WO2002048096A1 - Derives d'hydrazone et utilisation de ceux-ci dans des medicaments - Google Patents

Derives d'hydrazone et utilisation de ceux-ci dans des medicaments Download PDF

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WO2002048096A1
WO2002048096A1 PCT/JP2001/010667 JP0110667W WO0248096A1 WO 2002048096 A1 WO2002048096 A1 WO 2002048096A1 JP 0110667 W JP0110667 W JP 0110667W WO 0248096 A1 WO0248096 A1 WO 0248096A1
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disease
compound
calpain
general formula
treatment
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PCT/JP2001/010667
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Japanese (ja)
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Masayuki Nakamura
Jun Inoue
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Senju Pharmaceutical Co., Ltd.
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Publication of WO2002048096A1 publication Critical patent/WO2002048096A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/22—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with hetero atoms directly attached to ring nitrogen atoms
    • C07D295/28—Nitrogen atoms
    • C07D295/30—Nitrogen atoms non-acylated
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/12—Ophthalmic agents for cataracts
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
    • C07C311/19—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups

Definitions

  • the present invention relates to a novel hydrazone derivative having cysteine protease inhibitory activity, particularly calpain inhibitory activity.
  • the present invention also relates to a medicament containing the novel hydrazone derivative.
  • cysteine protease is involved in various diseases.
  • cysteine proteases virupain
  • cytoplasmic proteases widely distributed in living organisms, and is activated by virucidium ions.
  • this abnormal activation of calpain is involved in various diseases such as stroke, subarachnoid hemorrhage, Alzheimer's disease, ischemic disease, muscular dystrophy, cataract, platelet aggregation, and arthritis.
  • calpain inhibitors are effective in maintaining the lens transparency in an experimental cataract model by lens culture [Curr.
  • An object of the present invention is to provide a compound having a strong cysteine protease inhibitory activity, particularly a calpain inhibitory activity, and having an appropriate water solubility desired as a pharmaceutical.
  • the present inventors have made intensive efforts to solve the above problems, and as a result, have created a compound having a strong calpain inhibitory activity, and have further studied to complete the present invention.
  • R 1 represents hydrogen or a lower alkyl group
  • A is a morpholino group or a general formula (II)
  • B is a hydroxy lower alkyl group or a carbamoyl group, or a glycyl group optionally substituted with an amino group.
  • R 2 is a lower alkyl group.
  • Calpain-related diseases include ischemic disease, immune disease, Alzheimer's disease, osteoporosis, disease due to brain tissue disorder, cataract, glaucoma, chorioretinal disease, posterior ocular complications due to photocoagulation, and angiogenesis
  • ischemic disease immune disease
  • Alzheimer's disease osteoporosis
  • disease due to brain tissue disorder cataract, glaucoma, chorioretinal disease, posterior ocular complications due to photocoagulation, and angiogenesis
  • a pharmaceutical composition comprising the compound according to (1) or (2) and a pharmaceutically acceptable carrier;
  • a method for treating a disease associated with calpain which comprises administering to a mammal in need of treatment an effective amount of the compound according to (1) or (2),
  • Calpain-related diseases include ischemic disease, immune disease, Alzheimer's disease, osteoporosis, disease due to brain tissue disorder, cataract, glaucoma, choroidal disease, posterior ocular complications due to photocoagulation, and angiogenesis
  • ischemic disease immune disease
  • Alzheimer's disease osteoporosis
  • disease due to brain tissue disorder cataract, glaucoma, choroidal disease, posterior ocular complications due to photocoagulation, and angiogenesis
  • the lower alkyl group represented by R 1 means a linear or branched alkyl group having 3 to 5 carbon atoms, such as propyl, isopropyl, butyl, isobutyl, tert-butyl, Pentyl, isopentyl, neopentyl, tert-pentyl and the like can be mentioned, preferably a C 4 alkyl group, particularly preferably isoptyl. .
  • the hydroxy lower alkyl group represented by B is a hydroxy-3 alkyl group, such as hydroxymethyl, hydroxyethyl, hydroxypropyl, etc., and preferably hydroxyethyl. is there.
  • examples of the group which may be substituted by the amino group of the glycyl group represented by B include a lower alkyl group represented by R 2 in the above general formula (III).
  • the lower alkyl group means a linear or branched alkyl group having 1 to 6 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, isoptyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl. Hexyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, and 2-ethylbutyl. Preferably it is methyl.
  • the fluorophenyl group can be appropriately converted into, for example, a phenyl group, a chlorophenyl group, a bromophenyl group, a tolyl group, a trifluoromethylphenyl group and the like.
