Substituted indazoles useful for treatment and prevention of allergic and/or inflammatory diseases in animals

Abstract

The present application relates to the use of substituted indazoles for treatment and/or prophylaxis of allergic and/or inflammatory diseases in animals, especially for treatment and/or prophylaxis of atopic dermatitis, Flea Allergy Dermatitis, inflammatory bowel disease, osteoarthritis and inflammatory pain, non-infectious recurrent airway disease, insect hypersensitivity, asthma, respiratory disease, mastitis and endometritis in animals.

1 . A compound of the general formula (I) 
       
         
           
           
               
               
           
         
         in which: 
         R 1  is C 1 -C 6 -alkyl, where the C 1 -C 6 -alkyl group is unsubstituted or mono- or polysubstituted identically or differently by
 halogen, hydroxyl, an unsubstituted or mono- or poly-halogen-substituted C 3 -C 6 -cycloalkyl, or an R 6 , R 7 SO 2 , R 7 SO or R 8 O group, 
 or a group selected from: 
 
       
       
         
           
           
               
               
           
         
         R 2  and R 3  always have the same definition and are both either hydrogen or C 1 -C 6 -alkyl; 
         R 4  is halogen, cyano, an unsubstituted or a singly or multiply, identically or differently substituted C 1 -C 6 -alkyl or an unsubstituted or a singly or multiply, identically or differently substituted C 3 -C 6 -cycloalkyl, and the substituents are selected from the group of halogen and hydroxyl; 
         R 5  is hydrogen, halogen or an unsubstituted or mono- or poly-halogen-substituted C 1 -C 6 -alkyl; 
         R 6  is an unsubstituted or mono- or di-methyl-substituted monocyclic saturated heterocycle having 4 to 6 ring atoms, which contains a heteroatom or a heterogroup from the group of O, S, SO and SO 2 ; 
         R 7  is C 1 -C 6 -alkyl, where the C 1 -C 6 -alkyl group is unsubstituted or mono- or polysubstituted identically or differently by halogen, hydroxyl or C 3 -C 6 -cycloalkyl;
 or R 7  is C 3 -C 6 -cycloalkyl; 
 
         R 8  is C 1 -C 6 -alkyl, where the C 1 -C 6 -alkyl group is unsubstituted or mono- or polysubstituted identically or differently by halogen; 
       
       and a diastereomers, an enantiomers, a metabolites, a salt, a solvate, a solvate of the salts thereof, 
       for use in the treatment and/or prophylaxis of allergic and/or inflammatory diseases in an animal. 
     
     
         2 . The compound according to  claim 1 , where
 R 1  is C 1 -C 6 -alkyl, where the C 1 -C 6 -alkyl group is unsubstituted or mono- or polysubstituted identically or differently by fluorine, hydroxyl or an R 6 , R 7 SO 2 , R 7 SO or R 8 O group;   R 2  and R 3  always have the same definition and are both either hydrogen or C 1 -C 3 -alkyl;   R 4  is halogen, cyano or C 1 -C 3 -alkyl, where the C 1 -C 3 -alkyl group is unsubstituted or mono- or polysubstituted identically or differently by halogen or hydroxyl;   R 5  is hydrogen, fluorine, chlorine or C 1 -C 3 -alkyl;   R 6  is oxetanyl or tetrahydrofuranyl;   R 7  is C 1 -C 4 -alkyl, where the C 1 -C 4 -alkyl group is unsubstituted or monosubstituted by hydroxyl or by cyclopropyl or substituted by three fluorine atoms;   R 8  is an unsubstituted C 1 -C 4 -alkyl group or a tri-fluorine-substituted C 1 -C 4 -alkyl group.   
     
     
         3 . The compound according to  claim 1 , where R 4  is difluoromethyl, trifluoromethyl or methyl. 
     
     
         4 . The compound according to  claim 1 , where R 5  is hydrogen or fluorine. 
     
     
         5 . The compound according to  claim 1 , where R 2  and R 3  are both either hydrogen or methyl. 
     
