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
  • A61K31/425—Thiazoles
  • A61K31/428—Thiazoles condensed with carbocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • 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
  • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
  • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
  • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
  • A61K31/355—Tocopherols, e.g. vitamin E
• • 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
  • A61K31/40—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
• • 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
  • A61K31/42—Oxazoles
  • A61K31/423—Oxazoles condensed with carbocyclic rings
• • 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
  • A61K31/425—Thiazoles
  • A61K31/429—Thiazoles condensed with heterocyclic ring systems
• • 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
  • A61P3/08—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
  • A61P39/00—General protective or antinoxious agents
  • A61P39/06—Free radical scavengers or antioxidants

Definitions

• the present invention relates to a new association between a heterocyclic derivative and an antioxidant agent for obtaining pharmaceutical compositions useful in the treatment and / or prevention of obesity and overweight characterized by a body weight index greater than 25.
• Obesity is a major public health problem in all developed countries. Also growing steadily in developing countries, it is reaching an increasingly young population. Obesity is a well-established risk factor for cardiovascular disease and is associated with a significant increase in the risk of stroke, non-insulin-dependent diabetes, gallbladder stones, respiratory dysfunction, osteoarthritis, many forms of cancer and premature death.
• the pathological state of obesity is also associated with an increase in the oxidation of lipids and proteins which can be the source of significant plasma concentrations of 9- and 13-hydroxyoctadecadienoic acids (9-HODE and 13- HODE) (Totowa: Humano. Press., 1998, 147-155), key indexes of lipid peroxidation (J. Clin.
• a strategy aimed at reducing the body's "oxidation load" while promoting lipid and carbohydrate metabolism should lead to an exacerbation of the effects and consequently to weight loss in obese or overweight subjects.
• the present invention relates more particularly to the association between a derivative promoting lipid and carbohydrate metabolism of the organism and an antioxidant agent.
• the invention relates to the association between a derivative promoting lipid and carbohydrate metabolism having a heterocyclic structure and an antioxidant agent.
• heterocyclic derivatives promoting the lipid and carbohydrate metabolisms according to the invention are more particularly the compounds of formula (I) described in patent application WO 01/57002:
• R ' 2 X represents an oxygen or sulfur atom, or a group CJH 2 or CH (in 9 • which R' forms with R an additional bond),
• R 1 and R 2 identical or different, represent a hydrogen atom, a linear or branched (C ⁇ -C 6 ) alkyl group, aryl, linear or branched arylalkyl (Ci-Ce), aryloxy, arylalkyloxy (Ci-Ce) linear or branched, alkoxy (CC ⁇ ) linear or branched, hydroxy, amino, alkylamino (Ci-C 6 ) linear or branched or dialkylamino (Ci-C 6 ) linear or branched, or R 1 and R 2 together form an oxo group , thioxo or imino, R 2 can moreover form with R ′ 2 an additional bond,
• A represents an alkylene chain (C ⁇ -C 6 ) of which a CH 2 group can be replaced by a heteroatom chosen from oxygen or sulfur, or by a JNR group a (where R a represents a hydrogen atom or an alkyl group ( Ci-C 6 ) linear or branched), or by a phenylene or naphthylene group,
• B is an alkyl (Ci-C 6) linear or branched alkenyl or (C 2 -C 6) linear or branched, these groups being substituted by a group R 5,
• R 5 represents a group C— Z 'in which Z represents a sulfur atom
• Z or oxygen and Z ' represents an OR or JNO R' group
• R 6 represents a group C— Z "in which Z" represents a group Z 'or R
• R represents a hydrogen atom or an alkyl group (C ⁇ -C 6 ) linear or branched, alkenyl (C 2 -C 6 ) linear or branched, alkynyl (C 2 -C 6 ) linear or branched, aryl, arylalkyl (CC ⁇ ) linear or branched, arylalkenyl (C -C 6 ) linear or branched, arylalkynyl (C 2 -C 6 ) linear or branched, heteroaryl, heteroarylalkyl (Ci-C 6 ) linear or branched, heteroarylalkenyl (C 2 -C 6 ) linear or branched, heteroarylalkynyl (C 2 -C 6) ) linear or branched, cycloalkyl (C 3 -C 8 ), cycloalkyl (C 3 -C 8 ) alkyl (C 1 -C 6 ),
• R 3 and R 4 identical or different, represent a hydrogen or halogen atom, or a group R, OR or NRR '(where R and R' are as defined above), or R 3 and R 4 together with the carbon atoms which carry them, when they are carried by two adjacent carbon atoms, a cycle comprising 5 or 6 links and which may contain a heteroatom chosen from oxygen, sulfur and nitrogen,
• D represents: R ′ 2 a benzene ring and in this case X cannot represent a CH group as defined above, or D represents a pyridine, pyrazine, pyrimidine or pyridine ring, these five rings being unsubstituted or substituted by 1 to 3 identical groupings
• n 0, 1 or 2), cyano, nitro or halogen atoms,
• aryl is understood to mean a phenyl, naphthyl or biphenyl group, these groups possibly being partially hydrogenated,
• heteroaryl means any aromatic mono or bicyclic group containing 5 to 10 links, which can be partially hydrogenated on one of the rings in the case of bicyclic heteroaryl, and containing 1 to 3 heteroatoms chosen from oxygen, nitrogen and sulfur,
• the aryl and heteroaryl groups thus defined can be substituted by 1 to 3 groups chosen from linear or branched (Ci-Ce) alkyl, linear or branched (Ci-C 6 ) alkoxy, carboxy, formyl, JNR b Rc (in which R and Rc, identical or different, represent a hydrogen atom, a linear or branched (Ci-Ce) alkyl group, aryl or heteroaryl), ester, amido, nitro, cyano, OC (Me) 2 COOR "(where R” is as defined above), or halogen atoms,
• heterocyclic derivatives of the combination according to the invention are:
• the antioxidant agents according to the invention are more particularly anti-free radicals or free radical scavengers, anti-lipoperoxidizing agents, chelating agents or agents capable of regenerating endogenous antioxidants such as glutathione, vitamin C or vitamin E, as well as their addition salts with a pharmaceutically acceptable acid or base.
• hydrochloric hydrobromic, sulfuric, phosphonic, acetic, trifluoroacetic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, tartaric, maleic, citric, ascorbic, oxalic, methane acids. sulfonic, camphoric, etc.
• the antioxidant agent of the combination according to the invention is more preferably represented by quinone derivatives such as ubiquinone or coenzyme Q 10 , which acts as a free radical scavenger but which is also capable of regenerating vitamin E .
• the preferred combination according to the invention is dimethyl 2- ⁇ 4 - [(6-benzoyl-2-oxo-1,3-benzothiazol-3 (2H) -yl) ethoxy] benzyl ⁇ malonate and coenzyme Q 10 .
• the association according to the invention between a compound promoting lipid and carbohydrate metabolism and an antioxidant agent has quite surprising pharmacological properties: the Applicant has indeed demonstrated the existence of a synergy between the two compounds of the association allowing to obtain a very significant reduction in body fat making it useful in the treatment and / or prevention of obesity and overweight characterized by a body weight index greater than 25.
• Obesity in the United States affects 20% of men and 25% of women. Patients with body weight index (BMI weight (kg) / height 2 (m 2 )) greater than or equal to 30 are considered obese (hit. J. Obes., 1998, 22, 39-47; Obesity Lancet , 1997, 350, 423-
• Obesity can have several origins: they can occur following a deregulation of food intake, hormonal deregulation or as a result administration of treatment: type II anti-diabetic treatment with sulfonylureas leads to weight gain in patients. Similarly in type I (insulin-dependent) diabetes, insulin therapy is also a source of body weight gain in patients (In Progress in Obesity Research, 8 th International Congress on Obesity, 1999, 739-746; Aimais of Internai Medicine, 1998, 128, 165-175).
• Obesity and overweight are well-established risk factors for cardiovascular disease: they are associated with a significant increase in the risk of stroke, non-insulin-dependent diabetes because they predispose to insulin resistance , dyslipidemia and the appearance of macrovascular diseases (nephropathies, retinopathies, angiopathies).
• the combination according to the invention makes it possible to obtain weight loss which, even if moderate, significantly reduces all the risk factors associated with obesity (Int. J. Obes., 1997, 21, 55-9; Int. J. Obes., 1992, 21, S5-9).
• the combination according to the invention therefore finds its utility in the treatment and / or prevention of obesity and overweight characterized by a body weight index greater than 25.
• the invention therefore relates to the use of the association between a derivative promoting lipid and carbohydrate metabolism and an antioxidant agent for obtaining pharmaceutical compositions intended for the treatment and / or prevention of obesity and characterized overweight by a body weight index greater than 25 and less than 30.
• the combination according to the invention is useful in the treatment and / or prevention of obesity and overweight characterized by a body weight index greater than 25 and less than 30 induced by a therapeutic treatment, such as treatment of type I or II diabetes.
• the invention therefore relates to the use of the association between a derivative promoting lipid and carbohydrate metabolism and an antioxidant agent for obtaining pharmaceutical compositions intended for the treatment and / or prevention of obesity and characterized overweight by a body weight index greater than 25 and less than 30 induced by a therapeutic treatment, such as the treatment of type I or IL diabetes
• the invention also relates to pharmaceutical compositions containing the association between a derivative promoting lipid and carbohydrate metabolism and an antioxidant agent as defined above in combination with one or more pharmaceutically acceptable excipients.
• compositions according to the invention mention may be made more particularly of those which are suitable for oral, parenteral, nasal administration, simple or coated tablets, sublingual tablets, capsules, tablets, suppositories, creams, ointments , dermal gels, etc.
• the invention relates to pharmaceutical compositions containing a compound of formula (I) as defined above and an antioxidant agent such as coenzyme Q 10 or vitamin E in combination with one or more pharmaceutically acceptable excipients.
• the dosage varies according to the sex, age and weight of the patient, the route of administration, the nature of the therapeutic indication or any associated treatments and ranges from 0.1 mg to 1 g of each component of association by 24 hours in one or more takes.
• mice Male mice C57 Black 6 ob / ob from 8 to 12 weeks were used. After quarantining for one week, they were weighed and then randomized according to their weight, and 6 homogeneous groups (starting weight not significantly different) were formed. After being weighed, the different molecules to be tested are injected intraperitoneally once a day for 7 days. The molecules are injected into a 5% DMSO / 15% Solutol / Qsp H 2 O solution heated to 65 ° C to ensure good dissolution. The solution is further preheated before injection. The mice are weighed daily and the weight obtained after 7 days of treatment is noted.

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• Health & Medical Sciences (AREA)
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• Organic Chemistry (AREA)
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• Obesity (AREA)
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• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

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• 2002
  • 2002-10-11 FR FR0212648A patent/FR2845601B1/fr not_active Expired - Fee Related
• 2003
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