  • the compounds of the present invention also include compound (I) and salts thereof, and various solvates and polymorphs thereof.
  • the salt of the compound represented by the general formula (I) in the present invention is preferably a physiologically acceptable salt, such as a salt with an inorganic acid, a salt with an organic acid, or a salt with an acidic amino acid.
  • Can be Preferred examples of the salt with an inorganic acid include, for example, salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like.
  • salts with organic acids include, for example, formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, P— Salts with toluenesulfonic acid etc.
  • Preferable examples of the salt with an acidic amino acid include, for example, salts with aspartic acid, glumic acid and the like.
  • the compound of the present invention has, for example, the following general reaction formula
  • the compound represented by the general formula (IV) can be prepared by adding the compound represented by the general formula (IV) to an organic solvent or a mixture of organic solvent and water in the presence or absence of a base. ). And the desired compound represented by the general formula (I) can be obtained.
  • the compound represented by the general formula (IV) is described in, for example, JP-A-10-147564 (USP 6,057,290, USP 6,214,800). It can be produced by the method described.
  • Examples of the organic solvent include a conventional solvent such as dioxane, ethyl acetate, methanol, ethanol, dichloromethane, chloroform, N, N-dimethylformamide, and tetrahydrofuran, or a mixed solvent thereof. Preferred are dioxane, a mixed solvent of dioxane and methanol, and ethyl acetate.
  • Examples of the base include acetates such as sodium acetate and potassium acetate, trialkylamines such as triethylamine and diisopropylethylamine, organic bases such as pyridine, lutidine, picoline and 4-dimethylaminopyridine, and sodium hydrogen carbonate.
  • reaction temperature is generally in a range from cooling to heating, and preferably in a range from about 0 ° C. to about 3 Ot :.
  • the compound of the present invention and a salt thereof are novel compounds that have not been published in the literature, and are shown in Test Examples described later. Since it has such excellent calpain inhibitory activity, it is useful as a medicament as a calpain inhibitor by combining them as active ingredients and, if necessary, a carrier described below.
  • Pharmaceuticals containing the compound of the present invention include, for example, ischemic diseases, immune diseases, Alzheimer's disease, osteoporosis, and brain in mammals such as mice, rats, rabbits, dogs, cats, mice, humans, and humans.
  • Diseases due to tissue disorders eg cerebral vasospasm, cerebral thrombosis, cerebral infarction, cerebral obstruction, intracerebral hemorrhage, subarachnoid hemorrhage, hypertensive encephalopathy, transient ischemic attack, multiple infarct dementia, cerebral artery Sclerosis, Huntington's disease, etc., cataract, glaucoma (eg, open-angle glaucoma, low-tension glaucoma, closed-angle glaucoma, etc.), retinochoroidal disease (eg, retinal vascular obstruction, peritoneal peritonitis, Ea1) es disease, retinal vascular abnormalities such as ischemic ocular syndrome and retinal arteriolar aneurysm
  • prophylactic and therapeutic agent for posterior eye complications for example, macular edema, retinal detachment, optic neuritis, visual field abnormalities, abnormal light perception, abnormal color vision, etc.
  • a preventive and therapeutic agent for angiogenesis, retinal detachment, etc. Useful.
  • the medicament containing the compound of the present invention is administered systemically or locally.
  • parenteral administration such as intravenous injection, subcutaneous injection, and intramuscular injection is also possible. It is applied topically to the skin, mucous membranes, nose and eyes.
  • compositions containing the compound of the present invention include solid preparations such as powders, granules, tablets, capsules, suppositories and the like, and liquid preparations such as syrups, injections, eye drops, nasal drops and the like.
  • suitable coating agents include gelatin, sucrose, gum arabic, carnapalow, etc.
  • enteric coating agents eg, cellulose acetate fluorate, methacrylic acid copolymer, hydroxy Propylcellulose phthalate, carboxymethylethylcellulose, etc.
  • suitable excipients such as magnesium stearate, calcium stearate, talc, and light anhydrous anhydrous gay acid to improve fluidity and lubricity, and for pressurized fluidity
  • suitable excipients such as magnesium stearate, calcium stearate, talc, and light anhydrous anhydrous gay acid to improve fluidity and lubricity, and for pressurized fluidity
  • the above-mentioned disintegrants and the like are added as appropriate, mixed uniformly, or filled with granules or coated with a coating agent suitable for granules, or
  • a suitable capsule base eg, gelatin
  • coloring agents and preservatives can be added to these capsules.
  • the capsule can be an ordinary coated capsule, an enteric coated capsule, a gastric resistant capsule, or a controlled release capsule.
