Novel hydroxyindoles, their use as inhibitors of phosphodiesterase 4, and processes for preparing them

Abstract

The invention relates to substituted 4- or/and 7-hydroxyindoles, to processes for preparing them, to pharmaceutical preparations which comprise these compounds and to the pharmaceutical use of these compounds, which are inhibitors of phosphodiesterase 4, as active compounds for treating diseases which can be influenced by using the compounds according to the invention to inhibit phosphodiesterase 4 activity in immunocompetent cells (e.g. macrophages and lympho-cytes).

1 - 41 . (canceled)  
   
   
       42 . A hydroxyindole of formula 1,  
     
       
         
         
             
             
         
       
       wherein  
       n is 1 or 2, and  
       R 1  
 (i) is —C 1-10 -alkyl, which is straight-chain or branched and optionally substituted, once or more than once, by —OH, —SH, —NH 2 , —NHC 1-6 -alkyl, —N(C 1-6 -alkyl) 2 , —NHC 6-14 aryl, —N(C 6-14 aryl) 2 , —N(C 16 alkyl)(C 6-14 aryl), —NO 2 , —CN, —F, —Cl, —Br, —I, —O—C 1-6 -alkyl, —O—C 6-14 -aryl, —S—C 1-6 -alkyl, —S—C 6-14 aryl, —SO 3 H, —SO 2 C 1-6 alkyl, —SO 2 C 6-14 aryl, —OSO 2 C 1-6 alkyl, —OSO 2 C 6-14 aryl, —COOH, —(CO)C 15 alkyl or —O(CO)C 1-5 alkyl, by mono-, bi- or tricyclic saturated or monounsaturated or polyunsaturated carbocycles having 3-14 ring members, or by mono-, bi- or tricyclic saturated or monounsaturated or polyunsaturated heterocycles having 5-15 ring members and 1-6 heteroatoms which are preferably N, O and S, where the C 6-14 aryl groups and the carbocyclic and heterocyclic substituents can, for their part, be optionally substituted, once or more than once, by —C 1-6 -alkyl, —OH, —NH 2 , —NHC 1-6 -alkyl, —N(C 1-6 -alkyl) 2 , —NO 2 , —CN, —F, —Cl, —Br, —I, —O—C 1-6 -alkyl, —S—C 1-6 -alkyl, —SO 3 H, —SO 2 C 1-6 alkyl, —OSO 2 C 1-6 alkyl, —COOH, —(CO)C 1-5 alkyl or —O(CO)C 1-5 alkyl, and where the alkyl groups on the carbocyclic and heterocyclic substituents can, for their part, be optionally substituted, once or more than once, by —OH, —SH, —NH 2 , —F, —Cl, —Br, —I, —SO 3 H or —COOH, or  
 (ii) is —C 2-10 -alkenyl, which is monounsaturated or polyunsaturated, straight-chain or branched and optionally substituted, once or more than once, by —OH, —SH, —NH 2 , —NHC 1-6 -alkyl, —N(C 1-6 -alkyl) 2 , —NHC 6-14 aryl, —N(C 6-14 aryl) 2 , —N(C 1-6 alkyl)(C 6-14 aryl), —NO 2 , —CN, —F, —Cl, —Br, —I, —O—C 1-6 -alkyl, —O—C 6-14 -aryl, —S—C 1-6 -alkyl, —S—C 6-14 aryl, —SO 3 H, —SO 2 C 1-6 alkyl, —SO 2 C 6-14 aryl, —OSO 2 C 1-6 alkyl, —OSO 2 C 6-14 -aryl, —COOH, —(CO)C 1-5 -alkyl or —O(CO)C 1-5 alkyl, by mono-, bi- or tricyclic saturated or monounsaturated or polyunsaturated carbocycles having 3-14 ring members, or by mono-, bi- or tricyclic saturated or monounsaturated or polyunsaturated heterocycles having 5-15 ring members and 1-6 heteroatoms which are preferably N, O and S, where the C 6-14 aryl groups and the carbocyclic and heterocyclic substituents can, for their part, be optionally substituted, once or more than once, by —C 1-6 -alkyl, —OH, —NH 2 , —NHC 1-6 -alkyl, —N(C 1-6 -alkyl) 2 , —NO 2 , —CN, —F, —Cl, —Br, —I, —O—C 1-6 -alkyl, —S—C 1-6 -alkyl, —SO 3 H, —SO 2 C 1-6 alkyl, —OSO 2 C 1-6 alkyl, —COOH, —(CO)C 1-5 alkyl or —O(CO)C 1-5 alkyl, and where the alkyl groups on the carbocyclic and heterocyclic substituents can, for their part, be optionally substituted, once or more than once, by —OH, —SH, —NH 2 , —F, —Cl, —Br, —I, —SO 3 H or —COOH,  
 
