WO1992011248A1 - Nouveaux amides aliphatiques, leur procede de production et medicaments contenant ces composes - Google Patents

Nouveaux amides aliphatiques, leur procede de production et medicaments contenant ces composes Download PDF

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Publication number
WO1992011248A1
WO1992011248A1 PCT/EP1991/002390 EP9102390W WO9211248A1 WO 1992011248 A1 WO1992011248 A1 WO 1992011248A1 EP 9102390 W EP9102390 W EP 9102390W WO 9211248 A1 WO9211248 A1 WO 9211248A1
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WO
WIPO (PCT)
Prior art keywords
compounds
general formula
tetrazol
acceptable salts
physiologically acceptable
Prior art date
Application number
PCT/EP1991/002390
Other languages
German (de)
English (en)
Inventor
Hans Peter Wolff
Reinhard Heck
Hans-Frieder Kuehnle
Peter Freund
Original Assignee
Boehringer Mannheim 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 Boehringer Mannheim Gmbh filed Critical Boehringer Mannheim Gmbh
Publication of WO1992011248A1 publication Critical patent/WO1992011248A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/04—Five-membered rings

Definitions

  • New aliphatic amides processes for their preparation and medicaments containing these compounds
  • A is fluorine or hydrogen, n is an integer between 1 and 10 and
  • B represents a saturated or unsaturated, straight-chain or branched alkylene group having 1 to 12 carbon atoms, and their physiologically acceptable salts
  • the substances have a pronounced lipid-lowering effect and are therefore also suitable for the treatment of fat metabolism disorders.
  • Alkylene groups B are to be understood in particular as follows:
  • -CH 2 -CH CH-CH 2 -
  • -CH 2 -C CH-CH 2 -
  • -CH 2 -C C-CH 2 -.
  • Suitable physiologically acceptable salts are, in particular, alkali, alkaline earth or ammonium salts (and, if appropriate, salts with blood sugar-lowering biguanides).
  • 1H-tetrazol-5-yl used in this application should therefore also include the tautomeric form 2H-tetrazol-5-yl.
  • the invention furthermore relates to processes for the preparation of compounds of the general formula I by using an A in the general formula II in a manner known per se
  • Examples of reactive derivatives of carboxylic acids III include Halides, azides or reactive esters in question, especially the acid chlorides.
  • the reaction of carboxylic acid chlorides from carboxylic acids of the general formula III with compounds of the general formula II is advantageously carried out with the addition of acid-binding agents, such as e.g. Alkali acetate, sodium hydrogen carbonate, sodium carbonate or potassium carbonate.
  • acid-binding agents such as e.g. Alkali acetate, sodium hydrogen carbonate, sodium carbonate or potassium carbonate.
  • This function can also be used by organic bases such as Pyridine or triethylamine are taken over, the inert solvent being e.g. Ether, methylene chloride, dioxane or an excess of the tertiary amine is used.
  • the reaction medium used is e.g. Ethanol, butanone-2, dimethylformamide or aqueous mixtures thereof.
  • reaction of compounds of general formula IV with sodium azide is carried out in a high-boiling polar solvent such as e.g. N-methylpyrrolidone, carried out at higher temperatures, preferably at 100-200 ° C.
  • a high-boiling polar solvent such as e.g. N-methylpyrrolidone
  • the compounds of general formula I are mixed in a manner known per se with suitable pharmaceutical carrier substances, aroma, flavor and colorants and shaped, for example, as tablets or dragees or with addition. speaking auxiliary substances suspended or dissolved in water or oil, such as olive oil.
  • the substances of the general formula I can be administered orally and parenterally in liquid or solid form.
  • Water is preferably used as the injection medium, which contains the stabilizers, solubilizers and / or buffers customary for injection solutions.
  • Such additives are e.g. Tartrate or borate buffer, ethanol, dimethyl sulfoxide, complexing agents (such as ethylenediaminetetraacetic acid), high molecular weight polymers (such as liquid polyethylene oxide) for viscosity regulation or polyethylene derivatives of sorbitan hydrides.
  • Solid carriers are e.g. Starch, lactose, mannitol, methyl cellulose, talc, highly disperse silicic acid, higher molecular fatty acids (such as stearic acid), gelatin, agar, calcium phosphate, magnesium stearate, animal and vegetable fats or solid high molecular polymers (such as polyethylene glycols).
  • Preparations suitable for oral administration can, if desired, contain flavorings and sweeteners.
  • the dose administered depends on the age, health and weight of the recipient, the extent of the disease, the type of further treatments which may be carried out at the same time, the frequency of the treatments and the type of effect desired.
  • the daily dose of the active compound is usually 0.1 to 50 mg / kg body weight. Normally 0.5 to 40 and preferably 1.0 to 20 mg / kg / day are effective in one or more applications per day in order to obtain the desired results. example 1
  • mice Male C57BL / 6J ob / ob mice were obtained from Harlan Olac Ltd. at the age of 6-8 weeks. , Blackthorn, England. Animals with an age of 12-14 weeks were used for the study; five of the animals were housed in a cage under standard conditions. At the beginning of the experiment, the animals were weighed and 5 / ul of blood were obtained by docking the tip of the tail. The blood obtained was immediately diluted 1:51 with hemolysis reagent from Boehringer Mannheim GmbH Germany (digitonin 0.04 M, maleimide> 1.0 M, dissolved in agua dest.).
  • the blood glucose was then measured using the test combination Gluco-guant glucose from Boehringer Mannheim GmbH Germany (UV test, hexokinase method according to FH Schmidt, Klin. Wschr. .39., 1244, 1961) with an EPOS Analyzer 5060, Eppendorf Adjustbau, Hamburg. Animals with a blood glucose concentration of at least 250 mg / dl were included in the study. 10 animals in the control group received only the solubilizer methyl cellulose (1% w / v), 10 animals in the substance group a dose of 100 mg / kg. On the 5th day of the substance application, the animals were weighed again and blood was obtained for the blood glucose determination as described above.
  • a corresponding blood volume was obtained for the insulin determination after decapitation and separation of the carotids. After the blood obtained has been left to rest for at least 10 minutes, it is centrifuged at room temperature, 10 minutes and 9,000 ⁇ g. The serum is stored until the insulin concentration is determined by means of a commercially available insulin radioimmunoassay from Pharmacia-Diagnostiks AB, Uppsala, Sweden (Pharacia-Insulin-RIA 100) at -20 ° C.
  • the ob / ob mice which received only 1% methyl cellulose showed almost no changes in the blood glucose concentrations on the 5th day of application, whereas the blood glucose concentration showed that with 100 mg / kg Substantive group were reduced to about 110 mg / dl.
  • the insulin concentrations of the substance group were reduced to normoinsulinemic values.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne des composés répondant à la formule (I), dans laquelle A désigne fluor ou hydrogène; n est un nombre entier compris entre 1 et 10 et B désigne un groupe alcylène saturé ou insaturé à chaîne droite ou ramifiée ayant 1 à 12 atomes de carbone, ainsi que leurs sels physiologiquement acceptables, leur procédé de production et leur utilisation comme médicaments dans le traitement du diabète, du prédiabète et du diabète de la maturité.
PCT/EP1991/002390 1990-12-19 1991-12-12 Nouveaux amides aliphatiques, leur procede de production et medicaments contenant ces composes WO1992011248A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19904040619 DE4040619A1 (de) 1990-12-19 1990-12-19 Neue aliphatische amide, verfahren zu ihrer herstellung sowie arzneimittel, die diese verbindungen enthalten
DEP4040619.9 1990-12-19

