High penetration composition and uses thereof

Abstract

The present invention relates to compositions and uses of novel high penetration compositions or high penetration prodrugs (HPP), in particular HPPs for 4-aminophenol derivatives, which are capable of crossing biological barriers with high penetration efficiency. The HPPs herein are capable of being converted to parent active drugs or drug metabolites after crossing the biological barrier and thus can render treatments for the conditions that the parent drugs or metabolites can. Additionally, due to the ability of penetrating biological barriers, the HPPs herein are capable of reaching areas that parent drugs may not be able to access or to render a sufficient concentration at the target areas and therefore render novel treatments. The HPPs herein can be administered to a subject through various administration routes. For example, the HPPs can be locally delivered to an action site of a condition with a high concentration due to their ability of penetrating biological barriers and thus obviate the need for a systematic administration. For another example, the HPPs herein can be systematically administer to a biological subject and enter the general circulation with a faster rate.

1 . A high penetration composition comprising
 a) a moiety of an agent, wherein   b) a transportational unit;   wherein the functional unit is covalently linked to the transportational unit via a linker;   the functional unit comprises a moiety of an agent selected from a group consisting of a 4-aminophenyl derivative, an active 4-aminophenyl derivative metabolite, an agent that can be metabolized into a 4-aminophenyl derivative or an active 4-aminophenyl derivative metabolite;   the transportational unit comprises a protonatable amine group; and   the linker is or comprises a chemical bond that is capable of being cleaved after the high penetration composition penetrates across a biological barrier.   
   
   
       2 . The high penetration composition according to  claim 1 , wherein the chemical bond is selected from the group consisting of a covalent chemical bond, an ether bond, a thioether bond, an ester bond, a thioester bond, a carbonate bond, a carbamate bond, a phosphate bond and an oxime bond. 
   
   
       3 . The high penetration composition according to  claim 1 , wherein upon cleavage of the cleavable bond, the moiety of the agent is converted to the agent or a metabolite of the agent. 
   
   
       4 . The high penetration composition according to  claim 1 , wherein the functional unit comprises a lipophilic derivative of a moiety of the agent. 
   
   
       5 . The high penetration composition according to  claim 4 , wherein the lipophilic derivative is selected from the group consisting of carbonate, ester, amide, carbamate, N-mannich base, ether, thioether, thioester, phosphate, oxime and imine of the moiety of the agent. 
   
   
       6 . The high penetration composition according to  claim 1 , wherein the protonatable amine group is selected from the group consisting of a pharmaceutically acceptable substituted or unsubstituted primary amine group, a pharmaceutically acceptable substituted or unsubstituted secondary amine group, and a pharmaceutically acceptable substituted or unsubstituted tertiary amine group. 
   
   
       7 . The high penetration composition according to  claim 6 , wherein the protonatable amine group comprises a moiety having a structure selected from Structure Na, Structure Nb, Structure Nc, Structure Nd, Structure Ne, Structure Nf, Structure Ng, Structure Nh, Structure Ni, Structure Nj, Structure Nk, Structure NI, Structure Nm, Structure Nn, Structure No, Structure Np, Structure Nq, and Structure Nr. 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       including stereoisomers and pharmaceutically acceptable salts thereof, wherein: 
       R 11 -R 16  is independently selected from the group consisting of nothing, H, CH 2 COOR 11 , substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted alkoxyl, substituted and unsubstituted alkylthio, substituted and unsubstituted alkylamino, substituted and unsubstituted perfluoroalkyl, and substituted and unsubstituted alkyl halide, wherein any carbon or hydrogen may be further independently replaced with O, S, P, NR 11 , or any other pharmaceutically acceptable groups and R 11  and R 12  are not H at the same time. 
     
