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WO2008008033A1 - The use of naphtoquinones in the treatment and control of diabetes, insulin resistance and hyperglycemia - Google Patents

The use of naphtoquinones in the treatment and control of diabetes, insulin resistance and hyperglycemia Download PDF

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Publication number
WO2008008033A1
WO2008008033A1 PCT/SE2007/050507 SE2007050507W WO2008008033A1 WO 2008008033 A1 WO2008008033 A1 WO 2008008033A1 SE 2007050507 W SE2007050507 W SE 2007050507W WO 2008008033 A1 WO2008008033 A1 WO 2008008033A1
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Prior art keywords
derivative
glx
oxidase
nad
insulin resistance
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PCT/SE2007/050507
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French (fr)
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Mona Wilcke
Bo Svensson
Björn Walse
Tore Bengtsson
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Glucox Biotech Ab
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Priority to EP07769053A priority Critical patent/EP2046313A4/en
Publication of WO2008008033A1 publication Critical patent/WO2008008033A1/en

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    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
    • A61K31/37—Coumarins, e.g. psoralen
    • 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
    • A61P3/04—Anorexiants; Antiobesity 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
    • A61P3/06—Antihyperlipidemics
    • 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
    • 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

  • the present invention relates to naphthoquinon derivitives and closely related compounds or tautomers or stereoisomeric forms thereof for the prophylaxis or treatment of metabolic disorders mediated by insulin resistance or hyperglycaemia, comprising diabetes type 2, inadequate glucose tolerance, insulin resistance, obesity, polycystic ovary syndrome (PCOS), hypertension and the metabolic syndrome (also known as syndrome X).
  • the invention also relates to compositions comprising a naphthoquinone derivative, a fiavone derivative, warfarin or dicumarol, as an anti-diabetic agent, and to methods for prophylaxis or treatment of the above-mentioned medical conditions.
  • Type 1 or insulin-dependent diabetes
  • type 2 insulin- independent diabetes
  • Glucose enters the bloodstream after a meal, and the body's normal response is to release insulin from the pancreas. Insulin then acts as a key, opening cells to allow glucose in from the bloodstream. Once inside the cells, the glucose turns into energy that the body needs in order to function normally.
  • Type 1 diabetes occurs when the pancreas is unable to produce insulin, usually because of autoimmune destruction.
  • Type 2 diabetes which 90 percent of all diabetes patients suffer from, develops when muscle, fat and liver cells fail to respond normally to insulin. This failure to respond is called insulin resistance. The pancreas initially compensates for this by increasing the insulin output. However, over time these cells "burn out” and become unable to produce enough insulin to maintain normal glucose levels, indicating a serious and dangerous progression to type 2 diabetes.
  • Hyperglycemia is a condition in which the blood contains an abnormally high level of glucose. If not controlled, high blood glucose levels can damage blood vessels, preventing oxygen and other essential nutrients from reaching vital areas. This can cause complications affecting serious functions and body organs, including the kidneys, the circulation system, the nerves and the eyes.
  • Chronic hyperglycaemia is the main cause of increased oxidative stress in type 2 diabetes patients.
  • the over-production of Reactive Oxygen Species, ROS, and nitric oxide radicals leads to the damage of many cellular compounds including lipids, proteins and nucleic acids.
  • a growing body of research data demonstrates signs of increased oxidative stress in type 2 diabetes. It is likely that the oxidative stress is contributing to many of the vascular complications occurring in the late stages of the disease, but the evidence for oxidative stress as a causative factor in the development of insulin resistance and deterioration of beta cell function is still lacking.
  • Methods for treating type 2 diabetes typically include lifestyle changes, especially diet and exercise, as well as the administration of insulin or oral medications to help the body with the glucose administration. Most drugs used to treat type 2 diabetes do not contain insulin, and the pancreas still has to make insulin in order to function efficiently. In time, people with type 2 diabetes develop "beta-cell failure" or the inability of the pancreas to release insulin in response to high blood glucose levels. These people often require insulin injections, in combination with oral medications, or just insulin to manage their diabetes.
  • the many medicaments used in the treatment of diabetes comprise for example the following compounds: sulfonylurea, which lowers blood glucose by stimulating the pancreas to release more insulin; biguanides, which improve insulin's ability to move glucose into cells, especially muscle cells, and prevent the liver from releasing stored glucose; thiazolidinediones, which improve insulin resistance in muscle cells and in fat tissue, lower the amount of glucose released by the liver, and make adipocytes more sensitive to the effects of insulin; alpha-glycosidase inhibitors, which block enzymes that help digest starches, slowing the rise in blood glucose; and meglitinides, which lower blood glucose by stimulating the pancreas to release more insulin.
  • sulfonylurea which lowers blood glucose by stimulating the pancreas to release more insulin
  • biguanides which improve insulin's ability to move glucose into cells, especially muscle cells, and prevent the liver from releasing stored glucose
  • thiazolidinediones which improve insulin resistance in muscle cells and in
  • Naphthoquinones and derivatives thereof are known, and in some cases also in connection with the reduction of blood glucose levels.
  • One derivative, Shikonin has been shown to yield increase in glucose uptake in fat and myocardic cell cultures.
  • it has not been known that it could be implicated in insulin-resistance or improvement in blood hyperglycemia.
