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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
  • C07D213/72—Nitrogen atoms
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  • C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
  • C07D211/14—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
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  • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
  • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
  • C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
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  • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with 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
  • C07D211/40—Oxygen atoms
  • C07D211/44—Oxygen atoms attached in position 4
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  • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with 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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  • C07D215/16—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 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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  • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
  • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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  • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
  • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
  • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
  • C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
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  • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
  • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
  • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
  • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
  • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
  • C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
  • C07D317/58—Radicals substituted by nitrogen atoms
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  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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  • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
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  • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
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  • C07C2603/18—Fluorenes; Hydrogenated fluorenes

Definitions

• the present invention relates to compounds of the general formula I.
• R 4 can be substituted
• R 12 is H or CH 3 ;
• R 1 is H, (C 1 -C 6 ) alkyl or phenyl
• R 2 denotes H, (C 1 -C 6 ) alkyl or -C (O) (C 1 -C 3 ) alkyl, the alkyl groups contained being represented by a
• Phenyl group may be substituted
• R 3 is hydrogen, (C 1 -C 6 ) alkyl, through 1 to 3
• n 1, 2 or 3;
• Phenyl groups can be unsubstituted or substituted by one or two substituents, namely CH 3 , F, Cl, OCH 3 , SCH 3 , CF 3 , OH, NO 2 or can be substituted by
• R 8 and R 9 are those listed under the definition of R 7
• Cyclohexyl means, where if the R 14 is phenyl or
• A, R 3 and m are as defined above;
• R 1 denotes H, alkyl or phenyl
• R 2 is H
• inorganic acids such as hydrochloric acid
• organic acids such as maleic acid,
• alkyl and alkoxy included in the definitions include both branched and unbranched alkyl and alkoxy groups.
• Ph means phenyl, the ones contained in these groups
• Phenyl groups unsubstituted or by one, two or three groups
• R 4 can be substituted
• R 4 is independently (C 1 -C 3 ) alkyl, through 1 to 3
• (C 1 -C 3 ) are alkylthio or halogen, or two neighboring ones
• R 4 together are -O-CH 2 -O-; B -CH (R 12 ) -,
• R 12 is H or CH 3 ;
• R 1 is H, (C 1 -C 3 ) alkyl or phenyl
• R 2 denotes H, (C 1 -C 3 ) alkyl or -C (O) (C 1 -C 3 ) alkyl,
• Phenyl group may be substituted
• R 3 is hydrogen, (C 1 -C 3 ) alkyl, through 1 to 3
• n 1, 2 or 3; and Z is as defined above.
• R 1 is hydrogen
• R 2 is -C (O) CH 3 - or hydrogen
• R 3 is hydrogen, methyl, trifluoromethyl, methoxy
• n 1 or 2;
• Phenyl groups can be unsubstituted or substituted by one or two substituents, namely CH 3 , F, Cl, OCH 3 ,
• A means phenyl, benzyl, naphthyl or thienyl where that
• Phenyl and the phenyl ring of benzyl is unsubstituted or substituted by one, two or 3 groups R 4 ;
• B is -C (O) -CH 2 -;
• R 1 , R 2 , R 3 , R 4 , R 7 , R 8 and m are as defined above;
• R 1 is hydrogen and R 2 is hydrogen or methyl, preferably methyl
• R 4 is CH 3 , OCH 3 , OC 2 H 5 , CF 3 , F, Cl or Br or 2 adjacent R 4 -O- (CH 2 ) 1 or 2 -O- or (CH 2 ) 3 or are 4;
• R 3 is hydrogen, (C 1 -C 3 ) alkyl (preferably methyl), (C 1 -C 3 ) alkoxy (preferably methoxy), F, Cl or Br;
• the receptor affinity for the NK 1 receptor was determined on intact human lymphoblastoma cells (IM-9) which express NK 1 receptors, the displacement of 1 25 J-labeled substance P being measured.
• the compounds of the invention are valuable
• Substance P antagonism as well as neurokinin A or
• Respiratory diseases e.g. Asthma, bronchitis,
• Rhinitis cough or sputum, as well as inflammatory
• Eye diseases such as conjunctivitis, inflammatory skin diseases such as
• Painful conditions such as migraines or vascular
• the invention therefore also relates to the use of
• Salts possibly with the usual substances such as solubilizers, emulsifiers or other auxiliaries brought into solution, suspension or emulsion.
• Solvents come e.g. in question: water,
• physiological saline solutions or alcohols e.g.
• connections can be made by implants, e.g.
• the compounds of the invention can be any organic compounds of the invention.
• Cyanide sources can include potassium cyanide, sodium cyanide,
• Trimethylsilyl cyanide, acetone cyanohydrin and others are used, potassium cyanide is preferred.
• Acidic acids, citric acid, mineral acids, acidic salts such as sodium bisulfite, potassium bisulfite and others are used as acidic compounds; hydrochloric acid is preferably used.
• Solvents such as methanol, ethanol, diethyl ether, tert-butyl methyl ether, tetrahydrofuran, dioxane, methylene chloride or acetonitrile are preferably used as solvents, also in a mixture with water.
• Diethyl ether, tetrahydrofuran and ethanol, and also mixtures thereof, are preferably used in a mixture with water.
