WO2004080952A1 - Derives de phenylsulfonamide pour le traitement de la maladie d'alzheimer - Google Patents

Derives de phenylsulfonamide pour le traitement de la maladie d'alzheimer Download PDF

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Publication number
WO2004080952A1
WO2004080952A1 PCT/EP2004/002248 EP2004002248W WO2004080952A1 WO 2004080952 A1 WO2004080952 A1 WO 2004080952A1 EP 2004002248 W EP2004002248 W EP 2004002248W WO 2004080952 A1 WO2004080952 A1 WO 2004080952A1
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alkyl
formula
group
substituted
optionally
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PCT/EP2004/002248
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German (de)
English (en)
Inventor
Christopher Kallus
Nils Griebenow
Stephan-Nicholas Wirtz
Karlheinz Baumann
Mark Jean Gnoth
Friedrich Reinhard
Martin Hendrix
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Bayer Healthcare Ag
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Priority claimed from DE2003141535 external-priority patent/DE10341535A1/de
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Publication of WO2004080952A1 publication Critical patent/WO2004080952A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/21—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/34—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/30—Hetero atoms other than halogen
    • C07D333/34—Sulfur atoms

Definitions

  • the invention relates to phenylsulfonamide derivatives and processes for their preparation and their use for the manufacture of medicaments for the treatment and / or prophylaxis of diseases, in particular Alzheimer's disease.
  • AD Alzheimer's disease
  • memory loss characterized by memory loss, personality changes, language and orientation difficulties, poor decision-making and lack of drive. Up to 50% of those over the age of 85 are affected by neurodegeneration, with Alzheimer's disease being the dementia with the highest prevalence.
  • the histopathologically most striking characteristic of Alzheimer's disease are the "senile" amyloid plaques that are found in the brain and there, above all, in areas related to memory and thinking.
  • the main protein component of the plaques is the ß-amyloid peptide (Aß, ßA4) with a length of 40-42 amino acids and a molecular weight of approx. 4 kilo-Dalton (kDa).
  • Aß is also found in plasma and cerebrospinal fluid (CSF) from healthy individuals; however, its function is unknown.
  • Aß Alzheimer's patients
  • an increased production and / or a reduced breakdown of Aß leads to increased levels of the polypeptide in plasma and CSF, followed by oligomerization of the peptide and accumulation in the brain, which ultimately lead to the formation the plaque leads.
  • Either Aß oligomers or the " plaques eventually lead to neurodegeneration.
  • Aß is formed by proteolytic processing of the amyloid precursor protein (APP) in successive steps by various enzymes, which are called secretases.
  • secretases The last step in the generation of Aß takes place through the so-called ⁇ -secretase, which releases the carboxyl terminus of Aß by cleaving the peptide bond.
  • ⁇ -secretase Neither the gene encoding ⁇ -secretase nor the protein itself have been identified. Based on the available data, however, it can be assumed that this enzyme exists (see also M.S. Wolfe, J. Med. Chan. 2001, 44, 2039-2060).
  • Phenylsulfonamide derivatives as ⁇ -secretase inhibitors are described in WO 00/50391. Structurally different types of ⁇ -secretase inhibitors are, for example, from Rishton et al., /. Med. Chan. 2000, 43, 2297-2299 as well as from WO 01/77086, WO 01/77144 and WO 01/53255.
  • the present invention relates to compounds of the formula
  • R 1 is phenyl or heteroaryl, optionally selected from the group halogen, cyano, trifluoromethyl, trifluoromethoxy, Ci- -alkyl, independently of one another by radicals,
  • R 2 phenyl which is optionally selected independently of one another from the group halogen, cyano, trifluoromethyl, trifluoromethoxy, C 1 -C 6 alkyl, hydroxy C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, CC 6 alkoxy and C 1 -C 6 alkylthio is substituted,
  • R 3 is hydrogen, cyano, trifluoromethyl, C ⁇ -C 6 alkyl or C 3 -C 8 -cycloalkyl, where -C 6 - alkyl and C 3 -C 8 -cycloalkyl optionally substituted by radicals independently selected from the group of hydroxy, -C ö Alkoxy, cyano, trifluoromethyl, trifluoromethoxy, nitro, amino, amino -CC 6 alkyl, hydroxycarbonyl and (-C 6 -alkoxy) ⁇ carbonyl are substituted,
  • R 4 is hydrogen or CC 6 alkyl
  • R 5 is hydrogen, d-Cg-alkyl or C 3 -C 8 -cycloalkyl
  • R 6 is a radical of the formula
  • ACC 6 alkylene, BC 6 -C ⁇ o-arylene, heteroarylene or heterocyclylene which are each optionally substituted by radicals selected independently of one another from the group halogen, cyano, oxo, hydroxyl, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, trifluoromethyl and trifluoromethoxy,
  • R 9 represents hydrogen or -CC 6 alkyl
  • R 8 -OR 10 or a radical of the formula -NR U R 12 , wherein
  • R 10 is hydrogen, -C 6 alkyl, C 3 -C 0 cycloalkyl or heterocyclyl
  • R 11 and R 12 independently of one another for hydrogen, -CC 6 -alkyl or C 3 -C- 0 - cycloalkyl,
  • R 5 and R 6 together with the nitrogen atom to which they are attached form a heterocycle which is optionally substituted by radicals selected independently of one another from the group C 6 -C 1 -aryl, C 1 -C 6 -alkyl, oxo and hydroxy,
  • R 13 represents hydrogen or CC 6 alkyl
  • R 8 has the meanings given above
  • the compounds according to the invention can exist in stereoisomeric forms (enantiomers, diastereomers).
