Prophylactic and therapeutic treatment of infectious and other diseases with immunoeffector compounds

Abstract

Methods and compositions for treating or ameliorating diseases and other conditions, such as infectious diseases, autoimmune diseases and allergies are provided. The methods employ cyclic AGPs for selectively stimulating immune responses in animals and plants.

1 . A method for ameliorating or substantially preventing an infectious disease, autoimmune disease or allergic condition in a subject comprising contacting the subject with an effective amount of one or more compounds having the formula:  
       
         
           
           
               
               
           
         
         and pharmaceutically acceptable salts there of, wherein X is a member selected from the group consisting of —O— and —NH—;  
         Y is a member selected from the group consisting of —O— and —S—;  
         R 1 , R 2  and R 3  are each members independently selected from the group consisting of (C 2 -C 20 )acyl;  
         R 4  is a member selected from the group consisting of —H and —PO 3 R 7 R 8 , wherein R 7  and R 8  are each members independently selected from the group consisting of —H and (C 1 -C 4 )aliphatic groups;  
         R 5  is a member selected from the group consisting of —H, —CH 3  and —PO 3 R 9 R 10 , wherein R 9  and R 10  are each members independently selected from the group consisting of —H and (C 1 -C 4 )aliphatic groups;  
         R 6  is selected from H, OH, (C 1 -C 4 )oxyaliphatic groups, —PO 3 R 11 R 12 , —OPO 3 R 11 R 12 , —SO 3 R 11 , —OSO 3 R 11 , —NR 11 R 12 , —SR 11 , —CN, —NO 2 , —CHO, —CO 2 R 11 , and —CONR 11 R 2 , wherein R 11  and R 12  are each independently selected from H and (C 1 -C 4 )aliphatic groups, with the provisos that one of R 4  and R 5  is a phosphorus-containing group and that when R 4  is —PO 3 R 7 R 8 , R 5  is other than —PO 3 R 9 R 10 ;  
         wherein “* 1 ”, “* 2 ” and “* 3 ” represent chiral centers;  
         wherein n, m, p and q are each independently an integer from 0 to 6, with the proviso that the sum of p and m is from 0 to 6.  
       
     
     
         2 . The method of  claim 1 , wherein X and Y are —O—, R 1  is PO 3 R 7 R 8 , R 5  and R 6  are H, and n, m, p, and q are integers from 0 to 3.  
     
     
         3 . The method of  claim 2 , wherein R 7  and R 8  are —H.  
     
     
         4 . The method of  claim 2 , wherein n, m, p, and q are from 0 to 2.  
     
     
         5 . The method of  claim 2 , wherein n is 1, m is 2, and p and q are 0.  
     
     
         6 . The method of  claim 1  wherein R 1 , R 2  and R 3  are each C 6 -C 14  acyl.  
     
     
         7 . The method of  claim 1  wherein R 1 , R 2 ; and R 3  are each C 6 -C 12  acyl.  
     
     
         8 . The method of  claim 5  wherein R 1 , R 2 , and R 3  are each decanoyl residues.  
     
     
         9 . The method of  claim 5  wherein R 1 , R 2 , and R 3  are each dodecanoyl residues.  
     
     
         10 . The method of  claim 5 , wherein R 1 , R 2 , and R 3  are each tetradecanoyl residues.  
     
     
         11 . The method of  claim 5 , wherein * 1 , * 2 , and * 3  are in the R configuration.  
     
     
         12 . The method of  claim 5 , wherein Y is in the equatorial position.  
     
     
         13 . The method of  claim 5 , wherein ** is in the S configuration.  
     
     
         14 . The method of  claim 5 , wherein * 1 , * 2 , and * 3  are in the R configuration, wherein Y is in the equatorial position, and wherein ** is in the S configuration.  
     
     
         15 . The method of  claim 1 , wherein the infectious disease is caused by a bacteria, a virus, a parasite, or a fungus.  
     
     
         16 . The method of  claim 15 , wherein said bacteria is a gram negative bacteria, or a gram positive bacteria.  
     
     
         17 . The method of  claim 15 , wherein the infectious disease is caused by a bacteria selected from the group consisting of  Pseudomonas, Escherichia, Klebsiella, Enterobacter, Proteus, Serratia, Candida, Bacillus , and  Staphylococcus.    
     
     
         18 . The method of  claim 17 , wherein the infectious disease is pneumonia.  
     
     
         19 . The method of  claim 18 , wherein said pneumonia is nosocomial pneumonia.  
     
     
         20 . The method of  claim 19 , wherein said pneumonia is in an HIV-positive patient.  
     
     
         21 . The method of  claim 1 , wherein said infectious disease is a chronic infection.  
     
     
         22 . The method of  claim 21 , wherein said chronic infection comprises chronic hepatitis, human papillomavirus, oral or vaginal candidiasis, periodontal disease or chronic rhinosinusitis due to fungal colonization.  
     
     
         23 . The method of  claim 1 , wherein said allergic condition is selected from the group consisting of asthma, atopic dermatitis, seasonal allergic disorder and chronic rhinosinusitis.  
     
