WO2001041757A1 - Composition pharmaceutique contenant de la cyclodextrine - Google Patents

Composition pharmaceutique contenant de la cyclodextrine Download PDF

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Publication number
WO2001041757A1
WO2001041757A1 PCT/JP2000/008700 JP0008700W WO0141757A1 WO 2001041757 A1 WO2001041757 A1 WO 2001041757A1 JP 0008700 W JP0008700 W JP 0008700W WO 0141757 A1 WO0141757 A1 WO 0141757A1
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Prior art keywords
cyclodextrin
group
salt
acid
compound
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PCT/JP2000/008700
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English (en)
Japanese (ja)
Inventor
Masayuki Nakamura
Jun Inoue
Yukuo Yoshida
Masazumi Yamaguchi
Toshihiro Ishiguro
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Senju Pharmaceutical Co., Ltd.
Takeda Chemical Industries, Ltd.
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Application filed by Senju Pharmaceutical Co., Ltd., Takeda Chemical Industries, Ltd. filed Critical Senju Pharmaceutical Co., Ltd.
Priority to AU17350/01A priority Critical patent/AU1735001A/en
Publication of WO2001041757A1 publication Critical patent/WO2001041757A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/40—Cyclodextrins; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
    • 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
    • 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
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • 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

Definitions

  • the present invention relates to a compound represented by the following formula (I) (hereinafter referred to as compound (I)) or a salt thereof, which is useful as an agent for preventing or treating cysteine proteinase such as calpain. And a pharmaceutical composition having improved water solubility.
  • the present invention also relates to an injectable pharmaceutical composition containing compound (I) or a salt thereof, from which pyrogen has been removed.
  • the present invention relates to a method for improving the properties of the compound (I) or a salt thereof, such as water solubility, stability, and tissue-localization (eg, ocular-localization, and absorptivity).
  • R 1 represents an alkyl group or a C 10 aryl group which may have a substituent
  • R 4 may be an aryl group which may have a substituent, or may have a substituent.
  • a lower alkyl group which may have a substituent selected from the group consisting of a good cycloalkyl group and an aromatic heterocyclic group which may have a substituent.
  • a salt thereof is disclosed in JP-A-10-147564.
  • This compound has an inhibitory activity on cysteine proteases such as calpain, and diseases involving cystine proteases, such as ischemic diseases, immune diseases, Alzheimer's disease, osteoporosis, angiogenesis, retinopathy, retinal vein Obstruction, senile discoid macular degeneration, cerebral vasospasm, cerebral thrombosis, cerebral infarction, cerebral obstruction, brain Internal bleeding, arachnoid hemorrhage, hypertensive encephalopathy, transient ischemic attack, multiple infarct dementia, arteriosclerosis, Huntington's disease, brain tissue disorder, optic delusion, glaucoma, high eye I king ⁇ , It is known that it is useful as a preventive-therapeutic agent for retinal detachment and the like (JP-A-10-147564, W099 / 48522, W099 / 44626).
  • cysteine proteases such as calpain
  • diseases involving cystine proteases such
  • Japanese Patent Application Laid-Open No. 7-218589 discloses a method of combining a water-insoluble or poorly water-soluble compound with a branched cyclodextrin monobasic ruponic acid to obtain a water-soluble compound. Are disclosed.
  • pyrogens such as endotoxins are usually composed of water-soluble high-molecular-weight polysaccharides, and are extremely small.However, it is known that intravenous injection and the like cause fever and strongly impair kidney and liver functions. .
  • pyrogen is a colloid particle, and its removal is difficult.
  • a reverse osmosis membrane, a microfiltration membrane, an ultrafiltration membrane, etc. are used to remove porogen contained in an injectable composition, but the molecular weight cut off of the membrane is from 3,000 to 10,000.
  • the pore size is as wide as 10 to 100 angstroms, and it is not easy to select an appropriate filtration membrane.
  • compound (I) or a salt thereof is poorly water-soluble, it was not always suitable for preparation of an injection or the like.
  • the present inventors have conducted intensive studies in order to solve the above-mentioned problems, and as a result, the formula (I) which is insoluble or hardly soluble in water is obtained.
  • R ⁇ C_i may have an alkyl group or a substituent group. —, 4 aryl group; and 2 and R 3 are the same or different and are each a hydrogen atom or a C 4 R 2 and R 3 may form a ring having 3 to 7 carbon atoms together with the carbon atom to which they are attached, and R 4 may be a substituted or unsubstituted aryl group, And a lower alkyl group optionally having a substituent selected from the group consisting of a cycloalkyl group which may have a group and an aromatic heterocyclic group which may have a substituent.
  • Compound (I) or a salt thereof, and a cyclodextrin or a derivative thereof (hereinafter, also collectively referred to as a “cyclodextrin compound”) or a salt thereof. It was unexpectedly found that the properties of the compound (I) or a salt thereof, such as water solubility, stability, and tissue dispersibility (for example, dispersibility into the eye and oral absorption) were improved.
  • composition containing compound (I) or a salt thereof and a cyclodextrin compound or a salt thereof which has a molecular weight cut-off of about 1,000 to about 8,000. It was unexpectedly found that pyrogen can be efficiently removed by filtration through a filtration membrane.
  • the present inventors conducted further research based on these findings, and as a result, completed the present invention.
  • R 1 represents a C 4 alkyl group or a C 6 _, 4 aryl group which may have a substituent
  • R 2 and R 3 are the same or different and each represents a hydrogen atom or a C 4 represents an alkyl group, or R 2 and R 3 may form a ring having 3 to 7 carbon atoms together with the carbon atom to which they are bonded
  • R 4 represents an aryl group which may have a substituent.
  • a lower alkyl group optionally having a substituent selected from the group consisting of a cycloalkyl group optionally having a substituent and an aromatic heterocyclic group optionally having a substituent.
  • a pharmaceutical composition comprising a compound represented by the formula or a salt thereof, and cyclodextrin or a derivative thereof or a salt thereof;
  • the cyclodextrin or a derivative thereof is a hydroxyalkylcyclodextrin, a branched cyclodextrin, a sulfoalkylcyclodextrin, a galactosyl-glucosylcyclodextrin, a sulfated chi- or a cyclodextrin, or an alkylcyclodextrin.
  • the composition of the above (1) which is at least one selected from the group consisting of dextrin and branched cyclodextrin monocarboxylic acid,
  • Cyclodextrin or a derivative thereof is hydroxyalkylcyclodextrin, branched cyclodextrin, sulfobutylcyclodextrin, galactosyl-glucosylcyclodextrin, sulfated mono-, mono- or y-cyclodextrin And at least one selected from the group consisting of alkylcyclodextrins and alkylcyclodextrins,
  • the cyclodextrin or derivative thereof is at least one selected from the group consisting of hydroxyalkyl cyclodextrin, branched cyclodextrin, sulfoptyl cyclodextrin and galactosyl-glucosyl cyclodextrin.
  • Cyclodextrin or its derivative is 2-hydroxypropyl-3-cyclodextrin, 3-hydroxypropyl-1-/?-Cyclodextrin, —0—glucosyl; 5-cyclodextrin; 6-0—maltosyl-1-cyclodextrin; 6-0—sulfoptyl—cyclodextrin; and 6-0—galactosyl-glucosyl / —cyclodextrin At least one composition according to (5) above,
  • Drugs for ischemic diseases drugs for inflammatory diseases, drugs for muscular dystrophy, drugs for immune diseases, drugs for Alzheimer's disease, drugs for osteoporosis, angiogenesis.
  • Drugs for the treatment of diseases treatment for macular degeneration, treatment for cerebral vasoconstriction, treatment for cerebral thrombosis, treatment for cerebral infarction, treatment for cerebral obstruction, treatment for intracerebral hemorrhage, treatment for subarachnoid hemorrhage, treatment for hypertensive encephalopathy, Transient cerebral ischemic attack therapy Jie, multiple infarct dementia drug, arteriosclerosis drug, Huntington's disease drug, brain tissue disorder drug, dementia symptom drug, glaucoma drug, high eye
  • the composition according to the above (1) or (2) which is a therapeutic agent for anti-tension, a therapeutic agent for posterior ocular complications due to photocoagulation or a therapeutic agent for retinal detachment
  • composition according to the above (1) or (2) which is a composition for injection.
  • composition according to any one of the above (1) to (4) which comprises 0.1 to 20 mol of cyclodextrin or a derivative thereof or a salt thereof per 1 mol of compound (I) or a salt thereof,
  • composition according to any one of the above (1) to (4) which is an ophthalmic composition
  • Branched cyclodextrin monorubric acid is 6-0-cyclomaltohexaosyl-1- (6 ⁇ 1) -hi-D-darcosyl- (4 ⁇ 1) -O-a-D-glucuronic acid, 6 —P-cyclomaltoheptaosyl-1 (6 ⁇ 1) —Hiichi D—glucosyl
  • composition according to the above (1), wherein R 1 in the formula (I) is phenyl or naphthyl optionally substituted with fluorine, chlorine or methyl
  • composition according to the above (1), wherein R 1 in the formula (I) is a group selected from the group consisting of methyl, 4-fluorophenyl, 4-chlorophenyl, p-tolyl and 2-naphthyl,
  • composition according to the above (1) further comprising a pH adjuster
  • composition of the above (1) or (27), which is a lyophilized composition
  • composition according to the above (31) or (32), which is a lyophilized composition is a lyophilized composition
  • (37) a method for improving the pharmacological properties of the compound (I) or a salt thereof, which comprises using the compound (I) or a salt thereof in combination with cyclodextrin or a derivative thereof or a salt thereof;
  • the cyclodextrin or a derivative thereof is a hydroxyalkylcyclodextrin, a branched cyclodextrin, a sulfoalkylcyclodextrin, a galactosyl-glucosylcyclodextrin, a sulfated mono-, mono- or cyclo-cyclodextrin.
  • cyclodextrin or a derivative thereof is a hydroxyalkylcyclodextrin, a branched cyclodextrin, a sulfobutylcyclodextrin, a galactosyl-glucosylcyclodextrin, a sulfated chitin, or an arcyclodextrin and an alkyl.
