WO2003045433A1 - Remedes contre l'insuffisance cardiaque - Google Patents

Remedes contre l'insuffisance cardiaque Download PDF

Info

Publication number
WO2003045433A1
WO2003045433A1 PCT/JP2002/012360 JP0212360W WO03045433A1 WO 2003045433 A1 WO2003045433 A1 WO 2003045433A1 JP 0212360 W JP0212360 W JP 0212360W WO 03045433 A1 WO03045433 A1 WO 03045433A1
Authority
WO
WIPO (PCT)
Prior art keywords
adam
compound
weight
egf
test
Prior art date
Application number
PCT/JP2002/012360
Other languages
English (en)
Japanese (ja)
Inventor
Masafumi Kitakaze
Shigeki Higashiyama
Kohichiro Yoshino
Original Assignee
Nippon Organon K.K.
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 Nippon Organon K.K. filed Critical Nippon Organon K.K.
Priority to JP2003546934A priority Critical patent/JPWO2003045433A1/ja
Priority to AU2002349537A priority patent/AU2002349537A1/en
Publication of WO2003045433A1 publication Critical patent/WO2003045433A1/fr

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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure

Definitions

  • ADAM Disintegrin And Metalloprotease
  • ADAM Disintegrin And Metalloprotease
  • the present invention relates to a heparin-binding EGF (epidermal growth factor) -like growth factor (hereinafter abbreviated as HB-EGF) by inhibiting the protease activity of this Adam molecule, more specifically, Adam 12.
  • HB-EGF heparin-binding EGF (epidermal growth factor) -like growth factor
  • the present invention relates to a therapeutic agent for cardiac dysfunction associated with cardiac hypertrophy, which comprises, as an active ingredient, a compound having an action of suppressing the solubilization of the above. (Background technology)
  • Adam 17 is known as a tumor necrosis factor (TNF) convertase (solubilizing enzyme).
  • NTF tumor necrosis factor
  • Adam 10 is involved in the control of Notch signals and plays an important role in neurogenesis, and has also been suggested to be involved in processing of membrane proteins and degradation of extracellular matrix components. I have. It is already known that Adam 12 has protease activity, but its physiological significance is unknown.
  • One of the target molecules for processing by these Adam molecules is a growth factor.
  • a variety of growth factor families are known to date, including, for example, the EGF receptor (EGFR) ligand growth factor family (EGF, HB-EGF, transforming growth factor-, amphiregulation). It is known that phosphorus, epiregulin, etc.) are synthesized in vivo as a membrane-bound form, then processed, and solubilized.
  • EGFR EGF receptor
  • HB-EGF transforming growth factor-, amphiregulation
  • phosphorus, epiregulin, etc. are synthesized in vivo as a membrane-bound form, then processed, and solubilized.
  • solubilization enzyme growth factors Izumi (izumi), etc., HB EG Adam 9 solubilization process F are stated to be involved CEMB0 J., 17, 7260-7272 (1998 )] 0
  • Hypertrophy is Although it is primarily the adaptive response of the heart to various loads, the elucidation of the mechanism is important because long-term cardiac hypertrophy is also associated with chronic cardiac dysfunction and sudden death.
  • vasoconstrictive drugs such as phenylephrine, angiotensin II and endothelin-11 cause cardiac hypertrophy. All of these drugs are known to bind to G-protein coupled receptors (GPCRs) and then stimulate protein synthesis via a series of signal transductions to cause cardiac hypertrophy.
  • GPCRs G-protein coupled receptors
  • An object of the present invention is to provide a new therapeutic agent for cardiac dysfunction associated with cardiac hypertrophy.
  • the present inventors examined the effect of a solubilizing enzyme inhibitor of HB-EGF (PCT International Publication WOO 1/70269) on the phosphorylation of EGFR in cardiomyocytes, and found that fuenorefrin, angiotensin II. It was found that phosphorylation of EGFR by endothelin-11 was inhibited, but phosphorylation by recombinant HB-EGF (solubilized HB-EGF) was not affected.
  • HB-EGF solubilizing enzyme inhibitor of HB-EGF
  • Phosphorylation of EGFR by phenylephrine, angiotensin II, and endothelin-11 is also inhibited by neutralizing antibodies against HB-EGF, so that solubilized HB-EGF activates EGFR. It has been clarified that it has contributed to the development of the system.
  • the inventors identified the enzyme responsible for solubilizing HB-EGF in cardiomyocytes. It is known that the solubilization of HB-EGF is mediated by the S-form of protein kinase C (PKCS). It revealed that the enzyme was Adam 12.
  • PKCS protein kinase C
  • the therapeutic agent for cardiac dysfunction of the present invention comprises, as an active ingredient, an inhibitor for the protease activity of an Adam molecule, particularly a compound that inhibits the protease activity of Adam 12, which is a solubilizing enzyme for HB-EGF in cardiomyocytes. .