  • enteric coated capsules When enteric coated capsules are used, ribosomes coated with an enteric coating agent can be filled into ordinary capsules, capsules themselves can be coated with an enteric coating agent, or molded based on enteric polymers. .
  • a suppository base eg, cacao butter, macrogol, etc.
  • cacao butter e.g., cacao butter, macrogol, etc.
  • a stabilizer such as sodium edetate
  • a suspending agent such as gum arabic or carmellose
  • a flavoring agent such as simple syrup, dextrose
  • a fragrance such as simple syrup, dextrose
  • tonicity agents sodium chloride, potassium chloride, glycerin, mannitol, sorbitol
  • buffers phosphate buffer, acetate buffer, borate buffer, carbonate buffer, citrate buffer, tris buffer, dal permic acid, ip E.g., silonaminocaproic acid
  • preservatives laoxybenzoic acid esters, chlorobutanol, benzyl alcohol, benzalkonium chloride, sodium dehydroacetate, sodium edetate, boric acid, etc.
  • thickeners hydroxymethylcellulose, Hydroxyethyl cellulose, hydroxypropyl cellulose, polyvinyl alcohol, polyethylene glycol, etc.
  • stabilizers sodium hydrogen sulfite, sodium thiosulfate, sodium edetate, sodium citrate, ascor
  • the compound of the present invention has appropriate water solubility desired as a pharmaceutical, it can be advantageously produced particularly in the above-mentioned preparations such as syrups, injections, eye drops and nasal drops.
  • the amount of additives in the above syrups, injections, eye drops, and nasal drops depends on the type and use of the additives to be added, but it is sufficient to add a concentration that can achieve the purpose of the additives.
  • the isotonic agent is usually such that the osmotic pressure of about 229 ⁇ about 343mOsZ Kg ⁇ H 2 0, is added to about 0.5 5 to about 5. 0wZv%.
  • the buffer is about 0.01 to about 2.0 /%
  • the thickener is about 0.01 to about 1.Ow / v%
  • the stabilizer is about 0.001 to about 1.OwZv% Add about.
  • the pH adjuster is appropriately added and usually adjusted to about pH 3 to about 9, preferably pH 4 to about 8.
  • the dosage of the compound represented by the general formula (I) of the present invention varies depending on the target disease, symptom, administration subject, administration method, and the like. It is preferable to administer about 1 to about 10 Omg at a time. In the case of injection, for adults, it is preferable to administer about 0.1 to about 3 Omg once to three times a day. When used topically, ophthalmic solution adjusted to about 0.001 to about 1. Ow / v%, preferably about 0.01 to about 0.5%, is applied once to 20 to 50 times. 1, 1 day 2-6 It is good to give it twice.
  • N- (3-other 3- (2- (dimethylamino) acetylamino) -1- (2-methylpropyl) prop-2-ene-1-2-(((4-fluorophenyl) sulfonyl) amino) 3-Methylbutanamide (Compound 1) is excellent in water solubility.
  • Step 1 Dissolve valine (11.7 g, 10 Ommo 1) in 1 M aqueous sodium hydroxide solution (l O OmL), add purified water (15 OmL) and tetrahydrofuran (10 mL), and cool under ice-cooling. While stirring with, a 1M aqueous solution of sodium hydroxide (10 OmL) and a solution of 4-fluorobenzenesulfonyl chloride (17.5 g, 9 Ommo 1) in tetrahydrofuran (10 OmL) were simultaneously added dropwise. The solution was stirred at room temperature for about 18 hours to react. After completion of the reaction, the reaction solution was adjusted to pH 2-3 and extracted with ethyl acetate.
  • Step 2 N-((4-fluorophenyl) sulfonyl) -L-parin (1 5. Og, 55 mmo 1) and N-hydroxysuccinimide (7.6 g, 66 mmol) in tetrahydrofuran (20 OmL) And stirred under ice-cooling while stirring 1-ethyl-3- (3-dimethylaminopropyl) carboimide hydrochloride (12.
  • Step 3 N-((4-fluorophenyl) sulfonyl) -L-parin N-Hydroxysuccinimide (2.Og, 5.4 mmol) was converted to dichloromethan Dissolved in tan (50 mL) and added mouth isinol (0.82 g, 7. Ommol). The solution was stirred for about 2 hours to react. After completion of the reaction, the resultant was washed with dilute hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate and saturated saline, and then dried over anhydrous magnesium sulfate.
  • Step 4 N-((4-fluorophenyl) sulfonyl) -L-paryl-L-Mouth isinol (1.8 g, 4.8 mmol) was dissolved in dimethyl sulfoxide (20 mL) and dichloromethane (10 mL) and diisopropyl Ethiluamine (2.5 g, 19 mmo 1) was added. While stirring this solution at room temperature, a dimethyl sulfoxide solution (15 mL) of a sulfur trioxide pyridine complex (3.1 g, 19 mmo 1) was added, and the mixture was further stirred for about 40 minutes.
  • Step 1 N — ((4-fluorophenyl) sulfonyl) —L—parin
  • Droxysuccinimide ester (4.0 g, llmmol) was dissolved in ethyl acetate (15 OmL), and aminoacetaldehyde dimethyl acetal (1.4 g, 13 mmol) was added. The solution was stirred at room temperature for about 24 hours. The reaction solution was washed with 1 M hydrochloric acid, a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, dehydrated with anhydrous magnesium sulfate, and concentrated under reduced pressure.
  • Step 2 N- (2,2-dimethoxyethyl) 1-2-(((4-fluorophenyl) sulfonyl) amino) _3-methylbutaneamide obtained in Step 1 (3.1 g, 8.6 mmo 1 ) was dissolved in tetrahydrofuran (2 OmL) and water (1 OmL), and trifluoroacetic acid (1 OmL) was added. The solution was stirred at about 60 for about 5 hours. The reaction solution was diluted with ethyl acetate, washed with 1M hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated saline, dehydrated with anhydrous magnesium sulfate, and concentrated under reduced pressure.
