WO2004041309A1 - Medicaments comprenant une combinaison d'un inhibiteur de l'elastase et d'un inhibiteur enzymatique du systeme de coagulation sanguine et/ou du systeme de fibrinolyse - Google Patents

Medicaments comprenant une combinaison d'un inhibiteur de l'elastase et d'un inhibiteur enzymatique du systeme de coagulation sanguine et/ou du systeme de fibrinolyse Download PDF

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WO2004041309A1
WO2004041309A1 PCT/JP2003/014198 JP0314198W WO2004041309A1 WO 2004041309 A1 WO2004041309 A1 WO 2004041309A1 JP 0314198 W JP0314198 W JP 0314198W WO 2004041309 A1 WO2004041309 A1 WO 2004041309A1
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group
blood coagulation
sodium
formula
fibrinolytic enzyme
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PCT/JP2003/014198
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English (en)
Japanese (ja)
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Kazuhito Kawabata
Shigeru Matsumoto
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Ono Pharmaceutical Co., Ltd.
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Priority to AU2003277608A priority Critical patent/AU2003277608A1/en
Publication of WO2004041309A1 publication Critical patent/WO2004041309A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K31/222—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin with compounds having aromatic groups, e.g. dipivefrine, ibopamine
    • 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
    • A61K31/275—Nitriles; Isonitriles
    • 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
    • A61K31/435—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
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • 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
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4535—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom, e.g. pizotifen
    • 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
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • 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
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
    • A61K31/727—Heparin; Heparan
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors

Definitions

  • the present invention relates to a medicament comprising a combination of an elastase inhibitor and a blood coagulation and / or fibrinolytic enzyme inhibitor.
  • Equation (I A) For more information, see Equation (I A)
  • An abrotin derivative, an antithrombin II derivative, a heparin derivative, a danapaide sodium, a hirudin derivative, a toguchi nbomodulin derivative relates to a medicament comprising a combination of a blood coagulation system selected from sulfated saccharides or nontoxic salts thereof and a Z or fibrinolytic enzyme inhibitor.
  • a blood coagulation system selected from sulfated saccharides or nontoxic salts thereof and a Z or fibrinolytic enzyme inhibitor.
  • DIC generalized intravascular blood coagulation
  • Factors that lead to various organ damage include macrophages (neutrophil elastase derived from immune cells such as neutrophils, various cytokines), blood containing coagulation enzymes such as complement system enzymes, thrombin and plasmin, and fibrinolytic enzymes. Origin factors are considered.
  • Neutrophil elastase is capable of degrading not only elastin, collagen, proteodalican, and other components of the biomatrix, but also various enzymes of the capture system, coagulation and fibrinolysis, and acute lung injury frequently occurs in sepsis. In addition to causing neutrophils, it may play an important role in neutrophil injury to various organs. On the other hand, thrombin, plasmin, and C1-esterase not only cause thrombus formation and hemorrhage associated with DIC, but also activate complement, form various types of organs such as lungs, liver, and kidneys through microthrombus formation in various organs. May play an important role in ischemic injury in children.
  • the present inventors have proposed a combination of an elastase inhibitor and a blood coagulation or Z or fibrinolytic enzyme inhibitor to prevent not only acute lung injury and DIC associated with sepsis but also multiple organ disorders such as liver and kidney. And Z or treatment, and expected to have an excellent effect on improving the prognosis of patients, and found that effect, and completed the present invention.
  • the compound represented by formula (IA) inhibits human neutrophil elastase, and can be used as a prophylactic and therapeutic agent for pulmonary emphysema, atherosclerosis, rheumatoid arthritis, etc. Has been suggested (EP 347168).
  • a pharmaceutical composition of the compound represented by the formula (IA) and active protein C (hereinafter abbreviated as APC) is useful as a therapeutic agent for inflammatory disease or respiratory disease ( WO01 / 49315).
  • APC active protein C
  • sPLA 2 secreted phospholipase 2
  • sPLA 2 secreted phospholipase 2
  • the present inventors have conducted intensive studies in view of the above problems, and have found that the combination of an elastase inhibitor and a blood coagulation-type or Z- or fibrinolysis-type enzyme inhibitor has a new utility (only acute lung injury associated with sepsis or DIC).
  • the present inventors have found a medicament that shows excellent prevention and / or treatment of polyvisceral disorders such as liver and kidney, and an excellent improvement in the prognosis of patients, and completed the present invention.
