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 synthesized. The compounds of the general formulas (1, 2a, 2b, 2c, or 2d) “Structure 1, 2a, 2b, 2c, or 2d” indicated above can be prepared from
metal salts,
organic base salts, or immobilized base salts of NSAIAs with suitable
halide compounds. The positively charged amino groups in the pro-drugs in this invention largely increase the
solubility of the drugs in water and will bond 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 concentration 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 the 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 protonated. When the amino group is not protonated, the bonding between the amino group of the pro-drug and the
phosphate head group of the membrane will disassociate, and the pro-drug will 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-liquid concentrated
aqueous solution or suspension. These pro-drugs can be used for treating and preventing diabetes (type I or / and type II), abnormal blood glucose and lipid levels,
stroke, heart
attack, and other heart and vascular diseases Alzheimer's diseases, Parkinson's diseases and other neurodegenerative diseases,
psoriasis,
discoid lupus erythematosus,
systemic lupus erythematosus (SLE), autoimmune
hepatitis,
multiple sclerosis (MS), and other autoimmune diseases,
amyotrophic lateral sclerosis (ALS), oculopharyngeal
muscular dystrophy (OPMD), and other
muscle disorders, inflamed
hemorrhoids, cryptitis, other inflammatory conditions of the anorectum, and pruritus ani,
prostatitis, prostatocystitis,
varicose veins, autoimmune liver
inflammation, autoimmune
kidney inflammation,
vein inflammation and other inflammations,
skin cancers,
breast cancer, colon-
rectum cancer, oral
cancer, and other cancers,
scars, abnormal vascular
skin lesions, birthmarks, moles (nevi), skin tags, aging spots (liver spots), and other skin disorders. These pro-drugs can be administered transdermally without the help of
skin penetration enhancers.