WO2002072580A1 - Preventifs et/ou remedes contres des maladies renales et l'insuffisance renale - Google Patents

Preventifs et/ou remedes contres des maladies renales et l'insuffisance renale Download PDF

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Publication number
WO2002072580A1
WO2002072580A1 PCT/JP2002/001639 JP0201639W WO02072580A1 WO 2002072580 A1 WO2002072580 A1 WO 2002072580A1 JP 0201639 W JP0201639 W JP 0201639W WO 02072580 A1 WO02072580 A1 WO 02072580A1
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WO
WIPO (PCT)
Prior art keywords
group
prophylactic
methyl
acceptable salt
hydrogen
Prior art date
Application number
PCT/JP2002/001639
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English (en)
Japanese (ja)
Inventor
Chisei Ra
Toshio Kawashima
Original Assignee
Mitsubishi Pharma Corporation
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 Mitsubishi Pharma Corporation filed Critical Mitsubishi Pharma Corporation
Priority to KR1020037011199A priority Critical patent/KR100885007B1/ko
Priority to JP2002571496A priority patent/JP4171303B2/ja
Publication of WO2002072580A1 publication Critical patent/WO2002072580A1/fr

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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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

Definitions

  • the present invention provides a compound (I) represented by the following formula:
  • R 1 and R 3 are independently hydrogen or an alkynole group having 1 to 6 carbon atoms
  • R 2 and R 4 are independently hydrogen, halogen, an alkyl group having 1 to 6 carbon atoms, It is an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms or a phenyl group substituted by a hydroxyl group.
  • a prophylactic and / or therapeutic agent for renal disease and / or renal failure containing a pharmacologically acceptable salt thereof as an active ingredient or a drug containing a pharmacologically acceptable salt thereof as an active ingredient.
  • the mesangial region is one of the basic components of the glomerulus, and is composed of mesangial cells and mesangial matrix. Of these, mesangial cells are considered to be the supporting tissue of renal glomerular capillaries. In renal disease, this proliferation of mesangial cells and / or an increase in mesangial matrix is observed, eventually leading to glomerulosclerosis and renal failure. Therefore, suppressing the proliferation of mesangial cells is effective in preventing and / or treating various kidney diseases such as kidney disease and renal failure.
  • the potassium salt of 9-methyl-3_ (1H-tetrazol-5-yl) -14H-pyrido [1,2-a] pyrimidin-14_one (generic name: milolast)
  • mirolast potassium Is a drug widely used as a therapeutic drug for bronchial asthma, allergic rhinitis, etc., and is marketed in Japan as Aregizal (trade name) by the applicant, Mitsubishi Pharma Corporation.
  • Aregizal trade name
  • the present invention provides a novel agent for preventing and / or treating renal disease and renal failure, that is, a remedy for renal disease and renal failure comprising mirolast or a pharmacologically acceptable salt thereof as an active ingredient. And / or to provide a therapeutic agent. Disclosure of the invention
  • compound (I) or a pharmacologically acceptable salt thereof is effective in a model of renal disease accompanied by mesangial cell proliferation, and is effective for prevention and / or treatment of renal disease and renal failure.
  • the inventors have found that the present invention has been completed.
  • the gist of the present invention is as follows.
  • R 1 and R 3 are independently hydrogen or an alkyl group having 1 to 6 carbon atoms, and R 2 and R 4 are independently substituted with hydrogen, halogen, an alkyl group having 1 to 6 carbon atoms, or a hydroxyl group. Or an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, or a phenyl group.
  • a pharmacologically acceptable salt thereof as an active ingredient.
  • R 1 and R 3 are independently hydrogen or methyl
  • R 2 is hydrogen, chlorine, methyl, ethyl, propyl, butyl or phenyl
  • R 4 is hydrogen, chlorine, methyl 2.
  • glomerular disease and renal disease are treated as almost synonymous diseases because their boundaries are not clear.
  • the WHO uses two types of clinical symptom classification and histological classification, which are classified into five categories according to the mode of onset, changes in renal function over time, and the degree of proteinuria. Honcho Reference to renal disease in the detailed description includes all renal diseases included in this clinical symptom classification and histological classification. Here, the clinical symptom classification will be described.
  • This syndrome is characterized by obvious onset, such as hematuria, proteinuria, hypertension, decreased glomerular filtration rate, and sudden appearance of Na and water retention.
  • histological findings or diseases presenting this clinical picture include acute glomerulonephritis after streptococcal infection, crescentic glomerulonephritis, membranous proliferative glomerulonephritis, acute exacerbation of sclerosing glomerulonephritis, focal Proliferative glomerulonephritis, lupus nephritis, purpura nephritis, IgA nephropathy, hereditary nephritis (Alport syndrome), periarteritis nodosa, and Wegener granulomas.
  • histological findings or diseases presenting this clinical picture include focal proliferative glomerulonephritis, IgA nephropathy, IgM nephropathy, diffuse proliferative glomerulonephritis, membranous proliferative glomerulonephritis, focal filamentous nephritis Examples include globular sclerosis, sclerosing nephritis, Alport syndrome, lupus nephritis, basement membrane thinning syndrome, and no glomerular abnormalities.