  • the combination administration of these inhibitors has never been attempted and is a novel combination.
  • the present invention is summarized as follows.
  • the medicament comprising the combination of the elastase inhibitor of the present invention and a blood coagulation and / or fibrinolytic enzyme inhibitor has excellent action for preventing and / or treating acute lung injury and Z or DIC.
  • the present invention was found to be useful for preventing and treating Z or treating multiple organ disorders such as liver and kidney, and to improve the prognosis of z or patients.
  • a medicament comprising a combination of an elastase inhibitor and a blood coagulation or Z or fibrinolytic enzyme inhibitor
  • a pharmaceutical composition comprising, as an active ingredient, a combination of an elastase inhibitor and a blood coagulation and / or fibrinolytic enzyme inhibitor;
  • the elastase inhibitor has the formula (IA)
  • Y A is a sulfone / lefonyl (1-SO 2 —) group or Represents a group
  • R 1A and R 2A may be the same or different; (1) a hydrogen atom, (2) a C 1-16 alkyl group or (3)
  • X A represents a single bond, sulfo - Le (one 30 2 -) group, Ji 1-4 alkylene group one COOH group or base Nji / Les oxy Cal Poeru,
  • ⁇ ⁇ represents an integer of 1 to 5
  • 1 4 or 11 may be the same or different in the case of 2-5, respectively (a) a hydrogen atom or a C. 1 to 8 alkyl group,
  • R 43A represents a hydrogen atom, a C 1-4 alkyl group or an oenbenzyl group; ), A group represented by
  • R 45A represents a C 1-8 alkyl group or a p-gudinophenol group
  • R 47A represents a single bond or a C 1-4 alkyl group
  • R 48A represents a hydrogen atom or a C 1-4 alkyl group
  • R 49A is a hydroxyl group, a Cl-4 alkoxy group, an amino group, one or two C 1
  • R 47 A and R 49 A have the same meaning as described above. ).
  • R 1A and R 2A together with the nitrogen atom to which they are attached, are a heterocycle containing at least one nitrogen atom substituted with one COOH or unsubstituted Represents a heterocycle containing at least one nitrogen atom,
  • mA represents an integer of 1 force
  • R 3A may be the same or different when mA is 2 to 4, and each represents (1) a hydrogen atom, (2) a hydroxy group, (3) a C 1-6 alkyl group, and (4) a halogen atom. , (5) a C 1-4 alkoxy group, or (6) a C 2-5 alkoxy group. Or the non-toxic salt thereof, the medicament according to the above [I],
  • a blood coagulation and / or fibrinolytic enzyme inhibitor has the formula ( ⁇ )
  • X B is a hydrogen atom, a halogen atom, nitro, alkyl, alkoxy, force Norebokishi, hydroxy, Kano repo ethoxy, 6-guaiacolsulfonate - representing the Gino Cap Roy Honoré group. 6-Gua-dinocaproic acid fuel ester derivative Or the non-toxic salt thereof, the medicament according to the above [I],
  • a blood coagulation and Z or fibrinolytic enzyme inhibitor has the formula (nc)
  • a c 0, or an integer from 1 to 3,
  • R 3C represents a C 1-4 linear or branched alkyl group, a C 3-6 cycloalkyl group,
  • R 4C represents a hydrogen atom, a C 1-4 linear or branched alkyl group
  • R 1C or R 2C are the same or different, each
  • c c 0, 1, or 2;
  • R 5C represents a hydrogen atom, a C 1-4 linear or branched alkyl group, or a benzyl group
  • R 6 c represents a hydrogen atom, a C 1-4 linear or branched alkyl group
  • R 7 c represents a C 1-4 linear or branched alkyl group
  • R 8C or R 9C are the same or different, hydrogen atom, Cl-4 straight or branched chain Represents an alkyl group or an amino protecting group,
  • R 1GC represents a hydrogen atom, dimethyl, CF 3 .