   
   
       8 . The high penetration composition according to  claim 1 , wherein the functional unit is a moiety of a 4-aminophenol derivative having a structure selected from Group F-1 wherein Group F-1 includes the following structures: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       including stereoisomers and pharmaceutically acceptable salts thereof, wherein: 
       each R, R 5  and R 6  is independently selected from the group consisting of H, OH, Cl, F, Br, I, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted alkoxyl, substituted and unsubstituted alkylthio, substituted and unsubstituted alkylamino, substituted and unsubstituted perfluoroalkyl, and substituted and unsubstituted alkyl halide, wherein any carbon or hydrogen may be further independently replaced with O, S, N, P(O)OR 6 , CH═CH, C≡C, CHR 6 , CR 5 R 6 , aryl, heteroaryl, and cyclic groups; 
       each Y 1  to Y 8  is independently selected from the group consisting of H, halogen, CN, R 5 , CH 3 C≡C, CR 6 ≡C, P(O)OR 6 , CF 3 , CF 3 O, CH 3 , CF 3 CF 2 , CF 3 CF 2 O, CH 3 CH 2 , CH 3 CH 2 CH 2 , (CH 3 ) 2 CH, (CH 3 ) 2 CHCH 2 , CH 3 CH 2 CH(CH 3 ), (CH 3 ) 3 C, C 4 H 9 , C 5 H 11 , CH 3 CO, CH 3 CH 2 CO, R 5 CO, CH 3 COO, R 5 COO, R 5 COOCH 2 , R 6 NHCOOCH 2 , CH 3 COS, CH 3 O, R 50 , HO, CF 3 CH 2 SCH 2 , CHCl 2 , CH 2 COOR 6 , CH 3 S, R 5 S, HS, CH 3 OCH 2 CH 2 , R 5 OCH 2 , R 5 OCH 2 CH 2 , R 5 O(C═O), C 2 H 5 OCONH, CH 2 NHR 8 , CH 3 OCONH, CH 3 SO 2 , CH 3 SO, R 5 SO 2 , R 5 SO, NH 2 SO 2 , C 6 H 5 CH 2 , NH 2 , NHR 5 , cyclobutyl, cyclopropyl, 4-chlorophenyl, 4-fluorophenyl, CH 2 ═CH, CH 2 ═CHCH 2 , CH 3 CH═CH, NHR 5 SO 2 , N(R 5 ) 2 SO 2 , R 5 OCH 2 CH 2 CH 2 , and NO 2 ; 
       X is nothing or selected from a group consisting of O, 2-OCO—C 6 H 4 — and 2-OCO—C 6 H 4 —O—CO—C 6 H 4 —, wherein each of the benzene ring can be further substituted by one or plural of the same or different Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , Y 7 , or Y 8 ; and 
       the composition does not have the following structure: 
     
     
       
         
         
             
             
         
       
     
   
   
       9 . A high penetration composition having the following chemical structure: 
     
       
         
         
             
             
         
       
       including stereoisomers and pharmaceutically acceptable salts thereof, wherein: 
       T comprises a moiety having a structure selected from Group N as defined in  claim 7 ; 
       L 1  is selected from the group consisting of nothing, O, S, —N(L 3 )-, —N(L 3 )-CH 2 —O, —N(L 3 )-CH 2 —N(L 3 )-, —O—CH 2 —O—, —O—CH(L 3 )-O, —S—CH(L 3 )-O—; 
       L 2  is selected from the group consisting of nothing, O, S, —N(L 3 )-, —N(L 3 )-CH 2 —O, —N(L 3 )-CH 2 —N(L 3 )-, —O—CH 2 —O—, —O—CH(L 3 )-O, —S—CH(L 3 )-O—, —O-L 3 -, —N-L 3 -, —S— L 3 - and N(L 3 )-L 3 -; 
       L 4  is selected from the group consisting of C═O, C═S, 
     
     
       
         
         
             
             
         
       
       each L 3  is independently selected from the group consisting of nothing, H, CH 2 COOR 1 , substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, and substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted alkoxyl, substituted and unsubstituted alkylthio, substituted and unsubstituted alkylamino, substituted and unsubstituted perfluoroalkyl, substituted and unsubstituted alkyl halide, wherein any carbon or hydrogen may be further independently replaced with O, S, P, N L 3  or any other pharmaceutically acceptable groups; 
       F is a moiety of a 4-aminophenol derivative having a structure selected from Group F-1 wherein Group F-1 includes the following structures: 
     
