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WO1998035667A1 - Inhibiteurs de la ligase du monoxyde d'azote utilises dans le traitement des diabetes - Google Patents

Inhibiteurs de la ligase du monoxyde d'azote utilises dans le traitement des diabetes Download PDF

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Publication number
WO1998035667A1
WO1998035667A1 PCT/EP1997/000691 EP9700691W WO9835667A1 WO 1998035667 A1 WO1998035667 A1 WO 1998035667A1 EP 9700691 W EP9700691 W EP 9700691W WO 9835667 A1 WO9835667 A1 WO 9835667A1
Authority
WO
WIPO (PCT)
Prior art keywords
diabetes
treatment
pharmaceutically acceptable
aminoguanidine
synthase inhibitor
Prior art date
Application number
PCT/EP1997/000691
Other languages
English (en)
Inventor
Nicholas Charles Turner
Valerie Piercy
Original Assignee
Smithkline Beecham Plc
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 Smithkline Beecham Plc filed Critical Smithkline Beecham Plc
Priority to CA002280871A priority Critical patent/CA2280871A1/fr
Priority to PCT/EP1997/000691 priority patent/WO1998035667A1/fr
Priority to EP97904442A priority patent/EP0957909A1/fr
Priority to AU17251/97A priority patent/AU1725197A/en
Priority to JP53525798A priority patent/JP2001512450A/ja
Publication of WO1998035667A1 publication Critical patent/WO1998035667A1/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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • 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
    • 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
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • 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

