EP1218010A2 - 1,4-benzothiazepine zur behandlung von fettsuchtverwandten krankheiten - Google Patents

1,4-benzothiazepine zur behandlung von fettsuchtverwandten krankheiten

Info

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Withdrawn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
English (en)
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
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Knoll GmbH filed Critical Knoll GmbH
Publication of EP1218010A2 publication Critical patent/EP1218010A2/de
Withdrawn legal-status Critical Current

Links

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.

Landscapes

  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Diabetes (AREA)
  • Obesity (AREA)
  • Hematology (AREA)
  • Neurosurgery (AREA)
  • Psychiatry (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Addiction (AREA)
  • Emergency Medicine (AREA)
  • Endocrinology (AREA)
  • Child & Adolescent Psychology (AREA)
  • Nutrition Science (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
EP00945759A 1999-06-24 2000-06-16 1,4-benzothiazepine zur behandlung von fettsuchtverwandten krankheiten Withdrawn EP1218010A2 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GBGB9914745.6A GB9914745D0 (en) 1999-06-24 1999-06-24 Therapeutic agents
GB9914745 1999-06-24
PCT/EP2000/005541 WO2001000185A2 (en) 1999-06-24 2000-06-16 1,4-denzothiazepines to treat obesity related disorders

Publications (1)

Publication Number Publication Date
EP1218010A2 true EP1218010A2 (de) 2002-07-03

Family

ID=10855956

Family Applications (1)

Application Number Title Priority Date Filing Date
EP00945759A Withdrawn EP1218010A2 (de) 1999-06-24 2000-06-16 1,4-benzothiazepine zur behandlung von fettsuchtverwandten krankheiten

Country Status (7)

Country Link
EP (1) EP1218010A2 (de)
JP (1) JP2003513008A (de)
AU (1) AU5973600A (de)
CA (1) CA2376023A1 (de)
GB (1) GB9914745D0 (de)
MX (1) MXPA01013420A (de)
WO (1) WO2001000185A2 (de)

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
WO2008108445A1 (ja) * 2007-03-07 2008-09-12 Takeda Pharmaceutical Company Limited ベンゾオキサゼピン誘導体およびその用途
WO2010056631A1 (en) 2008-11-12 2010-05-20 Schering Corporation 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 (de) 2012-05-11 2014-03-19 Les Laboratoires Servier Mittel zur Behandlung von Erkrankungen durch Modulation von Ryanodin-Rezeptoren

Family Cites Families (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3361760A (en) * 1963-03-21 1968-01-02 Squibb & Sons Inc Benzothiazepines
US3794639A (en) * 1966-03-10 1974-02-26 Squibb & Sons Inc Benzoxazepines and benzothiazepines
JP2871811B2 (ja) * 1990-02-28 1999-03-17 サントリー株式会社 縮合７員環系化合物
GB9203347D0 (en) * 1992-02-17 1992-04-01 Wellcome Found Hypolipidaemic compounds
JP3093419B2 (ja) * 1992-03-30 2000-10-03 麒麟麦酒株式会社 １，４‐ベンゾチアゼピン誘導体
SK280522B6 (sk) * 1992-11-09 2000-03-13 The Boots Company Plc Deriváty 2,3,4,5-tetrahydro-1,4-benzotiazepínov, s
US5610153A (en) * 1992-12-11 1997-03-11 Ciba-Geigy Corporation Benzazepinone derivatives
IL108634A0 (en) * 1993-02-15 1994-05-30 Wellcome Found Hypolipidaemic heterocyclic compounds, their prepatation and pharmaceutical compositions containing them
ZA941003B (en) * 1993-02-15 1995-08-14 Wellcome Found Hypolipidaemic compounds
ZA956647B (en) * 1994-08-10 1997-02-10 Wellcome Found Hypolipidaemic compounds.
ATE242258T1 (de) * 1997-03-14 2003-06-15 Aventis Pharma Gmbh Hypolipidemische 1,4-benzothiazepin-1,1-dioxide
AU758160B2 (en) * 1997-08-22 2003-03-20 Kaken Pharmaceutical Co., Ltd. Novel amide derivatives

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO0100185A2 *

Also Published As

Publication number Publication date
CA2376023A1 (en) 2001-01-04
AU5973600A (en) 2001-01-31
WO2001000185A2 (en) 2001-01-04
GB9914745D0 (en) 1999-08-25
JP2003513008A (ja) 2003-04-08
WO2001000185A3 (en) 2002-04-11
MXPA01013420A (es) 2002-07-22

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