Compounds and methods for treatment of asthma, allergy and inflammatory disorders

Abstract

The present invention provides 1,4 substituted piperazines, 1,4 substituted piperidines, and 1-substituted,4-alkylidenyl piperidines compounds. The compounds of the invention are dual acting molecules having both leukotriene inhibition properties as well as antihistaminergic properties. The compounds of the invention are useful for treating conditions in which there is likely to be a histamine and/or leukotriene component. These conditions include preferably asthma, seasonal and perennial allergic rhinitis, sinusitus, conjunctivitis, food allergy, scombroid poisoning, psoriasis, urticaria, pruritus, eczema, rheumatoid arthritis, inflammatory bowel disease, chronic obstructive pulmonary disease, thrombotic disease and otitis media. Also provided are methods of treating asthma and rhinitis by administering an effective asthma and rhinitis-relieving amount of the compounds to a subject in need thereof.

We claim:  
     
         1 . A compound of formula I:  
       
         
           
           
               
               
           
         
       
       and the geometrical isomers, enantiomers, diastereomers, and pharmaceutically acceptable salts thereof, wherein: 
 X and X′ independently are hydrogen, halo, alkyl, alkenyl, alkynyl, alkoxy, trifluoromethyl or —(Y′) m —W′;  
 G and G′ together form  
                     
 D is —CH═ or ═N—;  
 R 1  and R 2  independently are hydrogen or together are —(CH 2 ) n - in which n is equal to 0, 1, 2, or 3;  
 m and m′ are independently 0 or 1;  
 Y and Y′ are -L 1 - or -L 2 -V(Z) t -L 3 - in which t is 0 or 1;  
 L 1  is alkylene, alkenylene, alkynylene, or one of the foregoing in which one or more methylenes are replaced by —O—, —S—, —S(O)—, —S(O) 2 —, —N(Q″)-, or —N(R 3 )—;  
 L 2  is (a) alkylene, alkenylene, alkynylene, or one of the foregoing in which one or more methylenes are replaced by —O—, —S—, —S(O)—, —S(O) 2 —, —N(Q′)-, or —N(R 4 )—, or (b) -L 4 -C(O)—N(Q′)- or -L 4 (Q′)-, or (c) a direct bond;  
 L 3  is (a) alkylene, alkenylene, alkynylene, or one of the foregoing in which one or more methylenes are replaced by —O—, —S—, —S(O)—, —S(O) 2 —, —N(Q″)-, or —N(R 5 )—, or (b) a direct bond;  
 L 4  is (a) alkylene; alkenylene, alkynylene, or one of the foregoing in which one or more methylenes are replaced by —O—, —S—, —S(O)—, —S(O) 2 —, —N(Q″)-, or —N(R 5 )—, or (b) a direct bond;  
 V is (a) a divalent arene, a divalent heteroarene, or a divalent saturated heterocycle when t is 0, or (b) a trivalent arene or trivalent heteroarene when t is 1;  
 Q, Q′, and Q″ independently are hydrogen, -AC(O)OR 6 , or -AC(O)NR 6 R 7 ;  
 W and W′ independently are —N(OM)C(O)N(R 8 )R 9 , —N(R 8 )C(O)N(OM)R 9 , —N(OM)C(O)R 8 , —C(O)NR 8 R 9 , or C(O)OR 8 , provided that at least one of W and W′ is —N(OM)C(O)N(R 8 )R 9 , —N(R 8 )C(O)N(OM)R 9 , or —N(OM)C(O)R 8 .  
 Z is -A″N(OM′)C(O)N(R 10 )R 11 , -A″N(R 10 )C(O)N(OM′)R 11 , -A″N(OM′)C(O)R 11 , -A′C(O)N(OM′)R 11 , -A′C(O)NR 10 R 11 , -A′C(O)OR 10 , halo, CH 3 , NR 3 R 4 , NR 3 C(O)R 4 , NO 2 , CN, CF 3 , S(O) 2 NR 3 R 4 , S(O) 2 R 3 , SR 3 , or S(O)R 3 .  
 A, A′ and A″ independently are a direct bond, alkylene, alkenylene, alkynylene, yloalkylaryl, yloarylalkyl, or diyloalkylarene or one of the foregoing in which one or more methylenes are replaced with —O—, —NH—, —S—, —S(O)—, or —S(O) 2 — and/or one or more methylidenes are replaced by ═N—;  
 M and M′ independently are hydrogen, a pharmaceutically acceptable cation, or a metabolically cleavable group; and  
 R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11  are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkylaryl, alkylarylalkyl, or one of the foregoing in which one or more methylenes are replaced by —O—, —NH—, —S—, —S(O)—, or —S(O) 2 — and/or one or more methylidenes are replaced by ═N—;  
 provided that, other than the oxygens bound to the sulfurs in —S(O)— and —S(O) 2 —, when one or more methylenes are replaced with —O—, —NH—, —S—, —S(O)—, or —S(O) 2 — and when one or more methylidenes are replaced with ═N—, such replacement does not result in two heteroatoms being covalently bound to each other;  
 and further provided that when m is 0, W is not —C(O)NR 8 R 9 , or —C(O)OR 8 , and further provided that in the substituent -AC(O)OOR 6 , R 6  cannot be hydrogen when A is a direct bond.  
 
