WO1997030018A1 - Acides 2,2-difluoroalcanecarboxyliques, procedes permettant de les preparer et medicaments les contenant - Google Patents

Acides 2,2-difluoroalcanecarboxyliques, procedes permettant de les preparer et medicaments les contenant Download PDF

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Publication number
WO1997030018A1
WO1997030018A1 PCT/EP1997/000725 EP9700725W WO9730018A1 WO 1997030018 A1 WO1997030018 A1 WO 1997030018A1 EP 9700725 W EP9700725 W EP 9700725W WO 9730018 A1 WO9730018 A1 WO 9730018A1
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WIPO (PCT)
Prior art keywords
alkyl
phenyl
group
radical
compounds
Prior art date
Application number
PCT/EP1997/000725
Other languages
German (de)
English (en)
Inventor
Edgar Voss
Johannes Pill
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
Priority to AU17902/97A priority Critical patent/AU1790297A/en
Publication of WO1997030018A1 publication Critical patent/WO1997030018A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/62—Halogen-containing esters
    • C07C69/65—Halogen-containing esters of unsaturated acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
    • C07C57/52—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing halogen
    • C07C57/58—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing halogen containing six-membered aromatic rings

Definitions

  • the present invention relates to 2,2-difluoroalkane carboxylic acids, processes for their preparation and medicaments which contain these compounds.
  • the invention relates to new 2,2-difluoroalkane carboxylic acids of the general formula I.
  • A an alkyl chain with 5-20 carbon atoms
  • a ' is a valence line, a vinylene or acetylene group or an alkyl chain with 1-10 carbon atoms,
  • B is a valence line, a methylene group, sulfur, oxygen or the group NR 1 ,
  • R 1 can be hydrogen, benzyl, phenyl or a C1-C4 alkyl radical, a carbonyl, sulfonamide, sulfoxide or sulfone group, an E or Z vinylene or an acetylene group, a CR- ⁇ R- * group,
  • R 2 is hydrogen, a C i -C4-alkyl radical or phenyl
  • R3 is a C1-C4-alkyl radical, benzyl, phenyl, hydroxy or a group NR 4 R 5 ,
  • R 4 can be hydrogen, benzyl, phenyl or a C j -C4 alkyl radical and R5 can be hydrogen or a C ⁇ -C4 alkyl radical,
  • Z can be an alkyl chain (CH2) n and n 1-5,
  • a halogen atom a cyano or rhodano group, aminocarbonyl; an isopropyl or tert-butyl radical; a C3-Cg-cycloalkyl radical which can be unsubstituted or substituted by phenyl or C1-C4-alkyl; a cyclohexenyl or cyclopentenyl radical, a phenyl ring which can be substituted by one or any combination of the following substituents: -CC4-alkyl,
  • C 1 -C 4 -alkyl substituents are understood to mean straight-chain or branched alkyl radicals; methyl and ethyl substituents are preferred.
  • Preferred compounds of the general formula I are compounds
  • A is an alkyl chain with 8-16, preferably 10-14 carbon atoms
  • a 'a valence line vinylene or acetylene
  • B valence line a methylene group, oxygen, sulfur, sulfoxide or sulfonyl
  • W is a C3-Cg-cycloalkyl or an optionally substituted phenyl radical, in particular 4-chlorophenyl, 4-methylthiophenyl, 4-C r C 4 -alkylphenyl,
  • the alkyl chain A or A 1 is preferably straight-chain, but can also be branched.
  • Halogen is to be understood as fluorine, chlorine, bromine or iodine.
  • the C3-Cg-cycloalkyl radicals mean cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, cyclopentyl and cyclohexyl are preferred.
  • physiologically usable salts of the compounds of the formula I are alkali metal, alkaline earth metal, ammonium and alkylammonium salts, such as the Na, K, Mg, Ca or tetramethylammonium salt.
  • esters are aliphatic alcohols, such as C 1 -C 6 -alkanols, in particular methyl, ethyl, propyl, butyl and isopropyl esters.
  • the carboxylic acid derivatives 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 stabilizing agents, solubilizers and / or buffers customary for injection solutions.
  • Such additives are e.g. B. tartrate or borate buffer, ethanol, dimethyl sulfoxide, complexing agents (such as ethylenediaminetetraacetic acid), high molecular weight polymers (such as liquid polyethylene oxide) for viscosity control or polyethylene derivatives of sorbitan hydrides.
  • Solid carriers are e.g. B.
  • 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 other treatments which may be carried out at the same time and the type of effect desired.
  • the daily dose of the active compound is usually 0.1 to 50 mg / kg body weight. Usually 0.5 to 40 and preferably 1.0 to 20 mg / kg / day are effective in one or more applications per day to achieve the desired results.
  • esters of difluoroacetic acid in the presence of strong bases.
  • the reaction is usually carried out in solvents such as diethyl ether, tetrahydrofuran, dimethoxyethane, diethylene glycol dimethyl ether or t-butyldimethyl ether at temperatures between -80 ° C. and -20 ° C.
  • the preferred base is lithium diisopropylamide (LDA).
  • LDA lithium diisopropylamide
  • the products are usually purified by flash chromatography on silica gel and / or recrystallization of the sodium salts from alcohols such as methanol, ethanol or isopropanol
  • the compounds of formula II are known from the literature or can be prepared by processes known per se.
  • the halogen compounds can be synthesized by Wittig reaction of an aromatic or aliphatic aldehyde W-CHO with the phosphonium salt of an ⁇ , ⁇ -dihalogen compound, optionally followed by subsequent catalytic hydrogenation of the double bond formed.
  • an aryl or alkyl bromide W-Br can be converted into the Grignard compound by magnesium and coupled to ct, ⁇ -dihalogen compounds under cuprate catalysis according to Schlosser (Angew Chem 86, 50 (1974))
  • Halogen compounds of the general formula II in which W is an aryl, alkyl or cycloalkyl radical are obtained by converting the corresponding bromine compound W-Br into the Grignard compound using magnesium and using cuprate catalysis according to Schlosser (Angew. Chem. 86 , 50 (1974) is coupled to an ⁇ , ⁇ -dihalogen compound.
  • the compounds of the formula II are those in which B represents a sulfur atom, these are prepared by reacting the thiols W-SH or W-A'-SH with the ⁇ -bromo-2,2-dichlorocarboxylic acid esters described in this invention.
  • Dipolar, aprotic solvents, preferably dimethylformamide, in the presence of inorganic bases such as sodium hydride or potassium carbonate are suitable for carrying out this reaction.
  • the thioethers obtained can be converted into the sulfoxides or sulfones in a known manner by oxidation with 3-chloroperbenzoic acid or hydrogen peroxide.
  • 2,2-Difluoro-12-phenyl-dodecanoic acid ethyl ester 7 2.19 g (14.9 mmol) of diethylaminosulfur trifluoride (DAST) were added dropwise to a solution of 4.33 g (13.6 mmol) 6 in 15 ml of dichloromethane with cooling. The clear yellow-orange colored solution was left 20 Stir h and then add 30 ml of water. The mixture was extracted three times with 30 ml of dichloromethane each time, dried over sodium sulfate and the solvent was evaporated in a vacuum. 5 3 g of a yellow oil were obtained which, after flash chromatography on silica gel (mobile phase: isohexane / ethyl acetate 95: 5), gave 3.7 g (80%) 7.
  • DAST diethylaminosulfur trifluoride
  • 2,2-difluoro-16-phenyl-hexadecanoic acid ethyl ester 11 1.90 g (5.10 mmol) 10 were dissolved in 1.5 ml dichloromethane and 0.82 g (5.3 mmol) diethylarnosulfur trifluoride (DAST) was added under nitrogen, the batch being cooled with a little ice water. The mixture was stirred at room temperature for 6 h. poured onto 100 ml ice water and extracted with ether. After drying over sodium sulfate, the solution m. evaporated and the residue purified by column chromatography on silica gel (eluent: heptane / ethyl acetate 50: 1). 1 40 g (70%) 11.
  • DAST diethylarnosulfur trifluoride
  • mice develop hyperglycemia, hyperinsulinemia and obesity [Herberg and Coleman, Metabolism 26, 59-99 (1977)] Die
  • the tests were carried out on obese female ob / ob mice (Jackson Laboratory, USA). The allocation to the individual test groups was based on the blood glucose level before the first substance application. Care was taken to ensure homogeneous distribution in the different groups.
  • the test substances were suspended in water after suspension Carboxymethyl cellulose (10 ml / kg) administered with a steel probe po for 5 consecutive days. To determine the blood sugar, insulin, triglycerides and free fatty acids, blood was drawn 2 hours after the last dose by opening the neck vessels. The parameters were determined using standard test kits from Boehringer Mannheim and Pharmazia. Example blood sugar "Insulin TG NEFA
  • TG triglycerides
  • NEFA non esterified fatty acids

