EP1218010A2 - 1,4-benzothiazepines to treat obesity related disorders - Google Patents

1,4-benzothiazepines to treat obesity related disorders

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Publication number
EP1218010A2
EP1218010A2 EP00945759A EP00945759A EP1218010A2 EP 1218010 A2 EP1218010 A2 EP 1218010A2 EP 00945759 A EP00945759 A EP 00945759A EP 00945759 A EP00945759 A EP 00945759A EP 1218010 A2 EP1218010 A2 EP 1218010A2
Authority
EP
European Patent Office
Prior art keywords
tetrahydro
benzothiazepine
alkyl
carbon atoms
chloro
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Withdrawn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
EP00945759A
Other languages
German (de)
French (fr)
Inventor
Ian Charles Kilpatrick
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.)
Abbott GmbH and Co KG
Original Assignee
Knoll GmbH
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Filing date
Publication date
Application filed by Knoll GmbH filed Critical Knoll GmbH
Publication of EP1218010A2 publication Critical patent/EP1218010A2/en
Withdrawn legal-status Critical Current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
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/554—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/34—Tobacco-abuse
    • 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
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to the use of 2,3,4,5-tetrahydro-1 ,4- benzothiazepines in the treatment of obesity, eating disorders such as bulimia, anorexia, snacking and binge eating, non-insulin dependent diabetes mellitus, hyperglycaemia, hyperlipidaemia, and stress, and as an aid to smoking cessation.
  • n 0, 1 or 2;
  • , and R2 independently represent H or alkyl of 1 to 4 carbon atoms (optionally substituted by one or more halo);
  • R ⁇ to R1 1 independently represent H, halo, cyano, nitro, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkanoyl of 1 to 4 carbon atoms, carboxy, alkanoyloxy of 1 to 4 carbon atoms, carbamoyl (optionally substituted with alkyl of 1 to 4 carbon atoms), or sulphamoyl (optionally substituted with alkyl of 1 to 4 carbon atoms); each alkyl, alkoxy, alkanoyl or alkanoyloxy optionally substituted with one or more halo; their stereoisomers; and pharmaceutically acceptable salts thereof; with the proviso that:
  • the present invention provides a method of treating obesity and related conditions comprising the administration to a mammal, particularly a human, in need thereof of a therapeutically effective amount of a compound of formula I
  • n 0, 1 or 2;
  • , and R2 independently represent H or alkyl of 1 to 4 carbon atoms (optionally substituted by one or more halo);
  • R8 to Ri 1 independently represent H, halo, cyano, nitro, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkanoyl of 1 to 4 carbon atoms, carboxy, alkanoyloxy of 1 to 4 carbon atoms, carbamoyl (optionally substituted with alkyl of 1 to 4 carbon atoms), or sulphamoyl (optionally substituted with alkyl of 1 to 4 carbon atoms); each alkyl, alkoxy, alkanoyl or alkanoyloxy optionally substituted with one or more halo; their stereoisomers; and pharmaceutically acceptable salts thereof.
  • related conditions means eating disorders such as bulimia, anorexia, snacking and binge eating, non-insulin dependent diabetes mellitus, hyperglycaemia, hyperlipidaemia, and stress, and as an aid to smoking cessation.
  • n 0 or 1 ;
  • Ri , R2, R ⁇ and R7 are each H;
  • R3 and R4 are independently H or methyl; or together represent imino, methylimino, phenylimino, hydroxyimino or methoxyimi ⁇ o;
  • R5 is H or methyl, or when R3 and R4 are independently H or methyl, R5 is H, methyl, formyl, acetyl, propionyl, benzoyl, methylsulphinyl, methylsulphonyl or ethylsulphonyl;
  • R8 is H, methyl, fluoro or chloro
  • R9, R10 and R11 are each H; or a pharmaceutically acceptable salt thereof.
  • Preferred compounds of formula I are selected from:
  • More preferred compounds of formula I are selected from:
  • Most preferred compounds of formula I are selected from: 4-acetyl-6-chloro-2,3,4,5-tetrahydro-1 ,4-benzothiazepine;
  • a particularly preferred compound of formula I is: 4-acetyl-6-chloro-2,3,4,5-tetrahydro-1 ,4-benzothiazepine; its stereoisomers; and pharmaceutically acceptable salts thereof.
  • n 0, 1 or 2;
  • , and R2 independently represent H or alkyl of 1 to 4 carbon atoms (optionally substituted by one or more halo);
  • R8 to R-11 independently represent H, halo, cyano, nitro, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkanoyl of 1 to 4 carbon atoms, carboxy, alkanoyloxy of 1 to 4 carbon atoms, carbamoyl (optionally substituted with alkyl of 1 to 4 carbon atoms), or sulphamoyl (optionally substituted with alkyl of 1 to 4 carbon atoms); each alkyl, alkoxy, alkanoyl or alkanoyloxy optionally substituted with one or more halo; their stereoisomers; and pharmaceutically acceptable salts thereof; with the proviso that:
  • Ri and R2 are independently H or methyl
  • R3 and R4 are independently H or methyl; or together represent imino, methylimino, phenylimino, hydroxyimino or methoxyimino;
  • R5 is H or methyl, and when R3 and R4 are H or methyl, R5 is H, methyl, formyl, acetyl, propionyl, benzoyl, methylsulphinyl, methylsulphonyl or ethylsulphonyl;
  • R6 and R7 are each H; and one of R8 to Rn is H, fluoro, chloro, bromo, iodo, methyl (optionally substituted with one or more halo), methoxy (optionally substituted by one or more halo),nitro, cyano, carboxy, acetyl, dimethylcarbamoyl or dimethylsulphamoyl; the remainder of Rs to
  • R-11 being H; their stereoisomers; and pharmaceutically acceptable salts thereof.
