EP0600973A1 - Procede de traitement de troubles metaboliques et du metabolisme - Google Patents

Procede de traitement de troubles metaboliques et du metabolisme

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Publication number
EP0600973A1
EP0600973A1 EP92917697A EP92917697A EP0600973A1 EP 0600973 A1 EP0600973 A1 EP 0600973A1 EP 92917697 A EP92917697 A EP 92917697A EP 92917697 A EP92917697 A EP 92917697A EP 0600973 A1 EP0600973 A1 EP 0600973A1
Authority
EP
European Patent Office
Prior art keywords
compounds
treatment
mice
obesity
insulin
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.)
Withdrawn
Application number
EP92917697A
Other languages
German (de)
English (en)
Inventor
Jerry R. Colca
Scott D. Larsen
Martin Durham Meglasson
Steven P. Tanis
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.)
Pharmacia and Upjohn Co
Original Assignee
Upjohn Co
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Filing date
Publication date
Application filed by Upjohn Co filed Critical Upjohn Co
Publication of EP0600973A1 publication Critical patent/EP0600973A1/fr
Withdrawn legal-status Critical Current

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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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/205—Amine addition salts of organic acids; Inner quaternary ammonium salts, e.g. betaine, carnitine
    • 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
    • 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
    • A61K31/11—Aldehydes
    • 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
    • A61K31/15—Oximes (>C=N—O—); Hydrazines (>N—N<); Hydrazones (>N—N=) ; Imines (C—N=C)
    • 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
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A—HUMAN NECESSITIES
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    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • 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
    • A—HUMAN NECESSITIES
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
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    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • 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
    • 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
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • 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
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    • 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 provides a new use for known compounds. More particularly, the present invention provides a method of treating or preventing certain metabolic disorders of human and animal metabolism, such as non-insulin dependent diabetes mellitus (NIDDM) by the ad- ministration of the compounds listed in Table 1, below and excess adiposity or obesity by the administration of the compounds listed in Table 2, below.
  • NIDDM non-insulin dependent diabetes mellitus
  • Other indications which may be treated by the subject method can include hyperglycemia, impaired glucose tolerance, hyperinsulinemia, insulin insensitivity, hyperamylinemia or hyperlipidemia.
  • NIDDM non-insulin dependent diabetes mellitus
  • Hyperglycemia is a condition where the blood glucose level is above the normal level in the fasting state, following ingestion of a meal, or during a provocative diagnostic procedure, e.g., a glucose tolerance test. It can occur in NIDDM as well as obesity. Hyperglycemia can occur without a diagnosis of NIDDM. This condition is called impaired glucose tolerance or pre-diabetes. Impaired glucose tolerance occurs when the rate of metabolic clearance of glucose from the blood is less than that commonly occurring in the general population after a standard dose of glucose has been orally or parenterally administered. It can occur in NIDDM as well as obesity, pre-diabetes and gestational diabetes.
  • Hvperinsulinemia is defined as having a blood insulin level that is above normal level in the fasting state, following ingestion of a meal or during a provocative diagnostic procedure. It can be seen in NIDDM or obesity and can be associated with or causal in hypertension or atherosclerosis. Hyperinsulinemia can occur without a diagnosis of diabetes. It may occur prior to the onset of NIDDM. Insulin insensitivity, also called insulin resistance, occurs when the insulin- dependent glucose clearance rate is less than that commonly occurring in the general population during diagnostic procedures such as a hyperinsulinemic clamp (See, e.g., DeFronzo, R. A. et al.. Am. J. Physiol. 232:E214-E233, (1979)) or a minimal model test.
  • Insulin insensitivity is considered also to occur when the blood glucose concentration is higher than that commonly occurring in the general population after intravenous administration of insulin (insulin tolerance test) or when the ratio of serum insulin-to glucose concentration is higher than that commonly occurring in the general population after a 10 16 hour fast Insulin insensitivity may be found in NIDDM or obesity and can also be associate with or causal to hypertension or atherosclerosis.
  • Hyperamylinemia is defined as having an abnormally high blood amylin level. Amylin is also known as diabetes associated peptide (DAP) and insulinoma associated polypeptide CLAP). Hyperamylinemia can be seen in NIDDM or obesity.
