US20030134879A1 - Use of C2-substituted indan-1-ol systems for preparing medicaments for the prophylaxis or treatment of obesity - Google Patents

Use of C2-substituted indan-1-ol systems for preparing medicaments for the prophylaxis or treatment of obesity Download PDF

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US20030134879A1
US20030134879A1 US10/231,183 US23118302A US2003134879A1 US 20030134879 A1 US20030134879 A1 US 20030134879A1 US 23118302 A US23118302 A US 23118302A US 2003134879 A1 US2003134879 A1 US 2003134879A1
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alkyl
cycloalkyl
compounds
cooh
fluorine
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Gerhard Jaehne
Volker Krone
Martin Bickel
Matthias Gossel
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Sanofi Aventis Deutschland GmbH
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Aventis Pharma Deutschland GmbH
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Assigned to AVENTIS PHARMA DEUTSCHLAND GMBH reassignment AVENTIS PHARMA DEUTSCHLAND GMBH ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: BICKEL, MARTIN, GOSSEL, MATTHIAS, KRONE, VOLKER, JAEHNE, GERHARD
Publication of US20030134879A1 publication Critical patent/US20030134879A1/en
Priority to US11/006,164 priority Critical patent/US7763662B2/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/255—Esters, e.g. nitroglycerine, selenocyanates of sulfoxy acids or sulfur analogues thereof
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • 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

  • C2-substituted indan-1-ol systems for preparing medicaments for the prophylaxis or treatment of obesity.
  • Other applications that describe similar compounds and methods of using these compounds include: 1) “C2-substituted idan-1-ones and their derivatives, processes for their preparation and their use as pharmaceuticals” of Gerhard Jaehne, Volker Krone, Martin Bickel, and Matthias Gossel filed Aug. 31, 2002, Attorney Docket Number 02481.1795; 2) “C2-substituted indan-1-ols and their derivatives, processes for their preparation and their use as pharmaceuticals” of Gerhard Jaehne, Volker Krone, Martin Bickel, and Matthias Gossel filed Aug.
  • Embodiments of the invention relate to the use of C2-substituted indan-1-ol systems and their physiologically acceptable salts and physiologically functional derivatives for preparing medicaments for reducing weight in mammals and for the prophylaxis or treatment of obesity.
  • EP 0009554 discloses indan-1-one and -1-ol derivatives as herbicides and analgesics.
  • EP 0313296 discloses indan-1-one and -1-ol derivatives as pharmaceuticals for asthma.
  • WO 97/20806 discloses cyclopentyl-substituted indan-1-one derivatives having inter alia antiinflammatory action.
  • an object of the present invention is to provide compounds which can be used for reducing weight in mammals and which, in particular, have a therapeutically utilizable anorectic action.
  • R1,R2,R3,R4 independently of one another are H, F, Cl, Br, I, CN; N 3 , NO 2 , OH, O(C 1 -C 8 )-alkyl, O(C 3 -C 4 and C 6 -C 8 )-cycloalkyl, O—CH 2 -phenyl, O-phenyl, O—CO—(C 1 -C 8 )-alkyl, O—CO—(C 3 -C 8 )-cycloalkyl, S(O) 0-2 (C 1 -C 8 )-alkyl, S(O) 0-2 (C 3 -C 8 )-cycloalkyl, NH 2 , NH—(C 1 -C 8 )-alkyl, NH—(C 3 -C 8 )-cycloalkyl, N-[(C 1 -C 8 )-alkyl] 2 , N-[(C 3 -C 8 )-cycloal
  • aryl radical or heterocycle is unsubstituted or substituted one to two times by F, Cl, Br, CN, OH, (C 1 -C 4 )-alkyl, CF 3 , O—(C 1 -C 4 )-alkyl, S(O) 0-2 (C 1 -C 6 )-alkyl, NH 2 , NH—SO 2 —(C 1 -C 4 )-alkyl,
