[go: up one dir, main page]

WO2008001752A1 - Treatment of chronic obstructive pulmonary disease by statin - Google Patents

Treatment of chronic obstructive pulmonary disease by statin Download PDF

Info

Publication number
WO2008001752A1
WO2008001752A1 PCT/JP2007/062768 JP2007062768W WO2008001752A1 WO 2008001752 A1 WO2008001752 A1 WO 2008001752A1 JP 2007062768 W JP2007062768 W JP 2007062768W WO 2008001752 A1 WO2008001752 A1 WO 2008001752A1
Authority
WO
WIPO (PCT)
Prior art keywords
hmg
coa reductase
reductase inhibitor
obstructive pulmonary
pulmonary disease
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/JP2007/062768
Other languages
French (fr)
Japanese (ja)
Inventor
Noritoshi Nagaya
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Daiichi Sankyo Co Ltd
National Cerebral and Cardiovascular Center
Original Assignee
Daiichi Sankyo Co Ltd
National Cerebral and Cardiovascular Center
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Daiichi Sankyo Co Ltd, National Cerebral and Cardiovascular Center filed Critical Daiichi Sankyo Co Ltd
Priority to JP2008522583A priority Critical patent/JP5336847B2/en
Publication of WO2008001752A1 publication Critical patent/WO2008001752A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • 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
    • A61K31/365—Lactones
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • 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
    • A61P3/06—Antihyperlipidemics
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D209/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with an alkyl or cycloalkyl radical attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/55—Acids; Esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D215/14—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/16—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D309/28—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D309/30—Oxygen atoms, e.g. delta-lactones

