EP1833474A1 - Pharmazeutische zusammensetzungen auf grundlage fluorierter sulfamide und sulfinimide - Google Patents

Pharmazeutische zusammensetzungen auf grundlage fluorierter sulfamide und sulfinimide

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Publication number
EP1833474A1
EP1833474A1 EP05850551A EP05850551A EP1833474A1 EP 1833474 A1 EP1833474 A1 EP 1833474A1 EP 05850551 A EP05850551 A EP 05850551A EP 05850551 A EP05850551 A EP 05850551A EP 1833474 A1 EP1833474 A1 EP 1833474A1
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Prior art keywords
composition according
group
formula
compounds
hydrogen atom
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French (fr)
Inventor
Hubert Blancou
Franck Guillen
Zohra Benfodda
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Centre National de la Recherche Scientifique CNRS
Universite Montpellier 2 Sciences et Techniques
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S3f Chimie Chimique De Fabrication De Produits Fluores Ste
Centre National de la Recherche Scientifique CNRS
Universite Montpellier 2 Sciences et Techniques
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Publication of EP1833474A1 publication Critical patent/EP1833474A1/de
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    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/02—Local antiseptics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/02—Antidotes
    • 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
    • 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
    • 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
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to pharmaceutical compositions comprising fluorinated sulfonamide and sulfonimide derivatives and the use of fluorinated sulfonamides and sulfonimides as metal enzyme inhibitors.
  • fluorocorticoids such as flurbiprofen or niflumic acid.
  • Phenothiazine-type fluorinated neuroleptics, fluorinated anti-depressants such as fluoxethine and fluoridated anxiolytics such as fluorinated benzodiazepines are also known.
  • fluorinated amphiphilic molecules are also experiencing a remarkable increase in the field of antibiotics, such as, for example, floxacillin and ofloxacin, norfloxacin and ciprofloxacin.
  • Glaucoma is an eye disease that is widespread in the world's population; in France, it affects 2% of the population over 40 years. It is the second leading cause of blindness in the world after cataracts.
  • Glaucoma is a disease of the optic nerve due to an increase in intraocular pressure. It is manifested by loss of visual field due to destruction of the optical fibers and can lead to blindness if effective treatment is not indicated. There is currently no cure but treatments to limit the progression of the disease.
  • Several classes of drugs can be used to treat glaucoma.
  • sympathomimetics alpha-2-adrenergic agents, beta-blockers, direct parasympathomimetics or acetylcholinesterase inhibitors, docasanoids or even F2 alpha prostaglandins.
  • Carbonic anhydrase inhibitors such as acetazolamide are also known.
  • trifluoromethanesulfonamide may be of interest as a carbonic anhydrase inhibitor (Maren et al., J. Biol Chem, Vol 268, No. 35, pp. 26233-26239, 1993) due to its solubility. in water associated with a weak acid dissociation constant (K a ).
  • EP 0 277 814 describes the use of trifluoromethanesulfonamide and its pharmaceutically acceptable salts for the topical treatment of glaucoma.
  • This compound however has the disadvantage of high toxicity.
  • this compound is extremely acidic and, therefore, difficult to formulate for topical application in the eye.
  • the object of the present invention is therefore to propose a pharmaceutical composition comprising novel metalloenzyme inhibiting agents which are efficient, have a reasonable toxicity, are water-soluble and not very acidic or even neutral.
  • it aims to propose the use of these compounds for the preparation of a medicament useful in pathologies involving metallo-enzymes.
  • compositions comprising, in a pharmaceutically acceptable vehicle, compounds of the following general formula (I):
  • Z 1 , Z 2 , Z 3 independently represent: - a hydrogen atom
  • X represents a hydrogen atom; a fluorine atom; -SO 2 NRiR 2 wherein Ri, R 2 identical or different independently represent a hydrogen atom, an alkyl group Ci-C 61 a pharmaceutically acceptable cation selected from alkali metal cations or alkaline earth metal, ammonium or amine protoated or quaternized; or a group -SO 2 -R 3 ;
  • - RF represents a linear or branched alkylene group poly- or perfluorinated C 1 -C 12 ;
  • Z 2 represents a hydrogen atom.