  • R2 and R3 together form the group —O—CH 2 —O—;
  • X is S, SO, or SO 2 ;
  • Y is (CH 2 ) p , where p is 0, 1, 2 or 3;
  • R5 is CF 3 , (C 1 -C 18 )-alkyl, or (C 3 -C 8 )-cycloalkyl, wherein the alkyl groups in each case have zero to seven hydrogen atoms replaced by fluorine;
  • compounds of the formula I for use in the methods of the invention are chosen from compounds of the formula I in which
  • R1, R4 independently of one another are
  • R2, R3 independently of one another are
  • one hydrogen may be replaced by OH, OC(O)CH 3 , O—CH 2 —Ph, NH 2 , NH—CO—CH 3 or N(COOCH 2 Ph) 2 ; or
  • heterocycle is unsubstituted or substituted one or two times by F, Cl, Br, CN, OH, (C 1 -C 4 )-alkyl, CF 3 , O—(C 1 -C 4 )-alkyl, S(O) 0-2 (C 1 -C 6 )-alkyl, NH 2 , NH—SO 2 —(C 1 -C 4 )-alkyl, COOH, CO—O—(C 1 -C 4 )-alkyl, or CO—NH 2 wherein the alkyl groups in each case have zero to seven hydrogen atoms replaced by fluorine;
  • R2 and R3 together form the group —O—CH 2 —O—; where in each case at least one of the radicals R1, R2, R3 and R4 is different from hydrogen;
  • X is S, SO, or SO 2 ;
  • Y is (CH 2 ) p , where p is 0, 1, 2 or 3;
  • R5 is (C 1 -C 18 )-alkyl, or (C 3 -C 4 — and C 6 -C 8 )-cycloalkyl, wherein the alkyl or cycloalkyl groups in each case have zero to seven hydrogen atoms replaced by fluorine;
  • compounds of the formula I for use in the methods of the invention are chosen from compounds of the formula I in which
  • R1, R4 independently of one another are H, F, Cl, or Br;
  • R2, R3 independently of one another are
  • alkyl groups in each case have zero to seven hydrogen atoms may be replaced by fluorine;
  • X is S, SO, or SO 2 ;
  • Y is (CH 2 ) p , where p is 0 or 1;
  • R5 is (C 1 -C 18 )-alkyl, or (C 3 -C 4 — and C 6 -C 8 )-cycloalkyl, wherein the alkyl or cycloalkyl groups have zero to seven hydrogen atoms replaced by fluorine;
  • (C 1 -C 4 )-alkyl and R8 is OH, O—(C 1 -C 6 )-alkyl or NH 2 ;
  • the invention relates to compounds of the formula I in the form of their racemates, racemic mixtures and pure enantiomers, and also to their diastereomers and mixtures thereof.
  • any stereoisomeric form includes racemates, racemic mixtures and pure enantiomers, and also 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 straight-chain or branched.
  • Heterocycle or heterocyclic radical is to be understood as meaning ring systems which, in addition to carbon, also contain heteroatoms, such as, for example, nitrogen, oxygen or sulfur. This definition furthermore includes ring systems in which the heterocycle or heterocyclic radical is fused with benzene rings.
  • heterocycles or heterocyclic radicals include, but are not limited to:
  • heteroaryls such as
  • Suitable pharmaceutically acceptable acid addition salts of the compounds of the invention include salts of inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, metaphosphoric acid, nitric acid and sulfuric acid and also of organic acids such as, for example, acetic acid, benzenesulfonic acid, benzoic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glycolic acid, isethionic acid, lactic acid, lactobionic acid, maleic acid, malic acid, methane-sulfonic acid, succinic acid, p-toluenesulfonic acid, tartaric acid and trifluoroacetic acid, furthermore L-ascorbic acid, salicylic acid, 1,2-benzisothia
  • suitable pharmaceutically acceptable basic salts are ammonium salts, alkali metal salts (such as sodium salts and potassium salts) and alkaline earth metal salts (such as magnesium salts and calcium salts).