Definitions

  • the present invention relates to a medicament for the treatment or prevention of chronic obstructive pulmonary disease, emphysema or chronic bronchitis comprising an HMG_CoA reductase inhibitor as an active ingredient, and a pharmacologically of an HMG_CoA reductase inhibitor
  • the present invention relates to a method for treating or preventing chronic obstructive pulmonary disease, emphysema or chronic bronchitis by administering an effective amount to a warm-blooded animal (particularly a human).
  • COPD chronic obstructive pulmonary disease
  • COPD chronic obstructive pulmonary disease
  • This condition is caused by a combination of irreversible and persistent airway obstruction and is clearly distinguished from asthma, which is defined as reversible airway obstruction (Nippon Rinsyo, 61 ⁇ , 12, p.2058).
  • reversible airway obstruction Nippon Rinsyo, 61 ⁇ , 12, p.2058.
  • 0 COPD is mainly caused by chronic cough, sputum and dyspnea, with symptoms such as decreased lung function and weight loss (Boer, WI, Expert Opin. Investig. Drugs, 2003, 12th) , No.
  • HMG-CoA reductase inhibitors are well known as therapeutic agents for hyperlipidemia (for example, patent literature). 1). It is reported that pravastatin, a representative HMG_CoA reductase inhibitor, has an inhibitory effect (preventive effect) on the development of arteriosclerosis, coronary artery disease, and diabetes in clinical trials for hyperlipidemic patients. (See Non-Patent Documents 1 to 3, for example). However, HMG-CoA reductase inhibitors such as pravastatin have not been known to show therapeutic or preventive effects on COPD. [0004] Patent Document 1: US Pat. No. 4,346,227
  • Non-patent literature l MacMahon, S. et al., Circulation, 1998, 97th, .1784-1790.
  • Non-patent document 2 Sh seal herd, J. et al., Lancet, 2002, 360, pp.1623- 1630.
  • Non-Patent Document 3 Freeman, D. J. et al., Circulation, 2001, 103, p.357-362.
  • the present inventors have conducted intensive research on drugs for the treatment or prevention of COPD, HMG-CoA reductase inhibitor power, improvement of lung function, and tissue of lung and bronchial epithelial cells Because of its excellent effects in terms of clinical improvement, etc., it can be used for the treatment or prevention (preferably treatment) of chronic obstructive pulmonary disease, emphysema or chronic bronchitis (preferably chronic obstructive pulmonary disease). It was found useful as a pharmaceutical.
  • the present invention has been completed based on the above findings.
  • the present invention provides:
  • HMG medicine for treating or preventing chronic obstructive pulmonary disease, emphysema or chronic bronchitis, comprising a CoA reductase inhibitor as an active ingredient
  • HMG medicine for treating or preventing chronic obstructive pulmonary disease containing a CoA reductase inhibitor as an active ingredient
  • HMG—CoA reductase inhibitor power described in (1) or (2) selected from the group consisting of pravastatin, lovastatin, sympastatin, flupastatin, cerivastatin, atorvastatin, pitapastatin, and rosuvastatin Medicine, or
  • HMG_CoA reductase inhibitor power The drug according to (1) or (2), which is pravastatin, is provided.
  • the present invention also provides
  • HMG a method for the treatment or prevention of chronic obstructive pulmonary disease, emphysema or chronic bronchitis by administering a pharmacologically effective amount of a CoA reductase inhibitor to a warm-blooded animal
  • HMG—CoA reductase inhibitor power described in (5) or (6) selected from the group consisting of pravastatin, lovastatin, sympastatin, flupastatin, cerivastatin, atorvastatin, pitapastatin, and rosuvastatin Method,
  • HMG_CoA reductase inhibitor power The method described in (5) or (6), which is pravastatin,
  • HMG—CoA reductase inhibitor power described in (10) or (11) selected from the group consisting of pravastatin, lovastatin, sympastatin, flupastatin, cerivastatin, atorvastatin, pitapastatin, and rospastatin Use or
  • the HMG-CoA reductase inhibitor which is an active ingredient of the present invention, is not particularly limited as long as it is a compound exhibiting an HMG-CoA reductase inhibitory action.
  • No. 4346227 JP-A-57-163374 (U.S. Pat. No. 4231938), JP-A-56-122375 (U.S. Pat. No. 4,444,784), JP-A-60-5 00015 Publication (U.S. Pat. No. 4739073), JP-A-1-216974 (U.S. Pat. No. 5,006530), JP-A-3-58967 (U.S. Pat. No. 5,527,995), JP-A 1-279866 No.
  • a compound having an inhibitory action on HMG-Co A reductase Or a pharmacologically acceptable salt or ester thereof preferably pravastatin, lovastatin , Sympastatin, fluvastatin, cerivastatin, atonolepastatin, pitapastatin, or rospastatin Yes, more preferably pravastatin or rospastatin, most preferably brapastatin.
  • Pravastatin is described in JP-A-57-2240 (US Pat. No. 4,346,227), (+) _ (3 scale, 513 ⁇ 4_3,5_dihydroxy_7 _ [(13,23,63,83, 8 & 13 ⁇ 4_6_Hydroxy-2-methyl-8 _ [(S) -2-methylbutyryloxy] -l, 2,6,7,8,8a-hexahydro-1-naphthinole] heptanoic acid, and its pharmacology Including acceptable salts or esters (for example, the sodium salt of pravastatin, etc.) Oral pastatin is described in JP-A-57-163374 (US Pat. No.
  • a 5-dihydroxy-6-heptenoic acid includes its pharmacologically acceptable salt or ester (e.g., monosodium salt of cerivastatin, etc.). Atorvastatin is described in JP-A-3-58967 (US Pat. No. 5,527,995) as (3R, 5S) _7_ [2- (4_fluorophenyl) -5_ (1-methylethyl) _3-phenol.
  • the “pharmacologically acceptable salt” of the present invention refers to a salt formed by reacting with a base when the HMG-CoA reductase inhibitor has a carboxyl group.
  • examples of such salts include alkali metal salts such as sodium salt, potassium salt and lithium salt, alkaline earth metal salts such as calcium salt and magnesium salt, metal salts such as aluminum salt and iron salt; Inorganic salts such as ammonium salt, t-octylamine salt, dibenzylamine salt, monorephorin salt, darcosamine salt, phenyldaricin alkyl ester salt, ethylenediamin salt, N-methyldalkamine salt, guanidine salt, jetylamine salt, triethinoleamine Salt, dicyclohexylamine, N, N'-dibenzylethylenediamine salt, black pro-in salt, pro-in salt, diethanolamine salt, N-benzylphenethylamine salt, piperazine salt, Organic salt
  • HMG-CoA reductase inhibitors of the present invention When the HMG-CoA reductase inhibitor has an illegal carbon, all of its racemates, optical isomers and mixtures thereof are HMG-CoA reductase inhibitors of the present invention. Is included. In addition, the hydrate and solvate of the above HMG-CoA reductase inhibitor are included in the HMG-CoA reductase inhibitor of the present invention.
  • one type of HMG-CoA reductase inhibitor can be used alone, or two or more types of HMG-CoA reductase inhibitors can be used.
  • two or more HMG-CoA reductase inhibitors are used, they can be used at the same time, or they can be used separately over time.
  • chronic obstructive pulmonary disease is a combination of pulmonary emphysema characterized by destruction of lung tissue, chronic bronchitis characterized by increased mucus secretion in the bronchi, and irreversible and persistent airway obstruction. It is a condition that arises and is clearly distinguished from asthma, which is defined as reversible airflow obstruction.
  • emphysema includes chronic obstructive emphysema
  • chronic bronchitis includes respiratory bronchiolitis and chronic asthmatic bronchitis.
  • the present invention shows that HMG_CoA reductase inhibitor (especially pravastatin) is excellent in improving lung function and histological improvement of epithelial cells of lung and bronchus. For the first time. That is, the present invention demonstrates for the first time the applicability of an HMG_CoA reductase inhibitor to COPD.
  • the HMG-CoA reductase inhibitor which is an active ingredient of the present invention is a known method [for example, Japanese Patent Laid-Open No. 57-2240 (US Pat. No. 4,346,227), Japanese Patent Laid-Open No. 57-163374. Publication (U.S. Pat. No. 4231938), JP-A-56-122375 (U.S. Pat. No. 4,444,784), JP-A-60-500015 (U.S. Pat. No. 4739073), JP-A-1 -2169 74 (U.S. Pat. No. 5,0065,30), JP-A-3-58967 (U.S. Pat. No.
  • JP-A-1-279866 U.S. Pat. Nos. 5,854,259 and 5,856,336) Description, JP-A-5-78841 (US Pat. No. 5,260,440), etc.] or a method according to them can be easily produced.
  • An HMG-CoA reductase inhibitor which is an active ingredient of the present invention, is used as a medicine [especially, treatment or prevention of chronic obstructive pulmonary disease, emphysema or chronic bronchitis (preferably chronic obstructive pulmonary disease).
  • a medicine especially, treatment or prevention of chronic obstructive pulmonary disease, emphysema or chronic bronchitis (preferably chronic obstructive pulmonary disease).
  • chronic obstructive pulmonary disease emphysema or chronic bronchitis (preferably chronic obstructive pulmonary disease).
  • a (preferably, therapeutic drug) it can be administered as a raw material, or can be mixed with an appropriate pharmacologically acceptable excipient, binder, etc.
  • a preparation such as tablets, capsules, granules, pills, powders, liquids, syrups lj, troches, suspensions, emulsions, inhalants or aerosols to be manufactured orally or It can be administered parenterally (preferably orally) as a preparation such as injection, suppository or patch prepared in the same manner.
  • compositions are produced by well-known methods using additives such as excipients, binders, disintegrants, lubricants, emulsifiers, stabilizers, flavoring agents, diluents, solvents for injections, and the like.
  • additives such as excipients, binders, disintegrants, lubricants, emulsifiers, stabilizers, flavoring agents, diluents, solvents for injections, and the like.
  • the excipient may be, for example, an organic excipient or an inorganic excipient.
  • Organic excipients include, for example, sugar derivatives such as lactose, sucrose, glucose, mannitol, sorbitol; corn starch, potato starch, alpha-ized starch, dextrin, carboxy Starch derivatives such as methyl starch; crystalline cellulose, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium, internal crosslinking force Cellulose derivatives such as ruboxymethylcellulose sodium; Rubber; dextrane; or pullulan.
  • inorganic excipient examples include silicate derivatives such as light anhydrous silicic acid, synthetic aluminum silicate, calcium silicate, and magnesium magnesium aluminosilicate; phosphates such as calcium phosphate; carbonates such as calcium carbonate; Alternatively, it may be a sulfate such as calcium sulfate.
  • the binder can be, for example, a compound shown in the excipients above; gelatin; polybulurpyrrolidone; or polyethylene glycol.
  • the disintegrant can be, for example, a compound shown in the excipients above; a chemically modified starch or cellulose derivative such as croscarmellose sodium, sodium carboxymethyl starch; or a cross-linked polyvinyl pyrrolidone .
  • Lubricants include, for example, talc; stearic acid; stearic acid metal salts such as calcium stearate and magnesium stearate; colloidal silica; waxes such as veegum and geiro; boric acid; glyconole; DL leucine; Carboxylic acids such as fumaric acid and adipic acid; sodium carboxylates such as sodium benzoate; sulfates such as sodium sulfate; lauryl sulfates such as sodium lauryl sulfate and magnesium lauryl sulfate; silicic anhydride, Silicates such as silicic acid hydrates; or starch derivatives in the above excipients.
  • Examples of the emulsifier include colloidal clays such as bentonite and beegum; metal hydroxides such as magnesium hydroxide and aluminum hydroxide; anionic surfactants such as sodium lauryl sulfate and calcium stearate.
  • a cationic surfactant such as salt benzenoreconium; or a nonionic surfactant such as polyoxyethylene alkyl ether, polyoxyethylene sorbitan fatty acid ester, sucrose fatty acid ester .
  • Stabilizers include, for example, parahydroxybenzoic acid esterols such as methylparaben and propylparaben; alcohols such as chlorobutanol and pendinoleanolenoconole; It can be phenols such as phenol, talesol; thimerosal; acetic anhydride; or sorbic acid.
  • the corrigent can be, for example, commonly used sweeteners, acidulants, fragrances and the like.
  • the diluent can be, for example, water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, or polyoxyethylene sorbitan fatty acid esters.
  • the solvent for injection can be, for example, water, ethanol, or glycerin.
  • the HMG_CoA reductase inhibitor which is an active ingredient of the present invention, can be administered to warm-blooded animals (particularly humans).
  • the dose varies depending on the patient's symptoms, age, etc., but in the case of oral administration, each dose has a lower limit of 0. Olmg / kg (preferably 0.05 mg / kg) and an upper limit of 500 mg / kg ( 100 mg / kg), preferably for parenteral administration, the lower limit is 0.002 mg / kg (preferably 0. Olmg / kg) and the upper limit is 100 mg / kg (preferably 20 mg).
  • / kg) can be administered to adults 1 to 6 times daily depending on symptoms.
  • the HMG-CoA reductase inhibitor which is an active ingredient of the present invention, exhibits excellent action in terms of improving lung function and histological improvement of lung and bronchial epithelial cells. It is useful as a medicament for the treatment or prevention (preferably treatment) of chronic obstructive pulmonary disease, emphysema or chronic bronchitis (preferably chronic obstructive pulmonary disease).
  • chronic obstructive pulmonary disease emphysema or chronic bronchitis (preferably chronic obstructive pulmonary disease).
  • FIG. 1 (FIG. 1A) Enlarged view of lung tissue; (FIG. 1B) Average alveolar diameter.
  • FIG. 2 (FIG. 2A) Lung volume; (FIG. 2B) Static lung compliance.
  • Example 1 The test described in Example 1 was performed with reference to the following documents 1 and 2.
  • Reference 1 Snider GL, Lucey EC, Stone PJ., Am. Rev. Respir. Dis “1986, 133, 149-1
  • a rat pulmonary emphysema model was prepared by intratracheal administration of porcine knee elastase (600 U / kg) according to the method described in Reference 1. Rats were orally administered pravastatin (50 mg / kg / day) or distilled water continuously for 4 weeks.
  • the lung volume of the rat was measured under the condition of an intrapulmonary pressure difference of 25 cmH0.
  • Lung compliance was also measured using a small animal ventilator (flexiVent; Scireq, Montreal, PQ, Canada). Lung compliance is an indicator of how easily the lungs grow, and the higher the value, the lower the lung function.
  • FIG. 1B shows mean alveolar diameter
  • FIG. 2A shows lung volume
  • FIG. 2B shows static lung compliance.
  • “Sham” indicates a group not administered with elastase (hereinafter referred to as “Sham group”)
  • “E1 astase” indicates a group administered with distilled water (hereinafter referred to as “Elastase group”).
  • “/ statin” indicates a group to which pravastatin was administered (hereinafter referred to as “Elastase / statin group”).
  • emphysema changes were induced in the lung by intratracheal injection of elastase.
  • the HMG-CoA reductase inhibitor which is an active ingredient of the present invention, has an inhibitory effect on the increase in mean alveolar diameter, lung volume, and static lung compliance. Therefore, the HMG_CoA reductase inhibitor, which is an active ingredient of the present invention, exhibits excellent effects in terms of improving lung function and histological improvement of lung and bronchial epithelial cells. It is useful as a medicament for the treatment or prevention (preferably treatment) of chronic obstructive pulmonary disease, emphysema or chronic bronchitis (preferably chronic obstructive pulmonary disease).
  • the obtained kneaded material is dried at 60 ° C for 1 hour with a ventilation dryer.
  • the resulting dried product is sized with a power mill (Dalton) fitted with a ⁇ lmm screen, and 129.35 parts of the resulting condylar grains and 0.65 parts of magnesium stearate (Japanese fats and oils) are mixed into a V-shaped mixer (Tokuju Seisakusho). Mix with.
  • the obtained mixture is tableted to produce a 7.0 mm diameter tablet.
  • Pravastatin sodium eg, aerosol propellants (eg, chlorofluorocarbons such as trichlorodifluoromethane and dichlorodifluoromethane), and optionally surfactants (eg, benzanolonium chloride) And prepared by well-known methods (for example, EP 556239). For example, it is as follows.
  • aerosol propellants eg, chlorofluorocarbons such as trichlorodifluoromethane and dichlorodifluoromethane
  • surfactants eg, benzanolonium chloride
  • Suspension obtained by mixing pravastatin sodium 0.005 part, sorbitan trioleate 0.1 part, and a mixture of monochloromethane and dichlorodifluoromethane (mixing ratio: 2/3; total 99.895 parts) Is injected into an aerosol container having a dosing valve.
  • the amount of one ejection is preferably 50 ⁇ 1.
  • the proportion of pravastatin sodium increases or decreases accordingly The power to do S.
  • HMG_CoA reductase inhibitor which is an active ingredient of the present invention, exhibits excellent effects in improving lung function and histological improvement of lung and bronchial epithelial cells, chronic obstructive pulmonary disease It is useful as a medicament for the treatment or prevention (preferably treatment) of emphysema or chronic bronchitis (preferably chronic obstructive pulmonary disease).

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Diabetes (AREA)
  • Obesity (AREA)
  • Hematology (AREA)
  • Emergency Medicine (AREA)
  • Pulmonology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Disclosed is a pharmaceutical composition for treatment or prevention of chronic obstructive pulmonary diseases. The pharmaceutical composition contains an HMG-CoA reductase inhibitor as an active ingredient.

Description

明 細 書  Specification

スタチンによる慢性閉塞性肺疾患治療  Treatment of chronic obstructive pulmonary disease with statins

技術分野  Technical field

[0001] 本発明は、 HMG_CoA還元酵素阻害剤を有効成分として含有する慢性閉塞性 肺疾患、肺気腫または慢性気管支炎の治療もしくは予防のための医薬、および、 H MG_CoA還元酵素阻害剤の薬理的に有効な量を温血動物（特に、ヒト）に投与す ることによる慢性閉塞性肺疾患、肺気腫または慢性気管支炎の治療もしくは予防の ための方法に関する。  [0001] The present invention relates to a medicament for the treatment or prevention of chronic obstructive pulmonary disease, emphysema or chronic bronchitis comprising an HMG_CoA reductase inhibitor as an active ingredient, and a pharmacologically of an HMG_CoA reductase inhibitor The present invention relates to a method for treating or preventing chronic obstructive pulmonary disease, emphysema or chronic bronchitis by administering an effective amount to a warm-blooded animal (particularly a human).

