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WO1998043649A2 - Composition inhibant la production de produits terminaux de glycosylation avancee comprenant un inhibiteur de la reaction de maillard et la vitamine b¿6? - Google Patents

Composition inhibant la production de produits terminaux de glycosylation avancee comprenant un inhibiteur de la reaction de maillard et la vitamine b¿6? Download PDF

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Publication number
WO1998043649A2
WO1998043649A2 PCT/JP1998/001365 JP9801365W WO9843649A2 WO 1998043649 A2 WO1998043649 A2 WO 1998043649A2 JP 9801365 W JP9801365 W JP 9801365W WO 9843649 A2 WO9843649 A2 WO 9843649A2
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group
lower alkyl
phenyl
alkyl group
ring
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WO1998043649A3 (fr
Inventor
Koichi Yasumura
Shintaro Ishikawa
Tadami Utsunomiya
Kazuhiko Hayashi
Tadashi Okada
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Otsuka Pharmaceutical Co Ltd
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Otsuka Pharmaceutical Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof

Definitions

  • the present invention relates to a novel AGE production inhibitory composition serving to inhibit the production of an advanced glycation endproduct (hereinafter referred to as "AGE"), which causes diabetic complications such as cataract, nephropathy, and retinopathy.
  • AGE advanced glycation endproduct
  • proteins are nonenzymatically saccharified.
  • the process of protein saccharification comprises the first stage which produces a product such as saccharified hemoglobin, which is clinically used as a measure for the control of diabetes, and the second stage which produces an AGE.
  • the AGE is considered to be produced as follows .
  • free amino groups present in a protein react with aldehyde groups of a reducing sugar such as glucose (glycation) nonenzymatically to form an Amadori rearrangement product via a Sciff base called an aldimine.
  • the Amadori rearrangement product undergoes complicated reactions including cleavage and condensation over a long period of time to yield the AGE. (These reactions are called the Maillard reaction.)
  • these reactions are called the Maillard reaction.
  • the AGE is known to be characterized, e.g. , by emitting fluorescence, having a brown color, forming molecular crosslinks, and being recognized by endothelial cells and macrophage receptors.
  • fluorescence having a brown color
  • molecular crosslinks forming molecular crosslinks
  • the AGE has a variety of biological activities including (1) enhancement of the permeability of endothelial cells, (2) enhancement of the coagulability of endothelial cells, (3) enhancement of neovascularization in endothelial cells ,
  • the AGE is considered to participate in the formation of various lesions , especially in the onset of diseases attributable to senescence and diabetic complications (e.g. , cataract, vascular lesion, nephropathy, retinopathy, neurosis, and arteriosclerosis).
  • diseases attributable to senescence and diabetic complications e.g. , cataract, vascular lesion, nephropathy, retinopathy, neurosis, and arteriosclerosis.
  • Aminoguanidine for example, is known as a Maillard reaction inhibitor, which inhibits AGE production (see Saishin Igaku, 49(2): 78-83 (1994)), and is expected to be useful for the prevention and treatment of those diseases.
  • the known Maillard reaction inhibitors including aminoguanidine have a problem that they produce various side effects although they can inhibit AGE production.
  • An object of the present invention is to provide an AGE production inhibitory composition having low side effects .
  • the present inventors made intensive studies in order to eliminate the problem described above. As a result, they have newly found that the side effects can be prevented or lessened by using a Maillard reaction inhibitor in combination with vitamin B 6 or a pharmaceutically acceptable salt thereof. The present invention has been completed based on this finding.
  • an AGE production inhibitory composition which comprises (a) a Maillard reaction inhibitor and (b) vitamin B 6 or a pharmaceutically acceptable salt thereof.
  • Fig. 1 is a graph showing the results of an examination of the AGE production inhibitory effect of an AGE production inhibitory composition according to the present invention in various concentrations , as determined with an ELISA tray reader (Titertek (registered trademark) , Multiscan MCC/340MKII) . Best Mode for Practicing Invention
  • the AGE production inhibitory composition of the present invention is useful for the treatment and/or prevention of various diabetic complications caused by AGE production, e.g., coronary diseases, peripheral circulatory disturbances, cerebrovascular disorders, diabetic neurosis, nephropathy, arteriosclerosis, ankylosis, cataract, and retinopathy, and diseases caused by senescence, e.g., atherosclerosis and senile cataract.
  • the AGE production inhibitory composition of the present invention is effective in preventing or lessening side effects such as vomiting, convulsions, death, and giving abnormal results in serum biochemical tests or hematologic tests.