  • the invention therefore relates to the enantiomers or diastereomers and their respective mixtures.
  • the stereoisomerically uniform constituents can be isolated in a known manner from such mixtures of enantiomers and / or diastereomers.
  • the invention also relates to tautomers of the compounds (I) and their salts, solvates and solvates of the salts.
  • preferred salts of the compounds (I) are physiologically acceptable salts.
  • Physiologically acceptable salts include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, e.g. Salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, ..acetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and benzoic acid.
  • Salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid ..acetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid,
  • Physiologically acceptable salts also include salts of conventional bases, such as, for example and preferably, alkali metal salts (for example sodium and potassium salts), alkaline earth metal salts (for example calcium and magnesium salts) and ammonium salts, derived from ammonia or organic amines having 1 to 16 carbon atoms, for example and preferably E ylarnin, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, dibenzylamine, N-methylnorpholm, arginine, lysine, ethylenediamine and N-methylpiperidine.
  • alkali metal salts for example sodium and potassium salts
  • alkaline earth metal salts for example calcium and magnesium salts
  • ammonium salts derived from ammonia or organic amines having 1 to 16 carbon atoms, for example and preferably E yl
  • solvates are solid or liquid forms of the compounds which have formed a complex through coordination with solvent molecules. Hydrates are a special form of solvate in which coordination with water has taken place.
  • the radicals have the following meaning:
  • C Cfi-alkyl, C Cd-alkyl and G-Cralkyl stand for a straight-chain or branched alkyl radical with 1 to 6, 1 to 4 or 1 to 3 carbon atoms.
  • a straight-chain or branched alkyl radical having 1 to 4, particularly preferably having 1 to 3, carbon atoms is preferred.
  • the following may be mentioned by way of example and preferably: methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentyl and n-hexyl.
  • G- alkylene stands for a straight-chain or branched alkanediyl radical having 1 to 6 carbon atoms, the two free valences of the alkanediyl radical on a carbon atom (geminal), on adjacent carbon atoms (vicinal) or on non-adjacent ones Can be carbon atoms.
  • a straight-chain or branched alkanediyl radical having 1 to 4 carbon atoms is preferred, particularly preferably a straight-chain or branched alkanediyl radical having 1 to 3 carbon atoms.
  • Cv-Cfi-cycloalkyl and C Cs-Cvcloalkyl stand for a monocyclic or optionally bicyclic cycloalkyl group with 3 to 10, 3 to 8, 3 to 6 and 3 to 5 carbon atoms in the context of the invention.
  • cyclopropyl cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl
  • bicyclo [2.1.1] hexyl bicyclo [2.2.1] heptyl
  • bicyclo [3.2.1] octyI bicyclo [2.2.2] octyl
  • bicyclo [3.2.2] nonyl bicyclo [3.3.1] nonyl
  • bicyclo [3.3.2] decyl and bicyclo [4.3.1] decyl bicyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl
  • bicyclo [2.1.1] hexyl bicyclo [2.2.1] heptyl
  • bicyclo [3.2.1] octyI bicyclo [2.2.2] o
  • -CurAryl stands in the context of the invention for an aromatic hydrocarbon radical having 6 to 10 carbon atoms.
  • Preferred aryl radicals are phenyl and naphthyl.
  • Cfi-C j n-arylene in the context of the invention represents a double-bonded aryl radical having 6 to 10 carbon atoms.
  • Preferred are o-phenylene, m-phenylene and p-phenylene.
  • Cr-C ⁇ -alkoxy and Cr-Cd-alkoxy in the context of the invention represent a straight-chain or branched alkoxy radical having 1 to 6 or 1 to 4 carbon atoms.
  • a straight-chain or branched alkoxy radical having 1 to 4 carbon atoms is preferred. Exemplary and preferably mentioned are: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, n-pentoxy and n-hexoxy.
  • CC I -C /; - alkoxy) carbonyl and fC r C -alkoxy) carbonyl in the context of the invention represent a straight-chain or branched alkoxy radical having 1 to 6 or 1 to 4 carbon atoms which is linked via a carbonyl group.
  • An alkoxycarbonyl radical having 1 to 4, particularly preferably 1 to 2, carbon atoms is preferred. The following may be mentioned by way of example and preferably: methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl and tert-butoxycarbonyl.
  • C r Cfi-alkylthio represents a straight-chain or branched alkylthio radical having 1 to 6 carbon atoms.
  • a straight-chain or branched alkylthio radical having 1 to 4 carbon atoms is preferred.