  • DAP diabetes associated peptide
  • CLAP insulinoma associated polypeptide
  • NIDDM neurodegenerative disease 2019
  • It is defined as a higher fat body mass-to-lean body mass ratio than that commonly occurring in the general population as measured by whole body specific gravity or other generally accepted means.
  • Hyperlipidemia is defined as having an abnormal level of lipids in the blood. Hyperlipidemia exists when the serum concentration of total cholesterol or total triglycerides or the serum concentration of LDL-cholesterol/HDL-cholesterol is higher than that commonly occurring in the general population. It can be seen in NTDDM or atherosclerosis.
  • the above disease states could be treated by either ameliorating or preventing the metabolic and biochemical disorders.
  • humans and animals which have not been diagnosed as having one of the above disease states but evidencing some or all of the disorders described above, could be benefitted by preventing the development of a currently recognized disease state. Therefore, a compound that is useful in the treatment of hyperglycemia, impaired glucose tolerance, hyperinsulinemia, insulin insensitivity, hyperamylinemia. excess adiposity or hyperlipidemia could also be used to treat or prevent NIDDM, obesity, hypertension or atherosclerosis.
  • the subject invention provides a method for preventing or treating NIDDM using Compounds 1-119, listed in Table 1, their free bases, or their pharmacologically acceptable esters and salts.
  • Compounds 1-119, their free bases, or their pharmacologically acceptable salts may be administered individually as the sole active ingredient in a composition or combined with other compounds selected from Table 1.
  • Compounds 1-119 are known compounds and their sources are identified in Table 1.
  • Compounds 1-119 to be used is between 0.1 and 500 mg/kg body weight daily.
  • the preferred dose is 1-50 mg/kg/day.
  • Compounds 1-119 may be administered orally, buccally, sublingually, parenterally, intranasally, intrarectaliy, or topically in any suitable pharmaceutical formulation.
  • the oral route is preferred.
  • the subject invention also provides a method of preventing or treating the obesity using
  • Compounds 1-128 to be used is between 0.1 and 500 mg/kg body weight daily.
  • the preferred dose is 1-50 mg/kg/day.
  • Compounds 1-128 may be administered orally, buccally, sublingually, parenterally, intranasally, intrarectally, or topically in any suitable pharmaceutical formulation.
  • the oral route is preferred.
  • Guanidine, monoguanidine and diguanidine compounds have been shown to produce hypoglycemia. See, e.g., Watanabe, C, J. Biol. Chem. 33:253-265 (1918); Bischoff, F. et al., Guanidine structure and hypoglycemia 81:325-349 (1929). However, these compounds were observed to be toxic. In 1957, biguanide derivatives, e.g. phenformin and metformin, were used clinically as anti-diabetic agents. Some members of this class continue to be used today while others have been withdrawn from the maricet or banned in the United States and most Western countries. See, e.g., Schafer, G., Diabete Metabol. (Paris) 9:148-163 (1983).
  • British patent 1,153,424 discloses the use of certain esters and amides of guanidino-aliphatic acids in the treatment of diabetes mellitus where hyperuremia is present The patent does not disclose that these compounds have an effect on hyperglycemia or any other symptom or pathological state related to diabetes.
  • a Canadian patent, 891509 the use of esters and amides of guanidinoaliphatic acids were disclosed for treating hyperuremia and hyperglycemia in diabetes mellitus.
  • the biologic activity of a guanidino alkanoic acid was known to be different and less favorable so as to be ineffective compared to its amide for treating hyperglycemia.
  • British patent, 1,195,199 discloses the use of guanidino alkanoic acids or their amides or esters in an insulin-containing, parenterally-administered composition for the treatment of hyperglycemia occurring in diabetes. According to this patent, the combining of a guanidino alkanoic acid, amide or ester with insulin reduces the risk of hypoglycemia as compared to insulin alone.
  • British patent 1,195,200 discloses the use of guanidino alkanoic acids in a composition containing a guanidino alkanoic acid amide or ester derivative for the treatment of hyperglycemia occurring in diabetes.
  • the present invention provides a method of treating or preventing the metabolic disorder of NTDDM by administering to an animal exhibiting diabetes, including humans, an effective amount of a compound of Table 1 or a pharmaceutically acceptable salt thereof.
  • Other indications for which these compounds may be useful can include hyperglycemia, impaired glucose tolerance, hyperinsulinemia, hyperamylinemia, excess adiposity and/or hyperlipidemia.
