High penetration prodrug compositions of retinoids and retinoid-related compounds

Abstract

The invention provides compositions of novel high penetration compositions (HPC) or high penetration prodrugs (HPP) of retinoids and retinoid-related compounds, which are capable of crossing biological barriers with high penetration efficiency. The HPPs 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, the HPPs 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 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 - 20 . (canceled) 
     
     
         21 . A high penetration composition of a retinoid or a retinoid-related compound comprising
 a) a functional unit;   b) a linker   c) a transportational unit;   wherein the functional unit is covalently linked to the transportational unit via the linker;   wherein the functional unit comprises a moiety of the retinoids or the retinoid-related compound;   wherein the transportational unit comprises a protonatable amine group; and   wherein the linker comprises a chemical bond that is capable of being cleaved after the high penetration composition penetrates across a biological barrier.   
     
     
         22 . The high penetration composition according to  claim 21 , 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. 
     
     
         23 . The high penetration composition according to  claim 21 , wherein upon cleavage of the cleavable bond, the moiety of the retinoids or the retinoid-related compound is converted to the retinoids or the retinoid-related compound. 
     
     
         24 . The high penetration composition according to  claim 21 , wherein the functional unit comprises a lipophilic derivative of a moiety of the retinoids or the retinoid-related compound. 
     
     
         25 . The high penetration composition according to  claim 24 , 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. 
     
     
         26 . The high penetration composition according to  claim 21  wherein the retinoids or the retinoid-related compound is selected from the group consisting of retinoids, retinoids metabolites, and agents that can be metabolized into a retinoid or a retinoid metabolite, and analogs thereof. 
     
     
         27 . The high penetration composition according to  claim 21 , wherein the protonatable amine group is selected from the group consisting of a substituted and unsubstituted primary amine group, a substituted and unsubstituted secondary amine group, and a substituted and unsubstituted tertiary amine group. 
     
     
         28 . The high penetration composition according to  claim 27 , wherein the protonatable amine group is selected from the group consisting of Structure Na, Structure Nb, Structure Nc Structure Nd, Structure Ne, Structure Nf, Structure Ng, Structure Nh, Structure Ni, Structure Nj, Structure Nk, Structure Nl, 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  are 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 0, S, P, NR 11 , or any other pharmaceutically acceptable groups. 
       
     
     
         29 . A high penetration composition having the following chemical structure: 
       
         
           
           
               
               
           
