathetic blockers (eg, clodin, reserpine, etc.).
  • peripheral circulation improving drug examples include icosapentate ethyl.
  • antioxidants examples include lipoic acid and probucol.
  • Examples of the therapeutic agent for diabetic neuropathy include mecobalamin and mexiletine hydrochloride.
  • the compounds of the present invention are also useful as food additives.
  • the food composition containing the compound of the present invention is useful as a food for preventing or treating diabetes.
  • Food in the present invention means all foods, but also includes general foods including so-called health foods, as well as specific health foods and nutritional functional foods stipulated in the Health Functional Food System of the Ministry of Health, Labor and Welfare. In addition, dietary supplements are also included. [0101]
  • the form of the food composition of the present invention is not particularly limited, and may be any form as long as it can be taken orally.
  • Examples include powders, granules, tablets, hard capsules, soft capsules, liquids (beverages, jelly drinks, etc.), candy, chocolate, etc., all of which can be produced by methods known per se in the art. .
  • the content of the compound of the present invention in the food composition is appropriately determined so as to obtain an appropriate dose within the indicated range.
  • the food composition of the present invention may use other food additives as necessary.
  • Such food additives include fruit juice, dextrin, cyclic oligosaccharides, sugars (monosaccharides and polysaccharides such as fructose and glucose), acidulants, flavors, matcha tea powder, etc. that improve the taste and texture.
  • Emulsifiers collagen, whole milk powder, thickening polysaccharides and agar, vitamins, eggshell calcium, calcium pantothenate, other minerals, royal jelly, propolis, honey, dietary fiber, agaritas, chitin, chitosan, flavonoids, Examples include strengths used as ingredients in normal health foods such as rotenoids, rutin, herbal medicine, chondroitin, and various amino acids.
  • ratatonii in the amidy reaction can be prevented by protecting the hydroxyl group and amino group of HIL with aminal in the aminalization step (a), so that the amide of HIL can be obtained in high yield.
  • Compound ( ⁇ ) which is a chemical compound.
  • the resulting compound ( ⁇ ) leads to compounds (I) to ( ⁇ ) by protecting and Z or modifying its N-terminus and Z- or C-terminus by methods known per se in the field of peptide synthesis. This comes out.
  • each step will be described in detail.
  • functional groups other than the sites involved in the reaction are protected and protected as necessary, at an appropriate stage. It may be deprotected.
  • isolation and purification may be performed by appropriately selecting or combining conventional methods such as crystallization, recrystallization, column chromatography, thin layer chromatography, and HPLC. Further, in each step, the next step without isolation and purification may be performed.
  • Step (a) comprises the first step of reacting 4-hydroxyisoleucine with compound (A) or its acetal form to form compound (IV), and the second step of introducing a protecting group into NH as necessary. It is a manufacturing method of a compound (V).
  • PG in compound represents a hydrogen atom and is equivalent to compound (IV).
  • Q 1 and Q 2 are a hydrogen atom or a substituent
  • I also, when it is alkyl group, compound (IV) is preferably fixture Q 1 and aspects of introducing protecting groups to NH of At least one of Q 2 may have a substituent, may be an aryl group or a substituent, may be a heterocyclic group or a substituent, and may be a cycloalkyl group. In some cases, a mode in which a protecting group is not introduced into NH of compound (IV) is preferred.
  • the first step is performed, for example, by mixing 4-hydroxysoloisine with compound (A) or its acetal form in a solvent under basic conditions.
  • the order of addition is not particularly limited.
  • Examples of the compound (A) include formaldehyde (including related compounds such as formalin aqueous solution, paraformaldehyde, and metaformaldehyde), acetone, and benzaldehyde optionally having a substituent (eg, Benzaldehyde, p-Methylbenzaldehyde, p-Chlorobenzaldehyde, o-Chlorobenzaldehyde, p-Fluorobenzaldehyde, ⁇ -Methoxybenzaldehyde, p-Cyanobenzaldehyde, p--Trobenzaldehyde , M--trobenzaldehyde, o--trobenzaldehyde, p-trifluoromethylbenzaldehyde, etc.), cycloalkyl aldehyde (eg, cyclohexyl aldehyde, cyclopentyl
  • Toro benzaldehyde preferably /,.
