WO1995023796A1 - Derive de guanylhydrazone - Google Patents

Derive de guanylhydrazone Download PDF

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Publication number
WO1995023796A1
WO1995023796A1 PCT/JP1995/000294 JP9500294W WO9523796A1 WO 1995023796 A1 WO1995023796 A1 WO 1995023796A1 JP 9500294 W JP9500294 W JP 9500294W WO 9523796 A1 WO9523796 A1 WO 9523796A1
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group
reference example
compound
ethyl acetate
solution
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PCT/JP1995/000294
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English (en)
Japanese (ja)
Inventor
Shuichi Ohuchida
Tomoyuki Hasegawa
Kazuo Kishimoto
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Ono Pharmaceutical Co., Ltd.
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Publication of WO1995023796A1 publication Critical patent/WO1995023796A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/80—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/92—Naphthofurans; Hydrogenated naphthofurans
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
    • C07D311/70—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with two hydrocarbon radicals attached in position 2 and elements other than carbon and hydrogen in position 6
    • C07D311/72—3,4-Dihydro derivatives having in position 2 at least one methyl radical and in position 6 one oxygen atom, e.g. tocopherols
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the present invention relates to a guanylhydrazone derivative useful as a medicament. More specifically, the present invention
  • HbAIc showed that the glucose bound to the N-terminal valine of the ⁇ -chain in an Amadori rearranged form [Koenig, RJ, Blobstein, SH, & Cerami, A., J. Biol. Chem., 252, 2992 (1977)] and that this reaction occurs nonenzymatically [Stevens, VJ, Vlassara, H., Abati, A , & Cerami, A., J. Biol. Chem., 252, 2998 (1977)], and the like, confirming that the Maillard reaction is occurring in vivo.
  • H H H H starts to form a dislocation product, 2 3 ⁇ 4 o o.
  • the protein is referred to as cross-linked polymerisation [a glycosylated product that has progressed through this polymer (abbreviated as AGE).
  • AGE glycosylated product that has progressed through this polymer
  • the Maillard reaction is a phenomenon that is also seen in healthy individuals, but is prominent in diabetic patients with elevated blood sugar levels and in protein sites with slow turnover.
  • diabetic mice are glycosylated 2.7 times more than normal mice [Monnier, VM et al., The Meillard Reaction in Foods and Nutrition, ACS Symposium Series, 215, 432, Am. Chem. So, Washington , DC (1983)], and serum albumin also has increased glycosylation in diabetic patients [Guthrow, CE et al., Pro Natl. Acad. Sci. U.S., 76, 4258 (1979)]. .
  • Crystallin in the ocular lens is a special protein that, once biosynthesized, does not metabolize at all.
  • glycosylation occurred in this crystallant 1 J it was confirmed that a change in the steric structure occurred, and that an enzyme was involved in the intramolecular SH group to form an S—S bond and the polymer was polymerized.
  • glucose binding is up to 10 times higher than normal, and intramolecular S—S binding is increased [Monnier, VM & Cerami, A. Clin. Endocrinol. Metab, ⁇ _ , 431 (1982)].
  • Elastin a collagen present in connective tissues, is a protein rich in lysine and hydroxy lysine, has a slow turnover, and has been found to bind to glucose in the renal glomerular basement membrane, skin tendons, etc.
  • Monnier, VM, Stevens, VJ, & Cerami, A., Maillard Reactions in Food, Prog. Food Nutr. Sci. 5., 315, Pergamon Press, London [Rosenburg, H., Modrak, J.B., Hassing, JM, Al-Turk, WA, & Stohs, SJ, Biochem. Biophys. Res. Commun., 9, 498 (1979)] 0
  • non-enzymatic glycosylation of neuronal myelin protein is considered as a cause of diabetic neuropathy [Monnier, VM et al., Clin. Endocrinol. Metab. II_, 431 (1982)].
  • Japanese Patent Application Laid-Open No. 62-142114 discloses a secondary glycosyl comprising a compound having an active nitrogen-containing group (an amino group bonded to a guanidino group) capable of reacting with an active carbonyl group in an Amadori rearrangement product.
  • a composition that suppresses the production of an end-product of the synthesis is suggested, and specifically, aminoguanidine, ⁇ -hydrazinohistidine and lysine are disclosed.