     
         6 . The compound according to  claim 2 , where
 R 1  is C 2 -C 6 -alkyl, where the C 2 -C 6 -alkyl group is unsubstituted, or
 the C 2 -C 6 -alkyl group is mono-, di- or tri-fluorine-substituted or 
 the C 2 -C 6 -alkyl group is monosubstituted by hydroxyl, R 6 , R 7 SO 2 , or R 8 O, 
 or R 1  is an oxetanyl-substituted C 1 -C 3 -alkyl group; 
   R 2  and R 3  always have the same definition and are both either hydrogen or methyl;   R 4  is an unsubstituted or mono- or poly-halogen-substituted C 1 -C 3 -alkyl group or a C 1 -C 3 -alkyl group substituted by one hydroxyl group or a C 1 -C 3 -alkyl group substituted by one hydroxyl group and three fluorine atoms;   R 5  is hydrogen, fluorine or C 1 -C 3 -alkyl;   R 7  is C 1 -C 3 -alkyl;   R 8  is C 1 -C 4 -alkyl, where the C 1 -C 4 -alkyl group is unsubstituted or mono-, di- or tri-fluorine-substituted.   
     
     
         7 . The compound according to  claim 6 , in which
 R 1  is a C 2 -C 5 -alkyl group substituted by hydroxyl or C 1 -C 3 -alkoxy or trifluoromethoxy or 2,2,2-trifluoroethoxy or trifluoromethyl or
 is a methyl-SO 2 -substituted C 2 -C 4 -alkyl group or 
 is an oxetan-3-yl-substituted C 1 -C 2 -alkyl group; 
   R 2  and R 3  always have the same definition and are both hydrogen or methyl;   R 4  is methyl, ethyl, trifluoro-C 1 -C 3 -alkyl, difluoro-C 1 -C 3 -alkyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxypropan-2-yl and 2,2,2-trifluoro-1-hydroxyethyl;   R 5  is hydrogen, fluorine or methyl.   
     
     
         8 . The compound according to  claim 7 , in which
 R 1  is 4,4,4-trifluorobutyl, 3-hydroxy-3-methylbutyl, 3-hydroxybutyl, 3-methoxypropyl, 3-hydroxypropyl, 3-hydroxy-2-methylpropyl, 3-hydroxy-2,2-dimethylpropyl, 3-trifluoromethoxypropyl, 2-methoxyethyl, 2-hydroxyethyl, 2-(methyl sulphonyl)ethyl or 3-(methyl sulphonyl)propyl;   R 2  and R 3  are both methyl or hydrogen;   R 4  is difluoromethyl, trifluoromethyl or methyl;   R 5  is hydrogen or fluorine.   
     
     
         9 . The compound according to  claim 8 , in which
 R 1  is 3-hydroxy-3-methylbutyl, 3-hydroxybutyl, 3-hydroxy-2-methylpropyl, 3-hydroxy-2,2-dimethylpropyl, 3-(methyl sulphonyl)propyl or 2-(methyl sulphonyl)ethyl;   R 2  and R 3  are both methyl;   R 4  is difluoromethyl or trifluoromethyl;   R 5  is hydrogen.   
     
     
         10 . The compound according to  claim 8 , in which
 R 1  is 3-hydroxy-3-methylbutyl, 3-hydroxybutyl, 3-hydroxy-2-methylpropyl, 3-hydroxy-2,2-dimethylpropyl, 3-(methyl sulphonyl)propyl or 2-(methyl sulphonyl)ethyl;   R 2  and R 3  are both methyl;   R 4  is methyl;   R 5  is fluorine, where R 5  is in the ortho position to R 4 .   
     