  • (45) a method for improving the water solubility of compound (I) or a salt thereof, which comprises using compound (I) or a salt thereof in combination with cyclodextrin or a derivative thereof or a salt thereof;
  • the cyclodextrin or a derivative thereof is a hydroxyalkylcyclo Selected from the group consisting of dextrins, branched cyclodextrins, sulfoalkylcyclodextrins, galactosyl-glucosylcyclodextrins, sulfated thio- or aracyclodextrins, alkylcyclodextrins and branched cyclodextrins. At least one of the methods of (4 5) above,
  • the cyclodextrin or a derivative thereof is derived from hydroxyalkylcyclodextrin, branched cyclodextrin, sulfobutylcyclodextrin, galactosyl-glucosylcyclodextrin, sulfated mono-, mono- or arcyclodextrin and alkylcyclodextrin.
  • the method of (46), wherein the method is at least one selected from the group consisting of
  • (52) a method for improving the stability of compound (I) or a salt thereof, which comprises using compound (I) or a salt thereof in combination with cyclodextrin or a derivative thereof or a salt thereof;
  • the cyclodextrin or a derivative thereof is a hydroxyalkylcyclodextrin, a branched cyclodextrin, a sulfoalkylcyclodextrin, At least one selected from the group consisting of galactosyl-glucosylcyclodextrin, sulfated HI, / 5- or arcyclodextrin, alkylcyclodextrin and branched cyclodextrin monocarboxylic acid ( 5 2) method,
  • the cyclodextrin or a derivative thereof comprises hydroxyalkylcyclodextrin, branched cyclodextrin, sulfobutylcyclodextrin, galactosyl-glucosylcyclodextrin, sulfated chi-, ⁇ -or arcyclodextrin and alkylcyclodextrin.
  • Hydroxyalkylcyclodextrin is hydroxymethyl monocyclodextrin, hydroxymethyl-5-cyclodextrin, hydroxymethyl luer cyclodextrin, 2-hydroxyethyl-cyclocyclotrin, 2-hydroxyxethyl / 2-cyclodextrin, 2-hydroxyxethyl-cyclodextrin, 2-hydroxypropyl-cyclodextrin, 2- Hydroxybu mouth pill /?-Cyclodextrin, 2-hydroxypropyl-1-y-cyclodextrin, 3-hydroxypropyl-cyclodextrin, 3-hydroxypropyl-1-cyclodextrin, 3-hydroxy Ciprovir-cyclodextrin, 2,3-dihydroxyprobiyl-cyclodextrin, 2,3-dihydroxyl-mouth bil-/-cyclodextrin or 2,3-dihydroxy-mouth xylobulin-piruacyclo Dextrin,
  • the branched cyclodextrin is 6-0-glucosyl-1-a-cyclodextrin, 6-0-glucosyl-/?-Cyclodextrin, 6-0-glucosyl-cyclodextrin, 6-0-maltosyl-cyclodextrin , 6-0-maltosyl-1-cyclodextrin, 6- ⁇ -maltosyl-cyclodextrin, 61-0-dimaltosyl-cyclodextrin, 6-0-dimaltosyl /?-Cyclodextrin Or 6-0-dimaltosylcyclodextrin,
  • the sulfoalkylcyclodextrin is 6-0-sulfobutyl-cyclodextrin, 6-0-sulfobutyl-5-cyclodextrin or 6-O-sulfobutyl-arcyclodextrin;
  • Galactosyl-glucosylcyclodextrin is 6-0-galactosyl-glucosyl-cyclodextrin, 6-galactosyl-glucosyl-/-cyclodextrin or 6-0-galactosyl-glucosyl-arcyclodextrin Is phosphorus,
  • the sulfated mono-, y-, or y-cyclodextrin is substituted with cyclodextrin sulfate, 3-cyclodextrin sulfate, arcyclodextrin sulfate, or a salt thereof (eg, 3-cyclodextrin). Lintertradeca sulfate, etc.)
  • Compound (I) is N- (2-naphthene lensulfonyl) -L-Varilu-L-one-isine (Compound 1), N- (4-fluorophenylsulfonyl) -L-valyl-L-Mouth-isina 1-yl (compound 2), N— (4-monophenylphenylsulfonyl) 1-L-valyl-L-one-isine (Compound 3), N— (4-methylphenylsulfonyl) 1-L-valylul-L-one-piece N- (2-naphthalene sulfonyl) N- (2-naphthalene sulfonyl) N- (4-Fluorophenyl
  • FIG. 1 is a graph showing the results of a blood migration test in Test Example 5.
  • the cyclodextrin compound used in the pharmaceutical composition of the present invention includes cyclodextrin and its derivatives.
  • the cyclodextrin derivative is a derivative in which the hydrogen atom of the hydroxyl group of cyclodextrin is substituted with an organic group.
  • the organic group include an alkyl group, a hydroxyalkyl group, a sulfoalkyl group, an ester sulfate residue (1-SO 2 —OH), and a sugar residue (eg, an erythrosyl group, a threosyl group, an arabinosyl group, a ribosyl group).
  • sugar residues such as galactosyl over glucosyl group; preferably, grayed Rukoshiru group, galactosyl group, glycerin port - gluco one heptosyl group, maltosyl group, dimaltosyl group, easy tosyl group, maltodextrin Torioshiru group, galactosyl - C 6 _ 24 sugar residues, such as Gurukoshi Le group; and particularly preferably, glucosyl group, maltosyl group, C 3, such as moth Lac tosyl over glucosyl group - a 12 sugar residues, these Sugar residues may have a local Bokishiru group), and the like carb
  • cyclodextrin derivative examples include, for example, hydroxyalkylcyclodextrin, branched cyclodextrin, sulfoalkylcyclodextrin, galactosyl-glucosylcyclodextrin, sulfated ⁇ -, / 5-, or cyclodextrin Phosphorus, alkyl cyclodextrin, branched cyclodextrin Bonic acid and the like are preferably used.
  • cyclodextrin, hydroxyalkylcyclodextrin, branched cyclodextrin, sulfoalkylcyclodextrin, galactosyl-darcosylcyclodextrin, alkylcyclodextrin and branched cyclodextrin used in the present invention include cyclodextrin. Includes those whose dextrin moieties consist of 6 to 12 glucoses, especially those whose cyclodextrin moieties consist of 6, 7 or 8 glucoses, each of which is 1, 5, or arcyclodextrin Those in which the cyclodextrin moiety is composed of 7 glucoses are particularly preferable.
  • cyclodextrin for example, cyclodextrin, cyclodextrin, arcyclodextrin and the like are used.
  • hydroxyalkyl cyclodextrin a derivative in which a hydrogen atom of the hydroxyl group of Shikurodekisu Bok phosphorus is substituted with hydroxycarboxylic alkyl group, ⁇ Hi Dorokishiaru kill groups are preferably mono- or dihydric Dorokishi 0 ⁇ _ 6 alkyl group, more preferably a mono- or dihydroxy C 4 alkyl group.
  • hydroxyalkyl cyclodextrin examples include, for example, hydroxymethyl monocyclodextrin, hydroxymethyl-1-cyclodextrin, hydroxymethyl-arcyclodextrin, 2-hydroxyethyl-cyclodextrin, 2-hydroxyethyl-cyclodextrin, and 2-hydroxyethyl-1-cyclodextrin , 2-hydroxyethyl-cyclodextrin, 2-hydroxypropyl-1- ⁇ -cyclodextrin, 2-hydroxypropyl bil / 5 / 5-cyclodextrin, 2-hydroxypropyl vir-cyclodextrin, 3 —Hydroxypropyl monocyclodextrin, 3-hydroxypropyl mouth / cyclodextrin, 3-hydroxybutyrylcyclodextrin, 2,3-dihydroxypropyl monocyclodextrin, 2,3-dihydroxypropyl-1-/?-Cyclodextrin, 2,3-d
  • Branched cyclodextrin is a glucose unit that constitutes cyclodextrin It is a cyclodextrin with sugar residues such as glucosyl, maltosyl, and dimaltosyl bonded to the 6-0 position.
  • Examples of the branched cyclodextrin include 6-0-glucosyl-cr-cyclodextrin, 6-0-glucosyl-/?-Cyclodextrin, 6- ⁇ -glucosyl-arcyclodextrin, and 6-0-maltosyl monocyclo.
  • the sulfoalkyl cycloalkyl de Kiss Bok phosphorus is a derivative in which a hydrogen atom of the cyclodextrin hydroxy groups is substituted with a sulfo group, the sulfo group is good Mashiku sulfo C Bok 6 alkyl group, more preferably a sulfo C ⁇ 4 alkyl group, particularly preferably sulfobutyl group.
  • sulfoalkylcyclodextrin examples include, for example, sulfobutylcyclodextrin such as 6-0-sulfobutyl- ⁇ -cyclodextrin, 6--1-sulfobutyl /?-Cyclodextrin, 6-0-sulfobutyl-arcyclodextrin, and the like. Is used.
  • galactosyl-glucosylcyclodextrin examples include 6-0-galactosyl-darcosyl-cyclodextrin, 6-0-galactosyl-glucosyl-glucosyl /?-Cyclodextrin, and 6-0-galactosyl-darcosyl-cyclo-cyclone. Dextrin or the like is used.
  • Sulfated 1,1, or arcyclodextrin is a cyclodextrin sulfate in which the hydroxyl group of 1,1, or arcyclodextrin and sulfuric acid are ester-linked.
  • the number of sulfate ester bonds per molecule is not particularly limited, but is preferably 1 to 14.
  • Examples of the sulfated mono-, mono- or mono-cyclodextrin salts include alkali metal salts such as sodium salt and potassium salt, and preferably sodium salt.
  • Sulfated heavier,?-Or y-cyclodextrins include, for example, -cyclodextrin tetrade Force sulfate is used.
  • the alkyl cyclodextrin a derivative in which a hydrogen atom of the hydroxyl group of Shikurodekisu Bok phosphorus is substituted with an alkyl group
  • the alkyl group is preferably ⁇
  • - is ⁇ al kill groups, more preferably C Bok 4 alkyl group .