  • R3 and R4 are H, or together are methylimino, phenylimino, hydroxyimino or methoxyimino;
  • R5 is H or methyl, and when R3 and R4 are H, R5 is H, methyl, formyl, acetyl, propionyl, benzoyl, methylsulphinyl, methylsulphonyl, or ethylsulphonyl;
  • R8 is H, methyl, fluoro or chloro;
  • Rg to Ri 1 are all H; their stereoisomers; and pharmaceutically acceptable salts thereof.
  • the compounds of the present invention may prepared and formulated into pharmaceutical formulations as described in WO94/11360.
  • the compound of formula I may be administered in any of the known pharmaceutical dosage forms.
  • the amount of the compound to be administered will depend on a number of factors including the age of the patient, the severity of the condition and the past medical history of the patient and always lies within the sound discretion of the administering physician but it is generally envisaged that the dosage of the compound to be administered will be in the range 0.1 to 1000 mg preferably 1 to 500 mg per day given in one or more doses.
  • Oral dosage forms are the preferred compositions for use in the present invention and these are the known pharmaceutical forms for such administration, for example tablets, capsules, granules, syrups and aqueous or oil suspensions.
  • the excipients used in the preparation of these compositions are theexcipients known in the pharmacist's art.
  • Tablets may be prepared from a mixture of the active compound with fillers, for example calcium phosphate; disintegrating agents, for example maize starch; lubricating agents, for example magnesium stearate; binders, for example microcrystalline cellulose or polyvinylpyrrolidone and other optional ingredients known in the art to permit tableting the mixture by known methods.
  • the tablets may, if desired, be coated using known methods and excipients which may include enteric coating using for example hydroxypropylmethylcellulose phthalate.
  • the tablets may be formulated in a manner known to those skilled in the art so as to give a sustained release of the compounds of the present invention.
  • Such tablets may, if desired, be provided with enteric coatings by known methods, for example by the use of cellulose acetate phthalate.
  • capsules for example hard or soft gelatin capsules, containing the active compound with or without added excipients, may be prepared by known methods and, if desired, provided with enteric coatings in a known manner.
  • the contents of the capsule may be formulated using known methods so as to give sustained release of the active compound.
  • the tablets and capsules may conveniently each contain 1 to 500 mg of the active compound.
  • the tablets and capsules each contain 5, 10, 15, 20, 25, 30, 50, 100 ,250 or ⁇ OOmg.
  • dosage forms for oral administration include, for example, aqueous suspensions containing the active compound in an aqueous medium in the presence of a non-toxic suspending agent such as sodium carboxy-methylcellulose, and oily suspensions containing a compound of the present invention in a suitable vegetable oil, for example arachis oil.
  • the active compound may be formulated into granules with or without additional excipients.
  • the granules may be ingested directly by the patient or they may be added to a suitable liquid carrier (for example, water) before ingestion.
  • the granules may contain disintegrants, eg an effervescent couple formed from an acid and a carbonate or bicarbonate salt to facilitate dispersion in the liquid medium.
  • the therapeutically active compounds of formula I may be formulated into a composition which the patient retains in his mouth so that the active compound is administered through the mucosa of the mouth.
  • Dosage forms suitable for rectal administration are the known pharmaceutical forms for such administration, for example, suppositories with cocoa butter or polyethylene glycol bases.
  • Dosage forms suitable for parenteral administration are the known pharmaceutical forms for such administration, for example sterile suspensions or sterile solutions in a suitable solvent.
  • Dosage forms for topical administration may comprise a matrix in which the pharmacologically active compounds of the present invention are dispersed so that the compounds are held in contact with the skin in order to administer the compounds transdermally.
  • a suitable transdermal composition may be prepared by mixing the pharmaceutically active compound with a topical vehicle, such as a mineral oil, petrolatum and/or a wax, e.g. paraffin wax or beeswax, together with a potential transdermal accelerant such as dimethyl sulphoxide or propylene glycol.
  • the active compounds may be dispersed in a pharmaceutically acceptable cream, gel or ointment base.
  • the amount of active compound contained in a topical formulation should be such that a therapeutically effective amount of the compound is delivered during the period of time for which the topical formulation is intended to be on the skin.
  • the therapeutically active compound of formula I may be formulated into a composition which is dispersed as an aerosol into the patients oral or nasal cavity.
  • Such aerosols may be administered from a pump pack or from a pressurised pack containing a volatile propellant.
  • the therapeutically active compounds of formula I used in the method of the present invention may also be administered by continuous infusion either from an external source, for example by intravenous infusion or from a source of the compound placed within the body.
  • Internal sources include implanted reservoirs containing the compound to be infused which is continuously released for example by osmosis and implants which may be (a) liquid such as an oily suspension of the compound to be infused for example in the form of a very sparingly water-soluble derivative such as a dodecanoate salt or a lipophilic ester or (b) solid in the form of an implanted support, for example of a synthetic resin or waxy material, for the compound to be infused.
  • the support may be a single body containing all of the compound or a series of several bodies each containing part of the compound to be delivered.
  • the amount of active compound present in an internal source should be such that a therapeutically effective amount of the compound is delivered over a long period of time.
  • compositions containing a therapeutically effective amount of a compound of Formula I may be used to treat obesity and related conditions including eating disorders such as bulimia, anorexia, snacking and binge eating, non-insulin dependent diabetes mellitus, hyperglycaemia, hyperiipidaemia, and stress in mammals particularly humans, and as an aid to smoking cessation in human beings.
  • eating disorders such as bulimia, anorexia, snacking and binge eating
  • non-insulin dependent diabetes mellitus such as hyperglycaemia, hyperiipidaemia, and stress in mammals particularly humans
  • the amount of active compound administered per day is in the range 1 to 1000 mg preferably 5 to 500 mg given in single or divided doses at one or more times during the day.