  • R 1D represents a hydrogen atom or a lower alkyl group
  • R 2D represents a hydrogen atom, a lower alkyl group, a lower alkoxy group, a carboxy group, an alkoxycarboyl group, a carboxyalkyl group or an alkoxycarboalkynol group,
  • R 3D represents a hydrogen atom, a carboxy group, an alkoxycarbol group, a carboxyalkyl group, an alkoxycarbinolealkyl group, a carboxyalkoxy group or an alkoxycarbonylalkoxy group,
  • R 4D represents a hydrogen atom, a hydroxyl group, a lower alkyl group or a lower alkoxy group
  • 110 represents 0, or an integer from 1 to 4,
  • a D represents a C 1-4 alkylene group which may be substituted with 1 to 2 hydroxyalkyl, carboxy, alkoxycarbol, carboxyalkyl or alkoxycarbonylalkyl groups;
  • X D represents a single bond, an oxygen atom, a sulfur atom or a carboyl group
  • Y D has an optionally substituted saturated or unsaturated 5- or 6-membered heterocyclic group or cyclic hydrocarbon group, an optionally substituted amino group or an optionally substituted substituent.
  • the group represented by represents a group selected from indolyl, benzofurul, benzoche ⁇ ⁇ ⁇ , benzimidazolyl, benzoxazolyl, benzothiazolyl, naphthyl, tetrahydronaphthyl and indanyl.
  • R 1E represents a hydrogen atom or a C1-C5 alkyl group
  • a r E represents a 1,2,3,4-tetrahydro-18-quinolyl group substituted at the 3-position with a methyl group or an ethyl group.
  • a blood coagulation and / or fibrinolytic enzyme inhibitor comprising: Aprotune derivative, (2) antithrombin m derivative, (3) heparin derivative, (4) danaparoid sodium, (5) hirudin derivative, (6) thrompomodulin derivative, (7) sulfated saccharide, or And the non-toxic salt of the above.
  • the elastase inhibitor which is one of the active ingredients of the present invention, is not particularly limited, and when combined, has new utility (not only for acute lung injury associated with sepsis and DIC, but also for multiple organ disorders such as liver and kidney). Prophylaxis and Z or treatment, and excellent efficacy in improving the prognosis of patients). In other words, an elastase inhibitor has an excellent effect on the prevention and treatment of acute lung injury and Z or DIC by combining it with a blood coagulation system and Z or fibrinolytic enzyme inhibitor.
  • the compound represented by the formula (IA) or a non-toxic salt thereof can be mentioned.
  • preferred compounds include the compounds specifically specified in EP 347168, for example, the compounds described in Examples.
  • N- [o- (4-bivaloyloxybenzene) sulfonylaminobenzoyl] glycine, a non-toxic salt thereof or a hydrate thereof is used.
  • N— [o— (4-bivaloyoxybenzen) sulfonylaminobenzoyl] glycine sodium salt tetrahydrate is particularly preferred.
  • the blood coagulation and Z or fibrinolytic enzyme inhibitors which are one of the active ingredients of the present invention, are not particularly limited. By combining them, new usefulness (acute lung injury associated with sepsis, DIC, ⁇ It is sufficient if it shows excellent prevention and / or treatment of multiple organ disorders such as kidneys, and excellent improvement in prognosis of patients.
  • blood coagulation and Z or fibrinolytic enzyme inhibitors when combined with elastase inhibitors, have excellent effects in the prevention and / or treatment of acute lung injury and Z or DIC, including liver, kidney, etc. It can be useful for the prevention and / or treatment of multiple organ disorders in patients with Z and / or Z that show improved prognosis in patients.
  • blood coagulation and z- or fibrinolytic enzyme inhibitors include blood coagulation enzyme inhibitors, fibrinolytic enzyme inhibitors, blood coagulation enzyme inhibitors and fibrinolytic enzyme inhibitors, and fibrinolytic enzyme inhibitors. Also included are blood coagulation enzyme inhibitors.
  • examples of the blood coagulation and Z or fibrinolytic enzyme inhibitors include a compound represented by the formula ( ⁇ ), a compound represented by the formula ( ⁇ ) and a non-toxic salt thereof, and a compound represented by the formula (nD).
  • a compound represented by the following formula, a compound represented by the formula ( ⁇ ), an aprotinin derivative, an antithrombin m derivative, a heparin derivative (for example, heparin and low-molecular-weight heparin), danaparoid sodium, a hirudin derivative, a thrombomodulin derivative, sulfuric acid Includes saccharides (eg, synthetic heparins) and their non-toxic salts.
  • preferred compounds include the compounds specifically specified in British Patent No. 1324714, for example, the compounds described in Examples. More preferably, 4-ethoxycarboylphenol ester of 6-gudinocaproic acid is used, and its mesylate salt is particularly preferred.
