Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—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
  • A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
• • 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
• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P5/00—Drugs for disorders of the endocrine system
  • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

• the present invention relates to the use of an indazolemethoxyalkanoic acid to prepare a pharmaceutical composition for reducing the blood triglyceride, cholesterol and/or glucose levels.
• R and R 1 which may be the same or different, are H or C1- 5 alkyl, and
• R" is H or Ci -4 alkyl, optionally, when R" is H, in the form of a salt thereof with a pharmaceutically acceptable organic or mineral base.
• document EP-B1-1 005 332 reports that the compound of formula (I) reduces the production of the protein MCP-1. More particularly, the said document describes the use of a compound of formula (I) to prepare a pharmaceutical composition for treating a disease chosen from the group comprising atherosclerosis, interstitial lung diseases, and post-operative complications in heart surgery, transplants, organ or tissue replacements, or prosthesis implants.
• IL-12 is a cytokine produced by monocytes, macrophages, neutrophils, dendritic cells and antibody-producing B cells, and also by keratinocytes and a number of tumoral cell lines (epidermoid carcinoma).
• IL-12 modulates the activation of the "natural killer” (NK) cells and T cells, and the induction of interferon-gamma (IFN- ⁇ ), which is a cytokine that participates in regulating the immune response.
• NK natural killer
• IFN- ⁇ interferon-gamma
• the present invention relates to the use of a compound of formula (I):
• R and R' which may be the same or different, are H or C 1 - 5 alkyl, and R" is H or C 1-4 alkyl, optionally, when R" is H, in the form of a salt thereof with a pharmaceutically acceptable organic or mineral base, to prepare a pharmaceutical composition for reducing the blood triglyceride, cholesterol and glucose levels.
• the present invention relates to a method of treatment for reducing the blood triglyceride, cholesterol and/or glucose levels in a human patient in whom the blood triglyceride, cholesterol and/or glucose levels are higher than normal, the said method comprising the administration of an effective dose of a compound of formula (I):
• R and R' which may be the same or different, are H or Ci -5 alkyl, and
• R" is H or Ci -4 alkyl, optionally, when R" is H, in the form of a salt thereof with a pharmaceutically acceptable organic or mineral base.
• the pharmaceutical compositions and, respectively, the method of treatment according to the present invention will be useful for treating diseases or pathological conditions such as, for example, obesity, metabolic syndrome, cardiovascular diseases, diabetes, insulin resistance and cancer.
• Obesity may be considered as a chronic pathological condition resulting from complex interactions between cultural, psychological and genetic factors.
• obesity In the last thirty years, there has been a great increase in interest in the pharmacological control of obesity and related health problems, moreover on account of the social costs associated with this condition.
• Much evidence has demonstrated that being overweight or obese substantially increases the risk of death caused by various conditions including diabetes, hypertension, dyslipidaemia, coronary cardiopathies, congestive heart insufficiency, myocardial infection, and even certain of forms of cancer.
• a higher body weight is also associated with increased mortality in general.
• adipocytes accumulate triglycerides and release free fatty acids, which are cholesterol precursors, that can play an important role in the development and progression of diabetes and its associated disorders.
• High levels of circulating lipids may be the consequence of various pathological conditions or, in turn, may be the cause of specific diseases.
• Disorders commonly related with high levels of lipids include cardiovascular diseases or conditions including coronary disorders, hypertension, thrombosis, ischaemic events, for instance infarction, strokes and organ insufficiency.
• the simultaneous presence of the symptoms described above may indicate a particular predisposition to diabetes and to cardiovascular disorders, a condition currently indicated as metabolic syndrome.
• the pharmaceutical compositions of the present invention are prepared in suitable dosage forms comprising an effective dose of at least one compound of formula (I) and at least one pharmaceutically acceptable inert ingredient.
• suitable dosage forms are tablets, capsules, coated tablets, granules, solutions and syrups for oral administration; medicated plasters, pastes, creams and ointments for transdermal administration; suppositories for rectal administration and sterile solutions for administration via the injection or aerosol route.
• Suitable dosage forms are those with sustained release and based on liposomes for administration via either the oral or injection route.
• the dosage forms may also contain other conventional ingredients, for instance preserving agents, stabilizers, surfactants, buffers, osmotic pressure-regulating salts, emulsifiers, sweeteners, colorants, flavourings and the like.
• the pharmaceutical composition according to the present invention may also contain other pharmacologically active ingredients whose simultaneous administration is useful.
• the amount of compound of formula (I) in the pharmaceutical composition according to the present invention may vary within a wide range as a function of known factors, for instance the type of disease to be treated, the severity of the disease, the body weight of the patient, the dosage form, the selected route of administration, the number of daily administrations and the efficacy of the selected compound of formula (I). However, a person skilled in the art may determine the optimum amount in a simple and routine manner.
• the amount of compound of formula (I) in the pharmaceutical composition according to the present invention will be such that it provides a level of administration of between 0.0001 and 100 mg/kg/day.
• the level of administration is between 0.05 and 50 mg/kg/day and even more preferably between 0.1 and 10 mg/kg/day.
• the dosage forms of the pharmaceutical composition according to the present invention may be prepared according to techniques that are well known to pharmaceutical chemists, including mixing, granulation, compression, dissolution, sterilization and the like.
• the activity of the compound of formula (I) was evaluated in vitro in human monocytes by means of gene expression analysis techniques using "GeneChip” and in vivo in Zucker rats, an experimental model of type-2 diabetes characterized by glucose intolerance and insulin resistance accompanied by hyperglycaemia and hyperlipidaemia.
• LPS lipopolysaccharide
• the cells were stimulated with LPS (100 ng/ml) for 4 hours in the presence or absence of bindarit (300 ⁇ M).
• the product was tested in the form of the sodium salt obtained by salification with equimolar sodium hydroxide and subsequent dilution in the medium used.
• the total RNA was extracted from cells using TRizol (Invitrogen Life Technologies) according to manufacturer's instructions, reverse- transcribed and prepared by GeneChip hybridization.
• bindarit is capable of significantly inhibiting the expression of LPS-induced IL-12 in human monocytes, reducing the levels of specific mRNA by about 100- fold.
• Test 2 Effect of bindarit on circulating levels of triglycerides, cholesterol and glucose in Zucker rats
• bindarit The activity of bindarit was tested in an experimental model in rats. The study was performed on rats 5 weeks old on arrival, of the Zucker strain homozygous for the "fa" allele (fa/fa), insulin-resistant, hyperinsulinaemic and obese, and on rats of the same age of the heterozygous Zucker control strain (fa/+), phenotypically normal, insulin-sensitive and slim.
• the obese Zucker rats were divided into two groups, one of which was fed with a standard rodent diet, and the other with a standard rodent diet supplemented with 0.5% bindarit.
• the slim Zucker rats of the same age were used as controls and fed with a standard rodent diet.
• Blood samples were taken from the animals periodically (at 6, 16, 28 and 40 weeks old) for enzymatic measurement of the circulating levels of triglycerides, cholesterol and glucose.
• Figures 2 and 3 show that the administration of bindarit induces a significant reduction in the circulating levels of triglycerides and cholesterol.
• Figure 4 shows that, as a consequence of the glucose intolerance and the insulin resistance characteristic of the strain of rats used, the obese animals show an increase in glycaemia.
• the treatment with bindarit induces a significant reduction in the glycaemia.
• the diabetic syndrome characteristic of the obese Zucker rats shows many similarities with human type-2 diabetes and is also accompanied by appreciable hyperlipidaemia.
• compositions are given to illustrate the invention in greater detail without, however, limiting it.
• Each tablet contains: a) Active substance:
• Liposomes for administration via the oral and/or injection route a) Active substance:
• Each sachet contains: a) Active substance:
• Each sachet contains: a) Active substance:
• Each vial contains: a) Active substance:

