WO1999064410A1 - BENZO(b)THIEPIN-1,1-DIOXIDDERIVATE, VERFAHREN ZU DEREN HERSTELLUNG, DIESE VERBINDUNGEN ENTHALTENDE ARZNEIMITTEL UND DEREN VERWENDUNG - Google Patents

BENZO(b)THIEPIN-1,1-DIOXIDDERIVATE, VERFAHREN ZU DEREN HERSTELLUNG, DIESE VERBINDUNGEN ENTHALTENDE ARZNEIMITTEL UND DEREN VERWENDUNG Download PDF

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Publication number
WO1999064410A1
WO1999064410A1 PCT/EP1999/003701 EP9903701W WO9964410A1 WO 1999064410 A1 WO1999064410 A1 WO 1999064410A1 EP 9903701 W EP9903701 W EP 9903701W WO 9964410 A1 WO9964410 A1 WO 9964410A1
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WO
WIPO (PCT)
Prior art keywords
acid residue
formula
compounds
alkyl
methyl
Prior art date
Application number
PCT/EP1999/003701
Other languages
German (de)
English (en)
French (fr)
Inventor
Wendelin Frick
Alfons Enhsen
Heiner Glombik
Hubert Heuer
Original Assignee
Aventis Pharma Deutschland 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
Priority to CA002334775A priority Critical patent/CA2334775C/en
Application filed by Aventis Pharma Deutschland Gmbh filed Critical Aventis Pharma Deutschland Gmbh
Priority to DK99927784T priority patent/DK1086092T3/da
Priority to PL344827A priority patent/PL196074B1/pl
Priority to AT99927784T priority patent/ATE227715T1/de
Priority to EP99927784A priority patent/EP1086092B1/de
Priority to US09/719,047 priority patent/US6387944B1/en
Priority to JP2000553419A priority patent/JP4374426B2/ja
Priority to AU45019/99A priority patent/AU753275B2/en
Priority to BRPI9912188-3A priority patent/BR9912188B1/pt
Priority to HU0102256 priority patent/HU229761B1/hu
Priority to DE59903411T priority patent/DE59903411D1/de
Publication of WO1999064410A1 publication Critical patent/WO1999064410A1/de
Priority to HK01107735A priority patent/HK1036799A1/xx