背景技術  Background art

[0002] 慢性閉塞性肺疾患（chronic obstructive pulmonary disease: COPD；以下、 COPDと もいう）は、肺組織の破壊により特徴づけられる肺気腫、気管支における粘液分泌の 亢進により特徴づけられる慢性気管支炎、および、不可逆的で持続的な気道閉塞の 組み合わせにより生じる病態であり、可逆的な気道閉塞として定義される喘息とは明 確に区別される（Nippon Rinsyo,第 61卷，第 12号， p.2058-2070) 0 COPDは、慢性の 咳、痰および呼吸困難を主症状とし、肺機能の低下および体重減少等の症状を伴う (Boer, W. I.， Expert Opin. Investig. Drugs, 2003年，第 12卷，第 7号， p.1067- 1086 ; Jeifery, P. Κ·, Respir. Crit. Care Med., 2001年，第 164卷， p.s28_s38等）。種々の医 薬の COPDへの適用が研究されている力 確立された COPDの治療薬は未だ見出さ れておらず、副作用の少ないより有効な COPDの治療薬の開発が望まれている (Alsa eedi, Α·ら., Am. J. Med., 2002年，第 113卷， ρ·59_65等）。 [0002] Chronic obstructive pulmonary disease (COPD; hereinafter also referred to as COPD) is emphysema characterized by destruction of lung tissue, chronic bronchitis characterized by increased mucus secretion in the bronchi, and This condition is caused by a combination of irreversible and persistent airway obstruction and is clearly distinguished from asthma, which is defined as reversible airway obstruction (Nippon Rinsyo, 61 卷, 12, p.2058). -2070) 0 COPD is mainly caused by chronic cough, sputum and dyspnea, with symptoms such as decreased lung function and weight loss (Boer, WI, Expert Opin. Investig. Drugs, 2003, 12th) , No. 7, p.1067-1086; Jeifery, P. IV, Respir. Crit. Care Med., 2001, No. 164, p.s28_s38, etc.). The ability to study the application of various medicines to COPD No established treatment for COPD has yet been found, and the development of a more effective treatment for COPD with fewer side effects is desired (Alsa eedi , J. et al., Am. J. Med., 2002, No. 113, ρ · 59_65, etc.).

[0003] (3—ヒドロキシ _ 3—メチルダルタリル _CoA)還元酵素阻害剤（以下、 HMG— C oA還元酵素阻害剤という）は、高脂血症治療薬としてよく知られている（例えば、特 許文献 1参照）。代表的な HMG_CoA還元酵素阻害剤であるプラバスタチンは、高 脂血症患者を対象とした臨床試験において、動脈硬化症、冠状動脈疾患および糖 尿病の発症抑制効果 (予防効果)を示すことが報告されてレ、る (例えば、非特許文献 1乃至 3参照）。し力 ながら、プラバスタチンのような HMG— CoA還元酵素阻害剤 力 COPDの治療もしくは予防効果を示すことは、知られていない。 [0004] 特許文献 1：米国特許第 4346227号明細書 [0003] (3-Hydroxy_3-methyldartalyl_CoA) reductase inhibitors (hereinafter referred to as HMG-CoA reductase inhibitors) are well known as therapeutic agents for hyperlipidemia (for example, patent literature). 1). It is reported that pravastatin, a representative HMG_CoA reductase inhibitor, has an inhibitory effect (preventive effect) on the development of arteriosclerosis, coronary artery disease, and diabetes in clinical trials for hyperlipidemic patients. (See Non-Patent Documents 1 to 3, for example). However, HMG-CoA reductase inhibitors such as pravastatin have not been known to show therapeutic or preventive effects on COPD. [0004] Patent Document 1: US Pat. No. 4,346,227

非特許文献 l : MacMahon, S.ら， Circulation, 1998年，第 97卷， .1784-1790.  Non-patent literature l: MacMahon, S. et al., Circulation, 1998, 97th, .1784-1790.

非特許文献 2： Sh印 herd, J.ら， Lancet, 2002年,第 360卷， p.1623- 1630.  Non-patent document 2: Sh seal herd, J. et al., Lancet, 2002, 360, pp.1623- 1630.

非特許文献 3： Freeman, D. J.ら， Circulation, 2001年,第 103卷, p.357- 362.  Non-Patent Document 3: Freeman, D. J. et al., Circulation, 2001, 103, p.357-362.

発明の開示  Disclosure of the invention

発明が解決しょうとする課題  Problems to be solved by the invention

[0005] 本発明者らは、 COPDの治療もしくは予防のための医薬について鋭意研究を行レ、、 HMG— CoA還元酵素阻害剤力 肺機能の改善、ならびに、肺および気管支の上 皮細胞の組織学的改善等の点において優れた作用を示すことから、慢性閉塞性肺 疾患、肺気腫または慢性気管支炎 (好適には、慢性閉塞性肺疾患）の治療もしくは 予防 (好適には、治療）のための医薬として有用であることを見出した。本発明は、上 記の知見に基づき完成された。 [0005] The present inventors have conducted intensive research on drugs for the treatment or prevention of COPD, HMG-CoA reductase inhibitor power, improvement of lung function, and tissue of lung and bronchial epithelial cells Because of its excellent effects in terms of clinical improvement, etc., it can be used for the treatment or prevention (preferably treatment) of chronic obstructive pulmonary disease, emphysema or chronic bronchitis (preferably chronic obstructive pulmonary disease). It was found useful as a pharmaceutical. The present invention has been completed based on the above findings.

課題を解決するための手段  Means for solving the problem

[0006] 本発明は、 [0006] The present invention provides:

(1) HMG— CoA還元酵素阻害剤を有効成分として含有する慢性閉塞性肺疾患、 肺気腫または慢性気管支炎の治療もしくは予防のための医薬、  (1) HMG—medicine for treating or preventing chronic obstructive pulmonary disease, emphysema or chronic bronchitis, comprising a CoA reductase inhibitor as an active ingredient,

(2) HMG— CoA還元酵素阻害剤を有効成分として含有する慢性閉塞性肺疾患の 治療もしくは予防のための医薬、  (2) HMG—medicine for treating or preventing chronic obstructive pulmonary disease containing a CoA reductase inhibitor as an active ingredient,

(3) HMG— CoA還元酵素阻害剤力 プラバスタチン、ロバスタチン、シンパスタチン 、フルパスタチン、セリバスタチン、アトルバスタチン、ピタパスタチン、および、ロスバ スタチンからなる群より選択される（1)または（2)に記載された医薬、または、  (3) HMG—CoA reductase inhibitor power described in (1) or (2) selected from the group consisting of pravastatin, lovastatin, sympastatin, flupastatin, cerivastatin, atorvastatin, pitapastatin, and rosuvastatin Medicine, or

(4) HMG_CoA還元酵素阻害剤力 プラバスタチンである（1)または（2)に記載さ れた医薬を提供する。  (4) HMG_CoA reductase inhibitor power The drug according to (1) or (2), which is pravastatin, is provided.

[0007] 本発明は、また、  [0007] The present invention also provides

(5) HMG— CoA還元酵素阻害剤の薬理学的に有効な量を温血動物に投与するこ とによる慢性閉塞性肺疾患、肺気腫または慢性気管支炎の治療もしくは予防のため の方法、  (5) HMG— a method for the treatment or prevention of chronic obstructive pulmonary disease, emphysema or chronic bronchitis by administering a pharmacologically effective amount of a CoA reductase inhibitor to a warm-blooded animal,

(6) HMG— CoA還元酵素阻害剤の薬理的に有効な量を温血動物に投与すること による慢性閉塞性肺疾患の治療もしくは予防のための方法、 (6) Administering a pharmacologically effective amount of an HMG-CoA reductase inhibitor to a warm-blooded animal A method for the treatment or prevention of chronic obstructive pulmonary disease by

(7) HMG— CoA還元酵素阻害剤力 プラバスタチン、ロバスタチン、シンパスタチン 、フルパスタチン、セリバスタチン、アトルバスタチン、ピタパスタチン、および、ロスバ スタチンからなる群より選択される（5)または（6)に記載された方法、  (7) HMG—CoA reductase inhibitor power described in (5) or (6) selected from the group consisting of pravastatin, lovastatin, sympastatin, flupastatin, cerivastatin, atorvastatin, pitapastatin, and rosuvastatin Method,

(8) HMG_CoA還元酵素阻害剤力 プラバスタチンである（5)または（6)に記載さ れた方法、  (8) HMG_CoA reductase inhibitor power The method described in (5) or (6), which is pravastatin,

(9)温血動物が、ヒトである（5)乃至（8)のレ、ずれかに記載された方法、  (9) The method according to any one of (5) to (8), wherein the warm-blooded animal is a human,

(10)慢性閉塞性肺疾患、肺気腫または慢性気管支炎の治療もしくは予防のための 医薬を製造するための HMG_CoA還元酵素阻害剤の使用、  (10) Use of an HMG_CoA reductase inhibitor for the manufacture of a medicament for the treatment or prevention of chronic obstructive pulmonary disease, emphysema or chronic bronchitis,

(11)慢性閉塞性肺疾患の治療もしくは予防のための医薬を製造するための HMG 一 CoA還元酵素阻害剤の使用、  (11) Use of an HMG-CoA reductase inhibitor for the manufacture of a medicament for the treatment or prevention of chronic obstructive pulmonary disease,

(12) HMG— CoA還元酵素阻害剤力 プラバスタチン、ロバスタチン、シンパスタチ ン、フルパスタチン、セリバスタチン、アトルバスタチン、ピタパスタチン、および、ロス パスタチンからなる群より選択される（10)または（11)に記載された使用、または、 (12) HMG—CoA reductase inhibitor power described in (10) or (11) selected from the group consisting of pravastatin, lovastatin, sympastatin, flupastatin, cerivastatin, atorvastatin, pitapastatin, and rospastatin Use or

(13) HMG CoA還元酵素阻害剤が、プラバスタチンである（ 10)または（ 11 )に記 載された使用 (13) The use described in (10) or (11), wherein the HMG CoA reductase inhibitor is pravastatin

を提供する。 I will provide a.