       R 2  and R 3  
 (i) are, in each case independently of each other, hydrogen or —C 1-5 -alkyl, 
 which is optionally substituted, once or more than once, by —OH, —SH, —NH 2 , —NHC 1-6 -alkyl, —N(C 1-6 -alkyl) 2 , —NO 2 , —CN, —F, —Cl, —Br, —I, —O—C 1-6 -alkyl, —S—C 1-6 -alkyl, -phenyl or -pyridyl,  
 -phenyl,  
 which is optionally substituted, once or more than once, by —C 1-3 -alkyl, —OH, —SH, —NH 2 , —NHC 1-3 -alkyl, —N(C 1-3 -alkyl) 2 , —NO 2 , —CN, —COOH, —COOC 1-3 -alkyl, —F, —Cl, —Br, —I, —O—C 1-3 -alkyl, —S—C 1-3 -alkyl or —O(CO)—C 1-3 -alkyl,  
 -pyridyl,  
 which is optionally substituted, once or more than once, by —C 1-3 -alkyl, —OH, —SH, —NO 2 , —CN, —COOH, —COOC 1-3 -alkyl, —F, —Cl, —Br, —I, —O—C 1-3 -alkyl, —S—C 1-3 -alkyl or —O(CO)—C 1-3 -alkyl,  
 where only one of R 2  and R 3  is hydrogen and where the alkyl groups on the carbocyclic and heterocyclic substituents can, for their part, be optionally substituted, once or more than once, by —OH, —SH, —NH 2 , —F, —Cl, —Br, —I, —SO 3 H, —COOH, —(CO)—C 1-5 -alkyl, or —O(CO)C 1-5 -alkyl, or  
 
 (ii) NR 2 R 3  together form a saturated or unsaturated five-membered or six-membered ring which can contain up to 3 heteroatoms, preferably N, S and O, and which is optionally substituted, once or more than once, by —C 1-3 -alkyl, —OH, —SH, —NO 2 , —CN, —COOH, —COOC 1-3 -alkyl, —F, —Cl, —Br, —I, —O—C 1-3 -alkyl, —S—C 1-3 -alkyl or —O(CO)—C 1-3 -alkyl,  
 
       R 4  and R 5  are —H or —OH, where at least one of the two must be —OH, or salts of the compounds according to formula 1.  
     
   
   
       43 . A compound according to  claim 42 , wherein said compound has an asymmetric carbon atom in the D form or L form, or D,L mixtures or, when more than one asymmetrical carbon atom is present, the diastereomeric forms.  
   
   
       44 . A compound according to  claim 42 , wherein n is 2.  
   
   
       45 . A compound according to  claim 42 , wherein R 4 =—OH and R 5 =—H.  
   
   
       46 . A compound according to  claim 42 , wherein —NR 2 R 3  is a phenylamino or pyridylamino which is substituted by one or more halogen atoms.  
   
   
       47 . A compound according to  claim 42 , wherein R 1  is a substituted benzyl radical.  
   
   
       48 . A compound according to  claim 47 , wherein the benzyl radical contains at least one substituent in the ortho position on the phenyl ring.  
   
   
       49 . A compound according to  claim 42  selected from the group consisting 
 N-(3,5-dichloropyridin-4-yl)-[1-(4-fluorobenzyl)-4-hydroxyindol-3-yl]carboxamide,    N-(3,5-dichloropyridin-4-yl)-[1-(4-chlorobenzyl)-7-hydroxyindol-3-yl]glyoxylamide,    N-(3,5-dichloropyridin-4-yl)-[1-(4-chlorobenzyl)-7-hydroxyindol-3-yl]carboxamide,    N-(3,5-dichloropyridin-4-yl)-[1-(4-fluorobenzyl)-4-hydroxyindol-3-yl]glyoxyamide,    N-(3,5-dichloropyridin-4-yl)-[1-(4-fluorobenzyl)-7-hydroxyindol-3-yl]glyoxylamide,    N-(3,5-dichloropyridin-4-yl)-[1-(2-fluorobenzyl)-7-hydroxyindol-3-yl]glyoxylamide,    N-(3,5-dichloropyridin-4-yl)-[1-(3-nitrobenzyl)-7-hydroxyindol-3-yl]glyoxylamide,    N-(3,5-dichloropyridin-4-yl)-[1-(2,6-difluorobenzyl)-7-hydroxyindol-3-yl]glyoxylamide,    N-(3,5-dichloropyridin-4-yl)-[1-(2,4-difluorobenzyl)-7-hydroxyindol-3-yl]glyoxylamide,    N-(3,5-dichloropyridin-4-yl)-[1-(2-chlorobenzyl)-7-hydroxyindol-3-yl]glyoxylamide,    N-(3,5-dichloropyridin-4-yl)-[1-(2,6-dichlorobenzyl)-7-hydroxyindol-3-yl]glyoxylamide,    N-(3,5-dichloropyridin-4-yl)-[1-(2-methylbenzyl)-7-hydroxyindol-3-yl]glyoxylamide,    N-(3,5-dichloropyridin-4-yl)-[1-(2,6-dimethylbenzyl)-7-hydroxyindol-3-yl]glyoxylamide,    N-(3,5-dichloropyridin-4-yl)-(1-hexyl-7-hydroxyindol-3-yl]glyoxylamide,    N-(3,5-dichloropyridin-4-yl)-(1-isobutyl-7-hydroxyindol-3-yl]glyoxylamide,    N-(3,5-dichloropyridin-4-yl)-(1-cyclopropylmethyl-7-hydroxyindol-3-yl]glyoxylamide,    N-(2,6-dichlorophenyl)-[1-(4-fluorobenzyl)-7-hydroxyindol-3-yl]glyoxylamide,    N-(2,6-dichlorophenyl)-[1-(2-fluorobenzyl)-7-hydroxyindol-3-yl]glyoxylamide,    N-(4-pyridyl)-[1-(2-fluorobenzyl)-7-hydroxyindol-3-yl]glyoxylamide,    N-(3,5-dichloropyridin-4-yl)-[1-(4-pyridylmethyl)-7-hydroxyindol-3-yl]glyoxylamide,    1-(4-fluorobenzyl)-7-hydroxyindol-3-yl]glyoxylic acid piperidide,    N-(3,5-dichloropyridin-4-yl)-[1-(4-hydroxybenzyl)-7-hydroxyindol-3-yl]glyoxylamide,    N-(3,5-dichloropyridin-4-yl)-[1-(2-chloro-6-fluorobenzyl)-7-hydroxyindol-3-yl]glyoxylamide,    N-(3,5-dichloropyridin-4-yl)-[1-(2-trifluoromethylbenzyl)-7-hydroxyindol-3-yl]glyoxylamide,    N-methyl-N-(pyridin-4-yl)-[1-(2-fluorobenzyl)-7-hydroxyindol-3-yl]glyoxylamide,    N-(2,6-dimethylpyridin-4-yl)-[1-(2-fluorobenzyl)-7-hydroxyindol-3-yl]glyoxylamide, and    N-(3,5-dichloropyridin-4-yl)-[1-(2-carboxybenzyl)-7-hydroxyindol-3-yl]glyoxylamide,    and physiologically tolerated salts thereof.    
   