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D337/00—Heterocyclic compounds containing rings of more than six members having one sulfur atom as the only ring hetero atom
    • C07D337/02—Seven-membered rings
    • C07D337/06—Seven-membered rings condensed with carbocyclic rings or ring systems
    • C07D337/08—Seven-membered rings condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/351—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom not condensed with another ring
    • 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
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • 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
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/04—Drugs for disorders of the urinary system for urolithiasis
    • 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
    • A61P3/06—Antihyperlipidemics
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06086—Dipeptides with the first amino acid being basic
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
    • C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
    • C08G65/32—Polymers modified by chemical after-treatment
    • C08G65/329—Polymers modified by chemical after-treatment with organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention relates to substituted benzo (b) thiepin-1, 1 -dioxide derivatives, their physiologically tolerable salts and physiologically functional derivatives.
  • the object of the invention was to provide further compounds which have a therapeutically utilizable hypolipidemic effect.
  • the task was to find new compounds which, compared to the compounds described in the prior art, already produce a higher fecal bile acid excretion at a lower dosage.
  • a reduction in dosage of the ED 200 value by at least a factor of 5 compared to the compounds described in the prior art was particularly desirable.
  • the invention therefore relates to compounds of the formula I
  • R 1 is methyl, ethyl, propyl, butyl
  • R 2 H OH, NH 2 , NH- (-C-C 6 ) alkyl
  • Tetraamino acid residue where the amino acid residue, diamino acid residue, triamino acid residue or tetraamino acid residue is optionally substituted one or more times by an amino acid protective group;
  • R 4 is methyl, ethyl, propyl, butyl
  • R 5 is methyl, ethyl, propyl, butyl
  • Preferred compounds of the formula I are those in which one or more radicals have the following meaning:
  • R 1 is ethyl, propyl, butyl;
  • R 2 H OH, NH 2 , NH-td-C ⁇ J alkyl;
  • Diamino acid residue optionally substituted one or more times by an amino acid protecting group
  • R 4 is methyl, ethyl, propyl, butyl
  • R 5 is methyl, ethyl, propyl, butyl
  • R 1 is ethyl, butyl
  • R 3 diamino acid residue, the diamino acid residue optionally being substituted one or more times by an amino acid protecting group;
  • R 4 is methyl;
  • R 5 is methyl
  • Suitable pharmaceutically acceptable acid addition salts of the compounds according to the invention are salts of inorganic acids, such as hydrochloric acid, hydrobromic, phosphoric, metaphosphoric, nitric, sulfonic and sulfuric acid, and organic acids, such as e.g.
  • the chlorine salt is used in a particularly preferred manner for medical purposes.
  • Suitable pharmaceutically acceptable basic salts are ammonium salts, alkali metal salts (such as sodium and potassium salts) and alkaline earth metal salts (such as magnesium and calcium salts).
  • Salts with a non-pharmaceutically acceptable anion also belong within the scope of the invention as useful intermediates for the production or purification of pharmaceutically acceptable salts and / or for use in non-therapeutic, for example in-vitro applications.
  • physiologically functional derivative denotes any physiologically compatible derivative of a compound according to the invention, for example an ester which, when administered to a mammal, such as for example humans, is capable (directly or indirectly) of such a compound or an active one Metabolites to form from this.
  • prodrugs of the compounds according to the invention are prodrugs of the compounds according to the invention. Such prodrugs can be metabolized in vivo to a compound according to the invention. These prodrugs may or may not be effective themselves.
  • the compounds of the invention may also exist in various polymorphic forms, e.g. as amorphous and crystalline polymorphic forms. All polymorphic forms of the compounds according to the invention belong to the scope of the invention and are a further aspect of the invention.
  • the amount of a compound of formula (I) required to achieve the desired biological effect depends on a number of factors, for example the specific compound chosen, the intended use, the mode of administration and the clinical condition of the patient .
  • the daily dose is in the range from 0.1 mg to 100 mg (typically from 0.1 mg and 50 mg) per day per kilogram of body weight, for example 0.1-10 mg / kg / day.
  • Tablets or capsules can contain, for example, from 0.01 to 100 mg, typically from 0.02 to 50 mg.
  • the aforementioned weight data relate to the weight of the benzo (b) thiepin ion derived from the salt.
  • the compounds of the formula (I) themselves can be used as the compound, but they are preferably in the form of a pharmaceutical composition with a compatible carrier.
  • the carrier must of course be compatible, in the sense that it is compatible with the other components of the composition and not harmful to health is for the patient.
  • the carrier can be a solid or a liquid or both and is preferably formulated with the compound as a single dose, for example as a tablet, which can contain from 0.05% to 95% by weight of the active ingredient.
  • Further pharmaceutically active substances can also be present, including further compounds of the formula (I).
  • the pharmaceutical compositions according to the invention can be prepared by one of the known pharmaceutical methods, which consist essentially in the fact that the constituents are mixed with pharmacologically acceptable carriers and / or auxiliaries.
  • compositions according to the invention are those which are suitable for oral and peroral (eg sublingual) administration, although the most suitable mode of administration in each individual case depends on the type and severity of the condition to be treated and on the type of the compound of formula (I) used in each case .
