Pyrido-imidazo rifamycins

Abstract

The present invention relates to novel pyrido-imidazo rifamycins, characterized by a highly selective antibacterial activity and low absorption by oral route.

1 . A method of treating a gastrointestinal disease or a skin, eye, vaginal or dental infection, comprising:
 administering to a therapeutically effective amount of an active ingredient to a subject in need thereof,   wherein the active ingredient is a compound of Formula (I) or pharmaceutically acceptable salts thereof   
       
         
           
           
               
               
           
         
       
       wherein 
       R and R 1  may be H, 
       
         
           
           
               
               
           
         
       
       with the proviso that: 
       when R= 
       
         
           
           
               
               
           
         
       
       then R 1 ═H and R 2 ═CH 3 CO— or H; 
       when R 1 = 
       
         
           
           
               
               
           
         
       
       then R═H and R 2 ═CH 3 CO— or H; 
       when R= 
       
         
           
           
               
               
           
         
       
       then R 1 ═H and R 2 ═CH 3 CO— or H; and 
       when R 1 = 
       
         
           
           
               
               
           
         
       
       then R═H and R 2 ═CH 3 CO— or H;
 wherein R 3  and R 4  are the same or different and selected from the group comprising hydrogen, linear or branched C 1 -C 10  alkyl, optionally substituted with one or more substituents selected from aminoalkyl, alkoxy, phenoxy, or sulfo, and aryl, optionally mono- or disubstituted with C 1 -C 4  alkyl or alkoxy groups, halogen, amino, nitro; or 
 R 3  and R 4  taken together with two consecutive carbon atoms of the pyridine core may form a phenyl ring, optionally substituted with C 1 -C 4  alkyl, or a 5- or 6-membered heterocyclic ring, optionally substituted with C 1 -C 4  alkyl, 
 R 5  is selected from the group comprising hydrogen, hydroxy, linear or branched C 1 -C 10  alkyl, optionally substituted with one or more substituents selected from aminoalkyl, alkoxy, phenoxy, or sulfo, and aryl optionally mono- or disubstituted with C 1 -C 4  alkyl or alkoxy groups, halogen, amino, nitro. 
 
     
     
         2 . The method according to  claim 1 , wherein the aryl, optionally mono- or disubstituted with C 1 -C 4  alkyl or alkoxy groups, halogen, amino, nitro, is selected from phenyl and benzyl. 
     
     
         3 . The method according to  claim 1 , wherein when R 3  and R 4  are taken together with two consecutive carbon atoms of the pyridine core to form a 5- or 6-membered heterocyclic ring, optionally substituted with C 1 -C 4  alkyl, said 5- or 6-membered heterocyclic ring is selected from the group comprising pyrrolidine, piperidine, piperazine, and morpholine. 
     
