WO1998043649A2 - Age production inhibitory composition comprising a maillard reaction inhibitor and vitamin b¿6? - Google Patents

Age production inhibitory composition comprising a maillard reaction inhibitor and vitamin b¿6? Download PDF

Info

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
Authority
WO
WIPO (PCT)
Prior art keywords
group
lower alkyl
phenyl
alkyl group
ring
Prior art date
Application number
PCT/JP1998/001365
Other languages
French (fr)
Other versions
WO1998043649A3 (en
Inventor
Koichi Yasumura
Shintaro Ishikawa
Tadami Utsunomiya
Kazuhiko Hayashi
Tadashi Okada
Original Assignee
Otsuka Pharmaceutical Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Otsuka Pharmaceutical Co., Ltd. filed Critical Otsuka Pharmaceutical Co., Ltd.
Priority to AU65185/98A priority Critical patent/AU6518598A/en
Publication of WO1998043649A2 publication Critical patent/WO1998043649A2/en
Publication of WO1998043649A3 publication Critical patent/WO1998043649A3/en

Links

Classifications

    • 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 .

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

An AGE production inhibitor composition which inhibits the production of an AGE, causative of diabetic complications such as cataract, nephropathy, and retinopathy, is provided. The composition comprises (a) a Maillard reaction inhibitor, e.g., a compound represented by formula (1), (2) or (3), or a pharmaceutically acceptable salt thereof, and (b) vitamin B6 or a pharmaceutically acceptable salt thereof, wherein the individual groups are as described in the specification.