  • preferred compounds include the compounds specifically specified in EP 48433, for example, the compounds described in Examples. More preferably, 6-amidino-2-naphthinole 4-guaezinobenzoate is mentioned, and its 2-mesinoleate is particularly preferred.
  • preferred compounds include the compounds specifically specified in EP 540051, for example, the compounds described in Examples. More preferably, (2S) 1-2- [4-(((3S) -1- (1-acetoimidoyl-1-3-pyrrolidyl) oxy] phenyl] -3-((7-amidino-2-naphthyl) propionic acid is exemplified. And its hydrochloride pentahydrate is particularly preferred.
  • preferred compounds include those specifically specified in JP-A-55-33499, for example, the compounds described in Examples.
  • the aprocen derivative, antithrombin m derivative, heparin derivative, hirudin derivative, and tongue modomodulin derivative are naturally-occurring proteins purified from mammals, and naturally-occurring proteins purified from mammals by recombinant DNA methods. And a recombinant protein purified using a host cell.
  • aprotune solution dried and concentrated human antithrombin m, heparin, low molecular weight heparin (eg, dalteparin sodium, reviparin sodium, enoxaparin sodium), revirgin, MR-33, Human genetically modified tombomodulin, CX-397, and the like.
  • Aprochen solution is a solution containing aprochen extracted from bovine lung or parotid gland.
  • Dry concentrated human antithrombin m is purified from human plasma and has a molecular weight of about 64,000 and belongs to ⁇ 2 glopurine.
  • Dalteparin sodium is a sodium salt of depolymerized heparin obtained by decomposing heparin derived from porcine intestinal mucosa by nitrite, and has an average relative molecular weight of about 5000, and is described in WO80 / 01383.
  • Reviparin sodium is a low molecular weight heparin produced by depolymerizing heparin derived from porcine intestinal mucosa by nitrite decomposition.
  • Enoxaparin sodium is a low molecular weight heparin having a molecular weight of 4000 to 6000, which is an improvement of natural heparin, and is described in EP 40144.
  • Revirdin is a hirudin produced by using yeast as a host using genetically modified DNA, and consists of a peptide of 65 amino acids, which is described in EP 324712. .
  • MR-33 is a natural thrombomodulin extracted and purified from human urine and described in European Patent No. 376251.
  • Human recombinant tombomodulin is a thrombomodulin produced by using recombinant DNA and using Chinese hamster ovary (CHO) cells as a host, and is described in WO88 / 05053.
  • CX-399 is a recombinant hirudin derivative derived from medicinal leech, consisting of 66 amino acids, and is described in WO92 / 08736.
  • the sodium danaparide of the present invention is a mixture of sulfurized dalcosaminoglycans having an average molecular weight of 6400 and extracted from pig small intestinal mucosa, and is described in EP 66908.
  • the sulfated saccharides of the present invention include, for example, synthetic heparins, and specifically include fondaperinux sodium.
  • Fondaperinux sodium is a heparin analog of pentasadride, which selectively inhibits blood coagulation factor Xa. It is described in U.S. Patent Nos. 4,818,816 and W098 / 53829.
  • the elastase inhibitor and the blood coagulation and / or fibrinolytic enzyme inhibitor used in the present invention include not only those that have been found to date but also those that will be found in the future based on the mechanism.
  • the elastase inhibitor and the blood coagulation and / or fibrinolytic enzyme inhibitor used in the present invention also include those in the form of a prodrug.
  • the elastase inhibitor of the present invention and a blood coagulation and Z or fibrinolytic enzyme inhibitor, acute lung injury, better prevention and Z or therapeutic effect on DIC, liver, It is effective in preventing and treating Z or treating multiple organ disorders such as kidney and improving the prognosis of Z or patients.
  • its effectiveness in the prevention and / or treatment of multiple organ disorders is very beneficial for improving the prognosis of patients with sepsis.
  • the combination of the present invention includes an elastase inhibitor and a blood coagulation enzyme inhibitor, an elastase inhibitor and a fibrinolytic enzyme inhibitor, an elastase inhibitor and a blood coagulation enzyme inhibitor and a fibrinolytic enzyme inhibitor, and an elastase inhibitor.
  • a combination of a blood coagulation enzyme inhibitor having a fibrinolytic enzyme inhibitory action is also included.
  • Preferred combinations are elastase inhibitors and blood coagulation enzyme inhibitors, elastase inhibitors and fibrinolytic enzyme inhibitors, and combinations of elastase inhibitors and blood coagulation enzyme inhibitors that have both fibrinolytic enzyme inhibitory effects. It is.
