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  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen 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
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  • C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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  • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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  • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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  • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
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Definitions

• the invention relates to new aryl and heteroarylsulfonates and processes for their preparation, and to new aryl and heteroarylsulfonates for treatment and / or
• Prophylaxis of diseases in particular for the treatment of pain and neurodegenerative diseases.
• ⁇ 9 -tetrahydrocannabinol ⁇ 9 -THC
• ⁇ 8 -THC the biologically active components in extracts from the Cannabis sativa plant
• Hashish and are responsible for the effects on the human central nervous system (CNS).
• CNS central nervous system
• Potential historical and contemporary therapeutic uses of cannabis preparations include Analgesia, vomiting, anorexia, glaucoma and movement disorders.
• the CB1 receptor and the CBla splice variant are predominantly located in the central nervous system.
• the CB2 receptor was found predominantly in peripheral tissue, especially in leukocytes, spleen and macrophages.
• CB1 and CB2 receptors have seven transmembrane regions and belong to the family of G protein receptors. Both receptors are negatively coupled via Gj / G 0 protein to adenylate cyclase and possibly negatively coupled to the presynaptic release of glutamate. CB1 receptors are also positively coupled with potassium channels and negatively coupled with N- and Q-type calcium.
• CB1 receptor agonists Several structural classes of CB1 receptor agonists are known to date: classic cannabinoids, such as ⁇ 9 -THC, non-classical cannabinoids, aminoalkyl indoles and eicosanoids.
• classic cannabinoids such as ⁇ 9 -THC
• non-classical cannabinoids non-classical cannabinoids
• aminoalkyl indoles aminoalkyl indoles
• eicosanoids eicosanoids
• WO-A-98/37061, WO-A-00/10967 and WO-A-00/10968 describe substituted aryloxyphenol sulfonic acid esters and their action as cannabinoid receptor agonists.
• EP-A-0 098 448 discloses substituted imidazol-2-yl-phenol alkanesulfonic acid esters and their effect on the contractility of the heart.
• US-A-3,346,612 discloses perfluorooctanesulfonic acid esters of 2- and 4-hydroxybiphenyl as flame retardants.
• the present invention relates to compounds of the general formula (I)
• A represents (C 6 -C ⁇ o) aryl or heteroaryl with 5 to 10 ring atoms
• aryl and heteroaryl are optionally bridged by a saturated or partially unsaturated bridge comprising 3 to 7 bridge atoms selected from the group consisting of carbon, nitrogen, oxygen and sulfur, and where aryl, heteroaryl and the bridge are optionally selected one or more times by radicals selected from the group (-C-C 8 ) alkyl, (C 2 -Cg) -alkenyl, (C 2 - C 8 ) -alkynyl, (-C-C 8 ) -alkoxy, (C] -C 8 ) -al anoyl, (C 3 -C 8 ) -cycloalkyl, halogen, nitro, cyano, hydroxy, trifluoromethoxy, -C0 2 R 2 , -CONR 3 R 4 , -S0 2 NR 5 R 6 , -NR 7 COR 8 , -NR 9 S0 2 R 10 and -NR n R 12 are substituted,
• R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 and R 14 are the same or different and are hydrogen, optionally by hydroxy or ( C ⁇ -C 4) -alkoxy substituertes (C ⁇ -C8) alkyl or (C 3 -C 8) -cycloalkyl,
• D stands for (C 6 -C ⁇ o) arylene or heteroarylene with 5 to 10 ring atoms, wherein
• R 15 is hydrogen, (CC 8 ) alkyl or (C 3 -C 8 ) cycloalkyl, and
• R 1 stands for (C 4 -C 8 ) alkyl, stands for (C 2 -C 8 ) alkyl, the carbon chain being selected from the group -O-, -S-, -SO by one or two heteroatoms or groups - and -S0 2 - is interrupted, represents (C 2 -C 8 ) alkenyl, or represents (C 2 -C 8 ) alkynyl,
• alkyl, alkenyl and alkynyl are optionally substituted one or more times by halogen and / or cyano
• the compounds according to the invention can exist in stereoisomeric forms which either behave like image and mirror image (enantiomers) or do not behave like image and mirror image (diastereomers).
• the invention relates to both
• Enantiomers or diastereomers or their respective mixtures These mixtures of the enantiomers and diastereomers can be separated into the stereoisomerically uniform constituents in a known manner.
• the compounds according to the invention can also be present in the form of their salts. in the
• salts with organic or inorganic bases or acids may be mentioned here.
• Physiologically acceptable salts are preferred in the context of the present invention.