  • salts having a pharmaceutically unacceptable anion are likewise included within the scope of the present invention, for example, as useful intermediates for preparing or purifying pharmaceutically acceptable salts and/or for use in nontherapeutic applications, such as in-vitro applications.
  • treating or treatment includes the treating of, for example, a patient inflicted with a disease or condition, as well as the prevention, prophylaxis, or protective treatment of a patient.
  • treatment of obesity includes reducing and/or maintaining the weight of a subject who is inflicted with obesity or is susceptible to obesity.
  • the treatment of obesity also includes inhibiting and/or slowing the weight gain of a subject who is inflicted with obesity or is susceptible to obesity.
  • Treatment of obesity also includes treating a subject susceptible to or predisposed to developing obesity, which could include patients in whom obesity has not yet presented as well as patients in whom the disease has been successfully treated but could redevelop or reoccur.
  • controlling weight includes reducing and/or maintaining the weight of a subject. Controlling weight also includes inhibiting and/or slowing the weight gain of a subject.
  • the phrase weight controlling compounds includes weight-reducing compounds.
  • physiologically functional derivative used herein relates to any physio-logically acceptable derivative of an inventive compound, for example an ester which on administration to a mammal, for example humans, is capable of forming (directly or indirectly) such a compound or an active metabolite thereof.
  • the physiologically functional derivatives also include prodrugs of the compounds of the invention.
  • prodrugs may be metabolized in vivo to a compound of the invention. These prodrugs may or may not be active themselves.
  • physiologically functional derivatives furthermore include, for example, glucuronides, sulfuric acid esters, glycosides and ribosides.
  • the compounds of the formula I may also be present in various polymorphous forms, for example as amorphous and crystalline polymorphous forms. All polymorphous forms of the compounds of the formula I are included within the scope of the invention and are another aspect of the invention.
  • the amount of a compound according to formula (I) which is required in order to attain the desired biological effect depends on a number of factors, for example the specific compound selected, the intended use, the type of administration and the clinical state of the patient.
  • the daily dose is in the range from 0.3 mg to 100 mg (typically from 3 mg to 50 mg) per day per kilogram of body weight, for example 3-10 mg/kg/day.
  • An intravenous dose can be, for example, in the range from 0.3 mg to 1.0 mg/kg and can be administered in a suitable manner 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.
  • ampules for injections can contain, for example, from 1 mg to 100 mg
  • orally administerable individual dose formulations such as, for example, tablets or capsules can contain, for example, from 1.0 to 1000 mg, typically from 10 to 600 mg.
  • the use of a compound of formula (I) as a prophylaxis may require a lower amount of a compound of formula (I), but still within the range disclosed above, for the patient of interest
  • the abovementioned masses relate to the mass of the free base or acid on which the salt is based.
  • the compound used for the prophylaxis or therapy of the abovementioned conditions may be the compounds according to formula (I) themselves, or, in one embodiment, they are present in the form of a pharmaceutical composition together with an acceptable carrier.
  • the carrier must be naturally acceptable, in the sense that it is compatible with the other ingredients of said composition and is not harmful to the patient's health.
  • the carrier may be a solid or a liquid or both and is preferably formulated with the compound as an individual dose, for example as a tablet which may contain from 0.05% to 95% by weight of the active compound. Further pharmaceutically active substances may also be present, including further compounds according to formula (I).
  • the pharmaceutical compositions of the invention may be prepared according to any of the known pharmaceutical methods which essentially comprise mixing the ingredients with pharmacologically acceptable carriers and/or excipients.
  • compositions of the invention are those which are suitable for oral, rectal, topical, peroral (e.g. sublingual) and parenteral (e.g. subcutaneous, intramuscular, intradermal or intravenous) administration, although the most suitable manner of administration depends in each individual case on the nature and severity of the condition to be treated and on the nature of the compound according to formula (I) used in each case.
  • Sugar-coated formulations and sugar-coated delayed-release formulations are included within the scope of the invention.