  • one or more blood coagulation and / or fibrinolytic enzyme inhibitors may be combined with the elastase inhibitor.
  • a preferred combination of the present invention is a compound represented by the formula (IA) as an elastase inhibitor and a blood coagulation enzyme inhibitor having both a blood coagulation system and a Z or fibrinolytic enzyme inhibitor as a fibrinolytic enzyme inhibitor.
  • a more preferred combination is N- [o- (4-bivaloyloxybenzene) sulfo-laminobenzyl] glycine, its non-toxic salt or hydrate thereof as an elastase inhibitor, and a blood coagulation system and Z or fibrinolytic system.
  • a particularly preferred combination is N- [o— (4-bivaloyloxybenzene) sulfo-laminobenzyl] glycine sodium salt tetrahydrate (ONO-5046) as an elastase inhibitor and a blood coagulation system.
  • Z or fibrinolytic enzyme inhibitor is dateparin sodium, reviparin sodium, enoxaparin sodium, or danaparoid sodium.
  • the alkyl group, the alkoxy group and the alkylene group include straight-chain and branched-chain ones.
  • isomers ( ⁇ , ⁇ , cis, trans) in double bonds, rings, and condensed rings, isomers due to the presence of asymmetric carbon (R, S, ⁇ , 0, enantiomer, diastereomer), Optically active forms with optical activity (D, L, d, 1 body), polar forms by chromatographic separation (high polar form, low polar form), equilibrium compounds, mixtures of any proportions of these, racemic mixtures All are included in the present invention.
  • non-toxic salt in the present invention examples include common salts and acid addition salts.
  • the compounds of the present invention are converted to the corresponding salts by known methods.
  • the salts are preferably non-toxic and water-soluble. Suitable salts include salts of alkali metals (such as sodium and potassium) and salts of alkaline earth metals (such as calcium and magnesium). Salts, ammonium salts, pharmaceutically acceptable organic amines (tetramethylammonium, triethylamine, methylamine, dimethylamine, cyclopentylamine, benzylamine, phenethylenamine, piperidine, monoethanolamine, diethanolamine, tris ( (Hydroxymethyl) amine, lysine, argyene, N-methyl-D-glucamine, etc.).
  • the compounds of the present invention are converted to the corresponding acid addition salts by known methods.
  • the acid addition salts are preferably non-toxic and water-soluble. Suitable acid addition salts include inorganic salts such as hydrochloric acid, hydrobromide, sulfate, phosphate, nitrate, or acetate, trifluoroacetate, lactate, tartrate, oxalate , Fumarate, maleate, citrate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate, isethionate, dalcmate, dalconate And organic acid salts such as
  • the compound of the present invention or a salt thereof can be converted into a hydrate by a known method.
  • the compound represented by the formula (IA) is described in European Patent No. 347168, the compound represented by the formula ( ⁇ ) is described in British Patent No. 1324714, and the compound represented by the formula ( ⁇ ) is disclosed in European Patent No. 48433.
  • the compound represented by the formula (IID) is described in EP-A-540051, and the compound represented by the formula (II) is prepared by the method described in JP-A-55-33499. Can be manufactured.
  • the toxicity of the medicament comprising the combination of the present invention is extremely low, and it can be determined that it is sufficiently safe to use as a medicament.
  • the elastase inhibitor and the blood coagulation and Z or fibrinolytic enzyme inhibitors may be administered in the form of a single preparation, or may be administered as separate preparations, that is, in the form of combined administration. May be taken.
  • This combination administration includes simultaneous administration and administration with a time difference.
  • administration with a time difference is performed by administering an elastase inhibitor first and then using a blood coagulation and / or fibrinolytic enzyme inhibitor. May be administered later, or the blood coagulation and Z or fibrinolytic enzyme inhibitors may be administered first, followed by the elastase inhibitor.
  • they are administered as separate preparations, that is, combined administration.
  • the present invention it is usually administered systemically or locally, in an oral or parenteral form.
  • a solid preparation for oral administration a liquid preparation for oral administration, an injection for parenteral administration, an external preparation, a suppository, an eye drop, an inhalant, etc. Used as
  • Solid preparations for oral administration include tablets, pills, capsules, powders, granules and the like.
  • Force capsules include hard capsules and soft capsules.
  • Tablets include sublingual tablets, buccal tablets, troches, buccal patches, and buccal tablets.