• Physiologically acceptable salts of the compounds according to the invention can be salts of the substances according to the invention with mineral acids, carboxylic acids or Be sulfonic acids. Particularly preferred are, for example, salts with 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, citric acid, fumaric acid, maleic acid or benzoic acid.
• Physiologically acceptable salts can also be metal or ammonium salts of the compounds according to the invention.
• metal or ammonium salts of the compounds according to the invention.
• particular preference is given to Sodium, potassium, magnesium or calcium salts, and ammonium salts derived from ammonia or organic amines, such as ethylamine, di- or
• Triethylamine di- or triethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine, lysine, ethylenediamine or 2-phenylethylamine.
• the present invention also includes ammonium compounds which can be prepared by converting the free amines by means of alkylation.
• the compounds according to the invention can also be present in the form of their hydrates and / or solvates.
• aryl stands for a monovalent, aromatic radical having 6 to 10 carbon atoms.
• Preferred aryl radicals are phenyl and naphthyl.
• (C 6 -C ⁇ o) arylene stands in the context of the invention for a divalent, aromatic radical having 6 to 10 carbon atoms. Examples include: benzene-1,2-diyl, benzene-1,3-diyl, benzene-1,4-diyl, naphthalene-1,2-diyl, naphthalene-1,3-diyl, naphthalene-1,4- diyl. Benzene-diyl (phenylene), in particular benzene-1,3-diyl, is preferred.
• 5- to 10-membered heteroaryl represents monovalent, 5- to 10-membered aromatic radicals containing heteroatoms, which can contain 1 to 4 heteroatoms, which are preferably selected from O, S and N.
• Heteroaryl can be via a Ring carbon or ring heteroatom be bound. The binding preferably takes place via a ring carbon atom.
• Examples include: fur-2-yl, fur-3-yl, thienyl, pyrrol-1-yl, pyrrol-2-yl, pyrrol-3-yl, imidazol-1-yl, imidazol-2-yl, pyrazolyl, Thiazolyl, oxazolyl, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, pyrazinyl, pyrimidinyl, pyridazinyl, indolicenyl, indol-1-yl, indol-2-yl, indol-4-yl, indole- 7-yl, benzo [b] thienyl, benzo [b] furyl, indazolyl, quinolyl, isoquinolyl, naphthyridinyl or quinazolinyl. Pyridyl and quinolyl are preferred.
• 5- to 6-membered heteroaryl stands for monovalent, 5- to 6-membered aromatic radicals containing heteroatoms, which may contain 1 to 4 heteroatoms, which are preferably selected from O, S and N. Binding is preferred via a ring carbon atom. Examples include:
• a saturated or partially unsaturated bridge comprising 3 to 7 bridge atoms, which connects adjacent ring atoms in aryl and heteroaryl, stands for a chain of hydrogen-saturated carbon and / or heteroatoms, which are preferably selected from O, S and N.
• the individual bridge atoms can be connected to one another by single bonds or in part by multiple bonds, preferably double bonds.
• the ring atoms bridged to one another in aryl or heteroaryl can be ortho, meta or peri to one another, ortho being preferred.
• Examples include: propane-1,3-diyl, l-aza-propane-l, 3-diyl, 2-aza-propane-l, 3-diyl, l-thia-propane-l, 3-diyl, 1- Oxa-propane-l, 3-diyl, butane-1,4-diyl, l-aza-4-oxa-butane-l, 4-diyl, l, 4-diaza-butane-l, 4-diyl, but- 2-ene-1,4-diyl, pentane-l, 5-diyl, hexane-l, 6-diyl, heptane-l, 7-diyl.
• bridged aryls or heteroaryls examples include: indan-4-yl, inden-4-yl, Indolin-5-yl, chroman-6-yl, chromen-6-yl, l, 2,3,4-tetrahydronaphthalin-5-yl, 5H-pyrido [2,3-d] [1,2,] oxazin-3 yl.
• the bridge is preferably saturated and the bridge comprises 3 to 5 carbon atoms, it being possible for one of the bridge carbon atoms to be replaced by an oxygen, sulfur or nitrogen atom.
• 5- to 10-membered heteroarylene stands for divalent, 5- to 10-membered, heteroatoms-containing aromatic radicals which can contain 1 to 4 heteroatoms, which can preferably be selected from O, S and N.
• Heteroarylene can Ring carbon and / or ring heteroatoms are bound. The binding preferably takes place via ring carbon atoms. The two adjacent groups can be bound ortho, meta or optionally para to the heteroarylene. Meta is preferred.
