HK1057210A - Aryl and heteroaryl sulfonates - Google Patents

Description

Aryl-and heteroaryl sulfonates

The present invention relates to novel aryl-and heteroaryl sulfonates and processes for their preparation, and to novel aryl-and heteroaryl sulfonates for use in the treatment and/or prevention of diseases, particularly in the treatment of pain disorders and neurodegenerative diseases.

Δ⁹-tetrahydrocannabinol (Δ)⁹-THC) and, to a small extent, Δ⁸-THC is also a bioactive ingredient in extracts of the Cannabis plant (Cannabis sativa) and produces effects on the human Central Nervous System (CNS). Traditional and modern practical therapeutic applications of cannabinoids include in particular analgesia, emesis, anorexia, glaucoma and dyskinesias.

To date, two subtypes and one splice variant of the cannabinoids have been identified. The CB1 receptor and the splice variant CB1a are located mainly in the central nervous system. The CB2 receptor has been found to be present primarily in peripheral tissues, particularly in leukocytes, spleen, and macrophages.

The CB1 and CB2 receptors have 7 transmembrane domains and belong to the family of G protein receptors. Two receptors through G_i/G_oProteins are negatively coupled to adenylate cyclase and possibly to presynaptic release of glutamate. The CB1 receptor is also positively coupled to potassium channels and negatively coupled to N-and Q-type calcium channels.

Several structures of CB1 receptor agonists have been disclosed: classical cannabinoids, e.g. delta⁹-THC; non-classical cannabinoids, aminoalkylindoles and eicosanoids. The latter includes the endogenous CB1 receptor agonist Anandamid.

WO-A-98/37061, WO-A-00/10967 and WO-A-00/10968 describe substituted aryloxy-phenol sulfonates and their use as cannabinoid lipid receptor agonists.

EP-A-0098448 discloses substituted imidazol-2-ylphenol alkanesulfonates and their effect on cardiac contractility.

Derivatives of imidazolyl-and pyrazolyl-phenolsulfonates and their herbicidal and pesticidal action are disclosed in WO-A-92/06962, WO-A-93/15074 and WO-A-94/05633.

US-A-3,346,612 discloses perfluorooctanesulfonates of 2-and 4-hydroxy-biphenyl as inflammatory blockers.

Certain substituted phenol nonafluorobutanesulfonates and butanesulfonates are disclosed in synthetic references J.org.chem.1998, 63, 203-208 and tetrahedrr.Lett.1999, 40, 6871-6874.

The invention relates to compounds of general formula (I) and salts thereof,

A-D-O-SO₂-R¹(I) wherein A represents (C)₆-C₁₀) Aryl or heteroaryl having 5 to 10 ring atoms,

wherein adjacent ring atoms in the aryl and heteroaryl groups optionally pass through a ring containing 3-7 bridging atoms

A saturated or partially unsaturated bridge, said bridge atoms being selected from the group consisting of carbon, nitrogen, oxygen and sulfur,

and

wherein aryl, heteroaryl and said bridge are optionally mono-or polysubstituted by groups selected from

Generation: (C)₁-C₈) Alkyl radicals, (C)₂-C₈) -alkenyl, (C)₂-C₈) -alkynyl, (C)₁-C₈)-

Alkoxy group, (C)₁-C₈) Alkanoyl radical, (C)₃-C₈) Cycloalkyl, halogen, nitro, cyano,

Hydroxy, trifluoromethoxy, -CO₂R²、-CONR³R⁴、-SO₂NR⁵R⁶、-NR⁷COR⁸、-NR⁹SO₂R¹⁰

and-NR¹¹R¹²Wherein (C)₁-C₈) The alkyl radical itself being optionally substituted by halogen, cyano, hydroxy or

-NR¹³R¹⁴The substitution is carried out by the following steps,

wherein

R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹、R¹²、R¹³And R¹⁴Same or different

And represents hydrogen, optionally substituted by hydroxyl or (C)₁-C₄) -alkoxy-substituted (C)₁-C₈) -alkyl radical

Or (a)C₃-C₈) -cycloalkyl, D represents (C)₆-C₁₀) Arylene or heteroarylene having 5 to 10 ring atoms, wherein arylene is

And the heteroarylene group is optionally mono-or polysubstituted with a group selected from: (C)₁-C₈) -an alkyl group,

(C₂-C₈) -alkenyl, (C)₂-C₈) -alkynyl, (C)₁-C₈) -alkoxy, (C)₁-C₈) -alkanoyl

Base, (C)₃-C₈) Cycloalkyl, halogen, nitro, cyano, hydroxy, trifluoromethyl, trifluoro

Methoxy and-CO₂R¹⁵，

Wherein

R¹⁵Represents hydrogen, (C)₁-C₈) -alkyl or (C)₃-C₈) -cycloalkyl, and R¹Is represented by (C)₄-C₈) -an alkyl group,

is represented by (C)₂-C₈) -alkyl, wherein the carbon chain is substituted by 1 or 2 groups selected from-O-, -S-, -SO-and

-SO₂-the heteroatoms or groups of (A) are spaced apart,

is represented by (C)₂-C₈) -alkenyl, or

Is represented by (C)₂-C₈) -an alkynyl group,

wherein alkyl, alkenyl and alkynyl are optionally mono-or polysubstituted with halogen and/or cyano,

except that D is phenylene and R¹A compound of the general formula (I) which is 1, 1, 2, 2, 3,3, 4, 4, 4-nonafluorobutyl, and

with the exception of 1, 1, 2, 2, 3,3, 4, 4, 5, 5, 6,6, 7, 7, 8, 8, 8-heptadecafluoro-1-octanesulfonic acid [1, 1 '-biphenyl ] -4-yl ester and 1, 1, 2, 2, 3,3, 4, 4, 5, 5, 6,6, 7, 7, 8, 8, 8-heptadecafluoro-1-octanesulfonic acid [1, 1' -biphenyl ] -2-yl ester.

The compounds of the invention may exist in stereoisomeric forms which are either image and mirror related (enantiomers) or not image or mirror related (diastereomers). The present invention relates to enantiomers or diastereomers or various mixtures thereof. These mixtures of enantiomers and diastereomers can be separated into stereoisomerically homogeneous components in a known manner.

The compounds of the invention may also exist in the form of their salts. Salts with organic or inorganic bases or acids may generally be included herein.

Within the scope of the present invention, physiologically acceptable salts are preferred. Physiologically acceptable salts of the compounds of the invention may be salts of the substances of the invention with inorganic acids, carboxylic acids or sulfonic acids. Particularly preferred examples are 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 of the invention. Particularly preferred examples are sodium, potassium, magnesium or calcium salts, and ammonium salts derived from ammonia or organic amines, such as ethylamine, di-and triethylamine, di-and triethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine, lysine, ethylenediamine or 2-phenylethylamine.

The invention also includes ammonium compounds that can be made by conversion of the free amine by alkylation.

The compounds of the invention may also exist in the form of their hydrates and/or solvates.

Within the scope of the present invention, the substituents generally have the following meanings:

(C ₆ -C ₁₀ ) -aryl radicalWithin the scope of the present invention, monovalent aromatic radicals having 6 to 10 carbon atoms are meant. Preferred aryl groups are phenyl and naphthyl.

(C ₆ -C ₁₀ ) -arylene radicalWithin the scope of the present invention, denotes divalent aromatic radicals having 6 to 10 carbon atoms. Examples which may be mentioned are: benzene-1, 2-diyl, benzene-1, 3-diyl, benzene-1, 4-diyl, naphthalene-1, 2-diyl, naphthalene-1, 3-diyl and naphthalene-1, 4-diyl. Preference is given to benzenediyl (phenylene), in particular benzene-1, 3-diyl.

5-to 10-membered heteroarylWithin the scope of the present invention are monovalent, 5-to 10-membered, heteroatom-containing aryl groups, which may contain 1 to 4 heteroatoms, preferably selected from O, S and N. The heteroaryl group may be bonded via a ring carbon atom and a ring heteroatom. Preferably via a ring carbon atom. Examples which may be mentioned are: furan-2-yl, furan-3-yl, thienyl, pyrrol-1-yl, pyrrol-2-yl, pyrrol-3-yl, imidazol-1-yl, imidazol-2-yl, pyrazolyl, thiazolyl, oxazolyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrazinyl, pyrimidinyl, pyridazinyl, indolinyl, indol-1-yl, indol-2-yl, indol-4-yl, indol-7-yl, benzo [ b]Thienyl, benzo [ b ]]Furyl, indazolyl, quinolyl, isoquinolyl, naphthyridinyl or quinazolinyl. Pyridyl and quinolyl groups are preferred.

5-to 6-membered heteroarylWithin the scope of the present invention are monovalent, 5-to 6-membered, heteroatom-containing aryl groups which may contain 1 to 4 heteroatoms preferably selected from O, S and N. Bonding via a ring carbon atom is preferred. Examples which may be mentioned are: furan-2-yl, furan-3-yl, thienyl, pyrrol-1-yl, pyrrol-2-yl, pyrrol-3-yl, imidazol-1-yl, imidazol-2-yl, pyrazolyl, thiazolyl, oxazolyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrazinyl, pyrimidinyl, pyridazinyl. Preferably a pyridyl group.

Saturated or partially unsaturated bridges containing 3 to 7 bridge atomsWhich connect adjacent ring atoms in aryl and heteroaryl groups, are within the scope of the inventionDenotes a chain of hydrogen-saturated carbon atoms and/or heteroatoms, preferably selected from O, S and N. The individual bridge atoms may be connected by single bonds or in some cases by multiple bonds, preferably double bonds. The ring atoms of the aryl and heteroaryl groups that are linked together may be in the ortho, meta or para position relative to each other, and are preferably ortho. Examples which may be mentioned are: propane-1, 3-diyl, 1-aza-propane-1, 3-diyl, 2-aza-propane-1, 3-diyl, 1-thia-propane-1, 3-diyl, 1-oxa-propane-1, 3-diyl, butane-1, 4-diyl, 1-aza-4-oxa-butane-1, 4-diyl, 1, 4-diaza-butane-1, 4-diyl, but-2-ene-1, 4-diyl, pentane-1, 5-diyl, hexane-1, 6-diyl, heptane-1, 7-diyl. Examples which may be mentioned of aryl or heteroaryl groups having a bridge are: indan-4-yl, indene-4-yl, indolin-5-yl, chroman-6-yl, chromen-6-yl, 1, 2, 3, 4-tetrahydronaphthalen-5-yl, 5H-pyrido [2, 3-d][1，2]Oxazin-3-yl. The bridge is preferably saturated and contains 3 to 5 carbon atoms, wherein one of the bridge carbon atoms may be replaced by an oxygen, sulfur or nitrogen atom.