  • alkylcyclodextrin examples include, for example, methyl-cyclodextrin, methyl /?-Cyclodextrin, methyl-arcyclodextrin, ethyl- ⁇ -cyclodextrin, ethyl-3-cyclodextrin, ethyl-y-cyclodextrin, and provir-yl.
  • Hycyclodextrin, Provir-1 / -cyclodextrin, propylcyclodextrin and the like are used.
  • the branched cyclodextrin monocarboxylic acid used in the present invention includes not only its free carboxylic acid but also its alkali metal (eg, lithium, sodium, potassium, etc.), alkaline earth metal (eg, calcium, magnesium, etc.), etc. Contains salt.
  • alkali metal eg, lithium, sodium, potassium, etc.
  • alkaline earth metal eg, calcium, magnesium, etc.
  • Contains salt e.g., branched cyclodextrin monocarboxylic acids may be used alone or in combination of two or more, and may be used in a state where a free carboxylic acid and a salt thereof are mixed.
  • the branched cyclodextrin monocarboxylic acid is a cyclodextrin having an organic group containing at least one carboxyl group at the 6-0 position of at least one glucose unit of the cyclodextrin ring.
  • the organic group containing at least one carboxyl group has 1 to 3 glucose units, and at least one of the hydroxymethyl groups of the glucose units in the organic group is oxidized to a carboxyl group. Is preferred.
  • branched cyclodextrin monocarboxylic acid examples include 6-0-cyclomaltohexaosyl- (61) -hi-D-glucosyl- (4 ⁇ 1) -O-hi-D-glucuronic acid (to cyclomalto Xiaosyl (6 ⁇ 1) —0—Hi D—Glucovira nosyl (4 ⁇ 1) —0—Hi D—Darcoviranoside uronic acid (hereafter, Hi C CyD G 2 — CO ⁇ H Abbreviations may be abbreviated; the abbreviations of the following compounds are also shown in parentheses), 6-0-cyclomaltoheptanyl osyl- (6-1) -hiichi D-glucosyl- (4 ⁇ 1) -1 0-hiichi D-glucuronic acid (cyclomaltoheptanol ⁇ 1) - 0- Fei one D- Gurukobiranoshiru one (4 ⁇ 1)
  • Glucose units 7 and arcyclodextrin are branched cyclodextrin monocarboxylic acids, and one glucose unit in the cyclodextrin ring is maltose. 1 ⁇ 6), and the hydroxymethyl group at the 6-position of the terminal glucose of the maltose is oxidized to a carboxyl group to form glucuronic acid.
  • Salts of cyclodextrin compounds include, for example, alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt, magnesium salt and barium salt; aluminum salt; trimethylamine, triethylamine, pyridine, bicoline, 2 Pharmaceutically acceptable salts such as salts with organic bases such as, 6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, ⁇ , ⁇ '-dibenzylethylenediamine And preferably an alkali metal salt, and more preferably a sodium salt.
  • alkali metal salts such as sodium salt and potassium salt
  • alkaline earth metal salts such as calcium salt, magnesium salt and barium salt
  • aluminum salt trimethylamine, triethylamine, pyridine, bicoline
  • Pharmaceutically acceptable salts such as salts with organic bases such as, 6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexy
  • cyclodextrin compound used in the present invention examples include hydroxyalkyl cyclodextrin, branched cyclodextrin, sulfoalkylcyclodextrin, galactosyl-glucosylcyclodextrin, sulfated mono-, ⁇ - and ⁇ -cyclo. It is preferably at least one selected from the group consisting of dextrin, alkylcyclodextrin and branched cyclodextrin monocarponic acid, and is composed of hydroxyalkylcyclodextrin, branched cyclodextrin, alkylcyclodextrin and branched cyclodextrin monocarboxylic acid. At least one selected from the group is more preferable, and at least one selected from the group consisting of hydroxyalkylcyclodextrin and branched cyclodextrin monocarboxylic acid is preferred. One is particularly preferred.
  • cyclodextrin compounds or salts thereof can be commercially available or can be produced according to a method known per se.
  • C I 4 alkyl group represented by R 1 is a linear or branched It may be branched, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl and the like.
  • Examples of the C 6 —, 4 aryl group represented by R 1 include phenyl, naphthyl, indenyl, and azulenyl, among which C ⁇ -, such as phenyl and naphthyl.
  • An aryl group is preferred.
  • ⁇ 6 _ 14 Ariru group optionally "substituent” have include halo gen atom (e.g., fluorine, chlorine, bromine, iodine), d - 3 alkylene old carboxymethyl
  • halogenated which may be C 6 alkyl, optionally halogenated C 2 - 6 alkenyl Le, optionally C 2 may be halogenated - fi alkynyl , but it may also be halogenated C 3 - Nkuroarukiru, C B - 14 7 reels (e.g., phenyl, 1 one-naphthyl, 2 one-naphthyl, 2-Bifue two Lil, 3 Bifue two Lil, 4 Bifue two lil , 2 ⁇ Nsuriru etc.), halogenated which may be C i-e alkoxy, C i-6 an alkoxy - carbonylation Lou C alkoxy (e.g., ethoxycarbonylmethyl O carboxy, etc.), hydroxy, C 6 - 14 Ariruokishi (eg, Fueni
  • - G alkyl one carbonyl eg, Asechiru, propionitrile Le etc.
  • C 3 _ 6 cycloalkyl - carbonyl e.g., cycloprothrin building carbonyl, Shikurobe Emissions chill carbonyl, cyclohexyl-carbonyl cyclohexane, etc.
  • C, - beta alkoxy one carbonitrile sulfonyl e.g., main-butoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert- butoxide deer Lupo sulfonyl, etc.
  • C 6 - 1 4 ⁇ Li one Roux carbonyl examples, Benzoiru, 1 one naphthoyl, 2-naphthoyl, etc.
  • C 7 _ 1 B 7 aralkyl one carbonyl e.g., full Eniruasechiru, 3-phenylpropyl propiony
  • aryl carbonylamino eg, penzylamino, naphthylamino, etc.
  • 100 alkoxycarbonyl eg, methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino, etc.
  • alkyl Sulfonylamino eg, methylsulfonylamino, ethylsulfonylamino Roh, etc.
  • C fi - 1 4 ⁇ Li one Le sulfonyl ⁇ amino e.g., phenylalanine sulfonyl ⁇ Mino, 2 one naphthylsulfonyl ⁇ amino, 1-naphthylsulfonyl ⁇ amino, etc.
  • Fi al Kill - Karuboniruo alkoxy eg, ⁇ Se butoxy, propionyl Ruo carboxy, etc.
  • C 6 - 1 4 ⁇ reel one carbonyl O carboxymethyl eg, Benzoiruokishi, naphthylcarbonyl O carboxy, etc.
  • C Bok alkoxy - carbonyl O carboxymethyl (eg, main Toxoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy, etc.), mono-C alkyl monorubumyloxy (eg, methylcarbamoyloxy, ethylcarbamoyloxy, etc.), and G-alkylalkyl rupamoyoxy (eg, , Dimethylcarbamoyloxy, getylcarbamoyloxy, etc.), C B — 14 aryl-carbamoyloxy (eg, phenylcarbamoy
  • alkyl which may be halogenated includes, for example, 1 to 5, preferably 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.).
  • Good alkyl eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butynole, pentyl, hexyl, etc.
  • Specific examples include methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, and 2-bromoethyl.
  • optionally halogenated C 2 _ B alkenyl optionally be includes, for example 1 a stone 5, preferably 1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine, iodine, etc.) have a which may be C 2 - 6 alkenyl (e.g., vinyl, propenyl, I Sopuro base sulfonyl, 2-butene one 1 one I le, 4-pentenoic one 1 one I le, hexene 5 - 1 - I le) And the like.
  • halogen atoms e.g., fluorine, chlorine, bromine, iodine, etc.
  • C 2 - 6 alkenyl e.g., vinyl, propenyl, I Sopuro base sulfonyl, 2-butene one 1 one I le, 4-pentenoic one 1 one I le, hexene 5 - 1 - I le
  • halogenated-6 alkynyl examples include those having 1 to 5, preferably 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.).
  • Good C 2 _ 6 alkynyl eg, 2-butyn-11-yl, 4-pentin-11-yl, 5-hexyn-11-yl, etc.
  • halogenated 3 _ 6 cycloalkyl examples include 1 to 5, preferably 1 to 3 halogen atoms (eg, fluorine, chlorine, hydrogen, iodine, etc.).
  • C 3 _fi cycloalkyl eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.
  • Specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4,4-dichlorocyclohexyl, 2,2,3,3-tetrafluorocyclopentyl, and 4-cyclohexyl cyclohexyl.
  • the “optionally halogenated C 6 alkoxy” includes, for example, 1 to 5, preferably 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.).
  • halogen atoms eg, fluorine, chlorine, bromine, iodine, etc.
  • a good ⁇ - alkoxy eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy, etc. is used.
  • Specific examples include, for example, methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-tri Fluoroethoxy, propoxy, isopropoxy, butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy and the like.
  • the “5- to 7-membered saturated cyclic amino” of the “optionally substituted 5- to 7-membered saturated cyclic amino” for example, in addition to one nitrogen atom and carbon atom, a nitrogen atom, sulfur One or two selected from atoms and oxygen atoms, and a 5- to 7-membered saturated cyclic amino which may contain 1 to 4 heteroatoms are used.
  • Specific examples include pyrrolidine-111-yl, piperidino , Pyridine, morpholino, thiomorpholino, hexahydroazebine-11-yl, and the like.
  • Examples of the “substituent” of the “optionally substituted 5- to 7-membered saturated cyclic amino” include C t- 6 alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.
  • C B _ 1 4 ⁇ Lil eg to, phenyl, 1 one-naphthyl, 2-naphthyl, 2 - Bifue two Lil, 3-bi-phenylene Lil, 4 -Biphenylyl, 2-anthryl, etc.