  • the active ingredient is not particularly limited as long as it is a compound that inhibits the proteinase activity of Adam 12 in humans.
  • These compounds can be administered orally or parenterally to humans.
  • Oral dosage forms include solid preparations such as tablets, granules, powders, fine granules and hard capsules, and liquid preparations such as syrups and soft capsules. These preparations can be prepared in a conventional manner. Tablets, granules, powders, or fine granules may be prepared from the above compound or a pharmaceutically acceptable salt thereof, for example, lactose, starch, crystalline cellulose, superaline. It is produced by mixing with commonly used pharmaceutical additives such as magnesium acid, hydroxypropylcellulose, talc and the like. Hardness capsules are produced by filling these fine granules or powders into capsules as appropriate.
  • the syrup is prepared by adding the above compound or its pharmaceutically acceptable solution to an aqueous solution containing sucrose,
  • a soft capsule is prepared by dissolving or suspending an acceptable salt.
  • a soft capsule is prepared by dissolving the compound or a pharmaceutically acceptable salt thereof in a lipid excipient, for example, a vegetable oil, an oily emulsion, or glycol. It is manufactured by suspending and filling into soft capsules.
  • dosage forms for parenteral administration include injections, external preparations such as ointments, lotions and creams, suppositories such as suppositories and vaginal suppositories, and nasal administration preparations such as sprays.
  • These preparations can be manufactured by a conventional method.
  • the above-mentioned compound or a pharmaceutically acceptable salt thereof is dissolved in a physiological saline solution or a lipid excipient, for example, a vegetable oil, an oily emulsion, glycol, or the like.
  • a lipid excipient for example, a vegetable oil, an oily emulsion, glycol, or the like.
  • it is produced by emulsifying and aseptically enclosing in ampoules or vials.
  • An ointment is prepared by a conventional method by adding the above compound or a pharmaceutically acceptable salt thereof to a base such as petrolatum, paraffin, glycerin and the like, and adding an emulsifier, a preservative, etc., if necessary. Is performed.
  • the dose of the drug of the present invention varies depending on the dosage form, the age, sex or weight of the patient, or the symptom.
  • the active ingredient is 0.1 to 60 OmgZk g body weight day, preferably 10 to 20 OmgZk.
  • the appropriate amount of g body weight per day is given once a day or divided into 2 to 4 times a day.
  • the agent of the present invention significantly suppressed cardiac hypertrophy in a cardiac hypertrophy model mouse, and showed a recovery effect on cardiac function (Test Examples 1-3). Histological examination does not show any fibrosis or myofibril degradation. Therefore, the agent of the present invention is useful as a therapeutic agent for cardiac dysfunction associated with cardiac hypertrophy.
  • Test example 1 Cardiac hypertrophy inhibitory effect (change in left ventricular wall thickness)
  • thoracic aortic stenosis mouse TAC mouse
  • TAC mouse thoracic aortic stenosis mouse
  • TAC mice were C57B-6J male mice, 8 weeks old, weighing 20-25 g, and used a 27-gauge needle and suture at the site adjacent to the aorta between the left and right carotid arteries. It was prepared by stenosis.
  • Compound a was suspended in 0.5% carboxymethylcellulose and administered intraperitoneally to TAC mice at 10 mg / kg per day for 4 weeks, and the thickness of the left ventricular wall was measured by echocardiography. did.
  • Table 1 shows the measurement results. Treatment group (TAC mouse)
  • the test compound clearly showed an effect of suppressing left ventricular wall thickening.
  • test compound clearly showed an effect of suppressing an increase in heart weight.
  • Test Example 3 Protective effect of cardiac function
  • the test compound clearly showed an effect of suppressing a decrease in myocardial contraction rate.
  • one tablet contains 41- (N-hydroxyamino) 1-2 (R) -1-isobutyl-3-methylsuccinyl] -1-L-phenylglycine-1-N-methylamide (compound a) l O Omg Obtain tablets.
  • Active agent (Compound a) 00 parts by weight
  • microcrystalline cellulose 98 parts by weight of microcrystalline cellulose
  • Active agent 200 parts by weight
  • the main drug, lactose and corn starch are mixed, and hydroxypyrucel dissolved in 120 parts by weight of water is added and kneaded well.
  • the kneaded product is passed through a 20-mesh sieve, granulated, dried and sized to obtain a granule containing 20 Omg of the main drug in 50 Omg.
  • one capsule contains 100 mg of 4- (N-hydroxyamino) -2 (R) -isobutyl-1-methylsuccinyl] -one-phenylglycine-N-methylamide (Compound a)
  • a force capsule is obtained.
  • capsules are filled with 20 mg of the mixed powder of the formula (1) to obtain capsules.

