JP6720257B2 - NSAIA prodrugs with very fast skin and membrane penetration rates and novel pharmaceutical uses thereof - Google Patents

Description

The present invention is directed to the design and preparation of positively charged water-soluble prodrugs of non-steroidal anti-inflammatory drugs (NSAIA) with very fast skin and blood-brain barrier penetration rates, as well as diabetes (types I and II), blood glucose and Abnormal levels of blood lipids, stroke, heart and vascular diseases such as heart attack, Alzheimer's disease, Parkinson's disease and other neurodegenerative diseases, psoriasis, discoid lupus erythematosus, systemic lupus erythematosus (SLE), autoimmune disease hepatitis, strong Dermatosis, Sjogren's syndrome, rheumatoid arthritis, polymyositis, scleroderma, Hashimoto thyroiditis, juvenile diabetes, Addison's disease, vitiligo, pernicious anemia, glomerulonephritis, pulmonary fibrosis, multiple sclerosis (MS), clone Disease and other autoimmune diseases, amyotrophic lateral sclerosis (ALS), oropharyngeal muscular dystrophy (OPMD), myotonic dystrophy (MD), Duchenne muscular dystrophy (DMD), polymyositis (PM), Dermatomyositis (DM), inclusion body myositis (IBM) and other muscle diseases, hemorrhoids, inflammatory hemorrhoids, post-irradiation (artificial) post-proctitis, chronic ulcerative colitis, cryptitis, other anorectal Inflammatory conditions and pruritus ani, prostatitis, prostatic cystitis, esophageal varices, autoimmune hepatitis, autoimmune nephritis, colorectal inflammation, enteritis, phlebitis and other inflammation, skin cancer, breast cancer, colorectal cancer , Oral cancer, lung and other respiratory cancer, uterine cancer, genital cancer, urinary cancer, leukemia and other blood and lymphoid cancer and other cancer, wound, abnormal vascular skin lesions, bruise, mole ( New medicinal use in the treatment and prevention of nevus, skin tags, aging spots (melasma), and other skin disorders. These prodrugs can be administered transdermally without the aid of a transdermal absorption enhancer.

NSAIA is used to alleviate the signs and symptoms of rheumatoid arthritis, osteoarthritis and ankylosing spondylitis. NSAIA is used alone or as an adjunct in the treatment of gallstone colic, fever, and episiotomy pain. It is also used for the treatment of gout, acute migraine and renal colic, and post-operative inflammation in patients undergoing cataract extraction surgery. Aspirin is used to prevent heart and vascular disease.

Unfortunately, many side effects are associated with NSAIA use, such as indigestion, gastroduodenal bleeding, gastric ulcers, and very pronounced gastrointestinal disorders such as gastritis. Fishman (Fishman; Robert, US Pat. No. 7,052,715) is an addition to oral medications that requires significant concentration levels in the bloodstream to be reached for the purpose of effectively treating distal regions of pain or inflammation. Indicated a problem. This level is often much higher than would be needed if it were possible to precisely target a particular area of pain or injury. By Fishman and many reporters (Van Engelen et al., US Pat. No. 6416772; Macrides et al., US Pat. No. 6,346,278; Kirby et al., US Pat. No. 6444234, Pearson et al., US Pat. No. 6528040, and Botknecht et al. US Pat. No. 5,885,597) has attempted to develop a delivery system for transdermal application by formulation. Song et al. developed a transdermal drug delivery system for anti-inflammatory analgesics containing diclofenac diethylammonium salt (Song et al. US Pat. No. 6,723,337). Donati et al. developed a plaster for topical use containing heparin and diclofenac (Donati et al., US Pat. No. 6,592,891). Kawaji et al. developed an external oily patch containing diclofenac sodium salt (Kawaji et al., US Pat. No. 6,262,121). Effing et al. developed a device for transdermal delivery of diclofenac (Effing et al., US Pat. No. 6,193,996). However, it is very difficult to deliver therapeutically effective plasma concentrations of NSAIA in patients by formulation. Susan Milosovich et al. designed and prepared testosteronyl-4-dimethylaminobutyrate. HCl (TSBH) has a lipophilic moiety and a tertiary amine group present in a protonated form at physiological pH. They found that the prodrug (TSBH) diffuses through human skin approximately 60 times faster than the drug (TS) itself (Susan Milosovich et al., J. Pharm. Sci., Vol. 82, 227). Page, 1993).

NSAIA has been used as a medicine for over 100 years. NSAIA is indicated for relief of signs and symptoms of rheumatoid arthritis and osteoarthritis, mild relief of pain, reduction of fever, and treatment of dysmenorrhea. It is the most widely used drug in the world.

Unfortunately, a number of side effects associated with NSAIA use are very pronounced gastrointestinal disorders such as indigestion, heartburn, vomiting, gastroduodenal bleeding, gastric ulcers and gastritis. Gastroduodenal bleeding caused by NSAIA is generally painless but can lead to fecal blood loss, which can result in persistent deficiency anemia.

Transdermal delivery systems help avoid direct trauma to the gastrointestinal tract and inactivation of drugs caused by "first pass metabolism" in the gastrointestinal tract and liver. There are limitations to conventional transdermal drug delivery systems that use percutaneous absorption enhancers. First, the permeation rate is very slow (scale of μg/cm ² /hour). Second, large amounts of accelerators will enter the patient's body.

Transdermal delivery systems help avoid direct trauma to the gastrointestinal tract and inactivation of drugs caused by "first pass metabolism" in the gastrointestinal tract and liver. There are limitations to conventional transdermal drug delivery systems that use percutaneous absorption enhancers. First, the permeation rate is very slow (scale of μg/in ² /hour). Second, large amounts of accelerators can enter the patient's body, creating extra side effects. Thirdly, in the conventional transdermal drug delivery using the transdermal absorption enhancer, the high concentration enhancer in the formulation can assist the passage of the drug through the skin, but when the enhancer and the drug enter the skin, The concentration of the enhancer is very dilute, does not help the drug molecule to cross the more biological membrane, the drug molecule accumulates in the subcutaneous fat layer, and the accumulated drug is very serious and Even fatal side effects can occur.

The bioactivity of a drug measures the relative drug dose reaching the systemic circulation. However, systemic circulation is not the "site of action" for most drugs. Drug molecules, even when they reach the systemic circulation, must cross more biological membranes, which are less permeable than those of the digestive system and are often referred to as the "site of action". It interacts with intermolecular and intramolecular fluids before reaching the empty fluid, which causes most drugs to be metabolized by the intestinal mucosa, liver, kidneys and lungs before reaching the "site of action". This situation not only has a very low therapeutic effect, but also causes a toxic burden on the intestinal mucosa, liver, kidneys and lungs. If the permeation rate of the drug in various membranes can be increased, the therapeutic effect and clinical response of the drug will be greatly improved, so that the required dose of the drug will be smaller and the side effects will be reduced. Transdermal prodrug delivery, for prodrugs with very fast skin and membrane penetration rates, will be very useful for local as well as systemic diseases. Since these prodrugs are several dozen to several hundred times more effective than the parent drug, they usually require only a few tenths to a few hundredths of the drug, with very few side effects. This will be useful for transdermal drug delivery as well as for any other drug delivery system (oral, subcutaneous, intravenous, inhalation, and nasal).

The inventors have found that lipophilic moieties and primary, secondary, and tertiary amine groups (preferably tertiary amine groups) that exist in a protonated form (hydrophilic moieties) at physiological pH. It has been found that drugs with and can penetrate the barriers of the skin, blood brain and blood placenta very quickly (on the mg/cm ² /hour scale). The design principles of these prodrugs are shown below.
1. This prodrug is a lipophilic moiety and primary, secondary, and tertiary amine groups (preferably tertiary amine groups) that exist in a protonated form (hydrophilic moiety) at physiological pH. Must have and.
2. All NSAIA prodrugs have one or two (preferably one) primary, secondary, tertiary amine groups present in a protonated form (hydrophilic moiety) at physiological pH. ) Should only have.
3. The primary role of primary, secondary, and tertiary amine groups is to help drugs cross the skin, membranes, blood brain, placenta, wounds, or other barriers. The primary, secondary, tertiary amine groups can be any structure that is non-toxic and mediates the biological activity of the parent drug.

The inventors have disclosed as patents some of all NSAIA prodrugs having "Chemical structure 1" of general formula (1) (International Application Nos. PCT/IB2006/052732, PCT/IB2006/052318). , PCT/IB2006/052815, PCT/IB2006/052563, PCT/IB2006/052575, PCT/IB2006/053741, PCT/IB2006/053091, PCT/IB2006/053090, No. PCT/IB2006/052549).

