WO2004072013A1 - Compose de l'acide hydroxyeicosadienoique - Google Patents

Compose de l'acide hydroxyeicosadienoique Download PDF

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Publication number
WO2004072013A1
WO2004072013A1 PCT/JP2004/001312 JP2004001312W WO2004072013A1 WO 2004072013 A1 WO2004072013 A1 WO 2004072013A1 JP 2004001312 W JP2004001312 W JP 2004001312W WO 2004072013 A1 WO2004072013 A1 WO 2004072013A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
elastase
hydroxyeicosadienoic
acid
acid compound
Prior art date
Application number
PCT/JP2004/001312
Other languages
English (en)
Japanese (ja)
Inventor
Tohru Tanami
Naoya Ono
Tomomichi Chonan
Original Assignee
Taisho Pharmaceutical Co.,Ltd.
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 Taisho Pharmaceutical Co.,Ltd. filed Critical Taisho Pharmaceutical Co.,Ltd.
Publication of WO2004072013A1 publication Critical patent/WO2004072013A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/42—Unsaturated compounds containing hydroxy or O-metal groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/26—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having more than one amino group bound to the carbon skeleton, e.g. lysine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Definitions

  • the present invention relates to a hydroxyeicosagen acid conjugate, and more particularly, has an erasase inhibitory effect, is easy to purify, is easy to handle, is physically stable, and is useful as a pharmaceutical. Is a hydroxyeicosadic acid compound which is easy. Conventional technology
  • elastase neutrophil elastase
  • Elastase is an enzyme that mainly degrades proteins such as elastin, collagen, proteodarican, and fibronectin, which constitute the stroma of in vivo connective tissues such as lung, cartilage, vascular wall, skin, and ligament. It has also been shown to act on other proteins and cells.
  • elastase In vivo, elastase is controlled by its endogenous inhibitor proteins, a1-proteazyme, ⁇ 2-macroglobulin, secretory leukocyte protease, and the like. Maintains homeostasis. However, if the balance between elastase and endogenous inhibitors is impaired by a decrease in inhibitory levels of elastase at the site of inflammation, control of elastase action is disrupted and tissue is damaged.
  • elastase Diseases that have been suggested to be involved in the pathogenesis of elastase are: emphysema, adult respiratory distress syndrome, idiopathic pulmonary fibrosis, pulmonary fibrosis, chronic interstitial pneumonia, chronic bronchitis, chronic airway infection , Diffuse panbronchiolitis, bronchiectasis, asthma, rheumatism, nephritis, liver failure, chronic rheumatoid arthritis, arthrosclerosis, osteoarthritis, psoriasis, periodontitis, atherosclerosis, organ transplantation Rejection, premature rupture, bullous disease, shock, sepsis, systemic erythematosus, Crohn's disease, disseminated intravascular coagulation, cerebral infarction, heart disease, ischemia-reperfusion injury observed in renal disease, corneal scar Tissue formation and spondylitis are known.
  • elastase inhibitors are useful as therapeutic or preventive agents for these diseases.
  • research has been actively conducted in recent years, and various elastase inhibitors have been reported, but their effects are not necessarily satisfactory.
  • No clinically useful drug has yet been found as an elastase inhibitor composed of a fatty acid derivative.
  • this compound is a viscous oily substance and has a problem with stability over time, so that it is difficult to use it as a medicine. Disclosure of the invention
  • An object of the present invention is to provide a compound which has an elasase inhibitory activity, is easy to purify, is easy to handle, is physically stable, and is easily used as a pharmaceutical.
  • the present inventors have conducted intensive studies on (5Z, 14Z) -1 (16R) -16-hydroxyeicosa-5,14-genic acid esters and salts for the purpose of solving the above problem.
  • 5Z, 14Z)-(16R)-(16-hydroxyeicosa) -5,14-genic acid lysine salt represented by (I) is a specific, colorless powder, They have found that they have good physicochemical properties and are physiologically useful, and have completed the present invention.
  • the present invention provides a compound of the formula (I)
  • the hydroxyeicosadic acid compound of the present invention can be obtained by the method described in W099 / 59964, (5Z, 14Z)-(16R) —16-hydroxyeicosa-5,14-genic acid, It can be easily obtained by reacting (L) -lysine in an inert solvent such as methanol or ethanol.
  • the compounds of the present invention can be administered systemically or topically orally or parenterally, such as intrarectally, subcutaneously, intramuscularly, intravenously, and transdermally.
  • it can be orally administered in the form of tablets, powders, granules, powders, capsules, solutions, emulsions, suspensions, etc., which can be produced by a conventional method.
  • preparations for intravenous administration aqueous or non-aqueous solutions, emulsions, suspensions, solid preparations which are dissolved in an injection solvent immediately before use and the like can be used.
  • the compound of the present invention can also be formulated by forming an inclusion compound with a, j8 or arcyclodextrin or methylated cyclodextrin.
  • the aqueous or non-aqueous solution, emulsion, suspension and the like can be administered by injection or the like.
  • the dosage varies depending on age, body weight, etc., but is 0.0 mg / kg / day / adult for adults, administered once or several times a day.
  • Example 1 the effects of the present invention will be described more specifically with reference to examples and test examples, but the present invention is not limited by these descriptions.
  • Example 1 the effects of the present invention will be described more specifically with reference to examples and test examples, but the present invention is not limited by these descriptions.
  • Test Example 1 [Test of elastase production by stimulation with fMLP (N-formyl Met-Leu-Phe)] The compound (compound (1)) obtained in Example 1 and Example 18 in the specification of W099 / 59964 The compound (compound (1)) was used as the test drug, and rat neutrophils were dissolved in 1% case In solution was prepared 15 to 18 hours after intraperitoneal administration (120 ml / kg). After decapitation, cells were collected by peritoneal washing. Use cold PBS as the washing solution. Collect the peritoneal lavage fluid, centrifuge, and resuspend in HBSS at a cell concentration of 1 x cell Zml.
  • cytochalasin B final concentration for the purpose of priming.
  • f is the ML P a group without added plus 0.4% ethanol solution 10. after stirring, and incubated an additional 10 minutes. The reaction was stopped on ice, and the culture supernatant was collected by centrifugation.
  • Elastase activity in the culture supernatant is an elastase-specific substrate
  • the activity of inhibiting the release of Elasase was calculated by the following equation.
  • Inhibition rate (%) ⁇ 1- (A-C) / (B-C) ⁇ X100
  • A represents the fluorescence intensity when stimulated with ⁇ MLP (1 / iM).
  • B represents the fluorescence intensity when fMLP (1 and the compound were added.
  • C represents the fluorescence intensity when fMLP was not added.
  • the 50% inhibitory concentration (IC50 value) was calculated from the concentration-inhibition curve.
  • a stability test of the test drug was performed at 6, 2, and 3 months later.
  • the residual ratio of the test drug was measured as follows. Precisely weigh about lmg of each test drug and heat
  • UV absorption spectrophotometer (Detection wavelength: 200 nm)
  • Table 3 shows the residual ratio of compound (I) and compound (II) when stored for 3 months under heating (40 ° C) and heating and humidification (40%, 75% RH).
  • Compound (II) had a very low residual ratio, indicating poor stability.
  • the compound (I) of the present invention was found to have a high residual ratio and to be stable.
  • the compound according to the present invention has a sufficient elastase inhibitory effect, is easy to purify, and is physically stable. Therefore, according to the present invention, emphysema, adult respiratory distress syndrome, idiopathic pulmonary fibrosis, cystic pulmonary fibrosis, chronic interstitial pneumonia, chronic bronchitis, chronic airway infection, diffuse panbronchiolitis, bronchiectasis, Asthma, inflammation, nephritis, liver failure, rheumatoid arthritis, joints Sclerosis, osteoarthritis, psoriasis, periodontitis, atherosclerosis, rejection in organ transplantation, premature rupture of water, bullous disease, shock, sepsis, systemic lupus erythematosus, Crohn's disease, disseminated It has become possible to provide useful medicines for diseases such as intravascular coagulation, cerebral infarction, heart disease, renal disease, ischemia-reperfusion injury, formation of corneal scar