5-to 10-membered heteroarylenesWithin the scope of the present invention are meant divalent, 5-to 10-membered, heteroatom-containing aryl groups, which may contain 1-4 heteroatoms, preferably selected from O, S and N. The heteroarylene group may be bonded via a ring carbon atom and/or a ring heteroatom. Bonding via a ring carbon atom is preferred. Two adjacent radicals may be bonded to the heteroarylene in ortho, meta or optionally in para position. The meta position is preferred. Examples which may be mentioned are: 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-3, 4-diyl, pyridine-3, 5-diyl, pyridine-3, 6-diyl, pyrazine-diyl, pyrimidine-diyl, pyridazine-diyl, Indolicen-diyl, indole-1, 2-diyl, indole-2, 3-diyl, indole-4, 5-diyl, Indole-4, 6-diyl, indole-4, 7-diyl, benzo [ b ]]Thiophene-diyl, benzo [ b)]Furan-diyl, indazolin-diyl, quinoline-diyl, isoquinoline-diyl, naphthyridine-diyl orQuinazolin-diyl. Pyridine-diyl and quinoline-diyl are preferred.

5-to 6-membered heteroarylenesWithin the scope of the present invention are meant divalent, 5-to 6-membered, heteroatom-containing aryl groups containing 1-4 heteroatoms preferably selected from O, S and N. The heteroarylene group may be bonded via a ring carbon atom and/or a ring heteroatom. Bonding via a ring carbon atom is preferred. Two adjacent radicals may be bonded to the heteroarylene in ortho, meta or optionally in para position. The meta position is preferred. Examples which may be mentioned are: 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, 5-diyl, pyridine-3, 6-diyl, pyrazine-diyl, pyrimidine-diyl, pyridazine-diyl.

(C ₁ -C ₈ ) -alkyl or (C) ₁ -C ₆ ) -alkyl radicalIn the context of the present invention, straight-chain or branched alkyl radicals having 1 to 8 or 6 carbon atoms are meant. Straight or branched chain alkyl groups having 1 to 6 carbon atoms are preferred. Examples which may be mentioned are: methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-pentyl and n-hexyl.

(C ₄ -C ₆ ) -alkyl radicalWithin the scope of the present invention, straight-chain or branched alkyl radicals having from 4 to 6 carbon atoms are meant. Examples which may be mentioned are: n-butyl, isopentyl, n-pentyl, hexyl, heptyl, or octyl. N-butyl, n-pentyl and n-hexyl are preferred.

Partially fluorinated (C) ₄ -C ₈ ) -alkyl radicalWithin the scope of the present invention denotes straight-chain or branched alkyl groups having 4 to 8 carbon atoms, in which some of the hydrogen atoms of the alkyl group have been replaced by fluorine atoms but the alkyl group isContaining at least one hydrogen atom. Examples which may be mentioned are: 4, 4, 4-trifluorobut-1-yl, 4, 4, 4-trifluoro-3-trifluoromethyl-but-1-yl, 5, 5, 5-trifluoro-pent-1-yl, 4, 4, 5, 5, 5-pentafluoro-pent-1-yl. Preference is given to 4, 4, 4-trifluorobut-1-yl.

(C ₂ -C ₈ ) -alkenyl and (C) ₂ -C ₆ ) -alkenyl radicalWithin the scope of the present invention are straight-chain or branched alkenyl groups having 2 to 8 or 6 carbon atoms and one or optionally more double bonds. Straight-chain or branched alkenyl groups having 2 to 4 carbon atoms are preferred. Examples which may be mentioned are: 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 radicalIn the context of the present invention, straight-chain or branched alkenyl groups having 4 to 6 carbon atoms are meant. Examples which may be mentioned are: n-but-2-en-1-yl, isopentenyl, n-pentenyl or hexenyl. Preference is given to n-but-2-en-1-yl, n-pent-2-en-1-yl and n-hex-2-en-1-yl.

(C ₂ -C ₈ ) -alkynyl or (C) ₂ -C ₆ ) -alkynyl radicalWithin the scope of the present invention is meant straight-chain or branched alkynyl groups having 2 to 8 or 6 carbon atoms. Straight-chain or branched alkynyl groups having 2 to 4 carbon atoms are preferred. Examples which may be mentioned are: ethynyl, n-prop-2-yn-1-yl and n-but-2-yn-1-yl.

(C ₄ -C ₆ ) -alkynyl radicalWithin the scope of the present invention, straight-chain or branched alkynyl radicals having from 4 to 6 carbon atoms are meant. Examples which may be mentioned are: n-but-2-yn-1-yl, isopentynyl, n-pentynyl or hexynyl. Preference is given to n-but-2-yn-1-yl, n-pent-2-yn-1-yl and n-hexyl-2-yn-1-yl.

(C ₂ -C ₆ ) -alkanediylWithin the scope of the present invention, straight-chain or branched alkanediyl having from 2 to 6 carbon atoms is indicated. Preference is given to linear or branched alkanediyl having from 2 to 4 carbon atoms. Examples which may be mentioned are: ethylene, propylene, propane-1, 2-diyl, propane-2, 2-diyl, butane-1, 3-diyl, butane-2, 4-diyl, pentane-2, 4-diyl and 2-methyl-pentane-2, 4-diyl.

(C ₁ -C ₈ ) -alkoxy or (C) ₁ -C ₆ ) -alkoxy radicalWithin the scope of the present invention, represents straight-chain or branched alkoxy having 1 to 6 carbon atoms. Preference is given to linear or branched alkoxy having 1 to 8 or 6 carbon atoms. Examples which may be mentioned are: methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, n-pentoxy and n-hexoxy.

(C ₁ -C ₈ ) -alkanoyl or (C) ₁ -C ₆ ) -alkanoyl radicalWithin the scope of the present invention are represented straight-chain or branched alkanoyl groups having 1 to 8 or 6 carbon atoms. Examples which may be mentioned are: acetyl, propionyl, butyryl, isobutyryl, butylcarbonyl, isobutylcarbonyl, pentylcarbonyl, and hexylcarbonyl or heptylcarbonyl. Preference is given to straight-chain or branched alkanoyl having 1 to 4 carbon atoms. Acetyl and propionyl are particularly preferred.

(C ₃ -C ₈ ) -cycloalkyl and (C) ₃ -C ₆ ) -cycloalkyl radicalCycloalkyl radicals having 3 to 8 or 6 carbon atoms are meant within the scope of the present invention. Examples which may be mentioned are: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexylMesityl, cycloheptyl, cyclooctyl. Cyclopentyl and cyclohexyl are preferred.

Halogen elementFluorine, chlorine, bromine and iodine are meant within the scope of the invention. Chlorine or fluorine are preferred.

Tri- (C) ₁ -C ₆ ) Alkyl aminesTertiary amines in which the amino nitrogen is substituted by three identical or different alkyl groups are represented within the scope of the invention. Examples which may be mentioned are: triethylamine, diisopropylethylamine, tri-n-propylamine.

Preferred are compounds of the general formula (I) wherein A represents (C) and salts thereof₆-C₁₀) -aryl or 5-to 10-membered heteroaryl,

wherein aryl and heteroaryl are optionally mono-or polysubstituted with groups selected from: (C)₁-C₆)-

Alkyl, (C)₂-C₆) -alkenyl, (C)₂-C₆) -alkynyl, (C)₁-C₆) -alkoxy, (C)₁-

C₆) Alkanoyl radical, (C)₃-C₆) Cycloalkyl, halogen, nitro, cyano, hydroxy and trifluoromethyl

Oxy radical, wherein (C)₁-C₆) Alkyl is itself optionally substituted by halogen or hydroxy, D represents phenylene or 5-to 6-membered heteroarylene, where phenylene and heteroarylene are optionally substituted

One or more substituents selected from the group consisting of: (C)₁-C₆) Alkyl radicals, (C)₂-C₆) -an alkenyl group,

(C₂-C₆) -alkynyl, (C)₁-C₆) -alkoxy, (C)₃-C₆) -cycloalkyl, halogen, nitro,

Cyano, trifluoromethyl and trifluoromethoxy, and R¹Is represented by (C)₄-C₈) -alkyl, or

Is represented by (C)₂-C₈) -alkyl, wherein the carbon chain is interrupted by 1 or 2 heteroatoms selected from-O-and-S-)

Spaced apart, and

wherein alkyl is optionally mono-or polysubstituted with halogen,

except that D is phenylene and R¹A compound of the general formula (I) which is 1, 1, 2, 2, 3,3, 4, 4, 4-nonafluorobutyl, and

with the exception of 1, 1, 2, 2, 3,3, 4, 4, 5, 5, 6,6, 7, 7, 8, 8, 8-heptadecafluoro-1-octanesulfonic acid [1, 1 '-biphenyl ] -4-yl ester and 1, 1, 2, 2, 3,3, 4, 4, 5, 5, 6,6, 7, 7, 8, 8, 8-heptadecafluoro-1-octanesulfonic acid [1, 1' -biphenyl ] -2-yl ester.

Preference is likewise given to compounds of the general formula (I) and their salts in which A denotes a group having the formula (C)₆-C₁₀) Aryl or heteroaryl having 5-to 10-members,

wherein adjacent ring atoms in the aryl and heteroaryl groups optionally contain 3 to 5 bridging carbon atoms

Are connected to a saturation bridge of

Wherein aryl, heteroaryl and said bridge are optionally mono-to trisubstituted by groups selected from

Generation: (C)₁-C₆) Alkyl radicals, (C)₁-C₆) -alkoxy, (C)₁-C₆) Alkanoyl, halogen, nitro

Radical, cyano, hydroxy, trifluoromethoxy, -CONR³R⁴、-NR⁷COR⁸and-NR¹¹R¹²，

Wherein (C)₁-C₆) The alkyl radical itself being optionally substituted by halogen, hydroxy or-NR¹³R¹⁴The substitution is carried out by the following steps,

wherein

R³、R⁴、R⁷、R⁸、R¹¹、R¹²、R¹³And R¹⁴Are the same or different and represent hydrogen, optionally

By hydroxy-or (C)₁-C₄) -alkoxy-substituted (C)₁-C₆) -alkyl or (C)₃-C₈) -cycloalkanes

And D represents phenylene or 6-membered heteroarylene, wherein phenylene and heteroarylene are optionally selected from

The following groups are mono-to trisubstituted: (C)₁-C₄) Alkyl radicals, (C)₁-C₄) Alkoxy, halogen, nitro

A group selected from the group consisting of cyano, trifluoromethyl and trifluoromethoxy,

and R¹Represents optionally partially fluorinated (C)₄-C₈) -an alkyl group.