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       including stereoisomers and pharmaceutically acceptable salts thereof, wherein: 
       each R, R 5  and R 6  is independently selected from the group consisting of H, OH, Cl, F, Br, I, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted alkoxyl, substituted and unsubstituted alkylthio, substituted and unsubstituted alkylamino, substituted and unsubstituted perfluoroalkyl, and substituted and unsubstituted alkyl halide, wherein any carbon or hydrogen may be further independently replaced with O, S, N, P(O)OR 6 , CH═CH, C≡C, CHR 6 , CR 5 R 6 , aryl, heteroaryl, and cyclic groups; 
       each Y 1  to Y 8  is independently selected from the group consisting of H, halogen, CN, R 5 , CH 3 C═C, CR 6 ═C, P(O)OR 6 , CF 3 , CF 3 O, CH 3 , CF 3 CF 2 , CF 3 CF 2 O, CH 3 CH 2 , CH 3 CH 2 CH 2 , (CH 3 ) 2 CH, (CH 3 ) 2 CHCH 2 , CH 3 CH 2 CH(CH 3 ), (CH 3 ) 3 C, C 4 H 9 , C 5 H 1 , CH 3 CO, CH 3 CH 2 CO, R 5 CO, CH 3 COO, R 5 COO, R 5 COOCH 2 , R 6 NHCOOCH 2 , CH 3 COS, CH 3 O, R 5 O, HO, CF 3 CH 2 SCH 2 , CHCl 2 , CH 2 COOR 6 , CH 3 S, R 5 S, HS, CH 3 OCH 2 CH 2 , R 5 OCH 2 , R 5 OCH 2 CH 2 , R 5 O(C═O), C 2 H 5 OCONH, CH 2 NHR 8 , CH 3 OCONH, CH 3 SO 2 , CH 3 SO, R 5 SO 2 , R 5 SO, NH 2 SO 2 , C 6 H 5 CH 2 , NH 2 , NHR 5 , cyclobutyl, cyclopropyl, 4-chlorophenyl, 4-fluorophenyl, CH 2 ═CH, CH 2 ═CHCH 2 , CH 3 CH═CH, NHR 5 SO 2 , N(R 5 ) 2 SO 2 , R 5 OCH 2 CH 2 CH 2 , and NO 2 ; 
       X is nothing or selected from a group consisting of O, 2-OCO—C 6 H 4 — and 2-OCO—C 6 H 4 —O—CO—C 6 H 4 —, wherein each of the benzene ring can be further substituted by one or plural of the same or different Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , Y 7 , or Y 8 ; and 
       the composition does not have the following structure: 
     
     
       
         
         
             
             
         
       
     
   
   
       10 . The high penetration composition of  claim 9  wherein the high penetration composition has a structure selected form the group consisting of Structure 1: 
     
       
         
         
             
             
         
       
       including stereoisomers and pharmaceutically acceptable salts thereof, wherein: 
       Transportational-unit has a structure selected from Group N; 
       R is selected from the group consisting of 0-20 carbon atoms alkyl, 1-20 carbon atoms alkyloxyl, 1-20 carbon atoms perfluoroalkyl, 1-20 carbon atoms alkyl halide, 6-20 carbon atoms aryl, and 2-20 carbon atoms heteroaryl moieties wherein any CH 2  may be independently replaced with O, S, NR 5 , or other groups; 
       X is selected from the group consisting of O, 2-OCO—C 6 H 4 —O and 2-OCO—C 6 H 4 —O—CO—C 6 H 4 —O, wherein the benzene ring can be further substituted by one or plural of the same or different Y 1 , Y 2 , Y 3 , or Y 4 ; 
       each Y 1  to Y 4  is independently selected from the group consisting of H, halogen, CN, R 5 , CH 3 C≡C, CR 6 ≡C, P(O)OR 6 , CF 3 , CF 3 O, CH 3 , CF 3 CF 2 , CF 3 CF 2 O, CH 3 CH 2 , CH 3 CH 2 CH 2 , (CH 3 ) 2 CH, (CH 3 ) 2 CHCH 2 , CH 3 CH 2 CH(CH 3 ), (CH 3 ) 3 C, C 4 H 9 , C 5 H 11 , CH 3 CO, CH 3 CH 2 CO, R 5 CO, CH 3 COO, R 5 COO, R 5 COOCH 2 , R 6 NHCOOCH 2 , CH 3 COS, CH 3 O, R 5 O, HO, CF 3 CH 2 SCH 2 , CHCl 2 , CH 2 COOR 6 , CH 3 S, R 5 S, HS, CH 3 OCH 2 CH 2 , R 5 OCH 2 , R 5 OCH 2 CH 2 , R 5 O(C═O), C 2 H 5 OCONH, CH 2 NHR 8 , CH 3 OCONH, CH 3 SO 2 , CH 3 SO, R 5 SO 2 , R 5 SO, NH 2 SO 2 , C 6 H 5 CH 2 , NH 2 , NHR 5 , cyclobutyl, cyclopropyl, 4-chlorophenyl, 4-fluorophenyl, CH 2 ═CH, CH 2 ═CHCH 2 , CH 3 CH═CH, NHR 5 SO 2 , N(R 5 ) 2 SO 2 , R 5 OCH 2 CH 2 CH 2 , and NO 2 ; 
       X 1  is selected from the group consisting of nothing, O, NH, NR 6  and S; 
       each R 5  and R 6  is independently selected from the group consisting of H, OH, Cl, F, Br, I, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted alkoxyl, substituted and unsubstituted alkylthio, substituted and unsubstituted alkylamino, substituted and unsubstituted perfluoroalkyl, and substituted and unsubstituted alkyl halide, wherein any carbon or hydrogen may be further independently replaced with O, S, N, P(O)OR 6 , CH═CH, C≡C, CHR 6 , CR 5 R 6 , aryl, heteroaryl and cyclic groups. 
     
