WO2012163088A2 - Médicament pour le traitement de maladies rénales et cardiaques et ses utilisations - Google Patents

Médicament pour le traitement de maladies rénales et cardiaques et ses utilisations Download PDF

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Publication number
WO2012163088A2
WO2012163088A2 PCT/CN2012/001010 CN2012001010W WO2012163088A2 WO 2012163088 A2 WO2012163088 A2 WO 2012163088A2 CN 2012001010 W CN2012001010 W CN 2012001010W WO 2012163088 A2 WO2012163088 A2 WO 2012163088A2
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WO
WIPO (PCT)
Prior art keywords
compound
formula
kidney disease
disease
heart disease
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CN2012/001010
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English (en)
Chinese (zh)
Other versions
WO2012163088A3 (fr
Inventor
梁广
潘勇
王怡
赵承光
李校堃
蔡露
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.)
Wenzhou Medical College
Original Assignee
Wenzhou Medical College
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 Wenzhou Medical College filed Critical Wenzhou Medical College
Publication of WO2012163088A2 publication Critical patent/WO2012163088A2/fr
Publication of WO2012163088A3 publication Critical patent/WO2012163088A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61K31/12—Ketones
    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
    • 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
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the present invention relates to the field of medical technology, and in particular to the use of a compound of the formula (I) or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment or prevention of kidney disease and heart disease.
  • Heart disease and kidney disease are among the leading causes of death and disease in patients with diabetes today.
  • kidney disease and heart disease There are many causes of kidney disease and heart disease, including chemical, congenital, and concomitant (such as long-term hyperglycemia or other abnormal metabolism).
  • Nephropathy is characterized by progressive glomerulosclerosis and tubulointerstitial fibrosis, which is accompanied by a decrease in proteinuria and GFR, which ultimately leads to end stage renal failure.
  • Cardiomyopathy is characterized by its early abnormal diastolic function, accompanied by a slight abnormality of contractile function, which reduces longitudinal fiber function. Histological studies have shown that extracellular matrix deposition in the heart of patients with long-term hyperglycemia is increased, mainly fibrillar collagen, accompanied by cardiac hypertrophy.
  • the compound of formula (I) can effectively treat heart disease and kidney disease, especially kidney disease and heart disease in patients with long-term blood sugar, and can inhibit sugar-induced kidney and heart damage, especially Surprisingly, the compound is not treated by lowering blood sugar, and it is more directly treated for kidney disease and heart disease, and can be foreseen in combination with other drugs that lower blood sugar. Summary of the invention
  • the object of the present invention is to provide a novel use of (2E,6E)-2,6-bis(2-(trifluoromethyl)benzylidene)cyclohexanone (a compound of formula (I)) and other drugs use.
  • the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment or prevention of kidney disease or heart disease
  • the use of the invention is in the manufacture of a medicament for the treatment or prevention of kidney disease.
  • the present invention also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for ameliorating the symptoms of kidney disease or heart disease.
  • the use of the invention is in the manufacture of a medicament for ameliorating the symptoms of kidney disease.
  • the kidney disease is induced by hyperglycemia.
  • the symptom of nephropathy is renal fibrosis.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof does not statistically significantly lower blood glucose. That is, it is preferred that the use in the present invention is in the preparation of a medicament which does not statistically significantly lower blood glucose, for example, the present invention provides a compound of the formula (I) or a pharmaceutically acceptable salt thereof for use in preparation for use in preparation Use in medicines that treat or prevent kidney disease or heart disease but do not statistically significantly lower blood sugar.
  • the compound of the formula (I) or a pharmaceutically acceptable salt thereof is not statistically significantly reduced in body weight. That is, it is preferred that the use in the present invention is in the preparation of a medicament which does not statistically significantly reduce body weight, for example, the present invention provides a compound of the formula (I) or a pharmaceutically acceptable salt thereof for use in preparation for use in preparation Use in a drug that treats or prevents kidney disease or heart disease but does not statistically significantly reduce body weight.
  • the use of the invention is the use of a compound of formula (I).
  • the medicament in the use of the invention contains an effective amount of a compound of formula (I).
  • the effective dose may be the amount of the drug in a unit dosage form (e.g., one tablet, one needle, one pill, or one dose), or may be the unit dose (e.g., unit weight dose) of the patient in need of treatment/prevention.
  • the drug manufacturer can easily convert the unit weight dose of the patient to be treated/prevented into the amount of the drug in a unit dosage form by the average body weight of the patient population to be treated/prevented, for example, the average of the adult patient.