  • some of these known derivatives may have the stated effect, or at least some effect, many of said derivatives also exhibit toxic properties. Therefore, there is a need for treatments comprising alternative compounds that are both efficient as well as non-toxic.
  • the present invention meets this need by providing selected effective and non-toxic naphthoquinone (also called naphthalenedione) derivatives and closely related compounds such as fiavone derivatives, warfarin, dicumarol, which increase glucose uptake and decrease blood glucose levels in a treated subject.
  • naphthoquinone also called naphthalenedione
  • closely related compounds such as fiavone derivatives, warfarin, dicumarol
  • said compounds may be used in a method of preventing, postponing, or treating conditions characterized by hyperglycemia, and metabolic disorders mediated by insulin resistance or hyperglycaemia, comprising type 2 diabetes, inadequate glucose tolerance, insulin resistance, diabetes-related diseases such as atherosclerosis, microangiopathy, diabetic retinopathy and the like, obesity, polycystic ovary syndrome (PCOS) and the metabolic syndrome (syndrome X).
  • type 2 diabetes inadequate glucose tolerance
  • insulin resistance diabetes-related diseases such as atherosclerosis, microangiopathy, diabetic retinopathy and the like
  • obesity polycystic ovary syndrome
  • SCOS polycystic ovary syndrome
  • this invention relates to anti-diabetic derivatives, and tautomers and stereoisomeric forms, of 1 ,4-naphthoquinones and closely related compounds such as fiavone derivatives, warfarin, dicumarol and 1 ,2-naphtoquinone, and pharmaceutically acceptable salts thereof, such as a hydrochloride, e.g. a salt of the carboxy group thereof.
  • 1 ,4-naphthoquinone affect Reactive Oxygen Species (ROS) production or inhibits electron transfer in fiavone binding proteins by inhibiting the production of superoxide or hydrogen peroxide.
  • ROS Reactive Oxygen Species
  • Said anti-diabetic compounds of the invention can also be combined with alkylating agents, intercalating agents, metal coordination complexes, pyrimidine nucleosides, purine nucleosides, inhibitors of nucleic acid-associated enzymes and proteins, and agents affecting structural proteins and cytoplasmic enzymes.
  • Allopurinol is for example known to inhibit the formation of ROS by xantine oxidase, a fiavone binding enzyme.
  • a combination of 1 ,4-naphthoquinones compounds and allopurinol is expected to have a synergistic effect on inhibition of NADH/NADPH containing enzymes (fiavone binding enzymes) producing ROS.
  • the pharmaceutical composition may also comprise inhibitors of HMG-CoA reductase including statins such as lovastatin, simvastatin, atorvastatin, or other inhibitors of ROS- producing enzymes, such as gliotoxin and phenothiazines such as phenothiazine, trifluroperazine, avastatin, valsartan and/or a derivative of any one of the above-mentioned compounds or known inhibitors or antagonists of the ROS generating enzyme NAD(P)H- oxidase e.g. apocynin.
  • statins such as lovastatin, simvastatin, atorvastatin, or other inhibitors of ROS- producing enzymes, such as gliotoxin and phenothiazines such as phenothiazine, trifluroperazine, avastatin, valsartan and/or a derivative of any one of the above-mentioned compounds or known
  • inhibitors or antagonists of NAD(P)H-oxidase are those selected from the group consisting of pyridine, imidazole, diethylpyrocarbonate, chloromercuribenzoic acid, 4- (2-aminomethyl)-sulfonyl fluoride and acetovanillone, including derivatives thereof.
  • the inhibitor or antagonist is e.g. a compound having an inhibitory effect on the ROS-generating activity of the mitochondrial respiratory complex 1-4, NAD(P)H oxidase or the NAD(P)H oxidase complex.
  • the inhibitor or antagonist could exert its effect by interacting with the active site or a regulatory site, or both sites, of the NAD(P)H oxidase.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound according to the present invention, or a salt of said compound, and any pharmaceutically acceptable carriers, diluents, buffers or excipients.
  • the compounds or the pharmaceutical compositions according to the invention may be used in the manufacturing of a medicament for prophylaxis or treatment of the above-mentioned medical conditions.
  • the present invention relates to the use of a naphtoquinone derivative or a tautomer or a stereoisomeric form thereof comprising a compound of the general formula (1)
  • Rl represents hydrogen, hydroxy, methyl, propyl, butyl, isobutyl, tert-butyl, 2,2- dimethylpropyl, methoxy, chloro, nitrilo, 4-hydroxyphenyl, 4-nitrophenyl, 3-methyl-2- butenyl, 4-methyl-3-pentenyl or l-acetyl-4-methyl-3-pentenyl
  • R2 represents hydrogen, hydroxy, methyl, ethyl, methoxy, chloro, nitrilo, 4-nitrophenyl or 3- methyl-2-butenyl, or Rl and R2, taken together, form a phenyl ring,
  • R3 represents hydrogen, hydroxy, methoxy, acetyl, amino, nitro or toluensulfonyl and R4 represents hydrogen or hydroxyl with the proviso that Rl and R2 are not simultaneously chloro when R3 and R4 are hydroxy.