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Le composé de l'acide hydroxyeicosadiènoïque de cette invention est représenté par la formule (I). Ce composé présente une activité inhibitrice de l'élastase suffisante, est facile à purifier et est stable physiquement. Il peut être utilisé comme médicament.
PCT/JP2004/001312 2003-02-14 2004-02-09 Compose de l'acide hydroxyeicosadienoique WO2004072013A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2003037186 2003-02-14
JP2003-037186 2003-02-14

Publications (1)

Publication Number Publication Date
WO2004072013A1 true WO2004072013A1 (fr) 2004-08-26

Family

ID=32866350

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2004/001312 WO2004072013A1 (fr) 2003-02-14 2004-02-09 Compose de l'acide hydroxyeicosadienoique

Country Status (1)

Country Link
WO (1) WO2004072013A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015071766A1 (fr) * 2013-11-15 2015-05-21 Dignity Sciences Limited Sels acceptables sur le plan pharmaceutique d'acides gras hydroxylés polyinsaturés

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2002515480A (ja) * 1998-05-15 2002-05-28 ユニバーシティ オブ バーモント １６−ヒドロキシエイコサテトラエン酸の新規アナログ

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2002515480A (ja) * 1998-05-15 2002-05-28 ユニバーシティ オブ バーモント １６−ヒドロキシエイコサテトラエン酸の新規アナログ

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015071766A1 (fr) * 2013-11-15 2015-05-21 Dignity Sciences Limited Sels acceptables sur le plan pharmaceutique d'acides gras hydroxylés polyinsaturés
US20150152034A1 (en) * 2013-11-15 2015-06-04 Dignity Sciences Limited Pharmaceutically Acceptable Salts of Fatty Acids
CN105899485A (zh) * 2013-11-15 2016-08-24 尊严科学有限公司 多不饱和羟基脂肪酸的药学上可接受的盐
JP2016538288A (ja) * 2013-11-15 2016-12-08 ディグニティ サイエンシス リミテッド 多価不飽和ヒドロキシ脂肪酸の薬学的に許容される塩
US10017453B2 (en) * 2013-11-15 2018-07-10 Ds Biopharma Limited Pharmaceutically acceptable salts of fatty acids
CN105899485B (zh) * 2013-11-15 2018-10-19 尊严科学有限公司 多不饱和羟基脂肪酸的药学上可接受的盐
CN109232278A (zh) * 2013-11-15 2019-01-18 Ds生物制药有限公司 多不饱和羟基脂肪酸的药学上可接受的盐
EP3546446A1 (fr) * 2013-11-15 2019-10-02 DS Biopharma Limited Sels pharmaceutiquement acceptables d'acides gras polyinsaturés hydroxy
US10544088B2 (en) 2013-11-15 2020-01-28 Ds Biopharma Limited Pharmaceutically acceptable salts of fatty acids
JP2020055825A (ja) * 2013-11-15 2020-04-09 ディーエス バイオファーマ リミテッド 多価不飽和ヒドロキシ脂肪酸の薬学的に許容される塩

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