  • Z 3 represents a hydrogen atom.
  • the compounds of formula (I) may include the corresponding pharmaceutically acceptable salts of organic or inorganic acid.
  • acid addition salts are in particular hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptanate, lactobionate, sulfamates, malonates, salicylates, propionates, methylenebis- b-hydroxynaphthoates, gentisic acid, isethionates, di-p-toluoyltart
  • sulphonamide derivatives also called sulphonamides, of formula (Ia) are especially preferred:
  • X represents a fluorine atom.
  • RF represents a linear polyfluorinated or perfluorinated alkylene group.
  • RF represents a perfluorinated alkylene group, more preferably having from 6 to 12 carbon atoms and more preferably from 6 to 8 carbon atoms.
  • R F represents a perfluorinated alkylene group of C 2 , C 3 or C 4 .
  • n represents an integer of 0 to 4 and is more preferably equal to 0 or 2.
  • X represents a group SO 2 NRiR 2 .
  • R 1, R 2 and / or Z 2 and Z 3 each preferably represent a hydrogen atom
  • the compound of formula (I) then represents a double sulfonamide, also called disulfamide.
  • R 1, R 2 and / or Z 2 and Z 3 may, according to another preferred variant, each represent a hydrogen atom and an alkali or alkaline earth metal cation.
  • RF is preferably C 2 to C 10 perfluorinated alkylene.
  • Examples of cations of alkali or alkaline earth metals include sodium, potassium, magnesium and lithium.
  • Examples of ammonium cations include ammonium
  • Z 1 and Z 2 are identical or different and each represents a group of formula (II).
  • the compounds of formula (Ic) below are:
  • X, X 1 , RF, R'F and n, n ' are the same or different and are as previously defined.
  • Z 1 and Z 2 are identical.
  • Z 2 represents a group -SO 2 R 3 where R 3 has the above definition.
  • the compounds of formula (I) have at least 10 fluorine atoms.
  • compositions according to the present invention comprise the compounds of formula (I) below:
  • alkyl represents saturated hydrocarbon radicals, straight or branched chain, of 1 to 12 carbon atoms, preferably 1 to 6 carbon atoms. Mention may in particular be made, when they are linear, the methyl, ethyl, propyl, butyl, pentyl, hexyl, octyl, nonyl, decyl, dodecyl, hexadecyl and octadecyl radicals.
  • alkyl radicals When they are branched or substituted by one or more alkyl radicals, mention may be made especially of the isopropyl, tert-butyl, 2-ethylhexyl, 2-methylbutyl, 2-methylpentyl, 1-methylpentyl and 3-methylheptyl radicals.
  • Alkylene refers to a branched or straight-chain bivalent hydrocarbon chain having 1 to about 6 carbon atoms. Preferred alkylene groups are lower alkylene groups having 1 to 6 carbon atoms. Typical examples of alkylene groups include methylene and ethylene. "Poly- or perfluorinated alkylene” means an alkyl radical as defined above and substituted with at least one fluorine atom. The "perfluorinated alkylene” groups denote a branched or linear bivalent carbon chain corresponding to the formula C n F 2n -, where n represents an integer ranging from 1 to 12.
  • the alkenyl radicals represent hydrocarbon radicals, in a linear or branched chain, and include one or more ethylenic unsaturations. Among the alkenyl radicals, mention may especially be made of allyl or vinyl radicals.
  • the alkynyl radicals represent hydrocarbon radicals, in a linear or branched chain, and comprise one or more unsaturations. acetylene. Among the alkynyl radicals, there may be mentioned acetylenyl.
  • the cycloalkyl radical is a saturated or partially unsaturated, non-aromatic, mono-, bi- or tricyclic hydrocarbon radical of 3 to 10 carbon atoms, such as in particular cyclopropyl, cyclopentyl, cyclohexyl or adamantyl, as well as the corresponding rings containing one or more unsaturations.