  • preference is given to acid-resistant and enteric formulations. Suitable enteric coatings include, for example, cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate and anionic polymers of methacrylic acid and methyl methacrylate.
  • Suitable pharmaceutical compounds for oral administration may be present in separate units as, for example, capsules, cachets, lozenges or tablets, which in each case contain a particular amount of the compound according to formula (I); as powders or granules; as solution or suspension in an aqueous or nonaqueous liquid; or as an oil-in-water or water-in-oil emulsion.
  • said compositions can be prepared according to any suitable pharmaceutical method which includes a step in which the active compound and the carrier (which may comprise one or more additional components) are contacted.
  • the compositions are prepared by uniform and homogeneous mixing of the active compound with a liquid and/or finely dispersed solid carrier, after which the product is shaped, if necessary.
  • a tablet for example, may be prepared by pressing or shaping a powder or granules of the compound, where appropriate with one or more additional components.
  • Pressed tablets can be prepared by tableting the compound in free-flowing form, for example a powder or granules, mixed, where appropriate, with a binder, lubricant, inert diluent and/or one or more surface active/dispersing agents in a suitable machine.
  • Shaped tablets can be prepared by shaping the pulverulent compound, moistened with an inert liquid diluent, in a suitable machine.
  • compositions which are suitable for peroral (sublingual) administration include lozenges which contain a compound according to formula (I) with a flavoring, usually sucrose and gum arabic or tragacanth, and pastilles which comprise the compound in an inert base such as gelatin and glycerol or sucrose and gum arabic.
  • Suitable pharmaceutical compositions for parenteral administration may, for example, comprise sterile aqueous preparations of a compound according to formula (I) which are isotonic with the blood of the intended recipient. These preparations may be administered intravenously, although they may also be administered subcutaneously, intramuscularly or intradermally as an injection. Said preparations may be prepared by mixing the compound with water and rendering the obtained 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 may be present as individual dose suppositories. These may 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 may be present as ointment, cream, lotion, paste, spray, aerosol or oil.
  • Carriers which may be used are petroleum jelly, lanolin, polyethylene glycols, alcohols and combinations of two or more of these substances.
  • the active compound is present at a concentration ranging from 0.1 to 15%, for example from 0.5 to 2%, by weight of the composition.
  • Transdermal administration is also possible.
  • Suitable pharmaceutical compositions for transdermal administration may be present as individual patches which are suitable for long-term close contact with the epidermis of the patient.
  • patches suitably contain the active compound in an optionally buffered aqueous solution, dissolved and/or dispersed in an adhesive or dispersed in a polymer.
  • a suitable active compound concentration in one embodiment ranges from approx. 1% to 35%, such as approx. 3% to 15%.
  • a particular possibility is the release of the active compound by electrotransport or iontophoresis, as described, for example, in Pharmaceutical Research, 2(6): 318 (1986).
  • the invention furthermore provides a process for preparing the compounds of the formula I which comprises obtaining the compounds of the formula I by proceeding according to the reaction schemes below:
  • R1, R2, R3 and R4 are as defined above are converted with a halogen, such as, for example, bromine or chlorine, into a compound of the formula III.
  • a halogen such as, for example, bromine or chlorine
  • the compounds of the formula III are converted further with metal salts of thiols of the formula H—X—Y—R5, where X is sulfur and Y and R5 are as defined above into compounds of the formula IV where X ⁇ S.
  • metal salts can be employed as such or they can be generated in solution in situ from the thiol and a base, such as, for example, aqueous sodium hydroxide.
  • compounds of the formula IV where X ⁇ S can be obtained by reacting compounds of the formula II with a base, such as, for example, lithium diisopropylamide, for example in tetrahydrofuran, and with a disulfide of the formula R5—Y—X—X—Y—R5 in which R5 and Y are as defined above and X ⁇ S; alternatively, instead of the disulfide, it is also possible to use a sulfenyl chloride of the formula Cl—X—Y—R5 where X ⁇ S and Y and R5 are as defined above (see, for example, D. Seebach et al.; Chem. Ber. 109,1601-1616 (1976)).