   
       50 . A process for preparing a compound according to  claim 42  comprising reacting an indole-3-carboxylic acid of formula 2:  
     
       
         
         
             
             
         
       
       with an acid chloride to form the analogous indole-3-carbonyl chloride of the formula 3 
       
         
           
           
               
               
           
         
       
       reacting the compound of formula 3 with a primary and a secondary amine to form the corresponding amide and eliminating a protecting group to form a compound of formula 1, wherein n=1.  
     
   
   
       51 . A process according to  claim 42 , wherein said acid chloride is thionyl chloride or oxalyl chloride to synthesize the indole-3-carbonyl chlorides according to formula 3.  
   
   
       52 . A process according to  claim 42 , wherein said indole-3-carbonyl chloride according to formula 3 are reacted with primary or secondary amines in the presence of an auxiliary base.  
   
   
       53 . A process according to  claim 42 , wherein said indole-3-carbonyla chloride is reacted with a primar or secondary amine in the presence of an excess of amine.  
   
   
       54 . A process according to  claim 53 , wherein the excess amine is a tertiary amine.  
   
   
       55 . A process according to  claim 52 , wherein indole-3-carbonyl chloride is reacted in the presence of an inorganic base.  
   
   
       56 . A process for preparing a compound according to  claim 42 , comprising reacting an indole formula 4  
     
       
         
         
             
             
         
       
       with oxalyl chloride to form the analogous indol-3-ylglyoxylyl chloride of formula 5  
       
         
           
           
               
               
           
         
       
       reacting the compound of formula 5 with a primary or secondary amine to form the corresponding amide and eliminating a protecting group to form a compound according to formula 1, wherein n is 2.  
     
   
   
       57 . A process according to  claim 56 , wherein indol-3-ylglyoxylyl chlorides according to formula 5 are reacted with primary or secondary amines in the presence of an auxiliary base.  
   
   
       58 . A method for inhibiting PDE 4 comprising administering a sufficient amount of a compound of  claim 42  to a subject to inhibit PDE 4.  
   
   
       59 . A method for treating a disease associated with the activity of eosinophils, comprising administering a therapeutically effective amount of a compound according to  claim 42  to a subject in need thereof.  
   
   
       60 . A method for treating a disease associated with the activity of neutrophils comprising administering a therapeutically effective amount of a compound according to  claim 42  to a subject in need thereof.  
   
   
       61 . A pharmaceutical dosage form comprising at least one compound according to  claim 42  and at least one of a customary, physiologically tolerated excipient, diluent or auxiliary substance.  
   
   
       62 . A process for producing a pharmaceutical dosage form comprising admixing at least one compound according to  claim 42  with a customary pharmaceutical carrier substance, a diluent or an auxiliary substance to form a therapeutically desirable pharmaceutical preparation.  
   
   
       63 . A method of treating modifying the activity of PDE 4 in a subject in need thereof comprising administering the dosage form of  claim 61  to a subject in need thereof, optionally with a different therapeutically active agent.