EP1424999A1 - Verwendung von c2-substituierten indan-1-one-systemen zur herstellung von medikamenten zur prophylaxe oder behandlung von obesitas - Google Patents

Verwendung von c2-substituierten indan-1-one-systemen zur herstellung von medikamenten zur prophylaxe oder behandlung von obesitas

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Publication number
EP1424999A1
EP1424999A1 EP02772166A EP02772166A EP1424999A1 EP 1424999 A1 EP1424999 A1 EP 1424999A1 EP 02772166 A EP02772166 A EP 02772166A EP 02772166 A EP02772166 A EP 02772166A EP 1424999 A1 EP1424999 A1 EP 1424999A1
Authority
EP
European Patent Office
Prior art keywords
alkyl
cycloalkyl
replaced
cooh
fluorine
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Withdrawn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
EP02772166A
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German (de)
English (en)
French (fr)
Inventor
Gerhard Jaehne
Volker Krone
Martin Bickel
Matthias Gossel
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.)
Sanofi Aventis Deutschland GmbH
Original Assignee
Aventis Pharma Deutschland GmbH
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Filing date
Publication date
Application filed by Aventis Pharma Deutschland GmbH filed Critical Aventis Pharma Deutschland GmbH
Publication of EP1424999A1 publication Critical patent/EP1424999A1/de
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/2264—Obesity-gene products, e.g. leptin
    • 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
    • A61K31/095—Sulfur, selenium, or tellurium compounds, e.g. thiols
    • A61K31/10—Sulfides; Sulfoxides; Sulfones
    • 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
    • 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
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • 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
    • A61P9/12—Antihypertensives

Definitions

  • the invention relates to the use of C2-substituted indan-1-one systems and their physiologically acceptable salts and physiologically functional derivatives for the production of medicaments for weight loss of mammals and for the prophylaxis or treatment of obesity.
  • indan-1-one and -1-ol derivatives are disclosed as herbicides and analgesics.
  • indan-1-one and -1-ol derivatives are disclosed as anti-asthma drugs.
  • the invention therefore relates to the use of the compounds of the formula I,
  • R1, R2, R3, R4 are independently H, F, Cl, Br, J, CN; N 3, N0 2, OH, 0 (d- C8) alkyl, 0 (C 3 -C 8) -cycloalkyl, 0-CH 2 -phenyl, O-phenyl, O-CO-
  • Alkynyl each one to seven hydrogen atoms may be replaced by fluorine, or a hydrogen by OH, OC (0) CH 3 , 0-CH 2 -Ph, NH 2 , NH-CO-CH 3 or N (COOCH 2 Ph) 2 replaced can be; Phenyl, 1- or 2-naphthyl,
  • R 5 CF 3 , (-C-C ⁇ s) alkyl, (C 3 -C 8 ) -cycloalkyl, wherein in the alkyl groups one to seven hydrogen atoms may be replaced by fluorine;
  • Alkyl groups one to seven hydrogen atoms may be replaced by fluorine;
  • R2, R3 are independently H; F, Cl, Br, J; CN; N 3 , NO 2 , 0 (-CC 8 ) -alkyl, 0 (C 3 -C 8 ) -cycloalkyl, O-CO-
  • Hydrogen atoms may be replaced by fluorine; or a hydrogen may be replaced by OH, OC (O) CH 3lO -CH 2 -Ph, NH 2 , NH-CO-CH 3 or N (COOCH 2 Ph) 2 ; Phenyl, 1- or 2-naphthyl, 5-tetrazolyl, 1 - [(dC f -Alkylj- ⁇ -tetrazolyl,
  • S (0) o -2 (C 1 -C 6 ) alkyl, NH 2 , NH-SO 2 - (CC 4 ) alkyl; COOH, CO-O- (dC 4 ) alkyl, CO-NH 2 may be substituted and in the
  • Alkyl groups one to seven hydrogen atoms may be replaced by fluorine;
  • R2 and R3 together form the group -0-CH 2 -0-; wherein at least one of the radicals R1, R2, R3 and R4 is always different from hydrogen;
  • C 8 ) alkyl COOH, CO-O (CC 8 ) -alkyl, CO-O- (C 3 -C 8 ) -cycloalkyl, CO-NH 2 , CO-NH (dC 8 ) -alkyl, CO-N [(CC 8 ) alkyl] 2 ; (dC 8) -alkyl, (C 3 -C 8) - cycloalkyl, in each case one can be up to seven hydrogen atoms are replaced by fluorine in the alkyl groups;
  • R1, R4 are independently H, F, Cl, Br; R2, R3 are independent of each other
  • Hydrogen atoms may be replaced by fluorine
  • radicals R1, R2, R3 and R4 are always different from hydrogen;
  • R 5 (C 1 -C 4) -alkyl; (C 3 -C 4 and C 6 -C 8 ) -cycloalkyl, wherein in the alkyl groups one to seven hydrogen atoms may be replaced by fluorine;
  • Phenyl a heterocyclic radical; and their physiologically acceptable salts for the manufacture of a medicament for the prophylaxis or treatment of obesity.