Description

DESCRIPTION
AGE PRODUCΗON INHIBITORY COMPOSIΗON COMPRISING A MAILLARD REACΗON INHIBITOR AND VITAMIN B6
Technical Field
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.
Background Art
It is well known that 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 . In the first stage, 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. In the second stage, 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.) However, details of the AGE- producing process are unclear.
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. However, the structure of the AGE has not been elucidated.
Recently, Neeper M. et. a.1. cloned the cDNA of an AGE receptor and made various investigations thereon (see J. B±ol . Chem. , 267:14998 (1992)).
It has been reported that 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 ,
(4) enhancement of the chemotaxis of endothelial cells,
(5) inactivation of EDRF (endothelium-derived relaxing factor), (6) enhancement of the chemotaxis of monocytes , (7) enhancement of the production and secretion of TNF (tumor necrosis factor) , IL-1 (Interleukin 1) , and PDGF (platelet-derived growth factor) by macrophages, and (8) reduction of the deformability of blood cells (see Salshln IgaJfcu, 49(2): 78-83 (1994)). However, the proteins which have been converted to an AGE differ from the original proteins in structure (having crosslinks) , and have abnormal properties and functions . For example, the denatured proteins have reduced solubility, are less susceptible to metabolism by lyases , and are apt to form covalent bonds with other proteins .
Because of these properties, 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).
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. However, the known Maillard reaction inhibitors including aminoguanidine have a problem that they produce various side effects although they can inhibit AGE production.
For example, there are case reports on side effects that intraperitoneal administration of aminoguanidine to mice in a dose of 50 mg per kg of body weight resulted in an increase in mortality as compared with control mice (see Autoimmu, 15:311-314 (1993)), and that eight-month administration of aminoguanidine to rats suffering from streptozocin-induced diabetes resulted in an increase in the incidence of renal tumor [see Diabetes , 43(Suppl 1):204 (1994)].
Disclosure of the Invention
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 B6 or a pharmaceutically acceptable salt thereof. The present invention has been completed based on this finding.
That is, this and other objects of the present invention have been accomplished by an AGE production inhibitory composition which comprises (a) a Maillard reaction inhibitor and (b) vitamin B6 or a pharmaceutically acceptable salt thereof.
Brief Description of Drawing
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. Furthermore, 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 :
Figure imgf000008_0001
wherein R1 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 represents : an amino group , a 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 a lower alkanoylamino group on the phenyl ring thereof , or a group represented by -N=R4 (wherein R4 represents a lower alkylidene group, a lower alkylidene group having one or two lower cycloalkyl groups , a lower cycloalkylidiene group, a diphenyl-lower alkylidene group, or a phenyl-lower alkylidene group) ;
R3 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-OR5 (wherein W represents a lower alkylene group; R5 represents a hydrogen atom, a lower alkyl group, or a phenyl-lower alkyl group; and b represents 0 or 1) , a group represented by -Z-CO-R3 {wherein Z represents a lower alkylene group; and Ra represents -Tyr(ORal)-ORbl, -Leu-ORb2, -Trp-ORb3, -Asp (ORa2) -ORb4, -Ph-Gly-ORb5 (wherein Ral and Ra2 each represents a hydrogen atom or a benzyl group; and Rbl , Rb2 , Rb3 , Rb4 , and Rb5 each represents a hydrogen atom or a lower alkyl group), or -N(R6)-R7 (wherein R6 represents a lower alkyl group, a carboxyl-lower alkyl group, a lower- alkoxycarbonyl-lower alkyl, a phenyl-lower alkyl group, a lower cycloalkyl group, 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, 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, a naphthyl group, a 3,4-dihydrocarbostyryl group, a morpholino group, or 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, an oxygen atom, and a sulfur atom; and R represents a hydrogen atom or a lower alkyl group) } , or a group represented by
Figure imgf000011_0001
{wherein B represents a lower alkylene group; R8 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-R9 (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
(wherein the phenyl ring may be condensed with a benzene ring or a cyclohexane ring) , a 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
(wherein the 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 } ;
X represents :
-S- or
-N(R10)- (wherein R10 represents a hydrogen atom or a lower alkoxycarbonyl-lower alkyl group) ; and represents a single bond or a double bond, with the proviso that when represents a single bond, A represents a carbonyl group , and when represents a double bond, A represents:
=C(RU)- {wherein R11 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
Figure imgf000012_0001
(wherein R12 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
R4 and R10 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 R3 and A represent a hydrogen atom and a carbonyl group, respectively, R1 is neither a hydrogen atom nor a lower alkoxycarbonyl-lower alkyl group; and
R3 and R11 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 :
Figure imgf000013_0001
wherein 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;
R14 represents : a group represented by -NHR16 {wherein R16 represents a hydrogen atom, a 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, a phenyl-lower alkanoyl group, or a group represented by -CO-NHR17 (wherein R17 represents a lower alkyl group, a phenyl group which may have at least one halogen atom on the phenyl ring thereof, a phenyl-lower alkyl group, or a naphthyl group) } or a group represented by -N=R18 {wherein R18 represents a lower alkylidene group, a lower alkylidene group having 1 or 2 lower cycloalkyl groups, a phenyl- lower alkylidene group which may have 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 on the phenyl ring thereof, a phenyl-lower alkenylidene group which may have at least one nitro group on the phenyl ring thereof, a lower alkenylidene group, a lower cycloalkylidene group, or a phenoxy-lower alkylidene group which may have at least one carboxyl group on the phenyl ring thereof} ;
R15 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 :
-S- or
-N(R19)- (wherein R19 represents a hydrogen atom, a lower alkyl group, a carboxyl-lower alkyl group, or a lower alkoxycarbonyl-lower alkyl group) ; and
R13 and R16, or R16 and R19 may bind to each other to form an oxoethylene group; when R13, R15, and Y are a hydrogen atom, two hydrogen atoms, and -S-, respectively, R14 is neither a group represented by -NHR16 (wherein R16 is a hydrogen atom or a phenylsulfonyl group which may have at least one lower alkoxy group on the phenyl ring thereof) nor a group represented by -N=R18 (wherein R18 is a lower alkylidene group, a phenyl-lower alkylidene group which may have at least one substituent selected from the group consisting of a halogen atom, a nitro group, a hydroxyl group, and a lower alkoxy group on the phenyl ring thereof, or a phenyl-lower alkenylidene group which may have at least one nitro group on the phenyl ring thereof) ; when R13, R14 , and Y are a hydrogen atom, a group represented by -N=R18, and -S- or -NH-, respectively, R15 and R18 are not a phenyl-lower alkylidene group at the same time ; and when R14 , R15 , and Y are a group represented by -NHR16, two hydrogen atoms, and -S-, respectively, R13 and R16 do not bond to each other to form an oxoethylene ring, or pharmaceutically acceptable salts thereof; and compounds represented by the following formula (3) disclosed in JP-A-6-305964 :
Figure imgf000017_0001
wherein R 20 represents : a hydrogen atom or a lower alkyl group;
R21 represents : a hydrogen atom, a lower alkyl group, a lower alkanoyl group, or a lower alkoxycarbonyl-lower alkyl group;
R22 represents a hydrogen atom, a lower alkyl group, or a lower alkanoyl group;
R23 represents a hydrogen atom, a lower alkanoyl group, a benzoyl group, or a group represented by
Figure imgf000017_0002
(wherein R24 represents a phenyl group or a lower alkoxy group) , and R22 and R23 may bond to each other to form a lower alkylidene group, a diphenylmethylene group, or a phenyl-lower alkylidene group; and
V represents :
-S- or
-N- (R25) - (wherein R25 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; and
R23 and R25 may bind to each other to form a 6-membered to 8-membered ring, or pharmaceutically acceptable salts thereof .
Among the above-mentioned Maillard reaction inhibitors, from the standpoint of compatibility with vitamin B6 or a pharmaceutically acceptable salt thereof, preferred examples include : aminoguanidine ,
2-isopropylidenehydrazono-5- (N-phenylcarbamoyl- methyl) thiazolidin-4-one,
5- [N- (2-carboxy-4-methylphenyl) carbamoylmethyl] - 2-isopropylidenehydrazonothiazolidin-4-one,
5- [N- (3 , 4-difluorophenyl) carbamoylmethyl] -2- isopropylidenehydrazonothiazolidin-4-one, 5- [N- (2-carboxy-4-chlorophenyl) carbamoylmethyl] - 2-isopropylidenehydrazonothiazolidin-4-one,
5- [N- (2-carboxy-4 , 5-dimethoxyphenyl) carbamoylmethyl] -2-isopropylidenehydrazonothiazolidin-4-one,
5- [N- (2-carboxy-4-fluorophenyl) carbamoylmethyl] - 2-isopropylidenehydrazonothiazolidin-4-one , and pharmaceutically acceptable salts thereof; and more preferred examples include:
2-isopropylidenehydrazono-5- (N-phenylcarbamoyl- methyl) hiazolidin-4-one, and pharmaceutically acceptable salts thereof.
The amount of the vitamin B6 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 .
The individual groups in formula (1) will be explained below in detail.
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 ,
5-isopropoxycarbonylpentyl ,
1 , 1-dimethyl-2-butoxycarbonylethyl ,
2-methyl-3-t-butoxycarbonylpropy1 ,
2-pentyloxycarbonylethyl, and hexyloxycarbonylmethy1.
Examples of the halogen atom 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 .
Examples of the lower alkoxy group 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 .
Examples of the lower alkylthio group 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 . Specific examples thereof include benzyl, 2-phenylethyl , 1-phenylethyl , 3-phenylpropy1 , 4-phenylbutyl , 1 , 1-dimethyl-2-phenylethyl , 5-phenylpen yl ,
6-phenylhexyl, 2-methyl-3-phenylpropyl, 2-phenylpropy1 , 2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 4-chlorobenzyl, 4-bromobenzyl, 4-iodobenzyl, 2- (2-fluorophenyl) ethyl , 3- (3-chlorophenyl)propyl , 4- (4-bromophenyl) butyl , 5- (4-iodophenyl) pentyl ,
6- (3-fluorophenyl) hexyl , , l-dimethyl-2- (2-chlorophenyl) ethyl , -methyl-3- (4-chlorophenyl) propyl , - (4-fluorophenyl) propyl , 2 , 5-difluorobenzyl , , 3-dichlorobenzyl , 2- (2 , 4-dibromophenyl) ethyl , - (2 , 6-difluorophenyl) ethyl , - (3 , 4-dichlorophenyl) propyl , 4- (3 , 5-dibromophenyl) butyl , - (3 , 4-difluorophenyl) pentyl , - (3 , 5-dichlorophenyl) hexyl , 2,4, 5-trifluorobenzyl , - (2 ,4 , 6-trichlorophenγl) ethyl, - (3 , 4 , 5-trifluorophenyl) propyl , 2-hydroxybenzyl , -hydroxybenzyl , 4-hydroxybenzyl , - (2-hydroxypheny1) ethyl , 3- (3-hydroxyphenyl) propyl , - (4-hydroxyphenyl) butyl , 5- (4-hydroxyphenyl) pentyl , - (3-hydroxyphenyl) hexyl , , l-dimethyl-2- (2-hydroxyphenyl) ethyl , -methyl-3- (4-hydroxyphenyl) propyl , - (4-hydroxyphenyl) propyl , 2 , 5-dihydroxybenzyl , , 3-dihydroxybenzyl , 2- (2 , 4-dihydroxyphenyl) ethyl , - (2 , 6-dihydroxyphenyl) ethyl , - (3 , 4-dihydroxyphenyl) propyl , - (3 , 5-dihydroxyphenyl) butyl , - (3 , 4-dihydroxyphenyl) pentyl , - (3 , 5-dihydroxyphenyl) hexyl , 2,4, 5-trihydroxybenzyl , - (2 , 4 , 6-trihydroxyphenyl) ethyl , - (3 , 4 , 5-trihydroxyphenyl) propyl , 2-nitrobenzyl , -nitrobenzyl, 4-nitrobenzyl, 2- (2-nitrophenyl) ethyl, - (3-nitrophenyl) propyl , 4- (4-nitrophenyl) butyl , - (4-nitrophenyl) pentyl , 6- (3-nitrophenyl) hexyl , , l-dimethyl-2- (2-nitrophenyl) ethyl , -methyl-3- (4-nitrophenyl) propyl, - (4-nitrophenyl) propyl , 2 , 5-dinitrobenzyl , , 3-dinitrobenzyl , 2- (2 , 4-dinitrophenyl) ethyl , - (2 , 6-dinitrophenyl) ethyl , 3- (3 , 4-dinitrophenyl) propyl , - (3 , 5-dinitrophenyl) butyl , 5- (3 , 4-dinitrophenyl) pentyl , - (3 , 5-dinitrophenyl) hexyl , 2,4, 5-trinitrobenzyl , - (2 , 4 , 6-trinitrophenyl) ethyl , - (3 , 4 , 5-trinitrophenyl) propyl , 2-methylbenzyl , -methylbenzyl , 4-methylbenzyl , 2- (2-methylphenyl) ethyl , - (3-methylphenyl) propyl , 4- (4-methylphenyl) butyl , - (4-methylphenyl) pentyl , 6- (3-methylphenyl) hexyl , , l-dimethyl-2- (2-methylphenyl) ethyl , -methyl-3- (4-methylphenyl) propyl , - (4-methylphenyl) propyl , 2,5-dimethylbenzyl , , 3-dimethylbenzyl , 2- (2 , 4-dimethylphenyl) ethyl , - (2 , 6-dimethylphenyl) ethyl , - (3 , 4-dimethylphenyl) propyl , - (3 , 5-dimethylphenyl) butyl , - (3 , 4-dimethylphenyl) pentyl , - (3 , 5-dimethylphenyl) hexyl , 2,4, 5-trimethylbenzyl , - (2 , 4 , 5-trimethylphenyl) ethyl , - (2 , 4 , 6-trimethylphenyl) propyl , 2-methoxybenzyl , -methoxybenzyl , 4-methoxybenzyl , 4-ethoxybenzyl , -propoxybenzyl , 4-isopropoxybenzyl , 4-butoxybenzyl , -t-butoxybenzyl, 4-pentyloxybenzyl , 4-hexyloxybenzyl, , 3-dimethoxybenzyl , 2 , 4-dimethoxybenzyl , , 5-diethoxybenzyl , 2 , 6-diethoxybenzyl , , 4-dimethoxybenzyl , 3 , 5-diethoxybenzyl , ,3, 4-trimethoxybenzyl , 2,3, 5-trimethoxybenzyl , ,3, 6-triethoxybenzyl , 3,4, 5-triethoxybenzyl , - (2-methoxyphenyl) ethyl , 3- (4-ethoxyphenyl) propyl , - (4-propoxyphenyl) butyl , 4- (4-butoxyphenyl) butyl , , l-dimethyl-2- (4-methoxyphenyl) ethyl , - (4-pentyloxyphenyl) hexyl , 3- (3 , 4-diethoxyphenyl) propyl , - (2 , 4 , 5-trimethoxyphenyl) ethyl , - (3 , 4 , 5-triethoxyphenyl) propyl , 2-methylthiobenzyl , - (2-ethylthio) benzyl , 4- (3-propylthio) benzyl , - (2-methylthiophenyl) ethyl , - (3-methylthiophenyl) propyl , 4- (4methylthiophenyl) butyl , - (4-methylthiophenyl)pentyl, - (3-methylthiophenyl) hexyl , , l-dimethyl-2- (2-methylthiophenyl) ethyl , -methyl-3- (4-methylthiophenyl) propyl , - (4-methylphenyl)propyl , 2 , 5-di (4-butylthio) benzyl , , 3-dimethylthiobenzyl , 2- (2 , 4-dimethylthiophenyl) ethyl , - (2 , 6-dimethylthiophenyl) ethyl , 4- (3 ,5-dimethylthiophenyl)butyl ,