• Examples include: furan-2,3-diyl, furan-3,4-diyl, thiophene-2,3-diyl, thiophene-2,4-diyl, thiophene-2,5-diyl, pyrrole-1,2- diyl, pyrrole-2,3-diyl, pyrrole-3,4-diyl, imidazole-diyl, pyrazole-diyl, pyridine-2,3-diyl, pyridine-2,4-diyl, pyridine-3,4-diyl, Pyridine-3,5-diyl, pyridine-3,6-diyl, pyrazine-diyl, pyrimidine-diyl, pyridazine-diyl, indolic-diyl, indole-1,2-diyl, indole-2,3-diyl, ind
• 5- to 6-membered heteroarylene represents divalent, 5- to 6-membered, aromatic radicals containing heteroatoms, which may contain 1 to 4 heteroatoms, which can preferably be selected from O, S and N.
• Heteroarylene can be used Ring carbon and / or ring heteroatoms are bound. The binding preferably takes place via ring carbon atoms. The two adjacent groups can be bound ortho, meta or optionally para to the heteroarylene. Meta is preferred.
• Examples include: furan-2,3-diyl, furan-3,4-diyl, thiophene-2,3-diyl, thiophene-2,4-diyl, thiophene-2,5-diyl, pyrrole-1,2- diyl, pyrrole-2,3-diyl, pyrrole-3,4-diyl, imidazole-diyl, pyrazole-diyl, pyridine-2,3-diyl, pyridine-2,4-diyl, pyridine-3,4-diyl, Pyridine-3,5-diyl, pyridine-3,6-diyl, pyrazine-diyl, pyrimidine-diyl, pyridazine-diyl.
• (Cr-C 8 ) -alkyl or (dC ⁇ -alkyl) stand for a straight-chain or branched alkyl radical with 1 to 8 or 6 carbon atoms.
• a straight-chain or branched alkyl radical with 1 to 6 carbon atoms is preferred - Examples include: methyl, ethyl, n-propyl, isopropyl, t-butyl, n-pentyl and n-hexyl.
• (C 4 -C 6 ) -alkyl represents a straight-chain or branched alkyl radical having 4 to 6 carbon atoms. Examples include: n-butyl, i-pentyl, n-pentyl, hexyl, heptyl or octyl. N-Butyl, n-pentyl and n-hexyl are preferred.
• Partially fluorinated (C 8 -C 8 ) -alkyl in the context of the invention represents a straight-chain or branched alkyl radical having 4 to 8 carbon atoms, the hydrogen atoms of the alkyl radical being partially replaced by fluorine atoms, but the alkyl radical containing at least one hydrogen atom.
• Examples include: 4,4,4-trifluorobut-l-yl, 4,4,4-trifluoro-3-trifluoromethyl-but-l-yl, 5,5,5-trifluoropent-l-yl, 4,4,5,5,5-pentafluoro-pent-l-yl. 4,4,4-Trifluoro-but-l-yl is preferred.
• (C 2 -C 8 ) alkenyl and (C 2 -C 6 ) alkenyl stand for a straight-chain or branched alkenyl radical having 2 to 8 or 6 carbon atoms and 1 or optionally more double bonds.
• a straight-chain or branched alkenyl radical having 2 to 4 carbon atoms is preferred. Examples include: vinyl, allyl, isopropenyl and n-but-2-en-1-yl, n-hex-3-en-1-yl, oct-4-en-2-yl.
• (C 4 -C 6 ) alkenyl represents a straight-chain or branched alkenyl radical having 4 to 6 carbon atoms.
• Examples include: n-but-2-enylyl, i-pentenyl, n-pentenyl, or hexenyl. Preferred are n-but-2-en-l-yl, n-pent-2-en-lyl and n-hex-2-en-l-yl.
• (Cg-CsValkynyl or (C 2 -C 6 ) -alkynyl in the context of the invention stands for a straight-chain or branched alkynyl radical with 2 to 8 or 6 carbon atoms. A straight-chain or branched alkynyl radical with 2 to 4 carbon atoms is preferred. Examples are mentioned : Ethynyl, n-prop-2-in-l-yl and n-but-2-in-l-yl.
• (C 4 -C 6 ) -alkynyl stands for a straight-chain or branched alkynyl radical having 4 to 6 carbon atoms.
• Examples include: n-but-2-ynyl, i-pentynyl, n-pentynyl, or hexynyl.
• Preferred are n-but-2-yn-l-yl, n-pent-2-yn-yl and n-hex-2-yn-yl.
• (C 2 -C 6 ) -alkanediyl represents a straight-chain or branched alkanediyl radical having 2 to 6 carbon atoms.
• a straight-chain or branched alkanediyl radical having 2 to 4 carbon atoms is preferred. Examples include: ethylene, propylene, propane-1,2-diyl, propane-2,2-diyl, butane-1,3-diyl, butane-2,4-diyl, pentane-2,4-diyl, 2- methyl-pentan-2,4-diyl.