本発明の有効成分である HMG— CoA還元酵素阻害剤は、 HMG— CoA還元酵 素阻害作用を示す化合物であれば、特に限定はなぐ例えば、特開昭 57-2240号公 報（米国特許第 4346227号明細書）、特開昭 57-163374号公報（米国特許第 4231938 号明細書）、特開昭 56-122375号公報（米国特許第 4444784号明細書）、特開昭 60-5 00015号公報（米国特許第 4739073号明細書）、特開平 1-216974号公報（米国特許 第 5006530号明細書）、特開平 3-58967号公報（米国特許第 5273995号明細書）、特 開平 1-279866号公報（米国特許第 5854259号及び第 5856336号明細書）、または、 特開平 5-178841号公報（米国特許第 5260440号明細書）に記載された、 HMG— Co A還元酵素阻害作用を有する化合物またはそれらの薬理上許容される塩もしくはェ ステルであり得、好適には、プラバスタチン、ロバスタチン、シンパスタチン、フルバス タチン、セリバスタチン、アトノレパスタチン、ピタパスタチン、または、ロスパスタチンで あり、より好適には、プラバスタチンまたはロスパスタチンであり、最も好適には、ブラ パスタチンである。 The HMG-CoA reductase inhibitor, which is an active ingredient of the present invention, is not particularly limited as long as it is a compound exhibiting an HMG-CoA reductase inhibitory action. No. 4346227), JP-A-57-163374 (U.S. Pat. No. 4231938), JP-A-56-122375 (U.S. Pat. No. 4,444,784), JP-A-60-5 00015 Publication (U.S. Pat. No. 4739073), JP-A-1-216974 (U.S. Pat. No. 5,006530), JP-A-3-58967 (U.S. Pat. No. 5,527,995), JP-A 1-279866 No. 5854259 and US Pat. No. 5,856,336, or Japanese Patent Application Laid-Open No. 5-178841 (US Pat. No. 5,260,440), a compound having an inhibitory action on HMG-Co A reductase Or a pharmacologically acceptable salt or ester thereof, preferably pravastatin, lovastatin , Sympastatin, fluvastatin, cerivastatin, atonolepastatin, pitapastatin, or rospastatin Yes, more preferably pravastatin or rospastatin, most preferably brapastatin.

プラバスタチンは、特開昭 57-2240号公報 (米国特許第 4346227号明細書）に記載 された、（+)_(3尺，51¾_3,5_ジヒドロキシ_7_[(13,23,63，83,8&1¾_6_ヒドロキシ-2-メチル-8 _[(S)-2-メチルブチリルォキシ ]-l，2，6,7,8,8a -へキサヒドロ- 1-ナフチノレ]ヘプタン酸で あり、その薬理上許容される塩もしくはエステル (例えば、上記プラバスタチンのーナ トリウム塩等）を包含する。口パスタチンは、特開昭 57-163374号公報 (米国特許第 42 31938号明細書）に記載された、（+)-(lS,3R,7S，8S,8aR)-l,2,3，7，8，8a-へキサヒドロ- 3, 7-ジメチル -8-[2- [(2R,4R)_テトラヒドロ- 4-ヒドロキシ -6-ォキソ -2H-ピラン- 2-ィル]ェ チル] _1_ナフチル （S)_2 -メチルブチレートであり、その薬理上許容される塩もしくは エステルを包含する。シンパスタチンは、特開昭 56-122375号公報（米国特許第 4444 784号明細書）に記載された、（+)-(lS,3R,7S，8S,8aR)-l,2,3，7，8，8a-へキサヒドロ- 3,7- ジメチル -8-[2-[(2R,4R)_テトラヒドロ- 4-ヒドロキシ -6-ォキソ -2H-ピラン- 2-ィル]ェチ ノレ] -1-ナフチル 2,2-ジメチルブチレートであり、その薬理上許容される塩もしくはェ ステルを包含する。フルパスタチンは、特開昭 60-500015号公報（米国特許第 473907 3号明細書）に記載された、（±)-(3R*，5S*，6E)-7-[3-(4-フルオロフェニル) -ト (1-メチ ルェチル) -1H-インドール- 2-ィル] -3,5-ジヒドロキシ -6-ヘプテン酸であり、その薬理 上許容される塩もしくはエステル (例えば、上記フルパスタチンの一ナトリウム塩等）を 包含する。セリバスタチンは、特開平 1-216974号公報（米国特許第 5006530号明細 書）に記載された、（3R，5S,6E)-7-[4-(4-フルオロフヱニル) -2,6-ジ -(1-メチルェチル） -5-メトキシメチルビリジン- 3-ィル] -3, 5-ジヒドロキシ -6-ヘプテン酸であり、その薬理 上許容される塩もしくはエステル (例えば、上記セリバスタチンの一ナトリウム塩等）を 包含する。アトルバスタチンは、特開平 3-58967号公報 (米国特許第 5273995号明細 書）に記載された、（3R，5S)_7_[2-(4_フルオロフヱ二ル)- 5_(1-メチルェチル )_3 -フエ ニル -4-フエニルァミノカルボニル -1H-ピロール- 1-ィル ]_3, 5 -ジヒドロキシヘプタン酸 であり、その薬理上許容される塩もしくはエステル (例えば、上記アトルバスタチンの 1 /2カルシウム塩等）を包含する。ピタパスタチンは、特開平 1-279866号公報（米国 特許第 5854259号及び第 5856336号明細書）に記載された、（E)_3，5_ジヒドロキシ _7_[ 4， -(4"-フルオロフェニル )-2 ' -シクロプロピルキノリン- 3 ' -ィル ]-6-ヘプテン酸であり 、その薬理上許容される塩もしくはエステル (例えば、上記ピタパスタチンの 1/2力 ルシゥム塩等）を包含する。ロスパスタチンは、特開平 5-178841号公報（米国特許第 5260440号明細書）に記載された、（+)-(3R,5S)-7-[4_(4_フルオロフヱニル) -6-イソプ 口ピル- 2_(N_メチル -N-メタンスルホニルァミノ)ピリミジン- 5-ィル ]_3,5 -ジヒドロキシ _6 (E)-ヘプテン酸であり、その薬理上許容される塩もしくはエステル (例えば、上記ロス パスタチンの 1/2カルシウム塩等）を包含する。 Pravastatin is described in JP-A-57-2240 (US Pat. No. 4,346,227), (+) _ (3 scale, 51¾_3,5_dihydroxy_7 _ [(13,23,63,83, 8 & 1¾_6_Hydroxy-2-methyl-8 _ [(S) -2-methylbutyryloxy] -l, 2,6,7,8,8a-hexahydro-1-naphthinole] heptanoic acid, and its pharmacology Including acceptable salts or esters (for example, the sodium salt of pravastatin, etc.) Oral pastatin is described in JP-A-57-163374 (US Pat. No. 42 31938), ( +)-(lS, 3R, 7S, 8S, 8aR) -l, 2,3,7,8,8a-Hexahydro-3,7-dimethyl-8- [2-[(2R, 4R) _tetrahydro- 4-hydroxy-6-oxo-2H-pyran-2-yl] ethyl] _1_naphthyl (S) _2-methylbutyrate, including pharmacologically acceptable salts or esters thereof. JP-A-56-122375 (US Pat. No. 4444) (+)-(LS, 3R, 7S, 8S, 8aR) -l, 2,3,7,8,8a-hexahydro-3,7-dimethyl-8- [ 2-[(2R, 4R) _Tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl] ethenole] -1-naphthyl 2,2-dimethylbutyrate, pharmacologically acceptable Flupastatin is described in (±)-(3R *, 5S *, 6E described in JP-A-60-500015 (US Pat. No. 4,473,907 3). ) -7- [3- (4-Fluorophenyl) -to (1-methylethyl) -1H-indole-2-yl] -3,5-dihydroxy-6-heptenoic acid, and its pharmacologically acceptable Salts such as the monosodium salt of flupastatin, etc. Cerivastatin is described in JP-A 1-216974 (US Pat. No. 5,0065,30), (3R, 5S, 6E) -7- [4- (4-Fluorophenyl) -2,6-di- (1-methylethyl) -5-methoxymethyl-bi-lysine - 3-I le] -3, a 5-dihydroxy-6-heptenoic acid includes its pharmacologically acceptable salt or ester (e.g., monosodium salt of cerivastatin, etc.). Atorvastatin is described in JP-A-3-58967 (US Pat. No. 5,527,995) as (3R, 5S) _7_ [2- (4_fluorophenyl) -5_ (1-methylethyl) _3-phenol. Nyl-4-phenylaminocarbonyl-1H-pyrrol-1-yl] _3,5-dihydroxyheptanoic acid, a pharmacologically acceptable salt or ester thereof (for example, 1/2 calcium salt of the above atorvastatin, etc. ). Pitapastatin is described in JP-A-1-279866 (US Pat. Nos. 5,854,259 and 5,856,336), (E) _3,5_dihydroxy_7_ [ 4,-(4 "-fluorophenyl) -2'-cyclopropylquinoline-3'-yl] -6-heptenoic acid, a pharmacologically acceptable salt or ester thereof (for example, 1 / Rospastatin is described in JP-A-5-78841 (US Pat. No. 5,260,440) as (+)-(3R, 5S) -7- [4_ (4 _Fluorophenyl) -6-Isopropylpyr-2_ (N_Methyl-N-methanesulfonylamino) pyrimidin-5-yl] _3,5-dihydroxy _6 (E) -heptenoic acid, its pharmacologically acceptable Salts (eg, ½ calcium salt of the above rospastatin).