  • the following may be mentioned as examples and preferably: methylthio, ethylthio, n-propylthio, isopropylthio r tert-butylthio, rt-pentylthio and n-hexylthio.
  • Hydroxy-C -Cfi-alkyl and hydroxy-C r CA-alkyl are within the scope of the invention a straight-chain or branched alkyl radical having 1 to 6 or 1 to 4 carbon atoms, which is substituted by a hydroxyl group.
  • a hydroxyalkyl radical with 1 to 4, particularly preferably with 1 to 2, carbon atoms is preferred.
  • hydroxymethyl 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl, 2-hydroxyprop-2-yl, 1-hydroxybutyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 1-hydroxybut-2-yl, 2-hydroxybut-2-yl, 3-hydroxybut-2-yl, l-hydroxybut-3-yl, l-hydroxy-2-methylprop-l-yl, 2-hydroxy-2-methylprop-l-yl, 3-hydroxy-2-methylprop-l-yl, l-hydroxy-2-methylprop-2-yl, 5-hydroxypentyl and 6-hydroxyhexyl.
  • aminoalkyl radical having 1 to 4 carbon atoms which is substituted by an amino group.
  • An aminoalkyl radical having 1 to 4, particularly preferably having 1 to 2, carbon atoms is preferred.
  • the following may be mentioned by way of example and preferably: aminomethyl, 1-aminoethyl, 2-aminoethyl, 1-aminopropyl, 2-arainopropyl, 3-aminopropyl, 2-aminoprop-2-yl, 1-aminobutyl, 2-aminobutyl, 3-aminobutyl, 4- Aminobutyl, l-aminobut-2-yl, 2-aminobut-2-yl, 3-aminobut-2-yl, l-arainobut-3-yl, 1-amino-2-methylprop-l-yl, 2-amino -2-methylprop-l-yl, 3-amino-2-methylprop-l-yl, l-amino
  • Heteroaryl stands for an aromatic, mono- or bicyclic radical with 5 to 10 ring atoms and up to 5 heteroatoms from the series S, O and or N.
  • a 5- to 6-membered heteroaryl radical with up to 3 heteroatoms is preferred.
  • the heteroaryl radical can be bonded via a carbon or via a nitrogen atom.
  • Non-limiting examples include furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, triazolyl, pyridyl, Pyrimidinyl, pyridazinyl, pyrazinyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, indolyl, indazolyl, quinolinyl, isoquinolinyl, naphthyridinyl, quinazolinyl, quinoxalinyl.
  • Heteroarylene in the context of the invention represents a double-bonded, mono- or bicyclic heteroaryl radical having 5 to 10 ring atoms and up to 5 heteroatoms from the series S, O and / or N.
  • a 5- to 6-membered heteroarylene radical is preferred with up to 4 heteroatoms.
  • Nonlimiting examples include pyridylene, pyrimidylene, pyridazinylene, pyrazinylene, thienylene, pyrrolylene, oxazolylene, thiazolylene, imidazolylene, isoxazolylene, isothiazolylene, tetrazolylene, isoxazolylene, furylene, pyrazolylene.
  • a heterocycle bonded via a nitrogen atom stands for a mono- or bicyclic, preferably monocyclic, non-aromatic heterocyclic radical having 4 to 7, preferably 5 to 6 ring atoms, with at least one ring nitrogen atom, via which the heterocyclyl radical is bonded , and with up to two, preferably up to a further ring heteroatom and / or hetero group from the series N, O, S, SO and S0 2 .
  • the heterocycle can be saturated or partially unsaturated.
  • Heterocyclylene in the context of the invention represents a double-bonded 5- to 7-membered, mono- or bicyclic, saturated or partially unsaturated heterocyclyl radical with up to three ring heteroatoms and / or hetero groups from the series N, O, S, SO and S0 2 , which can be linked both via ring carbon atoms and optionally via ring nitrogen atoms.
  • a 5- to 6-membered, monocyclic, saturated heterocyclylene radical having up to two ring heteroatoms from the N, O and S series is preferred, such as, for example and preferably, tetrahydrofurylen, pyrrolidinylene, piperidinylene, piperazinylene and morpholinylene.
  • Halogen in the context of the invention includes fluorine, chlorine, bromine and iodine. Chlorine or fluorine are preferred.
  • radicals in the compounds according to the invention are substituted, the radicals, unless otherwise specified, can be substituted one or more times in the same or different manner. A substitution with up to three identical or different substituents is preferred. Substitution with a substituent is very particularly preferred.