  • C- 6 alkyl-1-carbonyl eg, acetyl, propionyl, etc.
  • 5- to 10-membered aromatic heterocycle eg,
  • R 1 C f It may have a substituent group represented by R 1 C f; - 1 4 is a preferred embodiment of Ariru group, 4 one-fluorophenyl, 4 - black port phenyl, p- preparative Lil, 2- naphth And the like.
  • the C 4 alkyl group represented by R 2 and R 3 may be linear or branched, for example, methyl, ethyl, bromo, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl. And the like. Among them, propyl, isopropyl, butyl and tert-butyl are preferable, and isopropyl is particularly preferable.
  • R 2 and R 3 are as follows.
  • One is a hydrogen atom and the other is propyl, isopropyl, butyl, tert-butyl.
  • R 2 is propyl, isopropyl, butyl, tert-butyl; R 3 is a hydrogen atom.
  • R 2 is isopropyr and R 3 is a hydrogen atom.
  • Examples of the ring having 3 to 7 carbon atoms which R 2 and R 3 may form together with the nitrogen atom to which they are bonded include cyclopropylidene (cyclopropane ring), cyclobutylidene (cyclobutane (), cyclopentylidene (Cyclopentane ⁇ ), cyclohexylidene (cyclohexane ring), cycloheptylidene (cycloheptane ring), etc., among which cyclopentylidene (cyclopentane ring), cyclohexylidene (cyclohexane ⁇ ), etc. Is preferred.
  • the lower alkyl group represented by R 4 may be linear or branched, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isobentyl And C ⁇ -ealkyl groups such as neopentyl, tert-pentyl, hexyl, 4-methylpentyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, and 2-ethylbutyl.
  • C ⁇ 4 alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl are preferred, and methyl and isobutyl are particularly preferred.
  • Ariru group optionally groups have, phenyl, 1-naphthyl, C 6 _ 1 4 7 aryl group, such as 2-naphthyl. Among them phenylene Are preferred.
  • cycloalkyl group which may have, Shikuropu port building, cyclobutyl, cyclopentyl, C 3, such as cyclohexyl - include 6 Shikuroa alkyl group, with preference cyclohexyl .
  • Examples of the aromatic heterocyclic group which the lower alkyl group may have include at least one heteroatom selected from the group consisting of a nitrogen atom, an oxygen atom, a sulfur atom and the like in addition to the carbon atom. And a 10-membered monocyclic aromatic heterocyclic group and a condensed aromatic heterocyclic group.
  • Examples of the monocyclic aromatic heterocyclic group include pyrrolyl, furyl (eg, 1-furyl, 2-furyl), chenyl (eg, 2-phenyl, 3-phenyl), pyridyl (2-phenyl) Pyridyl, 3-pyridyl, 4-pyridyl), oxosazolyl, thiazolyl, imidazolyl, pyrazolyl, and the like.
  • condensed aromatic heterocyclic group examples include quinolyl (eg, 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 8-quinolyl), isoquinolyl (eg, 1-isoquinolyl, 3_isoquinolyl, 4-isoquinolyl, 5-isoquinolyl), indolyl (eg, 1-indolyl, 2— Indolyl, 3—indolyl), benzofuryl, indazolyl, quinazolyl, phthalazinyl, quinoxalyl, benzothiazolyl, benzozoenyl and the like. Of these, indolyl is preferred.
  • indolyl is preferred.
  • R 4 isobutyl, benzyl, cyclohexylmethyl, indole-3-ylmethyl and the like are preferably used.
  • the compound (I) include, for example, JP-A-10-147564 (European Patent Application Publication No. 717565, U.S. Pat. No. 6,057,290) And the following compounds 1 to 27 produced in Examples 1 to 27 of the present invention.
  • Example 1 N— (2-naphthene lensulfonyl) 1 L—Parrillo L—Mouth isocyanate (Compound 1)
  • Example 2 N- (4-fluorophenylsulfonyl) -l-valyl-l-mouth isinal (compound 2)
  • Example 11 1 N- (4-fluorophenylsulfonyl) -L-Varilu L-Fenilalaninal (Compound 10)
  • Examples of the salt of compound (I) include a metal salt, an ammonium salt, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, a salt with a basic or acidic amino acid, and the like.
  • the metal salt include alkali metal salts such as sodium salt and potassium salt; alkali metal salts such as calcium salt, magnesium salt and barium salt; aluminum salt and the like.
  • the salt with an organic base include, for example, trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, enolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexane.
  • Salts with hexylamine, N, N, dibenzylethylenediamine and the like can be mentioned.
  • Preferable examples of salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
  • Preferred examples of salts with organic acids include, for example, formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfone Acids and salts with p-toluenesulfonic acid and the like.
  • Preferred examples of the salt with a basic amino acid include, for example, salts with arginine, lysine, orditin and the like.
  • Preferred examples of the salt with an acidic amino acid include, for example, aspartic acid, glutamic acid, and the like. And salts thereof.
  • salts are preferred.
  • alkali metal salts eg, sodium salt, potassium salt, etc.
  • alkaline earth metal salts eg, calcium salt, magnesium salt, barium salt, etc.
  • a salt with an inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc.
  • Salts with organic acids such as phosphoric acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulphonic acid and p-toluenesulfonic acid.
  • the compound (I) or a salt thereof can be produced according to a method known per se, for example, the production method described in Japanese Patent Publication No. 10-147564 or a method analogous thereto.
  • the pharmaceutical composition of the present invention may contain a water-soluble substance or other water-insoluble or poorly water-soluble substance in addition to the compound (I) or a salt thereof.
  • the water-soluble substance is not particularly limited.
  • a substance useful as an active ingredient of an animal drug is appropriately selected. Specifically, the following are mentioned.
  • Tetracycline hydrochloride Ambicillin, Viracillin, etc.
  • Ephedrine hydrochloride Nos power bottle hydrochloride, Codin phosphate, Dihydrocodine phosphate, Isoproterenol hydrochloride, etc.
  • Chlorpromazine hydrochloride atrobin sulfate, etc.
  • Probranolol hydrochloride alprenolol hydrochloride, etc.
  • the water-insoluble or poorly water-soluble substance is not particularly limited, and a substance useful as an active ingredient of a drug or an animal drug having such properties is appropriately selected.
  • a substance having a solubility in water of 10 mg / m1 or less and in which improvement in water solubility is desired is used.
  • Antipyretic, analgesic, anti-inflammatory drugs Salicylic acid, sulubiline, flufenamic acid, diclofenac, indomethacin, atropine, scopolamine, morphine, pethidine, levorfuinol, ketoprofen, nabroxen, ibuprofen, oxymorphone or a salt thereof, etc.
  • Ephedrine Methylephedrine, Nos Power Bin, Kodin, Dihydrocodine, Aloclamide, Chlorfuezanol, Picoberidamine, Cloperastine, Protochlorol, Isoproterenol, Salbu Yumole, Tereptalin or its salt, etc.
  • Imipramine Imipramine, clomipramine, noxiptiline, phenelzine, etc.
  • Bopranolol alprenolol, bufetrol, oxprenolol, etc.
  • Steroid hormones such as dexamethasone, hexestrol, methimazol, benzomethasone, triamcinolone, triamcinolone acetate, fluocinolone acetate, prednisolone, hydrocortisone, estrolio One
  • vitamin A vitamin A bi evening Min A 2 and palmitic acid Retino Ichiru
  • vitamin D have D 2, D 3, D 4 and D 5
  • Vitamin E Hi-tocopherol,?-Tocopherol, a-tocophere, (5-tocophere, nicotinic acid dl-hi-tocopherol
  • vitamin K vitamin K physician ⁇ 2, ⁇ 3 and ⁇ 4 5Folic acid (Biyumin M) etc.
  • vitamins for example, 5, 6-trans-cholecalciferol Schiff Errol, 2, 5 - vitamin D 3 derivatives such as human mud Toxicogenomics Leka Rushifu Errol, 1 one shed over hydroxycarboxylic cholecalciferol shea Hue roll, 5, such as vitamins 0 2 derivatives such as 6-trans-E Lugo local shift Errol
  • Hydroxycam diaserine, megestrol acetate, nicerogoline, prostaglandins, etc.
  • arthritis drugs antirheumatic drugs, antiasthmatic drugs, frequent urination / incontinence drugs, atopic dermatitis drugs, and allergic rhinitis drugs are also used.
  • N-benzyloxycarbonyl-L-valyl-L-phenylalaninal (MDL 28170) or a salt thereof can also be used.
  • This compound A can be produced according to a method known per se, for example, a production method described in JP-A-2-256654 or JP-A-2-134398.
  • the following compounds B to R and the like can be used in place of compound (I) or a salt thereof, or in addition to compound (I) or a salt thereof.
  • Compound B can be produced according to a method known per se, for example, the production method described in US Pat. No. 5,081,284.
  • R 1 is R 4 — CO—, R 4 — 0—CO—, or R 4 — S 0 2 —
  • R may be substituted C fi — C 14 aryl group A C 1 -C 2 alkyl group which may be substituted with C 3 —C a cycloalkyl group; or a substituted or unsubstituted C R —C 14 aryl group.
  • R 2 represents a C i -C 6 alkyl group
  • R 3 represents a hydrogen atom or R 5 — C 0 — (R 5 represents an alkyl group of C 1 —)
  • A represents C i compound represented by representing] one C 3 alkyl group optionally C ⁇ one C 3 alkylene group which may have a salt thereof or a solvate or hydrate, (compound D) (W098 / 0 1 1 2 9, JP-A-10-101560).