  • Indenes of the formula VII can be converted by oxidative addition of compounds of the formula HX—Y—R5 in which X ⁇ S into compounds of the formula I in which X ⁇ SO 2 (see, for example, J. F. Ford et al. (Tetrahedron 4, 325-336 (1958)).
  • Inorganic acids suitable for forming salts are, for example: hydrohalic acids, such as hydrochloric acid and hydrobromic acid, and also sulfuric acid, phosphoric acid and amidosulfonic acid.
  • Organic acids suitable for salt formation which may be mentioned are, for example: formic acid, acetic acic, 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-benzisothiazol-3(2H)-one, 6-methyl-1,2,3-oxathiazin-4(3H)-one 2,2-dioxide.
  • Method A Column: Merck, LiChroCart 55-2, PuroSpher STAR, RP 18 e; measured at 254 nm; gradient: solvent A acetonitrile/water 90:10+0.5% formic acid; solvent B acetonitrile/water 10:90+0.5% formic acid; flow rate: 0.750 ml/min; time (min)/solvent B (%): 0.00/95.0, 0.50/95.0,1.75/5.0, 4.25/5.0, 4.50/95.0, 5.00/95.0; temperature: 40° C.:
  • Method B column: YMC J'sphere, 33 ⁇ 2, ODS H 80 4 ⁇ ; measured at 254 nm; gradient: solvent A acetonitrile+0.5% formic acid; solvent B water+0.5% formic acid; flow rate: 1.00 ml/min; time (min)/solvent B (%): 0.00/90.0, 2.50/5.0, 3.30/5.0, 3.35/90.0; temperature: 30° C.: TABLE 1 Examples Formula I Example R1 R2 R3 R4 X Y R5 m.p.
  • the compounds of the formula I are distinguished by beneficial actions on the metabolism of lipids, and they are particularly suitable for weight reduction and, after weight reduction, for maintaining a reduced weight in mammals and as anorectic agents.
  • the compounds are distinguished by their low toxicity and their few side effects.
  • the compounds may be employed alone or in combination with other weight-reducing or anorectic active compounds.
  • anorectic active compounds of this kind are mentioned, for example, in the Rote Liste, Chapter 01 under weight-reducing agents/appetite suppressants, herein incorporated by reference, and may also include those active compounds which increase the energy turnover of the organism and thus lead to weight reduction or else those which influence the general metabolism of said organism such that increased calorie intake does not cause an enlargement of the fat depots and a normal calorie intake causes a reduction in the fat depots of said organism.
  • the compounds may be suitable for controlling or the prophylaxis and, in particular, for the treatment of problems of excess weight or obesity.
  • the compounds may furthermore be suitable for the prophylaxis and, in particular, for the treatment of type II diabetes, of arteriosclerosis and for the normalization of lipid metabolism and for the treatment of high blood pressure.
  • the compounds of the formula I may be administered in combination with one or more further pharmacologically active substances which may be selected, for example, from the group consisting of antidiabetics, antiadipose agents, blood-pressure-lowering active compounds, lipid reducers and active compounds for the treatment and/or prevention of complications caused by diabetes or associated with diabetes.
  • pharmacologically active substances which may be selected, for example, from the group consisting of antidiabetics, antiadipose agents, blood-pressure-lowering active compounds, lipid reducers and active compounds for the treatment and/or prevention of complications caused by diabetes or associated with diabetes.
  • Suitable antidiabetics include insulins, amylin, GLP-1 and GLP-2 derivatives such as, for example, those disclosed by Novo Nordisk A/S in WO 98/08871 and also oral hypoglycemic active compounds.