     
         24 . The method of  claim 1 , wherein said autoimmune disease is selected from the group consisting of inflammatory bowel disease, rheumatoid arthritis, chronic arthritis, multiple sclerosis and psoriasis.  
     
     
         25 . The method of  claim 1 , wherein said compound is administered to said animal by a route selected from the group consisting of parenteral, oral, intravenous, infusion, intranasal, inhalation, transdermal and transmucosal.  
     
     
         26 . A method for prophylactic treatment of a bacterial or viral infection in a subject comprising contacting the subject with an effective amount of one or more compounds having the formula:  
       
         
           
           
               
               
           
         
         and a pharmaceutically acceptable salts there of, wherein X is a member selected from the group consisting of —O— and —NH—;  
         Y is a member selected from the group consisting of —O— and —S—;  
         R 1 , R 2  and R 3  are each members independently selected from the group consisting of (C 2 -C 20 )acyl;  
         R 4  is a member selected from the group consisting of —H and —PO 3 R 7 R 8 , wherein R 7  and R 8  are each members independently selected from the group consisting of —H and (C 1 -C 4 )aliphatic groups;  
         R 5  is a member selected from the group consisting of —H, —CH 3  and —PO 3 R 9 R 10 , wherein R 9  and R 10  are each members independently selected from the group consisting of —H and (C 1 -C 4 )aliphatic groups;  
         R 6  is selected from H, OH, (C 1 -C 4 )oxyaliphatic groups, —PO 3 R 11 R 12 , —OPO 3 R 11 R 12 , SO 3 R 11 , —OSO 3 R 12 , —NR 11 R 12 , —SR 11 , —CN, —NO 2 , —CHO, —CO 2 R 11 , and —CONR 11 R 12 , wherein R 11  and R 12  are each independently selected from H and (C 2 -C 4 )aliphatic groups, with the provisos that one of R 4  and R 5  is a phosphorus-containing group and that when R 4  is —PO 3 R 7 R 8 , R 5  is other than —PO 3 R 9 R 10 ;  
         wherein “* 1 ”, “* 2 ” and “* 3 ” represent chiral centers;  
         wherein n, m, p and q are each independently an integer from 0 to 6, with the proviso that the sum of p and m is from 0 to 6.  
       
     
     
         27 . The method of  claim 26 , wherein X and Y are —O—, R 4  is PO 3 R 7 R 8 , R 5  and R 6  are H, and n, m, p, and q are integers from 0 to 3.  
     
     
         28 . The method of  claim 27 , wherein R 7  and R 8  are —H.  
     
     
         29 . The method of  claim 27 , wherein n, m, p, and q are from 0 to 2.  
     
     
         30 . The method of  claim 28 , wherein n is 1, m is 2, and p and q are 0.  
     
     
         31 . The method of  claim 26 , wherein R 1 , R 2  and R 3  are each C 6 -C 14  acyl.  
     
     
         32 . The method of  claim 26 , wherein R 1 , R 2 ; and R 3  are each C 6 -C 12  acyl.  
     
     
         33 . The method of  claim 30 , wherein R 1 , R 2 , and R 3  are each decanoyl residues.  
     
     
         34 . The method of  claim 30 , wherein R 1 , R 2 , and R 3  are each dodecanoyl residues.  
     
     
         35 . The method of  claim 30 , wherein R 1 , R 2 , and R 3  are each tetradecanoyl residues.  
     
     
         36 . The method of  claim 30 , wherein * 1 , * 2 , and * 3  are in the R configuration.  
     
     
         37 . The method of  claim 30 , wherein Y is in the equatorial position.  
     
     
         38 . The method of  claim 30 , wherein ** is in the S configuration.  
     
     
         39 . The method of  claim 30 , wherein * 1 , * 2 , and * 3  are in the R configuration, wherein Y is in the equatorial position, and wherein ** is in the S configuration.  
     
     
         40 . The method of  claim 26 , wherein the infectious disease is caused by a bacteria, a virus, a parasite, or a fungus.  
     
     
         41 . The method of  claim 40 , wherein said bacteria is a gram negative bacteria, or a gram positive bacteria.  
     
     
         42 . The method of  claim 40 , wherein the infectious disease is caused by a bacteria selected from the group consisting of  Pseudomonas, Escherichia, Klebsiella, Enterobacter, Proteus, Serratia, Candida, Bacillus , and  Staphylococcus.    
     
     
         43 . The method of  claim 42 , wherein the infectious disease is pneumonia.  
     
     
         44 . The method of  claim 43 , wherein said pneumonia is nosocomial pneumonia.  
     