  • Examples of the acetal form of the compound (A) include methylal, acetone dimethyl acetal, benzaldehyde dimethyl acetal, trifluoroacetaldehyde ethyl hemiacetal, p-trobenzaldehyde dimethyl acetal, and the like.
  • the amount of compound (A) or its acetal compound to be used is generally 1 to 3 equivalents, preferably 1 to 1.5 equivalents, relative to 4-hydroxyisoleucine.
  • Examples of the base used for the basic conditions include sodium hydroxide, lithium hydroxide, lithium hydroxide, sodium hydrogen carbonate, sodium carbonate, potassium carbonate, and the like.
  • Sodium bicarbonate is preferred, with sodium or sodium bicarbonate being preferred.
  • the amount of base used is usually 1 to 5 equivalents, preferably 1 to 3 equivalents, relative to 4-hydroxyisoleucine.
  • the solvent may be any solvent that does not inhibit this reaction. Examples thereof include water, acetonitrile, acetone, dimethylformamide, 1,4 dioxane, and a mixed solvent of two or more of these. , Water, acetone, acetonitrile, or a mixed solvent of two or more of these.
  • the amount of the solvent to be used is usually 1 to 100 times weight, preferably 1 to 50 times weight, with respect to 4-hydroxyisoleucine.
  • the reaction temperature is usually in the range of 10 ° C to 50 ° C, preferably 0 ° C to 30 ° C.
  • the reaction time is usually 0.5 hours to 24 hours within the above temperature range.
  • the amino group protecting group is preferred and is a Boc group or Z group which is an embodiment will be described, but the second step is not limited thereto.
  • reaction is carried out by mixing compound (IV) and a protective reagent in a solvent under basic conditions.
  • the order of addition is not particularly limited.
  • Examples of the protective reagent include di-tert-butyl dicarbonate, benzyloxycarbonyl chloride and the like.
  • the amount of the protective reagent to be used is generally 1-10 equivalents, preferably 1-3 equivalents, relative to compound (IV).
  • bases used for basic conditions include sodium hydroxide and hydroxy hydroxide. And triethylamine.
  • the amount of the base to be used is generally 1 to 4 equivalents, preferably 1 to 2 equivalents, relative to compound (IV).
  • a catalytic amount of hydroxylamine may be added.
  • the amount of the catalyst to be used is generally 0.05 to 0.5 equivalent, preferably 0.05 to 0.2 equivalent, relative to compound (IV).
  • the solvent may be any solvent as long as it does not inhibit this reaction. Examples thereof include water, acetone, acetonitrile, dimethylformamide, 1,4 dioxane, and a mixture of two or more of these. Water, acetone, acetonitrile, or a mixed solvent of two or more of these is preferable.
  • the amount of the solvent to be used is generally 1 to: LOO double weight, preferably 1 to 50 times weight with respect to compound (IV).
  • the reaction temperature is usually in the range of 10 ° C to 50 ° C, preferably 0 ° C to 30 ° C.
  • the reaction time is usually 0.5 hours to 24 hours within the above temperature range.
  • the amidite step (b) is a method for producing compound (VII) by reacting compound (V) with compound (VI).
  • the amidation step (b) can be carried out by the method described in Peptides: Chemistry and Biology Wiley-VCH (2002) generally used for amidation reaction. Specifically, for example, it is carried out by mixing compound (V), compound (VI) and a condensing agent in a solvent.
  • the order of addition is not particularly limited.
  • the amount of compound (VI) to be used is generally 1 to 2 equivalents, preferably 1 to 1.2 equivalents, relative to compound (V).