  • Aryl denotes a hydrocarbon aromatic system, mono or bicyclic of 6 to 10 carbon atoms.
  • aryl radicals there may be mentioned the phenyl or naphthyl radical, more particularly substituted by at least one halogen atom.
  • heteroaryl radicals denote aromatic systems comprising one or more heteroatoms chosen from nitrogen, oxygen or sulfur, mono or bicyclic, of 5 to 10 carbon atoms.
  • heteroaryl radicals there may be mentioned pyrazinyl, thienyl, oxazolyl, furazanyl, pyrrolyl, 1,2,4-thiadiazolyl, naphthyridinyl, pyridazinyl, quinoxalinyl, phthalazinyl, rimidazo [1, 2 a) pyridine, imidazo [2,1-b] thiazolyl, cinnolinyl, triazinyl, benzofurazanyl, azaindolyl, benzimidazolyl, benzothienyl, thienopyridyl, thienopyrimidinyl, pyrrolopyridyl, imidazopyridyl, benzoazaindole, 1,2,4-tri
  • Preferred heteroaryl groups include thienyl, pyrrolyl, quinoxalinyl, furanyl, imidazolyl, indolyl, isoxazolyl, isothiazolyl, pyrazinyl, pyridazinyl, pyrazolyl, pyridyl, pyrimidinyl and quinazolinyl. , the quinolinyl, thiazolyl, carbazolyl, thiadiazolyl, and groups derived from the fusion with a phenyl ring, and more particularly quinolynyl, carbazolyl, thiadiazolyl.
  • pharmaceutically acceptable cation and “pharmaceutically acceptable carrier” is meant a cation or a suitable vehicle for use in contact with cells of humans and lower animals without toxicity, irritation, undue allergic response and the like, and are proportionate to a reasonable risk / benefit ratio.
  • the compounds of general formula (I) may be prepared by application or adaptation of all methods known per se and / or to those skilled in the art, in particular that described by Larock described in
  • the sulphonamide compounds may be prepared according to the process comprising the steps of: a) converting a compound of formula (III) into a compound of formula (IV): XR F - (CHa) n -SO 2 -CI> - XR F - (CH 2 ) n-SO 2 -F
  • the step of exchanging the chlorine atom with a fluorine atom may be carried out according to known methods.
  • suitable fluorination processes include:
  • the step of substituting chlorine with fluorine according to step a1) is preferably carried out in the presence of an alkali metal fluoride such as potassium fluoride, in acidic medium, in particular in the acid. glacial acetic.
  • an alkali metal fluoride such as potassium fluoride
  • substitution of the fluorine atom by NZ 2 Z 3 can be carried out according to conventional methods.
  • disulfamides the same conditions are used with a compound HaI-Rp-HaI instead of a compound XR F -HaI.
  • the compounds XR F -Hal or HaI-R F -HaI are known products or can be prepared according to known methods.
  • n-perfluoroalkyl iodides are commercially available.
  • alkali metal hydrogen sulfite sodium hydrogen sulfite (Na 2 S 2 O 4 ).
  • Step b2) The chlorination step according to step b2) can be carried out according to any known method, for example with Cl 2 gas, especially in water.
  • poly- or perfluoroalkanesulfonyl fluorides of formula (IV) are prepared from the corresponding alkanesulfonyl fluorides according to a process comprising an electrochemical fluorination step (ECF):
  • alkanesulfonyl fluoride compounds may be prepared according to the process comprising a step of converting the alkanesulfonyl chloride of formula (VI) to alkanesulfonyl fluoride of formula (V): RH-SO 2 CI ⁇ RH-SO 2 F
  • the compounds of formula (III) may be prepared according to the process comprising: a3) conversion of compound X-RF- (CH 2 VI to XR F - (CH 2 ) n -SCN; b3) conversion of compound XR F - (CH 2 ) n -SCN in XR F - (CH 2 ) ⁇ -Cl.
  • This synthetic route is particularly suitable for compounds of formula (III) in which n ⁇ 0.