Landscapes

  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Cardiology (AREA)
  • Epidemiology (AREA)
  • Hospice & Palliative Care (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

Des inhibiteurs (par exemple, un composé d'acide hydoxamique) pour l'activité de protéase des molécules Adam, notamment Adam 12, sont utiles en tant que remèdes contre l'insuffisance cardiaque associée à la cardiomégalie.
PCT/JP2002/012360 2001-11-29 2002-11-27 Remedes contre l'insuffisance cardiaque WO2003045433A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
JP2003546934A JPWO2003045433A1 (ja) 2001-11-29 2002-11-27 心機能不全治療薬
AU2002349537A AU2002349537A1 (en) 2001-11-29 2002-11-27 Remedies for heart failure

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2001-364167 2001-11-29
JP2001364167 2001-11-29

Publications (1)

Publication Number Publication Date
WO2003045433A1 true WO2003045433A1 (fr) 2003-06-05

Family

ID=19174398

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2002/012360 WO2003045433A1 (fr) 2001-11-29 2002-11-27 Remedes contre l'insuffisance cardiaque

Country Status (3)

Country Link
JP (1) JPWO2003045433A1 (fr)
AU (1) AU2002349537A1 (fr)
WO (1) WO2003045433A1 (fr)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997009066A1 (fr) * 1995-09-08 1997-03-13 Kanebo, Ltd. INHIBITEUR DE SOLUBILISATION DE LIGAND Fas
US6110964A (en) * 1998-04-10 2000-08-29 Pfizer Inc. Bicyclic hydroxamic acid derivatives
US6114361A (en) * 1998-11-05 2000-09-05 Pfizer Inc. 5-oxo-pyrrolidine-2-carboxylic acid hydroxamide derivatives
US6156798A (en) * 1998-04-10 2000-12-05 Pfizer Inc Cyclobutyl-aryloxyarylsulfonylamino hydroxamic acid derivatives