  • Chronic nephritis syndrome Those who have proteinuria, hematuria, and high blood pressure, and gradually fall into renal failure. Examples of histological findings or diseases that present this clinical picture include diffuse Reproductive glomerulonephritis, sclerosing nephritis, IgA nephropathy, membranous nephropathy, focal glomerulosclerosis, lupus nephritis, diabetic nephropathy, renal amyloidosis, Alport syndrome.
  • glomerular lesions with massive proteinuria, edema, hypoalbuminemia, and syndromes often associated with hypercholesterolemia examples include minimal change nephrotic syndrome, focal glomerulosclerosis, membranous nephropathy, diffuse proliferative glomerulonephritis, and membranous proliferative glomerulonephritis , IgA nephropathy, IgM nephropathy, cryoglobulinemia, lupus nephritis, purpura nephritis, diabetic nephropathy, amyloidosis, Alport syndrome, congenital nephrotic syndrome.
  • the disease names shown above are given as examples, and as long as the disease meets the definition-a disease state; the renal disease in the present specification is not limited thereto.
  • kidney disease includes these chronic nephritis and nephrotic syndrome.
  • the lip and the pharmacologically acceptable salt thereof used as the active ingredient are disclosed in Japanese Patent Application Laid-Open No. 54-36294, and Japanese Patent Application Laid-Open No. It can be easily manufactured according to the method described in Japanese Patent Application Laid-Open Publication No. H07-157, and a commercially available product can also be used.
  • Pharmaceutically acceptable salts include inorganic acid salts such as hydrochloric acid, nitric acid, and sulfuric acid, organic acid salts such as acetic acid, citric acid, fumaric acid, and tartaric acid, and sulfonic acids such as methanesulfonic acid and p-toluenesulfonic acid.
  • Salts and amino acid salts such as alanine, leucine, glutamic acid, and glutamine; and organic salts such as ammonium salts, ethylamine and ethanolamine, and metal salts such as alkali metal and alkaline earth metal. Is particularly preferred.
  • mirolast or a pharmacologically acceptable salt thereof May be isolated as hydrates or solvates or polymorphic substances, which are also included in the present invention.
  • the alkyl group having 1 to 6 carbon atoms is a linear or branched saturated aliphatic hydrocarbon group, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butynol group, and an isobutynol group. , Sec-petit / le, tert-butynole, pentynole, hexyl and the like.
  • Halogen is fluorine, chlorine, bromine and iodine.
  • the alkyl group having 1 to 6 carbon atoms substituted by a hydroxyl group is the above-mentioned alkyl group having 1 to 6 carbon atoms substituted by a hydroxyl group, for example, a hydroxymethyl group, a hydroxyethyl group, a hydroxypropyl And hydroxybutyl groups.
  • the alkoxy group having 1 to 6 carbon atoms is the above-mentioned alkyloxy group having 1 to 6 carbon atoms, such as methyloxy, ethyloxy, propyloxy, isopropyloxy, butyloxy, isobutyloxy, sec-butyl / Examples include a reoxy group, a tert-butyloxy group, a pentyloxy group, and a hexyloxy group.
  • R 1 examples include a hydrogen atom, a methyl group, an ethyl group, a propyl group and a butyl group, and more preferably a hydrogen or methyl group.
  • R 3 include hydrogen, a methyl group, E Ji group, include propyl or butyl group, more preferably Ru hydrogen or methyl der.
  • Preferred examples of R 4 include hydrogen, chlorine, methyl, ethyl, propyl, butyl, hydroxymethyl, hydroxyxetyl, hydroxypropyl, methyloxy, ethyloxy, and propyloxy.
  • Preferred are hydrogen, chlorine, methyl, ethyl, propyl, butyl, hydroxymethyl and methyloxy.
  • Preferred examples of the compound (I) include 9-methyl-3- (1H-tetrazole-51-yl) -14H-pyrido [1,2-a] pyrimidine-14-one.
  • compound (I) or a pharmacologically acceptable salt thereof can be prepared by mixing a usual pharmaceutical carrier, such as tablets, hard or soft capsules, granules, powders, fine granules or suppositories. It is also possible to prepare and use solid preparations or liquid preparations such as injections, inhalants, syrups, 7Rs, suspensions or emulsions.
  • the formulation carrier to be compounded includes, for example, excipients, binders, disintegrants, lubricants, coating agents, dissolution aids, emulsifiers, suspension agents, surfactants, absorption aids, A stabilizer or a solvent may be appropriately selected.
  • the dosage varies depending on the age, symptoms and dosage form, but 0.1 to 100 mg per day for oral administration and 0.01 to 100 mg per day for parenteral administration divided into one or several doses. Used.
  • the compound used in the present invention has high safety, and LD 5 of mirolast. The values were found to be 1317 mg / kg for oral administration of male rats and 533 mg / kg for intraperitoneal administration of male rats.
  • mimilast suppresses urinary protein, which is a parameter of nephritis progression, and suppresses nephritis induced by mesangial cell proliferation. From these results, it is expected that mirolast potassium will reduce glomerular sclerosis caused by the proliferation of mesangial cells and further reduce renal function decline.
  • a drug containing compound (I) containing mirolast or a pharmaceutically acceptable salt thereof as an active ingredient is a parameter of the progression of nephritis in a mesangial cell proliferative nephritis model. It suppresses urinary protein and can be used effectively as a preventive and / or therapeutic agent for renal failure caused by renal disease and exacerbation of renal disease.
  • This application was filed with a priority claim based on Japanese Patent Application No. 2001-49778.