  • Examples of the condensing agent include N, N, monodicyclohexylcarbodiimide (DCC), N- (3-dimethylaminopropyl) N, -ethylcarbodiimide hydrochloride (EDC), N, N ' Carbodiimide condensing agents such as isopropylcarbodiimide (DIPC), (benzotriazole-1-yloxy) tris (dimethylamino) phosphohexafluorophosphate (BOP), (benzotriazole 1-yloxy) tripyrrolidinophospho- Phospho-um salt condensing agents such as humhexafluorophosphate (PyBOP) and bromotripyrrolidinophospho-hexafluorophosphate (PyBroP), O— (benzotriazole-1-yl) ) — N, N, N, N, monotetramethyl hexafluorophosphate (HBTU),
  • EDC and DCC are preferred.
  • the amount of the condensing agent to be used is generally 1 to 2 equivalents, preferably 1 to 1.5 equivalents, relative to compound (V).
  • a base is preferably added to neutralize or accelerate the reaction.
  • the base include triethylamine, diisopropylethylamine, pyridine, N-methylmorpholine and the like.
  • the amount of the base to be used is generally 1 to 3 equivalents, preferably 1 to 2 equivalents, relative to compound (V) and Z or compound (VI).
  • an ester activator is preferably added to facilitate the reaction.
  • the ester activator include 1-hydroxybenzotriazole, 1-hydroxy-7-azabenzotriazole, 3 hydroxy3,4 dihydro-4-oxo1.2.3 benzotriazine, pentafluorophenol, N-hydroxymono 5 Norbornene 1,3 dicarboximide, N-hydroxysuccinimide and the like.
  • the amount of the ester activator to be used is generally 0.1 to 2 equivalents, preferably 1 to 1.5 equivalents, relative to compound).
  • the solvent may be any solvent that does not inhibit this reaction. Examples thereof include methylene chloride, acetonitrile, dimethylformamide, ethyl acetate and the like, or a mixed solvent of two or more thereof. Methylene is preferred.
  • the amount of the solvent to be used is generally 1.0 to LOO times weight, preferably 10 to 80 times weight, relative to compound (V).
  • the reaction temperature is usually in the range of 0 ° C to 50 ° C, preferably 10 ° C to 30 ° C.
  • the reaction time is usually 1 hour to 24 hours within the above temperature range.
  • compound (V) is once converted into a corresponding activated form, that is, active ester, acid halide, acid anhydride, acyl azide, etc., and then mixed with compound (VI) in a solvent.
  • active ester compounds (VIII) [0128] [Chemical 20]
  • E represents an active ester residue
  • Q 1 and Q 2 each independently represent a hydrogen atom, an alkyl group which may have a substituent, or a substituent.
  • a good aryl group, having a substituent! /, Or a heterocyclic group or a substituent, may be a cycloalkyl group
  • PG represents a hydrogen atom or an amino group protecting group.
  • the conversion step of compound (V) to active ester compound (VIII) can be carried out by using the condensing agent shown above in place of compound (VI) according to the method and conditions of the amidy step. This can be done by using an active esterifying agent.
  • active esterifying agent examples include N-hydroxysuccinimide, 1-hydroxybenzotriazole, 4--trophenol, pentafluorophenol, N-hydroxy-1-norbornene 2,3 dicarboxylic imide and the like. Details of other reaction conditions are omitted.
  • the step of converting the active ester compound (VIII) to the amido compound (VII) for example, the compound (VIII) and the compound (VI) are mixed under a basic condition in a solvent. Is done by.
  • the order of addition is not particularly limited.
  • the amount of compound (VI) to be used is generally 1-2 equivalents, preferably 1-1.1, relative to compound (VIII).
  • a base is preferably added to neutralize or accelerate the reaction.
  • the base include triethylamine, diisopropylethylamine, pyridine, N-methylmorpholine and the like. I can get lost.