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• Health & Medical Sciences (AREA)
• Pharmacology & Pharmacy (AREA)
• Veterinary Medicine (AREA)
• Public Health (AREA)
• General Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Medicinal Chemistry (AREA)
• Life Sciences & Earth Sciences (AREA)
• Diabetes (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Organic Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• General Chemical & Material Sciences (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Engineering & Computer Science (AREA)
• Hematology (AREA)
• Obesity (AREA)
• Epidemiology (AREA)
• Endocrinology (AREA)
• Emergency Medicine (AREA)
• Cardiology (AREA)
• Child & Adolescent Psychology (AREA)
• Heart & Thoracic Surgery (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Mixers Of The Rotary Stirring Type (AREA)

Priority Applications (18)

Applications Claiming Priority (2)

Related Child Applications (2)

Publications (2)

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Cited By (6)

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• 2006
  • 2006-11-24 IT IT002254A patent/ITMI20062254A1/it unknown
• 2007
  • 2007-11-13 SG SG2011086337A patent/SG176508A1/en unknown
  • 2007-11-13 BR BRPI0718522-7A patent/BRPI0718522A2/pt active Search and Examination
  • 2007-11-13 ES ES11185914T patent/ES2530623T3/es active Active
  • 2007-11-13 JP JP2009537517A patent/JP5192490B2/ja not_active Expired - Fee Related
  • 2007-11-13 PL PL07819835T patent/PL2097080T3/pl unknown
  • 2007-11-13 SI SI200731621T patent/SI2409698T1/sl unknown
  • 2007-11-13 EA EA200970506A patent/EA016885B1/ru not_active IP Right Cessation
  • 2007-11-13 CN CN2007800432200A patent/CN101541323B/zh not_active Expired - Fee Related
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  • 2007-11-13 MX MX2009004295A patent/MX2009004295A/es active IP Right Grant
  • 2007-11-13 AU AU2007323351A patent/AU2007323351B2/en not_active Ceased
  • 2007-11-13 WO PCT/EP2007/009908 patent/WO2008061671A2/en not_active Ceased
  • 2007-11-13 ES ES07819835T patent/ES2403584T3/es active Active
  • 2007-11-13 EP EP11185914.6A patent/EP2409698B1/en not_active Not-in-force
  • 2007-11-13 EP EP07819835A patent/EP2097080B1/en not_active Not-in-force
  • 2007-11-13 SI SI200731208T patent/SI2097080T1/sl unknown
  • 2007-11-13 UA UAA200905093A patent/UA97123C2/uk unknown
  • 2007-11-13 CA CA2666371A patent/CA2666371C/en not_active Expired - Fee Related
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  • 2007-11-13 US US12/444,442 patent/US8198310B2/en not_active Expired - Fee Related
  • 2007-11-13 DK DK11185914T patent/DK2409698T3/en active
  • 2007-11-13 PT PT111859146T patent/PT2409698E/pt unknown
  • 2007-11-13 KR KR1020097010871A patent/KR101413616B1/ko not_active Expired - Fee Related
  • 2007-11-22 AR ARP070105182A patent/AR063894A1/es not_active Application Discontinuation
• 2009
  • 2009-04-22 IL IL198286A patent/IL198286A/en active IP Right Grant
• 2012
  • 2012-05-08 US US13/466,503 patent/US8846745B2/en not_active Expired - Fee Related
• 2015
  • 2015-02-20 CY CY20151100184T patent/CY1116664T1/el unknown

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