  • R 1 is a hydrogen atom, R 8 —CO—, R 8 —0—CO—, R 8 —NH—C O— or R 8 —S 0 2 —
  • R 8 is C 3 —C 8 cycloalkyl group, C 3 - C cycloalkyl old alkoxy group B, Furuoreniru group, C, one C s alkoxy group which may have a substituent C 6 - C 14 Ariru group, have a substituent C u — C 14 aryloxy group, optionally substituted C 6 — C 14 arylthio group, optionally substituted C fi — C 14 An alkyl group of C—C 2, which may have one or more substituents selected from the group consisting of an arylsulfonyl group and an optionally substituted heterocyclic residue; C 3 — C 8 cycloalkyl group; optionally substituted C 6 — C i 4 aryl group; optionally substituted C B — replaced with
  • R 1 is C 2 —. Linear or branched acryl group, C 4 -C 15 branched, cyclic or polycyclic alkyloxycarbonyl group, substituted or unsubstituted benzyloxycarbonyl group, 2,2,2-trichloromethyl Etiloxycarbonyl, 2-
  • R 2 is a hydrogen atom, or R 1 and R 2 may be taken together to form a phthaloyl group, R 3 represents an isobutyl group, an n-butyl group, or an isopropyl group; however, the above R 1 can be an unsubstituted benzyloxycarbonyl group only when R 3 is an n-butyl group. , And
  • R 4 represents an n-butyl group] or a salt thereof (Compound J) (JP-A-2-268145, US Pat. No. 5,510,531, European Patent Application Publication No. 0393457) .
  • Q is an aryl group having 6-14 carbon atoms, a heteroaryl group having 6-14 ring atoms, 7-: L an aralkyl group having 5 carbon atoms, 2-7 carbon atoms A heteroalkyl group having an atom or an arylarylalkyl group in which the aryl moiety is not fused or fused to a heteroalkyl ring; m represents 0, 1, or 2;
  • R 1 and R 2 are independently a hydrogen atom, an alkyl group having 1 to 14 carbon atoms, a cycloalkyl group having 3 to 10 carbon atoms, or a natural or unnatural L-amino acid Represents a side chain, wherein the alkyl group and the cycloalkyl group are May be substituted with two or more J groups;
  • J group is halogen, lower alkyl group, aryl group, heteroaryl group, amino group optionally substituted with 1 to 3 aryl groups or lower alkyl group, guanidino group, alkoxycarbonyl group, alkoxy group, hydroxyl group, Or a salt thereof (compound 0) (WO98 / 08941, US Patent No. 5744339, European Patent Application Publication No. 0958354).
  • R 2 represents a hydrogen atom, alkyl (the alkyl is one or more groups selected from amino, guanidino, halo, hydroxy, alkyloxy, nitro, alkylsulfonyl and arylsulfonyl, or a protected derivative thereof) Or a group selected from cycloalkyl, cycloalkylalkyl, or aryl and arylalkyl (the aryl ring may be substituted with amino, guanidino, halo, hydroxy, or halogen) Alkyl, alkyloxy, nitro, alkylsulfonyl and arylsulfonyl, or one or two groups selected from the protected derivative thereof).
  • Salt Compound P) (W096 / 303 53, JP-T-111-150334-17, State Patent Application Publication No. 08 17 778).
  • R 1 is a hydrogen atom or methyl
  • R 2 is ethyl, propyl, isobutyryl, imidazo-1-yl, imidazole-4-yl, virazol-3 _ , Thiazole-4-yl, chen-1-yl, ethoxycarbonyl, t-butylcarbonylmethyl, benzyloxycarbonylmethyl or t-butoxy, and 3 is isobutyl, cyclohexylmethyl or benzyl.
  • R 4 is nitro, amino or a group of the formula N (R 5 ) (R H ); and A is a group
  • R b is alkyl, alkoxyalkyl or optionally substituted phenyl, phenylalkyl or phenylsulfonylalkyl
  • R G is alkyl, alkoxyalkyl, optionally substituted Good phenyl, phenylalkyl or phenylsulfonylalkyl, alkanol, alkoxycarbonyl, arylalkoxycarbonyl, optionally substituted benzimidazolonyl or optionally acylated amino acid or acylated
  • R 6 is Arukanoiru, alkoxycarbonyl When others are ⁇ reel alkoxycarbonyl, A is can not be a group (b), the dotted line can be an additional bond, R 7 is phenyl, a substitution phenyl, benzyl or naphthyl, and R 8 is a hydrogen atom, an alkoxy carbonyl alkyl, alkylcarbonyl, cycloalkyl carbonylation Ruarukiru, heterocycloalkylcarbonyl alkyl, ⁇ reel carbonyl ⁇ alkyl, ⁇ iminocarbonyl alkyl, substituted aminocarbonyl alkyl, Aminoa Le kill carbonylalkyl, substituted amino Alkylcarbonylalkyl, aminoalkylsulfonylalkyl, substituted aminoalkylsulfonylalkyl, alkoxycarbonylhydroxyalkyl, alkylcarbonylhydroxyalkyl, cycloalky
  • the pharmaceutical composition of the present invention is obtained by combining the above cyclodextrin compound with a compound by a known method. It can be produced by mixing with the product (I) or a salt thereof. Preparation of an inclusion compound of compound (I) or a salt thereof with a cyclodextrin compound can be carried out, for example, generally by the following four methods.
  • the acidic inclusion compound is dissolved in aqueous ammonia, to which a cyclodextrin compound is added and freeze-dried. In the process of lyophilization, excess ammonia is removed, and an inclusion compound of the ammonium salt of the inclusion compound is obtained.
  • the inclusion compound is dissolved in a lipophilic organic solvent (eg, ethyl ether, etc.), mixed with a saturated aqueous solution of a cyclodextrin compound, vigorously shaken for 10 minutes to several hours, and then left to stand in a cool place overnight. Then, the inclusion reaction product is precipitated, and then separated by centrifugation and filtration. The obtained powder is dissolved in water to obtain an aqueous solution of the clathrate compound.
  • a lipophilic organic solvent eg, ethyl ether, etc.
  • An aqueous solution of an inclusion compound is obtained by mixing an aqueous solution of a cyclodextrin compound and an aqueous solution of an inclusion compound.
  • the inclusion compound means not only the inclusion body and the complex itself, but also a mixture of the inclusion body, the complex, the free inclusion compound and Z or the free cyclodextrin compound. . That is, the obtained powder and aqueous solution may contain, in addition to the clathrate and the complex, the clathrate or the free cyclodextrin compound which is an unclathrate or a non-sutoglobin.
  • Such powders, including the powder itself are extremely water-soluble and have the property of dissolving instantaneously in water.
  • “to be used in combination” refers to compound (I) or a salt thereof and cyclode.
  • Mixing a xtrin compound or a salt thereof, forming an inclusion compound, or using compound (I) or a salt thereof and a cyclodextrin compound or a salt thereof as a mixture thereof or in the form of an inclusion compound. means.
  • the pharmaceutical composition of the present invention may be the aqueous solution itself obtained as described above, or may be a solution obtained by dissolving the obtained powder in a suitable solvent, and, if desired, a pharmacologically acceptable carrier. May be appropriately added.
  • the pharmaceutical composition of the present invention has low toxicity, and the compound (I) or a salt thereof is mixed with a pharmacologically acceptable carrier as it is or according to a method known per se, to obtain a pharmaceutical composition such as a tablet (sugar-coated tablet). , Film-coated tablets), powders, granules, capsules (including soft capsules), liquids, injections, suppositories (including rectal suppositories), sustained release, syrups, external preparations for skin It can be safely administered orally or nonperiodically (eg, topically, rectally, intravenously, etc.) as a nasal formulation, mucosal application formulation, eye drops, eye ointment and the like.
  • a pharmaceutical composition such as a tablet (sugar-coated tablet). , Film-coated tablets), powders, granules, capsules (including soft capsules), liquids, injections, suppositories (including rectal suppositories), sustained release
  • Examples of the pharmacologically acceptable carrier that may be used in the production of the preparation of the present invention include various organic or inorganic carrier substances commonly used as preparation materials, such as excipients and solid lubricants in solid preparations. , Binders and disintegrants, or solvents in liquid preparations, solubilizers, opacity agents, tonicity agents, buffers and soothing agents. Further, if necessary, usual additives such as preservatives, antioxidants, coloring agents, sweeteners, adsorbents, and wetting agents can be used in appropriate amounts.
  • Excipients include, for example, lactose, sucrose, D-mannitol, starch, corn starch, crystalline cellulose, light caffeic anhydride and the like.
  • lubricant examples include magnesium stearate, calcium stearate, talc, colloid silica and the like.
  • binders include crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropyl cellulose, hydroxydipropyl methylcellulose, polyvinyl alcohol, starch, sucrose, gelatin, methylcellulose, and carboxymethylcellulose. And the like.
  • Disintegrators include, for example, starch, carboxymethylcellulose, calcium carboxymethylcellulose, sodium carboxymethylstarch, L-hydroxypropyl cellulose and the like.
  • solvent examples include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil, and olive oil.
  • solubilizing agent examples include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like.
  • emollient examples include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminobrobionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glycerin monostearate; for example, polyvinyl alcohol, Examples include hydrophilic polymers such as polyvinyl biethylene lidone, carboxymethylcellulose-sodium nitrate, methylcellulose, hydroxymethylcellulose, hydroxyshethylcellulose, and hydroxypropylcellulose.
  • tonicity agent examples include glucose, D-sorbitol, sodium chloride, glycerin, D-mannitol and the like.
  • buffers such as phosphate, acetate, carbonate, and citrate.
  • Examples of the soothing agent include benzyl alcohol and the like.
  • preservative examples include paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid, benzalkonium chloride, benzethonium chloride and the like.
  • antioxidant examples include sulfite, sodium edetate, ascorbic acid, sodium tocopherol and the like.
  • the composition of the present invention is preferably an injectable composition, particularly a composition for intravenous injection.
  • the composition preferably further contains a pH adjuster.
  • the pH adjuster include nuglumine, sodium hydroxide, potassium hydroxide, aqueous ammonia, sodium hydrogen carbonate, sodium carbonate, triethanolamine, monoethanolamine, diisopropanolamine, triisopropanolamine, L-arginine. , Hydrochloric acid, phosphoric acid, acetic acid, boric acid, carbonic acid and the like.
  • the amount of the pH adjuster to be used is 0.01 to 10 mol, preferably 0.1 to 5 mol, per 1 mol of the cyclodextrin compound or a salt thereof.