  • Reference Compound 1 (0.5 g, 1.3 mmo 1) was dissolved in a mixture of dioxane (2 OmL) and water (1 OmL), and N, N-dimethyldaricin hydrazide hydrochloride (0.28 g, 1 .5 mmo1) and sodium acetate (0.55 g, 6.7 mmo1) were added. The solution was stirred at room temperature for about 30 minutes. The reaction solution was diluted with ethyl acetate, washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residual white solid was recrystallized from ethyl acetate to obtain the desired compound 1 (0.27 g, 43%) as colorless crystals.
  • Reference compound 1 (0.80 g, 2. lmmol) was dissolved in ethyl acetate (20 mL), and hydrazinoethanol (0.20 g, 2.6 mmol) was added. This solution was stirred at room temperature for about 30 minutes. The reaction mixture was diluted with ethyl acetate, washed with a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained solid was crystallized from ethyl acetate to obtain Compound 3 (0.55 g, 60%) as colorless crystals.
  • Reference compound 2 (0.4 g, 1.3 mmo 1) was dissolved in dioxane (2 OmL) and water (1 OmL), and N, N-dimethylglycine hydrazide hydrochloride (0.26 g, 1.4 mmo 1) was added. Sodium acetate (1.0 g, 13 mmo 1) was added. The solution was stirred at room temperature for about 30 minutes. The reaction mixture was diluted with ethyl acetate, washed with a saturated aqueous solution of sodium hydrogencarbonate and brine, dehydrated with anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained solid was crystallized from ethyl acetate to obtain Compound 4 (0.27 g, 51%) as colorless crystals.
  • Reference compound 1 (1.0 g, 27 mm 01) was dissolved in dioxane (2 OmL), methanol (5. OmL) and water (5. OmL), and N-amino morpholine (0.33 g) was dissolved. , 3.2 mmo1) and sodium acetate (2.2 g, 27 mmo1). The solution was stirred at room temperature for about 30 minutes. The reaction solution was diluted with ethyl acetate, washed with a saturated aqueous solution of sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained solid is crystallized from ethyl acetate, Compound 5 (0.50 g, 41%) was obtained as colorless crystals.
  • Reference compound 1 (1.0 g, 2.7 mmo 1) was dissolved in dioxane (2 OmL), methanol (5. OmL) and water (5. OmL), and semicarbazide hydrochloride (0.33 g, 3. 2mmo1) and sodium acetate (2.2g, 27mmo1) were added. The solution was stirred at room temperature for about 30 minutes. The reaction solution was diluted with ethyl acetate, washed with a saturated aqueous solution of sodium hydrogen carbonate and a saturated saline solution, dehydrated with anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained solid was crystallized from ethyl acetate to obtain Compound 6 (0.85 g, 74%) as colorless crystals.
  • Test Example 1 Measurement of ⁇ -calpain inhibitory activity
  • the inhibitory activity of calpain was measured according to the method described in the literature CAnal. Biochei. Vol. 208, 387-392 (1993)]. That is, 200 L of a reaction solution containing 0.5 mg ZmL casein, 50 mM Tris-HC1 (pH 7.4), 2 OmM dithiothreitol, and 0.03 enzyme unit ⁇ -calpain, and dimethyl containing various concentrations of the test drug. Sulfoxide solution 2.5 iL and 2 OmM salt ⁇ : 50 ah of calcium aqueous solution was added to a 96-well plate.
  • Inhibition rate ⁇ 1— (measured value—blank value) / (control value—blank value) ⁇ ⁇ 100 The results are shown in Table 1. Table 1. -Calpain inhibitory activity of the compounds of the present invention
  • Standard solution Approximately 1 Omg of each test compound was precisely weighed, adjusted to 1 OmL with the mobile phase, and 10 L of this solution was analyzed by HPLC.
  • Test compound solubility (mg / mL)
  • Reference compound 1 has a stronger calpain inhibitory activity than that of the compound of the present invention, but its solubility was 0.1 OmgZmL irrespective of pH, but the compound of the present invention is practically usable as a pharmaceutical preparation. It was found that the water solubility was improved at a certain pH of 4 to 7.
  • Compound 1 has high calpain inhibitory activity and high water solubility near pH 4, which is a practical area for pharmaceutical preparations.
  • the above ingredients are used as a tablet material, mixed uniformly, and formed into tablets by a conventional method. Sugar coating may be applied as necessary.
  • the above components are aseptically mixed and dissolved by a conventional method to produce eye drops.
  • diseases involving calpain include ischemic disease, immune disease, and Alzheimer's disease. It can be advantageously used for osteoporosis, diseases caused by brain tissue disorders, cataracts, glaucoma, retinochoroidal diseases, posterior segment complications due to photocoagulation, and diseases involving angiogenesis. While a number of specific embodiments of the present invention have been described in detail, those skilled in the art will recognize that specific embodiments illustrated therein can be made without departing from the novel teachings and advantages of the present invention. Since it is possible to make various modifications and changes, all such modifications and changes are intended to be included within the spirit and scope of the invention as defined by the following claims.