  • Examples of the Maillard reaction inhibitor used in the AGE production inhibitory composition of the present invention include: aminoguanidine derivatives disclosed, e.g. , in JP-A-62-142114 (the term "JP-A” as used herein means an "unexamined published Japanese patent application") , JP-A-64-56614 , and JP-A-64-83059; compounds represented by the following formula (1) disclosed in JP-A-7-133264 :
  • R 1 represents : a hydrogen atom, a lower alkoxycarbonyl-lower alkyl group, a phenyl-lower alkyl group which may have 1 to 3 substituents selected from the group consisting of a halogen atom, a hydroxyl group, a nitro group, a lower alkyl group, a lower alkoxy group, and a lower alkylthio group on the phenyl ring thereof, or a phenyl group which may have 1 to 3 substituents selected from the group consisting of a halogen atom, a hydroxyl group, a nitro group, a lower alkyl group, a lower alkoxy group, and a lower alkylthio group;
  • R 3 represents : a hydrogen atom, a lower alkyl group, a lower alkenyl group, a phenyl-lower alkoxy-lower alkyl group, a phenyl group which may have at least one hydroxyl group, a 5-membered or 6-membered unsaturated heterocyclic-lower alkyl group having 1 or 2 hetero atoms selected from the group consisting of a nitrogen atom and a sulfur atom (wherein the heterocyclic ring may be condensed with a benzene ring and a hydroxyl group may be located as a substituent on the heterocyclic ring or the benzene ring condensed with the heterocyclic ring) , a group represented by -W- (NH) b -CO-OR 5 (wherein W represents a lower alkylene group; R 5 represents a hydrogen atom, a lower alkyl group, or a phenyl-lower alkyl group; and b represents 0 or
  • R 8 represents a hydroxyl group, a nitro group, an amino group, a halogen atom, a lower alkyl group, a lower alkoxy group, a phenoxy group, a phenyl-lower alkyl group, a lower alkylthio group, a phenylthio group which may have at least one halogen atom, a benzoylamino group which may have 1 to 3 halogen atoms , or a group represented by -O-D-R 9 (wherein D represents a lower alkylene group; and R represents a phenyl group which may have 1 to 3 substituents selected from the group consisting of a halogen atom, a hydroxyl group, a nitro group, a lower alkyl group, a lower alkoxy group, and a lower alkylthio group on the phenyl ring thereof
  • phenyl ring may be condensed with a benzene ring or a cyclohexane ring
  • heterocyclic ring may be condensed with a benzene ring and may have 1 to 5 substituents selected from the group consisting of a hydroxyl group and a lower alkyl group on the heterocyclic or the benzene ring condensed with the heterocyclic ring) , a lower cycloalkyl group, or a naphthoquinone group) ; and n represents 0 or an integer of 1 to 3 ⁇ ;
  • R 10 represents a hydrogen atom or a lower alkoxycarbonyl-lower alkyl group
  • R 10 represents a hydrogen atom or a lower alkoxycarbonyl-lower alkyl group
  • A represents a carbonyl group
  • A represents:
  • R 11 represents a lower alkyl group which may have 1 to 3 halogen atoms , a lower alkoxycarbonyl-lower alkyl, a carboxy-lower alkyl group, a pyridyl group, a thienyl group, a thiazolyl group, a phenylcarbamoyl-lower alkyl group which may have 1 or 2 lower alkoxy groups on the phenyl ring thereof, or a group represented by
  • R 12 represents a halogen atom, a hydroxyl group, a nitro group, a lower alkyl group, a lower alkoxy group, a lower alkylthio group, a carboxyl group, a phenylthio group, or a phenyl-lower alkoxy group which may have 1 to 3 halogen atoms on the phenyl ring thereof; and m represents 0 or an integer of 1 to 3) ⁇ ; and
  • R 4 and R 10 may bind to each other to form a 6-membered to 8-membered ring, with the proviso that A represents a carbonyl group in this case; when R 3 and A represent a hydrogen atom and a carbonyl group, respectively, R 1 is neither a hydrogen atom nor a lower alkoxycarbonyl-lower alkyl group; and
  • R 3 and R 11 may bind to each other to form a 5-membered to 8-membered ring, or pharmaceutically acceptable salts thereof; compounds represented by the following formula (2) disclosed in JP-A-5-201993 :
  • R represents a hydrogen atom, a lower alkyl group, a carboxy-lower alkyl group, a lower alkoxycarbonyl-lower alkyl group, a phenoxy-lower alkanoyl group, a phenoxy-lower alkanoyl group having at least one lower alkoxycarbonyl group on the phenyl ring thereof , or a lower cycloalkyl group;
  • R 15 represents : two hydrogen atoms , a phenyl-lower alkylidene group which may have at least one substituent selected from the group consisting of a halogen atom and a halogenated lower alkyl group on the phenyl ring thereof, or a phenyl-lower alkenylidene group; and
  • Y represents :
  • R 19 represents a hydrogen atom, a lower alkyl group, a carboxyl-lower alkyl group, or a lower alkoxycarbonyl-lower alkyl group
  • R 20 represents : a hydrogen atom or a lower alkyl group
  • R 21 represents : a hydrogen atom, a lower alkyl group, a lower alkanoyl group, or a lower alkoxycarbonyl-lower alkyl group;
  • R 22 represents a hydrogen atom, a lower alkyl group, or a lower alkanoyl group
  • R 23 represents a hydrogen atom, a lower alkanoyl group, a benzoyl group, or a group represented by
  • R 24 represents a phenyl group or a lower alkoxy group
  • R 22 and R 23 may bond to each other to form a lower alkylidene group, a diphenylmethylene group, or a phenyl-lower alkylidene group
  • V represents :
  • R 25 represents a hydrogen atom, a lower alkyl group, a lower alkoxycarbonyl-lower alkyl group, or a phenyl-lower alkyl group which may have at least one halogen atom as a substituent on the phenyl ring thereof;
  • R 23 and R 25 may bind to each other to form a 6-membered to 8-membered ring, or pharmaceutically acceptable salts thereof .
  • Maillard reaction inhibitors from the standpoint of compatibility with vitamin B 6 or a pharmaceutically acceptable salt thereof, preferred examples include : aminoguanidine ,
  • the amount of the vitamin B 6 or a pharmaceutically acceptable salt thereof contained in the AGE production inhibitory composition of the present invention is preferably from 0.1 to 200 parts by weight based on 100 parts by weight of the Maillard reaction inhibitor .
  • Examples of the lower alkoxycarbonyl-lower alkyl group include alkoxycarbonylalkyl groups in which the alkoxy moiety has 1 to 6 carbon atoms and the alkyl moiety has 1 to 6 carbon atoms . Specific examples thereof include methoxycarbonylmethyl , ethoxycarbonylmethyl , 3-methoxycarbonylpropyl , 4-ethoxycarbonylbutyl , 6-propoxycarbonylhexyl ,
  • halogen atom examples include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom, regardless of whether it is present as an independent substituent or present in other groups .