5- (3 , 4-dimethylthiophenyl) pentyl ,
6- (3 , 5-dimethylthiophenyl) hexyl ,
2,4,5-tri (βhexylthio) benzyl,
2- (2 , 4 , 6-trimethylthiophenyl) ethyl , and
3- (3 , 4 , 5-trimethy1thiophenyl) propyl .
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 . Specific examples thereof 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 , 2,3, 5-trifluorophenyl ,
3,4,5-trichlorophenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxypheny1 , 2 , 5-dihydroxypheny1 , 2 , 3-dihydroxyphenyl , 2,4, 5-trihydroxyphenyl ,
2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 2, 3-dinitrophenyl, 2 ,4 ,5-trinitrophenyl, 2-methylphenyl, 3-methylphenyl , 4-methylphenyl , 3-ethylphenyl , 4-ethylphenyl , 4-propylphenyl , 4-butylphenyl , 4-pentylphenyl, 4-hexylphenyl, 4-isopropylphenyl, 4-t-butylphenyl , 2 , 3-dimethylphenyl , 2,5-dimethylphenyl , 2 , 6-dimethylphenyl , 3,4-dimethylphenyl ,
3 , 5-diethylphenyl , 2,3, 5-trimethylphenyl ,
3, 4, 5-trimethylphenyl, 2-methoxyphenyl, 3-methoxyphenyl , 4-methoxyphenyl , 3-ethoxyphenyl , 4-ethoxyphenyl , 4-propoxyphenyl , 4-butoxyphenyl , 4-pentyloxyphenyl , 4-hexyloxyphenyl, 4-isopropoxyphenyl , 4-t-butoxyphenyl, 2 , 3-dimethoxyphenyl , 2,4-dimethoxyphenyl ,
2 , 5-dimethoxyphenyl , 2 , 6-dimethoxyphenyl ,
3 , 5-diethoxyphenyl , 2,3, 5-trimethoxyphenyl ,
3,4, 5-trimethoxyphenyl , 2-methylthiophenyl ,
3-ethylthiophenyl, 4-propylthiophenyl, 4-butylthiophenyl, 4-pentylthiophenyl , 4-hexylthiophenyl ,
2 , 3-dimethylthiophenyl , 2 , 4-dimethylthiophenyl ,
3, 4-dimethylthiophenyl, and 3,4 ,5-trimethylthiophenyl .
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 .
Examples of the 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 include phenylsulfonylamino , 2-fluorophenylsulfonylamino , 3-fluorophenylsulfonylamino , 4-fluorophenylsulfonylamino , 2-chlorophenylsulfonylamino , 3-chlorophenylsulfonylamino , 4-chlorophenylsulfonylamino , 4-bromophenylsulfonylamino , 4-iodophenylsulfonylamino , 2-hydroxyphenylsulfonylamino , 3-hydroxyphenylsulfonylamino ,
4-hydroxyphenylsulfonylamino , 2-aminophenylsulfonylamino , 3-aminophenylsulfonylamino , 4-aminophenylsulfonylamino , 2-acetylaminophenylsulfonylamino , 3-acetylaminophenylsulfonylamino , 4-acetylaminophenylsulfonylamino , 2-butyrylaminophenylsulfonylamino , and 4-butyrylaminophenylsulfonylamino .
Examples of the lower alkylidene group 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.
Examples of the lower alkylidene group having 1 or 2 lower cycloalkyl groups 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,
3-cyclopentylpropylidene, 4-cyclohexylbutylidene , 1 , 1-dimethylcycloheptylethylidene ,
5-cyclooctylpentylidene, 6-cyclohexylhexylidene,
2-methyl-3-cyclohexylpropylidene , dicyclopropylmethylene, and 2-dicyclopropylethylidene.
Examples of the lower cycloalkylidene group include cycloalkylidene groups having 3 to 8 carbon atoms , such as cyclopropylidene , cyclobutyliden , cyclopentylidene, cyclohexylidene, cycloheptylidene, and cyclooctylidene .
Examples of the diphenyl-lower alkylidene group 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 .
Examples of the phenyl-lower alkylidene group 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,
1-phenylethylidene, 3-phenylpropylidene ,
4-phenylbutylidene , 1 , 1-dimethyl-2-phenylethylidene , 5-phenylpentylidene, 6-phenylhexylidene ,
2-methyl-3-phenylpropylidene, and 2-phenylpropylidene.
Examples of the lower alkenyl group 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.
Examples of the phenyl-lower alkoxy-lower alkyl group 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 ,
1-phenylethoxymethyl , 3-phenylpropoxymethyl ,
4-phenylbutoxymethyl , 1 , 1-dimethyl-2-benzyloxypropyl , 5-benzyloxypentyl, 6-benzyloxyhexyl, and
2-methyl-3-benzyloxypropyl .
Examples of the 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 (wherein the heterocyclic ring may be condesed 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) 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 ,
2- (3-pyridinyl) ethyl , 3- (3-pyridinyl) propyl ,
4- (3-pyridinyl) butyl , 5- (3-pyridinyl)pentyl ,
6- (3-pyridinyl) hexyl , 1-methyl-2- (3-pyridinyl) propyl , 2-hydroxy-3-pyridinylmethyl , 4-hydroxy-3-pyridinylmethyl , 6-hydroxy-3-pyridinylmethyl , 2-thienylmethyl ,
2- (2-thienyl) ethyl , 3- (2-thienyl) propyl , 4- (2-thienyl) butyl , 5- (2-thienyl) pentyl ,
6- (2-thienyl) hexyl, l-methyl-2- (2-thienyl) propyl, 3-hydroxy-2-thienylmethyl , 5-hydroxy-2-thienylmethyl , 1-imidazolylmethyl , 2-imidazolylmethyl ,
4-imidazolylmethyl , 5-imidazolylmethyl ,
2- (4-imidazolyl)ethyl, 3- (2-imidazolyl) propyl,
4- (4-imidazolyl) butyl, 5- (4-imidazolyl) pentyl,
6- (4-imidazolyl) hexyl, l-methyl-2- (4-imidazolyl) propyl, 2-hydroxy-4-imidazolylmethyl , 1-indolylmethyl ,
3-indolylmethyl, 2- (3-indolyl) ethyl, 3- (3-indolyl) propyl, 4- (3-indolyl) butyl, 5- (3-indolyl) pentyl ,
6- (3-indolyl) hexyl , 4-hydroxy-3-indolylmethyl ,
2-hydroxy-3-indolylmethyl , 6-hydroxy-3-indolylmethyl , 2-pyrrolylmethyl, 5-pyrazolylmethyl, 2-pyrimidinylmethyl , 2-pyrazinylmethyl, 2-thiazolylmethyl, 2-quinolylmethyl, 2-benzimidazolylmethyl , and 3-benzothienylmethyl .
Examples of the phenyl-lower alkyl group 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 ,
5-phenylpentyl, 6-phenylhexyl, 2-methyl-3-phenylpropyl, and 2-phenylpropyl . Examples of the carboxy-lower alkyl group 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,
1 , l-dimethyl-2-carboxyethyl , 5-carboxypentyl ,
6-carboxyhexyl, and 2-methyl-3-carboxypropyl .
Examples of the lower cycloalkyl group include cycloalkyl groups having 3 to 8 carbon atoms , such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl , and cyclooctyl .
Examples of the lower alkoxycarbonyl group 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 .
Examples of the phenyl-lower alkoxy group 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
2-methyl-3-phenylpropoxy. Examples of the halogenated lower alkyl group 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 . Specific examples thereof include 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
3-fluoro-2-methylpropyl .
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, 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, a straight-chain or branched alkylthio groups having 1 to 6 carbon atoms, a carboxyl group, an alkoxycarbonyl group in which the alkoxy moiety is a straight-chain or branched alkoxy group having 1 to 6 carbon atoms , a phenylalkoxy group in which the alkoxy moiety is a straight-chain or branched alkoxy group having 1 to 6 carbon atoms, an alkylenedioxy group, a morpholino group, a straight-chain or branched halogenoalkyl group which have 1 to 3 halogen atoms and in which the alkyl moiety has 1 to 6 carbon atoms , a straight-chain or branched carboxyalkyl group in which the alkyl moiety has 1 to 6 carbon atoms, an alkoxycarbonylalkyl group 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 , a 6-hydroxy-2,5,7,8-tetramethyl-2-chromanylmethoxy group, and a 6-alkanoyloxy-2 ,5, 7 , 8-tetramethyl-2- chromanylmethoxy group in which the alkanoyloxy moiety is an alkanoyloxy group having 1 to 6 carbon atoms. Specific examples thereof 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 ,
2,3, 5-trifluorophenyl , 3,4, 5-trichlorophenyl ,
2-hydroxyphenyl , 3-hydroxyphenyl , 4-hydroxyphenyl , 2 , 5-dihydroxyphenyl , 2 , 3-dihydroxyphenyl ,
2, 4, 5-trihydroxyphenyl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 2 , 3-dinitrophenyl , 2 , 4 , 5-trinitrophenyl, 2-methylphenyl , 3-methylphenyl , 4-methylphenyl , 3-ethylphenyl, 4-ethylphenyl, 4-propylphenyl , 4-butylphenyl , 4-pentylphenyl , 4-hexylphenyl , 4-isopropylphenyl, 4-t-butylphenyl, 2 ,3-dimethylphenyl, 2 , 5-dimethylphenyl , 2 , 6-dimethylphenyl ,
3 , 4-dimethylphenyl , 3,5-diethylphenyl ,
2,3,5-trimethylphenyl , 3,4,5-trimethylphenyl ,
2-methoxyphenyl , 3-methoxyphenyl , 4-methoxyphenyl , 3-ethoxyphenyl , 4-ethoxyphenyl , 4-propoxyphenyl , 4-butoxyphenyl , 4-pentyloxyphenyl , 4-hexyloxyphenyl , 4-isopropoxyphenyl , 4-t-butoxyphenyl ,
2 , 3-dimethoxyphenyl , 2,4-dimethoxyphenyl ,
2 , 5-dimethoxyphenyl , 2 , 6-dimethoxyphenyl ,
3 , 5-diethoxyphenyl , 2,3, 5-trimethoxyphenyl , ,4,5-trimethoxyphenyl , 2-methylthiophenyl , -ethylthiophenyl, 4-propylthiophenyl, 4-butylthiophenyl, -pentylthiophenyl , 4-hexylthiophenyl , , 3-dimethylthiophenyl , 2 , 4-dimethylthiophenyl , , 4-dimethylthiophenyl , 3,4, 5-trimethylthiophenyl , -carboxypheny1 , 3-carboxypheny1 , 4-carboxypheny1 , , 3-dicarboxyphenyl , 3 , 4-dicarboxyphenyl , , 4-dicarboxyphenyl , 2-methoxycarbonylphenyl , -methoxycarbonylphenyl , 4-methoxycarbonylphenyl , -ethoxycarbonylphenyl , 3-ethoxycarbonylphenyl , -ethoxycarbonylphenyl , 4-isopropoxycarbonylphenyl , -pentyloxycarbonylphenyl , 4-propoxycarbonylphenyl , -t-butoxycarbonylphenyl , 4-hexyloxycarbonylphenyl , , 4-dimethoxycarbonylphenyl , 2,4-dimethoxycarbonylphenyl , , 3-dimethoxycarbonylphenyl , -methoxycarbonyl-4-ethoxycarbonylphenyl , , 4-diethoxycarbonylphenyl , 2,4-diethoxycarbonylphenyl , , 3-diethoxycarbonylphenyl , 2-benzyloxyphenyl , -benzyloxyphenyl, 4-benzyloxyphenyl, 2 ,4-dibenzylphenyl, , 6-dibenzylphenyl , 4- (2-phenylethoxy)phenyl , - (3-phenylpropoxy) phenyl , 4- (4-phenylbutoxy) phenyl , - (5-ρhenylpentyloxy) phenyl , 2 , 3-methylenedioxyphenyl , , 4-methylenedioxyphenyl , 2 , 3-ethylenedioxyphenyl , , 4-methylenedioxyphenyl , 2 , 3-propylenedioxyphenyl , , 4-propylenedioxyphenyl , 2-morpholinophenyl , 3-morpholinophenyl , 4-morpholinophenyl ,
2-chloromethylphenyl , 2-fluoromethylphenyl ,
2-bromomethylphenyl , 4-iodomethylphenyl ,
2-dichloromethylphenyl , 3-difluoromethylphenyl ,
4-dibromomethylphenyl , 3-trichloromethylphenyl ,
3-trifluoromethylphenyl , 4-trifluoromethylphenyl ,
4- (1 , 2-dichloroethyl) phenyl , 2- (3-fluoropropyl) phenyl ,
3- (4-chlorobutyl) phenyl , 4- (5-chloropentyl) phenyl,
4- (6-bromohexyl) phenyl , 2 , 3 , 4-trichloromethylphenyl ,
2-carboxymethylphenyl , 3-carboxymethylphenyl ,
4-carboxymethylphenyl , 3 , 5-dicarboxymethylphenyl ,
4- (2-carboxyethyl) phenyl , 3- (4-carboxybutyl) phenyl ,
4- (6-carboxyhexyl) phenyl , 2-methoxycarbonylmethylphenyl ,
4-methoxycarbonylmethylphenyl ,
2 , 6-dimethoxycarbonylmethyl ,
4-ethoxycarbonylmethylphenyl ,
3-butoxycarbonylmethylphenyl ,
4- (4-ethoxycarbonylbutyl) phenyl ,
3- (6-hexyloxycarbonylhexyl) phenyl ,
3- (6-hexyloxycarbonylhexyl) phenyl ,
3- (6-hydroxy-2 ,5,7, 8-tetramethylchroman-2- yl) methoxyphenyl ,
4- (6-hydroxy-2 ,5,7, 8-tetramethylchroman-2- yl) methoxyphenyl , 3- (6-propionyloxy-2 ,5,7, 8-tetramethylchroman-2- yl) methoxyphenyl ,
4- (6-hexanoyloxy-2 ,5,7, 8-tetramethylchroman-2- yl) methoxyphenyl ,
4- (6-acetoxy-2 ,5,7, 8-tetramethylchroman-2- yl) methoxyphenyl ,
2-carboxy-4-methylphenyl , 2-carboxy-6-methylphenyl ,
4-carboxy-6-methylphenyl , 2-carboxy-4-ethylphenyl ,
2-carboxy-4-chlorophenyl , 3-carboxy-4-bromophenyl ,
4-carboxy-6-chlorophenyl , 2-carboxy-4-bromophenyl ,
2-methoxycarbonyl-5-methylphenyl,
3-methoxycarbonyl-6-methylphenyl ,
2-methoxycarbonyl-6-chlorophenyl ,
3-methyl-5-fluorophenyl ,
2-carboxy-3-fluoro-4-methylphenyl , and
2-carboxy-4-methyl-6-methoxyphenyl .
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 ,
3- (3-pyridinyl) propyl , 4- (3-pyridinyl)butyl , 5- (3-pyridinyl) pentyl , 6- (3-pyridinyl) hexyl , l-methyl-2- (3-pyridinyl) propyl , 2-thienylmethyl ,