  • the present invention provides the use of a compound of Formula I in the manufacture of a medicament for use in the treatment of obesity and related conditions including eating disorders such as bulimia, anorexia, snacking and binge eating, non-insulin dependent diabetes mellitus, hyperglycaemia, hyperiipidaemia, and stress, and as an aid to smoking cessation.
  • eating disorders such as bulimia, anorexia, snacking and binge eating, non-insulin dependent diabetes mellitus, hyperglycaemia, hyperiipidaemia, and stress, and as an aid to smoking cessation.
  • the present invention also provides a method of treating obesity and related conditions including eating disorders such as bulimia, anorexia, snacking and binge eating, non-insulin dependent diabetes mellitus, hyperglycaemia, hyperiipidaemia and stress which comprises the administration of a therapeutically effective amount of a compound of Formula I to a patient in need thereof.
  • eating disorders such as bulimia, anorexia, snacking and binge eating, non-insulin dependent diabetes mellitus, hyperglycaemia, hyperiipidaemia and stress which comprises the administration of a therapeutically effective amount of a compound of Formula I to a patient in need thereof.
  • the present invention also provides a method of reducing the craving to smoke in human beings which comprises the administration of a therapeutically effective amount of a compound of Formula I to a patient in need thereof.
  • the present invention also provides a method of reducing weight gain after smoking cessation in human beings which comprises the administration of a therapeutically effective amount of a compound of Formula I to a patient in need thereof.
  • the compounds of the present invention may be useful in the treatment or prevention of metabolic diseases and conditions arising therefrom, for example non exercise activity thermogenesis and increased metabolic rate.
  • the compounds of the present invention may be useful in preventing cardiovascular disease, and in reducing platelet adhesiveness, in aiding weight loss after pregnancy and in aiding weight loss after smoking cessation.

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Abstract

The present invention provides a method of treating obesity and related conditions such as bulimia, anorexia, snacking, binge eating, non insolin dependent diabetes meltitus, hyperglycaemia, stress, hyperlipidaemia, and to aid to smoking cessation comprising the administration to a mammal, particularly a human, in need thereof of a therapeutically effective amount of a compound of formula (I) in which: n=0, 1 or 2; R1 and R2 independently represent H or alkyl of 1 to 4 carbon atoms (optionally substituted by one or more halo); R3 and R4 independently represent H or alkyl of 1 to 4 carbon atoms; or together represent a group of formula =NR12 where R12 represents H, hydroxy, alkyl of 1 to 4 carbon atoms, a phenyl or alkoxy of 1 to 4 carbon atoms; each alkyl, phenyl and alkoxy being optionally substituted with one or more halo; R5 represents: (a) H, (b) alkyl of 1 to 4 carbon atoms, (c) a group of formula-COR13 in which R13 represents H, alkyl of 1 to 4 carbon atoms or phenyl, when R3 and R4 represent H or alkyl (optionally substituted with one or more halo, or (d) or a group of formula -S(O)pR14 in which p=1 or 2 and R14 is alkyl of 1 to 4 carbon atoms or phenyl, when R3 and R4 represent H or alkyl (optionally substituted with one or more halo); each alkyl and phenyl being optionally substituted with one or more halo; R6 and R7 are each H; R8 to R11 independently represent H, halo, cyano, nitro, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkanoyl of 1 to 4 carbon atoms, carboxy, alkanoyloxy of 1 to 4 carbon atoms, carbamoyl (optionally substituted with alkyl of 1 to 4 carbon atoms), or sulphamoyl (optionally substituted with alkyl of 1 to 4 carbon atoms); each alkyl, alkoxy, alkanoyl or alkanoyloxy optionally substituted with one or more halo; their stereoisomers; and pharmaceutically acceptable salts thereof.

Description

Therapeutic Agents
The present invention relates to the use of 2,3,4,5-tetrahydro-1 ,4- benzothiazepines in the treatment of obesity, eating disorders such as bulimia, anorexia, snacking and binge eating, non-insulin dependent diabetes mellitus, hyperglycaemia, hyperlipidaemia, and stress, and as an aid to smoking cessation.
Compounds of formula I
in which: n = 0, 1 or 2;
R-| , and R2 independently represent H or alkyl of 1 to 4 carbon atoms (optionally substituted by one or more halo); R3 and R4 independently represent H or alkyl of 1 to 4 carbon atoms; or together represent a group of formula =NRi2 where R12 represents H, hydroxy, alkyl of 1 to 4 carbon atoms, phenyl or alkoxy of 1 to 4 carbon atoms; each alkyl, phenyl andalkoxy being optionally substituted with one or more halo; R5 represents: (a) H, (b) alkyl of 1 to 4 carbon atoms, (c) a group of formula-CORi 3 in which R13 represents H, alkyl of 1 to 4 carbon atoms or phenyl, when R3 and R4 represent H or alkyl (optionally substituted with one or more halo, or (d) or a group of formula -S(0)pRi4 in which p = 1 or 2 and R14 is alkyl of 1 to 4 carbon atoms or phenyl, when R3 and R4 represent H or alkyl (optionally substituted with one or more halo); each alkyl and phenyl being optionally substituted with one or more halo; Rβ and R7 are each H;
Rδ to R1 1 independently represent H, halo, cyano, nitro, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkanoyl of 1 to 4 carbon atoms, carboxy, alkanoyloxy of 1 to 4 carbon atoms, carbamoyl (optionally substituted with alkyl of 1 to 4 carbon atoms), or sulphamoyl (optionally substituted with alkyl of 1 to 4 carbon atoms); each alkyl, alkoxy, alkanoyl or alkanoyloxy optionally substituted with one or more halo; their stereoisomers; and pharmaceutically acceptable salts thereof; with the proviso that:
(i) when n = 0; at least one of Ri to Ri 1 is other than H; are disclosed in WO94/1 1360 for the treatment of seizures and neurological disorders.