Particular preference is given to compounds of the formula (I) and salts thereof in which A represents phenyl, indanyl or 1, 2, 3, 4-tetrahydronaphthyl,

wherein said ring is optionally selected from (C)₁-C₄) -alkyl, halogen, cyano, trifluoromethyl

And trifluoromethoxy, D represents 1, 3-phenylene, wherein the phenylene is optionally substituted by a group selected from (C)₁-C₄) -alkyl, halogen,

Cyano, trifluoromethyl and trifluoromethoxy radicals are at most disubstituted,

and R¹Represents 4, 4, 4-trifluorobut-1-yl or n-pentyl.

A process for the preparation of compounds of the general formula (I) has additionally been found, which is characterized in that: [A] a compound of the general formula (II)

A-D-OH (II) wherein

A and D have the abovementioned meanings, with a compound of the formula (III) in an inert solvent in the presence of a suitable base,

X¹-SO₂-R¹(III) wherein X¹Represents a leaving group, and R¹Has the above-mentioned meaning, or [ B]A compound of the general formula (IV)

A-X²(IV) in which A has the abovementioned meaning, and X²Represents a group selected from-B (OR)¹⁶)₂、-SnR¹⁷ ₃、-ZnR¹⁸and-SiR¹⁹Cl₂A group of (1), wherein

R¹⁶Represents hydrogen or (C)₁-C₆) -alkyl, or

Two R¹⁶Together represent (C)₂-C₆) -alkanediyl or benzene-1, 2-diyl, and

R¹⁷、R¹⁸and R¹⁹Is represented by (C)₁-C₆) An alkyl group, with a compound of formula (V) in an inert solvent in the presence of a palladium catalyst and a base,

X³-D-O-SO₂-R¹(V) wherein X³Is a suitable leaving group, and D and R¹Having the above-mentioned meaning, and optionally in [ A]Or [ B]Thereafter, the substituents in the reaction product are derivatized by conventional methods.

The process of the invention can be illustrated, for example, by the following reaction scheme: [ A ]][B]

Inert solvents in the context of the present invention are solvents which do not change or only change negligibly under the selected reaction conditions.

Examples of inert solvents suitable for process [ a ] are ethers, such as diethyl ether, ethylene glycol monomethyl or dimethyl ether, dioxane or tetrahydrofuran; or hydrocarbons, such as benzene, p-cresol, toluene, xylene, cyclohexane or petroleum fractions; or halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride; or dimethyl sulfoxide, dimethylformamide, hexamethylphosphoric triamide, ethyl acetate, pyridine, triethylamine or picoline. Mixtures of the above solvents or two-phase systems with water may additionally be used. Particular preference is given to dichloromethane, dichloromethane/water, tetrahydrofuran, dioxane and dioxane/water.

Is suitable for reaction [ A]The base of (A) is an organic amine, in particular tris (C)₁-C₆) Alkylamines, such as triethylamine or diisopropylethylamine; or a heterocyclic compound 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 an alcohol, such as sodium methoxide or ethoxide. Triethylamine and sodium hydroxide are preferred.

The base is generally used in an amount of from 0.1 to 5 mol, based in each case on 1mol of the compound of the formula (II).

Process [ A ] can also optionally be carried out in the presence of a phase transfer catalyst. An example of a suitable phase transfer catalyst is an ammonium salt, preferably tetrabutylammonium bromide.

Suitable leaving groups X¹Is, for example, halogen, preferably chlorine, or a sulfonate group (sulfonato), preferably trifluoromethanesulfonate.

The reaction can be carried out under normal pressure, but can also be carried out under elevated or reduced pressure (for example 0.5 to 3 bar). Generally at atmospheric pressure.

Process [ A ] is carried out at a temperature of from 0 ℃ to 100 ℃, preferably from 0 ℃ to 30 ℃ and at atmospheric pressure.

Method [ B ] is a reductive coupling of compounds of the general formulae (IV) and (V), as described, for example, in L.S.Hegedus, Organometallics in Synthesis, M.Schlosser, Ed., Wiley, 1994. Palladium-catalyzed reductive coupling reactions with boronic acids ("Suzuki coupling") are disclosed, for example, in: tetrahedron, Lett, 1985, 26, 2667-; chem.Commun.1984, 1287-1289; suzuki and T.N.Mitchell in "Metal-catalyzed cross-linking reactions", Ed.F.Diederich, P.J.Stang, Wiley-VCH, Weinheim 1998, pages 49 and 167.

Examples of inert solvents which prove suitable for the reaction step [ B ] are the following solvents: organic solvents, such as ethers, for example diethyl ether, ethylene glycol mono-or dimethyl ether, dioxane or tetrahydrofuran; or hydrocarbons, such as benzene, p-methyl ether, toluene, xylene, cyclohexane or petroleum fractions; or halogenated hydrocarbons, such as dichloromethane, chloroform, carbon tetrachloride, or dimethyl sulfoxide, dimethylformamide, hexamethylphosphoric triamide, ethyl acetate, pyridine, triethylamine or picoline. Mixtures of the solvents mentioned can additionally be used, optionally also with water. Dimethoxyethane is particularly preferred.

Examples which may be mentioned as palladium catalysts are Pd (II) compounds, e.g. Cl₂Pd(PPh₃)₂And Pd (OAc)₂Or compounds of the Pd (O) type, e.g. Pd (PPh)₃)₄And Pd₂(dba)₃。

For the method [ B]Alkali metal carbonates and bicarbonates, in particular sodium carbonate; alkali metal hydroxides, especially sodium hydroxide; or organic amines, especially tri- (C)₁-C₆) Alkylamines, such as triethylamine.

Leaving group X³Can be, for example, halogen, preferably bromine or iodine, or trifluoromethanesulfonate.

The base is generally used in an amount of from 0.1 to 5 mol, preferably from 1 to 3 mol, based in each case on 1mol of the compound of the formula (IV).

The reaction can be carried out under normal pressure, but can also be carried out under elevated or reduced pressure (for example 0.5 to 3 bar). Normal pressure is generally used.

The reaction is carried out at a temperature of-20 ℃ to 120 ℃, preferably 0 ℃ to 90 ℃.

The derivatization reaction of the reaction product of the reaction [ A ] or [ B ] can be carried out by conventional methods and includes reduction, oxidation, hydrolysis and/or condensation.

The compounds of the formula (II) are known compounds or can be prepared by customary known methods, for example by means of compounds of the formula (VI)

A-X⁴(VI) in which A has the abovementioned meaning, and X⁴Has a pair of X³With the same or different meanings as defined above, with a compound of the general formula (VII)

X⁵-D-O-R²⁰(VII) in which X⁵Has a pair of X²Is as defined in (1), D is as defined above, R is²⁰Represents a suitable hydroxyl-protecting group, preferably methyl, benzyl, allyl, methoxymethyl

2-trimethylsilylethoxymethyl or trimethylsilyl group, under the conditions given for process [ B ], and subsequent deprotection of the hydroxyl protecting group under appropriate conditions.

The introduction of hydroxyl protecting Groups and their elimination is well known (e.g., T.W.Greene, P.G.M.Wuts, 'Protective Groups in Organic Synthesis', 2 nd edition, New York, 1991 and references cited therein; J.Org.Chem.1999, 64, 9719-.

Conversely, the compounds of the formula (II) can also be prepared by reacting compounds of the formula (VIII)

A-X⁶(VIII) in which A has the abovementioned meaning, and X⁶Has a pair of X²Is the same as or different from the latter, with a compound of the general formula (IX)

X⁷-D-O-R²¹(IX) wherein X⁷Has a pair of X³Is defined in and related to the latterOr different, D has the meaning given above, R²¹Has the pair R²⁰Is the same as or different from the latter, in a process [ B ]]Under the conditions given.

In the case where A of the compounds of the formula (II) represents oxazole, thiazole or pyrazole, these compounds may also be prepared by reacting a compound of the formula (X)

H₂N-C(O)-D-O-R²⁰(X) wherein D and R²⁰Each having the above-mentioned meaning, with a compound of the general formula (XI)

X⁸-CH₂-C(O)-R²²(XI) wherein X⁸Has a pair of X³Given meanings, and R²²Is represented by (C)₁-C₈) Alkyl radicals, (C)₂-C₈) Alkenyl, (C)₂-C₈) Alkynyl, trifluoromethyl or

(C₃-C₈) Cycloalkyl to give a compound of the general formula (XII)D, R therein²⁰And R²²Each having the above-mentioned meaning, or a compound of the formula (XIII)

X⁹-CH₂-C(O)-D-O-R²⁰(XIII) wherein X⁹Has a pair of X³Given definitions and D and R²⁰Each having the above-mentioned meaning, with compounds of the general formula (XIV)

R²³-C(S)-NH₂(XIV) wherein R²³Has the pair R²²The meanings given give compounds of the general formula (XV)D, R therein²⁰And R²³Each having the above-mentioned meaning, or a compound of the general formula (XVI)

R²⁴-C(O)-CH₂-C(O)-D-O-R²⁰(XVI) wherein D and R²⁰Each having the above meaning, R²⁴Has the pair R²²With the meanings given, with hydrazine, hydrazine hydrate or hydrazine salts to give compounds of the general formula (XVII)D, R therein²⁰And R²⁴Each having the abovementioned meaning, and finally eliminating the hydroxyl-protecting group R in each of the compounds of the formula (XII), (XV) or (XVII) under suitable conditions²⁰。

The compounds of the formulae (X), (XI), (XIII), (XIV) and (XVI) are commercially available, known from the literature or can be prepared in analogy to known processes from the literature.