• the reaction can be carried out at temperatures from -10 ° C. to 40 ° C., preferably temperatures in the range from 0 ° C. to room temperature are used. Becomes
• trimethylsilyl cyanide is used as the "cyanide source"
• the synthesis of the aminonitriles III can also be obtained via the intermediate stage of an imine or immonium salt, which is obtainable from the carbonyl compound Ha and the amine Ilb, by addition of cyanide.
• known methods can first be used to produce a cyanohydrin from the carbonyl compound IIa with cyanide, which can then react with the amine Ilb to give the aminonitrile III.
• the aminonitriles III are reduced to the diamines IV in step b.).
• the methods customary for the reduction of nitriles to amines can be used for this step.
• Catalytic hydrogenation is suitable, preferably with Raney nickel as catalyst, preferably in the presence of Ammonia, the reduction with borane-dimethyl sulfide complex, borane-tetrahydrofuran complex, sodium borohydride, preferably in the presence of catalysts such as cobalt chloride or Raney nickel, with lithium aluminum hydride, especially also in
• Lithium aluminum hydride in the presence of an equivalent amount of conc. Sulfuric acid is preferred.
• Preferred solvents are ethers
• reaction temperature can range from -78 ° C to
• Reflux temperature preferably at temperatures from -5 ° C to 10 ° C.
• the diamines IV can also be obtained by addition of the amine Ilb to a nitroolefin VII (step e.)) By methods described in the literature and subsequent reduction of the nitro group by methods which are also customary in the literature (step f.)).
• Methylene chloride used.
• the reaction is carried out at temperatures between -20 ° C and 40 ° C, preferably at room temperature.
• B represents a group -C (O) -, -C (O) -CH 2 - or -C (O) -CH 2 -CH 2 -, the diamine IV in step c.) With a carboxylic acid
• the carboxylic acid is activated in the form of its acid chloride or it is activated with carbonyldiimidazole, dicyclohexylcarbodiimide, diphenylphosphoryl azide, diisovaleryl chloride, diethylphosphoryl cyanide and others from which
• Activation and coupling is preferably carried out in the presence of auxiliary bases such as triethylamine, pyridine etc., and in the case of acid chlorides also aqueous alkali hydroxide solution. Triethylamine is preferably used.
• the reaction can be carried out in solvents such as dimethylformamide, tetrahydrofuran or acetonitrile
• dimethylformamide is preferred.
• the diamine IV can be used in step c.) Using methods known from the literature
• X is a leaving group such as chlorine, bromine, iodine, O-tosylate, O-triflate, O-mesylate, etc.
• an aroid can also be initially prepared as described above by reacting the diamine IV with a carboxylic acid.
• the methods known from the literature for the reduction of amides can be used.
• Acetic acid or trifluoroacetic acid or with borane or borane-tetrahydrofuran complex or borane-dimethyl sulfide complex is substituted by reacting with borane or borane-tetrahydrofuran complex or borane-dimethyl sulfide complex.
• the diamine IV can preferably also be used with a corresponding carbonyl compound
• the imine is preferably prepared in inert solvents such as benzene, toluene or xylene (or other suitable means for azeotropic removal of the water
• Solvents using a water separator; or in methylene chloride, tetrahydrofuran, dioxane or tert-butyl methyl ether in the presence of a water-binding agent such as molecular sieve and the like. a., or also in alcohols.
• a water-binding agent such as molecular sieve and the like.
• Reduction of the imine are reducing agents such as sodium borohydride, sodium cyanoborohydride, lithium aluminum hydride, zinc and
• Lithium aluminum hydride, zinc and hydrochloric acid, formic acid and hydrogen in the presence of metal catalysts are
• Suitable reducing agents Sodium cyanoborohydride in a solvent such as is preferably used as the reducing agent
• Hydrochloric acid preferably adjusted to a value of 7-8.
• the reaction temperature is chosen between -10 ° C and 40 ° C, preferably at room temperature.
• step d. For the introduction of the radical R 2 in step d.), What has been said above for step c.) Applies accordingly.
• the introduction of the radical R 2 can also initially be carried out in step g.) Using the methods mentioned above, the compound IX thus substituted is then converted into VI in step h.)
• Examples 2 to 57 are prepared in an analogous manner.
• reaction mixture is then concentrated in vacuo, stirred with 40 ml of water and with 3 x 20 ml of ethyl acetate
• Hydrochloric acid precipitated a hydrochloride It is suctioned off, the substance is dissolved in a little chloroform / methanol 3: 1 and the substance is chromatographed with chloroform / methanol / conc. Ammonia solution
• Example 65 The preparation is carried out analogously to Example 58.
• Example 65 The preparation is carried out analogously to Example 58.
• Diisopropyl ether precipitates the 2- (3,5-bistrifluoromethyl-phenyl) -2 '- (2-methoxyphenyl) -2' - (4-cyclohexylpiperazin-1-yl) diethylamine as the hydrochloride. It is suctioned off, washed with diisopropyl ether and dried at about 50 ° C in a vacuum. 75 mg of the substance are obtained as a pale beige solid (yield 28%)
• the preparation is carried out analogously to Example 66.
• Fraction 1 is dissolved in 5 ml of acetone and from it with
• Example 94 The preparation is carried out analogously to Example 58.
• Example 94 The preparation is carried out analogously to Example 58.
• Example 100 The preparation is carried out analogously to Example 58.
• Example 100 The preparation is carried out analogously to Example 58.
• Example 100
• Example 1 prepared.
• Examples 103-180 are prepared analogously.
• Example 22-7 are dissolved in 3 ml of DMSO and 168 mg (3.0 mmol) of powdered potassium hydroxide are added. While cooling, 0.19 ml (3.0 mmol) of methyl iodide are added dropwise and the mixture is then stirred for about 16 h at room temperature. Then about 10 ml of water is added, a viscous substance settling out. The solvent is decanted off and the residue is taken up in ethyl acetate. The organic phase is washed with water, over

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