  • Coated formulations and coated slow-release formulations also fall within the scope of the invention.
  • Formulations which are resistant to acid and gastric juice are preferred.
  • Suitable enteric coatings include cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethyl cellulose phthalate, and anionic polymers of methacrylic acid and methyl methacrylate.
  • Suitable pharmaceutical compounds for oral administration can be present in separate units, such as, for example, capsules, capsules, lozenges or tablets, each containing a certain amount of the compound of the formula (I); as powder or granules; as a solution or suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil emulsion.
  • these compositions can be prepared by any suitable pharmaceutical method which comprises a step in which the active ingredient and the carrier (which may consist of one or more additional ingredients) are brought into contact.
  • the compositions are characterized by uniform and homogeneous Mixing the active ingredient with a liquid and / or finely divided solid carrier, after which the product is shaped if necessary.
  • a tablet can be made by compressing or molding a powder or granules of the compound, optionally with one or more additional ingredients.
  • Compressed tablets can be prepared by tabletting the compound in free flowing form, such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent and / or a (several) surface active / dispersing agent in a suitable machine.
  • Molded tablets can be made by molding the powdered compound moistened with an inert liquid diluent in a suitable machine.
  • compositions suitable for oral (sublingual) administration include lozenges containing a compound of formula (I) with a flavor, usually sucrose and acacia or tragacanth, and lozenges containing the compound in an inert base such as gelatin and include glycerin or sucrose and gum arabic.
  • the invention further relates to both isomer mixtures of the formula I and the pure stereoisomers of the formula I, and also diastereomer mixtures of the formula I and the pure diastereomers.
  • the mixtures are separated by chromatographic means.
  • amino acids or amino acid residues are e.g. the stereoisomeric forms, i.e. D or L forms, meaning the following compounds:
  • the shorthand notation of the amino acids was carried out according to the commonly used notation (see Schröder, Lübke, The Peptides, Volume I, New York 1965, pages XXII-XXIII; Houben-Weyl, Methods of Organic Chemistry, Volume XV / 1 and 2, Stuttgart 1974 ).
  • the amino acid pGlu stands for pyroglutamyl, NaI for 3- (2-naphthyl) alanine, Azagly-NH 2 for a compound of the formula NH 2 -NH-CONH 2 and D-Asp for the D-form of aspartic acid.
  • peptides are acid amides and break down into amino acids during hydrolysis.
  • a diamino acid residue, a triamino acid residue, a tetraamino acid residue means peptides which are composed of 2 to 4 of the above-mentioned amino acids.
  • Suitable protective groups for amino acids are primarily:
  • Preferred amino protecting groups are the benzyloxycarbonyl (Z) radical which can be eliminated by catalytic hydrogenation, the 2- (3,5-dimethyloxyphenyl) propyl (2) oxycarbonyl (Ddz) or trityl (Trt) radical and which can be removed by weak acids the 9-fluorenylmethyloxycarbonyl (Fmoc) radical which can be split off by secondary amines is used.
  • the invention further relates to processes for the preparation of benzo (b) thiepin-1,1-dioxide derivatives of the formula I:
  • a process for the preparation of the compounds of formula I characterized in that an amine of formula II, in which R 1 , R 2 , R 4 and R 5 have the meanings given for formula I, with a compound of formula III, in which R 3 and Z have the meanings given for formula I, are converted to a compound of the formula I with elimination of water and, if appropriate, the compound of the formula I obtained is converted into a physiologically tolerable salt or a physiologically functional derivative.
  • R 3 is a monoamino acid
  • this radical can optionally also be extended stepwise to the diamino acid residue, triamino acid residue or tetraamino acid residue even after binding to the amine of the formula II.
  • the compounds of the formula I and their pharmaceutically acceptable salts and physiologically functional derivatives represent ideal medicaments for the treatment of lipid metabolism disorders, in particular hyperlipidemia.
  • the compounds of the formula I are also suitable for influencing the serum cholesterol level and for prevention and treatment arteriosclerotic phenomena.
  • the compounds can optionally also be administered in combination with statins, such as simvastatatin, fluvastatin, pravastatin, cerivastatin, lovastatin or atorvastine.
  • statins such as simvastatatin, fluvastatin, pravastatin, cerivastatin, lovastatin or atorvastine.
  • the compounds according to the invention were tested biologically by determining the ED 2 excretion. This test examines the effect of the compounds according to the invention on the bile acid transport in the ileum and the fecal excretion of bile acids in the rat after oral administration twice a day. The diastereomer mixtures of the compounds were tested.
  • the solutions / suspensions were administered in a dose of 5 ml / kg per os.
  • mice Male Wistar rats (Kastengrund, Hoechst AG, weight range 250-350g) were in groups of 6 animals and from 10 days before the start of treatment (day 1) with an inverted day / night rhythm (4-. 6- dark, 16- - 4 - kept bright and received a standard feed mix (Altromin, Germany). Three days before the start of the experiment (day 0), the animals were divided into groups of 4 animals each. Classification of animals in treatment groups:
  • the excretion of 14 C taurocholic acid was expressed as a percentage of the corresponding values of the control group (treated with vehicle).
  • the ED 2 oo ie the dose that increases the faecal excretion of 14 C taurocholic acid to 200% of the control group, is calculated by interpolation from a sigmoid or linear dose-response curve.
  • the calculated ED 2 ⁇ corresponds to a dose that doubles the faecal excretion of bile acids.
  • Table 1 shows measured values of the ED 20 o excretion. Table 1 :
PCT/EP1999/003701 1998-06-10 1999-05-28 BENZO(b)THIEPIN-1,1-DIOXIDDERIVATE, VERFAHREN ZU DEREN HERSTELLUNG, DIESE VERBINDUNGEN ENTHALTENDE ARZNEIMITTEL UND DEREN VERWENDUNG WO1999064410A1 (de)