         
         including stereoisomers and pharmaceutically acceptable salts thereof, wherein: 
         F comprises a moiety of a retinoid or a retinoid-related compound, having a structure selected from the group consisting of Structure F2, Structure F3, Structure F4, Structure F5, Structure F6, Structure F7, Structure F8, Structure F9, Structure F10, Structure F11, Structure F12, Structure F13, Structure F14, Structure F15, Structure F16, Structure F17, Structure F18, Structure F19, Structure F20, Structure F21, Structure F22, Structure F23, Structure F24, Structure F25, Structure F26, Structure F27, Structure F28, Structure F29, Structure F30, Structure F31, Structure F32, Structure F33, Structure F34, Structure F35, Structure F36, Structure F37, Structure F38, Structure F39, Structure F40 and Structure F41: 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       including stereoisomers and pharmaceutically acceptable salts thereof, wherein:
 R 1  is selected from the group consisting of H, substituted and unsubstituted alkyl, substituted and unsubstituted alkyloxyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl and substituted and unsubstituted heteroaryl residues; 
 R 2  is selected from the group consisting of H, substituted and unsubstituted alkyl, substituted and unsubstituted alkyloxyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl and substituted and unsubstituted heteroaryl residues; 
 X is selected from the group consisting of 0, S, and NH; 
 X 1 -X 8  are independently selected from the group consisting of H, OH, Cl, Br, F, I, substituted and unsubstituted alkyl, substituted and unsubstituted perfluoroalkyl, and substituted and unsubstituted alkyloxy; 
 R 4  is selected from the group consisting of H, OH, Cl, Br, F, I, substituted and unsubstituted alkyl, substituted and unsubstituted alkyloxy, substituted and unsubstituted perfluoroalkyl, and substituted and unsubstituted alkyl halide; 
 R 5  is selected from the group consisting of H, OH, Cl, Br, F, I, substituted and unsubstituted alkyl, substituted and unsubstituted alkyloxy, substituted and unsubstituted perfluoroalkyl, and substituted and unsubstituted alkyl halide; 
 R 21  and R 22  are independently selected from the group consisting of H, OH, Cl, Br, F, I, substituted and unsubstituted alkyl, substituted and unsubstituted alkyloxy, substituted and unsubstituted perfluoroalkyl, and substituted and unsubstituted alkyl halide; 
 R 6  and R 6 ′ taken together is oxygen (═O) or taken alone are the same or different and independently selected from the group consisting of H, Cl, Br, F, I, OH, substituted and unsubstituted alkyl, substituted and unsubstituted alkyloxy, and substituted and unsubstituted alkyl halide; 
 R 7  and R 7 ′ taken together is oxygen (═O) or taken alone are the same or different and independently selected from the group consisting of H, Cl, Br, F, I, OH, substituted and unsubstituted alkyl, substituted and unsubstituted alkyloxy, and substituted and unsubstituted alkyl halide; 
 R 5  and R 5 ′ taken together is oxygen (═O) or taken alone are the same or different and independently selected from the group consisting of H, Cl, Br, F, I, OH, substituted and unsubstituted alkyl, substituted and unsubstituted alkyloxy, and substituted and unsubstituted alkyl halide; 
 R 9  and R 9 ′ taken together is oxygen (═O) or taken alone are the same or different and independently selected from the group consisting of H, Cl, Br, F, I, OH, substituted and unsubstituted alkyl, substituted and unsubstituted alkyloxy, and substituted and unsubstituted alkyl halide; 
 R 10  and R 10 ′ taken together is oxygen (═O) or taken alone are the same or different and independently selected from the group consisting of H, Cl, Br, F, I, OH, substituted and unsubstituted alkyl, substituted and unsubstituted alkyloxy, and substituted and unsubstituted alkyl halide; 
 T R  is selected from the group consisting of —CH 2 ═C—, —CH═CH—, —C≡C—, —C(═O)NH—, —C(═S)NH—, —C(═O)O—, —OC(═O)—, —C(═O)S—, —C(═O)CH 2 —, and —CH 2 C(═O)—; 
 HA is selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, nitric acid, sulfic acid, bisulfic 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; 
 any CH 2  groups may be replaced with 0, S, or NH; 
 T is selected from the group consisting of nothing, H, substituted and unsubstituted alkyl, substituted and unsubstituted alkyloxyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, Structure Na, Structure Nb, Structure Nc, Structure Nd, Structure Ne, Structure Nf, Structure Ng, Structure Nh, Structure Ni, Structure Nj, Structure Nk, Structure Nl, Structure Nm, Structure Nn, Structure No, Structure Np, Structure Nq, and Structure Nr: 
 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         each R 11 —R 16  is independently selected from the group consisting of nothing, H, CH2COOR 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 0, S, P, NR 11 , or any other pharmaceutically acceptable groups; 
         L 1  is selected from the group consisting of nothing, 0, S, —N(L 3 )-, —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—; 
         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 5 )-, —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 5 -; 
         L 4  is selected from the group consisting of C═O, C═S, 
       
       
         
           
           
               
               
           
         
         for each L 1 , L 2 , L 4 , L 3  and L 5  are independently selected from the group consisting of 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, wherein any carbon or hydrogen may be further independently replaced with O, S, P, NL 3 , or any other pharmaceutically acceptable groups; 
         L 6  is 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)OL 7 , CH═CH, C≡C, CHL 7 , CL 5 L 7 , aryl, heteroaryl, or cyclic groups; 
         L 7  is 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)OL 6 , CH═CH, C≡C, CHL 6 , CL 6 L 5 , aryl, heteroaryl, or cyclic groups. 
       