  • the body weight can be 60 kg, so by multiplying the average body weight by the unit weight dose of the adult, the content in the drug for the unit dosage form for the adult can be obtained.
  • the patient may be a mammal such as a human, rabbit, dog or mouse.
  • a mammal such as a human, rabbit, dog or mouse.
  • the human body weight dose can be derived from the dose of experimental animals.
  • the conversion relationship with an adult is about 12:1; for a commonly used experimental animal rat, according to the above document, Its conversion relationship with adults is about 6:1.
  • the effective dose in terms of content may be 10ug-lg, preferably 0.1 mg to 500 mg, more preferably 1 mg to 100 mg.
  • the medicament in the use of the invention will usually also contain a pharmaceutically acceptable carrier.
  • a pharmaceutically acceptable carrier refers to a non-toxic filler, stabilizer, diluent, adjuvant or other formulation adjuvant.
  • diluents, excipients such as water, physiological saline, etc.
  • fillers such as starch, sucrose, etc.
  • binders such as cellulose derivatives, alginates, gelatin and/or polyvinylpyrrolidone
  • humectants such as Glycerin
  • a disintegrant such as agar, calcium carbonate and/or sodium hydrogencarbonate
  • an absorption enhancer such as a quaternary ammonium compound
  • a surfactant such as hexadecanol
  • an adsorbent carrier such as kaolin and/or soap clay
  • talcum powder calcium stearate/magnesium, polyethylene glycol, and the like.
  • the pharmaceutical composition of the present invention may further contain other excipients such as a flavoring agent, a sweetener and the like.
  • the pharmaceutical composition can be formulated into various dosage forms depending on the purpose of the treatment, the route of administration, preferably in the form of a unit dosage form, such as a lyophilizate, a tablet, a capsule, a powder, according to a technique known in the art.
  • the emulsion composition, the aqueous injection or the spray, more preferably the pharmaceutical composition is an injection dosage form (e.g., lyophilized powder injection) or an oral dosage form (e.g., tablet, capsule).
  • the medicament may be administered by conventional routes, in particular enterally, for example orally, for example in the form of a tablet or capsule, or parenterally, for example in the form of an injectable solution or suspension, topically applied, for example as a lotion or Gel, or in the form of a nasal or test.
  • Figure 1 shows the effect of compounds of formula (I) on the metabolism of hyperglycemic rats.
  • Figure 2 shows the effect of the compound of formula (I) on renal tissue abnormalities and renal fibrosis in hyperglycemia rats.
  • Example 1 The compounds of the present invention did not affect blood glucose and body weight of rats. SD rats were randomly divided into 5 groups of 5 rats each, respectively: Blank control group (referred to as SD or con): healthy rats;
  • Kidney disease control group (abbreviated as DM): According to the method described by Wang Kang et al. (Chinese Journal of Integrated Traditional and Western Nephrology, 2010, 11(1): 14-17), mice were pathogenic with streptozotocin. ;
  • Low-dose treatment group (abbreviated as 0.2): same as DM, causing disease in rats, and administering the compound of formula (I) to rats at a dose of 0.2 mg/kg/day 7 days after the disease;
  • the medium-dose treatment group (referred to as 1): the same as DM, causing the disease of the mice, and administering the compound of the formula (I) to the rats at a dose of lmg/kg/day 7 days after the disease;
  • High-dose treatment group (abbreviated as 1): The same as DM, causing the disease in rats, and the compound of formula (I) was administered orally to the rats at a dose of 5 mg/kg/day 7 days after the disease.
  • the serum glucose, serum creatinine, body weight, and kidney/weight ratio were measured during the period. The results are shown in Figure 1. There was no significant difference in blood glucose levels between the treatment group and the diabetic group, and there was no significant difference in body weight. Meanwhile, the kidney/body weight ratio of the nephrotic control group was significantly increased relative to the normal group ( ⁇ 0.05). ), indicating that hyperglycemia is harmful to the kidneys, but administration of the compound of formula (I) significantly reduced the kidney/body weight ratio (especially 5 mg/kg/d a y ) of each treatment group (p ⁇ 0.05).
  • Example 2 The compounds of the present invention significantly improved rat kidney disease and fibrosis. Grouped and tested according to Example 1. After 6 weeks of administration, each group of rats was sacrificed, and kidney tissues were taken and fixed with 4% formalin solution. Paraffin-embedded, 5 ⁇ sections were stained with glycogen (PAS), sapphire red (Sirius red) and hematoxylin & eosin (H&E) and microscopically examined.
  • PAS glycogen
  • sapphire red Sirius red
  • H&E hematoxylin & eosin
  • the results are shown in Figure 2.
  • the renal tissue has obvious glycogen accumulation, increased IV collagen and structural abnormalities (including glomerular sclerosis, enlargement and thickening of the basement membrane, and severe inflammatory cell infiltration).
  • the administration of the compound of formula (I) significantly improved the symptoms of renal tissue damage, inflammatory cell infiltration and mesangial matrix expansion in the rats of each treatment group. This indicates that the compound of formula (I) is capable of preventing the deterioration of renal fibrosis due to hyperglycemia.

