主权项 |
1. A method for penetrating a biological barrier, comprising administering to the biological barrier a high penetration pharmaceutical 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 F1, 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:
R1 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; R2 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 O, S, and NH; X1-X8 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; R4 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; R5 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; R21 and R22 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; R6 and R6′ 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; R7 and R7′ 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; R8 and R8′ 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; R9 and R9′ 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; R10 and R10′ 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; TR is selected from the group consisting of —CH2═C—, —CH═CH—, —C≡C—, —C(═O)NH—, —C(═S)NH—, —C(═O)O—, —OC(═O)—, —C(═O)S—, —C(═O)CH2-, and —CH2C(═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 CH2 groups may be replaced with O, 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 NI, Structure Nm, Structure Nn, Structure No, Structure Np, Structure Nq, and Structure Nr: each R11-R16 is independently selected from the group consisting of nothing, H, CH2COOR11, 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, NR11, or any other pharmaceutically acceptable groups; L1 is selected from the group consisting of nothing, O, S, —N(L3)-, —N(L3)-CH2—O, —N(L3)-CH2—N(L5)-, —O—CH2—O—, —O—CH(L3)-O, —S—CH(L3)-O—; L2 is selected from the group consisting of nothing, O, S, —N(L3)-, —N(L3)-CH2—O, —N(L3)-CH2—N(L5)-, —O—CH2—O—, —O—CH(L3)-O, —S—CH(L3)-O—, —O-L3-, —N-L3-, —S-L3- and —N(L3)-L5-; L4 is selected from the group consisting of C═O, C═S, for each L1, L2, L4, L3 and L5 are independently selected from the group consisting of nothing, H, CH2COOL6, 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, NL3, or any other pharmaceutically acceptable groups; L6 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)OL7, CH═CH, C≡C, CHL7, CL5L7, aryl, heteroaryl, or cyclic groups; L7 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)OL6, CH═CH, C≡C, CHL6, CL6L5, aryl, heteroaryl, or cyclic groups. |