The compounds of the general formula (II) in which A and D are linked via a heteroatom (for example a nitrogen atom) and a carbon atom are known compounds and can be obtained in analogy to known methods from the literature: for example, the synthesis of 1-phenylpyrazole derivatives is disclosed in K.Kirschke, Methoden der Organischen Chemie (method of organic chemistry) (Houben-Weyl) (E.Schaumann eds.) Thieme Verlag, Stuttgart 1994, p. 399-763; the synthesis of 1-phenylpyrrole derivatives is disclosed in heterocyles 1996, 75-82 or chem. pharm. Bull.1973, 21, 1516; the synthesis of 1-phenylimidazole derivatives is disclosed in J.Med.chem.1989, 32, 575-.

The compounds of the formulA (III) are commercially available, known in the literature or can be synthesized analogously to known methods in the literature (see, for example,. J.Chem.Soc.C 1968, 1265; chem.Ber.1967, 100, 1696; fluoroalkanesulfonyl chlorides are obtainable, for example, by the methods described in WO-A-98/37061 or DE-A-1942264).

Compounds of the formulae (VI) and (IX) when X⁴And X⁷Iodine or bromine, are commercially available, known in the literature or can be obtained by methods described in the literature (see, for example, J. March, 'Advanced Organic Chemistry', 4 th edition, Wiley, 1992, page 531-534 and references cited therein). When X is present⁴And X⁷When representing triflates, the compounds of the formulae (VI) and (IX) can be obtained in a known manner from the correspondingAlcohols (using triflate as a leaving group, see e.g.Synth. 1990, 1145-1147). The corresponding alcohols are commercially available, known in the literature or can be obtained by methods known in the literature (for example, reference is made to the synthesis of phenols, see for example J. March, 'Advanced Organic Chemistry', 4 th edition, Wiley, 1992, page 1295 and the references cited therein).

The compounds of the general formulae (VII) and (VIII) are commercially available, known from the literature or can be prepared analogously to known methods from the literature (see, for example, for aromatic boronic acid compounds and hydrocarbylboronic acid esters J.chem.Soc.C 1966, 566; J.org.chem.1973, 38, 4016; J.org.chem.1995, 60, 7508; tetrahedrr.Lett.1997, 3447; or for tributyltin compounds tetrahedrr.Lett.1990, 31, 1347).

In another aspect, the present invention relates to compounds of the general formula (I) wherein A represents (C) and salts thereof for the treatment and/or prevention of diseases₆-C₁₀) -aryl or 5-to 10-membered heteroaryl,

wherein adjacent ring atoms in the aryl and heteroaryl groups optionally pass through a ring containing 3-7 bridging atoms

A saturated or partially unsaturated bridge, said bridge atoms being selected from the group consisting of carbon, nitrogen, oxygen and sulfur,

and

wherein aryl, heteroaryl and said bridge are optionally mono-or polysubstituted by groups selected from

Generation: (C)₁-C₈) Alkyl radicals, (C)₂-C₈) -alkenyl, (C)₂-C₈) -alkynyl, (C)₁-C₈)-

Alkoxy group, (C)₁-C₈) Alkanoyl radical, (C)₃-C₈) Cycloalkyl, halogen, nitro, cyano,

Hydroxy, trifluoromethoxy, -CO₂R²、-CONR³R⁴、-SO₂NR⁵R⁶、-NR⁷COR⁸、-NR⁹SO₂R¹⁰

and-NR¹¹R¹²Wherein (C)₁-C₈) The alkyl radical itself being optionally substituted by halogen, cyano, hydroxy or

-NR¹³R¹⁴Is substituted in which R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹、R¹²、R¹³And R¹⁴Are the same or different and

and represents hydrogen, optionally substituted by hydroxyl or (C)₁-C₄) -alkoxy-substituted (C)₁-C₈) -alkyl or

(C₃-C₈) -cycloalkyl, D represents (C)₆-C₁₀) Arylene or 5-10 membered heteroarylene, wherein arylene and heteroarylene are

Optionally mono-or polysubstituted with a group selected from: (C)₁-C₈) Alkyl radicals, (C)₂-C₈) -alkenes

Base, (C)₂-C₈) -alkynyl, (C)₁-C₈) -alkoxy, (C)₁-C₈) Alkanoyl radical, (C)₃-C₈)-

Cycloalkyl, halogen, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy and-CO₂R¹⁵Wherein

R¹⁵Represents hydrogen, (C)₁-C₈) -alkyl or (C)₃-C₈) -cycloalkyl, and R¹Is represented by (C)₃-C₈) -an alkyl group,

is represented by (C)₂-C₈) -alkyl, wherein the carbon chain is substituted by 1 or 2 groups selected from-O-, -S-, -SO-and

-SO₂-the heteroatoms or groups of (A) are spaced apart,

is represented by (C)₂-C₈) -alkenyl, or

Is represented by (C)₂-C₈) -an alkynyl group,

wherein alkyl, alkenyl and alkynyl are optionally mono-or polysubstituted with halogen and/or cyano.

Preferred compounds of the general formula (I) for the treatment and/or prophylaxis of diseases are: wherein A represents (C)₆-C₁₀) -aryl or 5-to 10-membered heteroaryl,

wherein aryl and heteroaryl are optionally mono-or polysubstituted with groups selected from: (C)₁-C₆)-

Alkyl, (C)₂-C₆) -alkenyl, (C)₂-C₆) -alkynyl, (C)₁-C₆) -alkoxy, (C)₃-

C₆) Cycloalkyl, halogen, nitro, cyano, hydroxy and trifluoromethoxy, wherein (C)₁-C₆)-

Alkyl is itself optionally substituted by halogen or hydroxy, D represents phenylene or 5-to 6-membered heteroarylene, wherein phenylene and heteroarylene are optionally substituted

One or more substituents selected from the group consisting of: (C)₁-C₆) Alkyl radicals, (C)₁-C₆) -an alkenyl group,

(C₁-C₆) -alkynyl, (C)₁-C₆) -alkoxy, (C)₁-C₆) Alkanoyl radical, (C)₃-C₆) -cycloalkanes

Alkyl, halogen, nitro, cyano, trifluoromethyl and trifluoromethoxy, and R¹Is represented by (C)₃-C₈) -alkyl, or

Is represented by (C)₂-C₈) -alkyl, wherein the carbon chain is interrupted by 1 or 2 heteroatoms selected from-O-and-S-)

Spaced apart, and

wherein alkyl is optionally mono-or polysubstituted with halogen.

Particularly preferred compounds of the formula (I) are those in which D represents a meta-substituted phenylene or a 5-to 10-membered heteroaryl group.

Particular preference is furthermore given to compounds of the general formula (I) in which D is phenylene or 6-membered heteroarylene, in which A and-O-SO₂-R¹In the phenylene or heteroarylene group are in the meta position to each other.

This can be illustrated, for example, by the following structural formula:

particular preference is likewise given to compounds of the formula (I) in which R¹Is represented by (C)₄-C₆) -alkyl, wherein the carbon chain is optionally substituted by 1 or 2 substituents selected from-O-, -S-,

-SO-and-SO₂-the heteroatoms or groups of (A) are spaced apart,

is represented by (C)₄-C₆) -alkenyl, or

Is represented by (C)₄-C₆) -an alkynyl group,

wherein alkyl, alkenyl and alkynyl are optionally mono-or polysubstituted with halogen and/or cyano,

with the proviso that the alkyl, alkenyl and alkynyl groups are not perfluorinated.

Very particular preference is given to those in which R¹A compound of formula (I) representing 4, 4, 4-trifluorobutan-1-yl or n-pentyl.

Surprisingly, the compounds of the present invention exhibit valuable pharmacological effects which have not been foreseen to date.

They are characterized by the CB1 receptor, and in some cases, a highly potent agonist of the CB2 receptor. They can be used alone or in combination with other drugs for the prevention and treatment of acute and/or chronic pain and neurodegenerative diseases, in particular for the treatment of pain caused by cancer and chronic neuropathic pain, for example, pain associated with diabetic neuropathy, herpes zoster pain, peripheral nerve injury, central pain (as a result of cerebral ischemia) and trigeminal neuralgia, and other chronic pain, for example lumbago, back pain (lower back pain) or rheumatic pain.

The compounds of the invention are also suitable for the treatment of primary and/or secondary disorders of the brain, for example during or after central vasospasm, migraine, spasticity, hypoxia and/or hypoxia for which the cause is not mentioned, perinatal asphyxia, autoimmune diseases, metabolic and organic diseases associated with brain injury, and brain injury caused by primary brain diseases such as epilepsy and atherosclerosis and/or atherosclerotic lesions. The compounds of the invention are also suitable for the treatment of chronic or psychotic disorders, such as depression, neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease or Huntington's disease, multiple sclerosis, Amyotrophic Lateral Sclerosis (ALS), neurodegeneration caused by acute and/or chronic viral or bacterial infections and multi-infarct dementia.

In addition, they can be used in medicaments for the prevention and treatment of emesis, nausea, glaucoma, asthma, anorexia, convulsions, rheumatism, sedation and dyskinesia.

The substances according to the invention are also suitable for the treatment of diseases which are caused by bacterial and/or viral infections and which are directly and/or indirectly based on or involve a disturbance of the immune system, such as local or systemic autoimmune diseases (e.g. all variant lupus erythematosus), inflammatory and/or autoimmune-related diseases of the joints (e.g. primary chronic polyarthritis, trauma-related inflammation), inflammatory and/or autoimmune-related diseases of the skeletal and muscular system, inflammatory and/or autoimmune-related processes of the internal organs (e.g. crohn's disease, nephrotic nephritis) and of the external organs (e.g. allergic reactions due to the uptake of antigens in the air) and inflammatory and/or autoimmune-related processes of the central nervous system (e.g. multiple sclerosis, glomerulonephritis), Alzheimer's disease, psychotic disorders) and inflammatory and/or autoimmune-related pathological processes of the sensory organs, primary and/or secondary and/or autoimmune diseases of the hematopoietic system and of the immune system itself (e.g., rejection, AIDS), and skin diseases of inflammatory and/or immune origin. These substances also act on the secondary symptoms of these diseases, such as pain.