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997009066A1 (fr) * 1995-09-08 1997-03-13 Kanebo, Ltd. INHIBITEUR DE SOLUBILISATION DE LIGAND Fas
US6110964A (en) * 1998-04-10 2000-08-29 Pfizer Inc. Bicyclic hydroxamic acid derivatives
US6156798A (en) * 1998-04-10 2000-12-05 Pfizer Inc Cyclobutyl-aryloxyarylsulfonylamino hydroxamic acid derivatives
US6114361A (en) * 1998-11-05 2000-09-05 Pfizer Inc. 5-oxo-pyrrolidine-2-carboxylic acid hydroxamide derivatives

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
GILPIN BRENT J. ET AL.: "A novel, secreted form of human ADAM 12(Meltrin alpha) provokes myogenesis in vivo", THE JOURNAL OF BIOLOGICAL CHEMISTRY, vol. 273, no. 1, 1998, pages 157 - 166, XP002229017 *
MASANORI ASAKURA ET AL.: "Cardiac hypertrophy is inhibited by antagonism of ADAM12 processing of HB- EGF: Metalloproteinase inhibitors as a new therapy", NATURE MEDICINE, vol. 8, no. 1, January 2002 (2002-01-01), XP002965243 *
SPINALE FRANCIC G. ET AL.: "Matrix metalloproteinase inhibition during the development of congestive heart failure", CIRCULATION RESEARCH, vol. 85, 1999, pages 364 - 376, XP002965242 *

Also Published As

Publication number Publication date
JPWO2003045433A1 (ja) 2005-04-07
AU2002349537A1 (en) 2003-06-10

Similar Documents

Publication Publication Date Title
KR100902799B1 (ko) 키마제 저해제 및 ａｃｅ 저해제를 유효성분으로 함유하는약제
EA017893B1 (ru) Композиции, содержащие ингибитор jnk и циклоспорин
AU2012290987B2 (en) Left ventricular diastolic function improving agent
JP2006176542A (ja) フェニルエテンスルホンアミド誘導体含有医薬
HU221202B1 (en) Synergetic pharmaceutical combination containing a benzolsulfonamid-derivative and cilazapril
JP2008526953A (ja) 炎症性疾患のプラジカンテルでの治療
CN1356908A (zh) 包含低分子量凝血酶抑制剂及其药物前体的药用制剂
JP2021522247A (ja) 肝疾患における好中球エラスターゼ阻害薬の使用
WO2003055481A1 (fr) Inhibiteurs de fibrose des organes
JP2003081838A (ja) グルコサミン製剤
JPH06234636A (ja) インターロイキン８を阻害するためのレフルノミドの使用
JP2002543148A (ja) カルボキシペプチダーゼｕ阻害剤とトロンビン阻害剤とを含有する医薬製剤
WO2003045433A1 (fr) Remedes contre l'insuffisance cardiaque
AU2011270133B2 (en) Sustained-release therapeutic agent for hypertension and renal dysfunction
JPH06507381A (ja) 熱性疾患の処置のための医薬品としてのプロスタサイクリン−およびカルバサイクリン誘導体
JP2009500414A (ja) 有機化合物の組み合わせ
JPWO2003024445A1 (ja) 抗血栓薬とピラゾロン誘導体との組み合わせ薬剤
WO2019201333A1 (fr) Dérivé de glp-1 et son utilisation thérapeutique
JP2016034930A (ja) 血糖値低減剤
CN109172573A (zh) 一种口服抗血栓药物及其用途
WO1999045928A1 (fr) INHIBITEURS DE PRODUCTION D'ANTICORPS IgE ET INHIBITEURS DE MALADIES AUTO-IMMUNES
TW201206432A (en) Association of xanthine oxidase inhibitors and angiotensin II receptor antagonists and use thereof
CN108047315B (zh) 一类多肽药物Athycaltide及其用途
TW592702B (en) Pharmaceutical composition for treating diabetes
CN115286550A (zh) 一种用于治疗肥胖的化合物、组合物及其用途

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ OM PH PL PT RO RU SC SD SE SG SI SK SL TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR IE IT LU MC NL PT SE SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
WWE Wipo information: entry into national phase

Ref document number: 2003546934

Country of ref document: JP

122 Ep: pct application non-entry in european phase