• (-C-C 8 ) alkoxy or (C j -C 6 ) alkoxy is within the scope of the invention for a straight-chain or branched alkoxy radical having 1 to 6 carbon atoms.
• a straight-chain or branched alkoxy radical having 1 to 8 or 6 carbon atoms is preferred. Examples include: methoxy, ethoxy, n-propoxy, isopropoxy, t-butoxy, n-pentoxy and n-hexoxy.
• (-CC 8 ) alkanoyl or (-CC 6 ) alkanoyl stands for a straight-chain or branched alkanoyl radical having 1 to 8 or 6 carbon atoms. Examples include: acetyl, propionyl, butyryl, isobutyryl, butylcarbonyl,
• Isobutylcarbonyl pentylcarbonyl and hexylcarbonyl or heprylcarbonyl.
• a straight-chain or branched alkanoyl radical having 1 to 4 carbon atoms is preferred.
• Acetyl and propionyl are particularly preferred.
• (C -C 8 ) cycloalkyl and (C -C 6 ) cycloalkyl stand for a
• Cycloalkyl group with 3 to 8 or 6 carbon atoms examples include: Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl. Cyclopentyl and cyclohexyl are preferred.
• Halogen in the context of the invention includes fluorine, chlorine, bromine and iodine. Chlorine or fluorine are preferred.
• tri- (C 1 -C 6 ) -alkylamines are tertiary amines, the amino nitrogen being substituted by three identical or different alkyl radicals. Examples include: triethylamine, diisopropylethylamine, tri-n-propylamine.
• A represents (C 6 -C ⁇ o) aryl or 5- to 10-membered heteroaryl, aryl and heteroaryl optionally being selected one or more times by radicals selected from the group (-C ⁇ alkyl, (C 2 -C 6 ) - Alkenyl, (C 2 -C 6 ) alkynyl, (CC 6 ) alkoxy, (CC 6 ) alkanoyl, (C 3 -C 6 ) cycloalkyl, halogen, nitro, cyano, hydroxy and trifluoromethoxy are substituted, where ( C 1 -C 6 -alkyl in turn is optionally substituted by halogen or hydroxy,
• D represents phenylene or 5- to 6-membered heteroarylene, phenylene and
• Heteroarylene optionally one or more times by radicals selected from the group (C, -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, (C, -C 6 ) -
• R represents (C 4 -C 8 ) alkyl, or represents (C 2 -Cg) alkyl, the carbon chain being interrupted by one or two heteroatoms selected from the group -O- and -S-, and
• alkyl is optionally substituted one or more times by halogen
• A represents (C 6 -C ⁇ o) aryl or 5- to 10-membered heteroaryl
• aryl, heteroaryl and the bridge optionally one to three times by radicals selected from the group (-C-C 6 ) alkyl, (-C-C 6 ) -
• R 3 , R 4 , R 7 , R 8 , R 11 , R 12 , R 13 and R 14 are the same or different and are hydrogen, optionally substituted by hydroxy or (-C-C 4 ) - alkoxy (-C-C 6 ) - Is alkyl or (C 3 -C 8 ) cycloalkyl,
• D represents phenylene or 6-membered heteroarylene, where arylene and
• Heteroarylene optionally substituted one to three times by radicals selected from the group (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy, halogen, nitro, cyano, trifluoromethyl and trifluoromethoxy,
• R represents optionally partially fluorinated (C 4 -C 8 ) alkyl
• A represents phenyl, indanyl or 1,2,3,4-tetrahydronaphthyl
• D represents 1,3-phenylene, phenylene optionally being substituted up to two times by radicals selected from the group (C] -C) - alkyl, halogen, cyano, trifluoromethyl and trifluoromethoxy,
• R 1 represents 4,4,4-trifluorobut-1-yl or n-pentyl
• X 1 represents a leaving group
• X 2 represents a radical selected from the group -B (OR 16 ) 2 , -SnR 17 3 , -ZnR 18 and SiR 19 Cl 2 , in which
• R 16 represents hydrogen or (-CC 6 ) - alkyl, or zzwweeii RR 1166 --RReesstte together mean (C 2 -C 6 ) alkanediyl or benzene-1,2-diyl, and
• R 17 , R 18 and R 19 are (dC 6 ) -alkyl
• X is a suitable leaving group
• Inert solvents in the sense of the invention are those solvents which do not change or change only insignificantly under the chosen reaction conditions.