   
   
       11 . The high penetration composition of  claim 9  having the following Structure 1a: 
     
       
         
         
             
             
         
       
     
     including stereoisomers and pharmaceutically acceptable salts thereof, wherein:
 each R 1 , R 2  and R 3  is independently selected from the group consisting of H, alkyl, alkyloxyl, alkenyl and alkynyl radicals having 1 to 12 carbon atoms and aryl radicals; 
 X represents O or 2-OCO—C 6 H 4 —O; 
 n is selected from the group of integers; and 
 any CH 2  groups in R 1 -R 3  may be independently replaced with O, S, or NH. 
 
   
   
       12 . A pharmaceutical composition comprising a high penetration composition according any of  claim 1  and a pharmaceutically acceptable carrier. 
   
   
       13 . The pharmaceutical composition according to  12 , wherein the pharmaceutically acceptable carrier is polar. 
   
   
       14 . The pharmaceutical composition according to  claim 13 , wherein the pharmaceutically acceptable carrier is selected from the group of alcohol, acetone, ester, water, and aqueous solution. 
   
   
       15 . A method for penetrating a biological barrier, comprising administrating to the biological barrier a pharmaceutical composition according to  claim 1 . 
   
   
       16 . A method for treating a condition of a biological subject, comprising administrating to the biological subject a high penetration composition of a 4-aminophenol derivative according to  claim 9 . 
   
   
       17 . The method according to  claim 16 , wherein the condition is selected from the group consisting of autoimmune disease, pain, neurodegenerative diseases, injuries and fever. 
   
   
       18 . The method according to  claim 17 , wherein the autoimmune disease is selected from the group consisting of discoid lupus erythematosus, systemic lupus erythematosus (SLE), autoimmune hepatitis, cleroderma, Sjogren's syndrome, rheumatoid arthritis, polymyositis, scleroderma, Hashimoto's thyroiditis, juvenile diabetes mellitus, Addison disease, vitiligo, pernicious anemia, glomerulonephritis, pulmonary fibrosis, multiple sclerosis (MS) and Crohn's disease. 
   
   
       19 . The method according to  claim 17 , wherein neurodegenerative disease is selected from the group consisting of Alzheimer's diseases and Parkinson's diseases. 
   
   
       20 . The method according to  claim 17 , wherein the pharmaceutical composition is administered to the biological subject through a route selected from oral, enteral, buccal, nasal, topical, rectal, vaginal, aerosol, transmucosal, epidermal, transdermal, dermal, ophthalmic, pulmonary, subcutaneous, and parenteral administration. 
   
   
       21 . The method according to  claim 17 , wherein the 4-acetophenol derivative is N-Acetyl-p-aminophenol (acetaminophen). 
   
   
       22 . The method according to  claim 16  wherein the condition is a condition treatable by acetaminophen. 
   
   
       23 . The method according to  claim 22  wherein the condition treatable by acetaminophen is selected from the group consisting of gouty arthritis, pain and inflammation of arthritic and other inflammatory conditions, fever, injuries, Alzheimer's diseases, Parkinson's diseases and other neurodegenerative diseases.