式中、Ｒ_xは、Ｈ、ＣＨ₃、ＣＨ₃Ｏ、ＯＨ、ＣＨ₃ＣＨ₂、ＣＦ₃、ＣＨＦ₂、ＣＨ₂Ｆ、Ｃｌ、Ｆ、Ｂｒ、Ｆを表し；Ｒ_yは、Ｈ、１から１２の炭素原子を有するアルキル、アルキルオキシ、アルケニル、パーフルオロアルキル、ハロゲン化アルキル若しくはアルキニル残基、アリール又はヘテロアリール部分のいずれか一つを表し；Ｘ₁又はＸ₄は、ＣＨ₂、Ｓ、Ｏ、ＮＨ、又はＣＯを表し；Ｘ₂又はＸ₅は、ＣＨ、ＣＲ₈、又はＮを表し；Ｘ₃は、Ｏ、Ｓ、ＮＨ、又はＮＲ₈を表し；Ｙ、Ｙ₁、Ｙ₂、Ｙ₃、Ｙ₄、Ｙ₅、又はＹ₆は、独立してＨ、ＨＯ、ＣＨ₃ＣＯＯ、Ｒ_yＣＯＯ、ＨＳ、ＮＯ₂、ＣＮ、ＣＨ₃ＣＯＳ、ＮＨ₂、ＣＨ₃ＣＯＮＨ、Ｒ_yＣＯＮＨ、ＣＨ₃、ＣＨ₃ＣＨ₂、Ｃ₃Ｈ₇、Ｃ₄Ｈ₉、ＣＨ₃Ｏ、ＣＨ₃ＣＨ₂Ｏ、Ｃ₃Ｈ₇Ｏ、Ｃｌ、Ｆ、Ｂｒ、Ｉ、ＣＨ₃Ｓ、ＣＨＦ₂Ｏ、ＣＦ₃Ｏ、ＣＦ₃ＣＦ₂Ｏ、Ｃ₃Ｆ₇Ｏ、ＣＦ₃、ＣＦ₃ＣＦ_2、Ｃ₃Ｆ₇、Ｃ₄Ｆ₉、ＣＨ₃ＳＯ₂、Ｒ_yＳＯ₂、ＣＨ₃ＳＯ、Ｒ_yＳＯ、ＣＨ₃ＣＯ、ＣＨ₃ＣＨ₂ＣＯを表し；いずれのＡｒｙ−は、アキラル又はキラルであり；Ａｒｙ−がキラルであれば、一以上のキラル中心を有してもよく、単独の（Ｒ）若しくは（Ｓ）エナンチオマー又は（Ｒ）及び（Ｓ）エナンチオマーの混合物でもよい。 Wherein, R branched or straight-chain - (CH _{2) n} - represents a, - (CH _{2) n} - in n = 0,1,2,3,4,5,6,7,8,9, 10, 11, 12,... and any CH ₂ is O, S, NR ₈ , CH═CH, C≡C, CHR ₈ , CR ₈ R ₉ , an aryl or heteroaryl residue, or pharmacologically May be replaced with any other acceptable moiety; R ₁ or R ₂ is H, an alkyl, alkyloxy, alkenyl, perfluoroalkyl, halogenated alkyl, or alkynyl residue having 1 to 12 carbon atoms. , Aryl or heteroaryl moiety, any CH ₂ is O, S, CH═CH, C≡C, CHR ₈ , CR ₈ R ₉ , an aryl or heteroaryl moiety, or pharmacologically X may represent O, NH, NR ₈ , S, or absent; R ₈ represents H, OH, Cl, F, Br, I, 1 Represents any one of an alkyl, alkyloxy, alkenyl, perfluoroalkyl, halogenated alkyl or alkynyl residue, aryl or heteroaryl moiety having from 1 to 12 carbon atoms; R ₉ is H, OH, Cl, F , Br, I represents any one of an alkyl, alkyloxy, alkenyl, perfluoroalkyl, halogenated alkyl or alkynyl residue, aryl or heteroaryl moiety having 1 to 12 carbon atoms; HA is absent , HCl, HBr, HF, HI, HOAc, citric acid, or any pharmaceutically acceptable acid. All _{R, R 1, R 2,} R 8, R 9, or - (CH _{2) n} - groups are branched or straight chain, C, H, O, Cl , Br, F, I, P, S, N or any other pharmacologically acceptable atom and may contain single, double and/or triple bonds; all R, R ₁ , R ₂ , R ₈ , R _9, or - (CH _{2) n} - group may be achiral or chiral, if chiral groups may have one or more chiral centers, the single (R) or (S) enantiomer or It may be a mixture of (R) and (S) enantiomers; Ary- represents, but is not limited to,

In the formula, R _x represents H, CH ₃ , CH ₃ O, OH, CH ₃ CH ₂ , CF ₃ , CHF ₂ , CH ₂ F, Cl, F, Br, F; R _y is H, 1 Represents one of an alkyl, alkyloxy, alkenyl, perfluoroalkyl, halogenated alkyl or alkynyl residue, aryl or heteroaryl moiety having from 1 to 12 carbon atoms; X ₁ or X ₄ represents CH ₂ , S , O, NH, or CO; X ₂ or X ₅ represents CH, CR ₈ , or N; X ₃ represents O, S, NH, or NR ₈ ; Y, Y ₁ , Y ₂ , Y ₃ , Y ₄ , Y ₅ , or Y ₆ are independently H, HO, CH ₃ COO, R _y COO, HS, NO ₂ , CN, CH ₃ COS, NH ₂ , CH ₃ CONH, R _y. CONH, CH ₃ , CH ₃ CH ₂ , C ₃ H ₇ , C ₄ H ₉ , CH ₃ O, CH ₃ CH ₂ O, C ₃ H ₇ O, Cl, F, Br, I, CH ₃ S, CHF ₂ O, CF ₃ O, CF ₃ CF ₂ O, C ₃ F ₇ O, CF ₃ , CF ₃ CF _2, C ₃ F ₇ , C ₄ F ₉ , CH ₃ SO ₂ , R _y SO ₂ , CH ₃ SO, R _y SO, CH ₃ CO, CH ₃ CH ₂ CO; any Ary- is achiral or chiral; and if Ary- is chiral, it may have one or more chiral centers, It may be the (R) or (S) enantiomer or a mixture of the (R) and (S) enantiomers.

式中、Ｒは分岐又は直鎖の−（ＣＨ₂）_n−を表し、−（ＣＨ₂）_n−においてｎ＝０，１，２，３，４，５，６，７，８，９，１０…であり、いずれのＣＨ₂がＯ、Ｓ、ＣＨ＝ＣＨ、Ｃ≡Ｃ、ＣＨＲ₆、ＣＲ₆Ｒ₇、アリール又はヘテロアリール残基、又は他の環系と置き換えられてもよく；Ｒ₁は分岐又は直鎖の−（ＣＨ₂）_a−を表し、−（ＣＨ₂）_a−においてａ＝０，１，２，３，４，５，６，７，８，９，１０…であり、いずれのＣＨ₂がＯ、Ｓ、ＣＨ＝ＣＨ、Ｃ≡Ｃ、ＣＨＲ_6、ＣＲ₆Ｒ₇、アリール又はヘテロアリール残基、又は他の環系と置き換えられてもよく；Ｒ₂は分岐又は直鎖の−（ＣＨ₂）_b−を表し、−（ＣＨ₂）_b−においてｂ＝０，１，２，３，４，５，６，７，８，９，１０…であり、いずれのＣＨ₂がＯ、Ｓ、ＣＨ＝ＣＨ、Ｃ≡Ｃ、ＣＨＲ_6、ＣＲ₆Ｒ₇、アリール又はヘテロアリール残基、又は他の環系と置き換えられてもよく；Ｒ₃は分岐又は直鎖の−（ＣＨ₂）_c−を表し、−（ＣＨ₂）_c−においてｃ＝０，１，２，３，４，５，６，７，８，９，１０…であり、いずれのＣＨ₂がＯ、Ｓ、ＣＨ＝ＣＨ、Ｃ≡Ｃ、ＣＨＲ₆、ＣＲ₆Ｒ₇、アリール又はヘテロアリール残基、又は他の環系と置き換えられてもよく；Ｒ₄はＨ、１から１２の炭素原子を有するアルキル、アルキルオキシ、アルケニル、パーフルオロアルキル、ハロゲン化アルキル、若しくはアルキニル残基、アリール又はヘテロアリール部分のいずれか一つを表し、いずれのＣＨ₂がＯ、Ｓ、ＣＨ＝ＣＨ、Ｃ≡Ｃ、ＣＨＲ₆、ＣＲ₆Ｒ₇、アリール又はヘテロアリール部分、又は他の環部分と置き換えられてもよく；Ｒ₅は、Ｈ、１から１２の炭素原子を有するアルキル、アルキルオキシ、アルケニル、パーフルオロアルキル、ハロゲン化アルキル、若しくはアルキニル残基、アリール又はヘテロアリール部分のいずれか一つを表し、いずれのＣＨ₂がＯ、Ｓ、ＣＨ＝ＣＨ、Ｃ≡Ｃ、ＣＨＲ₆、ＣＲ₇Ｒ₆、アリール又はヘテロアリール部分、又は他の環部分と置き換えられてもよく；Ｒ₆は、Ｈ、１から１２の炭素原子を有するアルキル、アルキルオキシ、アルケニル、パーフルオロアルキル、ハロゲン化アルキル、若しくはアルキニル残基、アリール又はヘテロアリール部分のいずれか一つを表し、いずれのＣＨ₂がＯ、Ｓ、ＣＨ＝ＣＨ、Ｃ≡Ｃ、ＣＨＲ₆、ＣＲ₇Ｒ₅、アリール又はヘテロアリール部分、又は他の環部分と置き換えられてもよく、Ｒ₇は、Ｈ、１から１２の炭素原子を有するアルキル、アルキルオキシ、アルケニル、パーフルオロアルキル、ハロゲン化アルキル、若しくはアルキニル残基、アリール又はヘテロアリール部分のいずれか一つを表し、いずれのＣＨ₂がＯ、Ｓ、ＣＨ＝ＣＨ、Ｃ≡Ｃ、ＣＨＲ₆、ＣＲ₆Ｒ₅、アリール又はヘテロアリール部分、又は他の環部分と置き換えられてもよく、Ｘは、存在しない、Ｏ、ＮＨ、ＮＲ₆又はＳを表し；一般式（２ａ、２ｂ、２ｃ、又は２ｄ）の「化学構造２ａ、２ｂ、２ｃ、又は２ｄ」におけるＡｒｙ−は、一般式（１）の「化学構造１」におけるＡｒｙ−と同一に定義され、ＨＡは、存在しない、ＨＣｌ、ＨＢｒ、ＨＦ、ＨＩ、ＨＯＡｃ、クエン酸、又は薬理学的に許容できる任意の酸を表す。全てのＲ、Ｒ₁、Ｒ₂、Ｒ₃、Ｒ₄、Ｒ₅、Ｒ₆、Ｒ₇、又は−（ＣＨ₂）_n−基は、分岐又は直鎖であり、Ｃ、Ｈ、Ｏ、Ｃｌ、Ｂｒ、Ｆ、Ｉ、Ｐ、Ｓ、Ｎ又は任意の他の薬理学的に許容できる原子を含んでもよく、単結合、二重結合、及び／又は三重結合を含んでもよく；全てのＲ、Ｒ₁、Ｒ₂、Ｒ₃、Ｒ₄、Ｒ₅、Ｒ₆、Ｒ₇、又は−（ＣＨ₂）_n−基は、アキラル又はキラルでもよく；基がキラルであれば、一以上のキラル中心を有してもよく、単独の（Ｒ）若しくは（Ｓ）エナンチオマー又は（Ｒ）及び（Ｓ）エナンチオマーの混合物でもよい。 We have found that the primary role of primary, secondary, and tertiary amine groups is only to help the drug pass through the skin, membranes, blood brain, placenta, wounds, or other barriers. Therefore, it has been found that the primary, secondary, and tertiary amine groups can be any structure that is non-toxic and mediates the biological activity of the parent drug. Therefore, the inventors have designed and prepared various types of amine groups for this property. The novel NSAIA prodrugs have the "chemical structure 2a, 2b, 2c, or 2d" of general formula (2a, 2b, 2c, or 2d).