     
         4 . The method according to  claim 1 , wherein the active ingredient is selected from the group consisting of:
 4′-[(4-methyl-1-piperazinyl)iminomethyl]-4-desoxypyrido[1′,2′-1,2]imidazo[5,4-c]rifamycin SV;   4′-[(1-piperidinyl)iminomethyl]-4-desoxypyrido[1′,2′-1,2]imidazo[5,4-c]rifamycin SV;   4′-[(N,N-dimethylamino)iminomethyl]-4-desoxypyrido[1′,2′-1,2]imidazo[5,4-c]rifamycin SV;   4′-[(4-carboxyamidopyridyl)iminomethyl]-4-desoxypyrido[1′,2′-1,2]imidazo[5,4-c]rifamycin SV;   5′-[(N,N-dimethylamino)iminomethyl]-4-desoxypyrido[1′,2′-1,2]imidazo[5,4-c]rifamycin SV;   5′-[(1-piperidinyl)iminomethyl]-4-desoxypyrido[1′,2′-1,2]imidazo[5,4-c]rifamycin SV;   5′-[(N,N-dimethylamino)iminomethyl]-4-desoxypyrido[1′,2′-1,2]imidazo[5,4-c]rifamycin SV;   4′-[(4-methyl-1-piperazinyl)iminomethyl]-4-desoxypyrido[1′,2′-1,2]imidazo[5,4-c]rifamycin S;   25-desacetyl-5′-[(1-piperidinyl)iminomethyl]-4-desoxypyrido[1′,2′-1,2]imidazo[5,4-c]rifamycin SV;   25-desacetyl-5′-[(N,N-dimethylamino)iminomethyl]-4-desoxypyrido[1′,2′-1,2]imidazo[5,4-c]rifamycin SV;   4′-[(N-morpholinyl)iminomethyl]-4-desoxypyrido[1′,2′-1,2]imidazo[5,4-c]rifamycin SV;   5′-[(N-morpholinyl)iminomethyl]-4-desoxypyrido[1′,2′-1,2]imidazo[5,4-c]rifamycin SV;   25-desacetyl-4′-[(N-morpholinyl)iminomethyl]-4-desoxypyrido[1′,2′-1,2]imidazo[5,4-c]rifamycin SV;   25-desacetyl-5′-[(N-morpholinyl)iminomethyl]-4-desoxypyrido[1′,2′-1,2]imidazo[5,4-c]rifamycin SV;   4′-[(N-propyl,N-butyl)iminomethyl]-4-desoxypyrido[1′,2′-1,2]imidazo[5,4-c]rifamycin SV;   5′-[(N-propyl,N-butyl)iminomethyl]-4-desoxypyrido[1′,2′-1,2]imidazo[5,4-c]rifamycin SV;   25-desacetyl-4′-[(N-propyl,N-butyl)iminomethyl]-4-desoxypyrido[1′,2′-1,2]imidazo[5,4-c]rifamycin SV;   25-desacetyl-5′-[(N-propyl,N-butyl)iminomethyl]-4-desoxypyrido[1′,2′-1,2]imidazo[5,4-c]rifamycin SV;   4′-[(N,N-dipentyl)iminomethyl]-4-desoxypyrido[1′,2′-1,2]imidazo[5,4-c]rifamycin SV;   5′-[(N,N-dipentyl)iminomethyl]-4-desoxypyrido[1′,2′-1,2]imidazo[5,4-c]rifamycin SV;   25-desacetyl-4′-[(N,N-dipentyl)iminomethyl]-4-desoxypyrido[1′,2′-1,2]imidazo[5,4-c]rifamycin SV;   25-desacetyl-5′-[(N,N-dipentyl)iminomethyl]-4-desoxypyrido[1′,2′-1,2]imidazo[5,4-c]rifamycin SV;   4′-[(4-ethyl-1-piperazinyl)iminomethyl]-4-desoxypyrido[1′,2′-1,2]imidazo[5,4-c]rifamycin SV;   5′-[(4-ethyl-1-piperazinyl)iminomethyl]-4-desoxypyrido[1′,2′-1,2]imidazo[5,4-c]rifamycin SV;   25-desacetyl-4′-[(4-ethyl-1-piperazinyl)iminomethyl]-4-desoxypyrido[1′,2′-1,2]imidazo[5,4-c]rifamycin SV;   25-desacetyl-5′-[(4-ethyl-1-piperazinyl)iminomethyl]-4-desoxypyrido[1′,2′-1,2]imidazo[5,4-c]rifamycin SV;   4′-[(4-propyl-1-piperazinyl)iminomethyl]-4-desoxypyrido[1′,2′-1,2]imidazo[5,4-c]rifamycin SV;   5′-[(4-propyl-1-piperazinyl)iminomethyl]-4-desoxypyrido[1′,2′-1,2]imidazo[5,4-c]rifamycin SV;   25-desacetyl-4′-[(4-propyl-1-piperazinyl)iminomethyl]-4-desoxypyrido[1′,2′-1,2]imidazo[5,4-c]rifamycin SV; and   25-desacetyl-5′-[(4-propyl-1-piperazinyl)iminomethyl]-4-desoxypyrido[1′,2′-1,2]imidazo[5,4-c]rifamycin SV; or pharmaceutically acceptable salts thereof.   
     
     
         5 . The method according to  claim 1 , wherein the active ingredient is selected from the group consisting of 4′-[(alkyloxy-iminomethyl]-4-desoxypyrido[1′,2′-1,2]imidazo[5,4-c]rifamycin SV and 4′-[N-alkyliminomethyl]-4-desoxypyrido[1′,2′-1,2]imidazo[5,4-c]rifamycin SV. 
     
     
         6 . The method according to  claim 5 , wherein the active ingredient is selected from the group consisting of 4′-(N-methoxy)-iminomethyl-4-desoxypyrido[1′,2′-1,2]imidazo[5,4-c]rifamycin SV and 4′-(N-isopropyl)-iminomethyl]-4-desoxypyrido[1′,2′-1,2]imidazo[5,4-c]rifamycin SV. 
     
     
         7 . The method according to  claim 1 , wherein the active ingredient is 4′-hydroxymethyl-4-desoxypyrido[1′,2′-1,2]imidazo[5,4-c]rifamycin S or SV, or pharmaceutically acceptable salts thereof. 
     
     
         8 . The method according to  claim 1 , wherein the active ingredient is 4′-formyl-4-desoxypyrido[1′,2′-1,2]imidazo[5,4-c]rifamycin S or SV, or pharmaceutically acceptable salts thereof. 
     
     
         9 . The method according to  claim 1 ,
 wherein the method is a method of treating a gastrointestinal disease, and   wherein the gastrointestinal disease is selected from the group consisting of diseases due to dismicrobism, IBD, Crohn's disease, diverticulosis, and traveler's diarrhea.   
     