  • the compounds X-RF- (CH 2 ) H -I are commercially available or can be prepared according to known methods.
  • Steps a3) and b3) are reactions known to those skilled in the art and can be carried out according to conventional methods.
  • step a3) is carried out in the presence of an alkali metal thiocyanate, such as potassium thiocyanate, in an acidic organic medium.
  • step b3) can be carried out in the presence of a chlorinating agent such as sulfuryl chloride.
  • the compounds of formula X-RF-SO 2 -NH-Z 3 + (Ib) may be prepared according to the process comprising: a4) contacting an X-Rp-SO 2 -NH 2 compound with a BZ 3 base in a solvent, and optionally b4) recovery of the compound of formula (Ib) obtained.
  • the sulphonamide compound of formula X-RF-SO 2 -NH 2 (la) may be prepared according to the above-mentioned steps a 1) and b 1).
  • suitable bases include alkali metal hydrides, such as sodium hydrides and potassium hydrides, alkyl lithium compounds such as methyllithium and butyllithium, alkali metal alkoxides such as sodium methoxide and ethoxide sodium, alkali metal carbonates such as sodium carbonate.
  • the base BZ 3 is selected from CH 3 OZ 3 , CO 3 (Z 3 ) 2, ZsOH, NH 2 Z 3 .
  • Sulfinimides can be prepared according to known methods.
  • the sulfinimides of formula X-Rp-SO 2 -NH-SO 2 -Rp'-X 'and the corresponding sulfinimides can be prepared in particular according to the method described in the publication DesMarteaux et al (Li-quing Hu; Darryl
  • This method comprises: a5) reacting a sulfonamide compound X-RF-SO 2 -NH-Z 3 + (Ib) and a hexaalkyldisilazane, whereby an intermediate silica X-Rp-
  • X and X 1 represent a fluorine atom.
  • Acids which can be used for acid hydrolysis include mineral acids such as hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid; and sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid.
  • mineral acids such as hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid
  • sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid.
  • the preparation of sulphinimides in which n ⁇ 0 can be carried out according to conventional methods. In this regard, we can refer to the book by March, Jerry, Advanced Organic Chemistry, 3rd Ed., John Wiley and Sons
  • the thus prepared compounds can be recovered from the reaction mixture by conventional means.
  • the compounds can be recovered by distilling the solvent from the reaction mixture or, if necessary, after distilling off the solvent from the solution mixture, pouring the remainder into water followed by extraction with an organic solvent immiscible in water, and distilling the solvent from the extract.
  • the product can, if v souhajte be further purified by various techniques such as recrystallization, precipitation or the various chromatography techniques, notably column chromatography or preparative thin layer chromatography.
  • the compounds useful in the present invention may contain an asymmetric center. These asymmetric centers may be independently in the R or S configuration. It will be apparent to those skilled in the art that certain compounds which are useful according to the invention may also exhibit geometrical isomerism. It should be understood that the present invention includes individual geometric isomers and stereoisomers and mixtures thereof, including racemic mixtures of compounds of formula (I) above. These types of isomers can be separated from their mixture by the application or adaptation of known methods, for example chromatography or stabilization techniques, where they are prepared separately from the appropriate isomers of their intermediate. The base products or reagents used are commercially available and / or may be prepared by the application or adaptation of known methods, for example processes as described in the Reference Examples or their obvious chemical equivalents.
  • the invention relates to the use of the compounds of formula I:
  • R 3 represents alkyl, alkenyl or alkynyl linear or branched C 1 -C 12 cycloalkyl, C 3 -C 10 or an aryl group of C 6 -C O, alkyl (Ci-C 6 ) aryl (C 6 -C 4 ), heteroaryl C 5 -C 10 ; it being understood that at least one of the groups Z 1 , Z 2 , Z 3 represents a group of formula (II)
  • R 1, R 2 which may be identical or different, independently represent a hydrogen atom or a C 1 -C 6 alkyl group, a pharmaceutically acceptable cation chosen from alkali or alkaline earth metal, ammonium or protonated amine cations; or quaternized; or a group -SO 2 -R 3 ;
  • RF represents a linear or branched poly (C 1 -C 12) or perfluorinated alkylene group
  • the metallo-enzymes are more particularly selected from carbonic anhydrase, botulinum toxin, tetanus toxin, bacterial elastase, integrase and angiotensin converting enzyme and lethal factor of coal.