Wherein, R branched or straight-chain - (CH _{2) n} - represents a, - (CH _{2) n} - in n = 0,1,2,3,4,5,6,7,8,9, 10... and any CH ₂ may be replaced with O, S, CH═CH, C≡C, CHR ₆ , CR ₆ R ₇ , aryl or heteroaryl residues, or other ring systems; R ₁ branched or straight-chain - (CH _{2) a} - represents, - (CH _{2) a} - in a = 0,1,2,3,4,5,6,7,8,9,10 ... in And any CH ₂ may be replaced with O, S, CH═CH, C≡C, CHR _6, CR ₆ R ₇ , an aryl or heteroaryl residue, or other ring system; R ₂ is branched or linear - _{represents, - - (CH 2) b} (CH 2) b - in b = 0,1,2,3,4,5,6,7,8,9,10 ... a is any CH ₂ may be replaced by O, S, CH═CH, C≡C, CHR _6, CR ₆ R ₇ , an aryl or heteroaryl residue, or another ring system; R ₃ is branched or straight chain Bruno - (CH _{2) c} - represents _{a, - (CH 2) c -} c = 0,1,2,3,4,5,6,7,8,9,10 ... a is in any of the CH ₂ but O, S, CH = CH, C≡C, CHR 6, CR 6 R 7, aryl or heteroaryl residues, or other may be replaced with the ring system; R ₄ is H, 1 to 12 carbon Represents one of an alkyl, alkyloxy, alkenyl, perfluoroalkyl, halogenated alkyl, or alkynyl residue having an atom, an aryl or a heteroaryl moiety, and any CH ₂ is O, S, CH═CH, C ≡C, CHR ₆ , CR ₆ R ₇ , aryl or heteroaryl moieties, or other ring moieties; R ₅ is H, alkyl having 1 to 12 carbon atoms, alkyloxy, alkenyl, It represents any one of a perfluoroalkyl, an alkyl halide, or an alkynyl residue, an aryl or a heteroaryl moiety, and any CH ₂ is O, S, CH═CH, C≡C, CHR ₆ , CR ₇ R ₆ , Aryl or heteroaryl moieties, or other ring moieties; R ₆ is H, alkyl having 1 to 12 carbon atoms, alkyloxy, alkenyl, perfluoroalkyl, halogenated alkyl, or alkyl. Represents any one of a nyl residue, an aryl or a heteroaryl moiety, and any CH ₂ is O, S, CH═CH, C≡C, CHR ₆ , CR ₇ R ₅ , an aryl or heteroaryl moiety, or other R ₇ may be substituted for H, an alkyl, alkyloxy, alkenyl, perfluoroalkyl, alkyl halide, or alkynyl residue having 1 to 12 carbon atoms, an aryl or heteroaryl moiety. Represents any one and any CH ₂ may be replaced with O, S, CH═CH, C≡C, CHR ₆ , CR ₆ R ₅ , an aryl or heteroaryl moiety, or another ring moiety, X represents absent O, NH, NR ₆ or S; Ary- in “Chemical structure 2a, 2b, 2c, or 2d” of the general formula (2a, 2b, 2c, or 2d) is represented by the general formula ( The same is defined as Ary − in “Chemical Structure 1” of 1), and HA represents HCl, HBr, HF, HI, HOAc, citric acid, or any pharmacologically acceptable acid that is absent. All _{R, R 1, R 2,} R 3, R 4, R 5, R 6, R 7, or - (CH _{2) n} - groups are branched or straight chain, C, H, O, Cl , Br, F, I, P, S, N or any other pharmacologically acceptable atom and may contain single, double and/or triple bonds; all R, _{R 1, R 2, R 3} , R 4, R 5, R 6, R 7, or - (CH _{2) n} - group may be achiral or chiral, if groups chiral, one or more chiral centers Or may be a single (R) or (S) enantiomer or a mixture of (R) and (S) enantiomers.

Drug absorption requires passage of the drug in molecular form through the septum, either from the digestive tract or other sites. The drug must first dissolve, and if the drug has suitable biopharmaceutical properties, must pass from the high-concentration region to the low-concentration region through the membrane into the blood or systemic circulation. become. All biological membranes contain lipids as the major constituent. Molecules that play a predominant role in film formation all have a highly polar headgroup containing phosphates, and most often two hydrophobic hydrocarbon tails. The membrane is bilayer and the hydrophilic head groups face outward on the water soluble regions on both sides. Highly hydrophilic drugs cannot pass through the hydrophobic layer of the membrane, and due to their similarity, the highly hydrophilic drugs will remain within the hydrophobic membrane as part of the membrane, effectively Can not enter the cytoplasm.

One object of the present invention is to determine the solubility of NSAIA in gastric fluid that allows oral administration and the permeation rate of NSAIA through the membrane and skin barrier that enables transdermal (topical) administration. By increasing the side effects of NSAIA. The most important goal of the present invention is that it can penetrate the skin, cell membranes, especially the membranes of brain cells and nerve cells, stay in the systemic circulation for a very short time, and thus have several hundred times more efficacy than the parent drug. , Designing NSAIA prodrugs that usually require only a few tenths to a few hundredths of a drug dose and the occurrence of side effects can be greatly reduced. It is effective not only for transdermal drug delivery, but also for other drug delivery systems (oral, subcutaneous, intravenous, inhalation, and nasal, etc.) and treats many conditions that cannot be treated by the parent drug be able to. These novel NSAIA prodrugs generally have two structural features. That is, it has a lipophilic moiety and primary, secondary, or tertiary amine groups that are present in a form that is protonated at physiological pH (hydrophilic moiety). Such a hydrophilic-lipophilic balance is required for efficient passage through the membrane barrier (Susan Milosovich et al., J. Pharm. Sci. 82:227, 1993). The positively charged amino group makes the drug very soluble in water. The positive charge of the amino group on these prodrugs will combine with the negative charge of the phosphate headgroup of the membrane. Thus, the local concentrations on the outside of the membrane or skin are very high, facilitating passage of these prodrugs from high to low concentration regions. This binding destabilizes the membrane somewhat and allows some room for the lipophilic portion of the prodrug. When the membrane molecule moves, the membrane may be slightly "cracked" due to the binding of the prodrug. This causes the prodrug to enter the membrane. At pH 7.4, only about 99% of the amino groups are protonated. When the amino group is not protonated, the bond between the amino group of the prodrug and the phosphate headgroup of the membrane is dissociated and the prodrug will enter the membrane completely. When the amino group of the prodrug moves to the opposite side of the membrane and is protonated, the prodrug is then drawn into the semi-fluid concentrated aqueous solution or suspension, the cell matrix. Due to the short stay in the digestive tract, the prodrug does not cause damage to gastric mucosal cells. The permeation rate of the novel prodrug through human skin was measured in vitro using Franz modified permeation cells from human skin tissue (thickness 360-400 μm) in the ventral and dorsal thigh regions. The receiving fluid was composed of 2% bovine serum albumin in 10 mL of normal saline and stirred at 600 rpm. The cumulative amount of prodrug and drug entering the skin over time was determined by a selective high performance liquid chromatography method. The apparent flux value of NSAIA prodrug was 0.1 to 50 mg/cm ² /hour. This result suggests that the prodrug diffuses through human skin at least several hundred times faster than its parent drug. This result suggests that the positive charge on the dialkylaminoethyl group has an important role in the passage of the drug across the membrane and skin barrier.

The novel NSAIA prodrugs can penetrate the skin barrier, blood-brain barrier, and blood-placental barrier. The in vitro permeation rates of the prodrug and its parent drug through intact rat skin were compared. A 20% prodrug or its parent drug in 1 mL of ethanol was applied to an area of about 5 cm ^{2 on} the back of a rat (about 200 g) to construct a donor. After 4 hours, the rats were killed, 5 mL of methanol was added to 1 mL of blood, 1 g of liver, 1 g of kidney, 1 g of brain (liver, kidney or brain were washed 3 times with a buffer of pH 7.2) and the mixture was homogenized. The samples were then ultracentrifuged for 5 minutes and analyzed using HPLC. The results are shown in Tables 1 to 5.

20% of aspirin, diclofenac, ketoprofen, fenoprofen, or ibuprofen in 1 mL of ethanol was applied to the rat dorsal area about 5 cm ² . After 4 hours, the rats were killed, 5 mL of methanol was added to 1 mL of blood, 1 g of liver, 1 g of kidney, 1 g of brain (liver, kidney or brain were washed 3 times with a buffer of pH 7.2) and the mixture was homogenized. These drugs were not found in the tissues or plasma of any rat. This result indicates that NSAIA prodrugs can penetrate skin barriers, blood-brain barrier, and other membrane barriers very rapidly, while parental NSAIA cannot penetrate skin barriers in detectable amounts. It is shown that.