  • JP-A-2-765 discloses a compound represented by the general formula (C)
  • R 1C is substituted with 1 to 3 halogen atoms, C1-4 alkyl groups, or alkoxy groups, nitro groups, phenoxy groups, amino groups, hydroxyl groups, or C2-4 acylamino groups. or represents a substituted you have not carbocyclic or heterocyclic ring
  • X e represents a single bond
  • Motoma other represents a C2 ⁇ 4 alkenylene group
  • Tsuteji 1-4 such together
  • R 1C and X c Represents an alkyl group
  • R 2C is substituted or substituted with 1 to 3 hydrogen atoms, C 1-4 alkyl groups or halogen atoms, C 1-4 alkyl groups or alkoxy groups, hydroxyl groups or nitro groups. Represents an unsubstituted phenyl group.
  • the compound group represented by has Maillard reaction inhibitory activity.
  • R 1D represents hydrogen or an acyl group
  • R 2D represents hydrogen or a lower alkyl group
  • X D represents a lower alkyl group, a carboxy group, a carboxymethyl group, or a halogen atom, a lower alkyl group, or a hydroxy group.
  • the present inventors have conducted research to find a novel compound that has an excellent inhibitory effect on the Maillard reaction and is highly safe. I found something to achieve. It has also been found that the derivative also has an antioxidant effect.
  • the guanylhydrazone derivative of the compound of the present invention is a novel compound that has never been known before. More specifically, the Rie group in the compound represented by the above formula (C) represents various heterocycles containing a heterocycle containing an oxygen atom, but specifically synthesized has a pyridine ring. Only things. Further, in the compound represented by the formula (C), the bond between the nitrogen atom at the 4-position and Xc at the 5-position represents a single bond. On the other hand, it is essential that the R 4 group in the R 1 group in the compound (I) of the present invention has a heterocyclic ring containing an oxygen atom.
  • the compound (I) of the present invention represents a double bond in the bond between the nitrogen atom at the 4-position and the carbon atom at the 5-position to which R 1 R 2 is bonded, indicating that the compound of the formula (C) It can be said that the chemical structure is significantly different from.
  • R 1 represents R 4 — A—
  • A represents a single bond, a Cl-6 alkylene group, or a phenyl C2-8 alkylene group,
  • R 5 represents a hydrogen atom or a C 1-4 alkyl group
  • R 6 is a hydrogen atom, an Cl ⁇ 4 alkyl or C2 ⁇ 5 Ashiru group
  • R 7 is a hydrogen atom, Cl ⁇ 4 alkyl group, one Z -.
  • OR 8 group One Y- COOR 9 group or a Y- CONR ⁇ R represents 11 groups
  • Z represents a Cl-5 alkylene group
  • Y represents a single bond or a C 1-4 alkylene group
  • R 8 represents a hydrogen atom or a C2-5 acyl group
  • R 9 represents a hydrogen atom or a C 1-4 alkyl group
  • R lfl and R 11 each independently represent a hydrogen atom or a Cl-4 alkyl group
  • n an integer of 1 to 9
  • n an integer of 0 to 2
  • R 2 is a hydrogen atom, a Cl-4 alkyl group, a phenyl group, a phenyl Cl-47 alkyl group, a 5- to 7-membered monocyclic hetero ring containing one or two nitrogen atoms, or a nitrogen atom 1 or 2 Represents a Cl-4 alkyl group substituted with a 5- to 7-membered monocyclic ring to a tetracyclic ring,
  • R 1 and R 2 together with the carbon atom to which they are attached, represent a C5-fucycloalkyl group to which R 4 is fused;
  • R 3 represents a hydrogen atom, a Cl-4 alkyl group or a C2-5 acyl group. Provided, however, that the A represents a phenyl C2 ⁇ 8 alkylene group, phenyl group shall be bonded to the carbon atom bonded to the R 2. ]
  • a guanylhydrazone derivative represented by the following, a non-toxic salt thereof or an acid addition salt thereof,
  • the alkyl group, the alkoxy group, the alkylene group, and the alkylene group include straight-chain and branched-chain groups, and include the double bond in the alkenylene group and the compound (I) of the present invention.
  • Double bonds in the amino groups at positions 5 and 5 include those that are E, Z and EZ mixtures. It also includes isomers resulting from the presence of asymmetric carbon atoms, such as when a branched alkyl group is present.
  • the Cl-4 alkyl group represented by R 2 , R 3 , R 5 , R 6 , R 7 , R 9 , R 10 and R 11 is a methyl, ethyl, propyl, butyl group Maybe these are isomeric groups.
  • the C2-5 acyl group represented by R 3 , R 6 and R 8 is acetyl, propionyl, butyryl, valeryl and isomers thereof.