The present invention provides a method of treating obesity and related conditions comprising the administration to a mammal, particularly a human, in need thereof of a therapeutically effective amount of a compound of formula I
in which: n = 0, 1 or 2;
R-| , and R2 independently represent H or alkyl of 1 to 4 carbon atoms (optionally substituted by one or more halo); R3 and R4 independently represent H or alkyl of 1 to 4 carbon atoms; or together represent a group of formula =NR-|2 where R12 represents H, hydroxy, alkyl of 1 to 4 carbon atoms, phenyl or alkoxy of 1 to 4 carbon atoms; each alkyl, phenyl andalkoxy being optionally substituted with one or more halo; R5 represents: (a) H, (b) alkyl of 1 to 4 carbon atoms, (c) a group of formula-COR-13 in which R13 represents H, alkyl of 1 to 4 carbon atoms or phenyl, when R3 and R4 represent H or alkyl (optionally substituted with one or more halo, or (d) or a group of formula -S(0)pRi4 in which p = 1 or 2 and R14 is alkyl of 1 to 4 carbon atoms or phenyl, when R3 and R4 represent H or alkyl (optionally substituted with one or more halo); each alkyl and phenyl being optionally substituted with one or more halo; RQ and R7 are each H;
R8 to Ri 1 independently represent H, halo, cyano, nitro, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkanoyl of 1 to 4 carbon atoms, carboxy, alkanoyloxy of 1 to 4 carbon atoms, carbamoyl (optionally substituted with alkyl of 1 to 4 carbon atoms), or sulphamoyl (optionally substituted with alkyl of 1 to 4 carbon atoms); each alkyl, alkoxy, alkanoyl or alkanoyloxy optionally substituted with one or more halo; their stereoisomers; and pharmaceutically acceptable salts thereof.
The term "related conditions" as used herein means eating disorders such as bulimia, anorexia, snacking and binge eating, non-insulin dependent diabetes mellitus, hyperglycaemia, hyperlipidaemia, and stress, and as an aid to smoking cessation.
In a preferred group of compounds of formula I
n is 0 or 1 ; Ri , R2, Rβ and R7 are each H;
R3 and R4 are independently H or methyl; or together represent imino, methylimino, phenylimino, hydroxyimino or methoxyimiπo;
R5 is H or methyl, or when R3 and R4 are independently H or methyl, R5 is H, methyl, formyl, acetyl, propionyl, benzoyl, methylsulphinyl, methylsulphonyl or ethylsulphonyl;
R8 is H, methyl, fluoro or chloro; and
R9, R10 and R11 are each H; or a pharmaceutically acceptable salt thereof. Preferred compounds of formula I are selected from:
6-chloro-2,3,4,5-tetrahydro-1 ,4-benzothiazepine;
6-chloro-2,3,4,5-tetrahydro-1 ,4-benzothiazepine 1 -oxide;
6-fluoro-2, 3,4, 5-tetrahydro-1 ,4-benzothiazepine; 4-formyl-2,3,4,5-tetrahydro-1 ,4-benzothiazepine;
4-acetyl-6-chloro-2,3,4,5-tetrahydro-1 ,4-benzothiazepine;
4-acetyl-6-chloro-2, 3, 4, 5-tetrahydro-1 ,4-benzothiazepine 1 -oxide;
4-acetyl-6-fluoro-2, 3, 4, 5-tetrahydro-1 ,4-benzothiazepine;
6-chloro-4-methylsulphinyl-2, 3, 4, 5-tetrahydro-1 ,4-benzothiazepine; 4-methylsulphonyl-2,3,4,5-tetrahydro-1 ,4-benzothiazepine 1 -oxide;
4-ethylsulphonyl-2, 3,4, 5-tetrahydro-1 ,4-benzothiazepine;
6-chloro-3-hydroxyimino-2, 3, 4, 5-tetrahydro-1 ,4-benzothiazepine;
3-hydroxyimino-6-methyl-2,3,4,5-tetrahydro-1 ,4-benzothiazepine;
3-methylimino-2,3,4,5-tetrahydro-1 ,4-benzothiazepine; and 6-chloro-3-phenylimino-2,3,4,5-tetrahydro-1 ,4-benzothiazepine; their stereoisomers; and pharmaceutically acceptable salts thereof.
More preferred compounds of formula I are selected from:
6-chloro-2, 3,4, 5-tetrahydro-1 ,4-benzothiazepine; 6-chloro-2, 3, 4, 5-tetrahydro-1 ,4-benzothiazepine 1-oxide;
6-fluoro-2, 3, 4, 5-tetrahydro-1 ,4-benzothiazepine;
4-formyl-2, 3,4, 5-tetrahydro-1 ,4-benzothiazepine;
4-acetyl-6-chloro-2,3,4,5-tetrahydro-1 ,4-benzothiazepine;
6-chloro-4-methylsulphinyl-2, 3, 4, 5-tetrahydro-1 ,4-benzothiazepine; 6-chloro-3-hydroxyimino-2,3,4,5-tetrahydro-1 ,4-benzothiazepine; and
6-chloro-3-phenylimino-2, 3,4, 5-tetrahydro-1 ,4-benzothiazepine; their stereoisomers; and pharmaceutically acceptable salts thereof.