3-thienylmethyl , 4-thienylmethyl , 2- (2-thienyl) ethyl ,
3- (2-thienyl)propyl , 3- (2-thienyl)propyl ,
4- (2-thienyl) bu yl , 5- (2-thienyl) pentyl ,
6- (2-thienyl) hexyl , l-methyl-2- (2-thienyl) propyl ,
2-imidazolylmethyl , 4-imidazolylmethyl ,
5-imidazolylmethyl , 2- (1-imidazolyl) ethyl ,
3- (4-imidazolyl) propyl, 4- (4-imidazolyl) butyl,
5- (4-imidazolyl) pentyl, 6- (4-imidazolyl) hexyl , lmethyl-2- (1-imidazolyl) propyl, 2-pyrrolylmethyl ,
2-pyrimidinylmethyl , 2-pyrazinylmethyl ,
2-thiazolylmethyl, 2-furylmethyl, 3-furylmethyl ,
2- (2-furyl)methyl, 3- (3-furyl) propyl, 4- (2-furyl)butyl,
5- (3-furyl) pentyl , and 6- (2-furyl) hexyl .
Examples of the phenylthio group which may have at least one halogen atom include 2-chlorophenylthio, 3-chlorophenylthio , 4-chlorophenylthio ,
2-bromophenylthio , 3-fluorophenylthio ,
4-fluorophenylthio, and 4-iodophenylthio.
Examples of the phenylalkylthio group 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 ,
1 , l-dimethyl-2-phenylethylthio , 5-phenylpentylthio, 6-phenylhexylthio, 2-methyl-3-phenylpropylthio, and 2-phenylpropylthio .
Examples of the benzoylamino group which may have 1 to 3 halogen atoms include benzoylamino, 2-fluorobenzoylamino , 3-fluorobenzoylamino ,
4-fluorobenzoylamino , 2-chlorobenzoylamino ,
3-chlorobenzoylamino , 4-chlorobenzoylamino ,
4-bromobenzoylamino , 4-iodobenzoylamino ,
2 , 3-dichlorobenzoylamino , 3 , 4-dichlorobenzoylamino , 2 , 4-dichlorobenzoylamino , and 3,4, 5-trichlorobenzoylamino .
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 (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 ,
2,3, 5-trifluorophenyl , 3,4, 5-trichlorophenyl , -hydroxyphenyl , 3-hydroxyphenyl , 4-hydroxyphenyl , , 5-dihydroxyphenyl , 2 , 3-dihydroxyphenyl , ,4, 5-trihydroxyphenyl , 2-nitrophenyl , 3-nitrophenyl , -nitrophenyl, 2 , 3-dinitrophenyl , 2 , 4 ,5-trinitrophenyl, -methylphenyl , 3-methylphenyl , 4-methylphenyl , -ethylphenyl , 4-ethylphenyl , 4-propylphenyl , -butylphenyl , 4-pentylphenyl , 4-hexylphenyl , -isopropylphenyl, 4-t-butylphenyl, 2 ,3-dimethylphenyl , , 5-dimethylphenyl , 2 , 6-dimethylphenyl , , 4-dimethylphenyl , 3 , 5-diethylphenyl , ,3,5-trimethylphenyl , 3,4,5-trimethylphenyl , -methoxyphenyl , 3-methoxyphenyl , 4-methoxyphenyl , -ethoxyphenyl , 4-ethoxyphenyl , 4-propoxyphenyl , -butoxyphenyl , 4-pentyloxyphenyl , 4-hexyloxyphenyl , -isopropoxyphenyl , 4-t-butoxyphenyl , , 3-dimethoxy-phenyl , 2,4-dimethoxyphenyl , , 5-dimethoxyphenyl , 2 , 6-dimethoxyphenyl , , 5-diethoxyphenyl , 2,3,5-trimethoxyphenyl , ,4,5-trimethoxyphenyl , 2-methylthiophenyl , -ethylthiophenyl, 4-propylthiophenyl, 4-butylthiophenyl, -pentylthiophenyl , 4-hexylthiophenyl , , 3-dimethylthiophenyl , 2,4-dimethylthiophenyl , , 6-dimethylthiophenyl , 2,4, 6-trimethylthiophenyl , -naphthyl, 2-naphthyl, and ,6,7, 8-tetrahydro-2-naphthyl . 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 (wherein the 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 benenze ring condensed with the heterocyclic ring) 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-dihydrobenzopyranyl ,
5-methyl-2-pyrrolyl , 5-methyl-2-thienyl ,
5-methyl-2-pyridinyl , 3 , 5-dimethyl-2-pyridinyl ,
4 , 6-dihydroxy-2-pyridinyl , 6 , 8-dihydroxy-2-dihydrobenzopyranyl , and 6-hydroxy-2 , 5 , 7-trimethyl-2-hydrobenzopyranyl .
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 . Specific examples thereof include phenylcarbamoylmethyl , phenylcarbamoylethyl , phenylcarbamoylpropyl , phenylcarbamoylbutyl , phenylcarbamoylpentyl , phenylcarbamoylhexyl ,
2-methoxyphenylcarbamoylmethyl ,
3-methoxyphenylcarbamoylmethyl ,
4-methoxyphenylcarbamoylmethyl ,
4-ethoxyphenylcarbamoylmethyl ,
4-butoxyphenylcarbamoylmethyl ,
4-propoxyphenylcarbamoylmethyl ,
2-ethoxy-4-butoxypheny1carbamoylmethy1 ,
4-pentyloxyphenylcarbamoylmethyl ,
4-hexyloxyphenylcarbamoylmethyl ,
2 , 6-dimethoxyphenylcarbamoylmethyl , and
2- (2 , 4-dimethoxyphenylcarbamoyl) ethyl .
In this specification, 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.
When R1 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) :
Figure imgf000044_0001
(1-E) (1-C) (1-A) (1-D) (1-B)
The individual groups in formula (2) will be explained below in detail .
Examples of 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 ,
4-e hoxycarbonylbutyl , 6-propoxycarbonylhexyl ,
5-isopropoxycarbonylpentyl , 1 , 1-dimethyl-2-butoxycarbonylethyl ,
2-methyl-3-t-butoxycarbonylpropyl,
2-pentyloxycarbonylethyl , and hexyloxycarbonylmethyl .
Examples of the phenoxy-lower alkanoyl group 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 ,
3-methyl-4-phenoxybutyryl, 5-phenoxypentanoyl, and 2-methyl-4-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. Specific examples thereof include 2- (2-methoxycarbonylphenoxy) acetyl , 2- (3-methoxycarbonylphenoxy) acetyl , 2- (4-methoxycarbonylphenoxy) acetyl, 2- (3 , 4-dimethoxycarbonylphenoxy) acetyl , 2- (3 , 4 , 5-trimethoxycarbonylphenoxy) acetyl , 3- (2-propoxycarbonylphenoxy)propionyl ,
4- (4-pentyloxycarbonylphenoxy) butyryl , 5- (3-propoxycarbonylphenoxy) pentanoyl ,
6- (4-butoxycarbonylphenoxy) hexanoyl , and 2- (4-hexyloxycarbonylphenoxy) acetyl .
Examples of the phenyl-lower alkanoyl group 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 ,
4-chlorophenylsulfonyl , 2-fluorophenylsulfonyl , 3-bromophenylsulfonyl , 4-iodophenylsulfonyl ,
2 , 3-dichlorophenylsulfonyl , 3 , 4-difluorophenylsulfonyl , 3 , 5-dibromophenylsulfonyl , 3,4, 5-trichlorophenylsulfonyl , 3-methylphenylsulfonyl , 4-methylphenylsulfonyl ,
3-ethylphenylsulfonyl , 3-isopropylphenylsulfonyl , 4-hexylphenylsulfonyl , 3,4-dimethylphenylsulfonyl , 2 , 5-dimethylphenylsulfonyl ,
3,4, 5-trimethylphenylsulfonyl , 2-methoxyphenylsulfonyl , 3-methoxyphenylsulfonyl , 2-ethoxyphenylsulfonyl ,
4-hexylphenylsulfonyl , 3 , 4-dimethoxyphenylsulfonyl , 3,4, 5-trimethoxyphenylsulfonyl , 2-nitrophenylsulfonyl , 3-nitrophenylsulfonyl , 2 , 4-dinitrophenylsulfonyl , 2-chloro-6-methylphenylsulfonyl , and 3-chloro-2-methoxyphenylsulfonyl .
Examples of the 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 ,
3,4-dichlorophenyl, and 3,4 ,5-trichlorophenyl .
Examples of the lower alkylidene group 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-chlorobenzylidene, 4-fluorobenzylidene, 3-iodobenzylidene , 2- (3-chlorophenyl) ethylidene ,
1- (4-chlorophenyl) ethylidene, 3- (2-fluorophenyl) propylidene,
4- (3-fluorophenyl) butylidene,
1 , l-dimethyl-2- (4-fluorophenyl) ethylidene,
5- (2-bromophenyl) pentylidene,
6- (3-bromophenyl) hexylidene , 2-methyl-3- (4-bromophenyl) propylidene, trichloromethyl-benzylidene ,
2- (2-fluoromethylphenyl) ethylidene ,
1- (3-chloromethylphenyl) ethylidene ,
3- (3-bromomethylphenyl) propylidene,
4- [4- (2-fluoroethyl) phenyl] butylidene,
5- [4- (2-fluoroethyl) phenyl] butylidene,
4- [4- (2-fluoroethyl) phenyl] butylidene,
6- [3- (3-chloropropyl) phenyl] hexylidene ,
2-methyl-3- [3- (4-chlorohexyl) phenyl]propylidene,
2- (3 , 4-difluoromethylphenyl) ethylidene ,
2- (3,4 ,5-tri-chloromethylphenyl) ethylidene,
4-methoxybenzylidene , 3,4-dimethoxybenzylidene,
3,4, 5-trimethoxybenzylidene ,
1- (3-methoxyphenyl) ethylidene ,
2- (2-methoxyphenyl) ethylidene,
3- (2-ethoxyphenyl) propylidene,
4- (4-ethoxyphenyl) propylidene,
5- (3-ethoxyphenyl) pentylidene,
6- (4-isopropoxyphenyl) hexylidene, 4-butoxybenzylidene,
1 , l-dimethyl-2- (4-hexyloxyphenyl) ethylidene,
2-methyl-3- (3 , 4-dimethoxyphenyl) ethylidene ,
2- (3 , 4-diethoxyphenyl) ethylidene, 2-carboxybenzylidene,
3-carboxybenzylidene , 4-carboxybenzylidene,
1- (2-carboxyphenyl) ethylidene,
3- (2 , 4-dicarboxyphenyl) propylidene , 2-methoxycarbonylbenzylidene ,
2- (2-ethoxycarbonyl) benzylidene, 2-nitrobenzylidene,
3,4, 5-trinitrobenzylidene , 1- (2-nitrophenyl) ethylidene,
3- (2 , 4-dinitrophenyl) propylidene ,
4- (3-nitrophenyl) pentylidene,
6- (3-nitrophenyl) hexylidene , 6- (3-nitrophenyl) hexylidene ,
2-methoxy-3-chlorobenzylidene , 2-hydroxybenzylidene ,
2- (3 , 4-dihydroxyphenyl) ethylidene ,
2- (4-hydroxyphenyl) propylidene , 2 , 4-dihydroxybenzylidene ,
3,4, 5-trihydroxybenzylidene,
4-methoxycarbonylbenzylidene ,
3 , 4-dimethoxycarbonylbenzylidene,
3- (2-ethoxycarbonylphenyl) propylidene,
6- (4-isopropoxycarbonylphenyl) hexylidene, and
4-butoxycarbonylbenzylidene .
Examples of the 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 . Specific examples thereof include pheny1vinylidene, 4-nitrophenylvinylidene, 3-phenylallylidene,
3- (4-nitrophenyl) allylidene , 4-phenyl-2-butenylidene, l-methyl-3-phenylallylidene, 5-phenyl-2-pentenylidene, and 6-phenyl-2-hexenylidene.
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,
2-cycloheptenylidene, and 2-cyclooctenylidene.
Examples of the 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. Specific examples thereof include phenoxymethylene, 2-phenoxyethylidene, 1-phenoxyethylidene,
3-phenoxypropylidene, 4-phenoxybutylidene,
1 , l-dimethyl-2-phenoxyethylidene, 5-phenoxypentylidene, 6-phenoxyhexylidene, 2-methyl-3-phenoxypropylidene, 2-carboxyphenoxymethylene, 1- (3-carboxyphenoxy) ethylidene, 3- (2-carboxyphenoxy) propylidene,
4- (3-carboxyphenoxy)butylidene,
1 , l-dimethyl-2- (4-carboxyphenoxy) ethylidene,
5- (2-carboxyphenoxy) pentylidene,
6- (3-carboxyphenoxy) hexylidene, and
2-methyl-3- (4-carboxyphenoxy) propylidene .
Examples of the 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,
4-phenylbutylidene, 1 , l-dimethyl-2-phenylethylidene , 5-phenylpentylidene, 6-phenylhexylidene,
2-methyl-3-phenylpropylidene, 4-fluorobenzylidene , 4-chlorobenzylidene, 4-bromobenzylidene ,
4-iodobenzylidene , 2- (2-fluorophenyl) ethylidene,
1- (3-chlorophenyl) ethylidene, 3- (3-bromophenyl) propylidene, 4-fluoromethylbenzylidene, 4-difluoromethylmethylbenzylidene,
4-trifluoromethylbenzylidene,
4-trichloromethylbenzylidene,
2- (2-fluoromethylphenyl) ethylidene,
1- (3-chloromethylphenyl) ethylidene,
3- (3-bromomethylphenyl) propylidene,
4- [4- (2-fluoroethyl) phenyl] butylidene,
5- [4- (2-chloroethyl)phenyl]propylidene,
6- [3- (3-chloroρropyl) phenyl] hexylidene,
2-methyl-3- [3- (4-chlorohexyl) phenyl] propylidene,
2- (3 , 4-difluoromethylphenyl) ethylidene ,
2- (2 , 5-dibromomethylphenyl) ethylidene, and
2- (3 , 4 , 5-trichloromethylphenyl) ethylidene .
When R1 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) :
Figure imgf000054_0001
(2-A) (2-B) (2-C)
The individual groups in formula (3) will be explained below in detail .
Examples of 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 .
Examples of the 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. Specific examples thereof include benzyl, 2-fluorobenzyl, 3-bromobenzyl, 4-chlorobenzyl, 4-iodobenzyl, 2-phenylethyl , 1- (4-chlorophenyl) ethyl ,
3- (4-bromophenyl) propyl , 4- (2-fluorophenyl)butyl , 5- (3-bromophenyl) pentyl , 6-phenylhexy1 , and 2-methyl-3- (3-chlorophenyl) propyl .
More specific examples of the compound represented by formula (1) include the following: (1-1) : 5- (4-benzyloxybenzyl) -2-isopropylidene- hydrazonoimidazolidin-4-one (1-2) : 2-isopropylidenehydrazono-5-methylimidazolidin-
4-one (1-3) : 5-benzyl-2-isopropylidenehydrazonoimidazolidin-
4-one (1-4) : 5- (4-hydroxybenzyl) -2-isopropylidenehydrazono- imidazolidin-4-one (1-5) : 5- [4- (2,6-dichlorobenzyloxy)benzyl] -2- isopropylidenehydrazonoimidazolidin-4-one (1-6) : 5- [4- (chlorobenzyloxy) benzyl] -2-isopropylidene- hydrazonoimidazolidin-4-one (1-7) : 5- (4-hydroxyphenyl) -2-isopropylidenehydrazono- imidazolidin-4-one (1-8) : 2-isopropylidenehydrazono-5- (4-phenylthiobenzyl) imidazolidin-4-one
(1-9) : 5- [N- (4-ethoxycarbonylphenyl) carbamoylmethyl] - 2-isopropylidenehydrazonothiazolidin-4-one
(1-10) : 2-isopropylidenehydrazono-5- (N-propylcarbamoyl- methyl) thiazolidin-4-one
(1-11) : 2-isopropylidenehydrazono-5- [N- (2-oxo-l,2 ,3,4- tetrahydroquinolin-3-yl) carbamoylmethyl] - thiazolidin-4-one
(1-12) : 5- (N-cyclohexylcarbamoylmethyl) -2- isopropylidenehydrazonothiazolidin-4-one
(1-13) : 5- (N-ethoxycarbonylmethylcarbamoylmethyl) -2- isopropylidenehydrazonothiazolidin-4-one
(1-14) : 5-[N- (4-carboxyphenyl) carbamoylmethyl] -2- isopropylidenehydrazonothiazolidin-4-one
(1-15) : 5-carboxymethyl-3-ethoxycarbonylmethyl-2- isopropylidenehydrazonothiazolidin-4-one
(1-16) : 2-isopropylidenehydrazono-3-phenylthiazolidin- 4-one
(1-17) : 2-isopropylidenehydrazino-4-methylthiazole
(1-18) : 2-isopropylidenehydrazino-4-phenylthiazole
(1-19) : 4- (4-chlorophenyl) -2-isopropylidenehydrazino- thiazole
(1-20) : 2-isopropylidenehydrazino-4- (4-phenylthiophenyl) thiazole (1-21) : 4- (3, 4-dihydroxyphenyl) -2-isopropylidene- hydrazinothiazole (1-22) : 4- [4- (4-chlorobenzyloxy) phenyl] -2- isopropylidenehydrazinothiazole (1-23) : 2-isopropylidenehydrazino-4,5, 6, 7-tetrahydro- benzothiazole (1-24) : 3-benzyl-5- (4-hydroxybenzyl) -2-isopropylidene- hydrazonoimidazolidin-4-one (1-25) : 5- (4-hydroxybenzyl) -2-isopropylidenehydrazono-
3- (4-methoxybenzyl) imidazolidin-4-one (1-26) : 5- (4-benzyloxybenzyl) -2-isopropylidene- hydrazonothiazolidin-4-one (1-27) : 2-isopropylidenehydrazono-5- (4-methylthiobenzyl) thiazolidin-4-one (1-28) : 9-benzyloxymethyl-l , 4 ,5, 7-tetraazabicyclo-