  • Carbonic anhydrase is a zinc enzyme (Zn 2+ ) that catalyzes the hydration of carbon dioxide and the dehydration of bicarbonate. She is involved in cellular respiration.
  • Zn 2+ zinc enzyme
  • the inhibition of this enzyme by the compounds according to the invention is particularly useful for the treatment of glaucoma, especially topically.
  • Botulinum toxin, anthrax toxin and tetanus toxin are also zinc enzymes (Zn 2+ ), which have the effect of inducing paralysis at a very low dose.
  • Zn 2+ zinc enzymes
  • the inhibition of these toxins by the compounds according to the invention is particularly advantageous as an antidote, and could be useful as a means of protection in case of bacteriological warfare.
  • Bacterial elastase is a zinc enzyme (Zn 2+ ) that has the effect of destroying tissues and especially pseudomonas aeruginosae to facilitate necrosis.
  • Zn 2+ zinc enzyme
  • the inhibition of this enzyme by the compounds according to the invention is particularly useful for the treatment, in particular topical treatment, of wounds and eschars, as well as for the treatment of superinfections, in particular in cystic fibrosis.
  • Integrase is an enzyme with Mg 2+ which allows penetration of I 1 DNA
  • Angiotensin converting enzyme is a zinc enzyme (Zn 2+ ) that plays an important role in the kidney and in vascular regulation.
  • the inhibition of this enzyme by the compounds according to the invention can be applied in the pathogenesis of cardiovascular diseases, in particular in the treatment of arterial hypertension.
  • the compounds of formula (I) are therefore useful in the treatment of pathologies associated with the activity of these metallo-enzymes such as the treatment of glaucoma, cystic fibrosis, superinfections, AIDS, and cardiovascular diseases, in particular the high blood pressure.
  • the compounds of formula (I) may be used for the preparation of medicaments useful as antidotes against the metallo-enzymes which are toxins, such as, in particular, botulinum toxin, anthrax toxin and tetanus toxin.
  • the invention relates to the use of the compounds of formula (I) for the manufacture of a medicament for the treatment of glaucoma.
  • compositions according to the invention may be in forms intended in particular for parenteral, oral, topical or ocular administration.
  • the topical or ocular route is particularly preferred for the treatment of glaucoma.
  • the pharmaceutical composition may be in the form of a cream, ointment, gel or eye drops.
  • the pharmaceutical composition according to the invention may be in the form of solutes or suspensions injectable in multidose vials, in liquid, pasty or solid form and more particularly in the form of creams, milks, ointments, powders, soaked swabs, solutions, gels, spray, foam, suspension or solution.
  • the dosage may vary within the constant limits depending on the therapeutic indications and the route of administration, as well as the age and weight of the subject.
  • the following examples illustrate the invention without limiting it.
  • the starting materials used are known products prepared according to known procedures.
  • the chemical shifts are expressed in parts per million (ppm), the multiplicity of the signals is indicated by one (or more) lowercase letter (s): s (singlet), d (doublet), q (quadruplet), m (multiplet), I (large).
  • Enzymatic kinetics were monitored using a KONTRON UVIKON 860 ultraviolet spectrophotometer equipped with a thermostated cell at 25 ° C. The measurements were carried out at the wavelength of
  • the reaction medium is taken up in a mixture (v / v) of ethyl ether and 0.1N hydrochloric acid.
  • the ethereal phase containing the sulphonamide is dried using sodium sulphate and the solvent is then evaporated under reduced pressure; the expected sulphonamide is thus obtained.
  • the reaction is monitored by 19 F NMR of the crude reaction, it is practically instantaneous.