  • the method comprises the systemic administration of Compounds 1-119, listed in Table 1, their free bases, or their pharmacologically acceptable esters and salts to animals, including humans, suffering from NIDDM.
  • the present invention provides a method of treating or preventing a metabolic disorder such as excess adiposity or obesity in a patient susceptible to or experiencing said disorder comprising the systemic administration of Compounds 1-128, listed in Table 2, their free bases, or their pharmacologically acceptable esters and salts.
  • Compounds 1-119, their free bases, or their pharmacologically acceptable salts may be administered individually as the sole active ingredient in a composition for treating non-insulin dependent diabetes mellitus.
  • Table 1 compounds 1-119 of mis invention are either commercially available or may be prepared by methods published in the chemical literature as indicated below in Table 1.
  • Table 2 compounds 1-128, their free bases, or their pharmacologically acceptable salts may be administered individually as the sole active ingredient in a composition.
  • Table 2 compounds 1-128 of this invention are either commercially available or ma be re ared bv methods ublished in the chemical literature as indicated below in Table 2.
  • the subject compounds cause several biologic effects that are beneficial in the treatment of human disease. They improve plasma glucose level, insulin sensitivity, plasma amylin level, adiposity and plasma lipid level. All of these effects are beneficial in treating metabolic disorders or metabolism such as NIDDM and excess adiposity or obesity.
  • NIDDM is characterized by hyperglycemia in the fasting or post-prandial state and impaired glucose tolerance after oral or parenteral administration of a glucose solution.
  • the subject compounds, that are administered to KKA y mice, a rodent model of NIDDM decreases the non-fasting plasma glucose concentration and improves glucose tolerance.
  • the minimum effective dose in KKA y mice is 130 mg/kg/d when administered as an admixture in rodent chow. Higher doses produce a proportionately greater effect.
  • Doses that are less than the minimum effective dose in KKA y mice may be effective at decreasing blood glucose levels in other species, e.g., human, since elimination is rapid in rodents and may occur more slowly in other species.
  • NIDDM NIDDM
  • Reaven a progressive hyperinsulinemia
  • obesity See, e.g., Glass A., supra
  • atherosclerosis See, e.g., Reaven, supra and Stout, R. W., Diabetologia 16:141-150 (1979)] and may be etiological factors in these diseases.
  • 3-GPA ameliorates hyperinsulinemia in KKA y mice and decreases the plasma ratio of insulin-to-glucose concentration, indicating increased insulin sensitivity. Therefore, 3-GPA is useful in the treatment or in the prevention of NIDDM, hypertension, obesity, and atherosclerosis.
  • Hyperamylinemia may occur in NIDDM, decreasing tissue glucose metabolism [See, e.g., Leighton, B. et al., Nature 335:632-635 (1988)] and altering pancreatic hormone secretion [See, e.g., Clark, A., Diabetic Medicine 6:561-567 (1989)].
  • 3-GPA ameliorates
  • hyperamylinemia and therefore is beneficial in treating disease states in which plasma amylin concentration is increased.
  • Excess adiposity is an etiological factor in NIDDM and when extreme, represents a disease state in itself.
  • the subject compounds decrease adiposity by decreasing the level of lipids stored in fat and liver tissue.
  • the compounds are therefore beneficial in the treatment of obesity alone or in concert with NIDDM.
  • the effect of the subject compounds is selective for lipid-rich tissues ⁇ e.g., epididymal fat and fatty liver of ob/ob mice) while muscle mass is unaffected or only minimally affected.
  • LDL cholesterol concentration is an etiological factor in coronary artery disease.
  • the subject compounds decrease LDL-cholesterol levels in spontaneously hyperiipidemic mice and therefore is useful in treating or preventing
  • “Sole active pharmaceutical agent” means that the subject compounds or its salt, administered as claimed herein, is the only pharmaceutical agent in the composition.
  • a metabolic disorder i.e., hyperglycemia. impaired glucose tolerance, hyperinsulinemia, insulin insensitivity, hyperamylinemia. excess adiposity and/or hyperlipidemia means a human or animal who exhibits said metabolic disorder and is merefore likely to exhibit one of more of the disease states described above. Such patients are readily diagnosed by a physician or veterinarian of ordinary skill. "Treatment” means the amelioration or total avoidance of the metabolic disorder as described herein.
  • Prevention means the avoidance of a currently recognized disease state, as described herein, in a patient evidencing some or all of the metabolic disorders described above.