     
         11 . The compound according to  claim 1  which is selected from the group consisting of:
 1) N-[6-(2-Hydroxypropan-2-yl)-2-(2-methoxyethyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide; 
 2) N-[6-(Hydroxymethyl)-2-(2-methoxyethyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide; 
 3) N-[6-(2-Hydroxypropan-2-yl)-2-(3-methoxypropyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide; 
 4) N-[6-(Hydroxymethyl)-2-(3-methoxypropyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide; 
 5) N-[2-(2-Hydroxyethyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide; 
 6) N-[6-(2-Hydroxypropan-2-yl)-2-(3-hydroxypropyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide; 
 7) N-[2-(2-Hydroxyethyl)-6-(hydroxymethyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide; 
 8) N-[6-(2-Hydroxypropan-2-yl)-2-(oxetan-3-ylmethyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide; 
 9) N-[6-(Hydroxymethyl)-2-(oxetan-3-ylmethyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide; 
 10) N-{6-(2-Hydroxypropan-2-yl)-2-[3-(methylsulphonyl)propyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide; 
 11) N-[2-(3-Hydroxy-3-methylbutyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide; 
 12) N-{6-(2-Hydroxypropan-2-yl)-2-[2-(methyl sulphonyl)ethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide; 
 13) 6-(Difluoromethyl)-N-[2-(3-hydroxy-3-methylbutyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl]pyridine-2-carboxamide; 
 14) 6-(Difluoromethyl)-N-{6-(2-hydroxypropan-2-yl)-2-[2-(methyl sulphonyl)ethyl]-2H-indazol-5-yl}pyridine-2-carboxamide; 
 15) 6-(Difluoromethyl)-N-[6-(2-hydroxypropan-2-yl)-2-(3-hydroxypropyl)-2H-indazol-5-yl]pyridine-2-carboxamide; 
 16) N-[6-(2-Hydroxypropan-2-yl)-2-(4,4,4-trifluorobutyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide; 
 17) N-{6-(2-Hydroxypropan-2-yl)-2-[3-(trifluoromethoxy)propyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carb oxamide; 
 18) N-{6-(2-Hydroxypropan-2-yl)-2-[3-(2,2,2-trifluoroethoxy)propyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide; 
 19) 5-Fluoro-N-[2-(3-hydroxy-3-methylbutyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl]-6-methylpyridine-2-carboxamide; 
 20) N-[2-(3-Hydroxy-3-methylbutyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl]-6-methylpyridine-2-carboxamide; 
 21) 6-(2-Hydroxypropan-2-yl)-N-[6-(2-hydroxypropan-2-yl)-2-(4,4,4-trifluorobutyl)-2H-indazol-5-yl]pyridine-2-carboxamide; and 
 22) N-{2-[2-(1-Hydroxycyclopropyl)ethyl]-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide and 
 a diastereomer, an enantiomer, a metabolite, a salt, a solvate, and a solvate of the salt thereof. 
 
     
     
         12 . Compound of the general formula (I) as defined in  claim 1  for use in the treatment and/or prophylaxis of allergic and/or inflammatory diseases in domestic animals. 
     
     
         13 . Compound of the general formula (I) as defined in  claim 1  for use in the treatment and/or prophylaxis of allergic and/or inflammatory diseases in farm animals. 
     
     
         14 . Compound of the general formula (I) as defined in  claim 1 , for use in a method for treatment and/or prophylaxis of atopic dermatitis, Flea Allergy Dermatitis, inflammatory bowel disease, osteoarthritis and inflammatory pain, non-infectious recurrent airway disease, insect hypersensitivity, asthma, respiratory disease, mastitis and endometritis in animals. 
     
     
         15 . Compound of the general formula (I) as defined in  claim 1  for use in a method for treatment and/or prophylaxis of Canine Atopic Dermatitis, Flea Allergy Dermatitis in dogs or cats, inflammatory bowel disease in dogs or cats, osteoarthritis and inflammatory pain in dogs, cats, horses or cattle, non-infectious recurrent airway disease in horses, insect hypersensitivity in horses, feline asthma, bovine respiratory disease, mastitis in cattle, endometritis in cattle, and swine respiratory disease. 
     