     
         10 . The method according to  claim 1 ,
 wherein the method is a method of treating a skin, eye, vaginal or dental infection, and   wherein the skin, eye, vaginal or dental infection is an infection requiring a chronic treatment.   
     
     
         11 . A method of treating dry mastitis, vaginal diseases in cows, intestinal diseases in pets, or a method of auxinic therapy in animal husbandry, comprising:
 administering to a therapeutically effective amount of an active ingredient to a subject in need thereof,   wherein the active ingredient is a compound of Formula (I) or pharmaceutically acceptable salts thereof   
       
         
           
           
               
               
           
         
       
       wherein 
       R and R 1  may be H, 
       
         
           
           
               
               
           
         
       
       with the proviso that: 
       when R= 
       
         
           
           
               
               
           
         
       
       then R 1 ═H and R 2 ═CH 3 CO— or H; 
       when R 1 = 
       
         
           
           
               
               
           
         
       
       then R═H and R 2 ═CH 3 CO— or H; 
       when R= 
       
         
           
           
               
               
           
         
       
       then R 1 ═H and R 2 ═CH 3 CO— or H; and 
       when R 1 = 
       
         
           
           
               
               
           
         
       
       then R═H and R 2 ═CH 3 CO— or H;
 wherein R 3  and R 4  are the same or different and selected from the group comprising hydrogen, linear or branched C 1 -C 10  alkyl, optionally substituted with one or more substituents selected from aminoalkyl, alkoxy, phenoxy, or sulfo, and aryl, optionally mono- or disubstituted with C 1 -C 4  alkyl or alkoxy groups, halogen, amino, nitro; or 
 R 3  and R 4  taken together with two consecutive carbon atoms of the pyridine core may form a phenyl ring, optionally substituted with C 1 -C 4  alkyl, or a 5- or 6-membered heterocyclic ring, optionally substituted with C 1 -C 4  alkyl, 
 R 5  is selected from the group comprising hydrogen, hydroxy, linear or branched C 1 -C 10  alkyl, optionally substituted with one or more substituents selected from aminoalkyl, alkoxy, phenoxy, or sulfo, and aryl optionally mono- or disubstituted with C 1 -C 4  alkyl or alkoxy groups, halogen, amino, nitro. 
 
     
     
         12 . The method according to  claim 11 , wherein the aryl, optionally mono- or disubstituted with C 1 -C 4  alkyl or alkoxy groups, halogen, amino, nitro, is selected from phenyl and benzyl. 
     
     
         13 . The method according to  claim 11 , wherein when R 3  and R 4  are taken together with two consecutive carbon atoms of the pyridine core to form a 5- or 6-membered heterocyclic ring, optionally substituted with C 1 -C 4  alkyl, said 5- or 6-membered heterocyclic ring is selected from the group comprising pyrrolidine, piperidine, piperazine, and morpholine. 
     