The prodrug of “Chemical structure 1” of the general formula (1) is a compound of the inventors' patents (International Application Nos. PCT/IB2006/052732, PCT/IB2006/052318, PCT/IB2006/052815, PCT/IB2006/052563, PCT/IB2006/052575, PCT/IB2006/053741, PCT/IB2006/053091, PCT/IB2006/053090, PCT/IB2006/052549). It showed inflammatory, analgesic, antipyretic and antirheumatic activities. We have found that all of the prodrugs of "Chemical Structure 2a, 2b, 2c, or 2d" of general formula (2a, 2b, 2c, or 2d) are anti-inflammatory, analgesic, antipyretic, and antirheumatic. It has been found that it exhibits sexual activity. The main object of the present invention is the novel medicinal use of NSAIA prodrugs.

The relationship between inflammation and cancer is well known. Thea D. Dr. Tlsty gave a lecture (Keystone Symposia: Inflammation and Cancer, Breckenridge, CO, USA, Feb. 27-Mar. 3, 2005). Cyclooxygenase-2 (COX-2) is aromatase active, angiogenic, proliferative, It is described to stimulate invasion and prostaglandin synthesis. Increased prostaglandins lead to inhibition of cell death. Aspirin and other NSAIAs inhibit COX-1 and COX-2. The overall relative risk of colorectal cancer, esophageal cancer, ovarian cancer or other cancers is reduced in those who take aspirin for a long time. However, cancer cells may change their membrane structure so that NSAIA does not enter the cancer cells. The novel prodrugs of the present invention are capable of penetrating any membrane barrier, can be topically applied to the outer skin area at the location of the cancer, and have very low systemic exposure to allow large amounts of the prodrug to enter cancer cells. become.

To assess the antitumor activity of NSAIA prodrugs, human breast cancer cells (BCAP-37, 2-3 mm ³ of tumor tissue was used in each mouse) were used as nude mice (BALB, 12 groups, 7 mice in each group). Xenograft was performed subcutaneously in mice). After 14 days, the tumor had grown to a size of 50±10 mm ³ (0.05 ml). Then 30 μl of 5% (equivalent to 1.5 mg prodrug) diethylaminoethyl acetylsalicylate acetylsalicylate (P-1, in acetone); 1-piperidinepropyl 2[(2,6-dichlorophenyl)amino]benzeneacetate That. AcOH (P-2, in water), 1-pyrrolidinepropyl 2-(3-benzoylphenyl)propionate. AcOH (P-3, in water), 4-piperidine methyl 2-(3-phenoxyphenyl) propionate. AcOH (P-4, in water), 3-piperidine methyl 2-(ρ-isobutylphenyl) propionate. AcOH (P-5, in water), diethylaminoethyl 1-(p-chlorobenzoyl)-5-methoxy-2-methylindole 3-acetate. AcOH (P-11 in water), 2-(4-morpholinyl)ethyl(Z)-5-fluoro-2-methyl-1-[(4-methylsulfinyl)phenylmethylene]-1H-indene-3-acetate. AcOH (P-12, in water), diethylaminoethyl 2-(2,4-dichlorophenoxy)benzene acetate. AcOH (P-19 in water), diethylaminoethyl 2-(8-methyl-10,11-dihydro-11-oxodibenz(b,f)oxepin-2-yl)propionate. AcOH (P-37, in water), 1-pyrrolidinepropyl 2-[[(3-(trifluoromethyl)phenyl)amino]benzoate. AcOH (P-48 in water), 4-N,N-dimethylaminobutyryloxy-2-methyl-N-2-pyridinyl-2H,1,2-benzothiazine-3-carboxamide 1,1-dioxide. HCl (P-51 in acetone) was topically applied every 8 weeks to the transplanted area of human breast cancer cells (near the forepaw). Tumor sizes on day 42 are shown in Tables 6 and 7.

In the second antitumor experiment, human colon cancer cells (LS174J, 2-3 mm ³ of tumor tissue was used for each mouse) were subcutaneously xenografted into nude mice (BALB). After 7 days, the tumor had grown to a size of 55±10 mm ³ (0.055 ml). Then about 30 μL of 5% (equivalent to 1.5 mg prodrug) diethylaminoethyl acetylsalicylate acetylsalicylate (P-1, in acetone); 1-piperidinepropyl 2[(2,6-dichlorophenyl)amino]benzene. Acetate. AcOH (P-2, in water), 1-pyrrolidinepropyl 2-(3-benzoylphenyl)propionate. AcOH (P-3, in water), 4-piperidine methyl 2-(3-phenoxyphenyl) propionate. AcOH (P-4, in water), 3-piperidine methyl 2-(ρ-isobutylphenyl) propionate. AcOH (P-5, in water), diethylaminoethyl 1-methyl-5-(4-methylbenzoyl)-1H-pyrrole-2-acetate. AcOH (P-13 in water), 2-(4-morpholinyl)ethyl 2-amino-3-benzoylbenzeneacetate. AcOH (P-16 in water), diethylaminoethyl 2-(10,11-dihydro-10-oxodibenzo(b,f)thiepin-2-yl)propionate. AcOH (P-36), diethylaminoethyl 2-[(2,3-dimethylphenyl)amino]benzoate. AcOH (P-46 in water), diethylaminoethyl 2-[(2,6-dichloro-3-methylphenyl)amino]benzoate. AcOH (P-47 in water), N-(2-thiazoyl)-4-N,N-dimethylaminobutyryloxy-2-methyl-2H,1,2-benzothiazine-3-carboxamide 1,1-dioxide. HCl (P-52 in acetone) was topically applied every 8 weeks to the transplanted area of human colon cancer cells (near the paw). Tumor size on day 30 is shown in Tables 8 and 9.

これらの結果は、ＮＳＡＩＡプロドラッグが非常に強い抗腫瘍活性を有し、副作用がないかほとんどないことも示している。

These results also indicate that NSAIA prodrugs have very strong antitumor activity with no or few side effects.

The hypoglycemic effect of salicylate was first observed by German doctors over 100 years ago (Edmund J. Hengesh, "Principles of medicinal chemistry", 4th edition, page 591, Williams & Wilkins, 1995). Salicylate enhances glucose-stimulated insulin secretion and inhibits glucose production from lactate and alanine (HF Woods et al., Clin. Exp. Pharmacol Physiol. 1, 534, 1974). Certain salicylates lower plasma levels of free fatty acids, triglycerides, and cholesterol. An increase in the concentration of free fatty acids in plasma inhibits glucose utilization, and a decrease in the concentration can contribute to the hypoglycemic effect. Unfortunately, high doses of salicylate (5 g daily) are required to maintain proper control of blood glucose and blood lipid levels. Countless side effects such as stomach discomfort, nausea, vomiting and tinnitus frequently occur at this dose level. The novel prodrugs of the present invention have very fast skin and membrane penetration rates. It can reach its “site of action” very quickly and the pharmacological effects and clinical response of these prodrugs are greatly enhanced, thus requiring much lower drug doses (one hundredth of the parent drug). Therefore, the occurrence of side effects will be extremely reduced.

The prodrug of the present invention lowers blood glucose level in a rat model (SLAC/GK, type 2 diabetes, n=7). Diethylaminoethyl acetylsalicylate 50% acetone solution of acetylsalicylate (P-1, in acetone); 4-acetamidophenylsalicylyldimethylaminobutyrate. HCl (P-6), diethylaminoethyl 5-(2,4-difluorophenyl)acetyl salicylate. 5-(2,4-difluorophenyl)acetyl salicylate (P-8), diethylaminoethyl salicyl salicylate. AcOH (P-9), diethylaminoethyl salicylate. AcOH (P-10), diethylaminoethyl 5-acetamido-acetylsalicylate (P-58), diethylaminoethylacetylsalicylic salicylate. Acetyl salicyl salicylate (P-59), diethylaminoethyl acetyl salicyl salicylate. Acetylsalicylsalicylsalicylate (P-60) (equivalent to 20 mg/kg NSAIA) once a day (8:00 am) for 5 weeks, rat (shaved) back (about 1.5 cm ² ). Transdermally. Blood glucose levels were measured once every three days from week 2 to week 5 at 3 pm (without fasting). The results are shown in Table 10. Blood lipid levels were measured at the end of the 5th week. The results are shown in Table 11.

この結果は、ＮＳＡＩＡプロドラッグが、糖尿病ラットモデルにおいて非常に効果的に血糖値を低下させ、正常ラットの血糖値には影響しないことを示した。最も興味深いことは、処置を３０日間停止した後に、ラットの血糖値が通常レベル（７〜８ｍｍｏｌ／Ｌ、絶食なし）にとどまったことである。これは、本プロドラッグが血糖値を低下するだけでなく、糖尿病を治療できることも意味している。

The results showed that NSAIA prodrugs very effectively lowered blood glucose levels in a diabetic rat model and did not affect blood glucose levels in normal rats. Most interestingly, the blood glucose level of the rats remained at normal level (7-8 mmol/L, no fasting) after stopping the treatment for 30 days. This means that the prodrug not only lowers blood glucose levels, but can treat diabetes.

この結果は、ＮＳＡＩＡプロドラッグが、糖尿病ラットモデルにおいて非常に効果的に血中脂質濃度（全コレステロール及びトリグリセリド）を低下し、ＨＤＬレベルには影響しないことを示した。

The results showed that NSAIA prodrugs reduced blood lipid levels (total cholesterol and triglycerides) very effectively in diabetic rat models and did not affect HDL levels.