[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-isoproρylidenehydrazono- imidazolidin-4-one (1-32) : 5- [4- (4-chlorobenzoylamino) benzyl] -2- isopropylidenehydrazonoimidazolidin-4-one (1-33) : 2-isoρropylidenehydrazono-5- (N-phenylcarbamoyl- methyl) thiazolidin-4-one (1-34) : 5- (N-isopropylcarbamoylmethyl) -2- isopropylidenehydrazonothiazolidin-4-one (1-35) : 5- (N-benzylcarbamoylmethyl) -2-isopropylidene- hydrazonothiazolidin-4-one (1-36) : 5- [4- (4-chlorophenylthio) benzyl] -2- isopropylidenehydrazonoimidazolidin-4-one (1-37) : 2-isoρropylidenehydrazono-5- [N- (2-methoxy- carbonyl-4-methylphenyl) carbamoylmethyl] - thiazolidin-4-one (1-38) : 5- [N- (2-carboxy-4-methylphenyl) carbamoylmethyl] -2-isopropylidenehydrazonothiazolidin-4- one (1-39) : 5- (N-carboxymethylphenylcarbamoylmethyl) -2- isopropylidenehydrazonothiazolidin-4-one (1-40) : 2-isoρropylidenehydrazono-5- [N- (4-methyl- phenyl) carbamoylmethyl] thiazolidin-4-one (1-41) : 2-isopropylidenehydrazono-5- [4- (3-pyridyl- methoxy) benzyl] thiazolidin-4-one (1-42) : 2-isoρropylidenehydrazono-5- [4- (2-phenyl- ethoxy) benzyl] imidazolidin-4-one (1-43) : 5- (3-indolylmethyl) -2-isopropylidenehydrazono- imidazolidin-4-one (1-44) : 2-isoρropylidenehydrazono-5- [4- (2-thienyl- methoxy) benzyl] imidazolidin-4-one (1-45) : 5- (5-hydroxy-3-indolylmethyl) -2-isopropylidene- hydrazonoimidazolidin-4-one (1-46) : 5- (3,4-dihydroxybenzyl) -2-isopropylidene- hydrazonoimidazolidin-4-one (1-47) : 5- [N- (3, 4-difluorophenyl) carbamoylmethyl] -2- isopropylidenehydrazonothiazolidin-4-one (1-48) : 5- [N- (4-benzyloxyphenyl) carbamoylmethyl] -2- isopropylidenehydrazonothiazolidin-4-one (1-49) : 5- [N- (4-chlorophenyl) carbamoylmethyl] -2- isopropylidenehydrazonothiazolidin-4-one (1-50) : 2-isopropylidenehydrazono-5- [N- (4-methoxy- phenyl) carbamoylmethyl] thiazolidin-4-one (1-51) : 2-isopropylidenehydrazono-5- [N- (4-methyl- thiophenyl) carbamoylmethyl] thiazolidin-4-one (1-52) : 5- [N- (4-bromophenyl) carbamoylmethyl] -2- isopropylidenehydrazonothiazolidin-4-one (1-53) : 2-isopropylidenehydrazono-5- [N- (3,4,5-tri- chlorophenyl) carbamoylmethyl] thiazolidin-4-one (1-54) : 2-isopropylidenehydrazono-5- [N- (3,4-methylene- dioxyphenyl) carbamoylmethyl] thiazolidin-4-one (1-55) : 2-isopropylidenehydrazono-5- [N- (1-naphthyl) - carbamoylmethyl] thiazolidin-4-one (1-56) : 5- [N- (3,5-dichlorophenyl) carbamoylmethyl] -2- isopropylidenehydrazonothiazolidin-4-one (1-57) : 2-isopropylidenehydrazono-5- (N-methyl-N-phenyl- carbamoylmethyl) thiazolidin-4-one (1-58) : 2-isopropylidenehydrazono-5- [N- (3-pyridyl- methyl) carbamoylmethyl] thiazolidin-4-one (1-59) : 2-isopropylidenehydrazono-5- [N- (3-imidazol-l- yl) propylcarbamoylmethyl] thiazolidin-4-one (1-60) : 2-isopropylidenehydrazono-5- (N-morpholino- carbamoylmethyl) thiazolidin-4-one (1-61) : 2-isopropylidenehydrazono-5- [N- (2-thienyl- methyl) carbamoylmethyl] thiazolidin-4-one (1-62) : 2-isopropylidenehydrazono-5- [N- (4-morpholino- phenyl) carbamoylmethyl] thiazolidin-4-one (1-63) : 2-isopropylidenehydrazino-4- (3-pyridyl) thiazole (1-64) : 4- (4-carboxyphenyl) -2-isopropylidenehydrazino- thiazole (1-65) : 2-isopropylidenehydrazono-5- [N- (1-phenylethyl) - carbamoylmethyl] thiazolidin-4-one (1-66) : 5- (4-benzyloxybenzyl) -2-hydrazonoimidazolin-4- one hydrochloride (1-67) : 2-hydrazono-5- (N-phenylcarbamoylmethyl) - thiazolidin-4-one (1-68) : 2-isopropylidenehydrazono-5- [N- (2-methyl-5- methoxycarbonylphenyl) carbamoylmethyl] - thiazolidin-4-one (1-69) : 2-isopropylidenehydrazino-4-trifluoromethyl- thiazole (1-70) : 4-ethoxycarbonylmethyl-2-isopropylidene- hydrazinothiazole (1-71) : 4-carboxymethyl-2-isopropylidenehydrazino- thiazole (1-72) : 2-cyclopentylidenehydrazono-5- (4-benzyloxy- benzyl) imidazolidin-4-one (1-73) : 2-dicycloproρylmethylenehydrazono-5- (N-phenyl- carbamoylmethyl) thiazolidin-4-one (1-74) : 2-cyclohexylmethylenehydrazono-5- (N-phenyl- carbamoylmethyl) thiazolidin-4-one (1-75) : 5- (4-benzyloxycarbonylaminobutyl) -2- isopropylidenehydrazonoimidazolidin-4-one (1-76) : 2-isopropylidenehydrazono-5- (4-methoxycarbony1- aminobutyl) imidazolidin-4-one (1-77) : 2-isopropylidenehydrazono-5- (2-methylpropyl) - imidazolidin-4-one (1-78) : 5-isopropyl-2-isopropylidenehydrazono- imidazolidin-4-one (1-79) : 2-isopropylidenehydrazono-5- [2- (N-phenylcarbamoyl) ethyl] imidazolidin-4-one (1-80) : 5-benzyloxycarbonylmethyl-2-isopropylidene- hydrazonoimidazolidin-4-one (1-81) : 2-isopropylidenehydrazono-5-methoxycarbonyl- methylimidazolidin-4-one (1-82) : 5-carboxymethyl-2-isopropylidenehydrazono- imidazolidin-4-one (1-83) : 2-isopropylidenehydrazono-5- (N-phenylcarbamoyl- methyl) imidazolidin-4-one (1-84) : 5- (N-cyclopropylcarbamoylmethyl) -2- isopropylidenehydrazonoimidazolidin-4-one (1-85) : 5- (4-benzyloxybenzyl) -2- (4-bromobenzenesulfono- hydrazono) imidazolidin-4-one (1-86) : 2- (4-acetamidobenzenesulfonohyrazono) -5- (4- benzyloxybenzyl) imidazolidin-4-one (1-87) : 2-isopropylidenehydrazono-5- [N- (1-phenylethyl) ■ carbamoylmethyl] imidazolidin-4-one (1-88) : 5- (4-imidazolylmethyl) -2-isopropylidene- hydrazonoimidazolidin-4-one (1-89) : 2-isopropylidenehydrazono-5- [N- (2-methoxy- carbonylphenyl) carbamoylmethyl] thiazolidin-4- one (1-90) : 5- [N- (2-carboxypheny1) carbamoylmethyl] -2- isopropylidenehydrazonothiazolidin-4-one (1-91) : 5- [N- (5-carboxy-2-methylphenyl) carbamoylmethyl] -2-isopropylidenehydrazonothiazolidin-4- one
(1-92) : 5- [N- (3 , 4-dimethoxyphenyl) carbamoylmethyl] -2- isopropylidenehydrazonothiazolidin-4-one
(1-93) : 3-ethoxycarbonylmethyl-5- (N-phenylcarbamoyl- methyl) -4-isopropylidenehydrazonothiazolidin-4- one
(1-94) : 2-isopropylidenehydrazino-4- (3-thienyl) thiazole
(1-95) : 4- [N- (3 , 4-dimethoxyphenyl) carbamoylmethyl] -2- isopropylidenehydrazinothiazole
(1-96) : 2-isopropylidenehydrazino-4- (2-thiazolyl) - thiazole
(1-97) : 2-isopropylidenehydrazono-5- [N- (2-methoxy- carbonyl-4-methylphenyl) carbamoylmethyl] - imidazolidin-4-one
(1-98) : 5- [N- (l-ethoxycarbonyl-3-methylbutyl) carbamoylmethyl] -2-isopropylidenehydrazonothiazolidin-4- one
(1-99) : 5- [N-3-ethoxycarbonylphenyl) carbamoylmethyl] -4- isopropylidenehydrazonothiazolidin-4-one
(1-100): 5-{N- [l-ethoxycarbonyl-2- (4-benzyloxyphenyl) - ethyl] carbamoylmethyl } -2-isopropylidene- hydrazonothiazolidin-4-one (1-101) : 5-{N-[l-carboxy-2- (4-benzyloxyphenyl) ethyl] - carbamoylmethyl} -2-isopropylidenehydrazono- thiazolidin-4-one
(1-102) : 2-isopropylidenehydrazono-5-{N- [1-methoxy- carbonyl-2- (3-indolyl) ethyl] carbamoylmethyl} - thiazolidin-4-one
(1-103) : 5- [N- (l-carboxy-3-methylbutyl) carbamoylmethyl] - 2-isopropylidenehydrazonothiazolidin-4-one
(1-104) : 5-{N- [l-carboxy-2- (3-indolyl) ethyl] carbamoylmethyl}-2-isopropylidenehydrazonothiazolidin-4- one
(1-105) : 5- [N- (3-carboxyphenyl) carbamoylmethyl] -2- isopropylidenehydrazonothiazolidin-4-one
(1-106) : 2-isopropylidenehydrazono-5- [N- (2-methoxy- carbonylmethylphenyl) carbamoylmethyl] - thiazolidin-4-one
(1-107) : 5- [N- (2-carboxymethylphenyl) carbamoylmethyl] -2- isopropylidenehydrazonothiazolidin-4-one
(1-108) : 2-isopropylidenehydrazono-5 (R) - (N-phenyl- carbamoylmethyl) thiazolidin-4-one
(1-109) : 2-isopropylidenehydrazono-5 (S) - (N-phenyl- carbamoylmethyl) thiazolidin-4-one
(1-110) : 5- [N- (4-chloro-2-methoxycarbonylphenyl) - carbamoylmethyl] -2-isopropylidenehydrazono- thiazolidin-4-one (1-111) : 5- [N- (2-carboxy-4-chlorophenyl) carbamoylmethyl] -2-isopropylidenehydrazonothiazolidin-4- one
(1-112) : 2-isopropylidenehydrazono-5- [N- (2 , 3-dimethyl- phenyl) carbamoylmethyl] thiazolidin-4-one
(1-113) : 5- [N- (2-furanylmethyl) carbamoylmethyl] -2- isopropylidenehydrazonothiazolidin-4-one
(1-114) : 5- [N- (2, 6-dimethylphenyl) carbamoylmethyl] -2- isopropylidenehydrazonothiazolidin-4-one
(1-115) : 2-isopropylidenehydrazono-5- [N- (2-methoxy-5- methoxycarbonylphenyl) carbamoylmethyl] - thiazolidin-4-one
(1-116) : 5- [N- (5-carboxy-2-methoxyphenyl) carbamoylmethyl] -2-isopropylidenehydrazonothiazolidin-4- one
(1-117): 5- [N- (4 , 5-dimethoxy-2-ethoxycarbonylphenyl) - carbamoylmethyl] -2-isopropylidenehydrazono- thiazolidin-4-one
(1-118) : 5- [N- (2-carboxy-4 , 5-dimethoxyphenyl) carbamoylmethyl] -2-isopropylidenehydrazonothiazolidin-4- one
(1-119) : 5- [N- (2-benzyloxycarbonyl-l (S) -methoxycarbonyl- ethyl) carbamoylmethyl] -2-isopropylidene- hydrazonothiazolidin-4-one (1-120) : 5- [N- (α-ethoxycarbonylbenzyl) carbamoylmethyl] - 2-isopropylidenehydrazonothiazolidin-4-one
(1-121) : 5- [N- (α-carboxybenzyl) carbamoylmethyl] -2- isopropylidenehydrazonothiazolidin-4-one
(1-122) : 5- [N- (2-hydroxy-5-methoxycarbonylphenyl) - carbamoylmethyl] -2-isopropylidenehydrazono- thiazolidin-4-one
(1-123) : 5- [N- (5-carboxy-2-hydroxyphenyl) carbamoylmethyl] -2-isopropylidenehydrazonothiazolidin-4- one
(1-124) : 5- [N- (4-fluorophenyl) carbamoylmethyl] -2- isopropylidenehydrazonothiazolidin-4-one
(1-125) : 5- [N- (2-carboxy-4-methylphenyl) carbamoylmethyl] -2-isopropylidenehydrazonothiazolidin-4- one
(1-126) : 5- [N- (4-hydroxy-2-methoxycarbonylphenyl) - carbamoylmethyl] -2-isopropylidenehydrazono- thiazolidin-4-one
(1-127) : 5- [N- (2-carboxy-4-hydroxyphenyl) carbamoylmethyl] -2-isopropylidenehydrazonothiazolidin-4- one
(1-128) : 5-[N-[4-[ (6-acetoxy-2 ,5 , 7 , 8-tetramethylchroman- 2-yl) methoxy]phenyl] carbamoylmethyl] -2- isopropylidenehydrazonothiazolidin-4-one (1-129) : 5-[N-[4-[ (6-hydroxy-2 , 5 , 7 , 8-tetramethylchroman- 2-yl) methoxy]phenyl] carbamoylmethyl] -2- isopropylidenehydrazonothiazolidin-4-one
(1-130) : 2-isopropylidenehydrazono-5- [N- [3- (trifluoromethyl) phenyl] carbamoylmethyl] thiazolidin-4-one
(1-131) : 2-isopropylidenehyrazono-5- [N- (4-methoxy-2- methylphenyl) carbamoylmethyl] thiazolidin-4-one
(1-132) : 5- [N- (4-fluoro-2-methoxycarbonylphenyl) - carbamoylmethyl] -2-isopropylidenehydrazono- thiazolidin-4-one
(1-133) : 5- [N- (2-carboxy-4-fluorophenyl) carbamoylmethyl] -2-isopropylidenehydrazonothiazolidin-4- one
(1-134) : 5- [N- (3-fluoro-2-methoxycarbonylphenyl) - carbamoylmethyl] -2-isopropylidenehydrazono- thiazolidin-4-one
(1-135) : 5- [N- (2-carboxy-3-fluorophenyl) carbamoylmethyl] -2-isopropylidenehydrazonothiazolidin-4- one
(1-136) : 2-isopropylidenehydrazono-5- [N- (2-methoxy- carbonyl-5-methylphenyl) carbamoylmethyl] - thiazolidin-4-one
(1-137) : 5- [N- (2-carboxy-3-methylphenyl) carbamoylmethyl] -2-isopropylidenehydrazonothiazolidin-4- one (1-138) : 2-isopropylidenehydrazono-5- [N- [3-methoxy- carbonyl-5- (trifluoromethyl) phenyl] - carbamoylmethyl] thiazolidin-4-one
(1-139) : 5- [N-[3-carboxy-5- (trifluoromethyl) phenyl] - carbamoylmethyl] -2-isopropylidenehydrazono- thiazolidin-4-one
(1-140) : 2-isopropylidenehydrazono-5- [N- [4- (trifluoro- methyl) phenyl] carbamoylmethyl] thiazolidin-4-one
(1-141) : 2-isopropylidenehydrazono-5- [N- (4-methoxy-2- methoxycarbonylphenyl) carbamoylmethyl] - thiazolidin-4-one
(1-142) : 5- [N- (2-carboxy-3-methoxyphenyl) carbamoylmethyl] -2-isopropylidenehydrazonothiazolidin-4- one Specific examples of the compound represented by formula (2) include the following:
(2- -1) 2-isopropylidenehydrazonoimidazolidin-4-one
(2- -2) 2-benzylidenehydrazonoimidazolidin-4-one
(2- -3) 2-α-methylcinnamylidenehydrazonoimidazolidin-4- one
(2- -4) 2-cyclopentylidenehydrazonoimidazolidin-4-one
(2- -5) 2- (1-cyclopropylethylidenehydrazono) - imidazolidin-4-one
(2-6) : 2-cyclohexylmethylenehydrazonoimidazolidin-4- one (2-7) 2-cyclohexylidenehydrazonoimidazolidin-4-one (2-8) 2-n-butylidenehydrazonoimidazolidin-4-one (2-9) 2-dicyclopropylmethylenehydrazonoimidazolidin-
4-one
(2-10) : 2- (1-trifluoromethylethylidenehydrazono) - imidazolidin-4-one
(2-11) 2-hexafluoroisopropylidenehydrazono- imidazolidin-4-one
(2-12) : 2-benzylidenehydrazono-1-methoxycarbonylmethyl- imidazolidin-4-one
(2-13) 2-benzylidenehydrazono-1-carboxymethyl- imidazolidin-4-one
(2-14) 2-isopropylidenehydrazono-l-methoxycarbonyl- methylimidazolidin-4-one
(2-15) : 1-methoxycarbonylmethyl-2-α-methylcinnamyl- idenehydrazonoimidazolidin-4-one
(2-16) : 2- (4-carboxybenzylidenehyrazono) -1-carboxy- methylimidazolidin-4-one
(2-17) : 2-cinnamylidenehydrazono-5-cinnamylidene- imidazolidin-4-one
(2-18) 2-benzylidenehydrazono-5-benzylidene- thiazolidin-4-one
(2-19) : 2-cinnamylidenehydrazono-5-cinnamylidene- thiazolidin-4-one (2-20) : 2- (4-trifluoromethylbenzylidenehydrazono) -5- (4- trifluoromethylbenzylidene) thiazolidin-4-one (2-21) : 2-cinnamylidenehydrazono-5-cinnamylidene-l- methoxycarbonylmethylimidazolidin-4-one (2-22) : l-carboxymethyl-2-cinnamylidenehydrazono-5- cinnamylideneimidazolidin-4-one (2-23) : 2- (4-phenylsemicarbazono) thiazolidin-4-one (2-24) : 2- (4-naphthylsemicarbazono) thiazolidin-4-one (2-25) : 2- [4- (4-chlorophenyl) semicarbazono] thiazolidin-
4-one (2-26) : 2- (4-benzylsemicarbazono) thiazolidin-4-one (2-27) : 2- [4- (4-fluorophenyl) semicarbazono] thiazolidin-
