High penetration compositions and their applications

Abstract

The invention provides compositions or pharmaceutical compositions of novel high penetration compositions (HPC) of a parent compound, which are capable of crossing biological barriers with high penetration efficiency. The HPCs are capable of being converted to parent drugs or parent drug-related compounds such as metabolites after crossing one or more biological barriers and thus can render treatments for the conditions that the parent drugs or parent drug-related compounds can. Additionally, the HPCs are capable of reaching areas that their parent drugs or parent drug-related compounds may not be able to access or to render a sufficient concentration at the target areas and therefore render novel treatments. For example, HPCs of NSAIA have demonstrated indications such as treating hair loss and bold. A HPC can be administered to a subject through various administration routes, e.g., locally delivered to an action site of a condition with a high concentration or systematically administered to a biological subject and enter the general circulation with a faster rate.

1 - 25 . (canceled) 
     
     
         26 . A high penetration prodrug (HPP) compound of Structure L-4: 
       
         
           
           
               
               
           
         
       
       including stereoisomers and pharmaceutically acceptable salts thereof, wherein:
 F 4  is a structure selected from Structure F4-1, Structure F4-2, Structure F4-3, Structure F4-4, Structure F4-5, Structure F4-6, Structure F4-7, Structure F4-8, Structure F4-9, Structure F4-10, Structure F4-11, Structure F4-12, Structure F4-13, Structure F4-14, Structure F4-15, Structure F4-16, Structure F4-17, and Structure F4-18: 
 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       including stereoisomers and salts thereof;
 T is selected from Structure T-1, Structure T-2, Structure T-3, Structure T-4, Structure T-5, Structure T-7, Structure T-8, Structure T-10, Structure T-11, Structure T-13, Structure T-14, and Structure T-15: 
 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       wherein each HA is independently nothing or a pharmaceutically acceptable acid selected from hydrochloride, hydrobromide, hydroiodide, nitric acid, sulfuric acid, phosphoric acid, phosphorous acid, phosphonic acid, isonicotinic acid, acetic acid, lactic acid, salicylic acid, citric acid, tartaric acid, pantothenic acid, bitartaric acid, ascorbic acid, succinic acid, maleic acid, gentisinic acid, fumaric acid, gluconic acid, glucaronic acid, saccharic acid, formic acid, benzoic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzensulfonic acid, p-toluenesulfonic acid, and pamoic acid;
 L 41  is selected from nothing, N, N—O, N—N(L 3 ), N—S, N—O—CH 2 —O, N—S—CH 2 —O, N-L 3 , N-O-L 3 , N-N(L 3 )-L 5 , and L 3 ; 
 L 3  and L 5  are each independently selected from nothing, H, —CH 2 COOL 6 , 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; 
 Y and Y 1 -Y 14  are each independently selected from H, Cl, F, Br, I, CN, R 10 , CH 3 CC, CR 6 C, P(O)OR 6 , CF 3 , CF 3 O, CH 3 , CF 3 CF 2 , R 5 , R 6 , R 7 , R 8 , 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 OC(═O), CH 3 CH 2 OC(═O), R 5 OC(═O), R 6 C(═NOR 5 ), R 6 C(═NR 5 ), CH 3 COO, R 5 COO, R 5 COOCH 2 , R 6 NHCOOCH 2 , CH 3 COS, CH 3 O, R 5 O, HO, R 10 O, CF 3 CH 2 SCH 2 , CHCl 2 , CH 2 COOR 6 , CH 3 S, R 5 S, HS, R 10 S, CH 3 OCH 2 CH 2 , R 5 OCH 2 , R 10 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 10 , 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, X 1 , X 2 , X 3 , X 4 , X 5 , and X 6  are each independently selected from H, CH 3 , R 5 , CH 2 , CHR 6 , S, O, NR 6 , CO, CH, CR 6 , P(O)OR 6 , N, CH 2 ═C, CH═CH, CONH, CSNH, COO, OCO, COS, COCH 2 , and CH 2 CO; 
 R 3 , R 4 , R 5 , R 6 , R 7 , and R 8  are each independently selected from H, OH, Cl, F, Br, I, 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, and substituted and unsubstituted alkyl halide, wherein any carbon or hydrogen may be further independently replaced with O, S, N, P(O)OL 7 , CH═CH, C≡C, CHL 7 , CL 5 L 7 , aryl, heteroaryl, or cyclic groups; 
 L 2 , L 8 , L 9 , and L 10  are each independently selected from nothing, —O—, —S-, -N(L 3 )—, N(L 3 )—, —N(L 3 )-O—, —N(L 3 )-N(L 5 )—, —N(L 3 )-CH 2 —O—, —N(L 3 )-CH 2 -N(L 5 )—, —O-CH 2 —O—, —O-CH(L 3 )-O—, —S-CH(L 3 )-O—, —O-L 3 -, -S-L 3 -, -N(L 3 )-L 5 -, and L 3 ; 
 L 11 , L 12 , and L 13  are each independently selected from nothing, —C(═O)—, —C(═S)—, —C(═N(L 3 ))—, 
 
       
         
           
           
               
               
           
         
         R 10  and R 20  are each independently selected from nothing, H, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 6 CO, R 6 NHC(═O), R 6 OC(═O), —R 6 C(═NOR 5 ), R 6 C(═NR 5 ), R 6 C(═S), CNR 6 , and R 6 OC(═O)(CH 2 ) n C(═O), R 6 (O═)CO(CH 2 ) n C(═O); 
         R and R 11 -R 16  are each independently selected from nothing, H, 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, NRs, or any other pharmaceutically acceptable groups; and 
         m and n are each independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12; 
         with the proviso that when T is Structure T-1, F4 is not Structure F4-1. 
       