Most preferred compounds of formula I are selected from: 4-acetyl-6-chloro-2,3,4,5-tetrahydro-1 ,4-benzothiazepine;
4-acetyl-6-chloro-2,3,4,5-tetrahydro-1 ,4-benzothiazepine 1 -oxide; 4-methylsulphonyl-2,3,4,5-tetrahydro-1 ,4-benzothiazepine; 6-chloro-4-methylsulphonyl-2,3,4,5-tetrahydro-1 ,4-benzothiazepine; 6-chloro-4-methylsulphonyl-2,3,4,5-tetrahydro-1 ,4-benzothiazepine 1-oxide; and 6-fluoro-4-methylsulphonyl-2, 3,4, 5-tetrahydro-1 ,4-benzothiazepine; their stereoisomers; and pharmaceutically acceptable salts thereof.
A particularly preferred compound of formula I is: 4-acetyl-6-chloro-2,3,4,5-tetrahydro-1 ,4-benzothiazepine; its stereoisomers; and pharmaceutically acceptable salts thereof.
The present invention also provides pharmaceutical compositions for the treatment of obesity and related conditions comprising a therapeutically effective amount of compounds of formula I
in which: n = 0, 1 or 2;
R-| , and R2 independently represent H or alkyl of 1 to 4 carbon atoms (optionally substituted by one or more halo);
R3 and R4 independently represent H or alkyl of 1 to 4 carbon atoms; or together represent a group of formula =NR-|2 where R12 represents H, hydroxy, alkyl of 1 to 4 carbon atoms, phenyl or alkoxy of 1 to 4 carbon atoms; each alkyl, phenyl andalkoxy being optionally substituted with one or more halo; R5 represents: (a) H, (b) alkyl of 1 to 4 carbon atoms, (c) a group of formula-COR-13 in which R-13 represents H, alkyl of 1 to 4 carbon atoms or phenyl, when R3 and R4 represent H or alkyl (optionally substituted with one or more halo, or (d) or a group of formula -S(0)pRι,4 in which p = 1 or 2 and R14 is alkyl of 1 to 4 carbon atoms or phenyl, when R3 and R4 represent H or alkyl (optionally substituted with one or more halo); each alkyl and phenyl being optionally substituted with one or more halo; R6 and R7 are each H;
R8 to R-11 independently represent H, halo, cyano, nitro, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkanoyl of 1 to 4 carbon atoms, carboxy, alkanoyloxy of 1 to 4 carbon atoms, carbamoyl (optionally substituted with alkyl of 1 to 4 carbon atoms), or sulphamoyl (optionally substituted with alkyl of 1 to 4 carbon atoms); each alkyl, alkoxy, alkanoyl or alkanoyloxy optionally substituted with one or more halo; their stereoisomers; and pharmaceutically acceptable salts thereof; with the proviso that:
(i) when n = 0; at least one of Ri to R-] 1 is other than H; together with a pharmaceutically acceptable diluent or carrier.
Preferred pharmaceutical compositions for the treatment of obesity and related conditions comprise a therapeutically effective amount of compounds of formula I in which: n = O or 1 ;
Ri and R2 are independently H or methyl;
R3 and R4 are independently H or methyl; or together represent imino, methylimino, phenylimino, hydroxyimino or methoxyimino;
R5 is H or methyl, and when R3 and R4 are H or methyl, R5 is H, methyl, formyl, acetyl, propionyl, benzoyl, methylsulphinyl, methylsulphonyl or ethylsulphonyl;
R6 and R7 are each H; and one of R8 to Rn is H, fluoro, chloro, bromo, iodo, methyl (optionally substituted with one or more halo), methoxy (optionally substituted by one or more halo),nitro, cyano, carboxy, acetyl, dimethylcarbamoyl or dimethylsulphamoyl; the remainder of Rs to
R-11 being H; their stereoisomers; and pharmaceutically acceptable salts thereof.
More preferred pharmaceutical compositions for the treatment of obesity and related conditions comprise a therapeutically effective amount of compounds of formula I in which: n = 0 or 1 ; Ri , R2, Rβ and R7 are each H;
R3 and R4 are H, or together are methylimino, phenylimino, hydroxyimino or methoxyimino; R5 is H or methyl, and when R3 and R4 are H, R5 is H, methyl, formyl, acetyl, propionyl, benzoyl, methylsulphinyl, methylsulphonyl, or ethylsulphonyl; R8 is H, methyl, fluoro or chloro; Rg to Ri 1 are all H; their stereoisomers; and pharmaceutically acceptable salts thereof.