  • Examples of the lower alkyl group include straight-chain or branched alkyl groups having 1 to 6 carbon atoms . Specific examples thereof include , such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, and hexyl, regardless of whether it is present as an independent substituent or present in other groups .
  • lower alkoxy group examples include straight-chain or branched alkoxy groups having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, pentyloxy, and hexyloxy, regardless of whether it is present as an independent substituent or present in other groups .
  • lower alkylthio group examples include alkylthio groups in which the alkyl moiety is a straight-chain or branched alkyl group having 1 to 6 carbon atoms . Specific examples thereof include methylthio, ethylthio, propylthio, butylthio, isopropylthio, t-butylthio, pentylthio, and hexylthio.
  • Examples of the phenyl-lower alkyl group which may have 1 to 3 substituents selected from the group consisting of a halogen atom, a hydroxyl group, a nitro group, a lower alkyl group, a lower alkoxy group, and a lower alkylthio group on the phenyl ring thereof include phenyl-lower alkyl groups which may have 1 to 3 substituents selected from the group consisting of a halogen atom, a hydroxyl group, a nitro group, a straight-chain or branched alkyl group having 1 to 6 carbon atoms , a straight-chain or branched alkoxy group having 1 to 6 carbon atoms, and a straight-chain or branched alkylthio group having 1 to 6 carbon atoms, in which the alkyl moiety is a straight-chain or branched alkyl group having 1 to 6 carbon atoms .
  • Examples of the phenyl group which may have 1 to 3 substituents selected from the group consisting of a halogen atom, a hydroxyl group, a nitro group, a lower alkyl group, a lower alkoxy group, and a lower alkylthio group on the phenyl ring thereof include phenyl groups which may have 1 to 3 substituents selected from the group consisting of a halogen atom, a hydroxyl group, a nitro group, a straight-chain or branched alkyl group having 1 to 6 carbon atoms, a straight-chain or branched alkoxy group having 1 to 6 carbon atoms, and a straight- chain or branched alkylthio group having 1 to 6 carbon atoms .
  • phenyl 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 4-bromophenyl , 4-iodophenyl, 2 ,3-dichlorophenyl, 2 , 3-difluorophenyl , 2 , 5-dibromophenyl ,
  • Examples of the lower alkanoylamino group include amino groups which have a straight-chain or branched alkanoyl group having 1 to 6 carbon atoms, regardless of whether it is present as an independent substituent or present in other groups . Specific examples thereof include formylamino, acetylamino, propionylamino , butyrylamino, isobutyrylamino , pentanoylamino , t-butylcarbonylamino , and hexanoylamino .
  • phenylsulfonylamino group which may have at least one substituent selected from the group consisting of a halogen atom, a hydroxyl group, an amino group, and an alkanoylamino group
  • lower alkylidene group examples include straight-chain or branched alkylidene groups having 1 to 6 carbon atoms , such as methylene , ethylidene, propylidene, isopropylidene, butylidene, t-butylidene, pentylidene, and hexylidene.
  • lower alkylidene group having 1 or 2 lower cycloalkyl groups examples include straight-chain or branched alkylidene groups having 1 to 6 carbon atoms and having one or two cycloalkyl groups each having 3 to 8 carbon atoms . Specific examples thereof include 2-cyclopropylethylidene, 1-cyclobutylethylidene,
  • Examples of the lower cycloalkylidene group include cycloalkylidene groups having 3 to 8 carbon atoms , such as cyclopropylidene , cyclobutyliden , cyclopentylidene, cyclohexylidene, cycloheptylidene, and cyclooctylidene .
  • diphenyl-lower alkylidene group examples include diphenylalkylidene groups in which the alkylidene moiety is a straight-chain or branched alkylidene group having 1 to 6 carbon atoms . Specific examples thereof include 1 ,1-diphenylethylidene, 2 , 2-diphenylethylidene , 3 , 3-diphenylpropylidene, 4 , 4-diphenylbutylidene, 5 , 5-diphenylpentylidene, and 6 , 6-diphenylhexylidene .
  • phenyl-lower alkylidene group examples include phenylalkylidene groups in which the alkylidene moiety is a straight-chain or branched alkylidene group having 1 to 6 carbon atoms . Specific examples thereof include benzylidene, 2-phenylethylidene,
  • lower alkenyl group examples include straight-chain or branched alkenyl groups having 2 to 6 carbon atoms, such as vinyl, allyl, 2-butenyl, 3-butenyl, 1-methylallyl, 2-pentenyl, and 2-hexenyl.
  • phenyl-lower alkoxy-lower alkyl group examples include phenylalkoxyalkyl groups in which the alkoxy moiety is a straight-chain or branched alkoxy group having 1 to 6 carbon atoms and the alkyl moiety is a straight-chain or branched alkyl group having 1 to 6 carbon atoms .
  • Specific examples thereof include benzyloxymethyl , 2-phenylethoxymethyl ,
  • phenyl group which may have at least one hydroxyl group include 2-hydroxyphenyl , 3-hydroxyphenyl, and 4-hydroxyphenyl .
  • Examples of the 5-membered or 6-membered unsaturated heterocyclic-lower alkyl group having 1 or 2 hetero atoms selected from the group consisting of a nitrogen atom and a sulfur atom include straight-chain or branched alkyl groups having 1 to 6 carbon atoms and having a 5-membered or 6-membered unsaturated heterocycle having 1 or 2 hetero atoms selected from the group consisting of a nitrogen atom and a sulfur atom. Specific examples thereof include 2-pyridinylmethyl, 3-pyridinylmethy1 , 4-pyridinylmethy1 ,
  • 3-indolylmethyl 2- (3-indolyl) ethyl, 3- (3-indolyl) propyl, 4- (3-indolyl) butyl, 5- (3-indolyl) pentyl ,
  • phenyl-lower alkyl group examples include phenylalkyl groups in which the alkyl moiety is a straight-chain or branched alkyl group having 1 to 6 carbon atoms . Specific examples thereof include benzyl , 2-phenylethyl, 1-phenylethyl, 3-phenylpropyl , 4-phenylbutyl , 1 , l-dimethyl-2-phenylethyl ,
  • carboxy-lower alkyl group examples include carboxyalkyl groups in which the alkyl moiety is a straight-chain or branched alkyl group having 1 to 6 carbon atoms . Specific examples thereof include carboxymethyl, 2-carboxyethyl, 1-carboxyethyl, 3-carboxypropyl, 4-carboxybutyl,
  • Examples of the lower cycloalkyl group include cycloalkyl groups having 3 to 8 carbon atoms , such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl , and cyclooctyl .