• Inert solvents suitable for process [A] are, for example, ethers such as diethyl ether, glycol mono- or dimethyl ether, dioxane or tetrahydrofuran, or hydrocarbons such as benzene, p-cresol, toluene, xylene, cyclohexane or petroleum fractions or halogenated hydrocarbons such as methylene chloride, Chloroform, carbon tetrachloride, or dimethyl sulfoxide, dimethylformamide, hexamethylphosphoric triamide, ethyl acetate, pyridine, triethylamine or picoline.
• ethers such as diethyl ether, glycol mono- or dimethyl ether, dioxane or tetrahydrofuran
• hydrocarbons such as benzene, p-cresol, toluene, xylene, cyclohexane or petroleum fractions or halogenated hydro
• Methylene chloride, methylene chloride / water, tetrahydrofuran, dioxane and dioxane / water are particularly preferred.
• Suitable bases for reaction [A] are organic amines, in particular tri- (C 1 -C 6 ) alkylamines, such as, for example, triethylamine or diisopropylethylamine, or heterocycles, such as pyridine, methylpiperidine, piperidine or N-methylmorpholine, alkali metal or.
• Alkaline earth metal hydroxides or carbonates such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate or alcohols, such as sodium methoxide or sodium ethanolate. Triethylamine and sodium hydroxide are preferred.
• the bases are generally used in an amount of 0.1 mol to 5 mol, preferably 1 mol to 3 mol, in each case based on 1 mol of the compounds of the general formula (II).
• process [A] can also be carried out in the presence of a phase transfer catalyst.
• Suitable phase transfer catalysts are e.g. Ammonium salts, preferably tetrabutylammonium bromide.
• Suitable leaving group X 1 is, for example, a halogen, preferably chlorine, or a sulfonato group, preferably triflate.
• the reactions can be carried out at normal pressure, but also at elevated or reduced pressure (e.g. 0.5 to 3 bar). Generally one works at normal pressure.
• Process [A] is carried out in a temperature range from 0 ° C. to 100 ° C., preferably at 0 ° C. to 30 ° C. and under normal pressure.
• organic solvents such as ethers, such as e.g. Diethyl ether, glycol mono- or dimethyl ether, dioxane or tetrahydrofuran, or hydrocarbons such as benzene, p-cresol, toluene, xylene, cyclohexane or petroleum fractions or halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, or dimethyl sulfoxide, dimethylformamide, triamethylethylphosphide, Pyridine, triethylamine or picoline. It is also possible to use mixtures of the solvents mentioned, if appropriate also with water.
• ethers such as e.g. Diethyl ether, glycol mono- or dimethyl ether, dioxane or tetrahydrofuran
• hydrocarbons such as benzene, p-cresol, toluene, xylene, cyclohe
• Dimethoxyethane is particularly preferred.
• palladium catalysts examples include Pd (II) compounds, such as Cl 2 Pd (PPh 3 ) 2 and Pd (OAc) 2 , or Pd (0) compounds, such as Pd (PPh 3 ) 4 and Pd 2 (dba ) 3 .
• Alkali metal carbonates and hydrogen carbonates in particular sodium carbonate, alkali metal hydroxides, in particular sodium hydroxide, or organic amines, in particular tri- (C 1 -C 6 ) -alkylamines, such as, for example, triethylamine, are preferred as bases for the process [B].
• the leaving group X 3 can be, for example, halogen, preferably bromine or iodine, or a triflate.
• the bases are generally used in an amount of 0.1 mol to 5 mol, preferably from 1 mol to 3 mol, in each case based on 1 mol of the compounds of the general formula (IV).
• the reactions can be carried out at normal pressure, but also at elevated or reduced pressure (e.g. 0.5 to 5 bar). Generally one works at normal pressure.
• the reactions are carried out in a temperature range from -20 ° C to 120 ° C, preferably at 0 ° C to 90 ° C.
• Derivatizations of reaction products of reactions [A] or [B] are carried out according to customary methods and include reduction, oxidation, hydrolysis and / or condensation.
• X 4 has the meaning given for X 3 and is the same as or different from it,
• X 5 has the meaning given for X 2 and is the same as or different from it,
• R 20 represents a suitable hydroxyl protective group, preferably methyl, benzyl, allyl, methoxymethyl, 2-trimethylsilylethoxymethyl or trimethylsilyl,
• X 6 has the meaning given for X 2 and is the same as or different from it,
• X 7 has the meaning given for X 3 and is the same as or different from it,
• R 21 has the meaning given for R 20 and is the same as or different from it
• X has the meaning given for X, and R 22 for (-CC 8 ) alkyl, (C 2 -C 8 ) alkenyl, (C 2 -C 8 ) alkynyl, trifluoromethyl or
• X has the meaning given for X
• R 23 has the meaning given above for R 22 .