The pH of gastric juice is 1 to 3. The negative charge of the phosphate headgroup is neutralized by hydrogen ions, and the positive charge of the amino group of these prodrugs cannot bind to the phosphate headgroup of the membrane, so the prodrug can pass through the stomach wall. You can't, and you won't hurt or make your stomach sick. The pH of the duodenum is about 5-7 and the prodrug is able to cross the mucosa of the duodenum. Since the pancreas is in close proximity and most of the prodrugs enter it before it reaches the liver, kidneys, and systemic circulation, where the drug is metabolized, very few doses of these prodrugs are taken. Only the amount is needed and the side effects are very few and low. Diethylaminoethyl acetylsalicylate. Acetylsalicylate (P-1, in acetone) in 20% acetone; 4-acetamidophenylsalicylyldimethylaminobutyrate. HCl (P-6), diethylaminoethyl 5-(2,4-difluorophenyl)acetyl salicylate. 5-(2,4-difluorophenyl)acetyl salicylate (P-8), diethylaminoethyl salicyl salicylate. AcOH (P-9), diethylaminoethyl salicylate. AcOH (P-10), diethylaminoethyl 5-acetamido-acetylsalicylate (P-58), diethylaminoethylacetylsalicylic salicylate. Acetyl salicyl salicylate (P-59), diethylaminoethyl acetyl salicyl salicylate. Acetylsalicylsalicylsalicylate (P-60) (equivalent to 20 mg/kg NSAIA) was orally administered to rats (SLAC/GK, type 2 diabetes, n=7) daily with food for 5 weeks. Blood glucose levels were measured once every three days from week 2 to week 5 at 3 pm (no fasting). The results are shown in Table 12. Blood lipid levels were measured at the end of the 5th week. The results are shown in Table 13.

この結果は、プロドラッグが経口摂取され、親薬物よりも服用量がずっと少量であるときに、ＮＳＡＩＡプロドラッグが、糖尿病ラットモデルにおいて非常に効果的に血糖値を低下させ、正常ラットの血糖値には影響しないことを示した。

This result indicates that NSAIA prodrugs very effectively lower blood glucose levels in a diabetic rat model when the prodrugs are taken orally and at much lower doses than the parent drug, and in normal rats. It has not been affected.

この結果は、プロドラッグが経口摂取され、親薬物よりも服用量がずっと少量であるときに、ＮＳＡＩＡプロドラッグが、糖尿病ラットモデルにおいて非常に効果的に血中脂質濃度を低下することを示した。

The results showed that NSAIA prodrugs very effectively reduce blood lipid levels in a diabetic rat model when the prodrug is taken orally and at much lower doses than the parent drug. ..

The prodrug of the present invention lowers blood glucose levels in a rat model (SLAC:NOD-IDDM, type 1 diabetes, n=7). Diethylaminoethyl acetylsalicylate. Acetylsalicylate (P-1, in acetone) in 50% acetone; 4-acetamidophenylsalicylyldimethylaminobutyrate. HCl (P-6), diethylaminoethyl 5-(2,4-difluorophenyl)acetyl salicylate. 5-(2,4-difluorophenyl)acetyl salicylate (P-8), diethylaminoethyl salicyl salicylate. AcOH (P-9), diethylaminoethyl salicylate. AcOH (P-10), diethylaminoethyl 5-acetamido-acetylsalicylate (P-58), diethylaminoethylacetylsalicylic salicylate. Acetyl salicyl salicylate (P-59), diethylaminoethyl acetyl salicyl salicylate. Acetylsalicylsalicylsalicylate (P-60) (equivalent to 30 mg/kg NSAIA) once a day (8:00 am) for 7 weeks, rat (shaved) back (about 1.5 cm ² ). Was administered transdermally. Blood glucose levels were measured once every 3 days from week 4 to week 7 at 3 pm (without fasting). The results are shown in Table 14.

この結果は、ＮＳＡＩＡプロドラッグが、糖尿病（Ｉ型）マウスモデルにおいて非常に効果的に血糖値を低下することを示した。

The results showed that NSAIA prodrugs very effectively lower blood glucose levels in a diabetic (type I) mouse model.

Eighteen Chinese white rabbits weighing 3.0 to 3.5 kg (6 to 7 months old) were selected and divided into 3 groups (control, P-1 and P10 groups, n=6). One hour before the experiment, thrombus was created by aspirating venous blood (1 mL) into a sterile bottle to coagulate. To avoid rupture and slow lysis, autologous blood clots were stabilized in temperature-controlled (70°C) distilled water for 10 minutes. After anesthesia, the femoral circumflex vein was exposed and distally isolated, and an autologous thrombus (0.05 g/kg) was injected through an indwelling catheter (20GA) placed in the earlier isolated femoral circumflex vein. Diethylaminoethyl acetylsalicylate. Acetyl salicylate (P-1, in acetone, 20 mg/kg) and diethylaminoethyl acetyl salicyl salicylate. A 50% acetone solution of acetylsalicylic salicylate (P-59, 20 mg/kg) was topically applied to the back of the rabbit. Two days later, the rabbits were euthanized with an excess intravenous injection of sodium amobarbital (60 mg/kg). The lungs and heart were isolated and observed whether thrombi were present in the pulmonary arteries. The lungs were immersed in 10% formalin for 24 hours. Serial cross sections along the embolized pulmonary artery were embedded in paraffin and stained with hematoxylin-eosin. In the control group, platelet thrombi and mixed thrombi surrounded the infused coagulation and were present both in the proximal and distal directions in the large vessel and the dilated vessel wall. There was excessive proliferation of endothelial cells and fibrocytes in these vessels. In addition, there was acute pulmonary congestion. In the P-1 and P-59 groups, the lung tissue and blood vessel wall of both were normal. The results showed that the thrombotic effect and the progression of thrombosis associated with its embolism could be prevented by these NSAIA prodrugs. These prodrugs may be very useful in the prevention and treatment of blood coagulation, which is a major cause of stroke, heart attack and organ transplant rejection.

The prodrugs of the present invention can help to heal wounds and soften and shrink cuts and burns in a rabbit model. The average wound area of rabbits treated with this prodrug was only one-third that of control rabbits derived from the same cut in the Chinese White Rabbit model, which wound was similar to normal intact tissue. Is the flexibility of.

COX-1 and COX-2 play a very important role in the immune response of animals. NSAIA inhibits COX-1 and COX-2. The NSAIA prodrugs of the present invention may be very useful for the treatment of psoriasis, discoid lupus erythematosus, systemic lupus erythematosus (SLE), and other autoimmune diseases. High-concentration Malassezia suspension (Rosenberg, EW, et al., Mycopathologia, Vol. 72, pp. 147-154, 1980) was shaved on the dorsal skin of Chinese white rabbits (n=4×6) for 2 weeks. It was applied twice a day (7:00 am and 7:00 pm) to generate psoriasis-like lesions. Then 3-piperidinemethyl 2-(ρ-isobutylphenyl)propionate. AcOH (P-5), diethylaminoethyl 1-methyl-5-(4-methylbenzoyl)-1H-pyrrole-2-acetate. AcOH (P-13), diethylaminoethyl 5-(4-chlorobenzoyl)-1,4-dimethyl-1H-pyrrole-2-acetate. AcOH (P-14), diethylaminoethyl 1,8-diethyl-1,3,4,9-tetrahydropyrano-[3,4-b]indole-1-acetate. AcOH (P-15), diethylaminoethyl 2-amino-3-(4-bromo-benzoyl)benzeneacetate. AcOH (P-17), diethylaminoethyl 3-chloro-4-(2-propenyloxy)benzene acetate. AcOH (P-18), diethylaminoethyl 1-(4-chlorobenzoyl-5-methoxy-2-methyl-1H-indole-3-acetoxyacetate.AcOH (P-20), diethylaminoethyl 4-(4-chlorophenyl) )-2-Phenyl-5-thiazoleacetate.AcOH(P-21), diethylaminoethyl 3-(4-chlorophenyl)-1-phenyl-1H-pyrazole-4-acetate.AcOH(P-22) 5% The aqueous solution was applied to the same area 3 hours (10 am and 10 pm) after application of the concentrated Malassezia suspension (7 am and 7 pm), 10 days after application of these prodrugs. , The lesion was separated.

5% diethylaminoethyl acetylsalicylate acetylsalicylate (P-1, in acetone, 30 mg/kg), or 3-piperidine methyl 2-(ρ-isobutylphenyl) propionate for evaluation of anti- lupus erythematosus activity. AcOH (P-5, in water, 30 mg/kg) was topically applied twice daily to the skin on the back of mice with discoid lupus erythematosus and systemic lupus erythematosus (MRL/LPR, n=5×3). After 6 weeks all skin lesions and lupus nephritis were resolved in the prodrug treated mice, but the symptoms in control mice were worse.

These results indicate that these NSAIA prodrugs are promising agents for the treatment of psoriasis, discoid lupus erythematosus, systemic lupus erythematosus (SLE), multiple sclerosis (MS), and other autoimmune diseases in humans. Suggests that.

The development of cell death in amyotrophic lateral sclerosis (ALS) may include glutamate-mediated excitotoxicity, oxidative damage, and apoptosis. Cyclooxygenase-2 is present in spinal cord neurons and astrocytes and catalyzes the synthesis of prostaglandin E2. While prostaglandin E2 stimulates glutamate release from astrocytes, cyclooxygenase-2 also plays an important role in the production of proinflammatory cytokines, reactive oxygen species, and free radicals. Treatment with the selective cyclooxygenase-2 inhibitor celecoxib significantly inhibited prostaglandin E2 production in the spinal cord of ALS mice. Celecoxib treatment significantly delayed the onset of debilitation and weight loss, prolonging survival by 25%. The spinal cord of treated ALS mice showed marked preservation of spinal cord neurons and reduced astrocyte proliferation and microglial activation (Merit. E. Cudkowicz et al., Annals of neurology, No. 52). Vol. 771-778, 2002). These results suggest that inhibition of cyclooxygenase-2 may be beneficial to ALS patients. The NSAIA prodrugs of the present invention are capable of penetrating skin and nerve cell membrane barriers at very fast rates (most NSAIAs cannot penetrate nerve cells effectively) and can be administered transdermally without damaging the gastrointestinal tract. Therefore, these prodrugs are associated with multiple sclerosis (MS), Crohn's disease, and other autoimmune diseases, amyotrophic lateral sclerosis (ALS), oropharyngeal muscular dystrophy (OPMD), myotonic dystrophy (MSD). MD), Duchenne Muscular Dystrophy (DMD), Polymyositis (PM), Dermatomyositis (DM), Inclusion Body Myositis (IBM), and other very useful agents for the treatment of myopathy.