  • the Cl-4 alkylene group represented by Y is a methylene, ethylene, trimethylene, tetramethylene group or isomers thereof.
  • the Cl-5 alkylene group represented by Z is a methylene, ethylene, trimethylene, tetramethylene, pentamethylene group or an isomer thereof.
  • the Cl-6 alkylene group represented by A in R 1 is a methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene or isomer group thereof.
  • a phenyl C2-8 T alkylene group refers to an ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, octamethylene group substituted with one phenylene group, and It is an isomer group. In this case, the phenylene group is bonded to the carbon atom to which R 2 is bonded.
  • a phenyl C L ⁇ 4 alkyl group represented by R 2 ethylene which is substituted by one phenyl group, trimethylene, tetramethylene and isomeric groups thereof.
  • the 5- to 7-membered monocyclic heterocyclic ring containing 1 or 2 nitrogen atoms represented by R 2 includes pyrrole, imidazole, pyrazol, pyridine, pyridazine, and pyridyl. Midine, virazine, azepine, jia Zepin rings and the like.
  • a Cl-4 alkyl group substituted by a 5- to 7-membered monocyclic hetero ring containing one or two nitrogen atoms refers to a methyl, ethyl, propyl, or butyl group substituted by one of the above rings. And their isomeric groups.
  • R 1 The a C5 ⁇ off cycloalkyl group R 2 is engaged
  • R 4 is reduced to such connexion expressed together with the carbon atoms to which they are bonded, cyclopentyl fused by four one R, cyclohexyl, consequent b Heptyl group and isomers thereof.
  • the dotted line represents a single bond or a double bond.
  • the compound represented by the general formula (I) can be converted into a corresponding salt by a known method, if desired.
  • the salt is non-toxic and water-soluble.
  • Suitable salts include, for example, salts of alkali metals (such as potassium and sodium), salts of alkaline earth metals (such as calcium and magnesium), ammonium salts, and pharmaceutically acceptable organic amines (such as tetramethylammonium).
  • Triethylamine methylamine, dimethylamine, cyclopentylamine, benzylamine, phenethylamine, piperidine, monoethanolamine, diethanolamine, tris (hydroxymethyl) methylamine, lysine, arginine, N— Methyl-D-glucamine).
  • the compound represented by the general formula (I) may be converted into an acid addition salt by a known method, if desired.
  • the acid addition salts are preferably non-toxic and water-soluble. Suitable acid addition salts include, for example, inorganic salts such as hydrochloride, hydrobromide, hydrobromide, sulfate, phosphate, nitrate, or acetate, lactate, Tartrate, benzoate, citrate, methanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfate Organic salts such as fonate, isethionate, glucuronate, and gluconate.
  • the acid addition salt can be obtained by a known method, for example, reacting the compound represented by the general formula (I) with a desired acid in a suitable solvent in a stoichiometric amount.
  • Preferred compounds of the present invention include compounds represented by general formula (I-A)
  • R 7a represents a methyl group, a hydroxymethyl group, a (CH 2 ) 2 —COOH group, a — (CH 2 ) 2 —CONH 2 group, and other symbols have the same meanings as described above. However, two R 5 's may be the same or different.
  • a general formula (I-E) is a general formula (I-E)
  • Specific compounds of the present invention include guanylhydrazone derivatives, their non-toxic salts, their acid adduct salts, and the compounds described in Examples in Tables 1 to 10 below. table 1
  • the compound of the present invention represented by the general formula (I) has the general formula ( ⁇ )
  • R 6 and ⁇ or R 7 are groups which can be removed with an acid
  • the compound can be produced by subsequent acid treatment.
  • the compound is prepared by reacting with the compound shown in, followed by a subsequent acylation reaction, or, if R 6 and / or R 7 is a group that can be removed with an acid, followed by the acylation reaction followed by an acid treatment It can be manufactured by performing.
  • the reaction between the general formula ( ⁇ ) and the general formula (m) or the general formula (ffl-i) occurs in the presence of a tertiary amine (pyridine, triethylamine, etc.) in an alcoholic solvent (methanol, ethanol, etc.)
  • a tertiary amine pyridine, triethylamine, etc.
  • an alcoholic solvent methanol, ethanol, etc.
  • the treatment with an acid is carried out by reacting in an alcoholic solvent (such as methanol or ethanol) in the presence of an organic acid (such as acetic acid or trifluoroacetic acid) or an inorganic acid (such as hydrochloric acid or sulfuric acid).