  • the composition is miscible with an infusion and can be used as a mixture of the composition and an infusion.
  • the infusion is not particularly limited, and commercially available or ordinary infusion is used. Specific examples of the infusion include glucose injection, xylitol injection, D-mannitol injection, fructos injection, physiological saline, dextran 40 injection, dextran 70 injection, and amino acid injection. And Ringer's solution, Ringer's lactate and the like.
  • the composition ratio ⁇ of the composition is 1Z1 (v / v) -1/500 (v / v), preferably 1/20 (v / v) to: L / 100 (v / v) with respect to the infusion. .
  • carriers for the injection include, for example, solvents, dissolution aids, suspending agents, isotonic agents, buffers, soothing agents and the like.
  • the solvent include water for injection, physiological saline, Ringer's solution and the like.
  • the solubilizer include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like.
  • the tonicity agent include glucose, D-sorbitol, sodium chloride, glycerin, D-mannitol and the like.
  • the buffer include buffers such as phosphate, acetate, carbonate, and citrate.
  • the soothing agent include benzyl alcohol and the like.
  • the above-mentioned various components are mixed, if necessary, with a composition containing compound (I) or a salt thereof and a cyclodextrin compound or a salt thereof, and fractionated.
  • a composition containing compound (I) or a salt thereof and a cyclodextrin compound or a salt thereof Having a molecular weight of about 1,000 to about 8,000, preferably about 2,000 to about 7,000, more preferably about 3,000 to about 7,000,
  • a neurogen eg, endotoxin
  • a hollow fiber ultrafiltration membrane As such a hollow fiber ultrafiltration membrane, a commercially available one can be used as appropriate.
  • a hollow fiber ultrafiltration membrane SI P-0013 manufactured by Asahi Kasei Kogyo Co., Ltd. having a molecular weight cut off of 6,000; A type module (200x130mm) is used.
  • the pore size of the hollow fiber ultrafiltration membrane is usually about 10 to 100 angstroms, preferably about 20 to 60 angstroms.
  • hollow fiber ultrafiltration membrane module Although only one hollow fiber ultrafiltration membrane module may be used, two or more hollow fiber ultrafiltration membrane modules (for example, two to three, preferably two) may be used as needed. In particular, a combination of a hollow fiber ultrafiltration membrane having a molecular weight cut off of 6,000 and a hollow fiber ultrafiltration membrane having a molecular weight cut off of 3,000 is preferred.
  • the hollow fiber ultrafiltration membrane is immersed in, for example, sodium hypochlorite solution for about 1 to 30 hours, and then the pH of the permeate solution is adjusted with an aqueous solution for injection not containing pidinidine. Wash until about 7.0.
  • the pressure at the time of ultrafiltration is usually set to about 0.05 to 1.0 kg / cm 2 , preferably about 0.1 to 0.5 kg / cm 2 .
  • Filtration can be performed at room temperature, and is preferably performed under aseptic conditions.
  • the content of pyrogen in the injectable composition of the present invention is usually about 100 EUZg or less, preferably about 50 EUZg or less, particularly preferably about 30 EU / g or less.
  • the pyrogen content is expressed in EU / g and does not refer to the pyrogen content (EU) per g of composition.
  • the content of pyrogen in the composition for injection of the present invention can be determined by a method known per se. More specifically, the endotoxin is measured using endotoxin measuring reagents such as Toxic acid system Et-2 set (standard endotoxin) and Toxicara system LS-20 set manufactured by Seikagaku Corporation.
  • the concentration (EU) can be determined from the absorbance at 405 nm.
  • composition for injection of the present invention thus obtained is freeze-dried with a sterilized freeze-dryer.
  • It can be dried and stored in powder form, or it can be stored as it is in an injection container (eg, ampoule).
  • an injection container eg, ampoule
  • the content of compound (I) or a salt thereof in the pharmaceutical composition of the present invention varies depending on the form of the preparation, but is usually about 0.01 to about 100% by weight, preferably about 0.01% by weight, based on the whole preparation. It is about 0.1 to about 50% by weight, more preferably about 0.5 to about 20% by weight.
  • the content of the cyclodextrin compound or a salt thereof in the pharmaceutical composition of the present invention varies depending on the form of the preparation, but is usually about 1 to about 99.99% by weight, preferably about 10 to about 99% by weight, based on the whole preparation. It is about 90% by weight.
  • the mixing ratio of the cyclodextrin compound and the compound (I) or a salt thereof in the pharmaceutical composition of the present invention is not particularly limited and can be selected from a wide range. However, considering the water solubility of these substances, the compound (I) ) Or a salt thereof per mol of the cyclodextrin compound or a salt thereof is about 0.1 to about 20 mol, preferably about 1 to about 10 mol, more preferably about 4 to about 8 mol, and particularly preferably Mix in the range of about 5 to about 7.5 moles.
  • the content of other additives in the pharmaceutical composition of the present invention varies depending on the form of the preparation, but is usually about 1 to about 99.99% by weight, preferably about 10 to about 9% by weight, based on the whole preparation. It is about 0% by weight.
  • the pharmaceutical composition of the present invention has improved water solubility of compound (I) or a salt thereof and removes pyrogen, and therefore has high safety to the human body.
  • Humans and non-human mammals eg, rats, mice, guinea pigs, monkeys, mice, dogs
  • pharmaceuticals eg, agents for the prevention and treatment of various diseases
  • veterinary drugs eg, Bush, etc.
  • “Improved water solubility” means, for example, that the solubility of compound (I) or a salt thereof in an aqueous solution is usually about 2 times or more, preferably 10 times or more, more preferably about 20 times or more. More preferably, it is about 50-fold or more, particularly preferably 100-fold or more.
  • the pharmaceutical composition of the present invention may be a disease in which cysteine arotase such as calpain is involved, for example, ischemic disease (eg, ischemic heart disease), inflammatory disease, muscular dystrophy, immune disease, Alzheimer's disease, Osteoporosis, angiogenesis (eg, wound healing, inflammation, neovascularization associated with tumor growth, diabetic retinopathy, retinopathy of prematurity, retinal vein occlusion, senile discoid macular degeneration, etc.), cerebrovascular Atrophy, cerebral thrombosis, cerebral infarction, cerebral obstruction, intracerebral hemorrhage, subarachnoid rfiu hypertensive encephalopathy, transient cerebral apoplexy, multiple infarct dementia, arteriosclerosis, Huntington's disease, brain tissue disorders (Cerebral trauma, cerebral edema, brain tumor), retinal vein occlusion, circumcisional veinitis, Eales disease,
  • composition for injection of the present invention can be administered intravenously, intramuscularly, subcutaneously or intraorganically, or directly to a lesion.
  • the dosage of the pharmaceutical composition of the present invention varies depending on the administration subject, administration route, disease, and the like.
  • the dosage for an adult about 60 kg
  • each time about 0.1 to about 500 mg, preferably about 0.1 to about 300 mg, more preferably about 1 to about 15 as an active ingredient (compound (I) or a salt thereof) is used.
  • 0 mg more preferably about 1 to about 100 mg, particularly preferably 5 to 100 mg, which can be administered as an injection (for example, intravenous administration) in one to several divided doses. it can.
  • the desired effect can be usually obtained by administering 1 to 100 mg, preferably 10 to 50 Om, of the compound (I) or a salt thereof.
  • the dose of Compound (I) or a salt thereof is usually And then 0.001 to: I. 0 w / v%, preferably 0.01 to 0.5 w / v%, bile fluid prepared at a time of 20 to 50 il, 1H 5 to 6 It is good to instill the culm degree.
  • hollow fiber ultrafiltration membrane SIP-0013, molecular weight cut off 6,000 (code No. 259552 FLT, IL-22; module dimensions; 20 1 30 L (mm); volume: 1000 ml; pore size: 0.22 zm) to 3.5 L of sodium hypochlorite solution (4% Na 0 H containing 500 ppm of NaCIO) Solution) for 20 hours. Then, wash with 1.5 L of an endotoxin-free aqueous solution for injection until the pH of the passing solution becomes 7.0, and prepare a hollow fiber ultrafiltration membrane.
  • an aqueous solution obtained by dissolving 5 g of 2-hydroxypropyl-1-cyclodextrin powder in 50 ml of water for injection was sterilized using a cellulose / acetate membrane filter manufactured by Corning Costar, Inc. After filtration, the solution was passed through a hollow fiber ultrafiltration membrane: SIP-0013, which had been pretreated with a sodium hypochlorite solution in advance, fractionated by 10 ml each, and a total of 70 ml was collected. Then, freeze-dry overnight with a freeze dryer that has been sterilized in advance to obtain 4.6 g of a colorless powder of 2-hydroxypropyl-1 /?-Cyclodextrin.
  • a hollow fiber ultrafiltration membrane manufactured by Asahi Kasei Corporation SIP-001, fractional molecular weight 6, 000 (code No. 259552 FLT, IL-22; module dimensions; 20 ⁇ X 1 30 L (mm); capacity 1 000 ml; pore size 0.22 ⁇ . ⁇ ) with sodium hypochlorite solution 3.5 L (Na C 10 500 0 p pm In a 4% NaOH solution containing 20 hours.
  • the membrane is washed with 1.5 L of an endotoxin-free aqueous solution for injection until the pH of the passing solution becomes 7.0, and a hollow fiber ultrafiltration membrane is prepared.
  • Bubble yarn ultrafiltration membrane pre-treated with sodium solution Conducted through SIP-001, dispensed a total of 100 ml, and then freeze-dried overnight in a freeze-dryer that had been sterilized in advance Then, a preparation containing the compound 1 and 2-hydroxypropir-5-cyclodextrin is obtained as 0.34 g of colorless powder.
  • Compound 0.2 g is dissolved in ethanol 50 ml. Dissolve 15 g of 2-hydroxypropyl-cyclodextrin in 50 ml of distilled water for injection. The ethanol solution and the aqueous solution are combined and stirred for 30 seconds to form a homogeneous solution. The solution is evaporated to dryness under reduced pressure using a centrifugal evaporator and a tray-type vacuum dryer. 100 ml of physiological saline is added to the residue, and the mixture is dissolved by stirring at 25 ° C for 2 hours. After that, the solution is filtered through a membrane filter (0.45 im) and dispensed into an ampoule to prepare an injection.