The mechanism of inflammation has been proposed as an important mediator in the pathogenic cascade of Alzheimer's disease (McGeer PL, McGeer EG, “The inflammatory response systems of therapy der vines et al. , 1995; 21:195-218). In a study by in't Veld et al. (The New England Journal of Medicine, 2001; 345, 1515), they followed about 7,000 people at risk for Alzheimer's disease for nearly seven years. Their results suggested that NSAIA could reduce the relative risk to those who had a cumulative use of NSAIA before dementia onset for at least two years, or more than two years. When the neuroprotective capacity of NSAIA ceased in the year just before the onset of dementia, these compounds rendered them unprotected against progression in most people with the prodrome of the disease. The inventors believe that the reason for this is that the tissue surrounding the damaged nerve cells forms a scar to protect the nerve cells from further damage. Most NSAIAs have very slow penetration rates of the brain blood and nerve cell barriers and are unable to penetrate the scar barrier. These prodrugs of the present invention have a very fast rate of penetration of the skin, blood brain, nerve cell membranes, and scar barriers for the treatment of Alzheimer's disease, Parkinson's disease and other progressive neurodegenerative diseases. It is a very promising drug.

These prodrugs can help patients with spinal cord injuries whose healing is stopped by a protected scar around the injured spinal cord. While most NSAIAs are unable to penetrate scar barriers in therapeutically effective amounts, the prodrugs of the invention are capable of penetrating scar barriers, have anti-inflammatory activity and aid in wound healing. You can

NSAIA is not very effective for the treatment of the above-mentioned conditions, has serious side effects due to its inability to penetrate cell membranes, especially brain cells and nerve cells very effectively, and because the systemic circulation stays too long, Most of the drug will be metabolized by the intestinal mucosa, liver, kidneys, and lungs before reaching the "site of action." Not only does this situation produce very low pharmacological effects, but it also creates a toxic burden on the intestinal mucosa, liver, kidneys, lungs, and other body parts. These prodrugs penetrate skin, cerebral blood, brain cells, nerve cells and other membrane barriers very well, have hundreds of times the potency of the parent drug, and only tens of normal drug doses. It requires one-hundredth or one-hundredth, and the occurrence of side effects is greatly reduced. This would be beneficial not only for transdermal drug delivery, but also for any drug delivery system (oral, subcutaneous, intravenous, inhalation, and nasal, etc.) and better than could be treated by the respective parent drug. Many symptoms can be treated, and even some that cannot be treated with the respective parent drug.

The compounds represented by the above-mentioned general formulas 1, 2a, 2b, 2c, or 2d having the “chemical structure 1, 2a, 2b, 2c, or 2d” are N,N′-dicyclohexylcarbodiimide, N,N′-diisopropylcarbodiimide or other compounds. Can be prepared from NSAIA by a reaction to form an anhydride using a coupling reagent of, followed by reaction with a suitable alcohol, thiol, or amine.

The compound of the above-mentioned general formula 1, 2a, 2b, 2c, or 2d “chemical structure 1, 2a, 2b, 2c, or 2d” is a metal salt of NSAIA or an organic basic salt using a suitable halide. Alternatively, it can be prepared from an immobilized basic salt.

A compound having a general “chemical structure 1, 2a, 2b, 2c, or 2d” or at least one compound having a general “chemical structure 1, 2a, 2b, 2c, or 2d” is included as an active ingredient. The transdermal therapeutic application system of the composition can be used to treat any condition treatable by NSAIA in humans or animals, and the novel conditions described in this invention. These systems can be bandages or patches, which include a matrix layer containing one active ingredient and an impermeable backing layer. The most preferred system is the active ingredient reservoir, which has a permeable bottom facing the skin. By controlling the release rate, the system allows the NSAIA to reach a constant, therapeutically optimal blood concentration, increase efficacy and reduce NSAIA side effects. These systems can be worn on the wrist, ankles, arms, legs, or any part of the body.

NSAIA is not very effective for the treatment of the above-mentioned conditions, has serious side effects due to its inability to penetrate cell membranes, especially brain cells and nerve cells very effectively, and because the systemic circulation stays too long, Most of the drug will be metabolized by the intestinal mucosa, liver, kidneys, and lungs before reaching the "site of action." Not only does this situation produce very low pharmacological effects, but it also creates a toxic burden on the intestinal mucosa, liver, kidneys, lungs, and any other body part. These prodrugs penetrate skin, cerebral blood, brain cells, nerve cells and other membrane barriers very well, have hundreds of times the potency of the parent drug, and only tens of normal drug doses. It requires one-hundredth or one-hundredth, and the occurrence of side effects is greatly reduced. This will benefit not only transdermal drug delivery, but also any drug delivery system (oral, subcutaneous, intravenous, inhalation, and nasal, etc.) and can treat many conditions that cannot be treated by the parent drug. These prodrugs can be administered not only transdermally but also orally (which does not damage the stomach because it cannot penetrate into the stomach wall) for any type of medical treatment, and it is a major side effect of NSAIA, digestion. Very prominent gastrointestinal disorders such as bad, gastroduodenal hemorrhage, gastric ulcer, gastritis should be avoided. Another major benefit of transdermal administration of these prodrugs is that they are very easy to administer, especially to children.

In the figure, R, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ in “Chemical structure 1, 2a, 2b, 2c, or 2d” of the general formula (1, 2a, 2b, 2c, or 2d) is _{R 6, R 7, R 8} , R 9, X, HA, and Ary- is, R in claim 1 and claim _{2, R 1, R 2,} R 3, R 4, R 5, R 6, R ₇ , R ₈ , R ₉ , X, HA, and Ary- are defined as the same.

(Best form)
Diethylaminoethyl acetylsalicylate. Preparation of acetylsalicylic acid salt 180 g of 2-acetylsalicylic acid was dissolved in 1000 ml of chloroform. The mixture was cooled to 5°C. 103 g of 1,3-dicyclohexylcarbodiimide was added to the mixture. The mixture was stirred at room temperature for 2 hours. The solid waste was filtered off and washed with chloroform (3 x 300 ml). 59 g of diethylaminoethanol was added to the reaction mixture. The mixture was stirred at room temperature for 3 hours. The organic solution was evaporated. After drying, 220 g of the desired product were obtained (96%). Elemental analysis: C ₂₄ H ₂₉ NO _8, molecular weight: 459.18. Calculated% C:62.73, H:6.36, N:3.05, O:27.86, measured% C:62.70, H:6.40, Cl:N:3.01, O: 27.90.

(Mode of Invention)
1-piperidinepropyl 2[(2,6-dichlorophenyl)amino]benzene acetate. Preparation of AcOH 31.8 g (0.1 mol) of sodium 2[(2,6-dichlorophenyl)amino]benzeneacetate was suspended in 180 ml of chloroform. 28.6 g (0.1 mol) of 1-piperidine propyl bromide. HBr was added to the mixture and stirred at room temperature for 5 hours. The mixture was washed with 5% Na ₂ CO ₃ (1 x 300 ml) and water (3 x 100 ml). The mixture was dried over anhydrous Na ₂ SO ₄ . The sodium sulfate was filtered off and washed with chloroform (3 x 50 ml). 6 g acetic acid was added to the solution. The solution was concentrated in vacuo to 100 ml. Then 300 ml of hexane was added to the solution. The solid product was collected by filtration and washed with hexane (3 x 100 ml). After drying 40 g of the desired product were obtained (86%). Elemental analysis: C ₂₄ H ₃₀ Cl ₂ N ₂ O ₄ , molecular weight: 481.43, calculated% C: 59.88, H: 6.28, Cl: 14.73, N: 5.82, O: 13. 29, found% C: 59.83, H: 6.32, Cl: 14.71, N: 5.79, O: 13.35.

3-piperidine methyl 2-(ρ-isobutylphenyl) propionate. Preparation of AcOH 60 g of polymer bound triethylamine (3 mmol/g, 100-200 mesh) was suspended in 180 ml of chloroform. 20.6 g (0.1 mol) of 2-(ρ-isobutylphenyl)propionic acid was added to the mixture with stirring. 39 g (0.15 mol) 3-piperidine methyl bromide. HBr was added to the mixture and the mixture was stirred at room temperature for 5 hours. The polymer was filtered off and washed with acetone (3 x 50 ml). 300 ml of 5% Na ₂ CO ₃ was added to the solution with stirring. The mixture was stirred for 30 minutes. The chloroform solution was washed with water (3 x 100 ml) and dried over Na ₂ SO ₄ . The copper sulfate was filtered off and washed with chloroform (3 x 100 ml). 6 g acetic acid was added to the mixture. The solution was concentrated in vacuo to 100 ml. 300 ml of hexane was added to the solution. The solid product was collected by filtration and washed with hexane (3 x 100 ml). After drying 35 g of the desired product were obtained (96%). Elemental analysis: C ₂₁ H ₃₃ NO ₄ , molecular weight: 363.49, calculated% C: 69.39, H: 9.15, N: 3.85, O: 17.61, measured% C: 69.35, H: 9.18, N: 3.83, O: 17.64.