  • lower alkoxycarbonyl group examples include straight-chain or branched alkoxycarbonyl groups having 1 to 6 carbon atoms , such as methoxycarbonyl , ethoxycarbonyl , propoxycarbonyl , isopropoxycarbonyl , butoxycarbonyl, t-butoxycarbonyl, pentyloxycarbonyl, and hexyloxycarbonyl .
  • phenyl-lower alkoxy group examples include straight-chain or branched phenylalkoxy groups in which the alkoxy moiety has 1 to 6 carbon atoms . Specific examples thereof include benzyloxy, 2-phenylethoxy, 3-phenylpropoxy, 1-phenylisopropoxy, 4-phenylbutoxy, 5-phenylpentyloxy, 6-phenylhexyloxy, and
  • halogenated lower alkyl group examples include straight-chain or branched halogenated alkyl groups which have 1 to 3 halogen atoms and in which the alkyl moiety has 1 to 6 carbon atoms .
  • chloromethyl bromomethyl , iodomethyl , fluoromethyl , dichloromethyl , dibromomethyl , difluoromethyl , trichloromethyl , tribromomethyl , trifluoromethyl , 2-chloromethyl, 2-bromomethyl, 2-fluoromethyl, 1 ,2-dichloroethyl, 2 ,2-difluoroethyl, l-chloro-2-fluoroethyl, 3-fluoropropyl, 4-chlorobutyl, 5-chloropentyl, 6-bromohexyl, and
  • Examples of the lower alkylenedioxy group include alkylenedioxy group having 1 to 3 carbon atom , such as methylenedioxy, ethylenedioxy, and trimethylenedioxy.
  • Examples of the phenyl group which may have 1 to 3 substituents selected from the group consisting of a halogen atom, a hydroxyl group, a nitro group, a lower alkyl group, a lower alkoxy group, a lower alkylthio group, a carboxyl group, a lower alkoxycarbonyl group, a phenyl-lower alkoxy group, a lower alkylenedioxy group, a morpholino group, a halogenated lower alkyl group, a carboxy-lower alkyl group, a lower alkoxycarbonyl-lower alkyl group, a 6-hydroxy-2 ,5,7, 8-tetramethyl-2- chromanylmethoxy group, and a 6-lower alkanoyloxy- 2,5,7,8-tetramethyl-2-chromanylmethoxy group include phenyl groups which may have 1 to 3 substituents selected from the group consisting of a halogen atom,
  • Examples of the 5-membered or 6-membered unsatulated heterocyclic-lower alkyl group having 1 or 2 hetero atoms seltected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom include unsaturated heterocyclic alkyl groups in which the alkyl moiety has 1 to 6 carbon atoms . Specific examples thereof include 2-pyridinylmethyl, 3-pyridinylmethy1 , 4-pyridinylmethyl , 2- (3-pyridinyl) ethyl ,
  • phenylthio group which may have at least one halogen atom include 2-chlorophenylthio, 3-chlorophenylthio , 4-chlorophenylthio ,
  • phenylalkylthio group examples include phenylalkylthio groups in which the alkyl moiety is a straight-chain or branched alkyl group having 1 to 6 carbon atoms . Specific examples thereof include benzylthio, 2-phenylethylthio, 1-phenylethylthio, 3-phenylpropylthio , 4-phenylbutylthio ,
  • benzoylamino group which may have 1 to 3 halogen atoms include benzoylamino, 2-fluorobenzoylamino , 3-fluorobenzoylamino ,
  • phenyl group which may have 1 to 3 substituents selected from the group consisting of a halogen atom, a hydroxyl group, a nitro group, a lower alkyl group, a lower alkoxy group, and a lower alkylthio group on the phenyl ring thereof (wherein the phenyl ring may be condensed with a benzene ring or a cyclohexane ring) include phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 4-bromophenyl , 4-iodophenyl, 2 ,3-dichlorophenyl, 2 , 3-difluorophenyl , 2 , 5-dibromophenyl , 2 , 6-dichlorophenyl ,
  • Examples of the 5-membered or 6-membered, saturated or unsaturated heterocyclic group having one hetero atom selected from the group consisting of a nitrogen atom, a sulfur atom, and an oxygen atom include 2-pyrrolyl, 3-pyrrolyl, 2-thienyl, 2-furanyl, 3-furanyl, 2-pyridinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-tetrahydrothionyl, 2-tetrahydrofuranyl, 3-piperidinyl, 2-tetrahydrothiopyranyl, 2-tetrahydropyranyl, 3-indolyl, 2-dihydrobenzopyrany1 , 3-dihydrobenz
  • Examples of the phenylcarbamoyl-lower alkyl group which may have 1 or 2 lower alkoxy groups on the phenyl ring thereof include phenylcarbamoylalkyl groups in which the alkyl moiety has 1 to 6 carbon atoms and the phenyl ring may have 1 or 2 alkoxy groups each having 1 to 6 carbon atoms .
