Novel anti-infective and anti-inflammatory compounds

Abstract

Lysosomally accumulated substances that release a nitroxy group, or a short chain fatty acid or a product of anaerobic metabolism or a thiol or a sulfide often from an ester or similar labile linkage have anti-inflammatory, anti-cancer and anti-bacterial activity. They are useful in treating infectious, inflammatory and malignant disease.

1 . A compound, or salt thereof, comprising an amphiphilic lysosomally trapped compound (alc) conjugated via an ester, thioester, amide, or nitroester to one or more products of anaerobic metabolism (pams) of the same or different types. 
     
     
         2 . The compound as in  claim 1  in which the PAM is selected from one or more of Short Chain Fatty Acid (SCFA), NO, H 2 S, mercaptans, polyamines, decarboxylated amino acids, TLR ligands, or polyphenol metabolites like phenylpropionic acid. 
     
     
         3 . The compound as in  claim 1  in which the ALC is selected from a macrolide, polyamine, propranolol analog, chloroquine analog, amodiaquine, dextromethorphan, dextrorphan, paroxetine, fluoxetine, astemizole or imipramine analog. 
     
     
         4 . A method of stimulating immune or epithelial cells to form an anti-infective barrier or anti-infective response comprising contacting the cells with a compound of Formula 1, or salt thereof, wherein the contacting results in the intracellular release of a PAM comprising one or more of a molecule type selected from TLR ligands, SCFA, NO, H 2 S, sulfides, polyamines, decarboxylated amino acids or polyphenol metabolites like phenylpropionic acid from the compound of Formula 1, or salt thereof. 
     
     
         5 . The method as in  claim 4  comprising the intracellular release of one or more types of a short chain fatty acid moiety from the compound of Formula 1. 
     
     
         6 . The method as in  claim 5  comprising the intracellular release of a short chain fatty acid moiety containing 2 or more carbons from an appropriate carrier molecule. 
     
     
         7 . (canceled) 
     
     
         8 . The compound of  claim 1 , wherein the compound is one of the following:
 (Formula 2)   
       
         
           
           
               
               
           
         
         Wherein, 
         X=—N(CH 3 )—CH 2 —;
 —CH 2 —N[(CH 2 ) n —CH 3 ]— wherein n is 0-4; 
 —C(═O)—; 
 —C(═NOR 8 )—; 
 —C(═NR 12 )—; 
 
         R 1  is:
 -(C 1 -C 10 )alkyl; 
 -(C 1 -C 10 )alkyliden-OH; 
 -(C 1 -C 10 )alkyliden-ONO 2 ; 
 
         R 2  is:
 —H; 
 —NO (y)  with y=1 or 2; 
 —C(═O)OR 7 , —C(═S)OR 7 , —C(═O)R 7 , —C(═S)R 7 , —C(═O)(NH)R 7 , —C(═S)(NH)R 7 ; 
 
         R 3  is:
 —H; 
 —NO (y)  with y=1 or 2; 
 —C(═O)OR 7 , —C(═S)OR 7 , —C(═O)R 7 , —C(═S)R 7 , —C(═O)(NH)R 7 , —C(═S)(NH)R 7 ; 
 
         If Z=O, R 4  is:
 —H; 
 —NO (y)  with y=1 or 2; 
 —C(═O)OR 7 , —C(═S)OR 7 , —C(═O)R 7 , —C(═S)R 7 , —C(═O)(NH)R 7 , —C(═S)(NH)R 7 ; 
 
         R 5  is:
 —H; 
 —NO (y)  with y=1 or 2; 
 —C(═O)OR 7 , —C(═S)OR 7 , —C(═O)R 7 , —C(═S)R 7 , —C(═O)(NH)R 7 , —C(═S)(NH)R 7 ; 
 
         or Z=O or NR 9  and the R 4  and R 5  bearing atoms are connected via —C(═O)— (If Z=O: carbonate linkage, if Z=NR 9 : carbamate linkage);
 or the R 4  and R 5  bearing atoms are connected via W;
 W is: 
 —(—)CH-(C 1 -C 12 )alkyl; 
 —(—)CH-(C 3 -C 12 )alkenyl; 
 —(—)CH-(C 3 -C 12 )alkynyl; 
 —(—)CH-(C 1 -C 8 )[(C 1 -C 4 )alkoxy]alkyl; 
 —(—)CH-(C 1 -C 8 )[(C 1 -C 4 )alkoxy]alkenyl; 
 