     
     
         2 . The compound of  claim 1  having the formula I″:  
       
         
           
           
               
               
           
         
       
       wherein the substituents are as defined in  claim 1 , and the geometrical isomers, enantiomers, diastereomers, and pharmaceutically acceptable salts thereof.  
     
     
         3 . The compound according to  claim 1  having the formula II:  
       
         
           
           
               
               
           
         
       
       wherein the substituents are as defined in  claim 1 , and the geometrical isomers, enantiomers, diastereomers, and pharmaceutically acceptable salts thereof.  
     
     
         4 . The compound according to  claim 1  having the formula III:  
       
         
           
           
               
               
           
         
       
       wherein the substituents are as defined in  claim 1 , and the geometrical isomers, enantiomers, diastereomers, and pharmaceutically acceptable salts thereof.  
     
     
         5 . The compound according to  claim 3  wherein X is —Cl, X′ is hydrogen, m is 1 and W is —N(OH)C(O)NH 2 .  
     
     
         6 . The compound according to  claim 4  wherein X is —Cl, X′ is hydrogen, m is 1 and W is —N(OH)C(O)NH 2 .  
     
     
         7 . The compound according to  claim 3  wherein X is —Cl, X′ is hydrogen, m is 1, Y is -L 1 -, wherein L 1  is alkynylene, yloalkoxy, or yloalkoxyalkyl.  
     
     
         8 . The compound according to  claim 4  wherein X is —Cl, X′ is hydrogen, m is 1, Y is -L 1 -, wherein L 1  is alkynylene, yloalkoxy, or yloalkoxyalkyl.  
     
     
         9 . The compound according to  claim 3  wherein X is —Cl, X′ is hydrogen, m is 1, Y is -L 2 -V(Z) t -L 3 -, t is 0, V is 1,4-phenylene or 1,3-phenylene, L 2  is yloalkoxy, and L 3  is alkylene, alkenylene, or alkynylene.  
     
     
         10 . The compound according to  claim 4  wherein X is —Cl, X′ is hydrogen, m is 1, Y is -L 2 -V(Z) t -L 3 -, t is 0, V is 1,4-phenylene or 1,3-phenylene, L 2  is yloalkoxy, and L 3  is alkylene, alkenylene, or alkynylene.  
     
     
         11 . The compound according to  claim 3  wherein X is —Cl, X′ is hydrogen, m is 1, Y is -L 2 -V(Z) t -L 3 -, t is 0, V is 2,5-furylene, L 2  is alkylene, and L 3  is alkylene, alkenylene, or alkynylene.  
     
     
         12 . The compound according to  claim 4  wherein X is —Cl, X′ is hydrogen, m is 1, Y is -L 2 -V(Z) t -L 3 -, t is 0, V is 2,5-furylene, L 2  is alkylene, and L 3  is alkylene, alkenylene, or alkynylene.  
     
     
         13 . The compound according to  claim 3  wherein X is —Cl, X′ is hydrogen, m is 1, Y is -L 2 -V(Z) t -L 3 -, t is 1, L 2  is yloalkoxy, V is trivalent heteroarene, Z is -A′C(O)NR 10 R 11  or -A′C(O)OR 10 , and W is —N(OH)C(O)NH 2 .  
     
     
         14 . The compound according to  claim 4  wherein X is —Cl, X′ is hydrogen, m is 1, Y is -L 2 -V(Z) t -L 3 -, t is 1, L 2  is yloalkoxy, V is trivalent heteroarene, Z is -A′C(O)NR 10 R 11  or -A′C(O)OR 10 , and W is —N(OH)C(O)NH 2 .  
     