Prodrugs of "Chemical Structure 1, 2a, 2b, 2c, or 2d" of general formula (1, 2a, 2b, 2c, or 2d) are superior to NSAIA. They can be used as medicaments in the treatment of any human or animal condition treatable by NSAIA. These are diabetes (types I and II), abnormal levels of blood glucose and blood lipids, stroke and heart and vascular diseases such as heart attack, Alzheimer's disease, Parkinson's disease and other neurodegenerative diseases, psoriasis, discoid lupus erythematosus. , Systemic lupus erythematosus (SLE), autoimmune disease hepatitis, scleroderma, Sjogren's syndrome, rheumatoid arthritis, polymyositis, scleroderma, Hashimoto thyroiditis, juvenile diabetes, Addison's disease, vitiligo, pernicious anemia, glomerulonephritis , Pulmonary fibrosis, multiple sclerosis (MS), Crohn's disease, and other autoimmune diseases, amyotrophic lateral sclerosis (ALS), oropharyngeal muscular dystrophy (OPMD), myotonic dystrophy (MD), Duchenne muscular dystrophy (DMD), polymyositis (PM), dermatomyositis (DM), inclusion body myositis (IBM), and other myopathy, hemorrhoids, inflammatory hemorrhoids, irradiation (artificial) post-proctitis, chronic Ulcerative colitis, cryptitis, other anorectal inflammatory conditions and pruritus ani, prostatitis, prostatic cystitis, autoimmune hepatitis, autoimmune nephritis, phlebitis and other inflammation, spinal cord injury, wounds, Breast cancer, colorectal cancer, oral cancer, lung and other respiratory cancer, skin cancer, uterine cancer, genital cancer, urinary cancer, leukemia and other blood and lymphoid cancer and other cancers, and many others It can also be used for the treatment and prevention of symptoms. These prodrugs can be administered transdermally without the aid of a transdermal absorption enhancer.

式中、Ｒは分岐又は直鎖の−（ＣＨ₂）_n−を表し、−（ＣＨ₂）_n−においてｎ＝０，１，２，３，４，５，６，７，８，９，１０…であり、いずれのＣＨ₂がＯ、Ｓ、ＣＨ＝ＣＨ、Ｃ≡Ｃ、ＣＨＲ₆、ＣＲ₆Ｒ₇、アリール又はヘテロアリール残基、又は他の環系と置き換えられてもよく；Ｒ₁は分岐又は直鎖の−（ＣＨ₂）_a−を表し、−（ＣＨ₂）_a−においてａ＝０，１，２，３，４，５，６，７，８，９，１０…であり、いずれのＣＨ₂がＯ、Ｓ、ＣＨ＝ＣＨ、Ｃ≡Ｃ、ＣＨＲ₆、ＣＲ₆Ｒ₇、アリール又はヘテロアリール残基、又は他の環系と置き換えられてもよく；Ｒ₂は分岐又は直鎖の−（ＣＨ₂）_b−を表し、−（ＣＨ₂）_b−においてｂ＝０，１，２，３，４，５，６，７，８，９，１０…であり、いずれのＣＨ₂がＯ、Ｓ、ＣＨ＝ＣＨ、Ｃ≡Ｃ、ＣＨＲ₆、ＣＲ₆Ｒ₇、アリール又はヘテロアリール残基、又は他の環系と置き換えられてもよく；Ｒ₃は分岐又は直鎖の−（ＣＨ₂）_c−を表し、−（ＣＨ₂）_c−においてｃ＝０，１，２，３，４，５，６，７，８，９，１０…であり、いずれのＣＨ₂がＯ、Ｓ、ＣＨ＝ＣＨ、Ｃ≡Ｃ、ＣＨＲ₆、ＣＲ₆Ｒ₇、アリール又はヘテロアリール残基、又は他の環系と置き換えられてもよく；Ｒ₄はＨ、１から１２の炭素原子を有するアルキル、アルキルオキシ、アルケニル、パーフルオロアルキル、ハロゲン化アルキル、若しくはアルキニル残基、アリール又はヘテロアリール部分のいずれか一つを表し、いずれのＣＨ₂がＯ、Ｓ、ＣＨ＝ＣＨ、Ｃ≡Ｃ、ＣＨＲ₆、ＣＲ₆Ｒ₇、アリール又はヘテロアリール部分、又は他の環部分と置き換えられてもよく；Ｒ₅は、Ｈ、１から１２の炭素原子を有するアルキル、アルキルオキシ、アルケニル、パーフルオロアルキル、ハロゲン化アルキル、若しくはアルキニル残基、アリール又はヘテロアリール部分のいずれか一つを表し、いずれのＣＨ₂がＯ、Ｓ、ＣＨ＝ＣＨ、Ｃ≡Ｃ、ＣＨＲ₆、ＣＲ₇Ｒ₆、アリール又はヘテロアリール部分、又は他の環部分と置き換えられてもよく；Ｒ₆は、Ｈ、１から１２の炭素原子を有するアルキル、アルキルオキシ、アルケニル、パーフルオロアルキル、ハロゲン化アルキル、若しくはアルキニル残基、アリール又はヘテロアリール部分のいずれか一つを表し、いずれのＣＨ₂がＯ、Ｓ、ＣＨ＝ＣＨ、Ｃ≡Ｃ、ＣＨＲ₆、ＣＲ₇Ｒ₅、アリール又はヘテロアリール部分、又は他の環部分と置き換えられてもよく、Ｒ₇は、Ｈ、１から１２の炭素原子を有するアルキル、アルキルオキシ、アルケニル、パーフルオロアルキル、ハロゲン化アルキル、若しくはアルキニル残基、アリール又はヘテロアリール部分のいずれか一つを表し、いずれのＣＨ₂がＯ、Ｓ、ＣＨ＝ＣＨ、Ｃ≡Ｃ、ＣＨＲ₆、ＣＲ₇Ｒ₅、アリール又はヘテロアリール部分、又は他の環部分と置き換えられてもよく；Ｘは、存在しない、Ｏ、ＮＨ、ＮＲ₆又はＳを表し；ＨＡは、存在しない、ＨＣｌ、ＨＢｒ、ＨＦ、ＨＩ、ＨＯＡｃ、クエン酸、又は薬理学的に許容できる任意の他の酸を表し、全てのＲ、Ｒ₁、Ｒ₂、Ｒ₈、Ｒ₉、又は−（ＣＨ₂）_n−基は、分岐又は直鎖であり、Ｃ、Ｈ、Ｏ、Ｃｌ、Ｂｒ、Ｆ、Ｉ、Ｐ、Ｓ、Ｎ又は任意の他の薬理学的に許容できる原子を含んでもよく、単結合、二重結合、及び／又は三重結合を含んでもよく；全てのＲ、Ｒ₁、Ｒ₂、Ｒ₈、Ｒ₉、又は−（ＣＨ₂）_n−基は、アキラル又はキラルでもよく；基がキラルであれば、一以上のキラル中心を有してもよく、単独の（Ｒ）若しくは（Ｓ）エナンチオマー又は（Ｒ）及び（Ｓ）エナンチオマーの混合物でもよく、Ａｒｙ−は次式を表すが限定されず、

式中、Ｒ_xは、Ｈ、ＣＨ₃、ＣＨ₃Ｏ、ＨＯ、ＣＨ₃ＣＨ₂、ＣＦ₃、ＣＨＦ₂、ＣＨ₂Ｆ、Ｃｌ、Ｆ、Ｂｒ、Ｆを表し；Ｒ_yは、Ｈ、１から１２の炭素原子を有するアルキル、アルキルオキシ、アルケニル、パーフルオロアルキル、ハロゲン化アルキル若しくはアルキニル残基、アリール又はヘテロアリール部分のいずれか一つを表し；Ｘ₁又はＸ₄は、ＣＨ₂、Ｓ、Ｏ、ＮＨ、又はＣＯを表し；Ｘ₂又はＸ₅は、ＣＨ、ＣＲ₈、又はＮを表し；Ｘ₃は、Ｏ、Ｓ、ＮＨ、又はＮＲ₈を表し；Ｙ、Ｙ₁、Ｙ₂、Ｙ₃、Ｙ₄、Ｙ₅、又はＹ₆は、独立してＨ、ＨＯ、ＣＨ₃ＣＯＯ、Ｒ_yＣＯＯ、ＨＳ、ＮＯ₂、ＣＮ、ＣＨ₃ＣＯＳ、ＮＨ₂、ＣＨ₃ＣＯＮＨ、Ｒ_yＣＯＮＨ、ＣＨ₃、ＣＨ₃ＣＨ₂、Ｃ₃Ｈ₇、Ｃ₄Ｈ₉、ＣＨ₃Ｏ、ＣＨ₃ＣＨ₂Ｏ、Ｃ₃Ｈ₇Ｏ、Ｃｌ、Ｆ、Ｂｒ、Ｉ、ＣＨ₃Ｓ、ＣＨＦ₂Ｏ、ＣＦ₃Ｏ、ＣＦ₃ＣＦ₂Ｏ、Ｃ₃Ｆ₇Ｏ、ＣＦ₃、ＣＦ₃ＣＦ₂、Ｃ₃Ｆ₇、Ｃ₄Ｆ₉、ＣＨ₃ＳＯ₂、Ｒ_yＳＯ₂、ＣＨ₃ＳＯ、Ｒ_yＳＯ、ＣＨ₃ＣＯ、ＣＨ₃ＣＨ₂ＣＯを表し；いずれのＡｒｙ−は、アキラル又はキラルであり；Ａｒｙ−がキラルであれば、一以上のキラル中心を有してもよく、単独の（Ｒ）若しくは（Ｓ）エナンチオマー又は（Ｒ）及び（Ｓ）エナンチオマーの混合物でもよい、化合物。 Aspects of the present invention include the following, for example.
1. A compound having the "chemical structure 2a, 2b, 2c, or 2d" represented by the general formula (2a, 2b, 2c, or 2d):