 wherein alkyl, alkenyl, alkynyl are optionally substituted by one to five substituents selected independently from halogen, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkenyl, (C 1 -C 4 )alkynyl, (C 3 -C 7 )cycloalkyl, (C 1 -C 6 )heterocycloalkyl, (C 6 -C 10 )aryl, (C 1 -C 9 )heteroaryl, (C 1 -C 4 )alkoxy, hydroxy, nitro, cyano, azido, mercapto, —NR 14 R 15 , R 14 C(═O)—, R 14 C(═O)O—R 14 OC(═O)O—, R 14 NHC(═O)—, R 14 C(═O)NH—, R 14 R 15 NC(═O)—, R 14 OC(═O)—, and —xNO 2  with x=O;S;N; 
 
         R 6  is:
 —H; 
 —NO (y)  with y=1 or 2; 
 —C(═O)OR 7 , —C(═S)OR 7 , —C(═O)R 7 , —C(═S)R 7 , —C(═O)(NH)R 7 , —C(═S)(NH)R 7 ; 
 
         each R 7  is independently:
 —H; 
 -ferrocene; 
 -C 1 -C 10  alkyl, alkenyl, alkynyl, aryl, heteroaryl, alkylaryl, alkylheteroaryl wherein alkyl, alkenyl, alkynyl, aryl, heteroaryl, alkylaryl and alkylheteroaryl groups are optionally substituted by one to five substituents selected independently from: 
 ferrocene, halogen (as can be F, Cl, Br, I), (C 1 -C 4 )alkyl, (C 1 -C 4 )alkenyl, (C 1 -C 4 )alkynyl, (C 3 -C 7 )cycloalkyl, (C 1 -C 6 )heterocycloalkyl, (C 6 -C 10 )aryl, (C 1 -C 9 )heteroaryl, (C 1 -C 4 )alkoxy, hydroxyl (—OH), nitro (—NO 2 ), cyano (—CN), azido (—N 3 ), mercapto (—SH), —NR 14 R 15 , R 14 C(═O)—, R 14 C(═O)O—, R 14 OC(═O)O—, R 14 NHC(═O)—, R 14 C(═O)NH—, R 14 R 15 NC(═O)—, R 14 OC(═O)—, and —XNO (y)  with X=O; S; N and y=1 or 2; 
 
         R 8  is:
 —H; 
 —NO (y)  with y=1 or 2; 
 —C(═O)—R 7 ; 
 -(C 1 -C 12 )alkyl; 
 -(C 1 -C 12 )alkenyl; 
 -(C 1 -C 12 )alkynyl; 
 -(C 1 -C 8 )[(C 1 -C 4 )alkoxy]alkyl; 
 -(C 1 -C 8 )[(C 1 -C 4 )alkoxy]alkenyl; 
 -(C 6 -C 10 )aryl-(C 1 -C 5 )alkyl; 
 -(C 2 -C 9 )heteroaryl-(C 1 -C 5 )alkyl; 
 
         R 9  is:
 —H; 
 —NO (y)  with y=1 or 2; 
 —C(═O)—R 7 ; 
 -(C 1 -C 12 )alkyl; 
 -(C 1 -C 12 )alkenyl; 
 -(C 1 -C 12 )alkynyl; 
 -(C 1 -C 8 )[(C 1 -C 4 )alkoxy]alkyl; 
 -(C 1 -C 8 )[(C 1 -C 4 )alkoxy]alkenyl; 
 -(C 6 -C 10 )aryl-(C 1 -C 5 )alkyl; 
 -(C 2 -C 9 )heteroaryl-(C 1 -C 5 )alkyl; 
 