  • the invention relates to compounds of the formula I, in the form of their racemates, racemic mixtures and pure enantiomers, and to their diastereomers and mixtures thereof.
  • alkyl, alkenyl and alkynyl radicals in the substituents R1, R2, R3, R4, R5, R6, R7 and R8 can be both straight-chain and branched.
  • Heterocycle or heterocyclic radical is understood to mean ring systems which, in addition to carbon, also contain heteroatoms, such as, for example, nitrogen, oxygen or sulfur. Furthermore, ring systems also belong to this definition, in which the heterocyclic or the heterocyclic radical is condensed with benzene nuclei.
  • Preferred heterocycles or heterocyclic radicals are:
  • Suitable pharmaceutically acceptable Salts are particularly suitable for medical applications because of their higher water solubility compared to the starting or basic compounds. These salts must have a pharmaceutically acceptable anion or cation.
  • Suitable pharmaceutically acceptable Acid addition salts of the compounds of the formula I are salts of inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, metaphosphoric acid, nitric acid and sulfuric acid, and also organic acids, such as, for example, acetic acid, benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, Gluconic, glycolic, isethionic, lactic, lactobionic, maleic, malic, methanesulfonic, succinic, p-toluenesulfonic, tartaric and tri-fluoroacetic acid, furthermore L-ascorbic acid, salicylic acid, 1,2-benzisothiazole -3 (2H) -one and 6-methyl-1,2,3
  • Salts with a non-pharmaceutically acceptable anion are also within the scope of the invention as useful intermediates for the preparation or purification of pharmaceutically acceptable salts and / or for use in non-therapeutic, for example, in vitro applications.
  • physiologically functional derivative refers to any physiologically acceptable derivative of a compound of the invention, e.g. an ester which, when administered to a mammal, e.g. humans, is able to form (directly or indirectly) such a compound or an active metabolite thereof.
  • the physiologically functional derivatives also include prodrugs of the compounds according to the invention.
  • prodrugs can be metabolized in vivo to a compound of the invention. These prodrugs may or may not be effective.
  • the physiologically functional derivatives also include, for example, glucuronides, sulfuric acid esters, glycosides and ribosides.
  • the compounds of the formula I can also be present in various polymorphic forms, for example as amorphous and crystalline polymorphic forms. All polymorphic forms of the compounds of formula I are within the scope of the invention and are a further aspect of the invention.
  • the daily dose is in the range of 0.3 mg to 100 mg (typically 3 mg and 50 mg) per day per kilogram of body weight, eg 3-10 mg / kg / day.
  • an intravenous dose may range from 0.3 mg to 1.0 mg / kg, which may suitably be administered as an infusion of 10 ng to 100 ng per kilogram per minute.
  • Suitable infusion solutions for these purposes may contain, for example, from 0.1 ng to 10 mg, typically from 1 ng to 10 mg per milliliter.
  • Single doses may contain, for example, from 1 mg to 10 g of the active ingredient.
  • vials for injections, and orally administrable unit dose formulations, such as tablets or capsules may contain, for example, from 1.0 to 1000 mg, typically from 10 to 600 mg.
  • the abovementioned weights are based on the weight of the salt or free acid derived from the salt.
  • Compounds according to formula (I) themselves are used as a compound, but are preferably present with a compatible carrier in the form of a pharmaceutical composition.
  • the carrier must, of course, be compatible in the sense of being compatible with the other ingredients of the composition is compatible and is not harmful to the patient.
  • the carrier may be a solid or a liquid, or both, and is preferably formulated with the compound as a single dose, for example, as a tablet, which may contain from 0.05% to 95% by weight of the active ingredient.
  • Other pharmaceutically active substances may also be present, including further compounds according to formula (I).