Definitions

  • This invention relates to a novel method for the treatment of and/or prophylaxis of non-insulin dependant (NIDDM or Type II) diabetes, and in particular to the use of an NO synthase inhibitor, such as aminoguanidine, for the said treatment and/or prophylaxis.
  • NIDDM non-insulin dependant
  • an NO synthase inhibitor such as aminoguanidine
  • aminoguanidine Hydrazinecarboximidamide
  • Aminoguanidine is known to be an inhibitor of protein glycation and is under evaluation in animal models for the treatment of diabetic complications (Diabetes 42, 221-232 1993; Diabetologia 35, 946-950)
  • Aminoguanidine is known to be an NO synthase inhibitor (Eur. J Pharmacol., 233, 119-125) and to be useful for the treatment of disease states characterised by over production of NO (European J. of Pharmacology, 233, (1993), 119-125).
  • the inhibition of nitric oxide formation is particularly considered to be linked to the known activity of aminoguanidine in the treatment of diabetic complications European Patent Application, publication number.
  • Aminoguanidine is under evaluation in animal models for the treatment of diabetic complications (Diabetes 42:221-232 1993; Diabetologia 35:946- 950).
  • aminoguanidine or any other NO synthase inhibitor would have a beneficial effect on Type II diabetes itself.
  • the emphasis has been focused upon the complications of diabetes.
  • aminoguanidine shows potential for use in the treatment and/or prophylaxis of Type II diabetes per se.
  • aminoguanidine is indicated to delay or prevent the progression of non-insulin dependent diabetes from hyperinsulinaemia to overt diabetes. This novel and surprising effect is considered to be due to the NO synthase inhibitor activity of aminoguanidine on the Type II diabetic pancreas.
  • the present invention provides a method for the treatment and/or prophylaxis of Type II diabetes, which method comprises the administration, to a human or non-human mammal, of an effective non-toxic pharmaceutically acceptable amount of an NO synthase inhibitor or a pharmaceutically acceptable derivative thereof.
  • the invention provides a method for the prophylactic treatment of Type II diabetes, in particular delaying or preventing the progression from hyperinsulinaemia to hyperglycaemia.
  • Suitable, inhibitors of NO synthase include proteins and non-protein compounds, such as aminoguanidine, n-monomethylarginine, or other analogues of 1-arginine.
  • a particular NO synthase inhibitor is aminoguanidine.
  • 'NO synthase inhibitor' refers to an agent that inhibits the formation of nitric oxide from 1-arginine.
  • the NO synthase inhibitor activity of a compound is assessed in conventional tests such as inhibition of [ ⁇ H] 1 -arginine to [-1H] to citrulline or inhibition of nitric oxide generation by cells or tissue extracts or by recombinant nitric oxide synthase isoenzymes in vitro. ⁇ ASEB 1993;7:349-360.
  • a suitable pharmaceutically acceptable derivative is a pharmaceutically acceptable salt, or a pharmaceutically acceptable solvate thereof.
  • Suitable pharmaceutically acceptable salts include acid addition salts.
  • Suitable acid addition salts include pharmaceutically acceptable inorganic salts such as the sulphate, nitrate, phosphate, borate, hydrochloride and hydrobromide and pharmaceutically acceptable organic acid addition salts such as acetate, tartrate, maleate, citrate, succinate, benzoate, ascorbate, methane-sulphonate, a-keto glutarate and a- glycerophosphate, especially the maleate salt.
  • pharmaceutically acceptable inorganic salts such as the sulphate, nitrate, phosphate, borate, hydrochloride and hydrobromide
  • pharmaceutically acceptable organic acid addition salts such as acetate, tartrate, maleate, citrate, succinate, benzoate, ascorbate, methane-sulphonate, a-keto glutarate and a- glycerophosphate, especially the maleate salt.
  • Suitable pharmaceutically acceptable solvates include hydrates.
  • the NO synthase inhibitors used in the method of the invention may be prepared according to conventional methods such as the methods disclosed in the above mentioned publications for example aminoguanidine may be prepared according to the methods disclosed in J. Amer. Chem. Soc. 57,2730, (1935).
  • Salts and/or solvates may be prepared and isolated according to conventional procedures.
  • the present invention also provides an NO synthase inhibitor, such as aminoguanidine, or a pharmaceutically acceptable derivative thereof, for use in the treatment of and/or prophylaxis of Type II diabetes.
  • an NO synthase inhibitor such as aminoguanidine, or a pharmaceutically acceptable derivative thereof, for use in the treatment of and/or prophylaxis of Type II diabetes.
  • an NO synthase inhibitor such as aminoguanidine, or a pharmaceutically acceptable derivative thereof, for use in the manufacture of a medicament for the treatment and/or prophylaxis of Type II diabetes.
  • the NO synthase inhibitor such as aminoguanidine, or a pharmaceutically acceptable derivative thereof may be administered per s_ ⁇ or preferably as a pharmaceutical composition also comprising a pharmaceutically acceptable carrier.
  • the present invention also provides a pharmaceutical composition for the treatment and/or prophylaxis of Type II diabetes, which composition comprises an NO synthase inhibitor such as aminoguanidine, or a pharmaceutically acceptable derivative thereof, and a pharmaceutically acceptable carrier therefor.
  • an NO synthase inhibitor such as aminoguanidine
  • a pharmaceutically acceptable carrier therefor.
  • the term 'pharmaceutically acceptable embraces compounds, compositions and ingredients for both human and veterinary use: for example the term 'pharmaceutically acceptable salt' embraces a veterinarily acceptable salt.
  • composition may, if desired, be in the form of a pack accompanied by written or printed instructions for use.
  • compositions of the present invention will be adapted for oral administration, although compositions for administration by other routes, such as by injection and percutaneous absorption are also envisaged.
  • compositions for oral administration are unit dosage forms such as tablets and capsules.
  • Other fixed unit dosage forms, such as powders presented in sachets, may also be used.
  • the carrier may comprise a diluent, filler, disintegrant, wetting agent, lubricant, colourant, flavourant or other conventional adjuvant.
  • Typical carriers include, for example, microcrystalline cellulose, starch, sodium starch glycollate, polyvinylpyrrolidone, polyvinylpolypyrrolidone, magnesium stearate, sodium lauryl sulphate or sucrose.
  • composition will be formulated in unit dose form.
  • unit dose will normally contain an amount of the active ingredient in the range of from 0.1 to 1000 mg, more usually 0.1 to 500 mg, and more especially 0.1 to 250 mg.
  • the active ingredient may be administered as a pharmaceutical composition hereinbefore defined, and this forms a particular aspect of the present invention.
  • the NO synthase inhibitor such as aminoguanidine, or a pharmaceutically acceptable derivative thereof, may be taken in doses such as those described above, one to six times a day in a manner such that the total daily dose for a 70 kg adult will generally be in the range of from 0.1 to 6000 mg, and more usually about 1 to 1500 mg, generally about 0.5 to 10 mg. That is in the range of from 1.429 x 10' 3 to 85.714 mg/kg/day, more usually about 1.429 x 10" 2 to 21.429 mg/kg/day, generally about 7.143 x 10 -3 to 0.1429 mg/kg/day.
  • the obese db/db mouse is a genetic model of type 2 non-insulin dependent diabetes which is both insulin resistant and hyperglycaemic. Male animals were obtained at 6 weeks of age. Blood samples were taken by tail tip snip for measurement of pre- treatment blood glucose. Animals were allocated into treated and control groups such that the mean and standard deviation of the fasting blood glucose concentrations of each group was similar.
  • obese animals were normoglycaemic (blood glucose 10.4 ⁇ 0.97mM) but were hyperinsulinaemic compared to their lean litter mates (serum isulin 127 ⁇ 37 ng/ml in obese animals 3.05 ⁇ 1.03 ng/ml in leans).
  • the obese control group were hyperglycaemic (blood glucose 24.9 ⁇ 1.0 mM) and had markedly lower serum insulin levels (30.75 ⁇ 4.3 mM) compared to the pre-treatment values.
  • fasting blood glucose had risen to 28.1 ⁇ 2 mM and serum insulin concentrations had fallen further, to 11.7 ⁇ 1.8 ng/ml.