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

Abstract

L'invention concerne des composés représentés par la formule générale suivante: dans laquelle R1 et R3 représentent chacun, de manière indépendante, un hydrogène ou un groupe C¿1-6? alkyle, et R2 et R?4¿ représentent chacun, de manière indépendante, un hydrogène, un halogèno, un groupe C¿1-6 ?alkyle, C1-6 alkoxy ou phényle, ou des sels de ces composés, acceptables sur le plan pharmaceutique, efficaces dans des modèles de maladie rénale en association avec la prolifération de cellules mésangiales et donc utiles, en tant que préventifs et/ou remèdes, dans des maladies rénales et/ou l'insuffisance rénale.
PCT/JP2002/001639 2001-02-26 2002-02-25 Preventifs et/ou remedes contres des maladies renales et l'insuffisance renale WO2002072580A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
KR1020037011199A KR100885007B1 (ko) 2001-02-26 2002-02-25 신질환·신부전의 예방 또는 치료를 위한 약학 조성물
JP2002571496A JP4171303B2 (ja) 2001-02-26 2002-02-25 腎疾患・腎不全の予防剤及び／又は治療剤

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2001049778 2001-02-26
JP2001-49778 2001-02-26

Publications (1)

Publication Number Publication Date
WO2002072580A1 true WO2002072580A1 (fr) 2002-09-19

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Family Applications (1)

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PCT/JP2002/001639 WO2002072580A1 (fr) 2001-02-26 2002-02-25 Preventifs et/ou remedes contres des maladies renales et l'insuffisance renale

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JP (1) JP4171303B2 (fr)
KR (1) KR100885007B1 (fr)
WO (1) WO2002072580A1 (fr)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4122274A (en) * 1977-05-25 1978-10-24 Bristol-Myers Company 3-Tetrazolo-5,6,7,8-substituted-pyrido[1,2-a]pyrimidin-4-ones
JPH0769895A (ja) * 1993-08-27 1995-03-14 Tokyo Tanabe Co Ltd 炎症性腸疾患治療剤
JPH07101863A (ja) * 1993-10-01 1995-04-18 Tokyo Tanabe Co Ltd 肝疾患治療剤
WO1995032714A1 (fr) * 1994-05-31 1995-12-07 Tokyo Tanabe Company Limited Depresseur de l'arteriosclerose

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4122274A (en) * 1977-05-25 1978-10-24 Bristol-Myers Company 3-Tetrazolo-5,6,7,8-substituted-pyrido[1,2-a]pyrimidin-4-ones
JPH0769895A (ja) * 1993-08-27 1995-03-14 Tokyo Tanabe Co Ltd 炎症性腸疾患治療剤
JPH07101863A (ja) * 1993-10-01 1995-04-18 Tokyo Tanabe Co Ltd 肝疾患治療剤
WO1995032714A1 (fr) * 1994-05-31 1995-12-07 Tokyo Tanabe Company Limited Depresseur de l'arteriosclerose

Also Published As

Publication number Publication date
KR100885007B1 (ko) 2009-02-20
JPWO2002072580A1 (ja) 2004-07-02
KR20030076710A (ko) 2003-09-26
JP4171303B2 (ja) 2008-10-22

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