Publications (1)

Publication Number Publication Date
WO1992011248A1 true WO1992011248A1 (fr) 1992-07-09

Family

ID=6420706

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1991/002390 WO1992011248A1 (fr) 1990-12-19 1991-12-12 Nouveaux amides aliphatiques, leur procede de production et medicaments contenant ces composes

Country Status (3)

Country Link
AU (1) AU9051091A (fr)
DE (1) DE4040619A1 (fr)
WO (1) WO1992011248A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2383535A (en) * 2001-02-16 2003-07-02 Cxr Biosciences Ltd Medical use of fluorinated acids

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5366987A (en) * 1991-08-22 1994-11-22 Warner-Lambert Company Isoxazolyl-substituted alkyl amide ACAT inhibitors
DE19605700A1 (de) * 1996-02-16 1997-08-21 Boehringer Mannheim Gmbh 2,2-Difluoralkancarbonsäuren, Verfahren zu ihrer Herstellung und diese enthaltende Arzneimittel

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4764623A (en) * 1987-06-15 1988-08-16 American Home Products Corporation N-(1H-tetrazol-5-yl-alkylphenyl)polyfluoroalkanamides
EP0356989A2 (fr) * 1988-08-31 1990-03-07 Roche Diagnostics GmbH Sulphonamides comportant un reste de tétrazolyle, procédé de préparation et médicaments

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4764623A (en) * 1987-06-15 1988-08-16 American Home Products Corporation N-(1H-tetrazol-5-yl-alkylphenyl)polyfluoroalkanamides
EP0356989A2 (fr) * 1988-08-31 1990-03-07 Roche Diagnostics GmbH Sulphonamides comportant un reste de tétrazolyle, procédé de préparation et médicaments

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2383535A (en) * 2001-02-16 2003-07-02 Cxr Biosciences Ltd Medical use of fluorinated acids
JP2004531482A (ja) * 2001-02-16 2004-10-14 シーエックスアール バイオサイエンス リミテッド 方法
GB2383535B (en) * 2001-02-16 2005-09-21 Cxr Biosciences Ltd Pharmaceutical compositions containing fluorinated or perfluorinated carboxylic acids
JP4652665B2 (ja) * 2001-02-16 2011-03-16 シーエックスアール バイオサイエンス リミテッド 方法
US8487003B2 (en) 2001-02-16 2013-07-16 Cxr Biosciences Limited Treatment of cancer by administration of perfluorooctanoic acid

Also Published As

Publication number Publication date
DE4040619A1 (de) 1992-06-25
AU9051091A (en) 1992-07-22

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