  • said oral hypoglycemic active compounds include sulfonyl ureas, biguamides, meglitinides, oxadiazolidinediones, thiazolidinediones, glucosidase inhibitors, glucagon receptor antagonists, GLP-1 agonists, potassium channel openers such as, for example, those disclosed by Novo Nordisk A/S in WO 97/26265 and WO 99/03861, insulin sensitizers, activators of insulin receptor kinase, inhibitors of liver enzymes involved in the stimulation of gluconeogenesis and/or glycogenolysis, for example glycogen phosphorylase inhibitors, modulators of glucose uptake and glucose elimination, lipid metabolism-modifying compounds such as antihyperlipidemic active compounds and antilipidemic active compounds, for example HMGCoA-reductase inhibitors, inhibitors of cholesterol transport/cholesterol uptake, inhibitors of the reabsorption of bile acid or inhibitors of micro
  • the present compounds are administered in combination with insulin.
  • the compounds of the invention are administered in combination with a sulfonylurea such as, for example, tolbutamide, glibenclamide, glimepiride, glipizide, gliquidone, glisoxepide, glibornuride or gliclazide.
  • a sulfonylurea such as, for example, tolbutamide, glibenclamide, glimepiride, glipizide, gliquidone, glisoxepide, glibornuride or gliclazide.
  • the compounds of the present invention are administered in combination with a biguamide such as, for example, metformin.
  • the compounds of the present invention are administered in combination with a meglitinide such as, for example, repaglinide.
  • the compounds of the present invention are administered in combination with a thiazolidinedione such as, for example, troglitazone, ciglitazone, pioglitazone, rosiglitazone or the compounds disclosed by Dr. Reddy's Research Foundation in WO 97/41097, in particular 5-[[4-[(3,4-dihydro-3-methyl-4-oxo-2-quinazolinylmethoxy]phenyl]methyl]-2,4-thiazolidinedione.
  • a thiazolidinedione such as, for example, troglitazone, ciglitazone, pioglitazone, rosiglitazone or the compounds disclosed by Dr. Reddy's Research Foundation in WO 97/41097, in particular 5-[[4-[(3,4-dihydro-3-methyl-4-oxo-2-quinazolinylmethoxy]phenyl]methyl]-2,4-thiazolidinedione
  • the compounds of the present invention are administered in combination with a monoamine oxidase inhibitor such as disclosed, for example, in WO 01/12176.
  • a monoamine oxidase inhibitor such as disclosed, for example, in WO 01/12176.
  • Particularly suitable for this purpose 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 compounds of the present invention are administered in combination with an ⁇ -glucosidase inhibitor such as, for example, miglitol or acarbose.
  • an ⁇ -glucosidase inhibitor such as, for example, miglitol or acarbose.
  • the present compounds are administered in combination with an hCNTF (human ciliary neurotrophic factor) or derivatives thereof, such as, for example, CNTF AX15 or modified CNTF AX15 , such as disclosed, for example, in Lambert et al., PNAS 98, 4652-4657.
  • hCNTF human ciliary neurotrophic factor
  • the compounds of the present invention are administered in combination with an active compound which acts on the ATP-dependent potassium channel of the beta cells, such as, for example, tolbutamide, glibenclamide, glimepiride, glipizide, gliclazide or repaglinide.
  • an active compound which acts on the ATP-dependent potassium channel of the beta cells such as, for example, tolbutamide, glibenclamide, glimepiride, glipizide, gliclazide or repaglinide.
  • the compounds of the present invention are administered in combination with an antihyperlipidemic active compound or an antilipidemic active compound such as, for example, cholestyramine, colestipol, clofibrate, gemfibrozil, lovastatin, pravastatin, simvastatin, atorvastatin, cerivastatin, fluvastatin, probucol, ezetimibe or dextrothyroxine.
  • an antihyperlipidemic active compound or an antilipidemic active compound such as, for example, cholestyramine, colestipol, clofibrate, gemfibrozil, lovastatin, pravastatin, simvastatin, atorvastatin, cerivastatin, fluvastatin, probucol, ezetimibe or dextrothyroxine.