[0010] 本発明の「薬理上許容される塩」は、 HMG— CoA還元酵素阻害剤がカルボキシ ル基を有する場合に、塩基と反応させることにより形成される塩を示す。そのような塩 としては、例えば、ナトリウム塩、カリウム塩、リチウム塩のようなアルカリ金属塩、カル シゥム塩、マグネシウム塩のようなアルカリ土類金属塩、アルミニウム塩、鉄塩等の金 属塩；アンモニゥム塩のような無機塩、 t—ォクチルァミン塩、ジベンジルァミン塩、モ ノレホリン塩、ダルコサミン塩、フエニルダリシンアルキルエステル塩、エチレンジァミン 塩、 N—メチルダルカミン塩、グァニジン塩、ジェチルァミン塩、トリエチノレアミン塩、ジ シクロへキシルァミン塩、 N, N'—ジベンジルエチレンジァミン塩、クロ口プロ力イン塩 、プロ力イン塩、ジエタノールアミン塩、 N—ベンジルフエネチルァミン塩、ピぺラジン 塩、テトラメチルアンモニゥム塩、トリス（ヒドロキシメチル）ァミノメタン塩のような有機塩 等のアミン塩；及び、グリシン塩、リジン塩、アルギニン塩、オル二チン塩、グノレタミン 酸塩、ァスパラギン酸塩のようなアミノ酸塩であり得、好適には、アルカリ金属塩であ る。 HMG— CoA還元酵素阻害剤がプラバスタチンである場合、最も好適な塩は、ナ トリウム塩である。 The “pharmacologically acceptable salt” of the present invention refers to a salt formed by reacting with a base when the HMG-CoA reductase inhibitor has a carboxyl group. Examples of such salts include alkali metal salts such as sodium salt, potassium salt and lithium salt, alkaline earth metal salts such as calcium salt and magnesium salt, metal salts such as aluminum salt and iron salt; Inorganic salts such as ammonium salt, t-octylamine salt, dibenzylamine salt, monorephorin salt, darcosamine salt, phenyldaricin alkyl ester salt, ethylenediamin salt, N-methyldalkamine salt, guanidine salt, jetylamine salt, triethinoleamine Salt, dicyclohexylamine, N, N'-dibenzylethylenediamine salt, black pro-in salt, pro-in salt, diethanolamine salt, N-benzylphenethylamine salt, piperazine salt, Organic salts such as tetramethylammonium salt and tris (hydroxymethyl) aminomethane salt Amine salts; and glycine salts, lysine salts, arginine salts, Ol two Chin salt may be a Gunoretamin salts, amino acid salts such as Asuparagin acid salt, preferably, Ru alkali metal salts der. When the HMG-CoA reductase inhibitor is pravastatin, the most preferred salt is the sodium salt.

[0011] 以下に、主な HMG— CoA還元酵素阻害剤の平面構造式を示す。  [0011] The planar structural formulas of main HMG-CoA reductase inhibitors are shown below.

[化 1] [Chemical 1]

Figure imgf000007_0001
Figure imgf000007_0001

シンバス夕チン

Figure imgf000007_0002
Symbus Yu Chin
Figure imgf000007_0002

Figure imgf000008_0001
Figure imgf000008_0001

ピ夕バス夕チン ロスバス夕チン 上記 HMG— CoA還元酵素阻害剤が不正炭素を有する場合には、そのラセミ体、 光学異性体およびそれらの混合物の全ては、本発明の HMG— CoA還元酵素阻害 剤に包含される。また、上記 HMG— CoA還元酵素阻害剤の水和物および溶媒和 物は、本発明の HMG— CoA還元酵素阻害剤に包含される。  When the HMG-CoA reductase inhibitor has an illegal carbon, all of its racemates, optical isomers and mixtures thereof are HMG-CoA reductase inhibitors of the present invention. Is included. In addition, the hydrate and solvate of the above HMG-CoA reductase inhibitor are included in the HMG-CoA reductase inhibitor of the present invention.

[0013] 本発明の有効成分として、 1種の HMG— CoA還元酵素阻害剤を単独で用いるこ とができ、また、 2種以上の HMG— CoA還元酵素阻害剤を用いることもできる。 2種 以上の HMG— CoA還元酵素阻害剤を用いる場合には、同時に用いることもでき、 また、時間を置いて別々に用いることもできる。 [0013] As an active ingredient of the present invention, one type of HMG-CoA reductase inhibitor can be used alone, or two or more types of HMG-CoA reductase inhibitors can be used. When two or more HMG-CoA reductase inhibitors are used, they can be used at the same time, or they can be used separately over time.

本発明において、慢性閉塞性肺疾患は、肺組織の破壊により特徴づけられる肺気 腫、気管支における粘液分泌の亢進により特徴づけられる慢性気管支炎、および、 不可逆的で持続的な気道閉塞の組み合わせにより生じる病態であり、可逆的な気流 閉塞として定義される喘息とは明確に区別される。本発明において、肺気腫は、慢性 閉塞性肺気腫を含み、慢性気管支炎は、呼吸細気管支炎および慢性喘息性気管支 炎を含む。  In the present invention, chronic obstructive pulmonary disease is a combination of pulmonary emphysema characterized by destruction of lung tissue, chronic bronchitis characterized by increased mucus secretion in the bronchi, and irreversible and persistent airway obstruction. It is a condition that arises and is clearly distinguished from asthma, which is defined as reversible airflow obstruction. In the present invention, emphysema includes chronic obstructive emphysema, and chronic bronchitis includes respiratory bronchiolitis and chronic asthmatic bronchitis.

[0014] 現在、 COPDの病態を的確に反映する有効なモデルは多くは知られておらず、エス テラーゼ誘起性肺気腫モデルが最も有効な COPDの病態モデルであると考えられて いる。これまで、 HMG_CoA還元酵素阻害剤（特に、プラバスタチン）が当該モデ ルにおいて有効な作用を示すことは知られていない。また、 HMG— CoA還元酵素 阻害剤の肺疾患への適用が検討されてはレ、る力 用いられてレ、る病態モデル (例え ば、 LPS刺激モデル）はいずれも COPDの病態を的確に反映するものではなぐ示さ れた実験データはいずれも HMG— CoA還元酵素阻害剤の COPDへの適用可能性 を実証または示唆するものではない。本発明は、エステラーゼ誘起性肺気腫モデル において、 HMG_ CoA還元酵素阻害剤（特に、プラバスタチン）が肺機能の改善、 ならびに、肺および気管支の上皮細胞の組織学的改善等の点において、優れた作 用を示すことを初めて示した。すなわち、本発明は、 HMG_ CoA還元酵素阻害剤 の COPDへの適用可能性を初めて実証したものである。 [0014] Currently, many effective models that accurately reflect the pathology of COPD are not known, and the esterase-induced emphysema model is considered to be the most effective pathology model for COPD. To date, it has not been known that HMG_CoA reductase inhibitors (especially pravastatin) show an effective action in the model. In addition, the application of HMG-CoA reductase inhibitors to pulmonary diseases is being investigated, and the Rheo force is used. Neither LPS stimulation model) accurately reflects the pathology of COPD None of the experimental data shown demonstrates or suggests the applicability of HMG-CoA reductase inhibitors to COPD . In the esterase-induced pulmonary emphysema model, the present invention shows that HMG_CoA reductase inhibitor (especially pravastatin) is excellent in improving lung function and histological improvement of epithelial cells of lung and bronchus. For the first time. That is, the present invention demonstrates for the first time the applicability of an HMG_CoA reductase inhibitor to COPD.

[0015] 本発明の有効成分である HMG— CoA還元酵素阻害剤は、公知の方法 [例えば、 特開昭 57-2240号公報 (米国特許第 4346227号明細書）、特開昭 57-163374号公報（ 米国特許第 4231938号明細書）、特開昭 56-122375号公報 (米国特許第 4444784号 明細書）、特開昭 60-500015号公報（米国特許第 4739073号明細書）、特開平 1-2169 74号公報 (米国特許第 5006530号明細書）、特開平 3-58967号公報 (米国特許第 527 3995号明細書）、特開平 1-279866号公報（米国特許第 5854259号及び第 5856336号 明細書）、特開平 5-178841号公報（米国特許第 5260440号明細書)等]またはそれら に準じた方法に従い、容易に製造することができる。  [0015] The HMG-CoA reductase inhibitor which is an active ingredient of the present invention is a known method [for example, Japanese Patent Laid-Open No. 57-2240 (US Pat. No. 4,346,227), Japanese Patent Laid-Open No. 57-163374. Publication (U.S. Pat. No. 4231938), JP-A-56-122375 (U.S. Pat. No. 4,444,784), JP-A-60-500015 (U.S. Pat. No. 4739073), JP-A-1 -2169 74 (U.S. Pat. No. 5,0065,30), JP-A-3-58967 (U.S. Pat. No. 527 3995), JP-A-1-279866 (U.S. Pat. Nos. 5,854,259 and 5,856,336) Description, JP-A-5-78841 (US Pat. No. 5,260,440), etc.] or a method according to them can be easily produced.

[0016] 本発明の有効成分である HMG— CoA還元酵素阻害剤を医薬 [特に、慢性閉塞 性肺疾患、肺気腫または慢性気管支炎 (好適には、慢性閉塞性肺疾患）の治療もし くは予防 (好適には、治療）のための医薬]として使用する場合には、それ自体を原 末として投与することができ、あるいは適宜の薬理上許容される賦形剤、結合剤等と 混合して製造される錠剤、カプセル剤、顆粒剤、丸剤、散剤、液剤、シロップ斉 lj、トロ ーチ剤、懸濁剤、乳剤、吸入剤もしくはエアロゾル剤等の製剤として、経口的に、また は、同様に製造される注射剤、坐剤もしくは貼付剤等の製剤として、非経口的に (好 適には、経口的に）投与することができる。  [0016] An HMG-CoA reductase inhibitor, which is an active ingredient of the present invention, is used as a medicine [especially, treatment or prevention of chronic obstructive pulmonary disease, emphysema or chronic bronchitis (preferably chronic obstructive pulmonary disease). When used as a (preferably, therapeutic drug)], it can be administered as a raw material, or can be mixed with an appropriate pharmacologically acceptable excipient, binder, etc. As a preparation such as tablets, capsules, granules, pills, powders, liquids, syrups lj, troches, suspensions, emulsions, inhalants or aerosols to be manufactured orally or It can be administered parenterally (preferably orally) as a preparation such as injection, suppository or patch prepared in the same manner.

これらの製剤は、賦形剤、結合剤、崩壊剤、滑沢剤、乳化剤、安定剤、矯味矯臭剤 、希釈剤、注射剤用溶剤等の添加剤を用いて、周知の方法で製造される。  These preparations are produced by well-known methods using additives such as excipients, binders, disintegrants, lubricants, emulsifiers, stabilizers, flavoring agents, diluents, solvents for injections, and the like. .