They are preferably suitable for the treatment of pain, stiffness, cerebral ischemia, craniocerebral trauma and Parkinson's disease.

Furthermore, the compounds of the present invention are characterized by high metabolic stability and high oral bioavailability. They are therefore particularly suitable for oral therapy.

The in vitro effect of the compounds of the invention on cannabinoids can be confirmed by the following biological experiments:1. rat CB1 luciferase reporter assay

Stock cultures of rat CHOCB1 receptor cells were prepared by the method described in WO-A-98/37061, page 55.

The following protocol was used for the screening of substances: at 37 ℃ and 10% CO₂The stock cultures were then cultured in 50% Dulbecco's modified Eagle's medium/50% F-12(DMEM/F12) containing 10% FCS and split 1: 10 after 2-3 days each. Test cultures were seeded with 5000 cells per well in 96-well plates and cultured at 37 ℃ for 70 hours. The cultures were then carefully washed with phosphate buffered saline and reconstituted with serum-free hyper-CHO medium (Bio-Whittaker). The substances dissolved in DMSO were diluted 1X in the medium and pipetted into the test cultures (maximum DMSO final concentration in the test mixture: 0.5%). After 20 minutes, forskolin was added and the culture was then incubated for 3 hours at 37 ℃ in an incubator. Thereafter the supernatant was removed and the cells were lysed by adding 25. mu.l lysis reagent (25M triphosphate, pH 7.8 with 2mM DTT, 10% glycerol, 3% Triton. times.100). Immediately thereafter, luciferase substrate solution was added(2.5mM ATP, 0.5mM fluorescein, 0.1mM coenzyme A, 10mM tricin, 1.35mM MgSO)₄15mM DTT, pH 7.8) and briefly shaken, and luciferase activity was measured using a Hamamatsu photographic system.

To make G_iProtein inactivation, test cultures were treated with 5ng/ml (final concentration) of pertussis toxin for 16 hours prior to testing.

IC was calculated using the GraphPadprism program (Hill formula, specifically: Single sided Competition)₅₀The value is obtained.

Examples 3 and 17 had ICs of 2.4nM and 16nM, respectively, in this assay₅₀The value is obtained.hCB2 luciferase reporter assay

Human CHOluc9 was stably transfected with CB2 receptor cells. Transfection, clonal selection and experimental procedures were performed using methods analogous to the rat CB1 receptor. The pharmacological characterization and substance testing of the cells was carried out according to the following protocol:

at 37 ℃ and 10% CO₂The stock cultures were then cultured in 50% Dulbecco's modified Eagle's medium/50% F-12(DMEM/F12) containing 10% FCS and split 1: 10 after 2-3 days each. The test cultures were seeded with 5000 cells per well in 96-well plates in DMEM/F12 medium containing 5% FCS and cultured at 37 ℃ for 70 hours. The culture medium was subsequently removed from the culture and serum-free hyper-CHO medium (Bio-Whittaker) was added. The substances dissolved in DMSO (200 Xfinal concentration) were pipetted into the test cultures (maximum DMSO final concentration in the test mixture: 0.5%). After 20 minutes, forskolin was added and the culture was subsequently incubated for 3.5 hours at 37 ℃ in an incubator. Thereafter the supernatant was removed and the cells were lysed by adding 25. mu.l lysis reagent (25M triphosphate, pH 7.8 with 2mM DTT, 10% glycerol, 3% Triton. times.100). Immediately thereafter, 50. mu.l of a two-fold concentrated luciferase substrate solution (5mM ATP, 1mM luciferin, 0.2mM coenzyme, 10mM tricin, 1.35mM MgSO 2. sup. m. sup. MgSO)₄15mM DTT, pH 7.8) and briefly shaken, and luciferase activity was measured with a photomultiplier tube photographic assay system (Hamamatsu).

IC₅₀Values were measured using GraphPad Prism^TMProgram (Hill formula, specifically: one-sided competition) assay.3. Binding to rat brain cortex Membrane

Membrane proteins were prepared from different tissues and cells by standard methods. Buffer, labeled ligand, DMSO or test substance were pipetted together, after which 100 μ g of protein was added and the mixture was mixed well and incubated in a water bath at 30 ℃ for 60 minutes. After the incubation time was complete, the reaction was stopped by adding ice-cold incubation buffer to each tube. Filtration was followed by washing with 3/4ml of incubation buffer. The filtrate was transferred to a vial and radioactivity was measured in a liquid scintillation counter.

The metabolic stability of the compounds of the invention can be determined in the following in vitro assays:4. microsome stability study

The metabolic stability of the compounds of the invention can be determined in rat liver microsomes (analogously to j. pharmacol. exp. ther.1997, 283.46-58).

To determine the microsomal stability and extrapolate the maximum possible bioavailability (Fmax) in the liver due to the first pass effect (phase 1 reaction), the material was incubated at 37 ℃ for 15 minutes at low concentrations together with the microsomal protein, with the addition of co-factor.

Both incubation and sampling were performed on a modified automated pipettor supplied by the Canberra Packard company.

Bioavailability and other pharmacokinetic parameters of the compounds of the invention can be determined in vivo in the following manner:5. pharmacokinetics in ratsa) Intravenous infusion

The material was infused directly via the lateral tail vein for 15 minutes by Braun ü le. The selected dose and volume is accurately administered with a calibrated 20ml syringe. The infusion was performed using a Braun Melsungen No.152440/1 pump. b) Oral administration

The material was administered as a bolus using a feeding tube. c) Sampling and processing blood and plasma

Blood samples were collected from catheterized animals (jugular vein) into heparin-treated tubes. The blood was centrifuged and plasma prepared in a manner suitable for analysis (LC-MS). Plasma was stored at < -15 ℃ until analysis. d) Pharmacokinetic results of example 2

Microsomal data (rat liver microsomes) give maximum possible bioavailability up to 100%.

The pharmacokinetic parameters obtained from the in vivo experiments (rats) were: oral data: (dose: 3 mg/kg): AUC_{Is normal}：0.322kg*h/l，C_{max, normal}：0.0674kg/l，t_max: 3 hours, t_1/2：1.7h， F：100％I.v. data: (dose: 0.3 mg/kg): CL: 3.11/h/kg, V_ss：5.8l/kg，t_1/2: 2.2 hours.

The in vivo effect of the compounds of the invention can be demonstrated, for example, in the following animal models:6. hypothermia (rat)

In vivo agonism of the CB1 receptor was tested in a rat hypothermia test.

The test substance was administered (orally) 5 minutes after basal body temperature was measured with an esophageal thermometer. The control group also received orally only the solvent used for the test substance (Cremophors EL 1-10% + distilled water). Body temperature was measured 120 minutes and 240 minutes after oral administration. The size of each dose group was 5-7 animals (rats). Hypothermia-agonism test in rats

Examples	ED-1℃[mg/kg]
		2	5mg/kg

^a)Effective dose for lowering body temperature by 1 DEG C

The suitability of the compounds of the invention for the treatment of pain conditions can be demonstrated in the following animal models:7. axis microsurgery of sciatic nerve Branch in rat (Chronic pain model)

Under pentobarbital anesthesia, the sciatic trigeminal nerve was exposed and peroneal and tibialis fork microsurgery was performed after ligating the proximal end of the axonal site of the nerve. Control animals received sham surgery. Following treatment, animals undergoing axotomy developed chronic mechanical allodynia (allodyne) and thermal hyperalgesia.

Mechanical allodynia was tested by means of pressure sensors (electronic von Frey anesthesiometer, IITC Inc. -Life science Instruments, Woodland Hills, Calif., USA) compared to sham operated animals.

Thermal hyperalgesia can be measured by measuring the waiting time during which the rat removes his paw from the radiant heat source (plantar test, Ugo Basile (Miland)).

The substances were administered at different times prior to the pain test by various routes of administration (intravenous, intraperitoneal, oral, i.t., i.c.v., transdermal).

Example 2 the minimum effective dose to reduce hyperalgesia in this model is 1mg/kg orally (rapid dosing, 60 minutes prior to the trial).

The suitability of the compounds of the invention in the treatment of, for example, neurodegenerative diseases can be demonstrated in the model of permanent focal cerebral ischemiA (MCA-O) in rats or in the model of subdural hematomA (SDH) in rats (WO-A-98/37061, page 60 onwards).8. 6-hydroxydopamine (6-OH-DA) lesions in rats

Degeneration of dopaminergic nigrostriatal (nigrostriatal) and striatal pallidum (striatopallidal) neurotransmission is a major feature of parkinson's disease. A large degree of Parkinson's disease clinical presentation can be mimicked in an animal model by intracerebral injection of neurotoxin 6-OH-DA into rats.

Male rats (Harlan Winelmann, Germany; body weight at the start of the test: 200- & 250g) were used for the test. The test animals were kept under controlled conditions (humidity, temperature) and a 12 hour light/dark cycle. Those animals not involved in the test were free to obtain water and feed.

On the day of treatment, 30 minutes prior to the injury, pargyline (Sigma, St. Louis, MO, USA; 50mg/kg i.p.) and desipramine HCl (Sigma; 25mg/kgi.p.) were administered to the animals to inhibit 6-hydroxydopamine metabolism and prevent uptake of 6-hydroxydopamine into noradrenergic structures, respectively. After inducing anesthesia with sodium pentobarbital (50mg/kg i.p.), the test animals were mounted on stereotaxic frames. The nigrostriatal neurotransmission lesions were produced by a single-sided single-dose injection of 8. mu.g of 6-OH-DA HBr (Sigma, St. Louis, Mo, USA) dissolved in 4. mu.l of 0.01% strength ascorbic acid/saline solution. The solution was slowly injected at 1. mu.l/min. The injection site was determined as K * nig and Klippel: 2.4mm anterior, 1.49mm lateral, -2.7mm ventral. After injection, the hypodermic needle was left in place for 5 minutes to facilitate diffusion of the neurotoxin.

After treatment, animals were placed on hot plates and monitored simultaneously after regaining consciousness, and were returned to their cages and received feed and water ad libitum.

In the active substance (verum) group, animals received the substance starting on the first day after surgery until day 28 at the end of the test.