  • the pharmaceutical compositions according to the invention can be prepared by one of the known pharmaceutical methods, which consist essentially in that the ingredients are mixed with pharmacologically acceptable carriers and / or excipients.
  • compositions according to the invention are those which are suitable for oral, rectal, topical, peroral (eg sublingual) and parenteral (eg subcutaneous, intramuscular, intradermal or intravenous) administration, although the most suitable mode of administration in each individual case is of the type and severity of the treatment to be treated State and on the nature of the particular compound used according to formula (I) is dependent.
  • coated formulations and coated slow release formulations are within the scope of the invention.
  • Suitable pharmaceutical compounds for oral administration may be in separate units, such as capsules, cachets, lozenges or tablets, each containing a certain amount of the compound of formula (I); as a powder or granules; as a solution or suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil emulsion.
  • these compositions may be formulated by any suitable pharmaceutical method comprising a step in which the active ingredient and the carrier (consisting of one or more additional constituents can be) brought into contact.
  • the compositions are prepared by uniformly and homogeneously mixing the active ingredient with a liquid and / or finely divided solid carrier, after which the product is molded, if necessary.
  • a tablet can be made by compressing or molding a powder or granules of the compound, optionally with one or more additional ingredients.
  • Compressed tablets may be prepared by tableting the compound in free-flowing form, such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent and / or surfactant / dispersing agent in a suitable machine.
  • Molded tablets may be prepared by shaping the powdered compound moistened with an inert liquid diluent in a suitable machine.
  • compositions suitable for peroral (sublingual) are provided.
  • Administration include lozenges containing a compound of formula (I) with a flavor, usually sucrose and gum arabic or tragacanth, and lozenges comprising the compound on an inert base such as gelatin and glycerine or sucrose and gum arabic.
  • Suitable pharmaceutical compositions for parenteral administration preferably comprise sterile aqueous preparations of a compound according to formula (I) which are preferably isotonic with the blood of the intended recipient. These preparations are preferably administered intravenously, although the administration may also be subcutaneous, intramuscular or intradermal as an injection. These preparations may preferably be prepared by mixing the compound with water and rendering the resulting solution sterile and isotonic with the blood. Injectable compositions of the invention generally contain from 0.1% to 5% by weight of the active compound. Suitable pharmaceutical compositions for rectal administration are preferably as single dose suppositories. These can be prepared by mixing a compound according to formula (I) with one or more conventional solid carriers, for example cocoa butter, and shaping the resulting mixture.
  • Suitable pharmaceutical compositions for topical application to the skin are preferably as an ointment, cream, lotion, paste, spray, aerosol or oil.
  • Vaseline, lanolin, polyethylene glycols, alcohols, and combinations of two or more of these substances can be used as the carrier.
  • the active ingredient is generally present at a level of from 0.1% to 15% by weight of the composition, for example from 0.5% to 2%.
  • Suitable pharmaceutical compositions for transdermal applications may exist as single patches suitable for long-term close contact with the epidermis of the patient. Such patches suitably contain the active ingredient in an optionally buffered aqueous solution, dissolved and / or dispersed in an adhesive or dispersed in a polymer.
  • a suitable active ingredient concentration is about 1% to 35%, preferably about 3% to 15%.
  • the active ingredient may be released by electrotransport or iontophoresis as described, for example, in Pharmaceutical Research, 2 (6): 318 (1986).
  • the invention further provides a process for the preparation of the compounds of general formula I, which comprises compounds of general formula I according to the following reaction schemes:
  • R1, R2, R3 and R4 have the meaning given, with a halogen, such as. B. bromine or chlorine converted into a compound of formula III.
  • metal salts can be used as such or in solution in 5 situ from the thiol and a base such. For example, aqueous sodium hydroxide can be produced.
  • a base such as, for example, Lithium diisopropylamide in e.g. Tetrahydrofuran and a disulfide of the general formula R 5 -Y-X-X-Y-R 5, wherein R 5 and Y have the meanings indicated and X is S;
  • Acetic anhydride (Sviridova, A.V., et al., J. Org. Chem (Russ), English Transl., 7, 2577 (1971).
  • Suitable salts of inorganic acids include, for example, hydrohalic acids such as hydrochloric acid and hydrobromic acid, as well as sulfuric acid, phosphoric acid and sulfamic acid.
