| 摘要 |
The novel positively charged pro-drugs of NSAIAs in the general formulas (1, 2a, 2b, 2c, or 2d) "Structure 1, 2a, 2b, 2c, or 2d" were designed and sy nthesized. The compounds of the general formulas (1, 2a, 2b, 2c, or 2d) "Str ucture 1, 2a, 2b, 2c, or 2d" indicated above can be prepared from metal salt s, organic base salts, or immobilized base salts of NSAIAs with suitable hal ide compounds. The positively charged amino groups in the pro-drugs in this invention largely increase the solubility of the drugs in water and will bon d to the negative charge on the phosphate head group of membrane. Thus, the local concentration of the outside of the membrane or skin will be very high and will facilitate the passage of these pro-drugs from a region of high co ncentration to a region of low concentration. This bonding will disturb the membrane a little bit and may make some room for the lipophilic portion of t he pro-drug. When the molecules of membrane move, the membrane may "crack" a little bit due to the bonding of the pro-drug. This will let the pro- drug insert into the membrane. At pH 7.4, only about 99% of the amino group is pr otonated. W hen the amino group is not protonated, the bonding between the a mino group of the pro-drug and the phosphate head group of the membrane will disassociate, and the pro-drugwill enter the membrane completely. When the amino group of the pro-drug flips to the other side of the membrane and thus becomes protonated, then the pro-drug is pulled into the cytosol, a semi- l iquid concentrated aqueous solution or suspension. These pro-drugs can be us ed for treating and preventing diabetes (type I or/and type II), abnormal bl ood glucose and lipid levels, stroke, heart attack, and other heart and vasc ular diseases Alzheimer's diseases, Parkinson's diseases and other neurodege nerative diseases, psoriasis, discoid lupus erythematosus, systemic lupus er ythematosus (SLE), autoimmune hepatitis, multiple sclerosis (MS), and other autoimmune diseases, amyotrophic lateral sclerosis (ALS), oculopharyngeal mu scular dystrophy ( OPMD), and other muscle disorders, inflamed hemorrhoids, cryptitis, other inflammatory conditions of the anorectum, and pruritus ani, prostatitis, prostatocystitis, varicose veins, autoimmune liver inflammatio n, autoimmune kidney inflammation, vein inflammation and other inflammations , skin cancers, breast cancer, colon-rectum cancer, oral cancer, and other c ancers, scars, abnormal vascular skin lesions, birthmarks, moles (nevi), ski n tags, aging spots (liver spots), and other skin disorders. These pro-drugs can be administered transdermally without the help of skin penetration enha ncers. |