  • R 1 is phenyl or thienyl, which are optionally substituted independently of one another by radicals selected from the group consisting of fluorine, chlorine, bromine, cyano, trifluoromethyl, trifluoromethoxy and C 1 -C 4 -alkyl,
  • R 2 is phenyl, which is optionally selected independently of one another from the group fluorine, chlorine, bromine, cyano, trifluoromethyl, trifluoromethoxy, Cr -alkyl,
  • R 3 is hydrogen, cyano, trifluoromethyl, C 1 -C 6 -alkyl or C 3 -C 8 -cycloalkyl, where CC 6 - alkyl and C 3 -C 8 -cycloalkyl are optionally selected independently of one another from the group of hydroxy, C 1 -C 6 -alkoxy, cyano, trifluoromethyl, amino -CC 6 alkyl, hydroxycarbonyl and (-C 6 -alkoxy) carbonyl are substituted,
  • R 4 is hydrogen or dC 3 alkyl
  • R 5 is hydrogen, C r C 3 alkyl or C 3 -C 6 cycloalkyl and
  • R 6 is a radical of the formula
  • Chlorine, bromine, cyano, oxo, CC 4 -alkyl, CC 4 -alkoxy are substituted
  • D -Q-alkylene in which a CH 2 group is optionally replaced by an oxygen atom or by a group of the formula -NR 9 -, wherein
  • R 9 represents hydrogen or -CC 4 alkyl
  • R 8 -OR 10 or a radical of the formula -NR U R 12 , wherein
  • R 10 represents hydrogen, C r C 4 -alkyl, C 3 -C 6 -cycloalkyl or heterocyclyl
  • R 11 and R 12 independently of one another are hydrogen, C 1 -C 4 -alkyl or C 3 -C 6 - cycloalkyl
  • R 11 and R 12 together with the nitrogen atom to which they are attached form a piperidine, pyrrolidine or morpholine ring,
  • R 5 and R 6 together with the nitrogen atom to which they are attached form a heterocycle which is optionally substituted by radicals selected independently of one another from the group phenyl, C 1 -C 4 -alkyl, oxo and hydroxyl,
  • heterocycle containing R 5 and R 6 is mandatory with a radical of the formula
  • E -CC 4 alkylene in which a CH 2 group is optionally replaced by an oxygen atom or by a group of the formula -NR 13 -, wherein
  • R 13 represents hydrogen or C r C 6 alkyl
  • R 8 has the meaning given above
  • R 1 is phenyl which is optionally substituted in the 4-position by a radical selected from the group consisting of fluorine, chlorine, bromine and trifluoromethyl, or 2-thienyl which is in the 5-position is optionally substituted by a radical selected from the group consisting of fluorine, chlorine, bromine and trifluoromethyl,
  • R 3 is hydrogen or methyl
  • R 5 is hydrogen or Ci- alkyl
  • R 6 is a radical of the formula
  • R 8 -OR 10 or a radical of the formula -NR 11 R 12 , wherein
  • R 10 represents hydrogen, -CC 4 -alkyl or CC 6 -cycloalkyl
  • R 11 and R 12 independently of one another are hydrogen, - -alkyl or C 3 -C 6 -
  • R 11 and R 12 together with the nitrogen atom to which they are attached form a piperidine or morpholine ring
  • R 5 and R 6 together with the nitrogen atom to which they are attached form a heterocycle which is optionally substituted by radicals selected independently of one another from the group phenyl, C 1 -C 4 -alkyl, oxo and hydroxyl,
  • heterocycle containing R 5 and R 6 is mandatory with a radical of the formula
  • F is phenylene or pyridylene
  • R 8 has the meanings given above
  • R 1 is phenyl which is substituted in the 4-position by a radical selected from the group consisting of fluorine, chlorine, bromine and trifluoromethyl,
  • R 3 is hydrogen
  • Rl is phenyl which is substituted in the 4-position by trifluoromethyl
  • the invention further relates to processes for the preparation of the compounds according to the invention, characterized in that
  • R 5 and R 6 have the meanings given above and
  • Y 1 represents a suitable leaving group such as halogen
  • Y 2 and Y 3 are the same or different and are suitable for a suitable leaving group, such as halogen or a group of the formula
  • R 1 to R 4 and Y 3 have the meanings given above,
  • R 5 and R 6 have the meanings given above, or
  • R 3 , R 4 , R 5 and R 6 have the meanings given above,
  • G represents a suitable leaving group, preferably bromine, chlorine, mesyl or tosyl,
  • R 3 , R 4 , R 5 and R 6 have the meanings given above,
  • the compounds (II) can be prepared by combining compounds of the formula (VIU) in an inert solvent in the presence of triphenylphosphine and a di (C ! -C -alkyl) azodicarboxylate under Mitsunobu conditions with a compound of the formula
  • Hydroxy functions can be protected by protective groups using known methods and finally deprotected again (see, for example, T. W. Greene, P. Wuts, "Protective Groups in Organic Synthesis", 2nd ed., Wiley, New York, 1991).
  • R 1 has the meanings given above and
  • Y 4 represents a suitable leaving group, such as chlorine, bromine or iodine,
  • R3, R4 and L have the meanings given above,
  • R4 R, L and Y ⁇ have the meanings given above,
  • solvent for the acylation in process step [A] (D) + (m) / (JN) ⁇ (I) and (XV) + (IU) / (1V) ⁇ (LX) as well as for the sulfonylation in process step (XH) + (XIV) ⁇ (VHI) are inert organic solvents.
  • halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, trichloroethane, tetrachloroethane, 1,2-dichloroethane or trichlorethylene
  • ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or di- ethylene glycol dimethyl ether
  • hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, nitroalkanes such as nitromethane, esters such as ethyl acetate, ketones such as acetone, heteroaromatics such as pyridine, amides such as dimethylformamide, dialkyl sulfoxides such as dimethyl sulfoxide, or nitriles such as acetylene. It is also possible to use mixtures of the solvents
  • alkali or alkaline earth carbonates such as sodium, potassium or calcium carbonate
  • alkali hydrides such as sodium hydride
  • amides such as lithium bis (trimethylsilyl) amide or lithium diisopropylamide
  • organic amines such as pyridine, 4-N, N-dimethylamino-pyridine, 4 -Pyrrolidinopyridine, triethylamine, ethyldiisopropylamine, N-methylmorpholine, N-methylpiperidine, l, 5-diazabicyclo [4.3.0] non-5-ene (DB ⁇ ) or l, 8-diazabicyclo [5.4.0] undec-7-ene ( DBU), or organometallic compounds such as butyllithium or phenyllithium.
  • Pyridine is particularly preferred, optionally in the presence of catalytic amounts (approx. 10 mol%) of 4- N, N-dimethylaminopyridine or 4-pyrrolidino
  • the base is used in an amount of 1 to 10, preferably 1 to 3, mol per mol of the compound (II), (X) or (XIV).
  • catalytic amounts (about 10 mol%) of 4-N, N-dimethylaminopyridine are preferably used.
  • acylation in process step (E) + (ET) / (rV) ⁇ (I) and (XV) + (EI) / (IV) ⁇ (IX) and process step (XEI) + (XIV) ⁇ (VIE) take place generally in a temperature range from -30 ° C to + 100 ° C, preferably in a temperature range from 0 ° C to + 60 ° C.
  • the reactions can be carried out at normal, elevated or reduced pressure (e.g. from 0.5 to 5 bar). Generally one works at normal pressure.
  • inert solvents are suitable as solvents for process step [B] (V) + (E) ⁇ (VI) and (V) + (XV) ⁇ (XVI).
  • halogenated hydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane, trichloroethane, tetrachloroethane, 1,2-dichloroethane or trichlorethylene
  • ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or di ethylene glycol dimethyl ether
  • hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or Petroleum fractions, nitroalkanes such as nitromethane, esters such as ethyl acetate, ketones such as acetone, heteroaromatics such as pyridine, amides such as dimethylformamide
  • the usual inorganic or organic bases are suitable as bases for these process steps. These preferably include alkali or alkaline earth carbonates such as sodium, potassium or calcium carbonate, alkali hydrides such as sodium hydride, amides such as lithium um-bis (trimethylsilyl) amide or lithium diisopropylamide, organic amines such as pyridine, 4-N, N-dimethylaminopyridine, 4-pyrrolidinopyridine , Triethylamine, ethyldiisopropylamine, N-methylmorpholine, N-methylpiperidine, l, 5-diazabicyclo [4.3.0] non-5-ene (DB ⁇ ) or l, 8-diazabicyclo [5.4.0] undec-7-ene (DBU) , or organometallic compounds such as butyllithium or phenyllithium. Triethylamine and ethyldiisopropylamine are particularly preferred.
  • the base is used in an amount of 1 to 10, preferably 1 to 3, mol per mol of the compound (E) or (X).
  • the reaction generally takes place in a temperature range from -30 ° C. to + 100 ° C., preferably in a temperature range from 0 ° C. to + 60 ° C.
  • the reaction can be carried out at normal, elevated or reduced pressure (e.g. from 0.5 to 5 bar). Generally one works at normal pressure.
  • process step (VI) / (XVI) + (VE) ⁇ (I) is preferably used in the presence of equivalent amounts of methyl trifluoromethanesulfonate or methyl iodide Catalyst carried out.
  • Mitsunobu conditions generally mean the use of inert solvents in the presence of an azodicarboxylate, optionally in the presence of an additional reagent, preferably in a temperature range from 0 ° C. to room temperature at atmospheric pressure.
  • Additional reagents are customary additional reagents for Mitsunobu reaction conditions, such as triphenylphosphine, diphenyl- (2-pyridyl) -phosphine or (4-dimethylaminophenyl) -diphenylphosphine; triphenylphosphine is preferred.
  • Azodicarboxylates are, for example, diethylazodicarboxylate, dimethylazodicarboxylate, diisopropyl azodicarboxylate or di-tert-butylazodicarboxylate; diisopropylazodicarboxylate is preferred.
  • Inert solvents are, for example, halogenated hydrocarbons such as chloroform, ethers such as dioxane, tetrahydrofuran or 1,2-dimethoxyethane, hydrocarbons such as benzene, xylene or
  • nitroaromatics such as nitrobenzene, carboxamides such as dimethylformamide or Dimethylacetamide, alkyl sulfoxides such as dimethyl sulfoxide, aliphatic nitriles such as acetonitrile, esters such as ethyl benzoate or other solvents such as N-methylpyrrolidone, tetrahydrofuran is preferred.