  • the present invention also relates to the use of a fiavone derivative or a tautomer or a stereoisomeric form thereof comprising a compound of the general formula (2)
  • Rl represents hydrogen, hydroxy, methoxy or isopropoxy
  • R2 represents hydrogen or hydroxy
  • R3 represents hydrogen, hydroxy, methoxy or isopropoxy
  • R4 represents hydrogen, hydroxy, methoxy or isopropoxy
  • R5 represents hydrogen or methoxy
  • the present invention relates to the use of warfarin, dicumarol and 1,2- naphtoquinone having the following structures:
  • the compounds according to the present invention are believed to change the ROS levels produced from NAD and FAD binding proteins particularly xantine oxidase, the mitochondrial respiratory complex, the enzyme NAD(P)H- oxidase , oxidoreductase, and NAD(P)H-ubiquinone Examples
  • Example 1 Increase of glucose uptake in rat skeletal muscle cells.
  • Naphthoquinone and naphthalenedione derivatives thereof increase glucose uptake in rat skeletal muscle cells.
  • Cell culture medium fetal bovine serum, antibiotics, trypsin-EDTA were purchased from Life Technologies, bovine insulin and bovine serum albumin were purchased from Sigma.
  • 2- Deoxy-[ 3 H] glucose was purchased from NEN Life Science Products.
  • Tissue culture plastics were purchased from Becton Dickinson.
  • Rat skeletal muscle L6 cells were grown in minimal essential medium ( ⁇ -MEM Glutamax I) containing 10% fetal bovine serum at 37. degree. C, 5% CO. The cells were passaged three times a week by treatment with trypsin-EDTA and transfer of 1/3 of the cells to new flasks with fresh culture medium. For differentiation into myotubes, 30,000 cells were seeded in 1 ml in 24-well plates. When the cells were confluent, usually after 3 days, the medium was replaced by differentiation medium consisting of ⁇ -MEM, 2% fetal bovine serum and penicillin/streptomycin at a concentration of 100 U/ml and 100 ⁇ g/ml, respectively. The medium was replaced every 2 days. The cells were differentiated for 7-8 days before being used in experiments.
  • ⁇ -MEM Glutamax I containing 10% fetal bovine serum at 37. degree. C, 5% CO.
  • the cells were passaged three times a week by treatment with trypsin-EDTA and transfer of 1/3 of
  • the wells were emptied and 0.5 ml prewarmed PBS without Ca.sup.2+/mg.sup.2+ containing 1 ⁇ Ci/ml radioactive 2-deoxy-glucose added. After 10 min at 37. degree. C, the wells were emptied and washed three times with cold PBS. The cell monolayer was solubilized in 0.5 ml 0.5 M NaOH for 30 minutes at 60 degrees temperature. 500 microliter was mixed with 4 ml scintillation fluid (Optiphase, Wallac) and counted in a scintillation counter (Packard TriCarb).
  • FIG. 1 shows results for GLX-OlO; similar results were obtained for the other compounds of the invention. This increase is comparable to that caused by insulin. This effect is seen when cells are stimulated with 0.1-10 micromolar Naphthoquinone and Naphthalenedione derivatives for 2-20 h.
  • Naphthoquinone and Naphthalenedione derivatives enhances a constitutive activity of the insulin receptor and/or the intracellular insulin-signaling pathway.
  • Control untreated cells
  • Insulin cells treated with insulin for 1 h
  • Drug cells treated with 1 mmolar of Naphthoquinone and Naphthalenedione derivatives for 20 hours.
  • Example 3 Animal studies of effect on type 2 diabetes Studies were conducted in vivo, in an animal model of obesity characterized by insulin- resistance, described as ob/ob mice. Ob/ob mice of about 15 weeks were obtained from TACONICS, Copenhagen, DENMARK. The animals were injected intraperitoneally (i.p.) once daily with 8-hydroxy-2-methyl-l,4- naphtoquinone (10 mg/kg) or DMSO with 10% olive oil, for 4 days. On day 4, after the last injection, their blood glucose levels were monitored for 3 h by sampling from the tail. The glucose concentration was determined using a Glucometer AccuCheck (Roche). Without any overt side effects of the drug treatment, the treated animals exhibited significantly lower blood glucose levels than the control group 1-3 h after the last injection, showing a decrease in blood glucose levels ( Figure 3).
  • the software QikProp (from Schrodinger) was used to make rapid ADME (absorption, distribution, metabolism, excretion) predictions of the compounds according to the present invention. This is important in order to get a general idea about membrane passage and oral availability of the compounds. These results, together with a number of other predicted ADME properties that were found, indicated that the membrane permeability and human oral absorption was predicted to be high. The human oral absorption would most likely be above 50%.
  • GLX008 and GLXO 18 was predicted to have a lower membrane permeability and around 50 % human oral absorption.
  • Example 5 Biological in vivo assay. Experimental model of type 2 diabetes (oral postprandial glycemia in GK- rats) and insulin resistance.

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Abstract

The present invention relates to naphthoquinon derivit ives and closely related compounds or tautomers or stereoiso meric forms thereof for the prophylaxis or treatment of metabolic disorders mediated by insulin resistance or hyperglycaemia, comprising diabetes type 2, inadequate glucose tolerance, insulin resistance, obesity, polycyst ic ovary syndro me (PCOS), hypertensio n and the metabolic syndrome. The invention also relates to compositions comprising a naphthoquinone derivative, a flavone derivative, warfarin or dicumarol, as an anti-diabetic agent, and to methods for prophylaxis or treatment of the above-mentioned medical conditions.

Description

THE USE OF NAPHTOQUINONES IN THE TREATMENT AND CONTROL OF DIABETES, INSULIN RESISTANCE AND HYPERGLYCEMIA.