         R 12  is:
 —H; 
 —NO (y)  with y=1 or 2; 
 —C(═O)—R 7 ; 
 -(C 1 -C 12 )alkyl; 
 -(C 1 -C 12 )alkenyl; 
 -(C 1 -C 12 )alkynyl; 
 -(C 1 -C 8 )[(C 1 -C 4 )alkoxy]alkyl; 
 -(C 1 -C 8 )[(C 1 -C 4 )alkoxy]alkenyl; 
 -(C 6 -C 10 )aryl-(C 1 -C 5 )alkyl; 
 -(C 2 -C 9 )heteroaryl-(C 1 -C 5 )alkyl; 
 
         R 14 , R 15  are each independently:
 —H; 
 -(C 1 -C 12 )alkyl; 
 -(C 1 -C 12 )alkenyl; 
 -(C 1 -C 12 )alkynyl; 
 -(C 1 -C 8 )[(C 1 -C 4 )alkoxy]alkyl; 
 -(C 1 -C 8 )[(C 1 -C 4 )alkoxy]alkenyl; 
 -(C 6 -C 10 )aryl-(C 1 -C 5 )alkyl; 
 -(C 2 -C 9 )heteroaryl-(C 1 -C 5 )alkyl; 
 wherein alkyl, alkenyl, alkynyl, aryl and heteroaryl are optionally substituted by one to five substituents selected independently from halogen (as can be F, Cl, Br, I), (C 1 -C 4 )alkyl, (C 1 -C 4 )alkenyl, (C 1 -C 4 )alkynyl, (C 3 -C 7 )cycloalkyl, (C 1 -C 6 )heterocycloalkyl, (C 6 -C 10 )aryl, (C 1 -C 9 )heteroaryl, (C 1 -C 4 )alkoxy, hydroxyl (—OH), nitro (—NO 2 ), cyano (—CN), azido (—N 3 ), mercapto (—SH), and —XNO y  with X=O; S; N and y=1 or 2; 
 or N(R 14 R 15 ) is an aziridine, azetidine, pyrrolidine, piperidine, azepane or azocane, 1-substituted piperazine, or morpholine moiety. 
 
       
     
     
         9 . The compound of  claim 1 , wherein the compound is one of the following:
 1. Formula 3:   
       
         
           
           
               
               
           
         
         Wherein R 1 ,R 2 ,R 4 ,R 5 ,R 6 , X and Z are defined as in formula 2; 
         R 3a , R 3b =both —H;
 or if R 3a  is —H, then R 3b  is: 
 —OH; 
 —OR 14 ; 
 NR 14 R 15 ; 
 —C(═O)—R 7 ; 
 
         or R 3a =R 3b =(═O);
 =a cyclic or non-cyclic acetal; 
 (=NR 12 ); 
 =a cyclic or non-cyclic aminal; 
 —OC(═O)R 7 ; 
 OR 14 ; 
 
         and R 7 , R 14 , and R 15  are defined as in formula 2 in  claim 8 ; 
         or salt thereof. 
       
     
     
         10 . A compound as in: 
       
         
           
           
               
               
           