     
     
         27 . The high penetration prodrug compound of  claim 26 , wherein:
 F 4  is a structure selected from Structure F4-2, Structure F4-4, Structure F4-5, Structure F4-6, Structure F4-7, Structure F4-8, Structure F4-9, Structure F4-10, Structure F4-11, Structure F4-12, Structure F4-13, Structure F4-14, Structure F4-15, Structure F4-16, and Structure F4-17; and   T is selected from Structure T-1, Structure T-2, Structure T-3, Structure T-4, and Structure T-5.   
     
     
         28 . The high penetration prodrug compound of  claim 27 , wherein T is Structure T-1, Structure T-2, or Structure T4. 
     
     
         29 . The high penetration prodrug compound of  claim 26 , wherein T is Structure T-1; and F4 is Structure F4-1. 
     
     
         30 . The high penetration prodrug compound of  claim 26 , which is derived from a steroid parent drug selected from progesterone, desogestrel or, ethinylestradiol, cholesterol, adrenocorticoids, and sex hormones. 
     
     
         31 . The high penetration prodrug compound of  claim 26 , which is: 
       
         
           
           
               
               
           
         
       
     
     
         32 . A pharmaceutical composition comprising a high penetration prodrug compound of  claim 26 , or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 
     
     
         33 . A method of treating a disease or disorder treatable by a steroid drug, comprising administering to a biological subject in need of treatment a therapeutically effective amount of a high penetration prodrug compound of  claim 26 , or a stereoisomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. 
     
     
         34 . The method of  claim 33 , wherein the disease or disorder is selected from brain trauma, stroke, embryo implantation, early pregnancy, discoid lupus erythematosus, systemic lupus erythematosus, avoidance of pregnancy in women, multiple sclerosis, rheumatic arthritis, breast cancer, prostate cancer, and other cancers, hypoadrenalism, adrenalectomy, hypophysectomy, rheumatoid diseases, allergic manifestations, bursitis, spontaneous hypoglycemia, gout, sprue, allergy ulcerative colitis, dermatomyositis, periarteritis nodosa, idiopathic pulmonary fibrosis, idiopathic thrombocytopenic purpura, regional ileitis, female contraceptives and abortifacients, progestin antagonists, birth control, acquired hemolytic anemia, nephrosis, cirrhotic ascites, neurodermtitis, psoriasis, pneumonia, peritonitis, typhoid fever, and meningococcemia. 
     
     
         35 . The method of  claim 33 , wherein the disease or disorder is selected from brain trauma, stroke, embryo implantation, early pregnancy, discoid lupus erythematosus, systemic lupus erythematosus, avoidance of pregnancy in women, and multiple sclerosis. 
     
     
         36 . The method of  claim 33 , wherein the prodrug compound, or a stereoisomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, is applied to the biological subject by a transdermal, transmucosal, trans-nasal, trans-vaginal, trans-mouth, trans-rectal method. 
     
     
         37 . The method of  claim 33 , wherein the prodrug compound, or a stereoisomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, is applied to the biological subject by a topical method. 
     
     
         38 . The method of  claim 33 , wherein the prodrug compound, or a stereoisomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, is applied to the biological subject by oral, nasal, vaginal, rectal, parenteral, subcutaneous, intramuscular, intravenous, via inhalation or ophthalmic method. 
     
     
         39 . The method of  claim 33 , wherein the prodrug compound, or a stereoisomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, is used at a dosage equal to or lower than 50% dosage of its parent drug to be therapeutically effective. 
     
     
         40 . The method of  claim 33 , wherein the prodrug compound, or a stereoisomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, is used at a dosage equal to or lower than 25% dosage of its parent drug to be therapeutically effective. 
     
     
         41 . The method of  claim 33 , wherein the prodrug compound, or a stereoisomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, is used at a dosage equal to or lower than 10% dosage of its parent drug to be therapeutically effective. 
     
     
         42 . The method of  claim 33 , wherein the prodrug compound, or a stereoisomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, is used at a dosage equal to or lower than 5% dosage of its parent drug to be therapeutically effective. 
     
     
         43 . The method of  claim 33 , wherein the prodrug compound, or a stereoisomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, is used at a dosage equal to or lower than 2% dosage of its parent drug to be therapeutically effective. 
     
     
         44 . The method of  claim 33 , wherein the prodrug compound, or a stereoisomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, is used at a dosage equal to or lower than 1% dosage of its parent drug to be therapeutically effective. 
     
     
         45 . The method of  claim 33 , wherein the prodrug compound, or a stereoisomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, is used at a dosage equal to or lower than 0.1% dosage of its parent drug to be therapeutically effective.