  • the compounds of the present invention are administered in combination with more than one of the aforementioned compounds, for example in combination with a sulfonylurea and metformin, a sulfonylurea and acarbose, repaglinide and metformin, insulin and a sulfonylurea, insulin and metformin, insulin and troglitazone, insulin and lovastatin, etc.
  • the compounds of the invention may be administered in combination with one or more antiadipose agents or appetite-controlling active compounds.
  • Such active compounds 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, CCK agonists, serotonin re-uptake inhibitors, mixed serotonin and noradrenalin reuptake inhibitors, 5HT modulators, bombesin agonists, galanin antagonists, glucocorticoid receptor modulators, growth hormone, growth-hormone-releasing compounds, TRH agonists, uncoupling protein 2 or 3 modulators, leptin receptor agonists, leptin mimetics, dopamine agonists (bromocriptine, doprexin), lipase/amylase inhibitors
  • the antiadipose agent is leptin or modified leptin.
  • the antiadipose agent is dexamphetamine or amphetamine.
  • the antiadipose agent is fenfluramine or dexfenfluramine.
  • the antiadipose agent is sibutramine or the mono- and bis-demethylated active metabolite of sibutramine.
  • the antiadipose agent is orlistate.
  • the antiadipose agent is mazindol, diethylpropione or phentermine.
  • the compounds of the present invention may be administered in combination with one or more antihypertensive active compounds.
  • antihypertensive active compounds are betablockers such as alprenolol, atenol, timolol, pindolol, propanolol and metoprolol, ACE (angiotensin-converting enzyme) inhibitors such as, for example, benazepril, captopril, enalapril, fosinopril, lisinopril, quinapril and rampril, calcium channel blockers such as nifedipine, felodipine, nicardipine, isradipine, nimodipine, diltiazem and verapamil, and also alphablockers such as doxazosin, urapidil, prazosin and terazosin.
  • Soft gelatin capsules comprising 100 mg of active compound per capsule: per capsule Active compound 100 mg Triglyceride mixture fractionated from coconut fat 400 mg Capsule contents 500 mg
  • Emulsion comprising 60 mg of active compound per 5 ml: per 100 ml of emulsion Active compound 1.2 g Neutral oil q.s. Sodium carboxymethylcellulose 0.6 g Polyoxyethylene stearate q.s. Glycerol pure 0.2 to 2.0 g Flavoring q.s. Water (demineralized or distilled) to 100 ml
  • Rectal medicament comprising 40 mg of active compound per suppository: per suppository Active compound 40 mg Suppository base material ad 2 mg
  • Tablets comprising 40 mg of active compound per tablet: per tablet Lactose 600 mg Corn starch 300 mg Soluble starch 20 mg Magnesium stearate 40 mg 1000 mg
  • Coated tablets comprising 50 mg of active compound per coated tablet: per coated tablet Active compound 50 mg Corn starch 100 mg Lactose 60 mg Sec. calcium phosphate 30 mg Soluble starch 5 mg Magnesium stearate 10 mg Colloidal silica 5 mg 260 mg
  • Suitable for preparing the content of hard gelatin capsules are the following recipes: a) Active compound 100 mg Corn starch 300 mg 400 mg b) Active compound 140 mg Lactose 180 mg Corn starch 180 mg 500 mg
  • the compound of example 5 was obtained from 5-chloro-2-methanesulfinylindan-1-one by reduction with sodium borohydride as described in Example 1.3.