  • Compound 13 Omg is dissolved in ethanol 2 ml. Dissolve 75 mg of 2-hydroxypropyl /?-Cyclodextrin in 2 ml of purified water. The ethanol solution and the aqueous solution are combined to make a homogeneous solution. The solution is dried under reduced pressure using a centrifugal evaporator and a tray-type vacuum dryer. The dry solid is formed into tablets in the usual manner with the above amounts of starch, magnesium stearate and crystalline cellulose. The tablet may be coated with a commonly used enteric coating (eg, hydroxypropyl phthalate or virmethylcellulose), sugar coating or a film (eg, ethylcellulose) as necessary.
  • enteric coating eg, hydroxypropyl phthalate or virmethylcellulose
  • sugar coating eg, ethylcellulose
  • Compound 2 is dissolved in 20 ml of ethanol. Dissolve 25 g of 3-hydroxypropyl-1- / cyclodextrin in 30 ml of sterile purified water. The ethanol solution and water solution are combined and stirred for 30 seconds to make a homogeneous solution. This solution is dried under reduced pressure using a centrifugal evaporator and a shelf-type vacuum dryer. Dissolve 0.1 lg of sodium dihydrogen phosphate, 0.9 g of sodium chloride and 0.005 g of benzal konium chloride in about 80 ml of sterilized purified water, adjust the pH to 7 with sodium hydroxide, and adjust the pH to 7. Make up to 100 ml with sterile purified water. This solution is added to the residue dried under reduced pressure, and filtered through a membrane filter (0.45 m) to give eye drops.
  • Example 6 dissolving ophthalmic solution before use
  • Borax suitable amount (pH 7.8) Benzalkonium chloride 0.005 g
  • Compound 2 is dissolved in 20 ml of ethanol.
  • Compound 2 is dissolved in 30 ml of ethanol. Dissolve 6-0-sulfoptyl-cyclodextrin in 30 ml of sterile purified water. The ethanol solution and the aqueous solution are combined and stirred for about 30 seconds to obtain an average solution. This solution is evaporated to dryness in a centrifugal evaporator overnight and on a shelf-type vacuum dryer. Add about 70 ml of sterile purified water to the residue, 25. After stirring and dissolving in C, add sodium acetate, sodium chloride, methyl para-hydroxybenzoate and provyl para-hydroxybenzoate and dissolve. Adjust ⁇ to 5.0 with hydrochloric acid, and add sterile purified water to make the total volume 100 ml.
  • Compound 2 is dissolved in 300 ml of ethanol. Dissolve 6-0-galactosyl-glucosyl-?-Cyclodextrin in 300 ml of sterile purified water. The ethanol solution and the aqueous solution are combined and stirred for about 30 seconds to obtain an even solution. This solution Dry under reduced pressure with a centrifugal evaporator and a shelf-type vacuum dryer, and disperse and fill into 500 capsules.
  • Compound 2 is dissolved in 50 ml of ethanol. Dissolve sodium cyclodextrin tetrasulfate in 50 ml of distilled water for injection. The ethanol solution and aqueous solution are combined and stirred for about 30 seconds to make a homogeneous solution. This solution is dried under reduced pressure using a centrifugal evaporator and a shelf-type vacuum dryer. Add 100 ml of physiological saline to the residue, stir and dissolve at 25 ° C, filter through a membrane filter (0.45 m), and dispense into a sample to prepare an injection.
  • Example 11 1 Injection (lyophilized vial)
  • Compound 23 Omg is dissolved in ethanol 2 ml. 5— CyD— G 2 — Dissolve 75 Omg of CO ONa in 2 ml of purified water.
  • the ethanol solution and the aqueous solution are combined to make a uniform solution.
  • the solution is evaporated to dryness under reduced pressure using a centrifugal evaporator and a shelf vacuum dryer.
  • the dried solid is formed into tablets using the above amounts of starch, magnesium stearate and crystalline cellulose in a conventional manner.
  • the tablet may be coated, if necessary, with a commonly used enteric coating (for example, hydroxypropyl phthalate oral methylcellulose), sugar coating or a film (for example, ethyl cellulose).
  • Sterile purified water 100m Dissolve 0.1 g of compound 2 in 2 Oml of ethanol. Dissolve 0.2 g of 5—CyD—G 2 —C 2 OOH in 20 ml of distilled water for injection. The ethanol solution and the aqueous solution are combined and stirred for 30 seconds to make a homogeneous solution. The solution is evaporated to dryness under reduced pressure using a centrifugal evaporator and a tray-type vacuum dryer. Add 70 ml of sterile purified water to the residue, dissolve with stirring at 25 C, and add the above amount of concentrated glycerin, sodium edetate, and benzal conidium chloride to dissolve. After adjusting the pH to 6 with hydrochloric acid or sodium hydroxide, add distilled water to make the total volume 100 ml.
  • 3-Hydroxypropyl-1-cyclodextrin (hereinafter sometimes abbreviated as 3-HPCyD) (manufactured by Japan Food Processing Co., Ltd.) in water
  • aqueous solutions were prepared. After it with that of the aqueous solution 2. 4m l Compound 2 (6 Omg) ethanol 2. stirring c this mixture was added a solution prepared by dissolving 4 m 1 30 seconds homogeneous solution, centrifugal evaporator first and Tanashiki vacuum The residue was dried under reduced pressure using a drier. To each residue was added 2.4 ml of water, shaken at 25 ° C for 5 hours, allowed to stand for 15 hours, and filtered through a membrane filter (0.45 Aim). It was a saturated solution.
  • Methyl /?-Cyclodextrin (hereinafter sometimes abbreviated as Methy 1-/?-CyD) (manufactured by Shiosui Port Refining Co., Ltd.) is dissolved in water and each concentration (5, 10 , 15 and 20 w / v%).
  • Aqueous solution of each 2.2.4ml A solution of Compound 2 (60 mg) in 2.4 ml of ethanol was added. The mixture was stirred for 30 seconds to form a homogeneous solution, and then dried under reduced pressure with a centrifugal evaporator and a tray-type vacuum dryer.
  • the content of compound 2 was measured by high performance liquid chromatography (HPLC) as follows.
  • the sample solution was prepared by taking 1 ml of the filtrate and diluting to 1 Oml with the solvent of the mobile phase.
  • the standard solution was prepared by accurately weighing compound 2 (about 10 mg) and diluting appropriately to each concentration with the solvent of the mobile phase. These solutions were measured by the HPLC method, and the external standard method was used. Was used to calculate the content of compound 2 in each aqueous solution, and the solubility was determined.
  • Test Example 2 (Test for transfer to aqueous humor by instillation)
  • Table 2 shows the results of the aqueous humor transfer test of the suspension of Compound 2 and the aqueous solution of Compound 2.
  • the concentration of Compound 2 in the aqueous humor 30 minutes after instillation of the suspension was 54.8 nM. I got it.
  • the aqueous concentrations of compound 2 in the aqueous humor 30 minutes after instillation of the 3—HP — /? — CyD aqueous solution and the mo no——3—CyD aqueous solution were 143.3 nM and 109.8 nM, respectively.
  • the concentration in the aqueous humor was about 2-3 times higher than that of the suspension. This indicates that the pharmaceutical composition of the present invention has improved aqueous humor transfer by eye drops.
  • ⁇ ⁇ ⁇ Hydroxydextrin (Hiichi CyD) was dissolved in water to prepare aqueous solutions of each concentration (2.5, 5, and 10 wZv%).
  • aqueous solutions of each concentration (2.5, 5, and 10 wZv%).
  • compound 2 (6 Omg) dissolved in 2.4 ml of ethanol.
  • the mixture was stirred for 30 seconds to form a homogeneous solution, and then dried under reduced pressure using a centrifugal evaporator and a tray-type vacuum dryer.
  • 2.4 ml of water was added to each residue, and the suspension was shaken at 25 ° C for 5 hours, allowed to stand for 15 hours, filtered through a membrane filter (0.45 Aim), and the compound in the filtrate was removed. The content of 2 was measured.
  • Compound 2.0 50 mg was added to 2.0 ml of each aqueous solution to give a suspension.
  • the suspension was shaken at 25 ° C. for 5 hours and allowed to stand for 15 hours, then filtered through a membrane filter (0.45 urn), and the content of Compound 2 in the filtrate was measured.
  • Table 3 shows the solubility of Compound 2 in an aqueous solution of MA, PEG or PG. concentration
  • Solubility at 0% indicates solubility in water. 3 ⁇ 43 Solubility of Compound 2 in various aqueous solutions (mgZml)
  • the solubility of Compound 2 was also measured for an aqueous solution of hy-cyclodextrin (Hi-CyD), but there was no significant solubilizing effect as in the case of branched cyclodextrin-carboxylic acid.
  • the solubility of compound 2 was measured for aqueous solutions of N, N-dimethylacetamide (DMA), polyethylene glycol 300 (PEG) and propylene glycol (PG), which are common solubilizing agents for injections. was done. As a result, the effect of dissolving Compound 2 in water was almost nil.
  • DMA N, N-dimethylacetamide
  • PEG polyethylene glycol 300
  • PG propylene glycol
  • Test Example 4 (Test for transfer to aqueous humor by instillation)
  • a suspension of compound 2 and an aqueous solution of compound 2 CyD—G 2 —COOH were instilled in 50 L portions into one eye of a male tl-color rabbit (body weight 2 kg). Thirty minutes after instillation, the mice were sacrificed with pentoparbital, and the aqueous humor was collected. The concentration of Compound 2 in the aqueous humor was measured using high performance liquid chromatography (HPL C: NANOSPACE SI-1, SHISEID0) using a column switching system.
  • HPL C high performance liquid chromatography
  • Table 4 shows the results of the aqueous humor transfer test of the suspension of Compound 2 and the aqueous solution of 5-CyD—G 2 —COOH of Compound 2.