  • the amount of the base to be used is generally 1 to 5 equivalents, preferably 1 to 2 equivalents, relative to compound (VIII) and Z or compound (VI).
  • the solvent may be any solvent as long as it does not inhibit this reaction. Examples thereof include methylene chloride, acetonitrile, dimethylformamide, ethyl acetate and the like, or a mixed solvent thereof, and methylene chloride is preferable.
  • the amount of the solvent to be used is generally 1 to 100-fold weight, preferably 2 to 20-fold weight, relative to compound (VIII).
  • the reaction temperature is usually in the range of 0 ° C to 50 ° C, preferably 10 ° C to 30 ° C.
  • the reaction time is usually 1 hour to 24 hours within the above temperature range.
  • the deprotection step (c) is a method for producing a compound ( ⁇ ) in which, when PG of the compound (VII) is an amino group protecting group, PG is deprotected and the aminal group is deprotected.
  • the order of deprotection of PG and aminal groups may be carried out simultaneously after deprotection of PG, if the order of deprotection of aminal groups is preferable.
  • a per se known deprotection method suitable for the amino group protecting group to be employed can be employed without any particular limitation.
  • the Boc group can be deprotected by reacting with acids such as trifluoroacetic acid, hydrochloric acid, formic acid, hydrobromic acid, and liquid hydrogen fluoride at room temperature for 0.5 to 24 hours. it can.
  • the Z group it can be deprotected by a hydrogenation reaction using a catalyst such as noradium carbon, or a hydrobromic acid solution or liquid hydrogen fluoride.
  • Deprotection of the aminal group can be carried out, for example, by mixing compound (VII) or its PG deprotected form with an amine compound in a solvent.
  • the order of addition is not particularly limited.
  • Examples of amine compounds include hydroxylamine and acid addition salts thereof.
  • the amount of the amine compound used is usually 1-10 equivalents, preferably 1-5 equivalents, relative to compound (VII) or its PG deprotected form.
  • the solvent may be any solvent that does not inhibit this reaction.
  • methanol , Ethanol, water, acetonitrile, or a mixed solvent thereof, and methanol or water is preferable.
  • the amount of the solvent to be used is generally 1 to 200 times by weight, preferably 50 to 100 times by weight, relative to compound (VII) or its PG deprotected form.
  • the reaction temperature is usually in the range of 0 ° C to 100 ° C, preferably 10 ° C to 80 ° C.
  • the reaction time is usually 0.1 hour to 24 hours within the above temperature range.
  • deprotection of the aminal group can be carried out, for example, by catalytic reduction in a solvent in a hydrogen atmosphere.
  • Examples of the metal catalyst used for catalytic reduction include palladium, rhodium, platinum and the like.
  • the amount of the metal catalyst to be used is generally 0.01-1 equivalent, preferably 0.05-0.5 equivalent, relative to compound (VII) or its PG deprotected form.
  • the solvent may be any solvent as long as it does not inhibit this reaction. Examples thereof include methanol, ethanol, ethyl acetate, ethanol containing hydrogen chloride, and a mixed solvent of two or more thereof. Ethanol is preferred.
  • the amount of the solvent used is usually 5 to 200 times by weight, preferably 30 to LOO times the weight of the compound (VII) or its PG deprotected form.
  • the reaction temperature is usually in the range of 0 ° C to 50 ° C, preferably 10 ° C to 30 ° C.
  • the reaction time is usually 0.5 hours to 24 hours within the above temperature range.
  • Q 1 is a hydrogen atom
  • Q 2 is a ⁇ -trophenyl group, a cyclohexyl group, a phenol group, a 4-pyridyl group, a 4-chlorophenol group, a 4-methoxyphenyl group, a 4-methylphenol Group, 4 trifluoromethylphenyl group, 4 fluorophenyl group, 4 cyanophenol group, 2 —black-mouthed phenol group, 2-trophenyl group, 3-trophenyl group, 2 chalcone Or 2-furyl group
  • PG is a hydrogen atom
  • X ′ is a hydroxyl group, or Gly, Ala, Val, Leu, Ile, Met, Phe, Tyr, Trp, His, Lys ⁇ Arg, Ser ⁇ ⁇
  • a preferred embodiment is an amino acid residue selected from Thr, Asp, Glu, Asn, Gin, Cys, and Pro (carboxylic acid may be protected).