4-one (2-28) : 2- (4-butylsemicarbazono) thiazolidin-4-one (2-29) : l,4,5,7-tetraazabicyclo[4,3,0]nonan-5-ene-3,8- dione (2-30) : 2-benzylidenehydrazono-3-ethoxycarbonylmethyl-
1-methoxycarbonylmethylimidazolidin-4-one (2-31) : 2-benzylidenehyrazono-1,3-dicarboxymethyl- imidazolidin-4-one (2-32) : 7-ethoxycarbonylmethyl-l,4,5,7-tetraazabicyclo-
[4,3 , 0] nonan-5-ene-3 , 8-dione (2-33) : 7-carboxymethyl-l,4 ,5, 7-tetraazabicyclo-
[4,3 , 0] nonan-5-ene-3 , 8-dione (2-34) : 3-ethoxycarbonylmethyl-2-isopropylidene- hydrazonothiazolidin-4-one
(2-35) : 3-carboxymethyl-2-isopropylidenehydrazono- thiazolidin-4-one
(2-36) : 5-benzylidene-2-benzylidenehydrazono-3-carboxy- methylthiazolidin-4-one
(2-37) : 3- (5-carboxypentyl) -2-cinnamylidenehydrazono-5- cinnamylidenethiazolidin-4-one
(2-38) : 3- (3-carboxypropyl) -2-cinnamylidenehydrazono-5- cinnamylidenethiazolidin-4-one
(2-39) : 3-ethoxycarbonylmethyl-2-hydrazonothiazolidin- 4-one
(2-40) : 2H-thiazolo[2,3-c] [1,2 , 4] triazine-3, 6 (4H,7H) - dione
(2-41) : 2- (2 , 4-dinitrobenzenesulfonohydrazono) -3- ethoxycarbonylmethylthiazolidin-4-one
(2-42) : 3-carboxymethyl-2- (2, 4-dinitrobenzenesulfonohydrazono) thiazolidin-4-one
(2-43) : 3-carboxymethyl-2- (2-nitrobenzenesulfonohydrazono) thiazolidin-4-one
(2-44) : 2- (4-bromobenzenesulfonohydrazono) -3-carboxy- methylthiazolidin-4-one
(2-45) : 3-ethoxycarbonylmethyl-2-phenylacetylhydrazono- thiazolidin-4-one (2-46) : 3-ethoxycarbonylmethyl-2- (4-methoxybenzene- sulfonohydrazono) thiazolidin-4-one (2-47) : 3-ethoxycarbonylmethyl-2-cinnamylidene- hydrazono-5-cinnamylidenethiazolidin-4-one (2-48) : 3-carboxymethyl-2-cinnamylidenehydrazono-5- cinnamylidenethiazolidin-4-one (2-49) : 3-carboxymethyl-2- (4-fluorobenzylidene- hydrazono) -5- (4-fluorobenzylidene) thiazolidin-
4-one (2-50) : 2- (2 , 4-dinitrobenzenesulfonohydrazono) - thiazolidin-4-one (2-51) : 2- (4-toluenesulfonohydrazono) thiazolidin-4-one (2-52) : 2- (2, 4-dinitrobenzenesulfonohydrazono) - imidazolidin-4-one (2-53) : 3-ethoxycarbonylmethyl-2- (4-methoxycarbonyl- benzylidenehydrazono) thiazolidin-4-one (2-54) : 2- (4-carboxybenzylidenehyrazono) -3-carboxy- methylthiazolidin-4-one (2-55) : 3-carboxymethyl-2-salicylidenehydrazono- thiazolidin-4-one (2-56) : 3-cyclopentyl-2-isopropylidenehydrazono- thiazolidin-4-one (2-57) : 2-isopropylidenehydrazono-3-phenoxyacetyl- thiazolidin-4-one (2-58) : 2-isopropylidenehydrazono-3-methoxycarbonyl- phenoxyacetylthiazolidin-4-one (2-59) : 2-isopropylidenehyrazono-l-methoxycarbonyl- methyl-3-methylimidazolidin-4-one (2-60) : 2-isopropylidenehydrazono-3-methylimidazolidin-
4-one (2-61) : 2-isopropylidenehydrazono-l,3-dimethyl- imidazolidin-4-one (2-62) : 2- (4-carboxγbenzylidenehydrazono) thiazolidin-4- one (2-63) : 2- (4-carboxyphenoxyethylidenehydrazono) - thiazolidin-4-one (2-64) : 2- (3 , 4 , 5-trimethoxybenzylidenehydrazono) - thiazolidin-4-one (2-65) : 2-phenylpropylidenehydrazonothiazolidin-4-one (2-66) : 2- (2-nitrocinnamylidenehydrazono) thiazolidin-4- one (2-67) : 5-cinnamylidene-2- (2 ,4-dinitrobenzenesulfonohydrazono) -3-ethoxycarbonylmethylthiazolidin-4- one (2-68) : 2- (2, 4-dinitrobenzenesulfonohydrazono) -3- ethoxycarbonylmethyl-5- (2-α-methyl- cinnamylidene) thiazolidin-4-one Specific examples of the compound represented by formula (3) include the following: (3-1) : 2- [2- (N-benzoylthiocarbamoyl) hydrazino]benzo- thiazole (3-2) : 2- [2- (N-ethoxycarbonylthiocarbamoyl) hydrazino] - benzothiazole (3-3) : 2- (2-benzoylhydrazino) benzothiazole (3-4) : 2-isopropylidenehydrazinobenzimidazole (3-5) : 2-diphenylmethylidenehydrazinobenzimidazole (3-6) : 2- (2-methylhydrazino)benzimidazole (3-7) : 3-oxo-l,2, 3, 4-tetrahydro- [1,2,4] -triazino [4,3- a]benzimidazole (3-8) : 2-isopropylidenehydrazino-l-methylbenzimidazole (3-9) : 1-ethoxycarbonylmethyl-2- (1-ethoxycarbonyl- methyl-2-isopropylidenehydrazino) benzimidazole (3-10) : 2-hydrazino-5-methylbenzimidazole (3-11) : 2-isopropylidenehydrazino-5-methylbenzimidazole (3-12) : l-benzyl-2-isopropylidenehydrazinobenzimidazole (3-13) : l-benzyl-2- (1-ethoxycarbonylmethyl-2- isopropylidenehydrazino) benzimidazole (3-14) : 1- (4-chlorobenzyl) -2-isopropylidenehydrazino- benzimidazole The compounds represented by formulae (1) , (2) , and (3) include all isomers thereof, e.g. , stereoisomers , optical isomers , and geometrical isomers .
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) .
Examples of the 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.
Examples of the bases for use in salt formation include sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, and potassium hydrogen carbonate .
Examples of vitamin B6 used in the AGE production inhibitory composition of the present invention include six basic forms of vitamin B6, i.e., pyridoxine, pyridoxal, pyridoxamine , and phosphates thereof. These forms of vitamin B6 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 B6 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 .
Specifically, 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 .
Various forms of medical preparations can be selected according to intended purposes of remedy. Typical examples thereof include tablet, pill, powder, solution, suspension, emulsion, granule, capsule, suppository, injections (e.g. , solution and suspension) , and ointment.
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; humectants such as glycerol and starch; adsorbents such as starch, lactose, kaolin, bentonite, and colloidal silicic acid; and lubricants such as purified talc, stearic acid salts, boric acid powder, and polyethylene glycol. If desired and necessary, 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 .
When the composition of the present invention is molded into pills , 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.
When the composition is molded into suppositories , 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 B6 and then filling hard gelatin capsules or other hard capsules with the mixture .
When injections are prepared, a solution, emulsion, or suspension is pasteurized, and is preferably regulated so as to have the same osmotic pressure as the blood. For preparing these preparations, use can be made of diluents such as, e.g., water, aqueous lactic acid solution, ethyl alcohol, propylene glycol, ethoxyisostearyl alcohol, and polyoxyethylene sorbitan fatty acid esters. In this case, sodium chloride, glucose, or glycerol may be added to the medical preparations in an amount sufficient to prepare isotonic solutions. Alternatively, 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 .
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 B6 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. However, the composition is usually administered orally or parenterally either generally or locally. For example, when the composition is used in the form of a tablet, pill, solution, suspension, emulsion, granule, or capsule preparation, it is administered orally. When used in the form of an injection, 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 B6 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 .
Example
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 .
Synthesis Example Synthesis of 2-Isopropylidenehydrazono-5- (N-phenyl- carbamoylmethyl) thiazolidin-4-one (1-33) :
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 . Sixteen hours after, the reaction mixture was poured into a mixture of 2 N hydrochloric acid (100 ml) and ethyl acetate (100 ml) . The organic layer separated was taken out, washed with a saturated aqueous solution of sodium hydrogen carbonate, and then dried with anhydrous sodium sulfate. Subsequently, the solvent was distilled off at a reduced pressure. The residue was purified by silica gel chromatography (eluent: methylene chloride/methanol = 9/1) to thereby obtain the target compound. 1H-NMR (DMSO-d6) δ: 1.93, 1.95 (2s, 6H) , 2.87 (dd, 1H, Jgθm = 16.5 Hz, J = 9.57 Hz) , 3.16 (dd, 1H, J = 3.95 Hz) , 4.33 (dd, 1H) , 7.0-7.6 (m, 5H) , 10.11 (brs , 1H) , 11.70 (brs, 1H)
Preparation Example 2-Isopropylidenehydrazono-5- (N-phenyl- 5 g carbamoylmethyl) thiazolidin-4-one
Vitamin B6 (pyridoxine hydrochloride) 0.1 g Sodium lauryl sulfate 0.2 g
Magnesium stearate 0.2 g
Crystalline cellulose 4.6 g
The above ingredients were mixed in an ordinary way, and the mixture was tabletted to obtain tablets .
Test Example 1. AGE Production Inhibitory Function
Samples each comprising the compound obtained in Synthesis Example (hereinafter referred to as "Compound (1-33)") and vitamin B6 were examined in vitro for AGE production inhibitory effect using ELISA (enzyme-linked immunosorbent assay) . The test method and analysis method used are as follows . (i) Test Method
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.
On the other hand, 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. To each of these solutions was added 5 mM of vitamin B6 (pyridoxine hydrochloride) . Thus , sample solutions were prepared.
The sample solutions and the control solution were incubated at 37°C for 4 days, (ii) Analysis Method
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 μl/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.
The absorbance at 492 nm of each colored liquid was measured with an ELISA plate reader . The results obtained are shown in Fig. 1. The absorbances for the sample solutions are shown as relative values , with that for the control solution being taken as 100%. 2. Function of Producing or Inhibiting Side Effects (1) Function of Inhibiting Psychoneurologic Manifestation (Convulsion-inhibitory Effect) and Function of Inhibiting Vitamin B6 Deficiency (i) Administration Schedule
Each sample was forcibly administered orally to a beagle dog (male, aged 7 months) using a capsule, and the dog was fed 6 hours thereafter, (ii) Dose and Administration Period
In 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 .
In Comparative Example 1, 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 .
(iii) Measurement Method
The blood concentrations of pyridoxal phosphate
(PLP) and pyridoxal (PL) were determined in the administration period in accordance with the method described in Toshiharu Yagi and Kenji Sauda, Rinsho Kensa, 36(3) :244 (1992). Furthermore, the dogs were examined for convulsions caused by vitamin B6 deficiency during the administration period. The results obtained are shown in 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% .
Table 1
Figure imgf000086_0001
Table 2
Figure imgf000086_0002
As clear from the results shown in Tables 1 and 2 , in Example 1, in which Compound (1-33) was used in combination with vitamin B6, 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.
On the other hand, in 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. In Comparative Example 1, since the dog used was severely convulsed, the examination was stopped on the 23rd day in the administration period.
(2) Mitigation of GPT Level Abnormality (Mitigation of Abnormality in Serum Biochemical Test Results)
(i) Administration Method
A group of five SD male rats (aged 5 weeks) was used for each test. Compound (1-33) was suspended in 0.5% carboxymethyl cellulose solution, while pyridoxine hydrochloride (PN) and aminoguanidine hydrochloride were dissolved in water. The suspension and the aqueous solutions were forcibly administered orally to the rats in the amounts shown below.
In 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.
In Comparative Example 3, aminoguanidine was administered to still 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 .
After 1-week administration, blood was taken out of the aorta of each rat under light anesthesia with ether and centrifuged (3,000 rpm, for 15 minutes) to obtain a serum. The concentration of GPT (glutamate- pyruvate transaminase) in the serum was determined by a modification of the Reitman-Franker method. The results obtained are shown in Table 3.
Table 3
Figure imgf000088_0001
In Table 3, the rat body weight and the GPT concentration in the serum each is shown in terms of (average of five) ± (standard deviation). The data indicated by * had a significant difference of p<0.05, those indicated by ** had a significant difference of p<0.01, and those indicated by *** had a significant difference of p<0.001 (paired t-test) , based on the 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 .
In contrast, the rats in Comparative Example 2, in which Compound (1-33) alone was administered, and the rats in Comparative Example 3 , in which aminoguanidine alone was administered, showed a significant decrease in GPT concentration as compared with the control .
Industrial Applicability
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 .
Consequently, the 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 .
While the invention has been described in detail and with reference to specific embodiments thereof, it will be apparent to one skilled in the art that various changes and modifications can be made therein without departing from the spirit and scope thereof.