  • Suitable organic acids for salt formation are: formic acid, acetic acid, benzoic acid, p-toluenesulfonic acid, benzenesulfonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, citric acid, L-ascorbic acid, salicylic acid, isethionic acid, methanesulfonic acid, trifluoromethanesulfonic acid, 1,2-benzisothiazole -3 (2H) -one, 6-methyl-1,3,3-oxathiazine-4 (3H) -one-2,2-dioxide.
  • Method A Column: Merck, LiChroCart 55-2, PuroSpher STAR, RP 18 e; Measurement at
  • Time (min) / solvent B (%): 0.00 / 95.0, 0.50 / 95.0, 1.75 / 5.0, 4.25 / 5.0, 4.50 / 95.0,
  • Method B column: YMC J'sphere, 33x2, ODS H 80 4 ⁇ ; Measurement at 254 nm;
  • the compounds of the formula I are distinguished by favorable effects on the lipid metabolism, in particular they are suitable for weight reduction and after weight reduction to obtain a reduced weight in mammals and as anorectic agents.
  • the compounds are characterized by their low toxicity and their low side effects.
  • the compounds can be used alone or in combination with other weight-reducing or anorectic agents.
  • Such other anorectic agents are mentioned, for example in the Red List, Chapter 01 under weight loss / appetite suppressants and may also include such agents that increase the energy expenditure of the organism and thus lead to a weight reduction or even those that influence the general metabolism of the organism so that an increased calorie intake does not lead to an increase in fat deposits and a normal calorie intake to a reduction in fat deposits of the organism.
  • the compounds are suitable for the prophylaxis and in particular for the treatment of overweight or obesity.
  • the compounds are furthermore suitable for the prophylaxis and in particular for the treatment of type II diabetes, atherosclerosis and for the normalization of lipid metabolism and for the treatment of hypertension.
  • the compounds of the formula I can be used in combination with one or more further pharmacologically active
  • Substances which are selected, for example, from antidiabetics, antiadipositas, antihypertensives, lipid lowering agents and drugs for the treatment and / or prevention of complications caused by or associated with diabetes.
  • Suitable antidiabetics include insulins, amylin, GLP-1 and GLP-2 derivatives such as e.g. those disclosed in WO 98/08871 by Novo Nordisk A / S and orally active hypoglycemic agents.
  • the orally active hypoglycemic agents preferably comprise
  • Sulfonylfhureas biguanides, meglitinides, oxadiazolidinediones, thiazolidinediones, glucosidase inhibitors, glucagon receptor antagonists, GLP-1 agonists, potassium channel openers such as those disclosed in WO 97/26265 and WO 99/03861 by Novo Nordisk A / S , Insulin sensitizers, insulin receptor kinase activators, inhibitors of liver enzymes involved in the stimulation of gluconeogenesis and / or glycogenolysis, eg glycogen phosphorylase inhibitors, modulators of glucose uptake and glucose excretion, lipid metabolism altering compounds such as antihyperlipidemic agents and antilipidemic agents, For example, HMGCoA reductase inhibitors, inhibitors of cholesterol transport / the Cholesterol uptake, inhibitors of bile acid reabsorption or inhibitors of microsomal triglyceride transfer protein (MTP), compounds that
  • a sulphonylurea such as e.g. Tolbutamide, glibenclamide, glimepiride, glipizide, gliquidone, glisoxepid, glibornuride or gliclazide.
  • the present compounds are used in combination with a biguanide, e.g. Administered metformin.
  • the present compounds are used in combination with a meglitinide, such as e.g. Repaglinide administered.
  • a meglitinide such as e.g. Repaglinide administered.
  • the present compounds are used in combination with a thiazolidinedione, e.g. Troglitazone, ciglitazone, pioglitazone, rosiglitazone or those described in WO 97/41097 by Dr. med. Reddy's Research Foundation disclosed compounds, particularly 5 - [[4 - [(3,4-dihydro-3-methyl-4-oxo-2-quinazolinylmethoxy) phenyl] methyl] -2,4-thiazolidinedione.
  • a thiazolidinedione e.g. Troglitazone, ciglitazone, pioglitazone, rosiglitazone or those described in WO 97/41097 by Dr. med. Reddy's Research Foundation disclosed compounds, particularly 5 - [[4 - [(3,4-dihydro-3-methyl-4-oxo-2-quinazolinylmethoxy) phenyl]
  • the present compounds are administered in combination with a monoamine oxidase inhibitor, such as disclosed in WO 01/12176.
