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WO2006107059A1 - Medicament contre un trouble de la perfusion renale - Google Patents

Medicament contre un trouble de la perfusion renale Download PDF

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Publication number
WO2006107059A1
WO2006107059A1 PCT/JP2006/307166 JP2006307166W WO2006107059A1 WO 2006107059 A1 WO2006107059 A1 WO 2006107059A1 JP 2006307166 W JP2006307166 W JP 2006307166W WO 2006107059 A1 WO2006107059 A1 WO 2006107059A1
Authority
WO
WIPO (PCT)
Prior art keywords
renal
atom
active ingredient
kidney
vol
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/JP2006/307166
Other languages
English (en)
Japanese (ja)
Inventor
Shigeru Owada
Eiichi Murakami
Masato Kamibayashi
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.)
HETERO RESEARCH Co Ltd
Original Assignee
HETERO RESEARCH 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 HETERO RESEARCH Co Ltd filed Critical HETERO RESEARCH Co Ltd
Priority to JP2007511246A priority Critical patent/JPWO2006107059A1/ja
Publication of WO2006107059A1 publication Critical patent/WO2006107059A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
    • 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
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • 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
    • A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
    • A61P3/14—Drugs for disorders of the metabolism for electrolyte homeostasis for calcium homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • 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
    • A61P7/08—Plasma substitutes; Perfusion solutions; Dialytics or haemodialytics; Drugs for electrolytic or acid-base disorders, e.g. hypovolemic shock
    • 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
    • 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
    • A61P9/02—Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
    • 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
    • A61P9/08—Vasodilators for multiple indications
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the present invention is an organ disorder containing a dihydropyridine compound having an antagonistic action of calcium nocalmodulin (Ca 2+ / CaM) as an active ingredient, especially For the prevention and / or treatment of fl dysfunction such as nephritis and renal failure. Vegetables and; ': It relates to drugs for dialysis complications. ';': '' Background technology ⁇ ⁇ , ⁇ ⁇
  • 'Vasodilators are used for the treatment of hypertension including renal hypertension, essential hypertension and angina pectoris, etc. depending on their action selectivity. • There are no indications for the prevention and treatment of disability and dialysis complications; '' ⁇ : '.
  • the antioxidant activity of known dihydropyridine calcium antagonists measured using ESR is based on the calcium antagonism of each drug (Yousif FB et al., The Canadian Journal of Physiology and Pharmacology Vol. 64 27 3- 283 (1986), Mason M. et al., The Journal of Pharmacology and Experimental Therapeutics Vol. 275 1157-1166 (1995)).
  • kidney diseases such as renal diseases such as nephritis and renal failure, dialysis complications, etc. Or no drug is known to be effective for treatment.
  • kidney disease associated with systemic disease diabetic nephropathy, amyloidosis, gout kidney, kidney disorder associated with liver disease, Hemolytic uremic syndrome, purpura nephritis, renal disorder associated with collagen disease
  • renal failure acute renal failure, chronic renal failure
  • Other complications of dialysis include hypotension, carcinogenesis, infectious disease, or arteriosclerosis.
  • the present inventors have conducted extensive research aimed at suppressing and treating organ damage by a drug having a calcium // calmodulin antagonism. As a result, a dihydropyridine compound represented by the general formula (1) is obtained.
  • the present inventors have found that an excellent inhibitory effect is exhibited at a dose with little effect on blood pressure against renal dysfunction, and that it has an anti-radical action and the like, and the present invention has been completed. That is, the present invention provides the following general formula (1)
  • the medicine for renal dysfunction characterized by containing the dihydropyridine compound shown by these, or those optical isomers as an active ingredient.
  • the present invention provides an effective amount of the dihydropyridine compound represented by the general formula (1) or an optical isomer thereof to a subject such as a patient.
  • a treatment for renal dysfunction and acupuncture or prophylaxis characterized by administration to a patient. Effect of the invention .. '. +. ⁇ ⁇ + ⁇ .; + ::. ⁇ :: + ⁇ .: ..'. '.; ..
  • a virazole structure is bound to the steal side chain represented by the general formula Ci) of the present invention: 'The di-bidropiri dizyi' compound is the result of an experiment using a renal reperfusion model. ⁇ ⁇ ⁇ ⁇ At a dose that has little effect on blood pressure, it has both excellent inhibitory effect and diuretic action on renal damage caused by renal ischemia. . generated ⁇ a 'that:.. by the, is, of antioxidant capacity at the time of tissue damage.:.:.,' a drop ... 'to suppress. ⁇ '