     
     
         30 . The high penetration composition of  claim 29  wherein the retinoids wherein the retinoids comprise a structure selected from the group consisting of Structure R2, Structure R3, Structure R4, Structure R5, Structure R6, Structure R7, Structure R8, Structure R9, Structure R10, Structure R11, Structure R12, Structure R13, Structure R14, Structure R15, Structure R16, Structure R17, Structure R18, Structure R19, Structure R20, Structure R21, Structure R22, Structure R23, Structure R24, Structure R25, Structure R26, Structure R27, Structure R28, Structure R29, Structure R30, Structure R31, Structure R32, Structure R33, Structure R34, Structure R35, Structure R36, Structure R37, Structure R38, and Structure R39: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         31 . The high penetration composition of  claim 29  comprising a structure selected form the group consisting of Structure 2, Structure 3, Structure 4, Structure 5, Structure 6, Structure 7, Structure 8, Structure 9, Structure 10, Structure 11, Structure 12, Structure 13, Structure 14, Structure 15, Structure 16, Structure 17, Structure 18, Structure 19, Structure 20, Structure 21, Structure 22, Structure 23, Structure 24, Structure 25, Structure 26, Structure 27, Structure 28, Structure 29, Structure 30, Structure 31, Structure 32, Structure 33, Structure 34, Structure 35, Structure 36, Structure 37, Structure 38, and Structure 39: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         including stereoisomers and pharmaceutically acceptable salts thereof, wherein: 
         R is selected from the group consisting of nothing, substituted and unsubstituted alkyl, substituted and unsubstituted alkoxyl, substituted and unsubstituted perfluoroalkyl, substituted and unsubstituted alkyl halide, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl, and substituted and unsubstituted heteroaryl. 
       
     
     
         32 . A pharmaceutical composition comprising a high penetration composition according to  claim 29  and a pharmaceutically acceptable carrier. 
     
     
         33 . The pharmaceutical composition according to  claim 32 , wherein the pharmaceutically acceptable carrier is polar. 
     
     
         34 . The pharmaceutical composition according to  claim 32 , wherein the pharmaceutically acceptable carrier is selected from the group of alcohol, acetone, ester, water, and aqueous solution. 
     
     
         35 . A method for penetrating a biological barrier, comprising administering to the biological barrier a pharmaceutical composition according to  claim 32 . 
     
     
         36 . A method for screening a HPP of a retinoid or a retinoid-related compound for a desired character, comprising the following steps:
 1) covalently linking a functional unit comprising a retinoid or a retinoid-related compound to a transportational unit through a linker to form a test composition;   2) administering the test composition to a biological subject or a biological barrier; and   3) determining whether the test composition has a desired character.   
     
     
         37 . The method according to  claim 36 , wherein the desired character is selected from the group consisting of:
 1) the ability of the test composition to penetrate the biological barriers;   2) the ability of the test composition to convert to a parent drug or to an active agent;   3) the penetration rate of the test composition;   4) the efficiency of the test composition; and   5) the efficacy of the test composition.   
     
     
         38 . A method for diagnosing a condition in a biological subject, comprising the following steps:
 1) administering a composition according to any one of  claim 29  to the biological subject;   2) detecting the presence, location or amount of the composition in the biological subject; and   3) detecting a condition in the biological subject.   
     
     
         39 . The method according to  claim 38 , wherein the composition is labeled. 
     
     
         40 . A method for diagnosing a condition in a biological subject, comprising the following steps:
 1) administering a composition according to any one of  claim 32  to the biological subject;   2) detecting the presence, location or amount of the composition in the biological subject; and   3) detecting a condition in the biological subject.   
     
     
         41 . The method according to  claim 40 , wherein the composition is labeled. 
     
     
         42 . A method for treating a condition in a biological subject, comprising administering to the biological subject the high penetration composition according to  claim 29 . 
     