The loss of motion after damage was quantified using the assays described in each of the following documents: a) step test (front paw coordination test)

Barn é oud, etc.: effect of complete and partial impairment of the dopaminergic midbrain (mesoplencephalic) system on the competent forelimb in rats. Neuroscience 1995, 67, 837-. b) Accelerated rotation test (equilibrium test):

spooren et al: prototype mGlu₅Effect of receptor antagonist 2-methyl-6- (phenylethynyl) -pyridine on rotation, locomotor activity and rotation response in unilateral 6-OHDA-injured rats. Eur.j.pharmacol.2000, 406, 403-. c) Determination of the traction of the forepaws

Dunnet et al: a unilateral grasping strength test was used to assess unilateral nigrostriatal lesions in rats. Neurosci.lett.1998, 246, 1-4.

For example, example 2, which was orally administered at a dose of 1.0mg/kg 2 times a day in a step trial, improved the coordination of the forepaws.

The novel compounds can be converted in a known manner into the customary formulations, for example tablets, coated tablets, pills, granules, aerosols, syrups, emulsions, suspensions and solutions, by the use of inert, nontoxic, pharmaceutically acceptable carriers or solvents. Wherein 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, that is to say in an amount sufficient to achieve the stated dosage range.

The formulations may be prepared, for example, by extending the active substance with a solvent and/or carrier, optionally with the use of emulsifying and/or dispersing agents, such as in the case of water as diluent, optionally with the use of organic solvents as co-solvents.

Administration can be by conventional means, preferably oral, transdermal or parenteral, especially lingual or intravenous. However, oral or nasal inhalation, e.g. by means of a spray, may also be employed; or topically administered transdermally.

In general, it has been demonstrated that effective results can be obtained when the amount administered orally is about 0.001-10mg/kg, preferably about 0.005-3mg/kg of body weight.

However, the above amounts may be deviated from when necessary, depending on the body weight and administration mode, individual reaction to the drug, the nature of the preparation and the time or interval of administration. Therefore, in some cases it may be sufficient to use less than the minimum amount mentioned above, while in other cases it may be necessary to exceed the upper limit mentioned above. In the case of larger amounts of administration, it may be appropriate to dispense them as several single doses during the day.

The determination of the retention time of the starting compounds and of the preparation examples by HPLC was carried out under the following conditions: column: kromasil C1860 x 2; injection volume 1.00. mu.l; flow rate: 0.75 ml/min; eluent: a is 0.01M H₃PO₄Aqueous solution of (B ═ CH)₃CN; gradient [ t (min): A/B]：0：90/10；0.5：90/10，4.5：10/90；6.5：10/90；7.5：90/10。Starting compounds Example 1A3- (3-chlorophenyl) phenol a)3- (3-chlorophenyl) phenylmethyl ether

1.42ml of a 2M sodium carbonate solution, 12.5mg of dichlorobis (triphenylphosphine) palladium (II) and 236g (1.550mmol) of 3-methoxyphenylboronic acid (J.chem.Soc.Perkin I1996, 2591-97) are added to 250mg (1.293mmol) of 3-bromochlorobenzene in 2.5ml of dimethoxyethane under argon and the mixture is stirred for 18 hours at reflux. After cooling, the reaction mixture contained 3g of Extrelut^A cartridge of NT3(Merck) was filtered and the product was washed with dichloromethane. The solvent was distilled under reduced pressure. The residue was purified by chromatography on silica gel (0.04-0.063nm) with cyclohexane/dichloromethane 6/1 as mobile phase. Yield: 261mg (92.5% of theory) of R_f(cyclohexane/dichloromethane 6/1) ═ 0.36ms (ei): 219(M + H) HPLC, retention time 5.28 min b)3- (3-chlorophenyl) phenol

220mg (1.01mmol) of 3- (3-chlorophenyl) phenylmethyl ether from example 1Aa are dissolved in 2ml of glacial acetic acid and, after addition of 1.3ml of a 48% strength aqueous hydrobromic acid solution, are stirred at reflux temperature for 4 hours. The reaction mixture was evaporated to dryness under reduced pressure, the residue was mixed with 1.5ml of water and 10ml of dichloromethane and added to a reaction vessel containing 3g of Extrelut^NT3(Merck), andthe product was washed with dichloromethane. The solvent was distilled off under reduced pressure and the residue was purified by chromatography on silica gel (0.04-0.063nm) using cyclohexane/dichloromethane 10/1 as mobile phase. Yield: 204mg (98% of theory) R_f(cyclohexane/dichloromethane 10/1) ═ 0.24ms (ei): 205(M + H) HPLC, retention time 4.43 min

The compounds in Table 1A were obtained by the method of example 1A from the appropriate compound of formula (VI) with the appropriate compound of formula (VII), i.e.3-methoxyphenylboronic acid (3-MPB) or 4-methoxyphenylboronic acid (4-MPB; Tetrahedron 1992, 48, 8073-8078).Table 1A: ¹⁾J.Amer.Chem.Soc.1943，65，389²⁾prepared from 3-methyl-1, 2-benzisoxazol-4-ol (J.chem.Soc.Perkin I1973, 2220-2222)³⁾Prepared by N-methylation of 4-bromo-1H-indazole with iodomethane and potassium carbonate in DMF (J.heterocyclic. chem.1984, 21, 1063)Example 39ATrifluoromethanesulfonic acid (4-hydroxy-2-pyridyl) ester

5.91g (53.2mmol) of dihydroxypyridine are suspended in 54.2ml of pyridine and cooled to 0 ℃ under an argon atmosphere. 8.55ml (50.5mmol) of trifluoromethanesulfonic anhydride were added dropwise thereto over about 10 minutes. The mixture was then allowed to reach room temperature and stirred for 30 minutes. Water was added for workup, extracted with ethyl acetate, washed, dried and evaporated in a rotary evaporator. The residue is passed throughChromatography was carried out on 200g of silica gel (0.04-0.063nm) using cyclohexane/ethyl acetate (9: 1-1: 1). Yield: 3.47g (26.8% of theory)Example 40A4, 4, 4-trifluoro-1-butanesulfonic acid (2-trifluoromethylsulfonyloxy-4-pyridyl) ester

550mg (2.26mmol) of 4-hydroxy-2-pyridinyl trifluoromethanesulfonate (example 39A) are suspended in 15ml of dichloromethane at room temperature under argon. 2ml of a 40% aqueous tetrabutylammonium hydroxide solution are added dropwise thereto. 476mg (2.26mmol) of 4, 4, 4-trifluoro-1-butylsulfonyl chloride was then added and the reaction was allowed to proceed for 20 minutes. Water was added for workup, extracted with ethyl acetate, washed, dried and evaporated in a rotary evaporator. The residue is purified by chromatography on 20g of silica gel (0.04-0.063nm) using cyclohexane/ethyl acetate (2: 1-1: 1). Yield: 590mg (62.5% of theory)Example 41AMethyl-3- (4-ethyl-1, 3-oxazol-2-yl) phenyl etherA suspension of 1.81g (12.0mmol) of 2-methoxybenzamide and 1.81g (12.0mmol) of 1-bromo-2-butanone in 11ml of toluene is stirred at reflux for 24 hours. 70ml of dichloromethane are added and the mixture is taken up with NaHCO₃(5% strength aqueous solution) until the pH was adjusted to 9. After phase separation, the organic phase is washed with Na₂SO₄Dried and filtered, and the solvent evaporated under reduced pressure. The residue is purified by chromatography on silica gel (0.04-0.063nm) using cyclohexane/ethyl acetate 6: 1 as mobile phase. Yield: 900.9mg (32.7% of theory) R_f(cyclohexane/ethyl acetate 3: 1) ═ 0.55ms (dci): 204(M + H) HPLC, retention time 4.34 min¹H-NMR(300MHz，DMSO-d₆)：δ＝1.20(t，3H)，2.55(m，2H)，3.78(s，3H)，7.08(ddd，1H)，7.40-7.58(m，3H)，7.92(s，1H)。Example 42AMethyl-3- (4-trifluoromethyl-1, 3-oxazol-2-yl) phenyl ethera) A suspension of 1.81g (12.0mmol) of 3-methoxybenzamide and 1.76g (12.0mmol) of 1-chloro-3, 3, 3-trifluoroacetone in 11ml of tolueneStir at reflux for 24 hours. 70ml of dichloromethane are added and the mixture is taken up with NaHCO₃(5% strength aqueous solution) until the pH was adjusted to 9. The phases were separated, washed with saturated aqueous sodium chloride solution and the organic phase with Na₂SO₄And (5) drying. After filtration and evaporation of the solvent under reduced pressure, a residue is obtained which is purified by chromatography on silica gel (0.04-0.063nm) with cyclohexane/ethyl acetate 6: 1 as mobile phase. 3-methoxy-N- (3, 3, 3-trifluoro-2-oxopropyl) benzamide was obtained as the uncyclized product in 79.5% yield. b)1.72g (6.57mmol) of 3-methoxy-N- (3, 3, 3-trifluoro-2-oxopropyl) benzamide obtained in stage a) are stirred in 15ml of phosphorus oxychloride at reflux for 4 hours. After dilution with 20ml of ethyl acetate, the solvent was carefully added to 5ml of ice water. The organic phase is extracted 3 times with 20ml each of ethyl acetate and the combined organic phases are taken over Na₂SO₄And (5) drying. The solvent was distilled off under reduced pressure and the residue was purified by chromatography on silica gel (0.04-0.063nm) with cyclohexane/ethyl acetate 6: 1 as mobile phase. Yield: 1.20g (53.9% of theory) of R_f(cyclohexane/ethyl acetate 3: 1) ═ 0.70ms (dci): 244(M + H) HPLC with retention time of 4.73 min¹H-NMR(300MHz，DMSO-d₆)：δ＝3.86(s，3H)，7.19(ddd，1H)，7.40-7.66(m，3H)，9.04(m，1H)。Example 43AMethyl-3- (2-methyl-1, 3-thiazol-4-yl) phenyl ether