  • an alcoholic solvent such as methanol or ethanol
  • an organic acid such as acetic acid or trifluoroacetic acid
  • an inorganic acid such as hydrochloric acid or sulfuric acid
  • the acylation reaction is carried out by reacting with an acyl halide or an acid anhydride in an organic solvent (methylene chloride, methyl ether, tetrahydrofuran, etc.) in the presence of a tertiary amine (triethylamine, pyridine, etc.).
  • an organic solvent methylene chloride, methyl ether, tetrahydrofuran, etc.
  • a tertiary amine triethylamine, pyridine, etc.
  • the compound represented by the general formula (II) used as a starting material can be produced by the methods shown in the reaction formulas 1 to 12, or by a known method. For example, it can be produced by the method described herein.
  • R A represents a Cl-4 alkyl group
  • R B represents a C2-4 alkoxyalkyl group
  • R c represents a C2-5 acyl group
  • Y represents a single bond or a Cl-4 alkylene group
  • ZZ represents a C2-4 alkylene group
  • W represents a single bond or a methylene group
  • B represents a single bond or a Cl-6 alkylene group
  • BB represents a C2-8 alkylene group
  • R 6 - 1 represents an Cl ⁇ 4 alkyl group, C2-5 Ashiru group or C2 ⁇ 4 Arukokishiaru Kill group,
  • R 6 - 3 represents a C2 ⁇ 5 A group
  • R 6 - 4 represents a hydrogen atom, Cl ⁇ 4 alkyl group, C2-5 Ashiru group or C2 ⁇ 4 al Kokishiarukiru group,
  • R 7 - 1 represents a hydrogen atom or a C L ⁇ 4 alkyl group
  • R 7 - 2 represents a hydrogen atom, Cl ⁇ 4 alkyl group or R OOC- Y- group, R 7 - represents a 3 HO- Z- group,
  • R 7 — 4 represents a hydrogen atom, Cl- 4 alkyl group, R OOC— Y— group or HO— Z— group,
  • R 7 - 5 represents a hydrogen atom, Cl ⁇ 4 alkyl group, C2-5 Ashiruokishi one Z- group, C2-4 alkoxyalkyl O alkoxy one Z- group or R 9 OOC- Y- group,
  • R 7 - 6 represents an HOOC- Y- group
  • R 7 - 7 represents a RU RWNOC- Y- group
  • R 7 - 8 is hydrogen atom, Cl ⁇ 4 alkyl group, C2-5 Ashiruokishi one Z- group,
  • C2-4 alkoxyalkyloxy represents a Z-group, a RWOOC-Y- group or a RUR'ONOC-Y- group,
  • R 7-9 is a hydrogen atom, a Cl-4 alkyl group, a C2-5 alkoxylZ- group,
  • RHR NOC— represents a Y— group
  • R 7 - 1Q is a hydrogen atom, Cl ⁇ 4 alkyl group, C2-5 Ashiruokishi one Z- group,
  • RUR'ONOC— represents the Y— group
  • R 7 — 11 represents an RWOOC—Y— group
  • R 9 — 1 represents a Cl-4 alkyl group
  • R 13 represents a Cl-4 alkyl group
  • X represents a halogen atom
  • BBN stands for 9-borabicyclo [3.3.1] nonane.
  • the reaction product is purified by conventional means of purification, for example, distillation under normal pressure or reduced pressure, high-performance liquid chromatography using silica gel or magnesium silicate. It can be purified by a method such as chromatography, thin-layer chromatography, column chromatography or washing, recrystallization and the like. Purification may be performed for each reaction, or may be performed after completion of several reactions.
  • the inhibitory effect of the compound of the present invention on the Maillard reaction was confirmed by a screening system using various proteins and various sugars, and specific examples are shown below.
  • Lysozyme and fructose were dissolved in 0.2 M sodium phosphate buffer (pH 7.4) to a concentration of 10 mg / ml and 100 mM, respectively, and incubated at 37 ° C for 3 days. Electrophoresis was performed using polyacrylamide gel electrophoresis (SDS-PAGE). After electrophoresis, the cells were stained with 0.2% Coomassie Brilliant Blue R-250, and the amount of dimers produced was quantified using a densitometer.
  • the present compound was added before incubation, and the inhibitory effect on dimer formation at various concentrations was examined to determine the IC5Q value.
  • the antioxidant effect of the compound of the present invention was confirmed by a screening system for examining the lipid peroxide production inhibitory effect described below.