     
         15 . The compound according to  claim 3  wherein X and X′ are F, m is 1, Y is -L 2 -V(Z) t -L 3 -, t is 0, V is 1,4-phenylene or 1,3-phenylene, L 2  is yloalkoxy, and L 3  is alkylene, alkenylene, or alkynylene.  
     
     
         16 . The compound according to  claim 4  wherein X and X′ are F, m is 1, Y is -L 2 -V(Z) t -L 3 -, t is 0, V is 1,4-phenylene or 1,3-phenylene, L 2  is yloalkoxy, and L 3  is alkylene, alkenylene, or alkynylene.  
     
     
         17 . A compound selected from the group consisting of compounds 1, 5, 11, 12, 13, 17, 23, 24, 31, 32, 33, 34, 35, 36, 37, 40, 41, 42, 43, 44, 45, 46, 48, 49, 50, 52, 53, 54, 55, 56, 57, 58, 59, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, and 94.  
     
     
         18 . A compound selected from the group consisting of compounds 17, 32, 34, 35, 46, 52 and 80.  
     
     
         19 . A compound according to  claim 1  wherein 
 X and X′ independently are hydrogen, halo or —(Y′) m —W;  
 G and G together form  
                     
 D is —CH═ or ═N—;  
 R 1  and R 2  independently are hydrogen or together are —(CH 2 ) 2 —;  
 m and m′ are independently 0 or 1;  
 Y and Y′ are -L 1 - or -L 2 -V(Z) t -L 3 - in which t is 0 or 1;  
 L 1  is alkylene, alkenylene, alkynylene, or one of the foregoing in which one or more methylenes are replaced by —O—;  
 L 2  is (a) alkylene, alkenylene, alkynylene, or one of the foregoing in which one or more methylenes are replaced by —O— or —N(Q′)- or (b) -L 4 -C(O)—N(Q′)-;  
 L 3  is (a) alkylene, alkenylene, alkynylene, or one of the foregoing in which one or more methylenes are replaced by —O— or —N(Q″)-;  
 L 4  is alkylene;  
 V is (a) a divalent arene, a divalent heteroarene, or a divalent saturated heterocycle when t is 0, or (b) a trivalent arene or trivalent heteroarene when t is 1;  
 Q is hydrogen;  
 Q′, and Q″ independently are -AC(O)OR 6 , or -AC(O)NR 6 R 7 ;  
 W and W′ independently are —N(OM)C(O)N(R 8 )R 9 , —N(R 8 )C(O)N(OM)R 9 , —N(OM)C(O)R 8 , —C(O)NR 8 R 9 , or —C(O)OR 8 , provided that at least one of W and W′ is —N(OM)C(O)N(R 8 )R 9 , —N(R 8 )C(O)N(OM)R 9 , or —N(OM)C(O)R 8 .  
 Z is -A′C(O)NR 10 R 11 , -A′C(O)OR 10 , halo, NR 3 C(O)R 4 , NO 2 , CN or CF 3 ;  
 A and A′ independently are a direct bond, alkylene, alkenylene, alkynylene, or one of the foregoing in which one or more methylenes are replaced with —O—;  
 M and M′ independently are hydrogen, a pharmaceutically acceptable cation, or a metabolically cleavable group; and  
 R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 , if present, are independently hydrogen or alkyl in which one or more methylenes may be replaced by —O—;  
 provided that, other than the oxygens bound to the sulfurs in —S(O)— and —S(O) 2 —, when one or more methylenes are replaced with —O—, —NH—, —S—, —S(O)—, or —S(O) 2 — and when one or more methylidenes are replaced with ═N—, such replacement does not result in two heteroatoms being covalently bound to each other;  
 and further provided that when m is 0, W is not —C(O)NR 8 R 9 , or —C(O)OR 8 ,  
 and further provided that in the substituent -AC(O)OOR 6 , R 6  cannot be hydrogen when A is a direct bond.  
 
     
     
         20 . A compound according to  claim 19  wherein 
 X and X′ independently are —H or halo;  
 G and G together form  
                     
 Y is -L 2 -V(Z) t -L 3 - in which t is 0 or 1;  
 L 2  is C 1  to C 6  alkylene in which one or more methylenes may be replaced by —O— 
 V(Z) t  is phenylene optionally substituted by -A′C(O)NR 10 R 11 , -A′C(O)OR 10 , halo, NR 3 C(O)R 4 , NO 2 , CN or CF 3  or furylene or oxolanylene;  
 L 3  is C 1  to C 6  alkylene in which one or more methylenes may be replaced by —O— or C 2  to C 6  alkynylene;  
 W is —N(OM)C(O)N(R 8 )R 9 , —N(R 8 )C(O)N(OM)R 9  or —N(OM)C(O)R 8    
 A′ is methylene, vinylene or a direct bond.  
 R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 , if present, are independently hydrogen or C 1  to C 6  alkyl in which one or more methylenes may be replaced by —O—.  
 