  • one or more of the active substances may be intact or excipients (ratatose, mannitol, glucose, microcrystalline cellulose, starch, etc.), binders (hydroxypropylcellulose, polypropylpyrroli). Don, magnesium metasilicate aluminate, etc.), disintegrant (fiber calcium calcium dalicholate, etc.), lubricant (magnesium stearate, etc.), stabilizer, dissolution aid (glutamic acid, aspartic acid, etc.) etc. It is used after being formulated according to a conventional method.
  • a coating agent eg, sucrose, gelatin, hydroxypropizolesenololose, hydroxypropyl methinoresenololose phthalate
  • a coating agent eg, sucrose, gelatin, hydroxypropizolesenololose, hydroxypropyl methinoresenololose phthalate
  • capsules of absorbable materials such as gelatin.
  • Liquid preparations for oral administration include pharmaceutically acceptable solutions, suspensions, emulsions, syrups, elixirs and the like.
  • one or more of the active substances may be converted to a commonly used diluent (purified water, ethanol Or a mixture of them).
  • this liquid preparation may contain a wetting agent, a suspending agent, an emulsifying agent, a sweetening agent, a flavoring agent, a fragrance, a preservative, a buffering agent and the like.
  • Injections for parenteral administration include solutions, suspensions, emulsions, and solid injections that are used by dissolving or suspending in a solvent for use. Injectables are used by dissolving, suspending or emulsifying one or more active substances in a solvent.
  • the solvent for example, distilled water for injection, physiological saline, vegetable oil, propylene glycol, polyethylene glycol, alcohols such as ethanol and the like, and combinations thereof are used.
  • this injection may contain a stabilizer, a solubilizing agent (glutamic acid, aspartic acid, polysorbate 80 (registered trademark), etc.), a suspending agent, an emulsifier, a soothing agent, a buffer, a preservative, and the like. Good. They are manufactured by sterilization or aseptic processing in the final step.
  • a sterile solid preparation for example, a lyophilized product, can be manufactured and then used after dissolving in sterilized or sterile distilled water for injection or other solvents before use.
  • compositions for parenteral administration include topical solutions, ointments, salves, inhalants, sprays, suppositories, and the like, containing one or more active substances and formulated in a conventional manner. Includes pessaries for vaginal administration.
  • Sprays may contain a buffering agent that provides isotonicity with stabilizers such as sodium bisulfite, as well as commonly used diluents, for example, isotonic agents such as sodium chloride, sodium terate, or citric acid. It may be contained. Methods for producing spray agents are described in detail, for example, in U.S. Patent Nos. 2,686,691 and 3,095,355.
  • Dosage varies depending on age, body weight, symptoms, therapeutic effect, administration method, treatment time, etc., but usually, per adult, in the range of lmg to 100mg, once orally several times a day Parenteral administration once or several times daily, in the range of 0.1 mg to 100 mg per adult per dose (preferably, Intravenous administration) or continuous intravenous administration for 1 hour to 24 hours per day.
  • the dose varies depending on various conditions, so a smaller dose than the above-mentioned dose may be sufficient, or may be required beyond the range.
  • the dose of the elastase inhibitor varies depending on the drug, and the range in which each drug is generally used is preferably used, but for the treatment of the disease of the present invention, even if the drug is administered outside the range. Good.
  • the compounds of formula (IA) for the purposes of the present invention, they are preferably administered systemically or locally, in parenteral form. More preferably, it is an injection, and particularly preferably, it is continuously administered intravenously.
  • Dosage varies depending on age, body weight, symptoms, therapeutic effect, administration method, treatment time, etc., but usually, for adults (body weight 6 O kg), per person, in the range of 0.1 to 10 O mg / day,
  • Use parenteral administration preferably intravenous administration
  • 0.01 to: L mg / kg Zh is continuously administered intravenously over 24 hours.
  • N— [o— (4-Bivaloyloxybenzene) snorehoninole aminobenzoinole] glycine sodium salt tetrahydrate is administered intravenously at 0.2 mg Zkg gh per adult. It is a continuous administration over 4 hours.
  • the dosage of the blood coagulation system and Z or fibrinolytic enzyme inhibitors differs depending on the drug, and the range in which each drug is generally used is preferably used. It may be administered outside the range.
  • the compounds of formula (I) are preferably administered parenterally, systemically or locally. More preferably, it is an injection, and particularly preferably, it is continuously administered intravenously.