Especially preferred pharmaceutical compositions for the treatment of obesity and related conditions comprise a therapeutically effective amount of compounds of formula I selected from:
6-chloro-2, 3, 4, 5-tetrahydro-1 ,4-benzothiazepine;
6-chloro-2,3,4,5-tetrahydro-1 ,4-benzothiazepine 1-oxide;
6-fluoro-2, 3, 4, 5-tetrahydro-1 ,4-benzothiazepine; 6-methyl-2,3,4,5-tetrahydro-1 ,4-benzothiazepine;
6-chloro-4-methyl-2, 3,4, 5-tetrahydro-1 ,4-benzothiazepine;
4-formyl-2,3,4,5-tetrahydro-1 ,4-benzothiazepine;
4-acetyl-2, 3, 4, 5-tetrahydro-1 ,4-benzothiazepine;
4-acetyl-2,3,4,5-tetrahydro-1 ,4-benzothiapine 1-oxide; 4-acetyl-6-chloro-2,3,4,5-tetrahydro-1 ,4-benzothiazepine;
4-acetyl-6-chloro-2,3,4,5-tetrahydro-1 ,4-benzothiazepine 1 -oxide;
4-acetyl-6-fluoro-2, 3, 4, 5-tetrahydro-1 ,4-benzothiazepine;
4-acetyl-6-methyl-2, 3,4, 5-tetrahydro-1 ,4-benzothiazepine;
4-propionyl-2,3,4,5-tetrahydro-1 ,4-benzothiazepine; 6-chloro-4-propionyl-2,3,4,5-tetrahydro-1 ,4-benzothiazepine;
4-benzoyl-6-chloro-2, 3, 4, 5-tetrahydro-1 ,4-benzothiazepine;
6-chloro-4-methylsulphinyl-2, 3, 4, 5-tetrahydro-1 ,4-benzothiazepine;
4-methylsulphonyl-2, 3,4, 5-tetrahydro-1 ,4-benzothiazepine;
4-methylsulphonyl-2,3,4,5-tetrahydro-1 ,4-benzothiazepine 1-oxide; 6-chloro-4-methylsulphonyl-2, 3, 4, 5-tetrahydro-1 ,4-benzothiazepine;
6-chloro-4-methylsulphonyl-2,3,4,5-tetrahydro-1 ,4-benzothiazepine 1-oxide;
6-fluoro-4-methylsulphonyl-2,3,4,5-tetrahydro-1 ,4-benzothiazepine;
6-methyl-4-methylsulphonyI-2,3,4,5-tetrahydro-1 ,4-benzothiazepine;
4-ethylsulphonyl-2, 3,4, 5-tetrahydro-1 ,4-benzothiazepine; 6-chloro-4-ethylsulphonyl-2, 3, 4, 5-tetrahydro-1 ,4-benzothiazepine; 3-hydroxyimino-2, 3, 4, 5-tetrahydro-1 ,4-benzothiazepine; 6-chloro-3-hydroxyimino-2, 3,4, 5-tetrahydro-1 ,4-benzothiazepine; 3-hydroxyimino-6-methyl-2,3, 4, 5-tetrahydro-1 ,4-benzothiazepine; 3-methoxyimino-2,3,4,5-tetrahydro-1 ,4-benzothiazepine;
6-chloro-3-methoxyimino-2, 3,4, 5-tetrahydro-1 ,4-benzothiazepine; 3-methylimino-2, 3, 4, 5-tetrahydro- ,4-benzothiazepine; 6-chloro-3-phenylimino-2, 3,4, 5-tetrahydro-1 ,4-benzothiazepine; their stereoisomers; and pharmaceutically acceptable salts thereof.
The compounds of the present invention may prepared and formulated into pharmaceutical formulations as described in WO94/11360.
The compound of formula I may be administered in any of the known pharmaceutical dosage forms. The amount of the compound to be administered will depend on a number of factors including the age of the patient, the severity of the condition and the past medical history of the patient and always lies within the sound discretion of the administering physician but it is generally envisaged that the dosage of the compound to be administered will be in the range 0.1 to 1000 mg preferably 1 to 500 mg per day given in one or more doses.
Oral dosage forms are the preferred compositions for use in the present invention and these are the known pharmaceutical forms for such administration, for example tablets, capsules, granules, syrups and aqueous or oil suspensions. The excipients used in the preparation of these compositions are theexcipients known in the pharmacist's art. Tablets may be prepared from a mixture of the active compound with fillers, for example calcium phosphate; disintegrating agents, for example maize starch; lubricating agents, for example magnesium stearate; binders, for example microcrystalline cellulose or polyvinylpyrrolidone and other optional ingredients known in the art to permit tableting the mixture by known methods. The tablets may, if desired, be coated using known methods and excipients which may include enteric coating using for example hydroxypropylmethylcellulose phthalate. The tablets may be formulated in a manner known to those skilled in the art so as to give a sustained release of the compounds of the present invention. Such tablets may, if desired, be provided with enteric coatings by known methods, for example by the use of cellulose acetate phthalate. Similarly, capsules, for example hard or soft gelatin capsules, containing the active compound with or without added excipients, may be prepared by known methods and, if desired, provided with enteric coatings in a known manner. The contents of the capsule may be formulated using known methods so as to give sustained release of the active compound. The tablets and capsules may conveniently each contain 1 to 500 mg of the active compound. Preferably the tablets and capsules each contain 5, 10, 15, 20, 25, 30, 50, 100 ,250 or δOOmg.
Other dosage forms for oral administration include, for example, aqueous suspensions containing the active compound in an aqueous medium in the presence of a non-toxic suspending agent such as sodium carboxy-methylcellulose, and oily suspensions containing a compound of the present invention in a suitable vegetable oil, for example arachis oil. The active compound may be formulated into granules with or without additional excipients. The granules may be ingested directly by the patient or they may be added to a suitable liquid carrier (for example, water) before ingestion. The granules may contain disintegrants, eg an effervescent couple formed from an acid and a carbonate or bicarbonate salt to facilitate dispersion in the liquid medium.
The therapeutically active compounds of formula I may be formulated into a composition which the patient retains in his mouth so that the active compound is administered through the mucosa of the mouth.
Dosage forms suitable for rectal administration are the known pharmaceutical forms for such administration, for example, suppositories with cocoa butter or polyethylene glycol bases.
Dosage forms suitable for parenteral administration are the known pharmaceutical forms for such administration, for example sterile suspensions or sterile solutions in a suitable solvent. Dosage forms for topical administration may comprise a matrix in which the pharmacologically active compounds of the present invention are dispersed so that the compounds are held in contact with the skin in order to administer the compounds transdermally. A suitable transdermal composition may be prepared by mixing the pharmaceutically active compound with a topical vehicle, such as a mineral oil, petrolatum and/or a wax, e.g. paraffin wax or beeswax, together with a potential transdermal accelerant such as dimethyl sulphoxide or propylene glycol. Alternatively the active compounds may be dispersed in a pharmaceutically acceptable cream, gel or ointment base. The amount of active compound contained in a topical formulation should be such that a therapeutically effective amount of the compound is delivered during the period of time for which the topical formulation is intended to be on the skin.