Field of the invention The present invention relates to naphthoquinon derivitives and closely related compounds or tautomers or stereoisomeric forms thereof for the prophylaxis or treatment of metabolic disorders mediated by insulin resistance or hyperglycaemia, comprising diabetes type 2, inadequate glucose tolerance, insulin resistance, obesity, polycystic ovary syndrome (PCOS), hypertension and the metabolic syndrome (also known as syndrome X). The invention also relates to compositions comprising a naphthoquinone derivative, a fiavone derivative, warfarin or dicumarol, as an anti-diabetic agent, and to methods for prophylaxis or treatment of the above-mentioned medical conditions.
Background Diabetes comprises two distinct diseases, Type 1 (or insulin-dependent diabetes) and type 2 (insulin- independent diabetes), both of which involve the interruption of glucose homeostasis. Glucose enters the bloodstream after a meal, and the body's normal response is to release insulin from the pancreas. Insulin then acts as a key, opening cells to allow glucose in from the bloodstream. Once inside the cells, the glucose turns into energy that the body needs in order to function normally.
Type 1 diabetes occurs when the pancreas is unable to produce insulin, usually because of autoimmune destruction. Type 2 diabetes, which 90 percent of all diabetes patients suffer from, develops when muscle, fat and liver cells fail to respond normally to insulin. This failure to respond is called insulin resistance. The pancreas initially compensates for this by increasing the insulin output. However, over time these cells "burn out" and become unable to produce enough insulin to maintain normal glucose levels, indicating a serious and dangerous progression to type 2 diabetes.
Hyperglycemia is a condition in which the blood contains an abnormally high level of glucose. If not controlled, high blood glucose levels can damage blood vessels, preventing oxygen and other essential nutrients from reaching vital areas. This can cause complications affecting serious functions and body organs, including the kidneys, the circulation system, the nerves and the eyes.
Chronic hyperglycaemia is the main cause of increased oxidative stress in type 2 diabetes patients. The over-production of Reactive Oxygen Species, ROS, and nitric oxide radicals leads to the damage of many cellular compounds including lipids, proteins and nucleic acids. A growing body of research data demonstrates signs of increased oxidative stress in type 2 diabetes. It is likely that the oxidative stress is contributing to many of the vascular complications occurring in the late stages of the disease, but the evidence for oxidative stress as a causative factor in the development of insulin resistance and deterioration of beta cell function is still lacking.
Methods for treating type 2 diabetes typically include lifestyle changes, especially diet and exercise, as well as the administration of insulin or oral medications to help the body with the glucose administration. Most drugs used to treat type 2 diabetes do not contain insulin, and the pancreas still has to make insulin in order to function efficiently. In time, people with type 2 diabetes develop "beta-cell failure" or the inability of the pancreas to release insulin in response to high blood glucose levels. These people often require insulin injections, in combination with oral medications, or just insulin to manage their diabetes. The many medicaments used in the treatment of diabetes comprise for example the following compounds: sulfonylurea, which lowers blood glucose by stimulating the pancreas to release more insulin; biguanides, which improve insulin's ability to move glucose into cells, especially muscle cells, and prevent the liver from releasing stored glucose; thiazolidinediones, which improve insulin resistance in muscle cells and in fat tissue, lower the amount of glucose released by the liver, and make adipocytes more sensitive to the effects of insulin; alpha-glycosidase inhibitors, which block enzymes that help digest starches, slowing the rise in blood glucose; and meglitinides, which lower blood glucose by stimulating the pancreas to release more insulin.
Naphthoquinones and derivatives thereof are known, and in some cases also in connection with the reduction of blood glucose levels. One derivative, Shikonin, has been shown to yield increase in glucose uptake in fat and myocardic cell cultures. However, it has not been known that it could be implicated in insulin-resistance or improvement in blood hyperglycemia. However, although some of these known derivatives may have the stated effect, or at least some effect, many of said derivatives also exhibit toxic properties. Therefore, there is a need for treatments comprising alternative compounds that are both efficient as well as non-toxic.
Summary of the invention
The present invention meets this need by providing selected effective and non-toxic naphthoquinone (also called naphthalenedione) derivatives and closely related compounds such as fiavone derivatives, warfarin, dicumarol, which increase glucose uptake and decrease blood glucose levels in a treated subject.
According to one aspect, said compounds may be used in a method of preventing, postponing, or treating conditions characterized by hyperglycemia, and metabolic disorders mediated by insulin resistance or hyperglycaemia, comprising type 2 diabetes, inadequate glucose tolerance, insulin resistance, diabetes-related diseases such as atherosclerosis, microangiopathy, diabetic retinopathy and the like, obesity, polycystic ovary syndrome (PCOS) and the metabolic syndrome (syndrome X). This includes preventing or postponing insulin- independent diabetes mellitus development by decrease of insulin- insufficiency and normalization of tolerance to glucose in clinically healthy patients not having any enhanced basal levels of blood glucose.
More particularly, this invention relates to anti-diabetic derivatives, and tautomers and stereoisomeric forms, of 1 ,4-naphthoquinones and closely related compounds such as fiavone derivatives, warfarin, dicumarol and 1 ,2-naphtoquinone, and pharmaceutically acceptable salts thereof, such as a hydrochloride, e.g. a salt of the carboxy group thereof.