  • any convenient route of systemic administration is employed, e.g., orally, parenterally. intranasally or intrarectally.
  • the preferred form of administration is orally.
  • compositions containing the compounds may be administered in a sustained release formulation.
  • sustained release means a formulation in which the drug becomes biologically available to the patient at a measured rate over a prolonged period.
  • sustained release means a formulation in which the drug becomes biologically available to the patient at a measured rate over a prolonged period.
  • the subject compounds decrease body fat without affecting the lean mass, they are of great commercial benefit to the meat poultry, and fish producing industries in achieving its goal of producing leaner animal products.
  • the subject compounds can be administered admixed in the diet of farm animals or as a pharmaceutical preparation such as an oral tablet or capsule, by injection, or by implantable sustained release devices thereby increasing the protein content of the carcass while decreasing its fat content. This would produce muscle tissue with less fat. This benefit of the subject compounds would also impact on the potential health to the meat poultry, and fish consuming public.
  • farm animals is defined as animals which are raised for food production. The term includes, but is not limited to, such animals as cattle, poultry, fish, swine, and lamb.
  • the subject compounds increase exercise tolerance in normal mice.
  • the present invention may be useful in treating muscular dysfunction, such as post-poliomyelitis chronic muscle fatigue syndrome or muscular dystrophy, or in treating chronic muscular weakness associated with advanced age or chronic immobilization, or in increasing endurance and exercise in normal humans.
  • the subject compounds are also useful for improving the survival rate of mice maintained in a low oxygen environment and therefore is beneficial in treating or preventing disease states involving tissue hypoxia, e.g.. peripheral claudication and exercise intolerance in diabetic humans, and angina, myocardial infarction and stroke in diabetic and normal humans.
  • tissue hypoxia e.g.. peripheral claudication and exercise intolerance in diabetic humans
  • angina myocardial infarction and stroke in diabetic and normal humans.
  • glucose-dependent protein crosslinking alters the tertiary structure of several proteins .
  • This protein glycosylation may contribute to diabetic complication and complications of aging in non-diabetic humans, such as neuropathy, nephropathy, retinopathy, hypertension, and atherosclerosis.
  • the subject compounds are useful to block protein glycosy- lation and therefore be of benefit in treating or preventing this reaction.
  • the dosage regimen for the subject compounds in accord with this invention will depend on body weight.
  • Table 1 and Table 2 compounds in pharmaceutical dosage form can range from 1-500 mg/kg/day.
  • the preferred dose is 5-100 mg/kg/day. Any sustained released formulations can be used.
  • the Table 1 compounds were tested for effects that are beneficial in the treatment or prevention of NIDDM using one or more of three procedures.
  • Procedure 1 Compounds were administered orally to KKA y mice for 3 days. Compounds were mixed in the chow at 1-5 mg/g or unsupplemented chow was provided. The blood glucose concentration was determined before initiating treatment and on the third treatment day.
  • KKA y mice are rodent models of non-insulin dependent diabetes mellitus (Iwatsuka, H., Shino, A., and Suzuoki, Z.: General survey of diabetic features of yellow KK mice, Endocrinol. Japon. 17: 23-35, 1970).
  • Procedure 2 Compounds were administered orally to C57EL63-ob/ob mice for 4 days.
  • mice are rodent models of non-insulin dependent diabetes mellitus (Coleman, D. L.: Diabetes-obesity syndromes in mice. Diabetes 31, Suppl. 1: 1-6, 1982).
  • Procedure 3 Compounds were tested for their ability to antagonize carrier mediated transport of 3-guanidinopropionic acid into rat brain synaptosomes.
  • Rat brain synaptosoraes were prepared as described (Fjalland, B., Acta Pharmacol, et Toxicol. 42: 73-76, 1978). Synaptosomes were incubated in Krebs Ringer bicarbonate buffer with 5 mM glucose and 0.1% bovine serum albumin, pH 7.4, for 5 min at 25°C with test compounds at a concentration of 1 mM and [4- 14 C]-3-guanidinopropionic acid. Compounds that decreased synaptosomal accumulation of [4- 14 C]-3-guanidinopropionic acid by >20% were considered active.