  • the dosage varies depending on age, body weight, symptoms, therapeutic effect, administration method, treatment time, etc.
  • it is continuously administered intravenously at 2 to 100 mg / kg daily for 24 hours. More specifically, 6-guanidinocaproic acid 4-ethoxycarboylphenyl ester mesylate is to be continuously administered intravenously over 24 hours at a daily dose of SOS SmgZkg per adult per person.
  • the compounds of formula (nc) are preferably administered parenterally, systemically or locally. More preferably, it is an injection, and particularly preferably, it is continuously administered intravenously. Dosage varies depending on age, body weight, symptoms, therapeutic effect, administration method, treatment time, etc., but is usually for adults (body weight 60 kg) —per person, once per dose: 0.1 to: Parenteral administration (preferably intravenous administration) once or several times daily, or continuous intravenous administration for 1 hour to 24 hours daily. Preferably, it is continuously administered intravenously at 0.01 to lmg / kg over 24 hours. More specifically,
  • the compounds of formula (IID) are preferably administered parenterally, systemically or locally. More preferably, it is an injection, and particularly preferably, it is continuously administered intravenously. Dosage varies depending on age, body weight, symptoms, therapeutic effect, administration method, treatment time, etc., but is usually for adults (body weight 60 kg) —per person, once per dose: 0.1 to: Parenteral administration (preferably, intravenous administration) once or several times daily, or continuous intravenous administration in the range of 1 hour to 24 hours daily. Preferably, it is administered continuously at 0.5 to 3 Omg / kg intravenously over 24 hours.
  • (2 S) -2- [4-[[((3S) -111-acetoimidoyl-1-3-pyrrolidinyl) oxy] phenyl] -13- (7-amidino-2-naphthyl) propionate pentahydrate The substance is to be continuously administered intravenously over a period of 24 hours at 0.5 to 3 OmgZkg per adult.
  • the compounds of formula (I) are preferably administered parenterally, systemically or locally. More preferably, it is an injection, and particularly preferably, it is continuously administered intravenously.
  • the dosage varies depending on the age, body weight, symptoms, therapeutic effect, administration method, treatment time, etc., but is usually for adults (body weight 60 kg)-in the range of 0.1 to 10 Omg per day per person, once a day.
  • One or more parenteral administrations preferably, intravenous administration
  • continuous intravenous administration of 1B for 1 to 24 hours.
  • it is administered continuously at 1 to 80 mg Z kg intravenously over 24 hours.
  • (2 R, 4 R) 1-11 [N 2 — (3-Methyl-1,2,3,4-tetrahydro-18-quinoline-snolehoninole) 1-L-anoregininole] —4-methinolay 2-piperidine Carboxylic acid monohydrate is to be continuously administered intravenously over a period of 24 hours per adult at 0.01 to 0.1 mgZkg gh.
  • the aprotune solution is preferably administered parenterally, systemically or locally. More preferably, it is an injection, and particularly preferably, it is continuously administered intravenously.
  • the dosage varies depending on age, body weight, symptoms, therapeutic effect, administration method, treatment time, etc., but usually, from 1 dose per adult (body weight 6 O kg), in the range of 25 to 1 million units per day, Force several parenteral doses (preferably intravenous) or continuous intravenous administration for 1 hour to 24 hours. It is preferable to continuously administer 250,000 to 500,000 units per adult at a rate of 5000 to 10,000 units per minute.
  • dalteparin sodium for the purposes of the present invention, it is preferably administered parenterally, systemically or locally. More preferred are injections. Particularly preferred is continuous intravenous administration. Dosage varies depending on age, body weight, symptoms, therapeutic effect, administration method, processing time, etc.
  • parenteral administration in the range of 5 to 300 international units Zkg per day or intravenously in the range of 1 hour to 24 hours per day Administer continuously.
  • parenteral administration preferably intravenous administration
  • intravenously in the range of 1 hour to 24 hours per day
  • Administer continuously Preferably, per adult, 5 to 50 IU / day, once dose in the range of Zkg and 5 to 20 IU, continuous administration in the range of kg, or 25 to 200 IU / day / kg to be administered continuously.