  • phenylcarbamoylmethyl phenylcarbamoylethyl
  • phenylcarbamoylpropyl phenylcarbamoylbutyl
  • phenylcarbamoylpentyl phenylcarbamoylhexyl
  • amino acid residues and the like are indicated by the abbreviations therefor as provided for in the IUPAC and the IUB nomenclatures, or by symbols commonly used in the related fields . Examples thereof are as follows.
  • Tyr, Leu, Trp, Asp, Gly, and Ph-Gly represent tyrosine, leucine, tryptophan, aspartic acid, glycine, and phenylglycine, respectively.
  • R 1 and A in formula (1) represent a hydrogen atom and a carbonyl group, respectively, the compound represented by formula (1) can have the following isomeric structures shown by formulae (1-A) to (1-E) :
  • each of the lower alkyl group, the lower alkoxy group, the halogen atom, the carboxy-lower alkyl group, the lower cycloalkyl group, the phenyllower alkyl group, the lower alkylidene group having 1 or 2 lower cycloalkyl groups, and the phenyl-lower alkylidene group are the same as those enumerated above with regard to formula (1) .
  • Examples of the lower alkoxycarbonyl-lower alkyl group include alkoxycarbonylalkyl groups in which the alkoxy moiety has 1 to 6 carbon atoms and the alkyl moiety has 1 to 6 carbon atoms . Specific examples thereof include methoxycarbonylmethyl , ethoxycarbonylmethyl , 3-methoxycarbonylpropyl ,
  • phenoxy-lower alkanoyl group examples include phenoxyalkanoyl groups in which the alkanoyl moiety is a straight-chain or branched alkanoyl group having 2 to 6 carbon atoms . Specific examples thereof include 2-phenoxyacetyl, 3-phenoxypropionyl, 3-phenoxybutyryl , 4-phenoxybutyry1 , 2-phenoxybutyryl , 6-phenoxyhexanoyl , 2-phenoxypropionyl ,
  • Examples of the phenoxy-lower alkanoyl group having at least one lower alkoxycarbonyl group on the phenyl ring thereof include straight-chain or branched alkanoyl groups which have 2 to 7 carbon atoms and have a phenoxy group having at least one straight-chain or branched alkoxycarbonyl group, as a substituent, in which each alkoxy moiety has 1 to 6 carbon atoms , on the phenyl ring thereof.
  • phenyl-lower alkanoyl group examples include phenylalkanoyl groups in which the alkanoyl moiety is a straight-chain or branched alkanoyl group having 1 to 6 carbon atoms .
  • Specific examples thereof include phenylacetyl , 3-phenylpropionyl, 4-phenylbutyryl, 2 ,2-dimethyl-3-phenylpropionyl , 5-phenylpentanoyl , 6-phenylhexanoyl , and 2-methyl-3-phenylpropionyl .
  • Examples of the phenylsulfonyl group which may have 1 to 3 substituents selected from the group consisting of a halogen atom, a nitro group, a lower alkoxy group, and a lower alkyl group on the phenyl ring thereof include phenylsulfonyl groups which may have 1 to 3 substituents selected from the group consisting of a halogen atom, a nitro group, a straight-chain or branched alkoxy group having 1 to 6 carbon atoms, and a straight-chain or branched alkyl group having 1 to 6 carbon atoms on the phenyl ring thereof. Specific examples thereof include phenylsulfonyl , 2-chlorophenylsulfonyl , 3-chlorophenylsulfonyl ,
  • phenyl group which may have at least one halogen atom on the phenyl ring thereof include phenyl groups which may have 1 to 3 halogen atoms .
  • Speci ic examples thereof include phenyl , 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-bromophenyl, 4-iodophenyl, 2 , 3-dichlorophenyl , 2 , 4-dichlorophenyl ,
  • lower alkylidene group examples include straight-chain or branched alkylidene groups having 1 to 6 carbon atoms , such as methylene , ethylene, propylidene, isopropylidene, butylidene, t-butylidene, pentylidene, and hexylidene.
  • Examples of the phenyl-lower alkylidene group which has 1 to 3 substituents selected from the group consisting of a halogen atom, a carboxyl group, a lower alkoxycarbonyl group, a nitro group, a hydroxyl group, a lower alkoxy group, and a halogenated lower alkyl group include straight-chain or branched alkylidene groups which have 1 to 6 carbon atoms and have a phenyl group having 1 to 3 substituents selected from the group consisting of a straight-chain or branched alkoxy group having 1 to 6 carbon atoms, a straight-chain or branched halogenated alkyl group having 1 to 6 carbon atoms , a halogen atom, a carboxyl group, an alkoxycarbonyl group in which the alkoxy moiety has 1 to 6 carbon atoms , a nitro group, and a hydroxyl group.
  • Specific examples thereof include 2-chlorobenzyliden
  • phenyl-lower alkenylidene group which may have at least one nitro group on the phenyl ring thereof include phenylalkenylidene groups in which the alkenylidene moiety is a straight-chain or branched alkenylidene group having 2 to 6 carbon atoms and the phenyl ring may have 1 to 3 nitro groups .
  • Examples of the lower alkenylidene group include straight-chain or branched alkenylidene groups having 2 to 6 carbon atoms, such as vinylidene, allylidene, 2-butenylidene, 3-butenylidene, 2-pentenylidene, and 2-hexenylidene .
  • Examples of the lower cycloalkenylidene group include cycloalkenylidene groups having 3 to 8 carbon atoms, such as 2-cyclopropenylidene, 2-cyclobutenylidene, 2-cyclopentenylidene, 2-cyclohexenylidene,
  • phenoxy-lower alkylidene group which may have at least one carboxyl group on the phenyl ring thereof include phenoxyalkylidene groups in which the alkylidene moiety is a straight-chain or branched alkylidene group having 1 to 6 carbon atoms and the phenyl ring may have at least one carboxyl group.