  • Test compounds from Table 1 on blood glucose concentration in KKA y mice was measured and is shown in Table 3. Data are shown as the ratio of post-treatment blood glucose levels in treated (T) and control (C) mice. T/C-values ⁇ 0.80 are considered active. Compounds were tested using Procedure 1. Stage 1 indicates the compound was tested at 1 mg/g; Stage 2, at 2 mg/g; Stage 5, at 5 mg/g.
  • Table 1 compounds The effect of Table 1 compounds on blood glucose concentration in oblob mice was measured and is shown in Table 4. Data are shown as the ratio of post-treatment blood glucose levels in treated (T) and control (C) mice. T/C-values ⁇ 0.80 are considered active. Compounds were tested using Procedure 2.
  • Table 2 compounds were tested for effects that are beneficial in the treatment or prevention of excess adiposity or obesity using one or more of three procedures.
  • Procedure 1 Compounds were administered orally to KKA y mice for 3 days. Compounds were mixed in the chow at 1-5 mg/g or unsupplemented chow was provided. The body weight was determined before initiating treatment and on the third treatment day. Compounds that cause a decreased in body weight during the study period at any of the doses that was greater than the weight decrease, if any, occurring in control mice receiving unsupplemented chow were considered active.
  • KKA y mice are rodent models of obesity and diabetes (Iwatsuka, H., Shino, A., and Suzuoki, Z.: General survey of diabetic features of yellow KK mice, Endocrinol. Japon. 17: 23-35, 1970).
  • Procedure 2 Compounds were administered orally to C57BL6J-ob/ob mice for 4 days.
  • mice Compounds that cause a decreased in body weight during the study period that was greater than the weight decrease, if any, occurring in control mice receiving unsupplemented chow were considered active, oblob Mice are rodent models of obesity and diabetes (Cawthome, M. A.: The use of animal models in the detection and evaluation of compounds for the treatment of obesity, In: "Animal Models of Obesity", New York: Oxford University, pp. 79-90, 1979).
  • Procedure 3 Compounds were tested for their ability to antagonize carrier mediated transport of 3-guanidinopropionic acid into rat brain synaptosomes.
  • Rat brain synaptosomes were prepared as described (Fjalland, B., Acta Pharmacol, et Toxicol. 42: 73-76, 1978). Synaptosomes were incubated in Krebs Ringer bicarbonate buffer with 5 mM glucose and 0.1% bovine serum albumin, pH 7.4, for 5 min at 25 °C with test compounds at a concentration of 1 mM and [4- 1 4 C]-3-guanidinopropionic acid. Compounds that decreased synaptosomal accumulation of [4- 1 4 C]-3-guanidinopropionic acid by >20% were considered active.
  • Table 2 compounds The effect of the Table 2 compounds on body weight in KKA y mice was tested and is shown in Table 6.
  • Table 2 compounds were tested using Procedure 1. The first value indicates the compound was tested at 1 mg/g; the second value, at 2 mg/g; the fifth value, at 5 mg/g, etc. Percent (%) change is the body weight percent change.
  • the effect of the Table 2 compounds on body weight in oblob mice was tested and the values are shown in Table 7. Compounds were tested using Procedure 2.
  • Table 2 compounds The effect of the Table 2 compounds on synaptosomal uptake of [4- 14 C]-3- guanidinopropionic acid was tested and is shown in Table 8. Table 2 compounds decreasing [4- 14C]-3-guanidinopropionic acid uptake by >20% (i.e., ⁇ 80% of control value) are considered active. Table 2 compounds were tested using Procedure 3.

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  • Bioinformatics & Cheminformatics (AREA)
  • Hematology (AREA)
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  • General Chemical & Material Sciences (AREA)
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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
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Abstract

On décrit un procédé de traitement ou de prévention du diabète non-insulinodépendant (du Type II) par administration à un animal, y compris à l'homme, d'un composé sélectionné dans la Table 1 ou d'un sel pharmaceutiquement acceptable de celui-ci; on décrit également un procédé de traitement et de prévention de l'excès d'adiposité ou obésité par administration à un animal, y compris à l'homme, d'un composé sélectionné dans la Table 2 ou d'un sel pharmaceutiquement acceptable de celui-ci.
EP92917697A 1991-08-27 1992-08-11 Procede de traitement de troubles metaboliques et du metabolisme Withdrawn EP0600973A1 (fr)

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SE0004462D0 (sv) 2000-12-04 2000-12-04 Pharmacia Ab Novel method and use
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