[0017] 賦形剤は、例えば、有機系賦形剤または無機系賦形剤であり得る。有機系賦形剤 は、例えば、乳糖、白糖、ブドウ糖、マンニトール、ソルビトールのような糖誘導体；トウ モロコシデンプン、馬鈴薯デンプン、アルファ一化デンプン、デキストリン、カルボキシ メチルデンプンのようなデンプン誘導体；結晶セルロース、ヒドロキシプロピルセル口 ース、低置換度ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、 カルボキシメチルセルロース、カルボキシメチルセルロースカルシウム、内部架橋力 ルボキシメチルセルロースナトリウムのようなセルロース誘導体；アラビアゴム；デキスト ラン;または、プルランであり得る。無機系賦形剤は、例えば、軽質無水珪酸、合成珪 酸アルミニウム、珪酸カルシウム、メタ珪酸アルミン酸マグネシウムのような珪酸塩誘 導体；リン酸カルシウムのようなリン酸塩；炭酸カルシウムのような炭酸塩；または、硫 酸カルシウムのような硫酸塩であり得る。 [0017] The excipient may be, for example, an organic excipient or an inorganic excipient. Organic excipients include, for example, sugar derivatives such as lactose, sucrose, glucose, mannitol, sorbitol; corn starch, potato starch, alpha-ized starch, dextrin, carboxy Starch derivatives such as methyl starch; crystalline cellulose, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium, internal crosslinking force Cellulose derivatives such as ruboxymethylcellulose sodium; Rubber; dextrane; or pullulan. Examples of the inorganic excipient include silicate derivatives such as light anhydrous silicic acid, synthetic aluminum silicate, calcium silicate, and magnesium magnesium aluminosilicate; phosphates such as calcium phosphate; carbonates such as calcium carbonate; Alternatively, it may be a sulfate such as calcium sulfate.

[0018] 結合剤は、例えば、上記の賦形剤に示された化合物；ゼラチン；ポリビュルピロリド ン；または、ポリエチレングリコールであり得る。  [0018] The binder can be, for example, a compound shown in the excipients above; gelatin; polybulurpyrrolidone; or polyethylene glycol.

崩壊剤は、例えば、上記の賦形剤に示された化合物；クロスカルメロースナトリウム、 カルボキシメチルスターチナトリウムのような化学修飾された、デンプンもしくはセル口 ース誘導体;または、架橋ポリビニルピロリドンであり得る。  The disintegrant can be, for example, a compound shown in the excipients above; a chemically modified starch or cellulose derivative such as croscarmellose sodium, sodium carboxymethyl starch; or a cross-linked polyvinyl pyrrolidone .

[0019] 滑沢剤は、例えば、タルク；ステアリン酸;ステアリン酸カルシウム、ステアリン酸マグ ネシゥムのようなステアリン酸金属塩；コロイドシリカ；ビーガム、ゲイロウのようなヮック ス類；硼酸；グリコーノレ； DLロイシン；フマル酸、アジピン酸のようなカルボン酸類；安 息香酸ナトリウムのようなカルボン酸ナトリウム塩;硫酸ナトリウムのような硫酸塩;ラウリ ル硫酸ナトリウム、ラウリル硫酸マグネシウムのようなラウリル硫酸塩;無水珪酸、珪酸 水和物のような珪酸類;または、上記の賦形剤におけるデンプン誘導体であり得る。  [0019] Lubricants include, for example, talc; stearic acid; stearic acid metal salts such as calcium stearate and magnesium stearate; colloidal silica; waxes such as veegum and geiro; boric acid; glyconole; DL leucine; Carboxylic acids such as fumaric acid and adipic acid; sodium carboxylates such as sodium benzoate; sulfates such as sodium sulfate; lauryl sulfates such as sodium lauryl sulfate and magnesium lauryl sulfate; silicic anhydride, Silicates such as silicic acid hydrates; or starch derivatives in the above excipients.

[0020] 乳化剤は、例えば、ベントナイト、ビーガムのようなコロイド性粘土；水酸化マグネシ ゥム、水酸化アルミニウムのような金属水酸化物；ラウリル硫酸ナトリウム、ステアリン酸 カルシウムのような陰イオン界面活性剤；塩ィ匕ベンザノレコニゥムのような陽イオン界面 活性剤；または、ポリオキシエチレンアルキルエーテル、ポリオキシエチレンソルビタ ン脂肪酸エステル、ショ糖脂肪酸エステルのような非イオン界面活性剤であり得る。  [0020] Examples of the emulsifier include colloidal clays such as bentonite and beegum; metal hydroxides such as magnesium hydroxide and aluminum hydroxide; anionic surfactants such as sodium lauryl sulfate and calcium stearate. A cationic surfactant such as salt benzenoreconium; or a nonionic surfactant such as polyoxyethylene alkyl ether, polyoxyethylene sorbitan fatty acid ester, sucrose fatty acid ester .

[0021] 安定剤は、例えば、メチルパラベン、プロピルパラベンのようなパラヒドロキシ安息香 酸エステノレ類；クロロブタノ一ノレ、ペンジノレアノレコーノレ、フエニノレエチノレアノレコーノレの ようなアルコール類；塩化ベンザルコニゥム；フエノール、タレゾールのようなフエノー ル類；チメロサール；無水酢酸；または、ソルビン酸であり得る。 矯味矯臭剤は、例えば、通常使用される、甘味料、酸味料、香料等であり得る。 希釈剤は、例えば、水、エタノール、プロピレングリコール、エトキシ化イソステアリル アルコール、または、ポリオキシエチレンソルビタン脂肪酸エステル類であり得る。 注射剤用溶剤は、例えば、水、エタノール、または、グリセリンであり得る。 [0021] Stabilizers include, for example, parahydroxybenzoic acid esterols such as methylparaben and propylparaben; alcohols such as chlorobutanol and pendinoleanolenoconole; It can be phenols such as phenol, talesol; thimerosal; acetic anhydride; or sorbic acid. The corrigent can be, for example, commonly used sweeteners, acidulants, fragrances and the like. The diluent can be, for example, water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, or polyoxyethylene sorbitan fatty acid esters. The solvent for injection can be, for example, water, ethanol, or glycerin.

[0022] 本発明の有効成分である HMG_CoA還元酵素阻害剤は、温血動物（特に、ヒト） に投与することができる。その投与量は、患者の症状、年齢等により異なるが、経口 投与の場合には、各々、 1回当たり下限 0. Olmg/kg (好適には、 0. 05mg/kg)、上限 500mg/kg (好適には、 100mg/kg)を、非経口的投与の場合には、 1回当たり下限 0 . 002mg/kg (好適には、 0. Olmg/kg)、上限 100mg/kg (好適には、 20mg/kg)を、 成人に対して、 1日当たり 1乃至 6回、症状に応じて投与することができる。 [0022] The HMG_CoA reductase inhibitor, which is an active ingredient of the present invention, can be administered to warm-blooded animals (particularly humans). The dose varies depending on the patient's symptoms, age, etc., but in the case of oral administration, each dose has a lower limit of 0. Olmg / kg (preferably 0.05 mg / kg) and an upper limit of 500 mg / kg ( 100 mg / kg), preferably for parenteral administration, the lower limit is 0.002 mg / kg (preferably 0. Olmg / kg) and the upper limit is 100 mg / kg (preferably 20 mg). / kg) can be administered to adults 1 to 6 times daily depending on symptoms.

発明の効果  The invention's effect

[0023] 本発明の有効成分である HMG— CoA還元酵素阻害剤は、肺機能の改善、ならび に、肺および気管支の上皮細胞の組織学的改善等の点において優れた作用を示す ことから、慢性閉塞性肺疾患、肺気腫または慢性気管支炎 (好適には、慢性閉塞性 肺疾患）の治療もしくは予防 (好適には、治療）のための医薬として有用である。 本明細書は、本願の優先権の基礎である日本国特許出願、特願 2006- 180282の明 細書および/または図面に記載される内容を包含する。  [0023] The HMG-CoA reductase inhibitor, which is an active ingredient of the present invention, exhibits excellent action in terms of improving lung function and histological improvement of lung and bronchial epithelial cells. It is useful as a medicament for the treatment or prevention (preferably treatment) of chronic obstructive pulmonary disease, emphysema or chronic bronchitis (preferably chronic obstructive pulmonary disease). This specification includes the contents described in the specification and / or drawings of Japanese Patent Application No. 2006-180282, which is the basis of the priority of the present application.

図面の簡単な説明  Brief Description of Drawings

[0024] [図 1] (図 1A)肺組織の拡大図；（図 1B)平均肺胞径。  [FIG. 1] (FIG. 1A) Enlarged view of lung tissue; (FIG. 1B) Average alveolar diameter.

[図 2] (図 2 A)肺容積；（図 2B)静肺コンプライアンス。  [FIG. 2] (FIG. 2A) Lung volume; (FIG. 2B) Static lung compliance.

発明を実施するための最良の形態  BEST MODE FOR CARRYING OUT THE INVENTION

[0025] 以下、実施例および製剤例を挙げて、本発明をさらに詳細に説明するが、本発明 の範囲はこれらに限定されるものではない。 [0025] Hereinafter, the present invention will be described in more detail with reference to Examples and Formulation Examples, but the scope of the present invention is not limited thereto.

実施例 1に記載された試験は、下記の文献 1および 2を参照して行われた。 文献 1 : Snider GL, Lucey EC, Stone PJ.， Am. Rev. Respir. Dis" 1986， 133, 149-1 The test described in Example 1 was performed with reference to the following documents 1 and 2. Reference 1: Snider GL, Lucey EC, Stone PJ., Am. Rev. Respir. Dis "1986, 133, 149-1

69. ; 69.

文献 2 : Hayes JA, Korthy A, Snider GL" J. Pathol., 1975, 117, 1-14. 実施例 1で使用されるプラバスタチンは、特開昭 57-2240号公報（米国特許第 4346 227号明細書）に記載された方法に従って製造することができる。 Reference 2: Hayes JA, Korthy A, Snider GL "J. Pathol., 1975, 117, 1-14. Pravastatin used in Example 1 is disclosed in JP-A-57-2240 (US Pat. No. 4346). 227).