• R 24 has the meaning given above for R 22 .
• the compounds of the general formulas (VI) and (IX) are commercially available, known from the literature or can be obtained using processes known from the literature (see, for example, J. March, Advanced Organic Chemistry ', 4 th Ed., Wiley, 1992, pages 531-534 or the literature cited therein). If X 4 or X 7 stand for triflate, the compounds of the general formulas (VI) and (IX) can be obtained from the corresponding alcohols in a known manner (for the use of triflates as leaving groups, see, for example, Synth.
• the compounds of the general formulas (VII) and (VIII) are commercially available, known from the literature, or can be synthesized analogously to processes known from the literature (cf., for example, for aromatic boronic acids or boronic acid esters: J.Chem.Soc.C 1966, 566; J Org.Chem. 1973, 38, 4016; J Org. Chem. 1995, 60, 7508; Tetrahedr. Lett. 1997, 3447; or for tributyltin compounds: Tetrahedr.
• the invention relates to compounds of the general formula (I)
• A represents (C 6 -C ⁇ o) aryl or 5- to 10-membered heteroaryl
• ring atoms in aryl and heteroaryl are optionally substituted by a saturated or partially unsaturated bridge comprising 3 to 7 bridge atoms selected from the group carbon, nitrogen, oxygen and sulfur are bridged, and
• aryl, heteroaryl and the bridge are optionally mono- or polysubstituted by radicals selected from the group (C ⁇ -C8) alkyl, (C 2 -C 8) -alkenyl, (C 2 -
• R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 and R 14 are the same or different and hydrogen, optionally by hydroxy or
• (dC 4 ) alkoxy is substituted (dC 8 ) alkyl or (C 3 -C 8 ) cycloalkyl
• D stands for (C 6 -C ⁇ o) arylene or 5- to 10-membered heteroarylene, arylenes and heteroarylene optionally being selected one or more times by radicals selected from the group (C ⁇ -C 8 ) -alkyl, (C 2 - C 8 ) alkenyl, (C 2 -C 8 ) alkynyl, (CC 8 ) alkoxy, (C ⁇ -Cg) alkanoyl, (C -C 8 ) cycloalkyl, halogen, nitro, cyano, hydroxy, trifluoromethyl, Trifluoromethoxy and -C0 R 15 are substituted,
• R 15 is hydrogen, (CC 8 ) alkyl or (C 3 -C 8 ) cycloalkyl, and
• R 1 represents (C 3 -C 8 ) alkyl, stands for (C 2 -Cg) alkyl, the carbon chain being interrupted by one or two heteroatoms or groups selected from the group -O-, -S-, -SO- and -S0 2 -, for (C 2 -C 8 ) -alkenyl or (C 2 -C 8 ) -alkynyl,
• alkyl, alkenyl and alkynyl are optionally substituted one or more times by halogen and / or cyano
• A represents (C 6 -C ⁇ o) aryl or 5- to 10-membered heteroaryl
• aryl and heteroaryl are optionally selected one or more times by radicals selected from the group (dC ⁇ -alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, (C ⁇ -C 6 ) alkoxy, (C 6 -C 6 ) cycloalkyl, halogen, nitro, cyano, hydroxy and trifluoromethoxy are substituted, where (C 6 -C 6 ) alkyl in turn is optionally substituted by halogen or hydroxy,
• D represents phenylene or 5- to 6-membered heteroarylene, phenylene and
• Heteroarylene optionally one or more times by radicals selected from the group (C, -C 6 ) alkyl, (C, -C 6 ) alkenyl, (C 1 -C 6 ) alkynyl, (C, -C 6 ) - Alkoxy, (-CC 6 ) alkanoyl, (C 3 -C 6 ) cycloalkyl, halogen, nitro, cyano,
• R 1 represents (C 3 -C 8 ) alkyl
• alkyl is optionally substituted one or more times by halogen.
• R 1 stands for (C 4 -C 6 ) alkyl, the carbon chain optionally being interrupted by one or two heteroatoms or groups selected from the group -O-, -S-, -SO- and -SO 2 -, for ( C 4 -C 6 ) alkenyl, or represents (C 4 -C 6 ) alkynyl, where alkyl, alkenyl and alkynyl are optionally substituted one or more times by halogen and / or cyano,
• alkyl, alkenyl and alkynyl are not perfluorinated.
• R 1 means 4,4,4-trifluorobut-l-yl or n-pentyl.
• the compounds according to the invention show an unforeseeable, valuable pharmacological spectrum of action.
