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    PRO-DRUGS OF NSAIAS WITH VERY HIGH SKIN AND MEMBRANES PENETRATION RATES AND THEIR NEW MEDICINAL USES
    1.
    发明公开
    PRO-DRUGS OF NSAIAS WITH VERY HIGH SKIN AND MEMBRANES PENETRATION RATES AND THEIR NEW MEDICINAL USES 审中-公开
    NSAIDs的前体药物具有很高的皮肤和膜的普及率及新医疗用途

    公开(公告)号：EP2170826A1

    公开(公告)日：2010-04-07

    申请号：EP07825791.2

    申请日：2007-06-04

    申请人： Techfields Inc ,  Yu, Chongxi

    发明人： YU, Chongxi ,  XU, Lina

    IPC分类号： C07D209/32 ,  C07D231/12 ,  C07D471/08 ,  C07D487/08 ,  C07D213/74 ,  C07D215/10 ,  C07D217/12 ,  A61K31/44 ,  A61P29/00 ,  A61P3/00

    CPC分类号： C07D513/04 ,  C07D205/04 ,  C07D211/22 ,  C07D295/088 ,  C07D401/12 ,  C07D403/12 ,  C07D405/12 ,  C07D409/12 ,  C07D413/12 ,  C07D417/12 ,  C07D487/04 ,  C07D491/052

    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 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. W hen 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.

    PRO-DRUGS OF NSAIAS WITH VERY HIGH SKIN AND MEMBRANES PENETRATION RATES AND THEIR NEW MEDICINAL USES
    2.
    发明公开
    PRO-DRUGS OF NSAIAS WITH VERY HIGH SKIN AND MEMBRANES PENETRATION RATES AND THEIR NEW MEDICINAL USES 审中-公开

    公开(公告)号：EP4245752A2

    公开(公告)日：2023-09-20

    申请号：EP22170028.9

    申请日：2007-06-04

    申请人： Techfields Inc ,  Yu, Chongxi

    发明人： CHONGXI, Yu ,  XU, Lina

    IPC分类号： C07D209/32 ,  C07D231/12 ,  C07D471/08 ,  C07D487/08 ,  C07D213/74 ,  C07D215/10 ,  C07D217/12 ,  A61K31/44 ,  A61P29/00 ,  A61P3/00

    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 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 chargedamino 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.

    POSITIVELY CHARGED WATER-SOLUBLE PRODRUGS OF PROSTAGLANDINS AND RELATED COMPOUNDS WITH VERY HIGH SKIN PENETRATION RATES
    6.
    发明公开
    POSITIVELY CHARGED WATER-SOLUBLE PRODRUGS OF PROSTAGLANDINS AND RELATED COMPOUNDS WITH VERY HIGH SKIN PENETRATION RATES 有权
    带正电荷的前列腺素和相关链接的水溶性前体药物具有非常高的皮肤渗透速率

    公开(公告)号：EP2084124A1

    公开(公告)日：2009-08-05

    申请号：EP06809471.3

    申请日：2006-10-02

    申请人： Techfields Biochem Co. Ltd. ,  Yu, Chongxi

    发明人： YU, Chongxi ,  XU, Lina

    IPC分类号： C07C215/40 ,  C07C215/42

    CPC分类号： C07C405/0041

    摘要： The novel positively charged pro-drugs of prostaglandins, prostacyclins and related compounds in the general formula (2) 'Structure 2' were designed and synthesized. The compounds of the general formula (2) 'Structure 2' indicated above can be prepared from protected prostaglandins, prostacyclins, and related compounds, by reaction with suitable alcohols, thiols, or amines and coupling reagents, such as N, N'-Dicyclohexylcarbodiimide, N, N'-Diisopropylcarbodiimide, O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate, O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, Benzotriazol-1-yl-oxy-tris (dimethylamino)phosphonium hexafluorophosphate, et al. The positively charged amino groups of these pro-drugs not only largely increases the solubility of the drugs in water, but also bonds to the negative charge on the phosphate head group of membranes and pushes the pro-drug into the cytosol. The results suggest that the pro-drugs diffuse through human skin ~1000 times faster than do prostaglandins, prostacyclins, and related compounds. In plasma, more than 90% of these pro-drugs can change back to the parent drugs in a few minutes. The prodrugs can be used medicinally in treating any prostaglandins, prostacyclins, and related compounds-treatable conditions in humans or animals. The prodrugs can be administered transdermally for any kind of medical treatments and avoid most of the side effects of prostaglandins, prostacyclins, and related compounds. Controlled transdermal administration systems of the prodrug enable prostaglandins, prostacyclins, and related compounds to reach constantly optimal therapeutic blood levels to increase effectiveness and reduce the side effects of prostaglandins, prostacyclins, and related compounds. Another great benefit of transdermal administration of these pro-drugs is that administering medication, especially to children, will be much easier.