  • the fasted male Sprague Dawley rat was perfused from the portal vein with an ice-cooled 0.9% sodium chloride solution under ether anesthesia, and liver tissue was removed. The isolated liver was made into a 10% homogenate using an ice-cooled 1.15% aqueous potassium chloride solution. 200 mM of FeCl 2 was added to the obtained homogenate 1, and the mixture was incubated at 37 ° C. for 1 hour.
  • the toxicity of the compound of the present invention was sufficiently low, and it was confirmed that the compound can be safely used as a pharmaceutical.
  • the compounds of the present invention represented by the general formula (I), their non-toxic salts, and their acid addition salts inhibit the Maillard reaction, so that various diabetic complications such as coronary heart disease, peripheral circulation, etc.
  • the compounds of the present invention represented by the general formula (I), their non-toxic salts, and their acid addition salts also have an antioxidant action, that is, an action of suppressing the reaction of free radicals.
  • Treatment of various diseases caused by production such as atherosclerosis, diabetes, myocardial infarction, peripheral circulatory disorders, cerebrovascular disorders, cancer, inflammation, digestive disorders and aging and Z or Useful for prevention.
  • the compound of the present invention represented by the general formula (I), a non-toxic salt thereof, and an acid addition salt thereof for the above purpose is usually orally or parenterally administered systemically or locally.
  • the dosage varies depending on age, body weight, symptoms, therapeutic effect, administration method, treatment time, etc., but is usually orally administered to a single adult once to several times a day in the range of lmg to 1000mg at a time.
  • parenteral administration preferably intravenous administration
  • a dose smaller than the above dose range may be sufficient, or may be necessary beyond the range.
  • compositions When the compound of the present invention is administered, solid compositions, liquid compositions and other compositions for oral administration, injections, parenteral preparations, suppositories and the like for parenteral administration are used.
  • Solid compositions for oral administration include tablets, pills, capsules, powders, granules and the like.
  • Capsules include hard capsules and soft capsules.
  • the one or more active substances comprise at least one inert diluent, such as hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, magnesium aluminate metasilicate.
  • the composition may, in a conventional manner, be an additive other than an inert diluent, for example, a lubricant such as magnesium stearate, a disintegrant such as calcium cellulose glycolate, a dissolving agent such as glutamic acid or aspartic acid. It may contain adjuvants.
  • Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs and the like, and commonly used inert diluents (for example, purified Water, ethanol).
  • the composition may contain, in addition to the inert diluent, adjuvants such as wetting agents and suspending agents, sweetening agents, flavoring agents, fragrances, and preservatives.
  • compositions for oral administration include sprays which contain one or more active substances and are formulated in a manner known per se.
  • the composition may contain, in addition to the inert diluent, a buffer that provides isotonicity with stabilizers such as sodium bisulfite, for example, sodium chloride, sodium citrate, or citric acid. Good.
  • a buffer that provides isotonicity with stabilizers such as sodium bisulfite, for example, sodium chloride, sodium citrate, or citric acid.
  • stabilizers such as sodium bisulfite, for example, sodium chloride, sodium citrate, or citric acid.
  • the method for producing the spraying agent is described in detail, for example, in US Pat. Nos. 2,686,691 and 3,095,355.
  • Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions.
  • Aqueous solutions and suspensions include, for example, distilled water for injection and physiological saline.
  • the non-aqueous solution and suspension include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, and polysorbate 80.
  • Such compositions may also contain adjuvants such as preserving, wetting, emulsifying, dispersing, stabilizing, and solubilizing agents (eg, glutamic acid, aspartic acid). These are sterilized by, for example, filtration through a bacteria-retaining filter, blending of a bactericide or irradiation. They also produce sterile solid compositions that may be dissolved in sterile water or sterile injectable solvents before use. You can also.
  • compositions for parenteral administration include one or more active substances, topical solutions, salves such as ointments, and rectal administration for routine administration. It includes suppositories and pessaries for vaginal administration.
  • the solvent in the pressure box described in the column of separation by chromatography indicates the developing solvent used, and the ratio indicates the volume ratio.
  • the inside of the katakana described in the NMR section indicates the measurement solvent.
  • Reference Example 8 Reference Example 9
  • Reference Example 10 The title compound having the following physical properties was obtained in the same manner as Reference Example 11.
  • Reference Example 11 Using the compound produced in Reference Example 5, Reference Example 7 ⁇ Reference Example 8—Reference Example 9 ⁇ Reference Example 10 ⁇ Operation as in Reference Example 11 gave the title compound having the following physical properties. .