  • ⁇ preferred in (1) and R '. 'Are' combination example of the Rj are two:.
  • Toro group R 2 ' is a hydrogen atom,' is '.
  • R 2 is chlorine atom in atom, 1 ⁇ and' hydrogen R 2 is exemplified chlorine atom I can't wait. .. Suitable R 3
  • .Irihara Child, '.Ning Element : Can Fuse Fluoro Atom' can be ... R 1 and + 'Chlorine Atom: Can be expected to be longer lasting than other: . ⁇ ⁇ is experimental.
  • CV-1 59 is disclosed in Japanese Patent No. 3365732 as a therapeutic agent for brain reperfusion, but there is no mention of prevention or Z or treatment of ischemic organ failure, especially kidney damage. It has not been. Examples of suitable compounds of the present invention are shown below, but they can be appropriately selected from these according to the purpose.
  • dihydropyridine compound represented by the general formula (1) of the present invention is a known product. Depending on the technology, tablets, granules, powders, 'hard capsules, emma / resillons, softness' pushells, lipid dome spheres, liposomes, or suppositories can be used. ⁇ Oral administration method; sublingual administration method, suppository ⁇
  • ⁇ can be thrown according to the purpose.
  • Ryoyo formulation ' Hitoshi ij type mixing according to,' ⁇ , Ryoneri, granulation, tabletting molding, co ⁇ I '' - 'ing, It can be prepared by a known and commonly used formulation method such as dissolution, emulsification, high-frequency heating, high-pressure steam heating, sterilization, and centrifugation.
  • Specific formulation carriers include starches, sucrose, lactose, and crystallization cell ports.
  • Fermentation Vum. Carbonic acid. Dissolving aids such as sodium carbonate, water for injections, etc.: Luluco: Lu: Pro 'Pyreneglygo', sesame oil, corn oil, etc. of.. 'soluble:.: Les ⁇ Chi emissions ⁇ ⁇ ⁇ . (full ⁇ off:.. a ⁇ le i Li Shi)', Phosphor lysophosphatidic acid,: O '.
  • the dose of the compound of the present invention varies depending on the route of administration, the type and extent of the pathological condition to be treated, the age and sex of the patient, the body weight, the sensitivity to the administered drug, the timing of administration and the interval of administration, but is usually about an adult per day.
  • 1 pg to 4 O mg preferably about 1 pg to 2 mg in the intravenous administration method.
  • the subcutaneous administration method it is preferably about 2 pg to 4 mg.
  • the oral administration method it is preferably about 0.1 to 50 mg.
  • a suppository it is preferably about 0.1 to 2 O mg.
  • Examples of a pharmaceutical composition suitable for an orally administered preparation with high bioavailability include a readily soluble solid dispersion comprising the compound of the present invention and the polymer compound.
  • a pharmaceutical composition suitable for an orally administered preparation with high bioavailability include a readily soluble solid dispersion comprising the compound of the present invention and the polymer compound.
  • the present inventors have developed a renal reperfusion model. Experimented with 'As a result, in particular, as shown in the examples below, 1,4-dibidrow 2,6-dimethyl 4- (3-nitrophenyl) _ 3-methoxycarbonylpyridine:.:; -...
  • Urine volume and urinalysis In each group, urine is measured for urine accumulation, occult blood, and protein is tested, followed by protein quantification, Na, K, C1, Ca, Pi (inorganic phosphorus), NAG (N-acetyl j3-D glucosaminidase), C r (Creachun), C cr
  • a nitric oxide measuring device (MODEL NO-502: manufactured by Eikogaku Kagaku) and NO electrode, an oxygen partial pressure measuring device (MODEL P02-150D) and an oxygen electrode were used. That is, in each group of animals, a NO electrode and an oxygen electrode were inserted into the cortex of the left kidney exposed on the back, and the counter electrode was mounted in the incised skin and measured. In the sham group in which ischemia / reperfusion injury was not performed, the NO / oxygen concentration was measured at the time of sham surgery and 16 hours after that in the non-drug-administered control group and the drug-administered group. The results are shown in Table 5.
  • the dihydropyridine compound represented by the general formula (1) according to the present invention is useful for renal diseases such as renal failure, nephritis, and dialysis complications that occur due to degeneration disorder of kidney tissue. It is extremely useful as a new active compound for use in the treatment and prevention of ischemia and ischemic reperfusion injury prevention during Z or kidney transplantation.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Cardiology (AREA)
  • Diabetes (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Hematology (AREA)
  • Endocrinology (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Obesity (AREA)
  • Rheumatology (AREA)
  • Urology & Nephrology (AREA)
  • Emergency Medicine (AREA)
  • Vascular Medicine (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Pain & Pain Management (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