Without being bound by theory, it is hypothesised that these 1 ,4-naphthoquinones affect Reactive Oxygen Species (ROS) production or inhibits electron transfer in fiavone binding proteins by inhibiting the production of superoxide or hydrogen peroxide. As used herein, the term " 1 ,4-naphthoquinone" means the following structure:
Figure imgf000005_0001
Said anti-diabetic compounds of the invention can also be combined with alkylating agents, intercalating agents, metal coordination complexes, pyrimidine nucleosides, purine nucleosides, inhibitors of nucleic acid-associated enzymes and proteins, and agents affecting structural proteins and cytoplasmic enzymes. Allopurinol is for example known to inhibit the formation of ROS by xantine oxidase, a fiavone binding enzyme. O
Figure imgf000005_0002
Allopurinol
A combination of 1 ,4-naphthoquinones compounds and allopurinol is expected to have a synergistic effect on inhibition of NADH/NADPH containing enzymes (fiavone binding enzymes) producing ROS.
The pharmaceutical composition may also comprise inhibitors of HMG-CoA reductase including statins such as lovastatin, simvastatin, atorvastatin, or other inhibitors of ROS- producing enzymes, such as gliotoxin and phenothiazines such as phenothiazine, trifluroperazine, avastatin, valsartan and/or a derivative of any one of the above-mentioned compounds or known inhibitors or antagonists of the ROS generating enzyme NAD(P)H- oxidase e.g. apocynin.
Examples of known inhibitors or antagonists of NAD(P)H-oxidase are those selected from the group consisting of pyridine, imidazole, diethylpyrocarbonate, chloromercuribenzoic acid, 4- (2-aminomethyl)-sulfonyl fluoride and acetovanillone, including derivatives thereof. The inhibitor or antagonist is e.g. a compound having an inhibitory effect on the ROS-generating activity of the mitochondrial respiratory complex 1-4, NAD(P)H oxidase or the NAD(P)H oxidase complex. The inhibitor or antagonist could exert its effect by interacting with the active site or a regulatory site, or both sites, of the NAD(P)H oxidase.
According to another aspect, the present invention relates to a pharmaceutical composition comprising a compound according to the present invention, or a salt of said compound, and any pharmaceutically acceptable carriers, diluents, buffers or excipients.
According to a further aspect, the compounds or the pharmaceutical compositions according to the invention may be used in the manufacturing of a medicament for prophylaxis or treatment of the above-mentioned medical conditions.
Detailed description of the invention
The present invention relates to the use of a naphtoquinone derivative or a tautomer or a stereoisomeric form thereof comprising a compound of the general formula (1)
Figure imgf000006_0001
wherein Rl represents hydrogen, hydroxy, methyl, propyl, butyl, isobutyl, tert-butyl, 2,2- dimethylpropyl, methoxy, chloro, nitrilo, 4-hydroxyphenyl, 4-nitrophenyl, 3-methyl-2- butenyl, 4-methyl-3-pentenyl or l-acetyl-4-methyl-3-pentenyl, R2 represents hydrogen, hydroxy, methyl, ethyl, methoxy, chloro, nitrilo, 4-nitrophenyl or 3- methyl-2-butenyl, or Rl and R2, taken together, form a phenyl ring,
R3 represents hydrogen, hydroxy, methoxy, acetyl, amino, nitro or toluensulfonyl and R4 represents hydrogen or hydroxyl with the proviso that Rl and R2 are not simultaneously chloro when R3 and R4 are hydroxy.
The present invention also relates to the use of a fiavone derivative or a tautomer or a stereoisomeric form thereof comprising a compound of the general formula (2)
Figure imgf000007_0001
wherein
Rl represents hydrogen, hydroxy, methoxy or isopropoxy, R2 represents hydrogen or hydroxy, R3 represents hydrogen, hydroxy, methoxy or isopropoxy, R4 represents hydrogen, hydroxy, methoxy or isopropoxy and R5 represents hydrogen or methoxy.
Furthermore the present invention relates to the use of warfarin, dicumarol and 1,2- naphtoquinone having the following structures:
Figure imgf000008_0001
warfarin
Figure imgf000008_0002
dicumarol
Figure imgf000008_0003
1 , 2-naphtoquinone
For the above mentioned medical indications, particularly good results have been obtained with the following compounds:
Figure imgf000008_0004
Figure imgf000008_0006
Figure imgf000008_0005
GLX 018
Figure imgf000009_0001
Figure imgf000009_0002
GLX 109 GLX 110 GLX 115
Figure imgf000009_0003
GLX 117 GLX 118
Figure imgf000010_0001
Figure imgf000010_0002
Figure imgf000010_0003
GLX 501 GLX 503 GLX 600
Figure imgf000011_0001
GLX 505 GLX 506 GLX 507
Figure imgf000011_0002
GLX 508 shikonin
Figure imgf000011_0003
Figure imgf000012_0001
GLX 18
Figure imgf000012_0002
Without being bound to any theory, the compounds according to the present invention are believed to change the ROS levels produced from NAD and FAD binding proteins particularly xantine oxidase, the mitochondrial respiratory complex, the enzyme NAD(P)H- oxidase , oxidoreductase, and NAD(P)H-ubiquinone Examples
Example 1 - Increase of glucose uptake in rat skeletal muscle cells.
Naphthoquinone and naphthalenedione derivatives thereof increase glucose uptake in rat skeletal muscle cells.