  • phenyl-lower alkylidene group which may have at least one substituent selected from the group consisting of a halogen atom and a halogenated lower alkyl group on the phenyl ring thereof include phenylalkylidene groups which have a straight-chain or branched alkylidene moiety having 1 to 6 carbon atoms and may have 1 to 3 substituents selected from the group consisting of a halogen atom and a straight-chain or branched halogenated alkyl group having 1 to 6 carbon atoms on the phenyl ring thereof. Specific examples thereof include benzylidene, 2-phenylethylidene, 1-phenylethylidene, 3-phenylpropylidene,
  • R 1 in formula (2) is a hydrogen atom
  • the compound represented by formula (2) can have the following isomeric structures shown by formulae (2-A) to (2-C) :
  • each of the lower alkyl group, the lower alkoxy group, the lower alkylidene group, the halogen atom, the phenyl-lower alkylidene group, and the lower alkoxycarbonyl-lower alkyl are the same as those enumerated above with regard to formula (1) .
  • Examples of the lower alkanoyl group include straight-chain or branched alkanoyl groups having 1 to 6 carbon atoms, regardless of whether it is present as an independent substituent or present in other groups . Specific examples thereof include formyl , acetyl, propionyl, butyryl, isobutyryl , pentanoyl, t-butylcarbonyl , and hexanoyl .
  • phenyl-lower alkyl group which may have at least one halogen atom as a substituent on the phenyl ring thereof include phenylalkyl groups in which the alkyl moiety is a straight-chain or branched alkyl group having 1 to 6 carbon atoms and the phenyl ring may have at least one halogen atom as a substituent.
  • phenylalkyl groups in which the alkyl moiety is a straight-chain or branched alkyl group having 1 to 6 carbon atoms and the phenyl ring may have at least one halogen atom as a substituent.
  • Specific examples thereof include benzyl, 2-fluorobenzyl, 3-bromobenzyl, 4-chlorobenzyl, 4-iodobenzyl, 2-phenylethyl , 1- (4-chlorophenyl) ethyl ,
  • [4 ,3,0]nonan-5-ene-3,8-dione (1-29) : 2-isopropylidenehydrazono-5- (4-nitrobenzyl) - imidazolidin-4-one (1-30) : 5- (4-cyclohexylmethoxybenzyl) -2-isopropylidene- hydrazonoimidazolidin-4-one (1-31) : 5- (4-benzylbenzyl) -2-isopro ⁇ ylidenehydrazono- imidazolidin-4-one (1-32) : 5- [4- (4-chlorobenzoylamino) benzyl] -2- isopropylidenehydrazonoimidazolidin-4-one (1-33) : 2-iso ⁇ ropylidenehydrazono-5- (N-phenylcarbamoyl- methyl) thiazolidin-4-one (1-34) : 5- (N-isopropylcarbamoylmethyl) -2-
  • the compounds represented by formulae (1) , (2) , and (3) further include pharmaceutically acceptable addition salts thereof with acids or basic compounds . These salts can be easily formed by causing the following acids or bases to act on the compounds represented by formulae (1) to (3) .
  • acids for use in salt formation include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, and hydrobromic acid, and further include, in some cases , organic acids such as oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, and benzoic acid.
  • inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, and hydrobromic acid
  • organic acids such as oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, and benzoic acid.
  • bases for use in salt formation include sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, and potassium hydrogen carbonate .
  • vitamin B 6 used in the AGE production inhibitory composition of the present invention include six basic forms of vitamin B 6 , i.e., pyridoxine, pyridoxal, pyridoxamine , and phosphates thereof. These forms of vitamin B 6 include pharmaceutically acceptable addition salts thereof with acids . Examples of the acids for use in salt formation include the same inorganic and organic acids as those enumerated above.
  • the incorporation amount of vitamin B 6 or a pharmaceutically acceptable salt thereof in the AGE production inhibitory composition of the present invention is generally from 0.1 to 200 parts by weight, preferably from 1 to 100 parts by weight, more preferably from 2 to 50 parts by weight, based on 100 parts by weight of the Maillard reaction inhibitor.
  • the AGE production inhibitory composition of the present invention may further comprises a pharmaceutically acceptable carrier .
  • the AGE production inhibitory composition of the present invention is usually used in the form of any of general medical preparations .
  • Such medical preparations are produced using generally employed diluents or excipients , such as fillers , extenders , binders , humectants , disintegrators , surfactants , and lubricants .
  • Examples of carries which can be used in molding the composition into tablets include excipients such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, and silicic acid; binders such as water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethyl cellulose, shellac, methyl cellulose, calcium phosphate, and polyvinylpyrrolidone; disintegrators such as dried starch, sodium alginate, agar powder, laminaran powder, sodium hydrogen carbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, monoglyceride of stearic acid, starch, and lactose; disintegration inhibitors such as sucrose, stearin, cacao butter, and hydrogenated oils ; absorption accelerators such as quaternary ammonium salts and sodium lauryl sulfate; humectant
  • tablets of the composition can be covered with an ordinary coating to obtain coated tablets , e.g., sugar-coated tablets, gelatin-coated tablets, intestinal-juice-coated tablets, and film-coated tablets, or to obtain tablets covered with two or more coating layers .
  • examples of usable carriers include glucose, lactose, starch, cacao butter, hardened vegetable oils, kaolin, and talc; binders such as gum arable powder, tragacanth powder, gelatin, and ethyl alcohol; and disintegrators such as laminaran and agar.
  • examples of usable carriers include polyethylene glycol , cacao butter, higher alcohols, higher alcohol esters, gelatin, and semi-synthetic glycerides .
  • Capsules are usually prepared by the ordinary method comprising mixing various carriers shown above with any of compounds (1) to (3) according to the present invention and with vitamin B 6 and then filling hard gelatin capsules or other hard capsules with the mixture .
  • a solution, emulsion, or suspension is pasteurized, and is preferably regulated so as to have the same osmotic pressure as the blood.