  • Acetic anhydride (11.3 ml) was added to a solution of the compound prepared in Reference Example 1 (9.98 g) and 4-dimethylaminopyridine (DMAP; 0.76 g) in pyridine (50 ml) under water cooling. Stirred for 0 minutes. The reaction solution was poured into water and extracted with hexane / ethyl acetate. The organic layer is washed with 1 N hydrochloric acid, water and saturated saline, dried and concentrated to give the title having the following physical data. The compound was obtained.
  • DMAP 4-dimethylaminopyridine
  • Reference Example 3 Reference Example 7 ⁇ Reference Example 28 using the compound prepared in Reference Example 30 or the compound prepared in Reference Example 32, or use the compound prepared in Reference Example 32.
  • the compounds having the following physical properties were obtained in the same manner as in Reference Examples 3 to 7 using the obtained compounds.
  • Dimethyl sulfoxide (1.03 ml) was added to a solution of oxalyl chloride (632 / ⁇ ) in methylene chloride (10 ml) under an argon atmosphere. C, and the mixture was stirred for 30 minutes.
  • a methylene chloride solution (10 ml) of the compound (1.067 g) produced in Reference Example 35 was added dropwise to the above solution, and the mixture was stirred at 178 ° C for 1 hour.
  • Triethylamine (4.05 ml) was added dropwise to the reaction solution, and the mixture was stirred at room temperature for 30 minutes.
  • a saturated aqueous solution of ammonium chloride was added to the reaction solution, and the mixture was extracted with ethyl acetate.
  • PPA polyphosphoric acid
  • 17 (c), Reference Example 23, Reference Example 33 (a), Reference Example 33 (b), Reference Example 33 (c), Reference Example 34, Reference Example 36, Reference Example 37 ( a), Reference Example 37 (b), Reference Example 37 (c) and Reference Example 42 were carried out in the same manner as in Example 1 to obtain the following compounds.
  • the following components were mixed in a conventional manner and then tableted to obtain 100 tablets each containing 50 mg of the active ingredient.
  • the solution is sterilized by the conventional method, filled into ampoules in 5 ml portions, freeze-dried by the conventional method, and contains 20 mg of the active ingredient in one ampoule. 100 ampoules were obtained.

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Abstract

L'invention concerne un dérivé de guanylhydrazone représenté par la formule générale (I) et un sel de ce dernier, permettant de traiter ou de prévenir des maladies provoquées par diverses complications du diabète et du vieillissement en vertu de leur activité d'inhibition de la réaction de Maillard et certaines maladies dues à la production de péroxyde de lipide en vertu de leur activité d'antioxydation. Dans la formule (I) R1 représente R4-A- (A étant une seule liaison, alkylène ou phénylalkylène); et R4 étant un groupe de la formule générale (II); R2 représente hydrogène, alkyle, phényle, phénylalkyle, un anneau monocyclique azoté ou alkyle substitué par un hétéro-anneau monocyclique azoté, ou R1 et R2 avec l'atome de carbone auquel ils sont liés représentent cycloalkyle fusionné avec R?4; et R3¿ représente hydrogène, alkyle ou acyle. Lorsque A est phénylalkylène, le phényle est lié à l'atome de carbone auquel R2 est lié.
PCT/JP1995/000294 1994-03-01 1995-02-27 Derive de guanylhydrazone WO1995023796A1 (fr)

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Publication number Priority date Publication date Assignee Title
US8895556B2 (en) 2007-12-26 2014-11-25 Critical Outcome Technologies Inc. Compounds and method for treatment of cancer
US8987272B2 (en) 2010-04-01 2015-03-24 Critical Outcome Technologies Inc. Compounds and method for treatment of HIV

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WO1992019236A1 (fr) * 1991-05-07 1992-11-12 The Rockefeller University 2-alkylidene-aminoguanidines et procede d'utilisation

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WO1992019236A1 (fr) * 1991-05-07 1992-11-12 The Rockefeller University 2-alkylidene-aminoguanidines et procede d'utilisation

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8895556B2 (en) 2007-12-26 2014-11-25 Critical Outcome Technologies Inc. Compounds and method for treatment of cancer
US8987272B2 (en) 2010-04-01 2015-03-24 Critical Outcome Technologies Inc. Compounds and method for treatment of HIV
US9624220B2 (en) 2010-04-01 2017-04-18 Critical Outcome Technologies Inc. Compounds and method for treatment of HIV

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