Cell culture medium, fetal bovine serum, antibiotics, trypsin-EDTA were purchased from Life Technologies, bovine insulin and bovine serum albumin were purchased from Sigma. 2- Deoxy-[3H] glucose (specific activity 1102.6 GBq/mmol) was purchased from NEN Life Science Products. Tissue culture plastics were purchased from Becton Dickinson.
Rat skeletal muscle L6 cells were grown in minimal essential medium (α-MEM Glutamax I) containing 10% fetal bovine serum at 37. degree. C, 5% CO. The cells were passaged three times a week by treatment with trypsin-EDTA and transfer of 1/3 of the cells to new flasks with fresh culture medium. For differentiation into myotubes, 30,000 cells were seeded in 1 ml in 24-well plates. When the cells were confluent, usually after 3 days, the medium was replaced by differentiation medium consisting of α-MEM, 2% fetal bovine serum and penicillin/streptomycin at a concentration of 100 U/ml and 100 μg/ml, respectively. The medium was replaced every 2 days. The cells were differentiated for 7-8 days before being used in experiments.
On the day before the glucose transport assay, the wells of the culture plate were emptied and 1 ml serum free DMEM containing 5 mM glucose and penicillin/streptomycin was added. In some experiments the cells were treated over night with test compounds in 1 ml and additional treatments were added the next day to give a total volume of 2 ml. In these experiments, insulin (100-1000 nM) was added in 0.2 ml. When all treatments were performed after 2-20 h in serum free medium, a total volume of 1 ml was used. The wells were emptied and 0.5 ml prewarmed PBS without Ca.sup.2+/mg.sup.2+ containing 1 μCi/ml radioactive 2-deoxy-glucose added. After 10 min at 37. degree. C, the wells were emptied and washed three times with cold PBS. The cell monolayer was solubilized in 0.5 ml 0.5 M NaOH for 30 minutes at 60 degrees temperature. 500 microliter was mixed with 4 ml scintillation fluid (Optiphase, Wallac) and counted in a scintillation counter (Packard TriCarb). When differentiated L6 cells are incubated with the Naphthoquinone and Naphthalenedione derivatives a significant increase in glucose uptake can be observed. Figure 1 shows results for GLX-OlO; similar results were obtained for the other compounds of the invention. This increase is comparable to that caused by insulin. This effect is seen when cells are stimulated with 0.1-10 micromolar Naphthoquinone and Naphthalenedione derivatives for 2-20 h. On the basis of the above results it is postulated that Naphthoquinone and Naphthalenedione derivatives enhances a constitutive activity of the insulin receptor and/or the intracellular insulin-signaling pathway. Control: untreated cells, Insulin: cells treated with insulin for 1 h, Drug: cells treated with 1 mmolar of Naphthoquinone and Naphthalenedione derivatives for 20 hours.
Example 2: Phosphorylation of AMPK
Differentiated L6 cells were treated with Shikonin for 2 h before washed with phosphate- buffered saline and lysed directly by addition of radio immunoprecipitation assay buffer (I x phosphate-buffered saline, 1% (v/v) Igepal CA-630, 0.5% (v/v) sodium deoxycholate, 0.1% (v/v) sodium lauryl sulfate, ImM phenylmethylsulfonyl fluoride (PMSF), ImM sodium ortho vanadate, lμg/ml aprotinin). Cells were lysed and total cell lysates were mixed with sample buffer (62.5mM Tris pH6.8, 2% SDS, 10% glycerol, 5OmM dithiothreitol, 0.1% bromophenolblue), boiled and electrophoresed on 12% polyacrylamide gels and electro transferred to Hybond-P membranes (pore size 0.45μm; Amersham Biosciences Inc.). After blocking with 5% (v/v) non-fat dry milk in Tris-buffered saline for Ih at room temperature, membranes were incubated with anti-AMPK antibodies (1:500 dilution; Santa-Cruz) overnight at 4C and detected using a secondary antibody (horseradish peroxidase-linked anti- rabbit IgG) diluted 1:1000 and enhanced chemiluminescence (Amersham Biocsinces Inc.). The results are shown in Figure 2.
Example 3 - Animal studies of effect on type 2 diabetes Studies were conducted in vivo, in an animal model of obesity characterized by insulin- resistance, described as ob/ob mice. Ob/ob mice of about 15 weeks were obtained from TACONICS, Copenhagen, DENMARK. The animals were injected intraperitoneally (i.p.) once daily with 8-hydroxy-2-methyl-l,4- naphtoquinone (10 mg/kg) or DMSO with 10% olive oil, for 4 days. On day 4, after the last injection, their blood glucose levels were monitored for 3 h by sampling from the tail. The glucose concentration was determined using a Glucometer AccuCheck (Roche). Without any overt side effects of the drug treatment, the treated animals exhibited significantly lower blood glucose levels than the control group 1-3 h after the last injection, showing a decrease in blood glucose levels (Figure 3).
Example 4 - Prediction of oral availability and membrane passage in humans
The software QikProp (from Schrodinger) was used to make rapid ADME (absorption, distribution, metabolism, excretion) predictions of the compounds according to the present invention. This is important in order to get a general idea about membrane passage and oral availability of the compounds. These results, together with a number of other predicted ADME properties that were found, indicated that the membrane permeability and human oral absorption was predicted to be high. The human oral absorption would most likely be above 50%.