    POSITIVELY CHARGED WATER-SOLUBLE PRODRUGS OF ARYL- AND HETEROARYLACETIC ACIDS WITH VERY FAST SKIN PENETRATION RATE
    7.
    发明公开
    POSITIVELY CHARGED WATER-SOLUBLE PRODRUGS OF ARYL- AND HETEROARYLACETIC ACIDS WITH VERY FAST SKIN PENETRATION RATE 有权
    POSITIVE LOADED，芳基和杂芳基的水溶性前药具有非常快的皮肤渗透速率

    公开(公告)号：EP2049482A1

    公开(公告)日：2009-04-22

    申请号：EP06795612.8

    申请日：2006-08-08

    申请人： Techfields Biochem Co. Ltd ,  Yu, Chongxi

    发明人： YU, Chongxi ,  XU, Lina

    IPC分类号： C07D209/12 ,  C07D491/04 ,  C07D231/12

    CPC分类号： C07C219/10 ,  A61K38/05 ,  A61K38/13 ,  C07D207/337 ,  C07D209/28 ,  C07D231/12 ,  C07D231/56 ,  C07D277/30 ,  C07D491/04 ,  A61K2300/00

    摘要： The novel positively charged pro-drugs of aryl- and heteroarylacetic acids in the general formula(1) 'Structure 1' were designed and synthesized. The compounds of the general formula(1) 'Structure 1' indicated above can be prepared from functional derivatives of tolmetin, zomepirac, etodolac, amfenac, bromofenac, alclofenac, fenclofenac, acemetacin, indomethacin, sulindac, fentiazac, lonazolac, bendazac, 6MNA, ibufenac, and related compounds, (for example acid halides or mixed anhydrides), by reaction with suitable alcohols, thiols, or amines. The positively charged amino groups of these pro-drugs not only largely increases the solubility of the drugs, but also bonds to the negative charge on the phosphate head group of membranes and pushes the pro-drug into the cytosol. The results suggest that the pro-drugs diffuses through human skin ~100 times faster than does tolmetin, zomepirac, etodolac, amfenac, bromofenac, alclofenac, fenclofenac, acemetacin, indomethacin, sulindac, fentiazac, lonazolac, bendazac, or related compounds. It takes 2-4 hours for tolmetin, zomepirac, etodolac, amfenac, bromofenac, alclofenac, fenclofenac, acemetacin, indomethacin, sulindac, fentiazac, lonazolac, bendazac, 6MNA, ibufenac, and related compounds to reach the peak plasma level when they are taken orally, but these prodrugs only took about 40-50 minutes to reach the peak plasma level when they are taken transdermally. In plasma, more than 90% of these pro-drugs can change back to the drug in a few minutes. The prodrugs can be used medicinally in treating any NSAIAs-treatable conditions in humans or animals. The prodrugs can be administered not only orally, but also transdermally for any kind of medical treatments and avoid most of the side effects of NSAIAs, most notably GI disturbances such as dyspepsia, gastroduodenal bleeding, gastric ulcerations, and gastritis. Controlled transdermal administration systems of the prodrug enables tolmetin, zomepirac, etodolac, amfenac, bromofenac, alclofenac, fenclofenac, acemetacin, indomethacin, sulindac, fentiazac, lonazolac, bendazac, 6MNA, ibufenac, and related compounds to reach constantly optimal therapeutic blood levels to increase effectiveness and reduce the side effects of NSAIAs. Another great benefit of transdermal administration of these pro-drugs is that administering medication, especially to children, will be much easier.