Priority Applications (12)

Application Number Priority Date Filing Date Title
US09/719,047 US6387944B1 (en) 1998-06-10 1999-05-28 Benzo(b)thiepine-1,1-dioxide derivatives, a method for the production thereof, medicaments containing these compounds, and their use
DK99927784T DK1086092T3 (da) 1998-06-10 1999-05-28 Benzo(b)thiepin-1,1-dioxidderivater, fremgangsmåder til deres fremstilling, lægemidler indeholdende disse forbindelser og deres anvendelse
PL344827A PL196074B1 (pl) 1998-06-10 1999-05-28 Pochodne 1,1-ditlenku benzo(b)tiepiny, sposób ich wytwarzania, środek farmaceutyczny zawierający te związki oraz ich zastosowanie
AT99927784T ATE227715T1 (de) 1998-06-10 1999-05-28 Benzo(b)thiepin-1,1-dioxidderivate, verfahren zu deren herstellung, diese verbindungen enthaltende arzneimittel und deren verwendung
EP99927784A EP1086092B1 (de) 1998-06-10 1999-05-28 BENZO(b)THIEPIN-1,1-DIOXIDDERIVATE, VERFAHREN ZU DEREN HERSTELLUNG, DIESE VERBINDUNGEN ENTHALTENDE ARZNEIMITTEL UND DEREN VERWENDUNG
CA002334775A CA2334775C (en) 1998-06-10 1999-05-28 Benzo(b)thiepine-1,1-dioxide derivatives, a process for their preparation, pharmaceuticals comprising these compounds, and their use
JP2000553419A JP4374426B2 (ja) 1998-06-10 1999-05-28 ベンゾ（ｂ）チエピン−１，１−ジオキサイド誘導体、その製造方法、これらの化合物を含有する医薬およびその使用
HU0102256 HU229761B1 (hu) 1998-06-10 1999-05-28 Benzo(b)tiepin-1,1-dioxid-származékok, ezek elõállítására szolgáló eljárás, ezeket tartalmazó gyógyszerek és ezek alkalmazása
BRPI9912188-3A BR9912188B1 (pt) 1998-06-10 1999-05-28 compostos derivados de 1,1-diàxido de benzo(b)tiepina, processo para sua preparaÇço, e seu uso, medicamentos contendo-os e processo para a preparaÇço desses.
AU45019/99A AU753275B2 (en) 1998-06-10 1999-05-28 Benzo(b)thiepine-1,1-dioxide derivatives, a method for the production thereof, medicaments containing these compounds, and their use
DE59903411T DE59903411D1 (de) 1998-06-10 1999-05-28 BENZO(b)THIEPIN-1,1-DIOXIDDERIVATE, VERFAHREN ZU DEREN HERSTELLUNG, DIESE VERBINDUNGEN ENTHALTENDE ARZNEIMITTEL UND DEREN VERWENDUNG
HK01107735A HK1036799A1 (en) 1998-06-10 2001-11-06 Benzo(b)thiepine-1, 1-dioxide derivatives, a method for the production thereof, medicaments containing these compounds, and their use

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19825804A DE19825804C2 (de) 1998-06-10 1998-06-10 1,4-Benzothiepin-1,1-dioxidderivate, Verfahren zu deren Herstellung und diese Verbindungen enthaltende Arzneimittel
DE19825804.6 1998-06-10

Publications (1)

Publication Number Publication Date
WO1999064410A1 true WO1999064410A1 (de) 1999-12-16

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Family Applications (2)

Application Number Title Priority Date Filing Date
PCT/EP1999/003701 WO1999064410A1 (de) 1998-06-10 1999-05-28 BENZO(b)THIEPIN-1,1-DIOXIDDERIVATE, VERFAHREN ZU DEREN HERSTELLUNG, DIESE VERBINDUNGEN ENTHALTENDE ARZNEIMITTEL UND DEREN VERWENDUNG
PCT/EP1999/003743 WO1999064409A2 (de) 1998-06-10 1999-05-29 Benzothiepin-1,1-dioxidderivate, verfahren zu deren herstellung, diese verbindungen enthaltende arzneimittel und deren verwendung

Family Applications After (1)