         
         Where X is O or S; 
         When X=O, R 1  is —(C═O)CH 3 , —(C═O)CH 2 CH 3 , —(C═O)CH 2 CH 2 CH 3 , —(C═O)CH 2 CH 2 COOH, —(C═O)(C═O)CH 3 , —(C═O)CHCHCOOH, —(C═O)CH(OH)CH 3 , —(C═O)C(CH 3 ) 2 , —(C═O)CH 2 CH 2 CH 2 CH 3 , —(C═O)CH 2 C(CH 3 ) 2 , —(C═O)CH 2 CH 2 CH 2 CH 2 Y, or —(C═O)CH(ONO 2 )CH 3 ; 
         R 2 =R 3 =H; 
         Y=a 5-membered saturated ring containing a disulfide bond; or 
         When X=O, R 1  is —(C═O)CH 3 , —(C═O)CH 2 CH 3 , —(C═O)CH 2 CH 2 CH 3 , —(C═O)CH 2 CH 2 COOH, —(C═O)(C═O)CH 3 , —(C═O)CHCHCOOH, —(C═O)CH(OH)CH 3 , —(C═O)C(CH 3 ) 2 , —(C═O)CH 2 CH 2 CH 2 CH 3 , —(C═O)CH 2 C(CH 3 ) 2 , —(C═O)CH 2 CH 2 CH 2 CH 2 Y, or —(C═O)CH(ONO 2 )CH 3 ; 
         R 2 =CH 3 ; R 3 =H; or 
         When X=O, R 1 =NO 2 ; R 2  consists of linker —CH 2 CH 2 OR 4 , where R 4  is —(C═O)CH 3 , —(C═O)CH 2 CH 3 , —(C═O)CH 2 CH 2 CH 3 , —(C═O)CH 2 CH 2 COOH, —(C═O)(C═O)CH 3 , —(C═O)CHCHCOOH, —(C═O)CH(OH)CH 3 , —(C═O)C(CH 3 ) 2 , —(C═O)CH 2 CH 2 CH 2 CH 3 , —(C═O)CH 2 C(CH 3 ) 2 , or —(C═O)CH 2 CH 2 CH 2 CH 2 Y; R 3 =H; 
         Y =a 5-membered saturated ring containing a disulfide bond; or 
         When X=O, R 1  is —(C═O)CH 3 , —(C═O)CH 2 CH 3 , —(C═O)CH 2 CH 2 CH 3 , —(C═O)CH 2 CH 2 COOH, —(C═O)(C═O)CH 3 , —(C═O)CHCHCOOH, —(C═O)CH(OH)CH 3 , —(C═O)C(CH 3 ) 2 , —(C═O)CH 2 CH 2 CH 2 CH 3 , —(C═O)CH 2 C(CH 3 ) 2 , —(C═O)CH 2 CH 2 CH 2 CH 2 Y, or —(C═O)CH(ONO 2 )CH 3 ; 
         Y=a 5-membered saturated ring containing a disulfide bond; 
         R 2  consists of linker —CH 2 CH 2 OR 4 , where R 4 =NO 2 ; R 3 =H; or 
         When X=O, R 1  is NO 2 , R 2 =H or CH 3 , R 3 =OR 5 , where R 5  is —(C═O)CH 3 , —(C═O)CH 2 CH 3 , —(C═O)CH 2 CH 2 CH 3 , —(C═O)CH 2 CH 2 COOH, —(C═O)(C═O)CH 3 , —(C═O)CHCHCOOH, —(C═O)CH(OH)CH 3 , —(C═O)C(CH 3 ) 2 , —(C═O)CH 2 CH 2 CH 2 CH 3 , —(C═O)CH 2 C(CH 3 ) 2 , —(C═O)CH 2 CH 2 CH 2 CH 2 Y, or —(C═O)CH(ONO 2 )CH 3 ; 
         Y=a 5-membered saturated ring containing a disulfide bond; or 
         When X=S, R 1  is —(C═O)CH 3 , a metal salt, or forms a disulfide bridge with itself, R 2 =R 3 =H. 
       
     
     
         11 . The compound of  claim 3 , wherein the ALC is selected from a compound of Formula 5: 
       
         
           
           
               
               
           
         
         Wherein 
         Mac=a macrolide ring or macrolide ring system, for example, but not limited to azithromycin or gamithromycin, each without the desosamin residue. 
       
     
     
         12 . The compound of  claim 3 , wherein the ALC is selected from a compound of Formula 6: 
       
         
           
           
               
               
           