Claims

1. An AGE production inhibitory composition which comprises (a) a Maillard reaction inhibitor and
(b) vitamin B6 or a pharmaceutically acceptable salt thereof .
2. The AGE production inhibitory composition according to claim 1 , wherein the Maillard reaction inhibitor is aminoguanidine.
3. The AGE production inhibitory composition according to claim 1 , wherein the Maillard reaction inhibitor is : a compound represented by the following formula (1) :
Figure imgf000091_0001
wherein R1 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;
R2 represents : an amino group, a 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 a lower alkanoylamino group on the phenyl ring thereof, or a group represented by -N=R4 (wherein R4 represents a lower alkylidene group, a lower alkylidene group having one or two lower cycloalkyl groups , a lower cycloalkylidiene group, a diphenyl-lower alkylidene group, or a phenyl-lower alkylidene group) ;
R3 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-OR5 (wherein W represents a lower alkylene group; R5 represents a hydrogen atom, a lower alkyl group, or a phenyl-lower alkyl group; and b represents 0 or 1) , a group represented by -Z-CO-R3 {wherein Z represents a lower alkylene group; and Ra represents -Tyr (ORal) -ORbl , -Leu-ORb2 , -Trp-ORb3, -Asp (0Ra2) -ORb4 , -Ph-Gly-ORb5 (wherein Ral and Ra2 each represents a hydrogen atom or a benzyl group; and Rbl, Rb2, Rb3, Rb4, and Rb5 each represents a hydrogen atom or a lower alkyl group), or -N(R6)-R7 (wherein R6 represents a lower alkyl group, a carboxyl-lower alkyl group, a lower- alkoxycarbonyl-lower alkyl, a phenyl-lower alkyl group, a lower cycloalkyl group, 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, 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, a naphthyl group, a 3 , 4-dihydrocarbos yryl group, a morpholino group, or 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, an oxygen atom, and a sulfur atom; and R represents a hydrogen atom or a lower alkyl group) } , or a group represented by
Figure imgf000094_0001
{wherein B represents a lower alkylene group; R 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 (wherein D represents a lower alkylene group; and R9 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 (wherein the phenyl ring may be condensed with a benzene ring or a cyclohexane ring) , a 5-member d 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 (wherein the 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 } ;
X represents :
-S- or
-N(R10)- (wherein R10 represents a hydrogen atom or a lower alkoxycarbonyl-lower alkyl group) ; and represents a single bond or a double bond, with the proviso that when represents a single bond, A represents a carbonyl group, and when represents a double bond, A represents:
=C(R1:L)- {wherein R11 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
Figure imgf000096_0001
(wherein R12 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
R4 and R10 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 and A represent a hydrogen atom and a carbonyl group, respectively, R1 is neither a hydrogen atom nor a lower alkoxycarbonyl-lower alkyl group; and
R3 and R11 may bind to each other to form a 5-membered to 8-membered ring, or a pharmaceutically acceptable salts thereof; a compound represented by the following formula (2) :
Figure imgf000097_0001
wherein R13 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 thereo , or a lower cycloalkyl group; R14 represents : a group represented by -NHR16 {wherein R16 represents a hydrogen atom, a 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, a phenyl-lower alkanoyl group, or a group represented by -CO-NHR17 (wherein R17 represents a lower alkyl group, a phenyl group which may have at least one halogen atom on the phenyl ring thereof, a phenyl-lower alkyl group, or a naphthyl group) } or a group represented by -N=R18 {wherein R18 represents a lower alkylidene group, a lower alkylidene group having 1 or 2 lower cycloalkyl groups, a phenyl- lower alkylidene group which may have 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 on the phenyl ring thereof, a phenyl-lower alkenylidene group which may have at least one nitro group on the phenyl ring thereof, a lower alkenylidene group, a lower cycloalkylidene group, or a phenoxy-lower alkylidene group which may have at least one carboxyl group on the phenyl ring thereof} ; R15 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 :
-S- or
-N(R19)- (wherein R19 represents a hydrogen atom, a lower alkyl group, a carboxyl-lower alkyl group, or a lower alkoxycarbonyl-lower alkyl group) ; and
R13 and R16, or R16 and R19 may bind to each other to form an oxoethylene group; when R13, R15, and Y are a hydrogen atom, two hydrogen atoms, and -S-, respectively, R14 is neither a group represented by -NHR16 (wherein R16 is a hydrogen atom or a phenylsulfonyl group which may have at least one lower alkoxy group on the phenyl ring thereof) nor a group represented by -N=R18 (wherein R18 is a lower alkylidene group, a phenyl-lower alkylidene group which may have at least one substituent selected from the group consisting of a halogen atom, a nitro group, a hydroxyl group, and a lower alkoxy group on the phenyl ring thereof, or a phenyl-lower alkenylidene group which may have at least one nitro group on the phenyl ring thereof) ; when R13, R14 , and Y are a hydrogen atom, a group represented by -N=R18, and -S- or -NH-, respectively, R15 and R18 are not a phenyl-lower alkylidene group at the same time ; and when R1 , R , and Y are a group represented by -NHR16, two hydrogen atoms, and -S-, respectively, R13 and Rl╬┤ do not bond to each other to form an oxoethylene ring, or a pharmaceutically acceptable salts thereof; or a compound represented by the following formula (3) :
Figure imgf000100_0001
wherein R20 represents : a hydrogen atom or a lower alkyl group; R21 represents : a hydrogen atom, a lower alkyl group, a lower alkanoyl group, or a lower alkoxycarbonyl-lower alkyl group;
R22 represents a hydrogen atom, a lower alkyl group, or a lower alkanoyl group;
R23 represents a hydrogen atom, a lower alkanoyl group, a benzoyl group, or a group represented by
Figure imgf000101_0001
(wherein R 4 represents a phenyl group or a lower alkoxy group) , and
R22 and R23 may bond to each other to form a lower alkylidene group, a diphenylmethylene group, or a phenyl-lower alkylidene group; and
V represents :
-S- or
-N- (R25) - (wherein R25 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 ; and R23 and R25 may bind, to each other to form a 6-membered to 8-membered ring, or a pharmaceutically acceptable salt thereof.
4. An AGE production inhibitory composition which comprises :
(a) a compound represented by the following formula (1) :
Figure imgf000102_0001
wherein R1 represents : a hydrogen ato , 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; R2 represents : an amino group, a 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 a lower alkanoylamino group on the phenyl ring thereof, or a group represented by -N=R4 (wherein R4 represents a lower alkylidene group, a lower alkylidene group having one or two lower cycloalkyl groups , a lower cycloalkylidiene group, a diphenyl-lower alkylidene group, or a phenyl-lower alkylidene group) ;
R3 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-OR5 (wherein W represents a lower alkylene group; R5 represents a hydrogen atom, a lower alkyl group, or a phenyl-lower alkyl group; and b represents 0 or 1) , a group represented by -Z-CO-R3 {wherein Z represents a lower alkylene group; and Ra represents -Tyr(ORal)-ORbl, -Leu-ORb2 , -Trp-ORb3, -Asp (0Ra2) -ORb4 , -Ph-Gly-ORb5 (wherein Ral and Ra2 each represents a hydrogen atom or a benzyl group; and Rbl, Rb2, Rb3, Rb4, and Rb5 each represents a hydrogen atom or a lower alkyl group), or -N(R6)-R7 (wherein R6 represents a lower alkyl group, a carboxyl-lower alkyl group, a lower- alkoxycarbonyl-lower alkyl, a phenyl-lower alkyl group, a lower cycloalkyl group, 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, 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, a naphthyl group, a 3,4-dihydrocarbostyryl group, a morpholino group, or 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, an oxygen atom, and a sulfur atom; and R7 represents a hydrogen atom or a lower alkyl group) } , or a group represented by
Figure imgf000105_0001
{wherein B represents a lower alkylene group; R8 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-R9 (wherein D represents a lower alkylene group; and R9 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 (wherein the phenyl ring may be condensed with a benzene ring or a cyclohexane ring) , a 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 (wherein the 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 } ;
X represents :
-S- or
-N(R10)- (wherein R10 represents a hydrogen atom or a lower alkoxycarbonyl-lower alkyl group) ; and represents a single bond or a double bond, with the proviso that when represents a single bond, A represents a carbonyl group, and when represents a double bond, A represents:
=C(R13")- {wherein R11 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
Figure imgf000107_0001
(wherein R12 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
R4 and R10 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 R3 and A represent a hydrogen atom and a carbonyl group, respectively, R1 is neither a hydrogen atom nor a lower alkoxycarbonyl-lower alkyl group; and
R3 and R11 may bind to each other to form a 5-membered to 8-membered ring, or a pharmaceutically acceptable salts thereof; and (b) vitamin B6 or a pharmaceutically acceptable salt thereof.
5. An AGE production inhibitory composition which comprises :
(a) at least one compound selected from the group consisting of:
2-isopropylidenehydrazono-5- (N-phenylcarbamoyl- methyl) thiazolidin-4-one,
5- [N- (2-carboxy-4-methylphenyl) carbamoylmethyl] - 2-isopropylidenehydrazonothiazolidin-4-one,
5- [N- (3 , 4-difluorophenyl) carbamoylmethyl] -2- isopropylidenehydrazonothiazolidin-4-one,
5- [N- (2-carboxy-4-chlorophenyl) carbamoylmethyl] - 2-isopropylidenehydrazonothiazolidin-4-one,
5- [N- (2-carboxy-4 , 5-dimethoxyphenyl) carbamoylmethyl] -2-isopropylidenehydrazonothiazolidin-4-one, and
5- [N- (2-carboxy-4-fluorophenyl) carbamoylmethyl] - 2-isopropylidenehydrazonothiazolidin-4-one, or a pharmaceutically acceptable salt thereof, and
(b) vitamin B6 or a pharmaceutically acceptable salt thereof .
6. The AGE production inhibitory composition of any one of claims 1 to 5 , wherein the vitamin B6 or pharmaceutically acceptable salt thereof is contained in an amount of from 0.1 to 200 parts by weight based on 100 parts by weight of the Maillard reaction inhibitor.
7. The AGE production inhibitory composition of any one of claims 1 to 5 , which further comprises a pharmaceutically acceptable carrier.
8. Use of the AGE production inhibitory composition according to any one of claims 1 to 5 for preparing a medicament for preventing or lessening side effects caused by administration of a Maillard reaction inhibitor in humans or animals .
9. Use of the AGE production inhibitory composition according to any one of claims 1 to 5 for preparing a medicament for treating or preventing diabetic complications caused by AGE production or diseases caused by senescence in humans or animals .
PCT/JP1998/001365 1997-03-28 1998-03-26 Age production inhibitory composition comprising a maillard reaction inhibitor and vitamin b¿6? WO1998043649A2 (en)