  • the compounds according to the invention show an unforeseeable, valuable pharmacological and pharmacokinetic spectrum of action. They are therefore suitable for use as medicaments for the treatment and / or prophylaxis of diseases in humans and animals.
  • the compounds according to the invention inhibit ⁇ -secretase.
  • the compounds according to the invention are distinguished by advantageous properties with regard to their metabolic stability and or a potential introduction of liver enzymes.
  • the compounds according to the invention can be used alone or in combination with other active compounds for the treatment and or prevention of neurodegenerative diseases, in particular Alzheimer's disease.
  • the compounds according to the invention can be used alone or in combination with other medicaments for the treatment and / or prophylaxis of diseases which are associated with the increased formation, release, accumulation or deposition of amyloid peptides, such as e.g.
  • AD Alzheimer's disease and / or associated cognitive disorders which occur, for example, in situations / incidents / syndromes such as "mild cognitive impairment", age-associated learning and memory disorders, age-associated memory losses, Vascular dementia, traumatic brain injury, stroke, dementia that occurs after stroke ("post stroke dementia"), post-traumatic traumatic brain injury, general concentration disorders, concentration disorders in children with learning and memory problems, Attention Deficit Hyperactivity Disorder , Alzheimer's disease, dementia with Lewy bodies, dementia with degeneration of the frontal lobes including Pick's syndrome, Parkinson's disease, progressive nuclear palsy, dementia with corticobasal degeneration, amyotrophic lateral sclerosis (ALS), Huntington's disease, multiple sclerosis, Thalamic degeneration, Creutzfeld-Jacob dementia, HIV dementia or schizophrenia with dementia.
  • ALS amyotrophic lateral sclerosis
  • the compounds according to the invention can furthermore be used in combination. with other medicines that prevent the formation, release, accumulation or deposition of amyloid peptides in the brain.
  • other drugs which are inhibitors of the ⁇ - or ⁇ -secretase, drugs which, by their presence, complicate, delay or prevent the deposition of amyloid plaques.
  • a further use of the compounds according to the invention is possible in combination with a therapy which brings about an increased immune response to amyloid peptides.
  • the compounds according to the invention can be used in combination with. other medicinal products are used, which increase the learning and memory performance.
  • the present invention furthermore relates to medicaments which contain at least one compound according to the invention, preferably together with one or more pharmacologically acceptable auxiliaries or excipients, and to their use for the purposes mentioned above.
  • the active ingredient can act systemically and or locally.
  • it can be applied in a suitable manner, e.g. oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, transdermal, conjunctival, otic or as an implant.
  • the active ingredient can be administered in suitable administration forms for these administration routes.
  • Known application forms which deliver the active ingredient quickly and / or modified such as e.g. Tablets (non-coated and coated tablets, e.g. tablets or film-coated tablets provided with enteric coatings), capsules, dragees, granules, pellets, powders, emulsions, suspensions, solutions and aerosols.
  • Tablets non-coated and coated tablets, e.g. tablets or film-coated tablets provided with enteric coatings
  • capsules dragees, granules, pellets, powders, emulsions, suspensions, solutions and aerosols.
  • Parenteral administration can be done by bypassing a resorption step (intravenous, intraarterial, intracardial, intraspinal or intralumbal) or by switching on absorption (intramuscular, subcutaneous, intracutaneous, percutaneous, or intraperitoneal).
  • Suitable forms of application for parenteral administration include: Injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates and sterile powders.
  • Inhaled drug forms including powder inhalers, nebulizers
  • nasal drops / solutions sprays, lingual, sublingual or buccal tablets or capsules, suppositories, ear and eye preparations, vaginal capsules, aqueous suspensions (lotions, shake mixes), lipophilic suspensions, ointments Milk, pastes, powder or implants.
  • the active compounds can be converted into the administration forms mentioned in a manner known per se. This is done using inert, non-toxic, pharmaceutically suitable excipients. These include carriers (e.g. microcrystalline cellulose), solvents (e.g. liquid polyethylene glycols), emulsifiers (e.g. sodium dodecyl sulfate), dispersants (e.g. polyvinylpyrrolidone), synthetic and natural biopolymers (e.g. Albumin), stabilizers (for example antioxidants such as ascorbic acid), dyes (for example inorganic pigments such as iron oxides) or taste and / or odor corrections.
  • carriers e.g. microcrystalline cellulose
  • solvents e.g. liquid polyethylene glycols
  • emulsifiers e.g. sodium dodecyl sulfate
  • dispersants e.g. polyvinylpyrrolidone
  • synthetic and natural biopolymers e.g. Albumin
  • the amount is about 0.001 to 100, preferably about 0.005 to 30 mg / kg of body weight.
  • Device type MS Micromass ZQ
  • Device type HPLC Waters Alliance 2790
  • Column Grom-Sil 120 ODS-4 HE 50 mm x 2 mm, 3.0 ⁇ m
  • Eluent B acetonitrile + 0.05% formic acid
  • eluent A water + 0.05% formic acid
  • Gradient 0.0 min 5% B ⁇ 2.0 min 40% B ⁇ 4.5 min 90% B ⁇ 5.5 min 90% B; Oven: 45 ° C
  • Flow 0.0 min 0.75 mL / min - »4.5 min 0.75 mL / min ⁇ 5.5 min 1.25 mL / min
  • UV detection 210 nm.