     
         16 . Compound of the general formula (I) as defined in  claim 1  for use in a method for treatment and/or prophylaxis of Canine Atopic Dermatitis and Flea Allergy Dermatitis in dogs or cats. 
     
     
         17 . Compound of the general formula (I) as defined in  claim 1  for use in a method for treatment and/or prophylaxis of osteoarthritis and inflammatory pain in cattle, bovine respiratory disease, mastitis in cattle, endometritis in cattle, and swine respiratory disease. 
     
     
         18 . A method for the production of a medicament for treatment and/or prophylaxis of allergic and/or inflammatory disease in an animal, the method comprising producing the medicament with a compound of the general formula (I) as defined in  claim 1 . 
     
     
         19 . The method of  claim 18 , wherein the medicament is used for treatment and/or prophylaxis in an animal of a disease or disorder selected from the group consisting of atopic dermatitis, Flea Allergy Dermatitis, inflammatory bowel disease, osteoarthritis and inflammatory pain, non-infectious recurrent airway disease, insect hypersensitivity, asthma, respiratory disease, mastitis and endometritis. 
     
     
         20 . The method of  claim 18 , wherein the animal is a domestic animal. 
     
     
         21 . The method of  claim 18 , wherein the animal is a farm animal. 
     
     
         22 . The method of  claim 18  for treatment and/or prophylaxis of a disease or disorder selected from the group consisting of
 Canine Atopic Dermatitis, 
 Flea Allergy Dermatitis in a dog or a cat, 
 inflammatory bowel disease in a dog or a cat, 
 osteoarthritis and inflammatory pain in a dog, a cat, a horse, or cattle, 
 non-infectious recurrent airway disease in a horse, 
 insect hypersensitivity in a horse, 
 feline asthma, 
 bovine respiratory disease, 
 mastitis in cattle, 
 endometritis in cattle, and 
 swine respiratory disease. 
 
     
     
         23 . The method of  claim 18  for treatment and/or prophylaxis of Canine Atopic Dermatitis or Flea Allergy Dermatitis in a dog or a cat. 
     
     
         24 . Medicament comprising a compound of the formula (I) as defined in  claim 1  in combination with an inert, non-toxic, pharmaceutically suitable excipient, for use in a method of treatment and/or prophylaxis of allergic and/or inflammatory disease in an animal. 
     
     
         25 . Method for treatment and/or prevention of allergic and/or inflammatory disease in an animal by administering an effective amount of at least a compound of the formula (I) of  claim 1  to an animal in need thereof. 
     
     
         26 . A compound of the general formula (III) 
       
         
           
           
               
               
           
         
         in which 
         R 1  is 4,4,4-trifluorobutyl, 3-hydroxy-3-methylbutyl, 3-methoxypropyl, 3-hydroxypropyl, 3-hydroxybutyl, 3-hydroxy-2-methylpropyl, 3-hydroxy-2,2-dimethylpropyl, 3-trifluoromethoxypropyl, 2-methoxyethyl, 2-hydroxyethyl, 2-(methyl sulphonyl)ethyl, 3-(methyl sulphonyl)propyl or 2-(1-hydroxycyclopropyl)ethyl; 
         R 4  is difluoromethyl, trifluoromethyl or methyl; and 
         R 5  is hydrogen or fluorine; 
         and a diastereomer, an enantiomer, a metabolite, a salt, a solvate or a solvate of the salts thereof, 
         for use in the treatment and/or prophylaxis of allergic and/or inflammatory diseases in an animal. 
       
     
     
         27 . The Compound of  claim 26  selected from the group consisting of:
 methyl 5-{[(5-fluoro-6-methylpyridin-2-yl)carbonyl]amino}-2-(3-hydroxy-3-methylbutyl)-2H-indazole-6-carboxylate, and 
 methyl 2-(3-hydroxy-3-methylbutyl)-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazole-6-carboxylate, 
 for use in the treatment and/or prophylaxis of allergic and/or inflammatory diseases in an animal.