  • the configuration of a compound specified in the reaction formula indicates the configuration of the corresponding compound in the example.
  • the reaction mixture was separated with t-butyl methyl ether and water.
  • the obtained aqueous layer was acidified to pH 3 with 6 mol Zl hydrochloric acid and extracted with ethyl acetate.
  • This organic layer was dried over anhydrous sodium sulfate, the desiccant was removed by filtration, and then the solvent was distilled off to obtain 615 mg (2. ImmoU yield 42%) of the title compound.
  • H-cHIL (pNBA) — OH crude product (lOOmg) was dissolved in methylene chloride (6ml), glutamine t-butyl ester hydrochloride (80mg, 0.34mmol), 1-hydroxybenzotriazole (55mg, 0. 40 mmol), 1-ethyl-3- (3 dimethylaminopropyl) carbodiimide hydrochloride (70 mg, 0.37 mmol) and triethylamine (0.05 ml, 0.36 mmol) were sequentially added and allowed to react overnight at room temperature. .
  • Example 1 (1) In the same manner as in Example 1 (1), 80 0-1 0-11 (0.8 g, 3.08 mmol) was dissolved in methylene chloride (20 ml), and N- ⁇ --troarginine was dissolved. Methyl ester hydrochloride (0.83 g, 3.08 mmol) was added and cooled to 0 ° C. 1-Hydroxybenzotriazole (0.77 g, 5.69 mmol), 1-ethyl-3- (3 dimethylaminopropyl) carbodiimide hydrochloride (1.15 g, 6. OOmmol) and triethylamine ( 0.8 ml, 6.14 mmo 1) was sequentially added, and the mixture was reacted at room temperature overnight.
  • 1-Hydroxybenzotriazole (0.77 g, 5.69 mmol
  • 1-ethyl-3- (3 dimethylaminopropyl) carbodiimide hydrochloride (1.15 g, 6. OOm
  • Boc-cHIL-Arg (NO) —OMe (l. 24 g, 2. 60 mmol) was dissolved in THF (6 ml).
  • the mixture was treated with 1M aqueous lithium hydroxide solution (3 ml) at room temperature for 6 hours.
  • the reaction mixture was cooled to 0 ° C., neutralized with 1M aqueous hydrochloric acid solution, and partitioned with ethyl acetate.
  • the ethyl acetate layer was washed successively with water and saturated Japanese saline, then dried over anhydrous magnesium sulfate, and the ethyl acetate was distilled off to obtain a crude product of the title compound.
  • Boc-cHIL-Arg (NO) —OH (l. 23 g) dissolved in acetic acid (10 ml) and methanol (10 ml)
  • the catalyst amount of ⁇ % palladium Z carbon was added, and the system was replaced with hydrogen and stirred overnight.
  • HIL showed a residual rate of 89% after 30 minutes and 70% after 60 minutes.
  • Various H-HIL-Xa a-OH were all stable during the evaluation time.
  • Table 1 shows the residual rates of various H-HIL-Xaa-OH after 60 minutes.

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Abstract

La présente invention concerne des dérivés 4-hydroxyisoleucine stables ; et leur procédé de production. Les composés répondant à la formule (I) et les composés répondant à la formule (III) sont obtenus tout d'abord par la protection de la 4-hydroxyisoleucine avec un aminal et un groupe protecteur d'amine ; par la réaction de cette dernière avec n'importe quels dérivés acide aminé ou composés amine ; et ensuite par l'élimination de la protection. (Dans les formules, les symboles sont tels que définis dans la description.)