  • Instrument Micromass GCT, GC 6890; Column: Restek RTX-35MS, 30 mx 250 ⁇ m x 0.25 ⁇ m; constant flow with helium: 0.88 mL / min; Oven: 60 ° C; Inlet: 250 ° C; Gradient: 60 ° C (for 0.30 min), 50 ° C / min ⁇ 120 ° C, 16 ° C / min ⁇ 250 ° C, 30 ° C / min ⁇ 300 ° C (for 1.7 min).
  • Device type MS Micromass ZQ
  • Device type HPLC Waters Alliance 2795; Column: Phenomenex Synergi 2 ⁇ Hydro-RP Mercury 20mm x 4mm; Eluent A: 1 L water + 0.5 mL 50% formic acid, eluent B: 1 L acetonitrile + 0.5 mL 50% formic acid; Gradient: 0.0 min 90% A flow 1 mL / min - »2.5 min 30% A flow 2 mL / min -> 3.0 min 5% A flow 2 mL / min ⁇ 4.5 min 5% A flow 2 mL / min; Oven: 50 ° C; UV detection: 210 nm.
  • the mixture is stirred for 16 h at room temperature and the crude mixture is first purified by flash chromatography on silica gel (mobile phase: cyclohexane / ethyl acetate 9: 1) and then by preparative HPLC (YMC Gel ODS-AQ S-5/15 ⁇ m, gradient 0.1% formic acid) / Acetonitrile).
  • a solution of 160 mg (0.44 mmol) of the compound from stage d) in 7.5 ml of acetonitrile is successively mixed with 231 ⁇ l (1.33 mmol) of N, N-diisopropylethylamine and 170 mg (0.66 mmol) of N, N'-disuccinimidyl carbonate and at room temperature Stirred for 3 hours.
  • the mixture is then diluted with ethyl acetate, washed twice with saturated sodium bicarbonate solution, the combined aqueous phases are extracted again with ethyl acetate, the combined organic phases are dried over sodium sulfate and the solvent is removed in vacuo.
  • the crude product thus obtained is pure enough for further reactions.
  • a solution of 25 mg (45 ⁇ mol) of the compound from stage f) in 0.5 ml of THF is mixed with 0.4 ml of 1 N sodium hydroxide solution and stirred at 50 ° C. until the reaction is complete.
  • the mixture is then neutralized with 0.4 ml of 1 N hydrochloric acid and the THF is distilled off in vacuo after adding 2 ml of DMSO.
  • the residue is purified by preparative HPLC (YMC Gel ODS-AQ S-5/15 ⁇ m, gradient 0.1% formic acid / acetonitrile).
  • Example 1 The i? -Enantiomer of Example 1 is obtained in an analogous manner starting from 5-1,2-propanediol in step a).
  • Example 1 The S enantiomer of Example 1 is obtained in an analogous manner starting from R-1,2-propanediol in step a).
  • the mixture is stirred at room temperature for 16 h and, after evaporation and absorption in DMSO, the crude mixture is purified by preparative HPLC (YMC Gel ODS-AQ S-5/15 ⁇ m, gradient 0.1% formic acid / acetonitrile).
  • stage e) analogously to example 1, stage f).
  • Example 2 The S enantiomer of Example 2 is obtained in an analogous manner starting from i? -1, 2-propanediol in step a).
  • stage a) analogously to example 1, stage f).
  • stage a) analogously to example 1, stage g).
  • the crude product obtained is chromatographed on silica gel (mobile phase: cyclohexane / ethyl acetate 10: 1 ⁇ 7: 1, v / v).
  • the product-containing fraction is evaporated and mixed in a mixture of pentane and diethyl ether (20: 1, v / v).
  • the precipitated solid is filtered off and dried in vacuo.
  • the mixture is stirred at room temperature for 54 h and, after evaporation and absorption in DMSO, the crude mixture is purified by preparative HPLC (YMC Gel ODS-AQ S-5/15 ⁇ m, gradient 0.1% formic acid / acetonitrile).
  • stage b) analogously to example 1, stage d).
  • stage c) analogously to example 1, stage e).
  • stage d) analogously to example 1, stage f).
  • stage e The title compound is obtained from stage e) analogously to example 1, stage g).
  • human cell lines H4, HEK293
  • H4, HEK293 human cell lines which stably overexpress the 695 amino acid long, neuronal splice variant of human APP.
  • the familial Alzheimer double mutation "Swedish” was also introduced, in which the lysine and methionine residues at positions 595 and 596 of the APP695 molecule are replaced by the amino acids asparagine and leucine.