GLX008 and GLXO 18 was predicted to have a lower membrane permeability and around 50 % human oral absorption.
Example 5 - Biological in vivo assay. Experimental model of type 2 diabetes (oral postprandial glycemia in GK- rats) and insulin resistance.
When determining the anti-diabetic effect of Shikonin (5,8-Dihydroxy-2-(l-hydroxy-4- methyl-3-pentenyl)-l,4-naphthoquinone) in a model of hyperglycemia in GK rats, in vivo, the animals were injected intraperitoneally (i.p.) once daily with 5,8-Dihydroxy-2-(l-hydroxy-4- methyl-3-pentenyl)-l,4-naphthoquinone (10 mg/kg solubilized in DMSO and 10% olive oil or as in control rats; DMSO alone with 10% olive oil for 4 days. On day 4, after the last injection, their blood glucose levels were monitored for 3 h by sampling from the tail. The glucose concentration was determined using a Glucometer AccuCheck (Roche). After the Shikonin-treatment the animals exhibited lower blood glucose levels than in the control group 1-3 h after the last injection, showing a decrease in blood glucose levels.

Claims

1. Use of a naphtoquinone derivative or a tautomer or a stereoisomeric form thereof for the preparation of a medicament for the prophylaxis or treatment of metabolic disorders mediated by insulin resistance or hyperglycemia, said naphtoquinone derivative or tautomer and stereoisomeric form thereof comprising a compound of the general formula (1):
Figure imgf000016_0001
wherein
Rl represents hydrogen, hydroxy, methyl, propyl, butyl, isobutyl, tert-butyl, 2,2- dimethylpropyl, methoxy, chloro, nitrilo, 4-hydroxyphenyl, 4-nitrophenyl, 3-methyl-2- butenyl, 4-methyl-3-pentenyl or l-acetyl-4-methyl-3-pentenyl, R2 represents hydrogen, hydroxy, methyl, ethyl, methoxy, chloro, nitrilo, 4-nitrophenyl or 3- methyl-2-butenyl, or Rl and R2, taken together, form a phenyl ring,
R3 represents hydrogen, hydroxy, methoxy, acetyl, amino, nitro or toluensulfonyl and R4 represents hydrogen or hydroxy.
Use according to claim 1 , wherein the compound is selected
Figure imgf000017_0001
Figure imgf000017_0002
Figure imgf000018_0001
GLX 109 GLX 110 GLX 115
Figure imgf000018_0002
Figure imgf000018_0003
GLX 201
Figure imgf000019_0001
GLX 501 GLX 503 GLX 600
Figure imgf000019_0002
GLX 508 shikonin
3. Use according to claim 1, wherein the compound is selected from:
Figure imgf000019_0003
Figure imgf000020_0001
GLX 104
GLX 103
Figure imgf000020_0002
4. Use according to claim 3, wherein the compound is selected from:
Figure imgf000020_0003
5. Use according to any of the preceding claims, wherein the medicament is an anti-diabetic agent.
6. Use according to any claims 1-5, where said derivative is used for preparation of a medicament for the prophylaxis or treatment of metabolic disorders selected from type 2 diabetes, inadequate glucose tolerance, insulin resistance, obesity, polycystic ovary syndrome (PCOS), hypertension and the metabolic syndrome.
7. Use of a fiavone derivative or a tautomer or a stereoisomeric form thereof for the preparation of a medicament for the treatment of metabolic disorders mediated by insulin resistance or hyperglycemia, said fiavone derivative or tautomer or stereoisomeric form thereof comprising a compound of the general formula (2)
Figure imgf000021_0001
wherein
Rl represents hydrogen, hydroxy, methoxy or isopropoxy, R2 represents hydrogen or hydroxy, R3 represents hydrogen, hydroxy, methoxy or isopropoxy, R4 represents hydrogen, hydroxy, methoxy or isopropoxy and R5 represents hydrogen or methoxy.
Use according to claim 6, wherein the compound is selected from:
Figure imgf000021_0002
Figure imgf000022_0001
GLX 18
Figure imgf000022_0002
9. Use according to any of claims 7-8, wherein the medicament is an anti-diabetic agent.
10. Use according to any of claims 7-8, where said derivative is used for preparation of a medicament for the prophylaxis or treatment of metabolic disorders selected from type 2 diabetes, inadequate glucose tolerance, insulin resistance, obesity, polycystic ovary syndrome (PCOS), hypertension and the metabolic syndrome.
11. Use of warfarin, dicumarol or 1 ,2-naphtoquinone for the preparation of a medicament for treatment of metabolic disorders mediated by insulin resistance or hyperglycemia.
12. Use according to claim 11, wherein the medicament is an anti-diabetic agent.
13. Use according to claim 11, where said derivative is used for preparation of a medicament for the prophylaxis or treatment of metabolic disorders selected from type 2 diabetes, inadequate glucose tolerance, insulin resistance, obesity, polycystic ovary syndrome (PCOS), hypertension and the metabolic syndrome.
14. A pharmaceutical composition comprising a naphtoquinone derivative or a tautomer or a stereoisomeric form thereof defined in any of claims 1-4, and any pharmaceutically acceptable carriers, diluents, buffers or excipients.
15. The composition according to claim 14, further comprising an alkylating agent, an intercalating agent, a metal coordination complex, a pyrimidine nucleoside such as
Allopurinol, a purine nucleoside, an inhibitor of nucleic acid associated enzymes, and/or an inhibitor of nucleic acid associated proteins.