Landscapes

  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Diabetes (AREA)
  • Epidemiology (AREA)
  • Obesity (AREA)
  • Endocrinology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Hematology (AREA)
  • Emergency Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention concerne un procédé de traitement et/ou de prophylaxie de diabètes de type II comprenant l'administration, à un humain ou à mammifère non humain, d'une quantité pharmaceutiquement acceptable, non toxique, efficace d'un inhibiteur de ligase du monoxyde d'azote tel qu'une aminoguanadine ou l'un de ses dérivés pharmaceutiquement acceptable.
PCT/EP1997/000691 1997-02-13 1997-02-13 Inhibiteurs de la ligase du monoxyde d'azote utilises dans le traitement des diabetes WO1998035667A1 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
CA002280871A CA2280871A1 (fr) 1997-02-13 1997-02-13 Inhibiteurs de la ligase du monoxyde d'azote utilises dans le traitement des diabetes
PCT/EP1997/000691 WO1998035667A1 (fr) 1997-02-13 1997-02-13 Inhibiteurs de la ligase du monoxyde d'azote utilises dans le traitement des diabetes
EP97904442A EP0957909A1 (fr) 1997-02-13 1997-02-13 Inhibiteurs de la ligase du monoxyde d'azote utilises dans le traitement des diabetes
AU17251/97A AU1725197A (en) 1997-02-13 1997-02-13 Use of nitric oxid synthase inhibitors for the treatment of diabetes
JP53525798A JP2001512450A (ja) 1997-02-13 1997-02-13 糖尿病治療のための一酸化窒素シンターゼ阻害剤の使用

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/EP1997/000691 WO1998035667A1 (fr) 1997-02-13 1997-02-13 Inhibiteurs de la ligase du monoxyde d'azote utilises dans le traitement des diabetes

Related Child Applications (2)

Application Number Title Priority Date Filing Date
US09367295 A-371-Of-International 1999-10-07
US09/850,655 Continuation US20010025053A1 (en) 1999-10-07 2001-05-07 Use of nitric oxid synthase inhibitors for the treatment of diabetes

Publications (1)

Publication Number Publication Date
WO1998035667A1 true WO1998035667A1 (fr) 1998-08-20