実施例  Example

[0026] (実施例 1)ラット肺気腫モデルを用いた試験  Example 1 Test Using Rat Emphysema Model

(1)方法  (1) Method

試験には雄性ラット 170_220gを用いた。文献 1に記載された方法に従って、豚膝ェ ラスターゼ（600 U/kg)の気管内投与により、ラット肺気腫モデルを作製した。ラットに プラバスタチン (50mg/kg/day)または蒸留水を連続して 4週間、経口投与した。  In the test, 170_220g of male rats were used. A rat pulmonary emphysema model was prepared by intratracheal administration of porcine knee elastase (600 U / kg) according to the method described in Reference 1. Rats were orally administered pravastatin (50 mg / kg / day) or distilled water continuously for 4 weeks.

[0027] ラットの肺容積を肺内外圧較差 25cmH 0の条件下で測定した。また、肺のコンプラ イアンスを小動物用ベンチレーター（flexiVent ; Scireq， Montreal, PQ， Canada)を用 レ、て測定した。肺のコンプライアンスは、肺の伸びやすさを表す指標であり、数値が 大きいほど肺機能が低下していることを示す。 [0027] The lung volume of the rat was measured under the condition of an intrapulmonary pressure difference of 25 cmH0. Lung compliance was also measured using a small animal ventilator (flexiVent; Scireq, Montreal, PQ, Canada). Lung compliance is an indicator of how easily the lungs grow, and the higher the value, the lower the lung function.

[0028] (2)結果 [0028] (2) Results

本試験において肺の形態学的分析および機能分析を行った。図 1Bは、平均肺胞 径を、図 2Aは、肺容積を、図 2Bは、静肺コンプライアンスをそれぞれ示す。図 1およ び 2において、「Sham」は、エラスターゼを投与しない群（以下、 Sham群という）を、「E1 astase」は、蒸留水を投与した群（以下、 Elastase群という）を、「Elastase/statin」は、プ ラバスタチンを投与した群（以下、 Elastase/statin群という）をそれぞれ示す。本試験 においてエラスターゼの気管内注射により肺に肺気腫変化が誘導されたことは、形 態学的分析（図 1Bの中央カラムに示された平均肺胞径の増加）、および、機能分析 ( 図 2Aおよび図 2Bの中央カラムにそれぞれ示された肺容積および静肺コンプライア ンスの増加）により確認された。実験動物へのエラスターゼ等のタンパク質分解酵素 の気管内注射によって肺気腫が誘導されることはこれまでに十分に実証されており（ 文献 1)、また、上記の所見は文献 2に報告されている結果とも一致した。  In this study, lung morphological and functional analyzes were performed. FIG. 1B shows mean alveolar diameter, FIG. 2A shows lung volume, and FIG. 2B shows static lung compliance. In FIGS. 1 and 2, “Sham” indicates a group not administered with elastase (hereinafter referred to as “Sham group”), and “E1 astase” indicates a group administered with distilled water (hereinafter referred to as “Elastase group”). “/ statin” indicates a group to which pravastatin was administered (hereinafter referred to as “Elastase / statin group”). In this study, emphysema changes were induced in the lung by intratracheal injection of elastase. Morphological analysis (increase in mean alveolar diameter shown in the center column of Fig. 1B) and functional analysis (Fig. 2A And increased lung volume and static lung compliance shown in the center column of Figure 2B, respectively. It has been well demonstrated that pulmonary emphysema is induced by intratracheal injection of proteolytic enzymes such as elastase into experimental animals (Reference 1), and the above findings are reported in Reference 2. Both agreed.

[0029] Elastase群では肺胞壁の破壊を伴う気腔拡大の発生が観察され（図 1 Aの中央カラ ム）、平均肺胞径は、 Elastase群では Sham群と比較して有意に増大した力 Elastase/ statin群では Elastase群と比較して有意に縮小した（図 IB)。また、肺容積は、 Elastas e群では Sham群と比較して有意に増大したが、 Elastase/statin群では Elastase群と比 較して有意に縮小し、 Elastase/statin群の肺容積は、 Sham群と同程度であった（図 2 A)。さらに、静肺コンプライアンスは、 Elastase群では Sham群と比較して有意に増大 したが、 Elastase/statin群では Elastase群と比較して有意に縮小した（図 2B)。 [0029] In the Elastase group, airway enlargement accompanied by destruction of the alveolar wall was observed (center column in Fig. 1A), and the average alveolar diameter was significantly increased in the Elastase group compared to the Sham group. The force Elastase / statin group was significantly reduced compared to the Elastase group (Figure IB). The lung volume increased significantly in the Elastas e group compared to the Sham group, but decreased significantly in the Elastase / statin group compared to the Elastase group, and the lung volume in the Elastase / statin group (Fig. 2 A). Furthermore, static lung compliance increased significantly in the Elastase group compared to the Sham group, but decreased significantly in the Elastase / statin group compared to the Elastase group (Figure 2B).

[0030] 以上より本発明の有効成分である HMG— CoA還元酵素阻害剤が、平均肺胞径、 肺容積、および、静肺コンプライアンスの増大の抑制効果を有することが示された。し たがって、本発明の有効成分である HMG_ CoA還元酵素阻害剤は、肺機能の改 善、ならびに、肺および気管支の上皮細胞の組織学的改善等の点において優れた 作用を示すことから、慢性閉塞性肺疾患、肺気腫または慢性気管支炎 (好適には、 慢性閉塞性肺疾患）の治療もしくは予防 (好適には、治療）のための医薬として有用 である。  [0030] From the above, it was shown that the HMG-CoA reductase inhibitor, which is an active ingredient of the present invention, has an inhibitory effect on the increase in mean alveolar diameter, lung volume, and static lung compliance. Therefore, the HMG_CoA reductase inhibitor, which is an active ingredient of the present invention, exhibits excellent effects in terms of improving lung function and histological improvement of lung and bronchial epithelial cells. It is useful as a medicament for the treatment or prevention (preferably treatment) of chronic obstructive pulmonary disease, emphysema or chronic bronchitis (preferably chronic obstructive pulmonary disease).

[0031] (製剤例 1)錠剤  [0031] (Formulation Example 1) Tablet

プラバスタチンナトリウム 10部、乳糖 71.55部、低置換度ヒドロキシプロピルセルロー ス (LH21、信越化学工業） 20部、結晶セルロース（アビセル PH101、旭化成工業） 20 部、および、メタケイ酸アルミン酸マグネシウム（ノイシリン FL2、富士化学工業） 6.5部 をヘンシェルミキサー（三井鉱山）で混合した後、得られた混合物に 10%ヒドロキシプ 口ピルセルロース（日本曹達）水溶液 13部および適量の水を加え、ヘンシェルミキサ 一で練合する。得られた練合物を通気乾燥機で 60°Cで、 1時間乾燥する。得られた 乾燥物を Φ lmmのスクリーンを装着したパワーミル (ダルトン）で整粒して、得られた顆 粒 129.35部およびステアリン酸マグネシウム（日本油脂） 0.65部を V字型ミキサー（徳 寿製作所)で混合する。得られた混合物を打錠して、径 7.0mmの錠剤を製造する。  Pravastatin sodium 10 parts, lactose 71.55 parts, low substituted hydroxypropyl cellulose (LH21, Shin-Etsu Chemical) 20 parts, crystalline cellulose (Avicel PH101, Asahi Kasei Kogyo) 20 parts, and magnesium aluminate metasilicate (Neusilin FL2, Fuji Chemical Industry) After mixing 6.5 parts with a Henschel mixer (Mitsui Mine), add 13 parts of a 10% hydroxypropyl pill cellulose (Nihon Soda) aqueous solution and an appropriate amount of water to the resulting mixture, and knead with a Henschel mixer. . The obtained kneaded material is dried at 60 ° C for 1 hour with a ventilation dryer. The resulting dried product is sized with a power mill (Dalton) fitted with a Φ lmm screen, and 129.35 parts of the resulting condylar grains and 0.65 parts of magnesium stearate (Japanese fats and oils) are mixed into a V-shaped mixer (Tokuju Seisakusho). Mix with. The obtained mixture is tableted to produce a 7.0 mm diameter tablet.

[0032] (製剤例 2)エアロゾル剤  [Formulation Example 2] Aerosol

プラバスタチンナトリウム、エアロゾル用推進剤（例えば、トリクロ口モノフルォロメタン 、ジクロロジフルォロメタンのようなクロ口フルォロカーボン類）、および、必要に応じて 界面活性剤（例えば、塩化ベンザノレコニゥム）を用いて、周知の方法 (例えば、欧州 特許第 556239号明細書)で製造する。例えば、以下のとおりである。  Pravastatin sodium, aerosol propellants (eg, chlorofluorocarbons such as trichlorodifluoromethane and dichlorodifluoromethane), and optionally surfactants (eg, benzanolonium chloride) And prepared by well-known methods (for example, EP 556239). For example, it is as follows.

[0033] プラバスタチンナトリウム 0.005部、ソルビタントリオレエート 0.1部、並びに、トリクロ口 モノフルォロメタンおよびジクロロジフルォロメタンの混合物（混合比： 2/3；計 99.895 部）を混合して得られる懸濁液を投薬バルブを有するエアロゾル容器に注入する。 1 回の噴出量は、好ましくは、 50 μ 1である。プラバスタチンナトリウムの割合は適宜増減 すること力 Sできる。 [0033] Suspension obtained by mixing pravastatin sodium 0.005 part, sorbitan trioleate 0.1 part, and a mixture of monochloromethane and dichlorodifluoromethane (mixing ratio: 2/3; total 99.895 parts) Is injected into an aerosol container having a dosing valve. The amount of one ejection is preferably 50 μ1. The proportion of pravastatin sodium increases or decreases accordingly The power to do S.

本明細書で引用した全ての刊行物、特許および特許出願をそのまま参考として本 明細書にとり入れるものとする。  All publications, patents and patent applications cited herein are incorporated herein by reference in their entirety.