PCT/JP2007/054716 2006-03-10 2007-03-09 Derive 4-hydroxyisoleucine et son procede de production Ceased WO2007105650A1 (fr)

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Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008102671A1 (fr) * 2007-02-22 2008-08-28 Ajinomoto Co., Inc. Procédé de purification de 4-hydroxy-isoleucine
WO2009021740A2 (fr) 2007-08-15 2009-02-19 Sanofis-Aventis Nouvelles tétrahydronaphtalines substituées, leurs procédés de préparation et leur utilisation comme médicaments
WO2011107494A1 (fr) 2010-03-03 2011-09-09 Sanofi Nouveaux dérivés aromatiques de glycoside, médicaments contenants ces composés, et leur utilisation
DE102010015123A1 (de) 2010-04-16 2011-10-20 Sanofi-Aventis Deutschland Gmbh Benzylamidische Diphenylazetidinone, diese Verbindungen enthaltende Arzneimittel und deren Verwendung
WO2011157827A1 (fr) 2010-06-18 2011-12-22 Sanofi Dérivés d'azolopyridin-3-one en tant qu'inhibiteurs de lipases et de phospholipases
WO2011161030A1 (fr) 2010-06-21 2011-12-29 Sanofi Dérivés de méthoxyphényle à substitution hétérocyclique par un groupe oxo, leur procédé de production et leur utilisation comme modulateurs du récepteur gpr40
WO2012004270A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés 1,3-propanedioxyde à substitution spirocyclique, procédé de préparation et utilisation comme médicament
WO2012004269A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés d'acide ( 2 -aryloxy -acétylamino) - phényl - propionique, procédé de production et utilisation comme médicament
WO2012010413A1 (fr) 2010-07-05 2012-01-26 Sanofi Acides hydroxy-phényl-hexiniques substitués par aryloxy-alkylène, procédé de production et utilisation comme médicament
WO2012120056A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine tétra-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
WO2012120054A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine di- et tri-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
WO2012120053A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine ramifiés, procédé pour leur préparation, utilisation en tant que médicament, agents pharmaceutiques contenant ces dérivés et leur utilisation
WO2012120055A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine di- et tri-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
WO2012120052A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés d'oxathiazine substitués par des carbocycles ou des hétérocycles, leur procédé de préparation, médicaments contenant ces composés et leur utilisation
EP2567959A1 (fr) 2011-09-12 2013-03-13 Sanofi Dérivés d'amide d'acide 6-(4-Hydroxy-phényl)-3-styryl-1H-pyrazolo[3,4-b]pyridine-4-carboxylique en tant qu'inhibiteurs
WO2013037390A1 (fr) 2011-09-12 2013-03-21 Sanofi Dérivés amides d'acide 6-(4-hydroxyphényl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylique en tant qu'inhibiteurs de kinase
WO2013045413A1 (fr) 2011-09-27 2013-04-04 Sanofi Dérivés d'amide d'acide 6-(4-hydroxyphényl)-3-alkyl-1h-pyrazolo[3,4-b] pyridine-4-carboxylique utilisés comme inhibiteurs de kinase

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH03169871A (ja) * 1989-08-16 1991-07-23 Dr Karl Thomae Gmbh 新規１，３―オキサジン
JP2006508168A (ja) * 2002-12-02 2006-03-09 サーントル ナシオナル ドゥ ラ ルシェルシェ シャーンティフィク（セー．エンヌ．エール．エス．） ４−ヒドロキシイソロイシン及びその誘導体のジアステレオ異性体及びエナンチオマーの製造方法
US20060199853A1 (en) * 2005-02-18 2006-09-07 Charles Mioskowski Analogs of 4-hydroxyisoleucine and uses thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH03169871A (ja) * 1989-08-16 1991-07-23 Dr Karl Thomae Gmbh 新規１，３―オキサジン