     
     
         21 . A compound according to  claim 20  wherein 
 X is fluorine or chlorine;  
 X′ is hydrogen or fluorine;  
 Y is -L 2 -V(Z) t -L 3 - in which t is 0 or 1;  
 L 2  is C 1  to C 6  alkylene in which one methylene may be replaced by —O— 
 V(Z) t  is phenylene optionally substituted by -A′C(O)NR 10 R 11 , -A′C(O)OR 10 , halo, NR 3 C(O)R 4 , NO 2 , CN or CF 3  or furylene or oxolanylene;  
 L 3  is C 1  to C 6  alkylene in which one methylene may be replaced by —O— or C 2  to C 6  alkynylene;  
 W is —N(OH)C(O)NH 2 ;  
 A′ is methylene , vinylene or a direct bond  
 R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 , if present, are independently hydrogen or C 1  to C 6  alkyl in which one methylene may be replaced by —O—.  
 
     
     
         22 . A compound according to  claim 1  wherein 
 X and X′ independently are hydrogen, halo, alkyl, alkenyl, alkynyl, alkoxy or trifluoromethyl;  
 W is —N(OM)C(O)N(R 8 )R 9 , —N(R 8 )C(O)N(OM)R 9  or —N(OM)C(O)R 8 ;  
 
     
     
         23 . A compound according to  claim 1  wherein 
 L 4  is alkylene  
 Z is —N(OM′)C(O)N(R 10 )R 11 , —N(R 10 )C(O)N(OM′)R 11 , —N(OM′)C(O)R 11 , -A′C(O)N(OM′)R 11 , -A′C(O)NR 10 R 11  or -A′C(O)OR 10 .  
 
     
     
         24 . A compound according to  claim 1  wherein 
 X and X′ independently are —H, halo, alkyl, alkenyl, alkynyl, alkoxy or trifluoromethyl;  
 L 4  is alkylene  
 W is —N(OM)C(O)N(R 8 )R 9 , —N(R 8 )C(O)N(OM)R 9  or —N(OM)C(O)R 8 ;  
 Z is —N(OM′)C(O)N(R 10 )R 11 , —N(R 10 )C(O)N(OM′)R 11 , —N(OM′)C(O)R 11 , -A′C(O)N(OM′)R 11 , -A′C(O)NR 10 R 11  or -A′C(O)OR 10 .  
 
     
     
         25 . A compound according to  claim 1  wherein when M or M′ is a metabolically cleavable group this is selected from an organic or inorganic anion, a pharmaceutically acceptable cation, acyl, alkyl, phosphate, sulfate and sulfonate, NH 2 C(O)— or (alkyl)OC(O)—.  
     
     
         26 . A compound according to  claim 25  wherein acyl is (alkyl)C(O), including acetyl, propionyl and butyryl.  
     
     
         27 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound according to claims  1 .  
     
     
         28 . A method of simultaneously inhibiting both leukotriene- and histamine- mediated biological processes, the method comprising administering an effective leukotriene- and histamine- inhibiting amount of a compound according to  claim 1  to a subject in need of such inhibition.  
     
     
         29 . A method of treating asthma, seasonal and perennial allergic rhinitis, sinusitus, conjunctivitis, food allergy, scombroid poisoning, psoriasis, urticaria, pruritus, eczema, rheumatoid arthritis, inflammatory bowel disease, chronic obstructive pulmonary disease, thrombotic disease and otitis media, the method comprising administering to a patient suffering from asthma, seasonal and perennial allergic rhinitis, sinusitus, conjunctivitis, food allergy, scombroid poisoning, psoriasis, urticaria, pruritus, eczema, rheumatoid arthritis, inflammatory bowel disease, chronic obstructive pulmonary disease, thrombotic disease and otitis media, an amount of a compound according to  claim 1  sufficient to reduce or eliminate the asthma.  
     
     
         30 . A method according to  claim 29  wherein the disease to be treated is selected from asthma and seasonal and perennial rhinitis.