• Pain and neurodegenerative diseases in particular for the treatment of cancer-induced pain and chronic neuropathic pain, such as, for example, in diabetic neuropathy, post-herpetic neuralgia, peripheral nerve damage, central pain (as a result of cerebral ischemia) and trigeminal neuralgia, and other chronic pain, such as
• Lumbago lower back pain or rheumatic pain.
• the compounds according to the invention are also suitable for the therapy of primary and / or secondary pathological conditions in the brain, for example during or after cerebral vasospasm, migraine, spasticity, hypoxia and / or
• primary brain diseases such as convulsions and arterosclerotic and / or arteriosclerotic changes.
• neurodegenerative diseases such as Alzheimer's, Parkinson's or Huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis (ALS), neurodegeneration due to acute and / or chronic, viral or bacterial infections and multi-infarct dementia are also suitable for the compounds according to the invention.
• the substances according to the invention are also suitable for the treatment of diseases which are caused by bacterial and / or viral infection which are based on direct and / or indirect changes in the immune system or on faulty controls with the participation of the immune system, such as e.g. for local or systemic autoimmune diseases (e.g. lupus erythematosus in all its variants), inflammatory and / or autoimmune-related diseases of the
• Joints e.g. primarily chronic polyarthritis, traumatic inflammation
• inflammatory and / or autoimmune-related diseases of the bones and muscles e.g
• Antigens and the central nervous system (e.g. multiple sclerosis, Alzheimer's disease, psychiatric disorders) as well as the sensory organs, primary and / or secondary and / or autoimmunological disorders of the hematopoietic system and the immune system (e.g. rejection reactions, AIDS) itself, as well as skin disorders inflammatory and / or immunological genesis in humans and animals.
• the central nervous system e.g. multiple sclerosis, Alzheimer's disease, psychiatric disorders
• the sensory organs e.g. multiple sclerosis, Alzheimer's disease, psychiatric disorders
• primary and / or secondary and / or autoimmunological disorders of the hematopoietic system and the immune system e.g. rejection reactions, AIDS
• these substances act on the indirect symptoms of these diseases, e.g. Pain.
• the compounds according to the invention are notable for high metabolic stability and high oral bioavailability. This makes them particularly suitable for oral therapy.
• Receptors can be shown with the following biological assays:
• test protocol was used for the substance screening: The control cultures were grown in 50% Dulbecco's modified Eagle Medium / 50% F-12 (DMEM / F12) with 10% FCS at 37 ° C under 10% CO 2 and each after 2 split up to 3 days 1:10. Test cultures were sown with 5000 cells per well in 96-well plates and grown for 70 hours at 37 ° C. The cultures were then carefully washed with phosphate-buffered saline and reconstituted with serum-free Ultra-CHO medium (Bio-Whittaker). The substances dissolved in DMSO were diluted 1 x in medium and pipetted to the test cultures (maximum DMSO final concentration in the test mixture: 0.5%).
• luciferase substrate solution 2.5 mM ATP, 0.5 mM luciferin,
• Examples 3 and 17 in this test show ICsQ values of 2.4 nM and 16 nM, respectively.
• CH01uc9 cells were stably transfected with the human CB2 receptor. Transfection, clone selection and test development were carried out analogously to the work with the rat CBl receptor. The following test protocol was used for the pharmacological characterization of the cells and for substance testing:
• the starch cultures were grown in 50% Dulbecco's modified Eagle Medium 50% F-12 (DMEM / F12) with 10% FCS at 37 ° C under 10% CO 2 and split 1:10 after every 2 to 3 days.
• Test cultures were seeded with 5000 cells per well in 96-well plates in DMEM / F12 medium with 5% FCS and grown for 70 hours at 37 ° C. The medium was then removed from the cultures and replaced with serum-free Ultra-CHO medium (Bio-Whittaker). The substances dissolved in DMSO (200x final concentration) were pipetted into the test cultures (maximum DMSO final concentration in the test mixture: 0.5%) and 20 minutes later, forskolin was added. The cultures were then incubated in an incubator at 37 ° C.
• lysis reagent 25 mM trisphosphate, pH 7.8 with 2 mM DTT, 10% glycerol, 3% Triton X100.
• IC 50 values were calculated using the GraphPad Prism TM program (Hill equation; specifically: one site competition). 3. Binding to rat cortex membranes
• Membrane protein is prepared from different tissues or cells using standard methods. Buffer, labeled ligand, DMSO or test substance are pipetted together, then 100 ⁇ g protein are added, the mixture is mixed well and incubated for 60 min at 30 ° C. in a water bath. After the incubation period, the reaction is stopped by adding ice-cold incubation buffer to each tube. After filtering, wash with 3/4 ml incubation buffer. The filters are transferred to minivials, the radioactivity is combined in one
• the metabolic stability of the compounds according to the invention can be measured in rat liver microsomes (analogously to J. Ph ⁇ rm ⁇ col. Exp. Ther. 1997, 283, 46-58).