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EP2389171A4 (de) * 2009-01-26 2012-10-10 Univ Taipei Medical Verwendung von pterosinverbindungen zur behandlung von diabetes und adipositas

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DE10142663B4 (de) 2001-08-31 2004-08-19 Aventis Pharma Deutschland Gmbh C2-Disubstituierte Indan-1-ol-Systeme
TWI799691B (zh) * 2019-03-29 2023-04-21 景凱生物科技股份有限公司 具有側鏈烷基與烯基延伸的苯基衍生物及包括有其的藥學組合物

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4244960A (en) * 1978-07-27 1981-01-13 Schering, Aktiengesellschaft Indanyl derivatives and their use
US6331571B1 (en) * 1998-08-24 2001-12-18 Sepracor, Inc. Methods of treating and preventing attention deficit disorders
US6667345B2 (en) * 2001-03-31 2003-12-23 Aventis Pharma Deutschland Gmbh Derivatives of C2-substituted indan-1-ol systems for the prophylaxis or treatment of obesity
US6717008B2 (en) * 2001-08-31 2004-04-06 Aventis Pharma Deutschland Gmbh Derivatives of C2-substituted indan-1-ol compounds, methods for their preparation and use

Family Cites Families (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2345146A1 (fr) * 1976-03-23 1977-10-21 Logeais Labor Jacques Nouveau medicament a base d'(hydroxy-2 indanyl-2) 1-propanol
JPH01503777A (ja) * 1985-10-04 1989-12-21 マツジヨ‐ニ‐ウインスロツプ・ソチエタ・ペル・アチオニ 縮合脂環式アミノアルコール類
WO1989003681A1 (en) 1987-10-19 1989-05-05 Pfizer Inc. Substituted tetralins, chromans and related compounds in the treatment of asthma
WO1997020802A1 (en) * 1995-12-06 1997-06-12 Venantius Limited Indane dimer compounds and their pharmaceutical use
AU727775B2 (en) 1996-01-17 2000-12-21 Novo Nordisk A/S Fused 1,2,4-thiadiazine and fused 1,4-thiazine derivatives, their preparation and use
IL128332A0 (en) 1996-08-30 2000-01-31 Novo Nordisk As GLP-1 derivatives
IL127296A (en) 1996-12-31 2003-01-12 Reddy Research Foundation Heterocyclic compounds, process for their preparation and pharmaceutical compositions containing them
PL338013A1 (en) 1997-07-16 2000-09-25 Novo Nordisk As Derivatives of condensed 1,2,4-thiadiazine, their production and application
EP1078632A1 (de) 1999-08-16 2001-02-28 Sanofi-Synthelabo Verwendung von Monoamin Oxydase Inhibitoren zu Herstellung eines Medikaments zur Behandlung der Fettleibigkeit
DE10142667B4 (de) * 2001-08-31 2004-06-09 Aventis Pharma Deutschland Gmbh C2-substituierte Indan-1-ole und ihre Derivate und ihre Verwendung als Arzneimittel

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4244960A (en) * 1978-07-27 1981-01-13 Schering, Aktiengesellschaft Indanyl derivatives and their use
US6331571B1 (en) * 1998-08-24 2001-12-18 Sepracor, Inc. Methods of treating and preventing attention deficit disorders
US6667345B2 (en) * 2001-03-31 2003-12-23 Aventis Pharma Deutschland Gmbh Derivatives of C2-substituted indan-1-ol systems for the prophylaxis or treatment of obesity
US6717008B2 (en) * 2001-08-31 2004-04-06 Aventis Pharma Deutschland Gmbh Derivatives of C2-substituted indan-1-ol compounds, methods for their preparation and use

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2389171A4 (de) * 2009-01-26 2012-10-10 Univ Taipei Medical Verwendung von pterosinverbindungen zur behandlung von diabetes und adipositas
AU2010206549A9 (en) * 2009-01-26 2016-08-25 Dcb-Usa, Llc Use of pterosin compounds for treating diabetes and obesity
AU2010206549B2 (en) * 2009-01-26 2016-08-25 Dcb-Usa, Llc Use of pterosin compounds for treating diabetes and obesity

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WO2003020263A1 (de) 2003-03-13
US7763662B2 (en) 2010-07-27
ATE308321T1 (de) 2005-11-15
IL160605A (en) 2010-12-30
CA2458526A1 (en) 2003-03-13
ES2250710T3 (es) 2006-04-16
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IL160605A0 (en) 2004-07-25
EP1425007B1 (de) 2005-11-02
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MXPA04001852A (es) 2004-06-15

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