         
         Wherein 
         Mac=a macrolide ring or macrolide ring system, for example, but not limited to azithromycin or gamithromycin, each without the desosamin residue 
         R′=independently of each other
 —H; 
 —NO (y)  with y=1 or 2; 
 —C(═O)OR 3 , —C(═S)OR 3 , —C(═O)R 3 , —C(═S)R 3 , —C(═O)(NH)R 3 , —C(═S)(NH)R 3 ; 
 R 1 , R 2 =independently of each other H, OH, OR 4 , -C 1 -C 10  alkyl, alkenyl, alkynyl, aryl, heteroaryl, alkylaryl, alkylheteroaryl; 
 wherein alkyl, alkenyl, alkynyl, aryl, heteroaryl, alkylaryl and alkylheteroaryl groups are optionally substituted by one to five substituents selected independently from: fluorine, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkenyl, (C 1 -C 4 )alkynyl, (C 3 -C 7 )cycloalkyl, (C 1 -C 9 )heterocycloalkyl, (C 6 -C 10 )aryl, (C 1 -C 9 )heteroaryl, (C 1 -C 4 )alkoxy, hydroxyl (—OH), nitro (—NO 2 ), cyano (—CN), azido (—N 3 ), mercapto (—SH), (C 1 -C 4 )alkthio, —NR 4 R 5 , R 4 C(═O)—, R 4 C(═O)O—, R 4 OC(═O)O—, R 4 NHC(═O)—, R 4 C(═O)NH—, R 4 R 5 NC(═O)—, R 4 OC(═O)—, and —XNO (y)  with X=O; S; N and y=1 or 2; 
 or N(R 1 R 2 ) is an aziridine, azetidine, pyrrolidine, piperidine, azepane or azocane, 1-substituted piperazine, or morpholine moiety; 
 R 3 =-C 1 -C 10  alkyl, alkenyl, alkynyl, aryl, heteroaryl, alkylaryl, alkylheteroaryl wherein alkyl, alkenyl, alkynyl, aryl, heteroaryl, alkylaryl and alkylheteroaryl groups are optionally substituted by one to five substituents selected independently from: halogen, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkenyl, (C 1 -C 4 )alkynyl, (C 3 -C 7 )cycloalkyl, (C 1 -C 9 )heterocycloalkyl, (C 6 -C 10 )aryl, (C 1 -C 9 )heteroaryl, (C 1 -C 4 )alkoxy, hydroxyl (—OH), nitro (—NO 2 ), cyano (—CN), azido (—N 3 ), mercapto (—SH), (C 1 -C 4 )alkthio, —NR 6 R 7 , R 6 C(═O)—, R 6 C(═O)O—, R 6 OC(═O)O—, R 6 NHC(═O)—, R 6 C(═O)NH—, R 6 R 7 NC(═O)—, R 6 OC(═O)—, and —XNO (y)  with X=O; S; N and y=1 or 2; 
 
         R 4 , R 5 , R 6  and R 7  are each independently:
 —H; 
 -(C 1 -C 12 )alkyl; 
 -(C 1 -C 12 )alkenyl; 
 -(C 1 -C 12 )akynyl; 
 -(C 1 -C 8 )[(C 1 -C 4 )alkoxy]alkyl; 
 -(C 1 -C 8 )[(C 1 -C 4 )alkoxy]alkenyl; 
 -(C 6 -C 10 )aryl-(C 1 -C 5 )alkyl; 
 -(C 2 -C 9 )heteroaryl-(C 1 -C 5 )alkyl; 
 
         wherein alkyl, alkenyl, alkynyl, aryl and heteroaryl are optionally substituted by one to five substituents selected independently from ferrocene, halogen, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkenyl, (C 1 -C 4 )alkynyl, (C 3 -C 7 )cycloalkyl, (C 1 -C 9 )heterocycloalkyl, (C 6 -C 10 )aryl, (C 1 -C 9 )heteroaryl, (C 1 -C 4 )alkoxy, hydroxyl (—OH), (C 1 -C 6 )acyloxy, nitro (—NO 2 ), cyano (—CN), azido (—N 3 ), mercapto (—SH), and —XNO y  with X=O; S; N and y=1 or 2. 
       
     
     
         13 . The compound of  claim 8 , wherein the number of PAMs is 0. 
     
     
         14 . The compound of  claim 9 , wherein the number of PAMs is 0. 
     
     
         15 . A non-nitrate salt of a compound as in  claim 1 . 
     
     
         16 . A pharmaceutical composition comprising a compound of  claim 1 , or salt, solvate, or hydrate thereof, and a pharmaceutically acceptable carrier. 
     
     
         17 . The composition of  claim 16 , further comprising an additional therapeutic agent. 
     
     
         18 . A method of treating a disease, disorder, or symptom thereof in a subject comprising administering to the subject a compound of  claim 1 , or salt, solvate, or hydrate thereof. 
     
     
         19 . The method of  claim 18 , wherein the disease or disorder is an infectious disease, an inflammatory disease, or a malignant disease. 
     
     
         20 . The method of  claim 18 , further comprising administering an antibacterial compound. 
     
     
         21 . The method of  claim 18 , further comprising administering a macrolide compound.