A suspension of 1.17g (15.6mmol) thioacetamide and 2.75g (12.0mmol) 3-methoxy-bromoacetophenone in 40ml toluene was stirred at reflux for 24 h. 100ml of ethyl acetate and 15ml of water are added. After phase separation, 3 extractions with 30ml of ethyl acetate each time and the combined organic phases Na₂SO₄And (5) drying. After filtration, the solvent is evaporated off under reduced pressure and the residue is purified by chromatography on silica gel (0.04-0.063nm) with cyclohexane/ethyl acetate 7: 1 as mobile phase. Yield: 2.63g (98.5% of theory) of R_f(cyclohexane/ethyl acetate 5: 1) ═ 0.49ms (dci): 206(M + H) HPLC, retention time 4.23 min¹H-NMR(300MHz，MeOH-d₄)：δ＝2.75(s，3H)，3.84(s，3H)，6.89(ddd，1H)，7.31(dd，1H)，7.40-7.46(m，2H)，7.61(s，1H)。Example 44AMethyl-3- [3- (trifluoromethyl) -1H-pyrazol-5-yl]Phenyl ethers

A solution of 500mg (2.03mmol) of 4, 4, 4-trifluoro-1- (3-methoxyphenyl) -butane-1, 3-dione and 156.2mg (2.23mmol) of hydrazine hydrochloride in 35ml of ethanol is stirred at reflux for 24 hours. Ethanol was distilled off under reduced pressure, and the resulting residue was dissolved in 20ml of ethyl acetate. Wash 2 times with water and 1 time with saturated aqueous NaCl. Na for organic phase₂SO₄After drying and filtration, the solvent was distilled off under reduced pressure. Yield: 474.7mg (85.2% of theory) of R_f(cyclohexane/ethyl acetate 3: 1) ═ 0.27ms (dci): 243(M + H), 260(M + NH)₄) HPLC, retention time 4.40 min¹H-NMR(300MHz，DMSO-d₆)：δ＝3.82(s，3H)，6.98(m，1H)，7.25(s.1H)，7.36-7.47(m，3H)，14.07(br.s，1H)。Example 45A3- (4-ethyl-1, 3-oxazol-2-yl) phenolUnder argon, 9.47ml of boron tribromide (1.0M in CH)₂Cl₂To a solution of 583mg (2.87mmol) of 3- (4-ethyl-1, 3-oxazol-2-yl) phenylmethyl ether (example 41A) in 13ml of dichloromethane at 0 ℃. After 1 hour, the cooling bath was removed and the mixture was stirred at 25 ℃ for 4 hours. At 0 ℃ first 25ml of water are added, followed by 80ml of ethyl acetate. The phases are separated and the aqueous phase is extracted 3 times with 50ml each time of ethyl acetate. The combined organic phases were separated by MgSO₄After drying and filtration, the solvent was distilled off under reduced pressure. The residue is purified by chromatography on silica gel (0.04-0.063nm) using dichloromethane/methanol 25: 1 as mobile phase. Yield: 550.3mg (87.1% of theory) of R_f(dichloromethane/methanol 20: 1) ═ 0.42ms (dci): 190(M + H) HPLC, retention time 3.80 min¹H-NMR(300MHz，DMSO-d₆)：δ＝1.20(t，3H)，2.47-2.58(m，2H)，6.89(ddd，1H)，7.25-7.42(m.3H)，7.88(s，1H)，9.77(s，1H)。

The phenolic compounds in table 2A were prepared by the method of example 45A.Table 2A: preparation examples Example 14, 4, 4-trifluoro-1-butanesulfonic acid (3 '-chloro [1, 1' -biphenyl)]-3-yl) esters

84.00mg (0.41mmol) of 3- (3-chlorophenyl) phenol from example 1A are added at 0 ℃ to 1.0ml of dichloromethane, and 66.15mg (0.205mmol) of tetrabutylammonium bromide and 0.0613ml of 45% strength sodium hydroxide solution are added. After dropwise addition of A solution of 103.7mg (0.49mmol) of 4, 4, 4-trifluorobutanesulfonyl chloride (WO-A-98/37061, p. 131) in 1ml of dichloromethane, the mixture is stirred at 25 ℃ for 1.5 h. The reaction mixture was mixed with 1ml of water and charged with 3g of Extrelt^A cartridge of NT3(Merck) was filtered and washed thoroughly with dichloromethane, and the solvent was evaporated under reduced pressure. The residue was purified by chromatography on silica gel (0.04-0.063nm) using cyclohexane/dichloromethane 1/1 as mobile phase. Yield: 142.3mg (90.2% of theory) of R_f(cyclohexane/dichloromethane 1: 1) ═ 0.20ms (ei): 379(M + H) HPLC, retention time 5.14 min¹H-NMR(300MHz，DMSO-d₆)：δ＝2.10(m，2H)，2.50(m，2H)，3.75(t，2H)，7.3-7.9(m.8H)。

The compounds in table 2 were obtained by the method described in example 1.Table 2: ¹⁾prepared from example 40 by reaction with N-chlorosuccinamide in DMF at 100 deg.C²⁾Prepared from example 42 by reaction with iron powder in glacial acetic acid/water at 90 ℃³⁾Prepared from example 49 by reaction with propionyl chloride in pyridine at reflux⁴⁾Prepared from example 49 by reaction of methoxyacetyl chloride in pyridine at reflux⁵⁾Prepared from example 49 by reaction of butyryl chloride in pyridine at refluxExample 594, 4, 4-trifluoro-1-butanesulfonic acid (2- (4-tert-butylphenyl) -4-pyridinyl) ester

42.2mg (0.24mmol) of 4-tert-butylboronic acid, 90mg (0.22mmol) of 2-trifluoromethylsulfonyloxy-4-pyridyl 4, 4, 4-trifluoro-1-butanesulfonic acid (example 40A), 12.5mg (0.01mol) of tetraphenylpalladium (O) and 68.6mg (0.65mmol) of sodium carbonate in 5ml of dioxane were heated under argon at 80 ℃ for 2 hours. The reaction mixture is cooled, mixed with 0.5ml of water and filtered through a cartridge containing 3g of Extrelut NT3(Merck) and washed thoroughly with dichloromethane, and the solvent is distilled off under reduced pressure. The residue was purified by preparative HPLC and chromatography on silica gel (toluene). Yield: 15.4mg (17.8% of theory) MS (EI): 402(M + H) HPLC, retention time 5.47 min

The compounds in table 3 were obtained from example 40A by the method described in example 59:table 3: example 634, 4, 4-trifluoro-1-butanesulfonic acid (3- (4-ethyl-1, 3-oxazol-2-yl) phenyl) ester

1.66ml (6.34mmol) of tetrabutylammonium hydroxide (40% strength aqueous solution) are added to 200mg (1.06mmol) of 3- (4-ethyl-l-ethyl) -example 45A in dichloromethane (7.0ml)-1, 3-oxazol-2-yl) phenol. After 5 minutes 333.9mg (1.59mmol) of 4, 4, 4-trifluorobutanesulfonyl chloride were added and the mixture was stirred at 25 ℃ for 2 hours. 5ml of water are added to the reaction mixture and the aqueous phase is extracted 3 times with 25ml of dichloromethane each time. The combined organic phases are washed with Na₂SO₄After drying and filtration, the solvent was evaporated under reduced pressure. The residue is purified by chromatography on silica gel (0.04-0.063nm) using dichloromethane/ethyl acetate 100: 1/50: 1 as mobile phase. Yield: 210.2mg (53.8% of theory) R_f(cyclohexane/ethyl acetate 3: 1) ═ 0.34ms (ei): 363HPLC, Retention time 4.88 min¹H-NMR(300MHz，CDCl₃)：δ＝1.29(t，3H)，2.20-2.52(m，4H)，2.63(q，2H)，3.39(t，2H)，7.30-7.58(m，3H)，7.90(d，1H)，7.99(br.d，1H)。

The compounds in table 4 were obtained by the method described in example 63:table 4:

the above examples show the following¹H-NMR spectroscopic data:table 5:

examples
		2	1H-NMR(300MHz，DMSO-d6)：δ/ppm＝2.00-2.15(m，2H)，2.40-2.60(m，2H)，3.74(t，J＝7.5Hz，2H)，7.35-8.10(m，8H)
8	1H-NMR(200MHz，DMSO-d6)：δ/ppm＝1.95-2.20(m，2H)，2.35-2.65(m，2H)，3.73(t，J＝7.5Hz，2H)，7.32-7.87(m，8H)
		21	1H-NMR(200MHz，DMSO-d6)：δ/ppm＝1.90-2.20(m，2H)，2.33-2.67(m，2H)，3.71(t，J＝7.5Hz，2H)，7.35-7.80(m，8H)
53	1H-NMR(200MHz，DMSO-d6)：δ/ppm＝1.86-2.20(m，4H)，2.35-2.65(m，2H)，2.75-3.05(m，4H)，3.71(t，J＝7.5Hz，2H)，7.15-7.75(m，7H)
		55	1H-NMR(200MHz，DMSO-d6)：δ/ppm＝1.50-1.85(m，4H)，1.90-2.13(m，2H)，2.35-2.60(m，4H)，2.70-2.90(t，J＝6Hz，2H)，3.69(t，J＝7.5Hz，2H)，6.90-7.62(m，7H)

Claims (10)

1. A compound of the general formula (I) or a salt, hydrate and/or solvate thereof,

A-D-O-SO₂-R¹(I) a represents (C)₆-C₁₀) -aryl or 5-10 membered heteroaryl,

wherein adjacent ring atoms in the aryl and heteroaryl groups optionally pass through a ring containing 3-7 bridging atoms

A saturated or partially unsaturated bridge, said bridge atoms being selected from the group consisting of carbon, nitrogen, oxygen and sulfur,

and

wherein aryl, heteroaryl and said bridge are optionally mono-or polysubstituted by groups selected from

Generation: (C)₁-C₈) Alkyl radicals, (C)₂-C₈) -alkenyl, (C)₂-C₈) -alkynyl, (C)₁-C₈)-

Alkoxy group, (C)₁-C₈) Alkanoyl radical, (C)₃-C₈) Cycloalkyl, halogen, nitro, cyano,

Hydroxy, trifluoromethoxy, -CO₂R²、-CONR³R⁴、-SO₂NR⁵R⁶、-NR⁷COR⁸、-NR⁹SO₂R¹⁰

and-NR¹¹R¹²Wherein (C)₁-C₈) The alkyl radical itself being optionally substituted by halogen, cyano, hydroxy or

-NR¹³R¹⁴The substitution is carried out by the following steps,

wherein

R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹、R¹²、R¹³And R¹⁴Same or different