16. The composition according to claim 14, further comprising inhibitors of HMG- CoA reductase including statins such as lovastatin, simvastatin, atorvastatin, or other inhibitors of ROS-producing enzymes, such as glio toxin and phenothiazines such as phenothiazine, trifluroperazine, avastatin, valsartan and/or a derivative of any one of the above-mentioned compounds or known inhibitors or antagonists of the ROS generating enzyme NAD(P)H-oxidase e.g. apocynin.
17. The composition according to claim 14, further comprising an inhibitor or antagonist affecting the ROS-generating activity of NAD(P)H oxidase or the NAD(P)H oxidase complex, or interacts with the active site or a regulatory site, or both sites, of the NAD(P)H oxidase, such as pyridine, imidazole, diethylpyrocarbonate, chloromercuribenzoic acid, 4-(2-aminomethyl)-sulfonyl fluoride and acetovanillone, and/or derivatives thereof.
18. A pharmaceutical composition comprising a fiavone derivative or a tautomer or a stereoisomeric form thereof defined in any of claims 7-8, and any pharmaceutically acceptable carriers, diluents, buffers or excipients.
19. The composition according to claim 18, further comprising an alkylating agent, an intercalating agent, a metal coordination complex, a pyrimidine nucleoside such as
Allopurinol, a purine nucleoside, an inhibitor of nucleic acid associated enzymes, or an inhibitor of nucleic acid associated proteins.
20. The composition according to claim 18, further comprising inhibitors of HMG- CoA reductase including statins such as lovastatin, simvastatin, atorvastatin, or other inhibitors of ROS-producing enzymes, such as glio toxin and phenothiazines such as phenothiazine, trifluroperazine, avastatin, valsartan and/or a derivative of any one of the above-mentioned compounds or known inhibitors or antagonists of the ROS generating enzyme NAD(P)H-oxidase e.g. apocynin.
21. The composition according to claim 18, further comprising an inhibitor or antagonist affecting the ROS-generating activity of NAD(P)H oxidase or the NAD(P)H oxidase complex, or interacts with the active site or a regulatory site, or both sites, of the NAD(P)H oxidase, such as pyridine, imidazole, diethylpyrocarbonate, chloromercuribenzoic acid, 4-(2-aminomethyl)-sulfonyl fluoride and acetovanillone, and/or derivatives thereof.
22. A pharmaceutical composition comprising warfarin, dicumarol or 1,2- naphtoquinone, and optionally pharmaceutically acceptable carriers, diluents, buffers or excipients.
23. The composition according to claim 23, further comprising an alkylating agent and an intercalating agent, a metal coordination complex, a pyrimidine nucleoside such as Allopurinol, a purine nucleoside, an inhibitor of nucleic acid associated enzymes, or an inhibitor of nucleic acid associated proteins.
24. The composition according to claim 23, further comprising inhibitors of HMG- CoA reductase including statins such as lovastatin, simvastatin, atorvastatin, or other inhibitors of ROS-producing enzymes, such as glio toxin and phenothiazines such as phenothiazine, trifluroperazine, avastatin, valsartan and/or a derivative of any one of the above-mentioned compounds or known inhibitors or antagonists of the ROS generating enzyme NAD(P)H-oxidase e.g. apocynin.
25. The composition according to claim 23, further comprising an inhibitor or antagonist affecting the ROS-generating activity of NAD(P)H oxidase or the NAD(P)H oxidase complex, or interacts with the active site or a regulatory site, or both sites, of the NAD(P)H oxidase, such as pyridine, imidazole, diethylpyrocarbonate, chloromercuribenzoic acid, 4-(2-aminomethyl)-sulfonyl fluoride and acetovanillone, including derivatives thereof.
26. Method for prophylaxis or treatment of metabolic disorders, which method comprises administration to a subject in need thereof of a compound defined in any of claims 1-4 or a pharmaceutical composition defined in any of claims according to claims 14-17.
27. Method according to claim 26, wherein the metabolic disorders are selected from type 2 diabetes, inadequate glucose tolerance, insulin resistance, obesity, polycystic ovary syndrome (PCOS), hypertension and the metabolic syndrome.
28. Method according to any of claims 26-27, in which the subject being treated is a human or other mammal.
29. Method for prophylaxis or treatment of metabolic disorders, which method comprises administration to a subject in need thereof of a compound defined in any of claims 7-8 or a pharmaceutical composition defined in any of claims according to claims 18-21.
30. Method according to claim 29, wherein the metabolic disorders are selected from type 2 diabetes, inadequate glucose tolerance, insulin resistance, obesity, polycystic ovary syndrome (PCOS), hypertension and the metabolic syndrome.
31. Method according to any of claims 29-30, in which the subject being treated is a human or other mammal.
32. Method for prophylaxis or treatment of metabolic disorders, which method comprises administration to a subject in need thereof of a compound defined in claim 11 or a pharmaceutical composition defined in any of claims according to claims 22-25.
33. Method according to claim 32, wherein the metabolic disorders are selected from type 2 diabetes, inadequate glucose tolerance, insulin resistance, obesity, polycystic ovary syndrome (PCOS), hypertension and the metabolic syndrome.
34. Method according to any of claims 32-33, in which the subject being treated is a human or other mammal.
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