  • reviparin sodium is administered, preferably systemically or topically, in parenteral form. More preferably, it is an injection, and particularly preferably, it is continuously administered intravenously. -Dosage varies depending on age, body weight, symptoms, therapeutic effect, administration method, treatment time, etc., but usually, once per adult per day, in the range of 5 to 300 IU / kg. Parenteral administration (preferably intravenous administration) or continuous intravenous administration for 1 to 24 hours per day. Preferably, one dose per adult per day in the range of 5 to 50 IU / kg and continuous administration in the range of 5 to 20 IU / kg, or 25 to 200 IU / day Zk g is to be administered continuously.
  • enoxaparin sodium is preferably administered parenterally, systemically or locally. More preferably, it is an injection.
  • the dosage varies depending on the age, body weight, symptoms, therapeutic effect, administration method, treatment time, etc., but usually, one to several times parenteral in the range of 5 to 10 mg / B per adult. Or continuous intravenous infusion for 1 to 24 hours per day.
  • parenteral administration preferably subcutaneous injection, in the range of 10 to 80 mg per adult per day.
  • fondaperinux sodium is preferably administered parenterally, systemically or locally. More preferred are injections. Dosage depends on age, body weight, symptoms, therapeutic effect, administration method, treatment time, etc. Usually, parenteral administration of 1 to 10 mg per adult, once or several times daily, or continuous intravenous administration for 1 hour to 24 hours per adult I do. Preferably, parenteral administration is performed once to several times in the range of 1 to 5 mg, preferably subcutaneous injection.
  • the effect of the combination of the elastase inhibitor according to the invention with a blood coagulation and / or fibrinolytic enzyme inhibitor has been proven by animal experiments.
  • the effects of the present invention can also be confirmed by human clinical experiments.
  • a combination of an elastase inhibitor represented by the formula (IA) with a blood coagulation and / or fibrinolytic enzyme inhibitor represented by the formula ( ⁇ ), the formula (IIC) or the formula ( ⁇ ) The effect can be confirmed by an endotoxin-induced multi-organ injury model of galactosamine loading in rats—a trypsin and tacocholate-induced knee inflammation model in rats. It can also be confirmed by the following experimental model of multi-organ damage.
  • Rats fasted for about 24 hours are anesthetized by intraperitoneal administration of pentobarbital (40 mg / kg).
  • a catheter is attached to both femoral veins and a pterygoid needle is attached to the tail vein, and lipopolysaccharide (LPS; 0.3 mg / kg / h) and the test compound, or a control group, only the vehicle used for administration of the test compound can be used.
  • LPS lipopolysaccharide
  • the medicament of the present invention comprising a combination of an elastase inhibitor and a blood coagulation and / or fibrinolytic enzyme inhibitor has an excellent effect on the prevention and treatment of acute lung injury Z or DIC. It is useful for the prevention and / or treatment of multiple organ disorders such as liver and kidney, and also improves the prognosis of patients.

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Abstract

L'invention concerne un médicament comprenant une combinaison d'un inhibiteur de l'élastase renfermant, par exemple, un composé représenté par la formule générale (IA) ou un sel non toxique correspondant, et d'un inhibiteur enzymatique du système de coagulation sanguine et/ou du système de fibrinolyse renfermant, par exemple, des composés représentés par les formules générales (IIB), (IIC), (IID) et (IIE), un dérivé d'aprotinine, un dérivé d'antithrombine III, un dérivé d'héparine, un dérivé de danaparoïde sodique, un dérivé d'hirudine, un dérivé de thrombomoduline, un sucre sulfaté ou un sel non toxique correspondant. Le médicament susmentionné est utile pour prévenir et/ou traiter la lésion pulmonaire aiguë, la coagulation intravasculaire disséminée et la défaillance multiorganique dans le foie, le rein, etc., et pour améliorer le pronostic d'un patient.
PCT/JP2003/014198 2002-11-08 2003-11-07 Medicaments comprenant une combinaison d'un inhibiteur de l'elastase et d'un inhibiteur enzymatique du systeme de coagulation sanguine et/ou du systeme de fibrinolyse WO2004041309A1 (fr)

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Publication number Priority date Publication date Assignee Title
GB2445920A (en) * 2007-01-25 2008-07-30 Mucokinetica Ltd Amidino compounds for treatment of respiratory disease

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2013014550A (ja) * 2011-07-05 2013-01-24 Kao Corp アグリカン分解抑制剤

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2445920A (en) * 2007-01-25 2008-07-30 Mucokinetica Ltd Amidino compounds for treatment of respiratory disease
WO2008090366A1 (fr) * 2007-01-25 2008-07-31 Mucokinetica Ltd. Traitement pour maladie respiratoire

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