Application Number Title Priority Date Filing Date
PCT/EP1999/003743 WO1999064409A2 (de) 1998-06-10 1999-05-29 Benzothiepin-1,1-dioxidderivate, verfahren zu deren herstellung, diese verbindungen enthaltende arzneimittel und deren verwendung

Country Status (26)

Country Link
US (1) US6387944B1 (US06387944-20020514-C00010.png)
EP (2) EP1086092B1 (US06387944-20020514-C00010.png)
JP (2) JP4374426B2 (US06387944-20020514-C00010.png)
KR (2) KR100681721B1 (US06387944-20020514-C00010.png)
CN (2) CN1127497C (US06387944-20020514-C00010.png)
AR (2) AR018634A1 (US06387944-20020514-C00010.png)
AT (2) ATE227715T1 (US06387944-20020514-C00010.png)
AU (2) AU753275B2 (US06387944-20020514-C00010.png)
BR (2) BR9912188B1 (US06387944-20020514-C00010.png)
CA (2) CA2334775C (US06387944-20020514-C00010.png)
CZ (2) CZ297989B6 (US06387944-20020514-C00010.png)
DE (3) DE19825804C2 (US06387944-20020514-C00010.png)
DK (2) DK1086092T3 (US06387944-20020514-C00010.png)
ES (2) ES2182535T3 (US06387944-20020514-C00010.png)
HK (2) HK1036799A1 (US06387944-20020514-C00010.png)
HU (2) HU229761B1 (US06387944-20020514-C00010.png)
ID (2) ID28695A (US06387944-20020514-C00010.png)
IL (1) IL140078A (US06387944-20020514-C00010.png)
NO (1) NO327075B1 (US06387944-20020514-C00010.png)
NZ (1) NZ508681A (US06387944-20020514-C00010.png)
PL (2) PL196074B1 (US06387944-20020514-C00010.png)
PT (2) PT1086092E (US06387944-20020514-C00010.png)
RU (2) RU2215001C2 (US06387944-20020514-C00010.png)
TR (2) TR200003634T2 (US06387944-20020514-C00010.png)
WO (2) WO1999064410A1 (US06387944-20020514-C00010.png)
ZA (2) ZA200007060B (US06387944-20020514-C00010.png)

Cited By (55)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003018024A1 (de) * 2001-08-22 2003-03-06 Aventis Pharma Deutschland Gmbh Kombinationspräparate von 1,4- benzothiepin-1,1-dioxidderivaten mit weiteren wirkstoffen und deren verwendung
WO2003091232A2 (en) 2002-04-25 2003-11-06 Astrazeneca Ab Benzothiadiazepine derivatives, processes for their preparation and pharmaceutical compositions containing them
JP2004516280A (ja) * 2000-12-21 2004-06-03 アベンティス・ファーマ・ドイチユラント・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツング 新規な１，２−ジフェニルアゼチジノン、その調製方法、その化合物を含む薬剤、および脂質代謝障害を治療するためのその使用
US6906058B2 (en) 2000-03-08 2005-06-14 Astrazeneca Ab 1,5-Benzothiazepines and their use as hypolipidaemics
US7125864B2 (en) 2001-09-07 2006-10-24 Astrazeneca Ab Benzothiazepine derivatives for the treatment of hyperlipidemia
US7132416B2 (en) 2001-09-08 2006-11-07 Astrazeneca Ab Benzothiazepine and benzothiazepine derivatives with ileal bile acid transport (IBAT) inhibotory activity for the treatment hyperlipidaemia
US7192945B2 (en) 2000-12-21 2007-03-20 Astrazeneca Ab Benzothiazepine derivatives
US7192947B2 (en) 2002-06-14 2007-03-20 Astrazeneca Ab Peptides derivatives comprising thiazepine group for the treatment of hyperlipidemic conditions
US7192946B2 (en) 2001-09-04 2007-03-20 Astrazeneca Ab Benzothiazepine derivatives
US7226943B2 (en) 2001-09-07 2007-06-05 Astrazeneca Ab Benzothiepine ileal bile acid transport inhibitors
EP1894564A2 (en) 2003-04-05 2008-03-05 AstraZeneca AB Use of an ibat inhibitor for the treatment of prophylaxis of constipation
US8067584B2 (en) 2003-02-25 2011-11-29 Albireo Ab Benzothiazepine derivatives
WO2012064267A1 (en) 2010-11-08 2012-05-18 Albireo Ab A pharmaceutical combination comprising an ibat inhibitor and a bile acid binder
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