     
         45 . A composition formulated and administered in the absence of exogenous antigen comprising one or more compounds having the formula:  
       
         
           
           
               
               
           
         
         and pharmaceutically acceptable salts thereof wherein X is a member selected from the group consisting of —O— and —NH—;  
         Y is a member selected from the group consisting of —O— and —S—;  
         R 1 , R 2  and R 3  are each members independently selected from the group consisting of (C 2 -C 20 )acyl;  
         R 4  is a member selected from the group consisting of —H and —PO 3 R 7 R 8 , wherein R 7  and R 8  are each members independently selected from the group consisting of —H and (C 1 -C 4 )aliphatic groups;  
         R 5  is a member selected from the group consisting of —H, —CH 3  and —PO 3 R 9 R 10 , wherein R 9  and R 10  are each members independently selected from the group consisting of —H and (C 1 -C 4 )aliphatic groups;  
         R 6  is selected from H, OH, (C 1 -C 4 )oxyaliphatic groups, —PO 3 R 11 R 12 , —OPO 3 R 11 R 12 , —SO 3 R 11 , —OSO 3 R 11 , —NR 11 R 12 , —SR 11 , —CN, —NO 2 , —CHO, —CO 2 R′  1 , and —CONR 11 R 12 , wherein R 11  and R 12  are each independently selected from H and (C 1 -C 4 )aliphatic groups, with the provisos that one of R 4  and R 5  is a phosphorus-containing group and that when R 4  is —PO 3 R 7 R 8 , R 5  is other than —PO 3 R 9 R 10 ;  
         wherein “* 1 ”, “* 2 ”, and “**” represent chiral centers;  
         wherein n, m, p and q are each independently an integer from 0 to 6, with the proviso that the sum of p and m is from 0 to 6; in combination with a pharmaceutically acceptable carrier.  
       
     
     
         46 . The pharmaceutical composition of  claim 45 , wherein X and Y are —O—, R 4  is PO 3 R 7 R 8 , R 5  and R 6  are H, and n, m, p, and q are integers from 0 to 3.  
     
     
         47 . The pharmaceutical composition of  claim 46 , wherein R 7  and R 8  are —H.  
     
     
         48 . The pharmaceutical composition of  claim 46 , n, m, p, and q are from 0 to 2.  
     
     
         49 . The pharmaceutical composition of  claim 47 , wherein n is 1, m is 2, and p and q are 0.  
     
     
         50 . The pharmaceutical composition of  claim 45 , wherein R 1 , R 2  and R 3  are each C 6 -C 14  acyl.  
     
     
         51 . The pharmaceutical composition of  claim 45 , wherein R 1 , R 2 ; and R 3  are each C 6 -C 12  acyl.  
     
     
         52 . The pharmaceutical composition of  claim 49 , wherein R 1 , R 2 , and R 3  are each decanoyl residues.  
     
     
         53 . The pharmaceutical composition of  claim 49 , wherein R 1 , R 2 , and R 3  are each dodecanoyl residues.  
     
     
         54 . The pharmaceutical composition of  claim 49 , wherein R 1 , R 2 , and R 3  are each tetradecanoyl residues.  
     
     
         55 . The pharmaceutical composition of  claim 49 , wherein * 1 , * 2 , and * 3  are in the R configuration.  
     
     
         56 . The pharmaceutical composition of  claim 49 , wherein Y is in the equatorial position.  
     
     
         57 . The pharmaceutical composition of  claim 49 , wherein ** is in the S configuration.  
     
     
         58 . The pharmaceutical composition of  claim 49 , wherein * 1 , * 2 , and * 3  are in the R configuration, wherein Y is in the equatorial position, and wherein ** is in the S configuration.  
     
     
         59 . A pharmaceutical composition of  claim 45 , further comprising one or more surfactants.  
     
     
         60 . A pharmaceutical composition of  claim 59 , wherein said one or more surfactants is selected from the group consisting of dimyristoyl phosphatidyl glycerol (DPMG), dipalmitoyl phosphatidyl glycerol (DPPG), distearoyl phosphatidyl glycerol (DSPG), dirnyristoyl phosphatidylcholine (DPMC), dipalmitoyl phosphatidylcholine (DPPC), distearoyl phosphatidylcholine (DSPC); dimyristoyl phosphatidic acid (DPMA), dipalmitoyl phosphatidic acid (DPPA), distearoyl phosphatidic acid (DSPA); dimyristoyl phosphatidyl ethanolamine (DPME), dipalmitoyl phosphatidyl ethanolamine (DPPE) and distearoyl phosphatidyl ethanolamine (DSPE).  
     
     
         62 . A method for ameliorating or substantially preventing an infectious disease, autoimmune disease or allergic condition in a subject comprising contacting the subject with an effective amount of a cyclic AGP.  
     
     
         63 . The method of  claim 62  wherein said cyclic AGP is N-[(R)-3-dodecanoyloxytetradecanoyl]-(S)-2-pyrrolidinylmethyl 2-deoxy-4-O-phosphono-2-[(R)-3-dodecanoyloxy-tetradecanoylamino]-3-O-[(R)-3-dodecanoyloxytetradecanoyl]-β-D-glucopyranoside or a pharmaceuticaly acceptable salt thereof.  
     
     
         64 . The method of  claim 62  wherein said cyclic AGP is N-[(R)-3-decanoyloxytetradecanoyl]-(S)-2-pyrrolidinylmethyl 2-deoxy-4-O-phosphono-2-[(R)-3-decanoyloxytetradecanoylamino]-3-O-[(R)-3-decanoyloxytetradecanoyl]-β-D-glucopyranoside or a pharmaceutically acceptable salt thereof.