     
         14 . The method according to  claim 11 , wherein the active ingredient is selected from the group consisting of:
 4′-[(4-methyl-1-piperazinyl)iminomethyl]-4-desoxypyrido[1′,2′-1,2]imidazo[5,4-c]rifamycin SV;   4′-[(1-piperidinyl)iminomethyl]-4-desoxypyrido[1′,2′-1,2]imidazo[5,4-c]rifamycin SV;   4′-[(N,N-dimethylamino)iminomethyl]-4-desoxypyrido[1′,2′-1,2]imidazo[5,4-c]rifamycin SV;   4′-[(4-carboxyamidopyridyl)iminomethyl]-4-desoxypyrido[1′,2′-1,2]imidazo[5,4-c]rifamycin SV;   5′-[(N,N-dimethylamino)iminomethyl]-4-desoxypyrido[1′,2′-1,2]imidazo[5,4-c]rifamycin SV;   5′-[(1-piperidinyl)iminomethyl]-4-desoxypyrido[1′,2′-1,2]imidazo[5,4-c]rifamycin SV;   5′-[(N,N-dimethylamino)iminomethyl]-4-desoxypyrido[1′,2′-1,2]imidazo[5,4-c]rifamycin SV;   4′-[(4-methyl-1-piperazinyl)iminomethyl]-4-desoxypyrido[1′,2′-1,2]imidazo[5,4-c]rifamycin S;   25-desacetyl-5′-[(1-piperidinyl)iminomethyl]-4-desoxypyrido[1′,2′-1,2]imidazo[5,4-c]rifamycin SV;   25-desacetyl-5′-[(N,N-dimethylamino)iminomethyl]-4-desoxypyrido[1′,2′-1,2]imidazo[5,4-c]rifamycin SV;   4′-[(N-morpholinyl)iminomethyl]-4-desoxypyrido[1′,2′-1,2]imidazo[5,4-c]rifamycin SV;   5′-[(N-morpholinyl)iminomethyl]-4-desoxypyrido[1′,2′-1,2]imidazo[5,4-c]rifamycin SV;   25-desacetyl-4′-[(N-morpholinyl)iminomethyl]-4-desoxypyrido[1′,2′-1,2]imidazo[5,4-c]rifamycin SV;   25-desacetyl-5′-[(N-morpholinyl)iminomethyl]-4-desoxypyrido[1′,2′-1,2]imidazo[5,4-c]rifamycin SV;   4′-[(N-propyl,N-butyl)iminomethyl]-4-desoxypyrido[1′,2′-1,2]imidazo[5,4-c]rifamycin SV;   5′-[(N-propyl,N-butyl)iminomethyl]-4-desoxypyrido[1′,2′-1,2]imidazo[5,4-c]rifamycin SV;   25-desacetyl-4′-[(N-propyl,N-butyl)iminomethyl]-4-desoxypyrido[1′,2′-1,2]imidazo[5,4-c]rifamycin SV;   25-desacetyl-5′-[(N-propyl,N-butyl)iminomethyl]-4-desoxypyrido[1′,2′-1,2]imidazo[5,4-c]rifamycin SV;   4′-[(N,N-dipentyl)iminomethyl]-4-desoxypyrido[1′,2′-1,2]imidazo[5,4-c]rifamycin SV;   5′-[(N,N-dipentyl)iminomethyl]-4-desoxypyrido[1′,2′-1,2]imidazo[5,4-c]rifamycin SV;   25-desacetyl-4′-[(N,N-dipentyl)iminomethyl]-4-desoxypyrido[1′,2′-1,2]imidazo[5,4-c]rifamycin SV;   25-desacetyl-5′-[(N,N-dipentyl)iminomethyl]-4-desoxypyrido[1′,2′-1,2]imidazo[5,4-c]rifamycin SV;   4′-[(4-ethyl-1-piperazinyl)iminomethyl]-4-desoxypyrido[1′,2′-1,2]imidazo[5,4-c]rifamycin SV;   5′-[(4-ethyl-1-piperazinyl)iminomethyl]-4-desoxypyrido[1′,2′-1,2]imidazo[5,4-c]rifamycin SV;   25-desacetyl-4′-[(4-ethyl-1-piperazinyl)iminomethyl]-4-desoxypyrido[1′,2′-1,2]imidazo[5,4-c]rifamycin SV;   25-desacetyl-5′-[(4-ethyl-1-piperazinyl)iminomethyl]-4-desoxypyrido[1′,2′-1,2]imidazo[5,4-c]rifamycin SV;   4′-[(4-propyl-1-piperazinyl)iminomethyl]-4-desoxypyrido[1′,2′-1,2]imidazo[5,4-c]rifamycin SV;   5′-[(4-propyl-1-piperazinyl)iminomethyl]-4-desoxypyrido[1′,2′-1,2]imidazo[5,4-c]rifamycin SV;   25-desacetyl-4′-[(4-propyl-1-piperazinyl)iminomethyl]-4-desoxypyrido[1′,2′-1,2]imidazo[5,4-c]rifamycin SV; and   25-desacetyl-5′-[(4-propyl-1-piperazinyl)iminomethyl]-4-desoxypyrido[1′,2′-1,2]imidazo[5,4-c]rifamycin SV; or pharmaceutically acceptable salts thereof.   
     
     
         15 . The method according to  claim 11 , wherein the active ingredient is selected from the group consisting of 4′-[(alkyloxy-iminomethyl]-4-desoxypyrido[1′,2′-1,2]imidazo[5,4-c]rifamycin SV and 4′-[N-alkyliminomethyl]-4-desoxypyrido[1′,2′-1,2]imidazo[5,4-c]rifamycin SV. 
     
     
         16 . The method according to  claim 15 , wherein the active ingredient is selected from the group consisting of 4′-(N-methoxy)-iminomethyl-4-desoxypyrido[1′,2′-1,2]imidazo[5,4-c]rifamycin SV and 4′-(N-isopropyl)-iminomethyl]-4-desoxypyrido[1′,2′-1,2]imidazo[5,4-c]rifamycin SV. 
     
     
         17 . The method according to  claim 11 , wherein the active ingredient is 4′-hydroxymethyl-4-desoxypyrido[1′,2′-1,2]imidazo[5,4-c]rifamycin S or SV, or pharmaceutically acceptable salts thereof. 
     
     
         18 . The method according to  claim 11 , wherein the active ingredient is 4′-formyl-4-desoxypyrido[1′,2′-1,2]imidazo[5,4-c]rifamycin S or SV, or pharmaceutically acceptable salts thereof. 
     
     
         19 . The method according to  claim 11 ,
 wherein the method is a method of auxinic therapy in animal husbandry, and   
       wherein the animal husbandry is husbandry of chickens, turkeys, ducks, or rabbits.