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des médicaments contenant des composés représentés par la formule générale (I): [dans laquelle R1 représente hydrogène ou alkyle inférieur; et A est morpholino ou un groupe représenté par la formule générale (II): dans laquelle B représente alkyle inférieur hydroxylé, carbamoyle ou glycyle dont le groupe amino peut être substitué)]. Les composés susmentionnés ont une activité inhibitrice puissante contre les cystéine-protéases, en particulier la calpain, et une hydrosolubilité satisfaisante pour pouvoir être utilisés dans des médicaments.
PCT/JP2001/010667 2000-12-12 2001-12-06 Derives d'hydrazone et utilisation de ceux-ci dans des medicaments WO2002048096A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
AU2002221066A AU2002221066A1 (en) 2000-12-12 2001-12-06 Hydrazone derivatives and use thereof in medicines
JP2002549629A JPWO2002048096A1 (ja) 2000-12-12 2001-12-06 ヒドラゾン誘導体およびその医薬用途

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
JP2000377582 2000-12-12
JP2000-377582 2000-12-12
JP2001149683 2001-05-18
JP2001-149683 2001-05-18

Publications (1)

Publication Number Publication Date
WO2002048096A1 true WO2002048096A1 (fr) 2002-06-20

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2001/010667 WO2002048096A1 (fr) 2000-12-12 2001-12-06 Derives d'hydrazone et utilisation de ceux-ci dans des medicaments

Country Status (3)

Country Link
JP (1) JPWO2002048096A1 (fr)
AU (1) AU2002221066A1 (fr)
WO (1) WO2002048096A1 (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0771565A2 (fr) * 1995-10-25 1997-05-07 Senju Pharmaceutical Co., Ltd. Inhibiteur d'angiogenèse
EP0810221A1 (fr) * 1995-02-14 1997-12-03 Mitsubishi Chemical Corporation Derives heterocycliques contenant de l'oxygene

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0810221A1 (fr) * 1995-02-14 1997-12-03 Mitsubishi Chemical Corporation Derives heterocycliques contenant de l'oxygene
EP0771565A2 (fr) * 1995-10-25 1997-05-07 Senju Pharmaceutical Co., Ltd. Inhibiteur d'angiogenèse

Also Published As

Publication number Publication date
JPWO2002048096A1 (ja) 2004-04-15
AU2002221066A1 (en) 2002-06-24

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