The therapeutically active compound of formula I may be formulated into a composition which is dispersed as an aerosol into the patients oral or nasal cavity. Such aerosols may be administered from a pump pack or from a pressurised pack containing a volatile propellant.
The therapeutically active compounds of formula I used in the method of the present invention may also be administered by continuous infusion either from an external source, for example by intravenous infusion or from a source of the compound placed within the body. Internal sources include implanted reservoirs containing the compound to be infused which is continuously released for example by osmosis and implants which may be (a) liquid such as an oily suspension of the compound to be infused for example in the form of a very sparingly water-soluble derivative such as a dodecanoate salt or a lipophilic ester or (b) solid in the form of an implanted support, for example of a synthetic resin or waxy material, for the compound to be infused. The support may be a single body containing all of the compound or a series of several bodies each containing part of the compound to be delivered. The amount of active compound present in an internal source should be such that a therapeutically effective amount of the compound is delivered over a long period of time. In some formulations it may be beneficial to use the compounds of the present invention in the form of particles of very small size, for example as obtained by fluid energy milling.
The pharmaceutical compositions containing a therapeutically effective amount of a compound of Formula I may be used to treat obesity and related conditions including eating disorders such as bulimia, anorexia, snacking and binge eating, non-insulin dependent diabetes mellitus, hyperglycaemia, hyperiipidaemia, and stress in mammals particularly humans, and as an aid to smoking cessation in human beings. Whilst the precise amount of active compound administered in such treatment will depend on a number of factors, for example the age of the patient, the severity of the condition and the past medical history, and always lies within the sound discretion of the administering physician, the amount of active compound administered per day is in the range 1 to 1000 mg preferably 5 to 500 mg given in single or divided doses at one or more times during the day.
In yet another aspect, the present invention provides the use of a compound of Formula I in the manufacture of a medicament for use in the treatment of obesity and related conditions including eating disorders such as bulimia, anorexia, snacking and binge eating, non-insulin dependent diabetes mellitus, hyperglycaemia, hyperiipidaemia, and stress, and as an aid to smoking cessation.
The present invention also provides a method of treating obesity and related conditions including eating disorders such as bulimia, anorexia, snacking and binge eating, non-insulin dependent diabetes mellitus, hyperglycaemia, hyperiipidaemia and stress which comprises the administration of a therapeutically effective amount of a compound of Formula I to a patient in need thereof.
The present invention also provides a method of reducing the craving to smoke in human beings which comprises the administration of a therapeutically effective amount of a compound of Formula I to a patient in need thereof. The present invention also provides a method of reducing weight gain after smoking cessation in human beings which comprises the administration of a therapeutically effective amount of a compound of Formula I to a patient in need thereof. In addition the compounds of the present invention may be useful in the treatment or prevention of metabolic diseases and conditions arising therefrom, for example non exercise activity thermogenesis and increased metabolic rate.
The compounds of the present invention may be useful in preventing cardiovascular disease, and in reducing platelet adhesiveness, in aiding weight loss after pregnancy and in aiding weight loss after smoking cessation.
The following in vivo test supports the finding that compounds of formula I have efficacy in the treatment of obesity.
Marmosets given 4-acetyl-6-chloro-2,3,4,5-tetrahydro-1 ,4-benzothiazepine (50 mg/kg po) daily for 14 days showed reduced bodyweight gain.

Claims

Claims
1) A method of treating obesity and related conditions comprising the administration to a mammal, particularly a human, in need thereof of a therapeutically effective amount of a compound of formula I
in which: n = 0, 1 or 2;
R-| , and R2 independently represent H or alkyl of 1 to 4 carbon atoms (optionally substituted by one or more halo);
R3 and R4 independently represent H or alkyl of 1 to 4 carbon atoms; or together represent a group of formula =NRι,2 where R12 represents H, hydroxy, alkyl of 1 to 4 carbon atoms, phenyl or alkoxy of 1 to 4 carbon atoms; each alkyl, phenyl andalkoxy being optionally substituted with one or more halo;
R5 represents: (a) H, (b) alkyl of 1 to 4 carbon atoms, (c) a group of formula-CORi 3 in which R13 represents H, alkyl of 1 to 4 carbon atoms or phenyl, when R3 and R4 represent H or alkyl (optionally substituted with one or more halo, or (d) or a group of formula -S(0)pRi4 in which p = 1 or 2 and R14 is alkyl of 1 to 4 carbon atoms or phenyl, when R3 and R4 represent H or alkyl (optionally substituted with one or more halo); each alkyl and phenyl being optionally substituted with one or more halo; R6 and R7 are each H; R8 to R-i 1 independently represent H, halo, cyano, nitro, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkanoyl of 1 to 4 carbon atoms, carboxy, alkanoyloxy of 1 to 4 carbon atoms, carbamoyl (optionally substituted with alkyl of 1 to 4 carbon atoms), or sulphamoyl (optionally substituted with alkyl of 1 to 4 carbon atoms); each alkyl, alkoxy, alkanoyl or alkanoyloxy optionally substituted with one or more halo; their stereoisomers; and pharmaceutically acceptable salts thereof; with the proviso that:
(i) when n = 0; at least one of R-| to Ri 1 is other than H; together with a pharmaceutically acceptable diluent or carrier.
2) A method as claimed in claim 1 in which comprises a compound of formula I in which n is 0 or 1 ; i , R2> Rδ and R7 are each H; R3 and R4 are independently H or methyl; or together represent imino, methylimino, phenylimino, hydroxyimino or methoxyimino;
R5 is H or methyl, or when R3 and R4 are independently H or methyl, R5 is H, methyl, formyl, acetyl, propionyl, benzoyl, methylsulphinyl, methylsulphonyl or ethylsulphonyl; R8 is H, methyl, fluoro or chloro; and
Rg, R10 and Rn are each H; or a pharmaceutically acceptable salt thereof.