Family

ID=8166520

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1997/000691 WO1998035667A1 (fr) 1997-02-13 1997-02-13 Inhibiteurs de la ligase du monoxyde d'azote utilises dans le traitement des diabetes

Country Status (5)

Country Link
EP (1) EP0957909A1 (fr)
JP (1) JP2001512450A (fr)
AU (1) AU1725197A (fr)
CA (1) CA2280871A1 (fr)
WO (1) WO1998035667A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1537864A1 (fr) * 2003-12-03 2005-06-08 Franz-Peter Dr. Liebel Utilisation d'acides aminés et de composés contenant du soufre pour la prévention et la thérapie du Diabetes mellitus type II déficitaire de UDP Glucuronosyltransférase 1
EP1537865A1 (fr) * 2003-12-03 2005-06-08 Franz-Peter Dr. Liebel Utilisation de composés contenant du soufre et d'enzymes protéolytiques pour la prévention et la thérapie du Diabètes mellitus type II déficitaire de UDP-Glucuronosyltransférase 1

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991012800A1 (fr) * 1990-02-28 1991-09-05 The Upjohn Company Utilisation de l'acide 3-guanidinopropionique pour le traitement et la prevention de troubles metaboliques
WO1996013256A1 (fr) * 1994-10-28 1996-05-09 Centre National De La Recherche Scientifique (Cnrs) Medicaments contenant des inhibiteurs de la nitrique-oxyde synthase pour le traitement des pathologies d'immunodeficience
WO1996016031A1 (fr) * 1994-11-23 1996-05-30 Pharmacia & Upjohn Company Carboxylates d'aminoguanidine destines au traitement du diabete sucre non insulinodependant

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991012800A1 (fr) * 1990-02-28 1991-09-05 The Upjohn Company Utilisation de l'acide 3-guanidinopropionique pour le traitement et la prevention de troubles metaboliques
WO1996013256A1 (fr) * 1994-10-28 1996-05-09 Centre National De La Recherche Scientifique (Cnrs) Medicaments contenant des inhibiteurs de la nitrique-oxyde synthase pour le traitement des pathologies d'immunodeficience
WO1996016031A1 (fr) * 1994-11-23 1996-05-30 Pharmacia & Upjohn Company Carboxylates d'aminoguanidine destines au traitement du diabete sucre non insulinodependant

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
M.L. LUKIC ET AL.: "Inhibition of nitric oxide generation ...", BIOCHEM. BIOPHYS. RES. COMMUNICATIONS, vol. 178, no. 3, 15 August 1991 (1991-08-15), pages 913 - 920, XP000673245 *
MARAL KOCHAKIAN ET AL.: "Chronic dosing with aminoguanidine...", DIABETES, vol. 45, no. 12, December 1996 (1996-12-01), pages 1694 - 1700, XP002043815 *
N.E. CAMERON ET AL.: "Rapid reversal by aminoguanidine...", METABOLISM, vol. 45, no. 9, September 1996 (1996-09-01), pages 1147 - 1152, XP002043816 *
S. SWAMY-MRUTHINTI ET AL.: "Inhibition of cataracts in moderately diabetic rats by aminoguanidine", EXPERIMENTAL EYE RESEARCH, vol. 62, no. 4, 1996, pages 505 - 510, XP002043817 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1537864A1 (fr) * 2003-12-03 2005-06-08 Franz-Peter Dr. Liebel Utilisation d'acides aminés et de composés contenant du soufre pour la prévention et la thérapie du Diabetes mellitus type II déficitaire de UDP Glucuronosyltransférase 1
EP1537865A1 (fr) * 2003-12-03 2005-06-08 Franz-Peter Dr. Liebel Utilisation de composés contenant du soufre et d'enzymes protéolytiques pour la prévention et la thérapie du Diabètes mellitus type II déficitaire de UDP-Glucuronosyltransférase 1

Also Published As

Publication number Publication date
AU1725197A (en) 1998-09-08
CA2280871A1 (fr) 1998-08-20
EP0957909A1 (fr) 1999-11-24
JP2001512450A (ja) 2001-08-21

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