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

Abstract

La présente invention concerne la (2E,6E)-2,6-bis(2-(trifluorométhyl) benzylidène)cyclohexanone ou ses sels pharmaceutiquement acceptables destinés à être utilisés dans la préparation de médicaments pour traiter ou prévenir des maladies rénales ou cardiaques, ou à être utilisés dans des médicaments pour améliorer les symptômes de maladies rénales ou cardiaques.
PCT/CN2012/001010 2011-06-01 2012-07-27 Médicament pour le traitement de maladies rénales et cardiaques et ses utilisations Ceased WO2012163088A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201110146331.2 2011-06-01
CN201110146331.2A CN102293763B (zh) 2011-06-01 2011-06-01 肾病和心脏病的治疗药物及其用途

Publications (2)

Publication Number Publication Date
WO2012163088A2 true WO2012163088A2 (fr) 2012-12-06
WO2012163088A3 WO2012163088A3 (fr) 2013-01-24

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CN (1) CN102293763B (fr)
WO (1) WO2012163088A2 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021088495A1 (fr) * 2019-11-07 2021-05-14 温州医科大学 Forme cristalline i de dérivé de curcumine, son procédé de préparation et son utilisation

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102293763B (zh) * 2011-06-01 2014-10-29 温州医学院 肾病和心脏病的治疗药物及其用途
CN110664790A (zh) * 2019-07-10 2020-01-10 温州医科大学 一种2,6-二(2-(三氟甲基)苯亚甲基)环己酮在药物制备中的应用
CN115998687B (zh) * 2022-11-04 2024-08-09 温州医科大学 一种姜黄素衍生物的固体分散体及其制备和应用

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102038666B (zh) * 2009-10-18 2012-07-25 温州医学院 治疗或预防代谢疾病的药物及其应用
CN102293763B (zh) * 2011-06-01 2014-10-29 温州医学院 肾病和心脏病的治疗药物及其用途

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021088495A1 (fr) * 2019-11-07 2021-05-14 温州医科大学 Forme cristalline i de dérivé de curcumine, son procédé de préparation et son utilisation
US12540112B2 (en) 2019-11-07 2026-02-03 Wenzhou Medical University Crystal form I of curcumin derivative, preparation method therefor and application thereof

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Publication number Publication date
WO2012163088A3 (fr) 2013-01-24
CN102293763A (zh) 2011-12-28
CN102293763B (zh) 2014-10-29

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