And represents hydrogen, optionally substituted by hydroxyl or (C)₁-C₄) -alkoxy-substituted (C)₁-C₈) -alkanes

Radical or (C)₃-C₈) -cycloalkyl, D represents (C)₆-C₁₀) Arylene or 5-10 membered heteroarylene, wherein arylene and heteroarylene are

Optionally mono-or polysubstituted with a group selected from: (C)₁-C₈) Alkyl radicals, (C)₂-C₈) -alkenes

Base, (C)₂-C₈) -alkynyl, (C)₁-C₈) -alkoxy, (C)₁-C₈) Alkanoyl radical, (C)₃-C₈)-

Cycloalkyl, halogen, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy and-CO₂R¹⁵，

Wherein

R¹⁵Represents hydrogen, (C)₁-C₈) -alkyl or (C)₃-C₈) -cycloalkyl, and R¹Is represented by (C)₄-C₈) -an alkyl group,

is represented by (C)₂-C₈) -alkyl, wherein the carbon chain is substituted by 1 or 2 groups selected from-O-, -S-, -SO-and

-SO₂-the heteroatoms or groups of (A) are spaced apart,

is represented by (C)₂-C₈) -alkenyl, or

Is represented by (C)₂-C₈) -an alkynyl group,

wherein alkyl, alkenyl and alkynyl are optionally mono-or polysubstituted with halogen and/or cyano,

except that D is phenylene and R¹A compound of the general formula (I) which is 1, 1, 2, 2, 3,3, 4, 4, 4-nonafluorobutyl, and

except for 1, 1, 2, 2, 3,3, 4, 4, 5, 5, 6,6, 7, 7, 8, 8, 8-heptadecafluoro-1-octanesulfonic acid [1, 1 '-biphenyl ] -4-yl ester and 1, 1, 2, 2, 3,3, 4, 4, 5, 5, 6,6, 7, 7, 8, 8, 8-heptadecafluoro-1-octanesulfonic acid [1, 1' -biphenyl ] -2-yl ester.

2. A compound according to claim 1, wherein a represents (C), a salt, a hydrate and/or a solvate thereof₆-C₁₀) -aryl or 5-to 10-membered heteroaryl,

wherein adjacent ring atoms in the aryl and heteroaryl groups optionally contain 3 to 5 bridging carbon atoms

Are connected to a saturation bridge of

Wherein aryl, heteroaryl and said bridge are optionally mono-or polysubstituted by groups selected from

Generation: (C)₁-C₆) Alkyl radicals, (C)₁-C₆) -alkoxy, (C)₁-C₆) Alkanoyl, halogen, nitro

Radical, cyano radical, hydroxy radical, trifluoromethoxy radical, -GONR³R⁴、-NR⁷COR⁸and-NR¹¹R¹²Which is

In (C)₁-C₆) The alkyl radical itself being optionally substituted by halogen, hydroxy or-NR¹³R¹⁴Is substituted in which R³、R⁴、R⁷、R⁸、R¹¹、R¹²、R¹³And R¹⁴Are the same or different and represent hydrogen, optionally substituted

Hydroxy or (C)₁-C₄) -alkoxy-substituted (C)₁-C₆) -alkyl or (C)₃-C₈) -cycloalkyl, D represents phenylene or 6-membered heteroarylene, wherein phenylene and heteroarylene are optionally selected from

The following groups are mono-or polysubstituted: (C)₁-C₄) Alkyl radicals, (C)₁-C₄) Alkoxy, halogen, nitro

Alkyl, cyano, trifluoromethyl and trifluoromethoxy, and R¹Represents optionally partially fluorinated (C)₄-C₈) -an alkyl group.

3. A compound according to claim 1, wherein A represents phenyl, indanyl or 1, 2, 3, 4-tetrahydronaphthyl,

wherein said ring is optionally selected from (C)₁-C₄) -alkyl, halogen, cyano, trifluoromethyl

And trifluoromethoxy, D represents 1, 3-phenylene, wherein the phenylene is optionally substituted by a group selected from (C)₁-C₄) -alkyl, halogen,

Cyano, trifluoromethyl and trifluoromethoxy groups up to 2 times, and R¹Represents 4, 4, 4-trifluorobut-1-yl or n-pentyl.

4. A process for preparing the compounds as claimed in claim 1, characterized in that the compounds of the general formula (II) are prepared by reacting [ A ]

A-D-OH (II) wherein

A and D have the meanings indicated in claim 1, with a compound of the general formula (III) in an inert solvent in the presence of a suitable base,

X¹-SO₂-R¹(III) wherein X¹Represents a suitable leaving group, and R¹Has the meaning as claimed in claim 1, or [ B]A compound of the general formula (IV)

A-X²(IV) in which A has the meaning as claimed in claim 1, and X²Represents a group selected from-B (OR)¹⁶)₂、-SnR¹⁷ ₃、-ZnR¹⁸and-SiR¹⁹Cl₂A group of (1), wherein

R¹⁶Represents hydrogen or (C)₁-C₆) -alkyl, or

Two R¹⁶Together represent (C)₂-C₆) -alkanediyl or benzene-1, 2-diyl, and

R¹⁷、R¹⁸and R¹⁹Is represented by (C)₁-C₆) An alkyl group, with a compound of formula (V) in an inert solvent in the presence of a palladium catalyst and a base,

X³-D-O-SO₂-R¹(V) wherein X³Is a suitable leaving group, and D and R¹Has the meaning as claimed in claim 1, and, optionally, in [ A ]]Or [ B]Thereafter, the substituents in the reaction product are derivatized by conventional methods.

5. Compounds of formula (I) and salts, hydrates and/or solvates thereof for use in the treatment and/or prophylaxis of diseases,

A-D-O-SO₂-R¹(I) wherein A represents (C)₆-C₁₀) -aryl or 5-10 membered heteroaryl,

wherein adjacent ring atoms in the aryl and heteroaryl groups optionally pass through a ring containing 3-7 bridging atoms

A saturated or partially unsaturated bridge, said bridge atoms being selected from the group consisting of carbon, nitrogen, oxygen and sulfur,

and

wherein aryl, heteroaryl and said bridge are optionally mono-or polysubstituted by groups selected from

Generation: (C)₁-C₈) Alkyl radicals, (C)₂-C₈) -alkenyl, (C)₂-C₈) -alkynyl, (C)₁-C₈) -alkoxy, (C)₁-C₈) Alkanoyl radical, (C)₃-C₈) Cycloalkyl, halogen, nitro, cyano, hydroxy, trifluoromethoxy, -CO₂R²、-CONR³R⁴、-SO₂NR⁵R⁶、-NR⁷COR⁸、-NR⁹SO₂R¹⁰and-NR¹¹R¹²Wherein (C)₁-C₈) The alkyl radical itself being optionally substituted by halogen, cyano, hydroxy or-NR¹³R¹⁴Wherein R is²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹、R¹²、R¹³And R¹⁴Same or different

And represents hydrogen, optionally substituted by hydroxyl or (C)₁-C₄) -alkoxy-substituted (C)₁-C₈) -alkanes

Radical or (C)₃-C₈) -cycloalkyl, D represents (C)₆-C₁₀) Arylene or 5-10 membered heteroarylene, wherein arylene and heteroarylene are

Optionally mono-or polysubstituted with a group selected from: (C)₁-C₈) Alkyl radicals, (C)₂-C₈) -alkenes

Base, (C)₂-C₈) -alkynyl, (C)₁-C₈) -alkoxy, (C)₁-C₈) Alkanoyl radical, (C)₃-C₈)-

Cycloalkyl, halogen, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy and-CO₂R¹⁵Wherein

R¹⁵Represents hydrogen, (C)₁-C₈) -alkyl or (C)₃-C₈) -cycloalkyl, and R¹Is represented by (C)₃-C₈) -an alkyl group,

is represented by (C)₂-C₈) -alkyl, wherein the carbon chain is selected from 1 or 2from-O-, -S-, -SO-and

-SO₂-the heteroatoms or groups of (A) are spaced apart,

is represented by (C)₂-C₈) -alkenyl, or

Is represented by (C)₂-C₈) -an alkynyl group,

wherein alkyl, alkenyl and alkynyl are optionally mono-or polysubstituted with halogen and/or cyano.

6. Compounds of general formula (I) and salts, hydrates and/or solvates thereof for use in the treatment and/or prevention of diseases,

A-D-O-SO₂-R¹(I) wherein A represents (C)₆-C₁₀) -aryl or 5-10 membered heteroaryl,

wherein aryl, heteroaryl are optionally mono-or polysubstituted with groups selected from: (C)₁-C₆)-

Alkyl, (C)₂-C₆) -alkenyl, (C)₂-C₆) -alkynyl, (C)₁-C₆) -alkoxy, (C)₁-

C₆) Alkanoyl radical, (C)₃-C₆) Cycloalkyl, halogen, nitro, cyano, hydroxy, trifluoromethyl

Oxy radical, wherein (C)₁-C₆) -alkyl is itself optionally substituted by halogen, cyano or hydroxy, D represents phenylene or 5-6 membered heteroarylene, wherein phenylene or heteroarylene is optionally selected from

One or more of the following groups: (C)₁-C₆) Alkyl radicals, (C)₂-C₆) -alkenyl, (C)₂-C₆)-

Alkynyl, (C)₁-C₆) -alkoxy, (C)₃-C₆) Cycloalkyl, halogen, nitro, cyano,

Trifluoromethyl and trifluoromethoxy, R¹Is represented by (C)₄-C₈) -alkyl, or

Is represented by (C)₂-C₈) -alkyl, wherein the carbon chain is interrupted by 1 or 2 heteroatoms selected from-O-and-S-)

The components are separated from each other at intervals,

wherein alkyl is optionally mono-or polysubstituted with halogen.

7. A compound according to claim 2 or 3 for use in the treatment and/or prophylaxis of diseases.

8. A pharmaceutical composition comprising a mixture of at least one compound according to any one of claims 5 to 7 and at least one pharmaceutically acceptable substantially non-toxic carrier or excipient.

9. Use of a compound according to any one of claims 5 to 7 for the manufacture of a medicament for the treatment and/or prevention of pain conditions and/or neurodegenerative diseases.

10. Use of a compound according to any one of claims 5 to 7 in the manufacture of a medicament for the treatment and/or prophylaxis of parkinson's disease.