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne des médicaments utilisés dans le traitement du diabète sucré, qui contiennent pour principe actif un composé de la formule (I) dans laquelle A, B, A' et W ont la notation mentionnée dans les revendications. L'invention concerne par ailleurs de nouveaux composés de la formule (I) et des procédés permettant de les préparer.
PCT/EP1997/000725 1996-02-16 1997-02-15 Acides 2,2-difluoroalcanecarboxyliques, procedes permettant de les preparer et medicaments les contenant WO1997030018A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU17902/97A AU1790297A (en) 1996-02-16 1997-02-15 2,2-difluoroalkane carboxylic acids, process for their preparation and medicaments containing the same

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE1996105700 DE19605700A1 (de) 1996-02-16 1996-02-16 2,2-Difluoralkancarbonsäuren, Verfahren zu ihrer Herstellung und diese enthaltende Arzneimittel
DE19605700.0 1996-02-16

Publications (1)

Publication Number Publication Date
WO1997030018A1 true WO1997030018A1 (fr) 1997-08-21

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ID=7785538

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1997/000725 WO1997030018A1 (fr) 1996-02-16 1997-02-15 Acides 2,2-difluoroalcanecarboxyliques, procedes permettant de les preparer et medicaments les contenant

Country Status (3)

Country Link
AU (1) AU1790297A (fr)
DE (1) DE19605700A1 (fr)
WO (1) WO1997030018A1 (fr)

Citations (3)

* 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
DE4040619A1 (de) * 1990-12-19 1992-06-25 Boehringer Mannheim Gmbh Neue aliphatische amide, verfahren zu ihrer herstellung sowie arzneimittel, die diese verbindungen enthalten
WO1996015784A2 (fr) * 1994-11-09 1996-05-30 Boehringer Mannheim Gmbh Acides 2,2-dichloroalcanecarboxyliques, leur procede de preparation, medicaments les contenant, et leur utilisation dans le traitement de la resistance insulinique

Patent Citations (3)

* 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
DE4040619A1 (de) * 1990-12-19 1992-06-25 Boehringer Mannheim Gmbh Neue aliphatische amide, verfahren zu ihrer herstellung sowie arzneimittel, die diese verbindungen enthalten
WO1996015784A2 (fr) * 1994-11-09 1996-05-30 Boehringer Mannheim Gmbh Acides 2,2-dichloroalcanecarboxyliques, leur procede de preparation, medicaments les contenant, et leur utilisation dans le traitement de la resistance insulinique

Also Published As

Publication number Publication date
DE19605700A1 (de) 1997-08-21
AU1790297A (en) 1997-09-02

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