産業上の利用可能性 Industrial applicability

本発明の有効成分である HMG_CoA還元酵素阻害剤は、肺機能の改善、ならび に、肺および気管支の上皮細胞の組織学的改善等の点において優れた作用を示す ことから、慢性閉塞性肺疾患、肺気腫または慢性気管支炎 (好適には、慢性閉塞性 肺疾患）の治療もしくは予防 (好適には、治療）のための医薬として有用である。  Since the HMG_CoA reductase inhibitor, which is an active ingredient of the present invention, exhibits excellent effects in improving lung function and histological improvement of lung and bronchial epithelial cells, chronic obstructive pulmonary disease It is useful as a medicament for the treatment or prevention (preferably treatment) of emphysema or chronic bronchitis (preferably chronic obstructive pulmonary disease).

Claims

請求の範囲 The scope of the claims [I] HMG— CoA還元酵素阻害剤を有効成分として含有する慢性閉塞性肺疾患、肺 気腫または慢性気管支炎の治療もしくは予防のための医薬。  [I] HMG— A pharmaceutical agent for treating or preventing chronic obstructive pulmonary disease, emphysema or chronic bronchitis, comprising a CoA reductase inhibitor as an active ingredient. [2] HMG— CoA還元酵素阻害剤を有効成分として含有する慢性閉塞性肺疾患の治 療もしくは予防のための医薬。  [2] HMG— A drug for the treatment or prevention of chronic obstructive pulmonary disease containing a CoA reductase inhibitor as an active ingredient. [3] HMG— CoA還元酵素阻害剤力 プラバスタチン、ロバスタチン、シンパスタチン、 フルパスタチン、セリバスタチン、アトルバスタチン、ピタパスタチン、および、ロスバス タチンからなる群より選択される請求項 1または 2に記載された医薬。 [3] HMG—CoA reductase inhibitor potency The medicine according to claim 1 or 2, selected from the group consisting of pravastatin, lovastatin, sympastatin, flupastatin, cerivastatin, atorvastatin, pitapastatin, and rosbastatin . [4] HMG— CoA還元酵素阻害剤力 プラバスタチンである請求項 1または 2に記載さ れた医薬。 [4] The pharmaceutical agent according to claim 1 or 2, which is pravastatin, an HMG—CoA reductase inhibitor activity. [5] HMG— CoA還元酵素阻害剤の薬理学的に有効な量を温血動物に投与すること による慢性閉塞性肺疾患、肺気腫または慢性気管支炎の治療もしくは予防のための 方法。  [5] HMG— A method for the treatment or prevention of chronic obstructive pulmonary disease, emphysema or chronic bronchitis by administering a pharmacologically effective amount of a CoA reductase inhibitor to a warm-blooded animal. [6] HMG— CoA還元酵素阻害剤の薬理的に有効な量を温血動物に投与することに よる慢性閉塞性肺疾患の治療もしくは予防のための方法。  [6] HMG— A method for treating or preventing chronic obstructive pulmonary disease by administering to a warm-blooded animal a pharmacologically effective amount of a CoA reductase inhibitor. [7] HMG— CoA還元酵素阻害剤力 プラバスタチン、ロバスタチン、シンパスタチン、 フルパスタチン、セリバスタチン、アトルバスタチン、ピタパスタチン、および、ロスバス タチンからなる群より選択される請求項 5または 6に記載された方法。 [7] HMG—CoA reductase inhibitor power The method according to claim 5 or 6, which is selected from the group consisting of pravastatin, lovastatin, sympastatin, flupastatin, cerivastatin, atorvastatin, pitapastatin, and rosbastatin. . [8] HMG— CoA還元酵素阻害剤力 プラバスタチンである請求項 5または 6に記載さ れた方法。 [8] The method according to claim 5 or 6, wherein HMG—CoA reductase inhibitor is pravastatin. [9] 温血動物が、ヒトである請求項 5乃至 8のいずれかに記載された方法。  [9] The method according to any one of [5] to [8], wherein the warm-blooded animal is a human. [10] 慢性閉塞性肺疾患、肺気腫または慢性気管支炎の治療もしくは予防のための医薬 を製造するための HMG - Co A還元酵素阻害剤の使用。 [10] Use of an HMG-Co A reductase inhibitor for the manufacture of a medicament for the treatment or prevention of chronic obstructive pulmonary disease, emphysema or chronic bronchitis. [II] 慢性閉塞性肺疾患の治療もしくは予防のための医薬を製造するための HMG— C o A還元酵素阻害剤の使用。  [II] Use of an HMG—CoA reductase inhibitor for the manufacture of a medicament for the treatment or prevention of chronic obstructive pulmonary disease. [12] HMG— CoA還元酵素阻害剤力 プラバスタチン、ロバスタチン、シンパスタチン、 フルパスタチン、セリバスタチン、アトルバスタチン、ピタパスタチン、および、ロスバス タチンからなる群より選択される請求項 10または 11に記載された使用。 [13] HMG— CoA還元酵素阻害剤力 プラバスタチンである請求項 10または 11に記載 された使用。 [12] HMG—CoA reductase inhibitor power Use according to claim 10 or 11, selected from the group consisting of pravastatin, lovastatin, sympastatin, flupastatin, cerivastatin, atorvastatin, pitapastatin, and rosbastatin . [13] The use according to claim 10 or 11, which is pravastatin, an HMG—CoA reductase inhibitor power.
PCT/JP2007/062768 2006-06-29 2007-06-26 Treatment of chronic obstructive pulmonary disease by statin Ceased WO2008001752A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP2008522583A JP5336847B2 (en) 2006-06-29 2007-06-26 Treatment of chronic obstructive pulmonary disease with statins

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2006180282 2006-06-29
JP2006-180282 2006-06-29

Publications (1)

Publication Number Publication Date
WO2008001752A1 true WO2008001752A1 (en) 2008-01-03

Family

ID=38845516

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2007/062768 Ceased WO2008001752A1 (en) 2006-06-29 2007-06-26 Treatment of chronic obstructive pulmonary disease by statin

Country Status (2)

Country Link
JP (1) JP5336847B2 (en)
WO (1) WO2008001752A1 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2021024825A (en) * 2019-08-06 2021-02-22 国立大学法人京都大学 Mucociliary clearance function improver

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20060004834A (en) * 2004-07-10 2006-01-16 이상도 Pharmaceutical composition for the prevention and treatment of chronic obstructive pulmonary disease containing simvastatin as an active ingredient
WO2006008437A1 (en) * 2004-07-15 2006-01-26 Astrazeneca Ab Combinations of stattins with bronchodilators

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP4607436B2 (en) * 2002-08-02 2011-01-05 第一三共株式会社 Pharmaceutical composition containing an HMG-CoA reductase inhibitor

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20060004834A (en) * 2004-07-10 2006-01-16 이상도 Pharmaceutical composition for the prevention and treatment of chronic obstructive pulmonary disease containing simvastatin as an active ingredient
WO2006008437A1 (en) * 2004-07-15 2006-01-26 Astrazeneca Ab Combinations of stattins with bronchodilators

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
MORIMOTO K. ET AL.: "Lovastatin Enhances Clearance of Apoptotis Cells (Efferocytosis) with Implications for Chronic Obstructive Pulmonary Disease", JOURNAL OF IMMUNOLOGY, vol. 176, no. 12, 15 June 2006 (2006-06-15), pages 7657 - 7665, XP003020325 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2021024825A (en) * 2019-08-06 2021-02-22 国立大学法人京都大学 Mucociliary clearance function improver

Also Published As

Publication number Publication date
JPWO2008001752A1 (en) 2009-11-26
JP5336847B2 (en) 2013-11-06

Similar Documents

Publication Publication Date Title
ES2489265T3 (en) Association of HMG-CoA reductase inhibitors atorvastatin or simvastatin with a phosphodiesterase 4 inhibitor, such as roflumilast for the treatment of inflammatory lung diseases
KR101244508B1 (en) Remedy for hyperlipemia
JP5722034B2 (en) Stable pharmaceutical composition comprising one or more HMG-CoA reductase inhibitors
TWI290833B (en) Therapeutic agent for glomerular disease
WO2008001752A1 (en) Treatment of chronic obstructive pulmonary disease by statin
WO2021207271A1 (en) Organoselenide glutathione peroxidase mimetics for the treatment of inflammatory pulmonary disorders
CN102351771A (en) Atorvastatin calcium compound with high bioavailability
CN108778286A (en) Medicine for treating diabetic foot infection
AU2004233691B2 (en) Sugar intake-ability enhancer
WO2006006021A2 (en) Stabilized pharmaceutical compositions of preferably a statin
JP4892477B2 (en) Novel triglyceride lowering agent
AU2004233693B2 (en) Adiponectin production enhancer
JP2002145774A (en) Pharmaceutical composition
WO2002020009A1 (en) Medicinal compositions
WO2004014427A1 (en) Medicinal composition for lowering blood lipid level
AU2013203070B2 (en) Combination of HMG-CoA reductase inhibitors with phosphodiesterase 4 inhibitors for the treatment of inflammatory pulmonary diseases
TW201206430A (en) Association of xanthine oxidase inhibitors and statins and use thereof
WO2004012740A1 (en) MEDICINAL COMPOSITION CONTAINING HMG-CoA REDUCTASE INHIBITOR
US20060223882A1 (en) Amorphous simvastatin
EA009918B1 (en) Pharmaceutical compositions comprising higher primary aliphatic alcohols and hmg coa reductase inhibitor and process of preparation thereof
WO2006011551A1 (en) Pharmaceutical composition having anti-arteriosclerosis potency
JP2005232151A (en) Sugar uptake ability-reinforcing agent
CN1481240A (en) antilipidemic agent
JP2019131472A (en) Pharmaceutical composition
JP2006063066A (en) Medicinal composition having anti-arteriosclerotic action

Legal Events

Date Code Title Description
DPE2 Request for preliminary examination filed before expiration of 19th month from priority date (pct application filed from 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 07767574

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 2008522583

Country of ref document: JP

NENP Non-entry into the national phase

Ref country code: DE

NENP Non-entry into the national phase

Ref country code: RU

122 Ep: pct application non-entry in european phase

Ref document number: 07767574

Country of ref document: EP

Kind code of ref document: A1