3) A method as claimed in claim 1 in which the compound of formula I is selected from:
6-chloro-2, 3, 4, 5-tetrahydro- ,4-benzothiazepine;
6-chloro-2,3,4,5-tetrahydro-1 ,4-benzothiazepine 1-oxide;
6-fluoro-2,3,4,5-tetrahydro-1 ,4-benzothiazepine;
4-formyl-2,3,4,5-tetrahydro-1 ,4-benzothiazepine; 4-acetyl-6-chloro-2,3,4,5-tetrahydro-1 ,4-benzothiazepine;
4-acetyl-6-chloro-2,3,4,5-tetrahydro-1 ,4-benzothiazepine 1 -oxide;
4-acetyl-6-fluoro-2, 3,4, 5-tetrahydro-1 ,4-benzothiazepine;
6-chloro-4-methylsulphinyl-2, 3, 4, 5-tetrahydro-1 ,4-benzothiazepine;
4-methylsulphonyl-2, 3, 4, 5-tetrahydro-1 ,4-benzothiazepine 1-oxide; 4-ethylsulphonyl-2,3,4,5-tetrahydro-1 ,4-benzothiazepine;
6-chloro-3-hydroxyimino-2, 3, 4, 5-tetrahydro-1 ,4-benzothiazepine;
3-hydroxyimino-6-methyl-2,3,4,5-tetrahydro-1 ,4-benzothiazepine;
3-methyiimino-2,3,4,5-tetrahydro-1 ,4-benzothiazepine; and
6-chlorα-3-phenylimino-2, 3, 4, 5-tetrahydro-1 ,4-benzothiazepine; their stereoisomers; and pharmaceutically acceptable salts thereof.
4) A method as claimed in claim 1 in which the compound of formula I is selected from: 6-chloro-2,3,4,5-tetrahydro-1 ,4-benzothiazepine;
6-chloro-2,3,4,5-tetrahydro-1 ,4-benzothiazepine 1-oxide; 6-fluoro-2, 3, 4, 5-tetrahydro-1 ,4-benzothiazepine; 4-formyl-2,3,4,5-tetrahydro-1 ,4-benzothiazepine; 4-acetyl-6-chloro-2, 3, 4, 5-tetrahydro-1 ,4-benzothiazepine; 6-chloro-4-methylsulphinyl-2,3,4,5-tetrahydro-1 ,4-benzothiazepine; 6-chloro-3-hydroxyimino-2, 3, 4, 5-tetrahydro-1 ,4-benzothiazepine; and 6-chloro-3-phenylimino-2, 3, 4, 5-tetrahydro-1 ,4-benzothiazepine; their stereoisomers; and pharmaceutically acceptable salts thereof.
5) A method as claimed in claim 1 in which the compound of formula I is selected from:
4-acetyl-6-chloro-2, 3,4, 5-tetrahydro-1 ,4-benzothiazepine;
4-acetyl-6-chloro-2, 3,4, 5-tetrahydro-1 ,4-benzothiazepine 1-oxide;
4-methylsulphonyl-2,3,4,5-tetrahydro-1 ,4-benzothiazepine; 6-chloro-4-methylsulphonyl-2, 3,4, 5-tetrahydro-1 ,4-benzothiazepine;
6-chloro-4-methylsulphonyl-2,3,4,5-tetrahydro-1 ,4-benzothiazepine 1 -oxide; and
6-fluoro-4-methylsulphonyl-2, 3, 4, 5-tetrahydro-1 ,4-benzothiazepine; their stereoisomers; and pharmaceutically acceptable salts thereof.
6) A method as claimed in claim 1 in which the compound of formula I is selected from:
4-acetyl-6-chloro-2, 3, 4, 5-tetrahydro-1 ,4-benzothiazepine; and pharmaceutically acceptable salts thereof.
7) The use of a compound of Formula I as described in any one of claims 1-6 in the manufacture of a medicament for use in the treatment of obesity and related conditions including eating disorders such as bulimia, anorexia, snacking and binge eating, non-insulin dependent diabetes mellitus, hyperglycaemia, hyperiipidaemia, and stress, and as an aid to smoking cessation.
EP00945759A 1999-06-24 2000-06-16 1,4-benzothiazepines to treat obesity related disorders Withdrawn EP1218010A2 (en)

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GBGB9914745.6A GB9914745D0 (en) 1999-06-24 1999-06-24 Therapeutic agents
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PCT/EP2000/005541 WO2001000185A2 (en) 1999-06-24 2000-06-16 1,4-denzothiazepines to treat obesity related disorders

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US8710045B2 (en) 2004-01-22 2014-04-29 The Trustees Of Columbia University In The City Of New York Agents for preventing and treating disorders involving modulation of the ryanodine receptors
US7704990B2 (en) * 2005-08-25 2010-04-27 The Trustees Of Columbia University In The City Of New York Agents for preventing and treating disorders involving modulation of the RyR receptors
US8247403B2 (en) 2007-03-07 2012-08-21 Takeda Pharmaceutical Company Limited Benzoxazepine derivatives and use thereof
JP2012508692A (en) 2008-11-12 2012-04-12 シェーリング コーポレイション Inhibitors of fatty acid binding protein (FABP)
WO2013064231A1 (en) 2011-10-31 2013-05-10 Phenex Pharmaceuticals Ag SEVEN-MEMBERED SULFONAMIDES AS MODULATORS OF RAR-RELATED ORPHAN RECEPTOR-GAMMA (RORγ, NR1F3)
EP2708535A1 (en) 2012-05-11 2014-03-19 Les Laboratoires Servier Agents for treating disorders involving modulation of ryanodine receptors

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