  • diluents such as, e.g., water, aqueous lactic acid solution, ethyl alcohol, propylene glycol, ethoxyisostearyl alcohol, and polyoxyethylene sorbitan fatty acid esters.
  • sodium chloride, glucose, or glycerol may be added to the medical preparations in an amount sufficient to prepare isotonic solutions.
  • ordinary additives such as a solubilizer, buffering agent, and soothing agent may be added. It is also possible, if desired and necessary, to incorporate additives such as a colorant, preservative, perfume, flavor, and sweetening agent and other medicines into the medical preparations .
  • composition of the present invention When the composition of the present invention is formed into a paste, cream, or gel, examples of usable diluents include white petrolatum, paraffins, glycerol, cellulose derivatives, polyethylene glycol, silicone, and bentonite.
  • the amount of the Maillard reaction inhibitor and vitamin B 6 or a pharmaceutically acceptable salt thereof to be contained in the AGE production inhibitory composition of the present invention is not particularly limited and can be suitably selected in a wide range . However, the amount thereof is generally preferably from 1 to 70% by weight based on the amount of each medical preparation.
  • Methods for administering the AGE production inhibitory composition of the present invention are not particularly limited, and a suitable one is selected from various administration methods according to, for example, the age, sex, condition of the patient, the form of the preparation to be administered.
  • the composition is usually administered orally or parenterally either generally or locally.
  • the composition is administered intravenously, intramuscularly, intracutaneously, subcutaneously, or intraperitoneally, if desired after being mixed with an ordinary auxiliary solution.
  • the composition is furthermore administered intravenously as a suppository or administered as an ointment.
  • the AGE production inhibitory composition of the present invention can also be used in such a manner that the Maillard reaction inhibitor and vitamin B 6 or a pharmaceutically acceptable salt thereof are separately administered either simultaneously or at an interval .
  • the dose of the AGE production inhibitory composition of the present invention is suitably selected according to, for example, the age, weight, and conditions of the patient, the expected effect of remedy, administration method, treatment period. In general, however, the dose thereof is from 0.1 to 100 mg per day per kg of the body weight, and the daily administration is effected at a time or in multiple doses .
  • the AGE production inhibitory composition of the present invention will be explained below by reference to Synthetic Example, Preparation Example, and Test Example. However, the present invention is not limited thereto .
  • 1-Hydroxybenztriazole hydrochloride (0.27 g) was added to a solution of N,N-dimethylformamide (10 ml) containing 5-carboxymethyl-2-isopropylidenehydrazono- thiazolidin-4-one (0.37 g) synthesized by a method described in JP-A-46-15936 and aniline (0.15 g) , and then l-ethyl-3- (3 ' -dimethylaminopropyl) carbodiimide hydrochloride (0.34 g) was further added thereto. This mixture was stirred at room temperature .
  • Vitamin B 6 pyridoxine hydrochloride 0.1 g Sodium lauryl sulfate 0.2 g
  • the above ingredients were mixed in an ordinary way, and the mixture was tabletted to obtain tablets .
  • Bovine serum albumin (BSA) was dissolved in a 0.25 M phosphate-buffer (PBS) at a concentration of 0.1 g/ml. Fructose as a reducing sugar was dissolved therein to have a final concentration of 100 mM. Thus, a control solution was prepared.
  • solutions of Compound (1-33) were prepared which had concentrations of 0 mM, 0.3125 mM, 0.625 mM, 1.25 mM, 2.5 mM, 5 mM, and 10 mM, respectively.
  • concentrations of 0 mM, 0.3125 mM, 0.625 mM, 1.25 mM, 2.5 mM, 5 mM, and 10 mM were prepared.
  • vitamin B 6 pyridoxine hydrochloride
  • each sample solution diluted 100 times was placed in each of the wells of a 96-well microtiter tray in an amount of 0.15 ml , and then incubated for 2 hours . Thereafter, each well was rinsed three times with a 10 mM phosphate-buffer containing 0.05% Tween 20 (polyoxyethylene (20) sorbitan monolaurate) (the phosphate-buffer is hereinafter referred to as "buffer A”), and 0.3 ml of 0.4% gelatin solution was placed in each well to conduct blocking. Subsequently, 0.15 ml of an anti-AGE antibody was added, and incubation was conducted for 2 hours . Thereafter, each well was rinsed with buffer A.
  • Peroxidase-bonded anti-rabbit IgG antibody (0.15 ml) was then added and incubation was conducted. Two hours after, each well was rinsed with buffered solution A, and 0.15 ml of a color-developing solution (containing 0.4 mg/ml o-phenylenediamine and 0.2 ⁇ l/ml 30% aqueous hydrogen peroxide solution) was added to develop a color. Thereafter, 0.05 ml of 1 M sulfuric acid was added to terminate the reaction.
  • a color-developing solution containing 0.4 mg/ml o-phenylenediamine and 0.2 ⁇ l/ml 30% aqueous hydrogen peroxide solution
  • Example 1 Compound (1-33) and pyridoxine hydrochloride were administered simultaneously in amounts of 300 mg and 30 mg, respectively, per day per kg of body weight for 20 consecutive days, and then further administered in the respective two-fold amounts for 7 days .
  • Compound (1-33) was administered in an amount of 300 mg per day per kg of body weight for 20 consecutive days, and then further administered in the two-fold amount for 3 days .
  • PLP pyridoxal
  • PL pyridoxal
  • Tables 1 and 2 The found values of blood PLP and blood PL concentrations are shown as relative values , with the concentrations thereof before administration being taken as 100% .
  • Example 1 in which Compound (1-33) was used in combination with vitamin B 6 , the decreases of blood PLP and blood PL concentrations were slight even on the 24th day in the administration period, and no convulsions were observed even on the 27th day.