     
         43 . A method for treating a condition in a biological subject, comprising administering to the biological subject the pharmaceutical composition according to  claim 32 . 
     
     
         44 . The method according to  claim 43 , wherein the condition is selected from the group consisting of Vitamin A deficiency conditions, infection-related conditions, skin conditions, eye conditions, bone conditions, tumor and related conditions, hair loss, and metabolic disorders. 
     
     
         45 . The method according to  claim 44 , wherein the Vitamin A deficiency related condition is selected from the group consisting of nyctalopia, keratomalacia, keratinization, dry skin, lowered resistance to infection, decreased growth rate, slow bone development, thickening of bone, diminished production of cortical steroids, and fetal malformations. 
     
     
         46 . The method according to  claim 44 , wherein skin condition is selected from the group consisting of keratinization, dry skin, skin damage through sun exposure, photoaging, hyperpigmented macules (liver spot), premature wrinkles, elastosis and premature aging, wrinkles, drug-induced photosensitivity, diminished production of cortical steroids, epidermal wound healing, keloids, hyperkeratotic skin disease, Darier's disease, lamellar ichthyosis,  pityriasis rubra  pilaris, lichen planus, refractory rosacea, keratosis palmaris et plantaris, leukoplakia, xeroderma pigmentosum, Kaposi's sarcoma, AIDS-related Kaposi's sarcoma, systemic Kaposi's sarcoma, cutaneous T-cell lymphoma (CTCL), Mycosis fungoides, hyperproliferative skin diseases, psoriasis, basal cell carcinomas, disorders of keratinization and keratosis, neoplastic diseases, disorders of the sebaceous glands, acne vulgaris, recalcitrant cystic acne, acne and seborrhoic dermatitis. 
     
     
         47 . The method according to  claim 44 , wherein the infection-related condition is selected from the group consisting of herpes simplex infections and lowered resistance to infections. 
     
     
         48 . The method according to  claim 44 , wherein the eye condition is selected from the group consisting of nyctalopia, keratinization, xerophthalmia and Grover's disease. 
     
     
         49 . The method according to  claim 44 , wherein the bone condition is selected from the group consisting of bone thickening and myelodysplastic syndromes. 
     
     
         50 . The method according to  claim 44 , wherein the metabolism disorder conditions are selected from the group consisting of diabetes mellitus and type II diabetes. 
     
     
         51 . The method according to  claim 44 , wherein the tumor is selected from the group consisting of benign tumor, breast cancer, colon-rectum cancer, lung or other respiratory system cancers, skin cancer, basal cell carcinoma, cervical cancer, mycosis fungoides, Kaposi's sarcoma, AIDS-related Kaposi's sarcoma, systemic Kaposi's sarcoma, cutaneous T-cell lymphoma (CTCL), squamous cell skin cancer, second primary tumors, head and neck carcinoma, ovarian cancer, prostate cancer, and renal cell cancer. 
     
     
         52 . The method according to  claim 44 , wherein the 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. 
     
     
         53 . The method according to  claim 44 , wherein the retinoids is selected from the group consisting of retinol (vitamin A), retinal, retiferol, tretinoin (all-trans-retinoic acid), isotretinoin, 13-cis-retinoic acid, alitretinoin (9-cis-retinoic acid), etretinate, acitretin, tazarotene, bexarotene and Adapalene. 
     
     
         54 . The method according to  claim 44 , wherein the retinoids comprise a structure selected from the group consisting of Structure R2, Structure R3, Structure R4, Structure R5, Structure R6, Structure R7, Structure R8, Structure R9, Structure R10, Structure R11, Structure R12, Structure R13, Structure R14, Structure R15, Structure R16, Structure R17, Structure R18, Structure R19, Structure R20, Structure R21, Structure R22, Structure R23, Structure R24, Structure R25, Structure R26, Structure R27, Structure R28, Structure R29, Structure R30, Structure R31, Structure R32, Structure R33, Structure R34, Structure R35, Structure R36, Structure R37, Structure R38, and Structure R39 as defined in  claim 30 .