  • the reaction medium is filtered to remove the residual salts, the acetonitrile is distilled at atmospheric pressure.
  • the temperature of the preceding aqueous phase is brought between
  • the sulfonyl chloride is obtained by adding 7 g (0.2 mol) of chlorine gas to the solution. The temperature is then brought to 35 0 C (melting point of the chlorinated product).
  • the product is recovered by decantation. Gross yield: 85%, purity 90-95%.
  • the organic phase containing the sulfonyl fluoride is recovered by decantation, this phase is dried and used directly in the next step.
  • the ethanol is then distilled (78 0 C-0.3 mmHg) and the temperature is lowered to 70 ° C. After addition of 100 ml of water, is recovered by decantation thiocyanate.
  • the reaction medium is heated at 50 ° C. for 2 hours.
  • the sulphofluoride (C 6 H 3 C 2 H 4 SO 2 F) is recovered by decantation.
  • the products formed are taken up in 50 ml of water and 30 ml of ether.
  • the organic phase containing hexyl thiocyanate is dried with anhydrous sodium sulphate and the solvent is then evaporated off under reduced pressure.
  • the product is distilled (T ° eb 64 ° C./1.1 mmHg), which makes it possible to obtain pure hexylthiocyanate (15.47 g). Yield 89.4%.
  • reaction medium is left stirring for 45 minutes. Excess sulfuryl chloride is destroyed by adding 15 mL of water.
  • the product is then extracted with 30 ml of dichloromethane.
  • the products formed are taken up in 50 ml of water and 30 ml of ether.
  • the organic phase containing the octyl thiocyanate is dried using sodium sulphate and the solvent is then evaporated under reduced pressure.
  • ammonia formed is displaced by a stream of nitrogen and then trapped with a 1N aqueous solution of hydrochloric acid.
  • the crystals obtained are filtered, washed with ethyl ether and then dried under reduced pressure (0.1 mm Hg).
  • RWI N 19 F (CD 3 COCD 3 ): ⁇ (ppm): -125.9 (m, 2F, - (CF 2 ) 6 -CF 2 -CF 3 ); - 122.4 (m, 2F, - (CF) 2 ) S -CF 2 -CF 2 -CF 3 ); -121.5 (m, 6F, - (CF 2 ) 2 - (CF 2 ) 3 - (CF 2 ) 2 -CF 3 ); -120 (m, 2F, NH 2 SO 2 - (CF 2 HCF 2 HCF 2 ) S -CF 3 ); -113.52 (m, 2F, NH 2 SO 2 -CF 2 - (CF 2 ) 6 - CF 3 ); -80.82 (t, 3F, - (CF 2 ) T-CF 3 ).
  • This synthesis is carried out in three steps: synthesis of sodium n-perfluoroalkylsulfamidide, formation of the silica intermediate, and then reaction of the latter with perfluoroalkanesulfonyl fluoride.
  • the sodium salt of anhydrous n-perfluoroalkanesulfonamide is reacted in acetonitrile with an excess of freshly distilled hexamethyldisilazane (HMDS).
  • HMDS hexamethyldisilazane
  • the solvent is evaporated under reduced pressure.
  • the reaction mixture is taken up in a mixture of ethyl ether and 0.1N HCl.
  • the crystals obtained are purified on a silica column (60% ethyl acetate / 40% petroleum ether) and then washed. with ethyl ether.
  • Example 16 Inhibition of bovine carbonic anhydrase by sulfonamides and kinetic study Carbonic anhydrase is an enzyme which obeys the equation of
  • Carbonic anhydrase catalyzes not only the reversible hydration of CO 2 and the dehydration of HCO 3 , but also the hydrolysis of many esters and, in particular, paranitrophenyl acetate (NPA).
  • NPA paranitrophenyl acetate
  • the hydrolysis reaction generated by the carbonic anhydrase was therefore monitored at different concentrations by evolution of the absorbance or optical density (OD) of the reaction medium as a function of time at the wavelength specified above.