JP2006508168A (ja) * 2002-12-02 2006-03-09 サーントル ナシオナル ドゥ ラ ルシェルシェ シャーンティフィク（セー．エンヌ．エール．エス．） ４−ヒドロキシイソロイシン及びその誘導体のジアステレオ異性体及びエナンチオマーの製造方法
US20060199853A1 (en) * 2005-02-18 2006-09-07 Charles Mioskowski Analogs of 4-hydroxyisoleucine and uses thereof

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
GHOSAL S. ET AL.: "Fenugreekine, a new steroidal sapogenin-peptide ester of Trigonella foenum-graecum", PHYTOCHEMISTRY, vol. 13, no. 10, 1974, pages 2247 - 2251, XP003017776 *
HAHN H. ET AL.: "Partialsynthese der nikkomycine Bx und Kx sowie unnatürlicher stereoisomerer und strukturanaloga", LIEBIGS ANNALEN DER CHEMIE, no. 9, 1987, pages 803 - 807, XP003017775 *

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008102671A1 (fr) * 2007-02-22 2008-08-28 Ajinomoto Co., Inc. Procédé de purification de 4-hydroxy-isoleucine
WO2009021740A2 (fr) 2007-08-15 2009-02-19 Sanofis-Aventis Nouvelles tétrahydronaphtalines substituées, leurs procédés de préparation et leur utilisation comme médicaments
WO2011107494A1 (fr) 2010-03-03 2011-09-09 Sanofi Nouveaux dérivés aromatiques de glycoside, médicaments contenants ces composés, et leur utilisation
DE102010015123A1 (de) 2010-04-16 2011-10-20 Sanofi-Aventis Deutschland Gmbh Benzylamidische Diphenylazetidinone, diese Verbindungen enthaltende Arzneimittel und deren Verwendung
WO2011157827A1 (fr) 2010-06-18 2011-12-22 Sanofi Dérivés d'azolopyridin-3-one en tant qu'inhibiteurs de lipases et de phospholipases
WO2011161030A1 (fr) 2010-06-21 2011-12-29 Sanofi Dérivés de méthoxyphényle à substitution hétérocyclique par un groupe oxo, leur procédé de production et leur utilisation comme modulateurs du récepteur gpr40
WO2012004270A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés 1,3-propanedioxyde à substitution spirocyclique, procédé de préparation et utilisation comme médicament
WO2012004269A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés d'acide ( 2 -aryloxy -acétylamino) - phényl - propionique, procédé de production et utilisation comme médicament
WO2012010413A1 (fr) 2010-07-05 2012-01-26 Sanofi Acides hydroxy-phényl-hexiniques substitués par aryloxy-alkylène, procédé de production et utilisation comme médicament
WO2012120056A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine tétra-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
WO2012120054A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine di- et tri-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
WO2012120053A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine ramifiés, procédé pour leur préparation, utilisation en tant que médicament, agents pharmaceutiques contenant ces dérivés et leur utilisation
WO2012120055A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine di- et tri-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
WO2012120052A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés d'oxathiazine substitués par des carbocycles ou des hétérocycles, leur procédé de préparation, médicaments contenant ces composés et leur utilisation
EP2567959A1 (fr) 2011-09-12 2013-03-13 Sanofi Dérivés d'amide d'acide 6-(4-Hydroxy-phényl)-3-styryl-1H-pyrazolo[3,4-b]pyridine-4-carboxylique en tant qu'inhibiteurs
WO2013037390A1 (fr) 2011-09-12 2013-03-21 Sanofi Dérivés amides d'acide 6-(4-hydroxyphényl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylique en tant qu'inhibiteurs de kinase
WO2013045413A1 (fr) 2011-09-27 2013-04-04 Sanofi Dérivés d'amide d'acide 6-(4-hydroxyphényl)-3-alkyl-1h-pyrazolo[3,4-b] pyridine-4-carboxylique utilisés comme inhibiteurs de kinase

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