  • Comparative Example 1 in which Compound (1-33) was administered alone, the blood PLP and blood PL concentrations decreased considerably, and convulsions were observed three times and thirteen times on the 22nd and the 23rd days, respectively, in the administration period.
  • Comparative Example 1 since the dog used was severely convulsed, the examination was stopped on the 23rd day in the administration period.
  • Example 2 Compound (1-33) and pyridoxine hydrochloride were administered to a group of rats in amounts of 1,000 mg and 100 mg, respectively, per day per kg of rat weight. In Comparative Example 2, Compound (1-33) alone was administered to another group of rats in an amount of 1,000 mg per day per kg of rat weight.
  • a group of rats to which no drug was administered was used as a control .
  • Table 3 shows that the rats in Example 2 , in which pyridoxine hydrochloride and Compound (1-33) were used in combination, suffered almost no decrease in GPT concentration as compared with the control .
  • the AGE production inhibitory composition of the present invention is effective for preparing a medicament for preventing or lessening caused by administration of a Maillard reaction inhibitor in humans or animals .
  • composition is suitable for use preparing a medicament for treating or preventing diabetic complications caused by AGE production or diseases caused by senescence in humans or animals .

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Abstract

L'invention concerne une composition inhibitrice de la production de produits terminaux de glycosylation avancée (AGE) inhibant la production d'un AGE, responsable de complications diabétiques telles que la cataracte, la néphropathie et la rétinopathie. La composition renferme (a) un inhibiteur de la réaction de Maillard, par exemple, un composé correspondant à l'une des formules (1), (2) ou (3), ou un sel pharmaceutiquement acceptable dudit composé, et (b) la vitamine B6 ou un sel pharmaceutiquement acceptable de celle-ci: (dans laquelle chacun des groupes est tel que décrit dans le descriptif).
PCT/JP1998/001365 1997-03-28 1998-03-26 Composition inhibant la production de produits terminaux de glycosylation avancee comprenant un inhibiteur de la reaction de maillard et la vitamine b¿6? Ceased WO1998043649A2 (fr)

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AU65185/98A AU6518598A (en) 1997-03-28 1998-03-26 Age production inhibitory composition comprising a maillard reaction inhibitor and vitamin b6

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JP7860197 1997-03-28
JP9/78601 1997-03-28

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001095920A1 (fr) * 2000-06-16 2001-12-20 Basic, Robert Novel inhibiteur d'apoptose de cellules neuronales
EP1126856A4 (fr) * 1998-10-28 2008-05-14 Fox Chase Cancer Ct Composes et ses utilisations therapeutiques dans la prevention de complications d'un diabetique
US7527794B2 (en) 2001-07-31 2009-05-05 Wayne State University Hybrid proteins with neuregulin heparin-binding domain for targeting to heparan sulfate proteoglycans
US7615528B2 (en) 1997-02-05 2009-11-10 Fox Chase Cancer Center Methods for alleviating deleterious effects of 3-deoxyglucosone
US8063032B2 (en) 2009-02-11 2011-11-22 Sunovion Pharmaceuticals Inc. Histamine H3 inverse agonists and antagonists and methods of use thereof
US8541471B2 (en) 2003-05-07 2013-09-24 Osteologix A/S Water-soluble strontium salts for use in treatment of cartilage and/or bone conditions

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5272165A (en) * 1984-03-19 1993-12-21 The Rockefeller University 2-alkylidene-aminoguanidines and methods of use therefor
AU8449591A (en) * 1990-08-01 1992-03-02 Rockefeller University, The Advanced glycation inhibitors containing amino-benzoic acids and derivatives, and methods of use
JPH06502184A (ja) * 1991-02-22 1994-03-10 シャピロ，ハワード　ケイ． 神経性疾病の症候や原因上関係のある症候の治療のための薬用化合物の使用
TW221689B (fr) * 1991-08-27 1994-03-11 Otsuka Pharma Co Ltd
EP0638075B1 (fr) * 1993-02-26 2002-01-16 Otsuka Pharmaceutical Co., Ltd. Derives de thiazole ou d'imidazole inhibant la reaction de maillard
US5744451A (en) * 1995-09-12 1998-04-28 Warner-Lambert Company N-substituted glutamic acid derivatives with interleukin-1 β converting enzyme inhibitory activity

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7615528B2 (en) 1997-02-05 2009-11-10 Fox Chase Cancer Center Methods for alleviating deleterious effects of 3-deoxyglucosone
US8431527B2 (en) 1997-02-05 2013-04-30 Fox Chase Cancer Center Methods for alleviating deleterious effects of 3-deoxyglucosone
EP1126856A4 (fr) * 1998-10-28 2008-05-14 Fox Chase Cancer Ct Composes et ses utilisations therapeutiques dans la prevention de complications d'un diabetique
WO2001095920A1 (fr) * 2000-06-16 2001-12-20 Basic, Robert Novel inhibiteur d'apoptose de cellules neuronales
HRP20000410B1 (hr) * 2000-06-16 2012-06-30 Ba�i� Robert Novi inhibitor apoptoze živčanih stanica
US7527794B2 (en) 2001-07-31 2009-05-05 Wayne State University Hybrid proteins with neuregulin heparin-binding domain for targeting to heparan sulfate proteoglycans
US8541471B2 (en) 2003-05-07 2013-09-24 Osteologix A/S Water-soluble strontium salts for use in treatment of cartilage and/or bone conditions
US8063032B2 (en) 2009-02-11 2011-11-22 Sunovion Pharmaceuticals Inc. Histamine H3 inverse agonists and antagonists and methods of use thereof
US8404670B2 (en) 2009-02-11 2013-03-26 Sunovion Pharmaceuticals Inc. Histamine H3 inverse agonists and antagonists and methods of use thereof

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WO1998043649A3 (fr) 1998-12-17
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