  • a monoamine oxidase inhibitor such as disclosed in WO 01/12176.
  • Particularly suitable are [3 (S), 3a (S)] - 3-methoxymethyl-7- [4,4,4-trifluorobutoxy] -3,3a, 4,5-tetrahydro-1H-oxazolo [3,4 -a] quinolin-1-one, (R) -5- (methoxymethyl) -3- [6- (4,4,4-trifluorobutoxy) benzofuran-3-yl] oxazolidin-2-one or (R) -5 - (methoxymethyl) -3- [6-cyclopropylmethoxybenzofuran-3-yl] oxazolidin-2-one.
  • the present compounds are administered in combination with an o-glucosidase inhibitor such as miglitol or acarbos
  • the present compounds are administered in combination with a human ciliary neurotrophic factor hCNTF or derivatives thereof such as CNTF A x -ts or modified CNTFAXIS as disclosed, for example, in Lambert et al., PNAS 98, 4652-4657 ,
  • the present compounds are administered in combination with an agent that acts on the ATP-dependent potassium channel of the beta cells, such as e.g. Tolbutamide, glibenclamide, glimepiride, glipizide, gliclazide or repaglinide.
  • an agent that acts on the ATP-dependent potassium channel of the beta cells such as e.g. Tolbutamide, glibenclamide, glimepiride, glipizide, gliclazide or repaglinide.
  • the subject compounds are used in combination with an antihyperlipidemic agent or an antilipidemic agent, such as e.g. Cholestyramine, colestipol, clofibrate, gemfibrozil, lovastatin, pravastatin, simvastatin, atorvastatin, cerivastatin, fluvastatin, probucol, ezetimibe or dextrothyroxine.
  • an antihyperlipidemic agent or an antilipidemic agent such as e.g. Cholestyramine, colestipol, clofibrate, gemfibrozil, lovastatin, pravastatin, simvastatin, atorvastatin, cerivastatin, fluvastatin, probucol, ezetimibe or dextrothyroxine.
  • the present compounds are used in combination with more than one of the aforementioned compounds, e.g. in combination with a sulphonylurea and metformin, a sulphonylurea and acarbose, repaglinide and metformin, insulin and a sulphonylurea, insulin and metformin, insulin and troglitazone, insulin and lovastatin, etc.
  • the compounds according to the invention can be administered in combination with one or more antiadipositas or appetite regulating active ingredients.
  • agents may be selected from the group consisting of CART agonists, NPY antagonists, melanocortin 3 or 4 (MC3 or MC4) agonists, melanin-concentrating hormone (MCH) antagonists, orexin antagonists, H3 agonists, TNF Agonists, CRF agonists, CRF BP antagonists, urocortin agonists, / 3-adrenoceptor agonists, MSH (melanocyte-stimulating hormone) agonists, CCK agonists, serotonin reuptake inhibitors, mixed sertonine and norepinephrine reuptake inhibitors.
  • Inhibitors 5HT modulators, bombesin agonists, galanin antagonists, glucocorticoid receptor modulators, growth hormone, growth hormone releasing compounds, TRH agonists, modulators of decoupling proteins 2 or 3, leptin receptor agonists, leptin mimetics, dopamine agonists (bromocriptine, doprexin), Lipase / amylase inhibitors, cannabinoid receptor 1 antagonists, acylation stimulating protein (ASP) modulators, PPAR modulators, RXR modulators or TR- /? Agonists.
  • ASP acylation stimulating protein
  • the anti-adiposity is leptin or modified leptin.
  • the anti-adiposity is dexamphetamine or amphetamine.
  • Such agents may be selected from the group consisting of CART agonists, NPY antagonists, melanocortin 3 or 4 (MC3 or MC4) agonists, melanin-concentrating hormone (MCH) antagonists, orexin antagonists, H3 agonists, TNFs.
  • CART agonists NPY antagonists
  • MC3 or MC4 melanocortin 3 or 4
  • MCH melanin-concentrating hormone
  • H3 agonists TNFs.