• the substance is incubated in a low concentration of microsomal protein for 15 minutes with the addition of cofactors at 37 ° C.
• bioavailability of the compounds according to the invention and further pharmacokinetic parameters can be determined in vivo in the following way: 5.
• the substance is administered as a bolus via a throat tube.
• the blood is centrifuged and the plasma is suitably prepared for analysis (LC-MS-MS).
• the plasma is kept at ⁇ -15 ° C until analysis.
• Microsomal data (rat liver microsomes) predict a maximum possible availability of up to 100%.
• Iv data (dose: 0.3mg / kg): CL: 3.11 / h / kg, V ss : 5.81 / kg, t, / 2 : 2.2h.
• test substance p.o.
• a control group receives, likewise p.o., only the solvent of the test substances (Cremophore EL 1-10% + Aqua Dest.).
• Body temperature is increased 120 and 240 minutes after p.o. -Application measured.
• the group size per dose is 5-7 animals (rats).
• Nerves proximal to the axotomy site were ligated. Control animals are given a sham operation. After the operation, the axotomized animals develop chronic mechanical allodynia and thermal hyperalgesia.
• Thermal hyperalgesia can be determined by measuring the latency time within which a rat removes a paw from the area of a radiant heat source (Plantartest, Ugo Basile (Milan)).
• the substance is administered at different times before the pain test via different application routes (i.v., i.p., p.o., i.t, i.c.v., transdermal).
• Example 2 reduces the hyperalgesia in the model at a minimally effective dose of 1 mg / kg, p.o. (acute application, 60 minutes before test).
• the suitability of the compounds according to the invention for example for the treatment of neurodegenerative diseases, can be shown in the model of permanent focal cerebral ischemia in the rat (MCA-O) or in the model of the subdural hematoma in the rat (SDH) (WO-A-98/37061, S.60f).
• Parkinson's disease The degeneration of the dopaminergic nigrostriatal and striatopallidal neurotransmission is the main characteristic of Parkinson's disease.
• the clinical picture of Parkinson's disease can be largely in one
• Animal model can be simulated, in which the neurotoxin 6-OH-DA is injected intracerebrally in rats.
• mice Male rats (Harlan Winkelmann, Germany; weight at the start of the experiment: 200-250 g) were used for the experiments described. The experimental animals were kept under controlled conditions (air humidity, temperature) and a 12 hour light-dark cycle. The animals had - unless they were in an experiment - free access to water and feed.
• the lesion of the nigrostriatal neurotransmission occurred by a unilateral, single injection of 8 ⁇ g 6-OH-DA HBr (Sigma, St. Louis, MO, USA), dissolved in 4 ⁇ l of a 0.01% ascorbic acid saline solution. The solution was slowly injected at 1 ⁇ l / min. The coordinates of the injection according to König and Klippel are: 2.4 mm anterior, 1.49 mm lateral, -2.7 mm ventral. After the injection, the injection needle was left in situ for a further 5 minutes in order to facilitate the diffusion of the neurotoxin.
• example 2 improves the fine motor skills of the front paws in the staircase test after a dose of 1.0 mg / kg bid po.
• the new active compounds can be converted in a known manner into the customary formulations, such as tablets, dragées, pills, granules, aerosols, syrups, emulsions, suspensions and solutions, using inert, non-toxic, pharmaceutically suitable excipients or solvents.
• the therapeutically active compound should in each case be present in a concentration of about 0.5 to 90% by weight of the total mixture, ie in amounts which are sufficient to achieve the dosage range indicated.
• the formulations are prepared, for example, by stretching the active compounds with solvents and / or carriers, if appropriate using emulsifiers and / or dispersants, it being possible, for example if organic solvents to be used as diluents, to use organic solvents as auxiliary solvents.
• the application is carried out in the usual way, preferably orally, transdermally or parenterally, in particular perlingually or intravenously. However, it can also be done by inhalation via the mouth or nose, for example with the aid of a spray, or topically via the skin.
• Example 40A 2- ⁇ [(Trifluoromethyl) sulfonyl] oxy ⁇ -4-pyridinyl 4,4,4-trifluoro-1-butanesulfonate
• reaction mixture is treated with 1 ml of water and a cartridge filled with 3 g of Extrelut ® NT3 (Merck), filtered, washed well with dichloromethane and the solvent distilled off under reduced pressure.
• the backlog is through
• Example 42 2) prepared from Example 42 by reaction with iron powder in glacial acetic acid / water at 90 ° C.

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