Priority Applications (1)

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

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP9/78601 1997-03-28
JP7860197 1997-03-28

Publications (2)

Publication Number Publication Date
WO1998043649A2 true WO1998043649A2 (en) 1998-10-08
WO1998043649A3 WO1998043649A3 (en) 1998-12-17

Family

ID=13666431

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1998/001365 WO1998043649A2 (en) 1997-03-28 1998-03-26 Age production inhibitory composition comprising a maillard reaction inhibitor and vitamin b¿6?

Country Status (3)

Country Link
AR (1) AR012199A1 (en)
AU (1) AU6518598A (en)
WO (1) WO1998043649A2 (en)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1126856A1 (en) * 1998-10-28 2001-08-29 Fox Chase Cancer Center Compounds and their therapeutic use with diabetic complications
WO2001095920A1 (en) * 2000-06-16 2001-12-20 Basic, Robert Composition comprising clinoptolite, plant extracts and vitamin b complex for diabetic neuropathy
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

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992002216A2 (en) * 1990-08-01 1992-02-20 The Rockefeller University Advanced glycation inhibitors containing amino-benzoic acids and derivatives, and methods of use
WO1992014456A1 (en) * 1991-02-22 1992-09-03 Shapiro Howard K Use of pharmaceutical compounds in the treatment of symptoms of disorders related to neurological diseases and etiologically related symptomology
EP0531812A1 (en) * 1991-08-27 1993-03-17 Otsuka Pharmaceutical Co., Ltd. Maillard reaction inhibitor, process for producing it, composition containing it and the use thereof
US5272165A (en) * 1984-03-19 1993-12-21 The Rockefeller University 2-alkylidene-aminoguanidines and methods of use therefor
WO1994019335A1 (en) * 1993-02-26 1994-09-01 Otsuka Pharmaceutical Co., Ltd. Thiazole or imidazole derivatives as maillard reaction inhibitors
WO1997009981A1 (en) * 1995-09-12 1997-03-20 University Of Kansas Medical Center Advanced glycation end-product intermediaries and post-amadori inhibition

Patent Citations (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
WO1992002216A2 (en) * 1990-08-01 1992-02-20 The Rockefeller University Advanced glycation inhibitors containing amino-benzoic acids and derivatives, and methods of use
WO1992014456A1 (en) * 1991-02-22 1992-09-03 Shapiro Howard K Use of pharmaceutical compounds in the treatment of symptoms of disorders related to neurological diseases and etiologically related symptomology
EP0531812A1 (en) * 1991-08-27 1993-03-17 Otsuka Pharmaceutical Co., Ltd. Maillard reaction inhibitor, process for producing it, composition containing it and the use thereof
WO1994019335A1 (en) * 1993-02-26 1994-09-01 Otsuka Pharmaceutical Co., Ltd. Thiazole or imidazole derivatives as maillard reaction inhibitors
WO1997009981A1 (en) * 1995-09-12 1997-03-20 University Of Kansas Medical Center Advanced glycation end-product intermediaries and post-amadori inhibition

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
BOOTH ET AL: "In Vitro Kinetic Studies of Formation of Antigenic Advanced Glycation End Products (AGEs). Novel Inhibition of Post-Amadori Glycation Pathways" THE JOURNAL OF BIOLOGICAL CHEMISTRY, vol. 272, no. 9, 28 February 1997, pages 5430-5437, XP002068236 *
KHATAMI: "Inhibition of Nonenzymatic Glycolysation by Pyridoxal, Pyridoxal Phosphate and Aminoguanidine, a Potential Antivitamin B6 Agent" CURRENT STATUS OF PREVENTION AND TREATMENT OF DIABETIC COMPLICATIONS: PROCEEDINGS OF THE 3RD INTERNATIONAL SYMPOSIUM ON TREATMENT OF DIABETES MELLITUS, 13 - 15 July 1988, pages 649-654, XP002068235 *
NAKAMURA ET AL: "A Novel AGE-Inhibitor Prevents the Progression of Diabetic Nephropathy in Otsuka-Long-Evans-Tokushima-Fatty Rat" JASN, vol. 7, no. 9, 1996, page 1875 XP002079422 *

Cited By (10)

* 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
EP1126856A1 (en) * 1998-10-28 2001-08-29 Fox Chase Cancer Center Compounds and their therapeutic use with diabetic complications
EP1126856A4 (en) * 1998-10-28 2008-05-14 Fox Chase Cancer Ct Compounds and their therapeutic use with diabetic complications
WO2001095920A1 (en) * 2000-06-16 2001-12-20 Basic, Robert Composition comprising clinoptolite, plant extracts and vitamin b complex for diabetic neuropathy
HRP20000410B1 (en) * 2000-06-16 2012-06-30 Ba�i� Robert New inhibitor of apoptosis of nerve cells
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

Also Published As

Publication number Publication date
AR012199A1 (en) 2000-09-27
AU6518598A (en) 1998-10-22
WO1998043649A3 (en) 1998-12-17

Similar Documents

Publication Publication Date Title
US11505532B2 (en) SSAO inhibitor
TWI314553B (en) Tri(cyclo) substituted amide compounds
DE69723711T2 (en) ARALKYL AND ARALKYLIDES HETEROCYCLIC LACTAME AND IMIDES
EP0638075B1 (en) Thiazole or imidazole derivatives as maillard reaction inhibitors
AU2014342811B2 (en) Compositions and methods of modulating short-chain dehydrogenase activity
EP2203433B1 (en) 5-(4-(2-(3-methoxyphenyl)-2-oxoethoxy)benzyl)thiazolidine-2,4-dione for use in treating diabetes
EP1727820B1 (en) Amine derivatives with tyrosinkinase inhibiting activity
ZA200509290B (en) Isoquinoline derivatives and their use as GFAT inhibitors
KR102029611B1 (en) Ppar-sparing thiazolidinedione salts for the treatment of metabolic diseases
EP1311488B1 (en) Substituted imidazoles as tafia inhibitors
CN1264384A (en) Fused 1,2,4-thiadiazine derivatives, their preparation method and use
EP2010521A1 (en) Indazole compounds and methods for inhibition of cdc7
DE60313350T2 (en) PYRIMIDIN-2,4-DION DERIVATIVES AS MATRIX METALLOPROTEINASE INHIBITORS
EP2058308A1 (en) Benzimidazoledihydrothiadiazinone derivatives used as fructose-1,6-biphosphatase inhibitors and pharmaceutical compositions containing same.
WO1998043649A2 (en) Age production inhibitory composition comprising a maillard reaction inhibitor and vitamin b¿6?
US20230365575A1 (en) Imidazodiazepinediones and methods of use thereof
JP2002510623A (en) Antidiabetic drugs
GB2387172A (en) [(Aryl-/arylthio-)aryl]methylene substituted azole &amp; azine derivatives and their therapeutic use as antibacterials
JPH10324629A (en) Age formation-inhibitory composition
EP1346992A1 (en) Quinazoline derivatives, process for their preparation and pharmaceutical compositions containing them
JPH10182460A (en) 3-deoxyglucosone generation inhibitor
US7390824B1 (en) Method for treating diabetes employing an aP2 inhibitor and combination
KR101229282B1 (en) Novel salts of substituted 5-membered azacycle and use thereof in the treatment of diseases related to protein aging
JPH09509963A (en) Thiazolidinedione derivatives as anti-hyperglycemic agents
AU2004283822A1 (en) Glutamine fructose-6-phosphate amidotransferase (GFAT) inhibitors

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A2

Designated state(s): AU BR CA CN ID KR MX SG US

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): AT BE CH DE DK ES FI FR GB GR IE IT LU MC NL PT SE

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
AK Designated states

Kind code of ref document: A3

Designated state(s): AU BR CA CN ID KR MX SG US

AL Designated countries for regional patents

Kind code of ref document: A3

Designated state(s): AT BE CH DE DK ES FI FR GB GR IE IT LU MC NL PT SE

121 Ep: the epo has been informed by wipo that ep was designated in this application
122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase in:

Ref country code: CA