  • the cells were cultivated in "Dulbecco's Modified Eagles Medium” (DMEM, with 4500 mg / 1 glucose, 110 mg / 1 sodium pyruvate, 5 vol.% fetal calf serum (FCS), 1% non-essential amino acids), to which the selection marker geniticin G418 was added was [all cell culture methods were carried out according to standard methods; Sambrook, J., Fritsch, E.F., and Maniatis, T. (1989) Molecular cloning: A laboratory manual. Cold Spring Harbor Laboratory Press]. In order to test the effect of substances on the inhibition of APP processing, approximately 20,000 cells were diluted in a 96-multitite plate.
  • DMEM Dulbecco's Modified Eagles Medium
  • the culture medium was removed and replaced with a biotin- and senime-free medium in which the substances were diluted so that a concentration of 10 ⁇ M was achieved with a dimethyl sulfoxide (DMSO) content of 0.5%. 0.5% DMSO was used as a control.
  • DMSO dimethyl sulfoxide
  • 0.5% DMSO was used as a control.
  • dose-effect relationships of substances that showed an inhibition of Aß generation were investigated by using different concentrations. After 16 hours the supernatant was removed and analyzed.
  • the following components were used for the detection of the total amount of Aß: 50 ⁇ l of cell culture supernatant were treated with 25 ⁇ l of biotinylated antibody 4G8 (recognizes amino acids 17-25 of Aß), 25 ⁇ l of ruthenium complex-labeled antibody 6E10 (recognizes the N-terminus of Aß) and 50 ul magnetic streptavidin-coupled beads.
  • the following components were used for the detection of Aß40: 50 ⁇ l of cell supernatant were treated with 25 ⁇ l of biotinylated antibody G2-10 (recognizes the C-terminus of Aß 40), 25 ⁇ l of ruthenium complex-labeled antibody W02 (recognizes the N-terminus of Aß) and 50 ul magnetic streptavidin-coupled beads. A series of dilutions with synthetic Aß 40 was prepared in parallel. The samples were shaken at room temperature and then measured using the IGEN analyzer. Typically, each sample was measured three times in at least two independent experiments. The antibodies and solutions used were made according to the instructions of the analyzer manufacturer, IGEN, Inc. (Gaitersburg, Maryland, USA). The measurement was also carried out according to the manufacturer's instructions. The exemplary embodiments show ICso values of ⁇ 3 ⁇ M in this test.
  • test substances were incubated with rat liver microsomes. These incubations were carried out in a total volume of 1.5 ml at 37 ° C. on a modified Multiprobe E ® robot system (Canberra Packard).
  • NADP final concentration: 1 mM
  • the final acetonitrile concentration in the assay was ⁇ 1%.
  • F ⁇ well-stirred [%] (l- (CL blood well-stirred [L / (hx kg)] / Q H [L / (hx kg)])) x 100.
  • test substances to inhibit cytochrome P 450 isoforms, which are important for metabolism, is automatically examined in 96-well format. Two different assays are used here.
  • recombinant enzymes e.g. CYP1A2, 2C8, 2C9, 2C19, 2D6 or 3A4
  • substrates containing fluorescein or coumarin substructures are used.
  • a substrate concentration and 8 concentrations of the potential inhibitor are used in each case.
  • CYP1A2 phenacetin
  • CYP2C9 diclofenac
  • CYP2D6 dextromethophane
  • CYP3A4 midazolam
  • the compounds according to the invention can be converted into pharmaceutical preparations as follows:
  • Example 1 100 mg of the compound from Example 1, 50 mg lactose (monohydrate), 50 mg corn starch (native), 10 mg polyvinylpyrrolidone (PVP 25) and 2 mg magnesium stearate.
  • the mixture of active ingredient, lactose and starch is granulated with a 5% solution (m / m) of the PVP in water.
  • the granules are dried with the magnesium stearate for 5 min. long mixed.
  • This mixture is ve ⁇ resst with a conventional tablet press (format of the tablet see above).
  • a pressing force of 15 kN is used as a guideline for the compression.
  • a single dose of 100 mg of the compound according to the invention corresponds to 10 ml of oral suspension.
  • Rhodigel is suspended in ethanol, the active ingredient is added to the suspension. The water is added with stirring. The swelling of the Rhodigel is stopped for about 6 hours.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
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Abstract

L'invention concerne des dérivés de phénylsulfonamide et des procédés pour leur production ainsi que l'utilisation desdits dérivés pour le traitement et/ou la prophylaxie de maladies, notamment de la maladie d'Alzheimer.
PCT/EP2004/002248 2003-03-10 2004-03-05 Derives de phenylsulfonamide pour le traitement de la maladie d'alzheimer WO2004080952A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
DE10310288.4 2003-03-10
DE10310288 2003-03-10
DE10341535.1 2003-09-09
DE2003141535 DE10341535A1 (de) 2003-03-10 2003-09-09 Phenylsuflonamid-Derivate

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WO2004080952A1 true WO2004080952A1 (fr) 2004-09-23

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000050391A1 (fr) * 1999-02-26 2000-08-31 Merck & Co., Inc. Nouveaux composes de sulfonamide et utilisations correspondantes

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000050391A1 (fr) * 1999-02-26 2000-08-31 Merck & Co., Inc. Nouveaux composes de sulfonamide et utilisations correspondantes

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