  • the enzyme used is bovine carbonic anhydrase (4.86 WA), extracted from erythrocytes, at a concentration of 0.0625 mg / mL (the WA unit is defined as follows: a WA causes the pH variation of the Trizma buffer solution 8.3 to 6.3 per minute at 0 ° C.).
  • buffers such as Trizma / mercaptoethanol (Di (tri (hydroxymethyl) aminomethane) sulfate as well as sodium diethyl malonate helps to maintain the activity and stability of the enzyme.
  • the enzyme used (bovine carboanhydrase), the substrate (4-nitrophenylacetate) as well as the other reagents (Trizma sulfate buffer, mercaptoethanol, sodium diethyl malonate) were provided by Sigma AId nothing.
  • the study is based on the assay of esterase activity of carbonic anhydrase. Enzymatic kinetics is achieved by monitoring spectrophotometry
  • the enzyme is prepared in an aqueous solution composed of Trizma sulfate (0.05 M) / mercaptoethanol buffer (1 mM).
  • This solution is adjusted to pH 8.7 using a pH meter with 0.1 N NaOH solution.
  • the enzyme concentration used is 0.0625 mg of enzyme per ml of Trizma sulfate / mercaptoethanol buffer.
  • Substrate preparation The substrate solution, 4-nitrophenylacetate, was prepared daily because this ester hydrolyses weakly in light to give 4-para-nitro-phenol and acetic acid.
  • the solutions prepared are different depending on the concentration of ester.
  • the substrate was dissolved in a water / acetone mixture (v / v 98/2).
  • the substrate was dissolved in a water / acetone / diethyl malonate buffer mixture.
  • the other inhibitors used are not soluble in water without the addition of a co-solvent, we used DMSO at a concentration of 10% (V / V).
  • the substrate concentrations studied are 4.83. 10 “3 M; 7.5.10” 3 M; 4.5.10 “4 M; 3.75.10 “ 4 M; 2.625.10 “4 M; 1, 875.10 “ 4 M. a) Determination of the initial rates of the hydrolysis reaction of the substrate by the enzyme
  • the curves representing the OD as a function of time made it possible to calculate the initial speed of the reaction.
  • the first representation is from Lineweaver-Burk based on the equation:
  • Acetazolamide was chosen as reference (active ingredient of Diamox).
  • Acetazolamide is a noncompetitive inhibitor of carbonic anhydrase.
  • the concentration of 1.35 ⁇ 10 -6 mol was therefore chosen as the test concentration of the sulfonamides that we synthesized (C 6 F 13 SO 2 NH 2 , C 8 F 7 SO 2 NH 2 , C 8 F 17 SO 2 NKNa + , (C 2 F 4 SO 2 (NH 2 )) 2 , C 6 H 13 SO 2 NH 2 , C 8 H 17 SO 2 NH 2 ).

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EP05850551A 2004-12-21 2005-12-20 Pharmazeutische zusammensetzungen auf grundlage fluorierter sulfamide und sulfinimide Withdrawn EP1833474A1 (de)

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FR0413676A FR2879458B1 (fr) 2004-12-21 2004-12-21 Sulfamides et sulfinimides fluores
PCT/FR2005/003202 WO2006067330A1 (fr) 2004-12-21 2005-12-20 Compositions pharmaceutiques a base de sulfamides et sulfinimides fluores

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US4031036A (en) * 1975-06-09 1977-06-21 Minnesota Mining And Manufacturing Company Use of bis(fluoroaliphaticsulfonyl) imides in cationic polymerization
US4824866A (en) * 1987-02-02 1989-04-25 Riker Laboratories, Inc. Anti-glaucoma use of trifluoromethanesulfonamide
DE69721748T2 (de) * 1996-12-30 2004-03-11 Hydro-Québec, Montréal Oberflächenmodifizierte kohlenstoffmaterialien
US6300481B1 (en) * 1997-03-11 2001-10-09 New Japan Chemical Co., Ltd. Rare earth complexes
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WO2006067330B1 (fr) 2006-09-28
FR2879458A1 (fr) 2006-06-23

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