  • the concentration of Compound 2 in the aqueous humor 30 minutes after instillation of the suspension was 54.8 nM.
  • the concentration of Compound 2 in aqueous humor 30 minutes after instillation of? —CyD—G 2 —COOH aqueous solution was 99.4 nM, which was lower than that in the case of suspension administration. It was about twice as expensive. From this, it was found that the aqueous solution of the present invention had improved aqueous humor transferability by eye drops.
  • 3-cyd—G 2 —CO 2 OH (50 g) was dissolved by adding 200 ml of sterile purified water.
  • Compound 2 (2 g) was dissolved in ethanol 2 00 m 1, after the above / 3 -C yD-G 2 -CO 0 H solution was added a homogeneous solution, and concentrated to dryness under reduced pressure.
  • 200 ml of sterilized purified water was added to the residue to dissolve the residue, and the mixture was filtered through a 0.22 m membrane filter overnight to obtain an aqueous solution of compound 2; 5-CyD—G 2 —C 00H.
  • Suspension Compound 2 (2.0 g) was added to 200 ml of a solution prepared by dissolving 0.1 g of carboxymethylcellulose in 100 ml of sterilized purified water and uniformly dispersed. This solution was used as a suspension.
  • ⁇ -CyD——C0 aqueous solutions and suspensions were each dosed via a catheter to beagle dogs weighing approximately 10 kg at a dose of 100 mg Zkg.
  • Blood was collected at 0.5, 1, 2, 4 and 8 hours after administration. Plasma was separated from the collected blood, and the concentration of Compound 2 in the blood was measured by HPLC (NANOSPACE SI-1, SH1SEID0) using a column switching system.
  • FIG. 1 shows the measurement results of the blood concentration of Compound 2 in the group administered with the suspension (room 1) and the group administered with the ⁇ -CyD—G 2 —C 00H aqueous solution (group 1).
  • the blood concentration of the group administered with the aqueous solution of CyD and G 2 —C ⁇ H was higher than the group administered with the suspension at any measurement time.
  • the maximum blood concentration was shown 2 hours after administration, but the maximum blood concentration in the ⁇ -CyD—G 2 —COOH aqueous solution administration group was observed. (6.3 g / m 1) is about 4.5 times the maximum blood concentration (1.4 ⁇ g / ml) of the group administered with the suspension.
  • the concentrations of Compound 2 and PEG in the aqueous solution were 0.2 w / v% and 40 v / v%, respectively.
  • Sample solutions were prepared by taking 1 ml of the filling solution from each ampoule and diluting to 1 Oml with the mobile phase solvent.
  • the standard solution was prepared by precisely weighing compound 2 (about 20 mg), diluting it with acetonitrile to 10 ml, and further diluting 1 ml of this solution with the solvent of the mobile phase to 10 ml. .
  • These solutions were measured by the HPLC method under the conditions described in Test Example 1, the content of Compound 2 in each aqueous solution was determined, and the residual ratio was calculated.
  • Table 5 shows the results. 3 ⁇ 45 Stability of compound 2 in aqueous solution
  • the pharmaceutical composition of the present invention can be prepared by blending compound (I) or a salt thereof with cyclodextrin or a derivative thereof or a salt thereof to obtain a compound (I) or a salt thereof which has water solubility, stability, or tissue transportability. Has been improved.
  • the compound (I) or a salt thereof is combined with cyclodextrin or a derivative thereof or a salt thereof to obtain a compound having the water solubility, stability or tissue morphology of the compound (I) or a salt thereof.
  • Properties such as migratory properties (for example, ocular migratory properties, and absorptivity) can be improved.
  • the branched cyclodextrin monobasic rubonic acid used in the present invention has a low effect on living bodies, for example, an effect of destroying erythrocytes, and thus shows high safety against blood.
  • CyD—G 2 —COOH, etc. is extremely little decomposed by acids or enzymes. Therefore, also in this respect, the composition of the present invention is highly safe for animals including humans.
  • This application is based on Japanese Patent Application No. 3524-13, Japanese Patent Application No. 2000-35645, and Japanese Patent Application No. 2000-365690 filed in Japan, the contents of which are incorporated in full herein. Things.

Abstract

L'invention concerne une composition pharmaceutique contenant un composé de formule générale (I) ou un sel de ce composé et au moins un élément choisi parmi les cyclodextrines, leurs dérivés et leurs sels. [R1 est C¿1-4? alkyle ou éventuellement C6-14 aryle; R?2 et R3¿ représentent chacun hydrogène ou C¿1-4? alkyle ou, selon un autre mode de réalisation, R?2 et R3¿ avec l'atome de carbone auxquels ils sont liés, peuvent former un cycle ayant 3 à 7 atomes de carbone; et R4 est alkyle faible qui peut avoir un substituant choisi dans le groupe formé d'aryle, de cycloalkyle et de groupes hétérocycliques aromatiques]. Cette composition améliore la solubilité dans l'eau, la stabilité ou la distribution tissulaire du composé (I).
PCT/JP2000/008700 1999-12-10 2000-12-08 Composition pharmaceutique contenant de la cyclodextrine WO2001041757A1 (fr)

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WO2004091630A1 (fr) * 2003-04-18 2004-10-28 Advanced Medicine Research Institute Remedes a des affections, a usage ophtalmique
WO2006040839A1 (fr) * 2004-10-15 2006-04-20 Advanced Medicine Research Institute Gouttes oculaires et trousses de traitement de maladies oculaires
EP1334718A4 (fr) * 2000-10-26 2007-07-18 Senju Pharma Co Composition medicamenteuse contenant un compose dipeptidyl aldehyde
JP2008520546A (ja) * 2004-09-21 2008-06-19 アドバンスト メディカル オプティクス， インコーポレーテッド 粘弾性溶液またはゲル製剤およびそれを使って身体部位を処置する方法
JP2013513612A (ja) * 2009-12-11 2013-04-22 ニューロン システムズ， インコーポレイテッド 黄斑変性の処置のための組成物および方法
JP2013245213A (ja) * 2012-05-29 2013-12-09 Jx Nippon Oil & Energy Corp ビワ葉培養エキス−シクロデキストリン包接物
JP2014531401A (ja) * 2011-07-26 2014-11-27 アラーガン インコーポレイテッドＡｌｌｅｒｇａｎ，Ｉｎｃｏｒｐｏｒａｔｅｄ 眼送達のための２部製剤
US9364471B2 (en) 2005-05-26 2016-06-14 Aldeyra Therapeutics, Inc. Compositions and methods of treating retinal disease
US9604997B2 (en) 2012-12-20 2017-03-28 Aldeyra Therapeutics, Inc. Peri-carbinols
US9687481B2 (en) 2013-01-23 2017-06-27 Aldeyra Therapeutics, Inc. Toxic aldehyde related diseases and treatment
US10111862B2 (en) 2013-01-25 2018-10-30 Aldeyra Therapeutics, Inc. Traps in the treatment of macular degeneration
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US11129823B2 (en) 2016-05-09 2021-09-28 Aldeyra Therapeutics, Inc. Combination treatment of ocular inflammatory disorders and diseases
US11197821B2 (en) 2018-09-25 2021-12-14 Aldeyra Therapeutics, Inc. Formulations for treatment of dry eye disease
US11312692B1 (en) 2018-08-06 2022-04-26 Aldeyra Therapeutics, Inc. Polymorphic compounds and uses thereof
CN114557970A (zh) * 2022-03-17 2022-05-31 浙江长典药物技术开发有限公司 一种眼用丝裂霉素冻干粉及其制备方法
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EP1334718A4 (fr) * 2000-10-26 2007-07-18 Senju Pharma Co Composition medicamenteuse contenant un compose dipeptidyl aldehyde
US7572833B2 (en) * 2000-10-26 2009-08-11 Senju Pharmaceutical Co., Ltd. Drug composition comprising dipeptidyl aldehyde derivative
JPWO2004091630A1 (ja) * 2003-04-18 2006-08-17 株式会社最先端医学研究所 眼に適用する疾患治療剤
WO2004091630A1 (fr) * 2003-04-18 2004-10-28 Advanced Medicine Research Institute Remedes a des affections, a usage ophtalmique
JP2008520546A (ja) * 2004-09-21 2008-06-19 アドバンスト メディカル オプティクス， インコーポレーテッド 粘弾性溶液またはゲル製剤およびそれを使って身体部位を処置する方法
WO2006040839A1 (fr) * 2004-10-15 2006-04-20 Advanced Medicine Research Institute Gouttes oculaires et trousses de traitement de maladies oculaires
US9364471B2 (en) 2005-05-26 2016-06-14 Aldeyra Therapeutics, Inc. Compositions and methods of treating retinal disease
US11724987B2 (en) 2005-05-26 2023-08-15 Aldeyra Therapeutics, Inc. Compositions and methods of treating retinal disease
US10913722B2 (en) 2005-05-26 2021-02-09 Aldeyra Therapeutics, Inc. Compositions and methods of treating retinal disease
JP2013513612A (ja) * 2009-12-11 2013-04-22 ニューロン システムズ， インコーポレイテッド 黄斑変性の処置のための組成物および方法
JP2015057437A (ja) * 2009-12-11 2015-03-26 アルデクサ セラピューティクス， インコーポレイテッド 黄斑変性の処置のための組成物および方法
JP2016130266A (ja) * 2009-12-11 2016-07-21 アルデイラ セラピューティクス， インコーポレイテッド 黄斑変性の処置のための組成物および方法
US9814701B2 (en) 2009-12-11 2017-11-14 Aldeyra Therapeutics, Inc. Compositions and methods for the treatment of macular degeneration
US10314887B2 (en) 2011-07-26 2019-06-11 Allergan, Inc. Two part formulation system for ophthalmic delivery
JP2018062521A (ja) * 2011-07-26 2018-04-19 アラーガン、インコーポレイテッドＡｌｌｅｒｇａｎ，Ｉｎｃｏｒｐｏｒａｔｅｄ 眼送達のための２部製剤
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