L'invention concerne un produit pharmaceutique qui est utile dans la prévention et/ou le traitement de déficiences rénales, telle qu'une néphrite ou une insuffisance rénale. Elle propose un médicament destiné à un trouble de la perfusion rénale caractérisé en ce qu'il contient, comme ingrédient actif, tout composé de dihydropyridine selon la formule générale : (1) [dans laquelle R1 et R2, identiques ou différents l'un de l'autre, représentent un atome d'hydrogène, un atome nitro ou de chlore ; R3 représente un atome d'hydrogène, de chlore ou de fluor ; et n est un nombre entier de 6 à 8] ou un isomère optique de celui-ci.
PCT/JP2006/307166 2005-03-31 2006-03-29 Medicament contre un trouble de la perfusion renale Ceased WO2006107059A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP2007511246A JPWO2006107059A1 (ja) 2005-03-31 2006-03-29 腎灌流障害用薬

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2005-105438 2005-03-31
JP2005105438 2005-03-31

Publications (1)

Publication Number Publication Date
WO2006107059A1 true WO2006107059A1 (fr) 2006-10-12

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Family Applications (1)

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PCT/JP2006/307166 Ceased WO2006107059A1 (fr) 2005-03-31 2006-03-29 Medicament contre un trouble de la perfusion renale

Country Status (2)

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JP (1) JPWO2006107059A1 (fr)
WO (1) WO2006107059A1 (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH11189535A (ja) * 1997-12-25 1999-07-13 Masahito Kamibayashi 虚血性脳神経障害治療剤
WO2004004702A2 (fr) * 2002-07-09 2004-01-15 The Scripps Research Institute Procede pour empecher les lesions par ischemie et reperfusion

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH11189535A (ja) * 1997-12-25 1999-07-13 Masahito Kamibayashi 虚血性脳神経障害治療剤
WO2004004702A2 (fr) * 2002-07-09 2004-01-15 The Scripps Research Institute Procede pour empecher les lesions par ischemie et reperfusion

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
FUJIWARA K. ET AL.: "RENAL PROTECTIVE EFFECTS OF EFONIDIPINE IN PARTIALLY NEPHRECTOMIZED SPONTANEOUSLY HYPERTENSIVE RATS", CLIN. EXP. HYPERTENS., vol. 20, no. 3, 1998, pages 295 - 312, XP003002834 *
HASHIMOTO K. ET AL.: "Calcium to Sai kanryu Shogai", KO TO JUN, vol. 49, no. 1, 2001, pages 43 - 49, XP003002830 *
HAYASHI K. ET AL.: "Yogo ni Ataeru Eikyo to sono Taishoho Koketsuatsu to Jin'en", MED. PRACT., vol. 17, no. 11, 2000, pages 1893 - 1896, XP003002833 *
KASHIWABARA N.: "Jin'en (Kyusei . Mansei)", YAKKYOKU, vol. 53, no. SPECIAL EXTRA ISSUE, 2002, pages 638 - 647, XP003002832 *
SCHWERTSCHLAG U. ET AL.: "Beneficial Effects of Calcium Channel Blockers and Calmodulin Binding Drugs on in Vitro Renal Cell Anoxia", J. PHARMACOL. EXP. THER., vol. 238, no. 1, 1986, pages 119 - 124, XP003002831 *
TAGAWA S.: "Toseki Kanja no Koketsuatsu", JAPANESE JOURNAL OF CLINICAL MEDICINE, vol. 50, no. SPECIAL EXTRA ISSUE, 1992, pages 610 - 615, XP003002835 *

Also Published As

Publication number Publication date
JPWO2006107059A1 (ja) 2008-09-25

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