  • Agonists CRF agonists, CRF BP antagonists, urocortin
  • Agonists 3-adrenoceptor agonists, CCK agonists, serotonin reuptake inhibitors, mixed sertonine and norepinephrine reuptake inhibitors, 5HT modulators, bombesin agonists, galanin antagonists, glucocorticoid receptor modulators, growth hormone, growth hormone releasing compounds , TRH agonists, modulators of decoupling proteins 2 or 3, leptin receptor Agonists, leptin mimetics, dopamine agonists (bromocriptine, doprexin), lipase / amylase inhibitors, cannabinoid receptor 1 antagonists, acylation stimulating protein (ASP) modulators, PPAR modulators, RXR modulators, or TR - /? - agonists.
  • ASP acylation stimulating protein
  • the anti-adiposity is leptin or modified leptin.
  • the anti-adiposity is dexamphetamine or amphetamine.
  • the anti-adiposity is fenfluramine or dexfenfluramine.
  • the anti-adiposity is sibutramine or the mono- and bis-demethylated active metabolites of sibutramine.
  • the anti-obesity agent is orlistat.
  • the anti-obesity agent is mazindol, diethylpropion or phentermine.
  • antihypertensive agents are beta blockers such as alprenolol, atenol, timolol, pindolol, propanolol and metoprolol, ACE (angiotensin converting enzyme) inhibitors such as benazepril, captopril, enalapril, fosinopril, lisinopril, quinapril and rampril, calcium channel blockers such as nifedipine, felodipine, Nicardipine, isradipine, nimodipine, diltiazem and verapamil, as well as alpha-blockers such as doxazosin. ' Urapidil, prazosin and terazosin. Further, reference can be made to Remington: The Science and Practice of Pharmacy, 19th Edition, Gennaro, ed., Mack Publishing Co.
  • Dragees containing 50 mg of active ingredient per coated tablet: per Dragee active ingredient 50 mg
  • Example G Drops can be prepared according to the following recipe (100 mg of active ingredient in 1 ml
  • the anorectic effect was tested on female NMRl mice. After 24 hours of feed withdrawal, the test preparation was administered intraperitoneally (ip) or via gavage (po). In individual and with free access to Drinking water was offered to the animals 30 minutes after preparation of condensed milk. Condensed milk consumption was determined for half an hour for 7 hours and the general condition of the animals was observed. The measured milk consumption was compared with the untreated control animals.
  • Table 2 Anorectic effect, measured as reduction of cumulated milk consumption treated compared to untreated animals.
  • the compounds of Examples 12-28, 31-33 and 36 are obtained as described in Example 1 by reacting the corresponding ⁇ -bromo-indan-1-one with the sodium salt of the respective mercaptan.
  • the compounds of Examples 5 - 8, 10 - 11, 29, 30, 34 and 35 and 37 - 52 are obtained either by the method of Example 2 from the corresponding Sulfanylderivaten or, if it is methyl derivatives, by conversion of the corresponding ⁇ -Brom-indan-1-ones with the sodium salt of methanesulfinic acid.

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EP02772166A 2001-08-31 2002-08-17 Verwendung von c2-substituierten indan-1-one-systemen zur herstellung von medikamenten zur prophylaxe oder behandlung von obesitas Withdrawn EP1424999A1 (de)

Applications Claiming Priority (3)

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DE10142668 2001-08-31
DE10142668A DE10142668A1 (de) 2001-08-31 2001-08-31 Verwendung von C2-substituierten Indan-1-on-Systemen zur Herstellung von Medikamenten zur Prophylaxe oder Behandlung von Obesitas
PCT/EP2002/009208 WO2003020256A1 (de) 2001-08-31 2002-08-17 Verwendung von c2-substituierten indan-1-on-systemen zur herstellung von medikamenten zur prophylaxe oder behandlung von obesitas

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TWI522109B (zh) * 2009-01-26 2016-02-21 臺北醫學大學 蕨素化合物用於治療糖尿病及肥胖之用途
CN103333144B (zh) * 2013-06-17 2014-12-10 温州大学 一种2-硫基-3-卤代苯并呋喃化合物及其合成方法和用途

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AU2002336985B2 (en) 2006-11-16
IL160607A (en) 2011-03-31
JP4342306B2 (ja) 2009-10-14
MXPA04001853A (es) 2004-06-15
CA2458555A1 (en) 2003-03-13
IL160607A0 (en) 2004-07-25
WO2003020256A1 (de) 2003-03-13
US20030134882A1 (en) 2003-07-17
DE10142668A1 (de) 2003-03-20
PE20030336A1 (es) 2003-05-19
JP2005503396A (ja) 2005-02-03
US6946492B2 (en) 2005-09-20

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