Wherein, R branched or straight-chain - (CH _{2) n} - represents a, - (CH _{2) n} - in n = 0,1,2,3,4,5,6,7,8,9, 10... and any CH ₂ may be replaced with O, S, CH═CH, C≡C, CHR ₆ , CR ₆ R ₇ , aryl or heteroaryl residues, or other ring systems; R ₁ branched or straight-chain - (CH _{2) a} - represents, - (CH _{2) a} - in a = 0,1,2,3,4,5,6,7,8,9,10 ... in And any CH ₂ may be replaced with O, S, CH═CH, C≡C, CHR ₆ , CR ₆ R ₇ , aryl or heteroaryl residues, or other ring systems; R ₂ is branched or linear - _{represents, - - (CH 2) b} (CH 2) b - in b = 0,1,2,3,4,5,6,7,8,9,10 ... a is any CH ₂ may be replaced by O, S, CH═CH, C≡C, CHR ₆ , CR ₆ R ₇ , an aryl or heteroaryl residue, or another ring system; R ₃ is branched or straight chain Bruno - (CH _{2) c} - represents _{a, - (CH 2) c -} c = 0,1,2,3,4,5,6,7,8,9,10 ... a is in any of the CH ₂ but O, S, CH = CH, C≡C, CHR 6, CR 6 R 7, aryl or heteroaryl residues, or other may be replaced with the ring system; R ₄ is H, 1 to 12 carbon Represents one of an alkyl, alkyloxy, alkenyl, perfluoroalkyl, halogenated alkyl, or alkynyl residue having an atom, an aryl or a heteroaryl moiety, and any CH ₂ is O, S, CH═CH, C ≡C, CHR ₆ , CR ₆ R ₇ , aryl or heteroaryl moieties, or other ring moieties; R ₅ is H, alkyl having 1 to 12 carbon atoms, alkyloxy, alkenyl, Represents any one of a perfluoroalkyl, an alkyl halide, or an alkynyl residue, an aryl or a heteroaryl moiety, and any CH ₂ is O, S, CH═CH, C≡C, CHR ₆ , CR ₇ R ₆ , Aryl or heteroaryl moieties, or other ring moieties; R ₆ is H, alkyl having 1 to 12 carbon atoms, alkyloxy, alkenyl, perfluoroalkyl, halogenated alkyl, or alkyl. Represents any one of a nyl residue, an aryl or a heteroaryl moiety, and any CH ₂ is O, S, CH═CH, C≡C, CHR ₆ , CR ₇ R ₅ , an aryl or heteroaryl moiety, or other R ₇ may be substituted for H, an alkyl, alkyloxy, alkenyl, perfluoroalkyl, alkyl halide, or alkynyl residue having 1 to 12 carbon atoms, an aryl or heteroaryl moiety. Represents any one and any CH ₂ may be replaced with O, S, CH═CH, C≡C, CHR ₆ , CR ₇ R ₅ , an aryl or heteroaryl moiety, or another ring moiety; X represents absent, O, NH, NR ₆ or S; HA represents absent, HCl, HBr, HF, HI, HOAc, citric acid, or any other pharmacologically acceptable acid , All R, R ₁ , R ₂ , R ₈ , R ₉ , or —(CH ₂ ) _n — groups are branched or straight-chain and are C, H, O, Cl, Br, F, I, P. , S, N or any other pharmacologically acceptable atom and may contain single, double and/or triple bonds; all R, R ₁ , R ₂ , R ₈ , R ₉ , or a —(CH ₂ ) _n — group may be achiral or chiral; if the group is chiral, it may have one or more chiral centers and is a single (R) or (S) enantiomer. Alternatively, it may be a mixture of (R) and (S) enantiomers, and Ary- represents the following formula, but is not limited,

In the formula, R _x represents H, CH ₃ , CH ₃ O, HO, CH ₃ CH ₂ , CF ₃ , CHF ₂ , CH ₂ F, Cl, F, Br, F; R _y is H, 1 Represents one of an alkyl, alkyloxy, alkenyl, perfluoroalkyl, halogenated alkyl or alkynyl residue, aryl or heteroaryl moiety having from 1 to 12 carbon atoms; X ₁ or X ₄ represents CH ₂ , S , O, NH, or CO; X ₂ or X ₅ represents CH, CR ₈ , or N; X ₃ represents O, S, NH, or NR ₈ ; Y, Y ₁ , Y ₂ , Y ₃ , Y ₄ , Y ₅ , or Y ₆ are independently H, HO, CH ₃ COO, R _y COO, HS, NO ₂ , CN, CH ₃ COS, NH ₂ , CH ₃ CONH, R _y. CONH, CH ₃ , CH ₃ CH ₂ , C ₃ H ₇ , C ₄ H ₉ , CH ₃ O, CH ₃ CH ₂ O, C ₃ H ₇ O, Cl, F, Br, I, CH ₃ S, CHF _{2 O, CF 3 O, CF 3} CF 2 O, C 3 F 7 O, CF 3, CF 3 CF 2, C 3 F 7, C 4 F 9, CH 3 SO 2, R y SO 2, CH 3 SO, R _y SO, CH ₃ CO, CH ₃ CH ₂ CO; any Ary- is achiral or chiral; and if Ary- is chiral, it may have one or more chiral centers, A compound, which may be the (R) or (S) enantiomer or a mixture of the (R) and (S) enantiomers.

式中、Ｒは分岐又は直鎖の−（ＣＨ₂）_n−を表し、−（ＣＨ₂）_n−においてｎ＝０，１，２，３，４，５，６，７，８，９，１０，１１，１２，…であり、いずれのＣＨ₂がＯ、Ｓ、ＮＲ₈、ＣＨ＝ＣＨ、Ｃ≡Ｃ、ＣＨＲ₈、ＣＲ₈Ｒ₉、アリール又はヘテロアリール残基、又は薬理学的に許容できる任意の他の部分と置き換えられてもよく；Ｒ₁は、Ｈ、１から１２の炭素原子を有するアルキル、アルキルオキシ、アルケニル、パーフルオロアルキル、ハロゲン化アルキル、若しくはアルキニル残基、アリール又はヘテロアリール部分のいずれか一つを表し、いずれのＣＨ₂がＯ、Ｓ、ＣＨ＝ＣＨ、Ｃ≡Ｃ、ＣＨＲ₈、ＣＲ₈Ｒ₉、アリール又はヘテロアリール部分、又は薬理学的に許容できる任意の他の部分と置き換えられてもよく；Ｒ₂は、Ｈ、１から１２の炭素原子を有するアルキル、アルキルオキシ、アルケニル、パーフルオロアルキル、ハロゲン化アルキル若しくはアルキニル残基、アリール又はヘテロアリール部分のいずれか一つを表し、いずれのＣＨ₂がＯ、Ｓ、ＣＨ＝ＣＨ、Ｃ≡Ｃ、ＣＨＲ₈、ＣＲ₈Ｒ₉、アリール又はヘテロアリール部分、又は薬理学的に許容できる他の部分と置き換えられてもよく；Ｘは、Ｏ、ＮＨ、ＮＲ₈、Ｓ、又は存在しないことを表し；Ｒ₈は、Ｈ、ＯＨ、Ｃｌ、Ｆ、Ｂｒ、Ｉ、１から１２の炭素原子を有するアルキル、アルキルオキシ、アルケニル、パーフルオロアルキル、ハロゲン化アルキル若しくはアルキニル残基、アリール又はヘテロアリール部分のいずれか一つを表し；Ｒ₉は、Ｈ、ＯＨ、Ｃｌ、Ｆ、Ｂｒ、Ｉ、１から１２の炭素原子を有するアルキル、アルキルオキシ、アルケニル、パーフルオロアルキル、ハロゲン化アルキル若しくはアルキニル残基、アリール又はヘテロアリール部分のいずれか一つを表し；前記一般式（１）の「化学構造１」におけるＡｒｙ−は、請求項１に記載の前記一般式（２ａ、２ｂ、２ｃ、又は２ｄ）の「化学構造２ａ、２ｂ、２ｃ、又は２ｄ」と同一のＡｒｙ−として定義され；ＨＡは、存在しない、ＨＣｌ、ＨＢｒ、ＨＦ、ＨＩ、ＨＯＡｃ、クエン酸、又は薬理学的に許容できる任意の酸を表し；全てのＲ、Ｒ₁、Ｒ₂、Ｒ₈、Ｒ₉、又は−（ＣＨ₂）_n−基は、分岐又は直鎖であり、Ｃ、Ｈ、Ｏ、Ｃｌ、Ｂｒ、Ｆ、Ｉ、Ｐ、Ｓ、Ｎ又は任意の他の薬理学的に許容できる原子を含んでもよく、単結合、二重結合、及び／又は三重結合を含んでもよく；全てのＲ、Ｒ₁、Ｒ₂、Ｒ₈、Ｒ₉、又は−（ＣＨ₂）_n−基は、アキラル又はキラルでもよく；基がキラルであれば、一以上のキラル中心を有してもよく、単独の（Ｒ）若しくは（Ｓ）エナンチオマー又は（Ｒ）及び（Ｓ）エナンチオマーの混合物でもよい、化合物。 2. A compound having the “chemical structure 1” of the general formula (1),

Wherein, R branched or straight-chain - (CH _{2) n} - represents a, - (CH _{2) n} - in n = 0,1,2,3,4,5,6,7,8,9, 10, 11, 12,... and any CH ₂ is O, S, NR ₈ , CH═CH, C≡C, CHR ₈ , CR ₈ R ₉ , an aryl or heteroaryl residue, or pharmacologically R ₁ may be replaced with any other acceptable moiety; R ₁ is H, alkyl having 1 to 12 carbon atoms, alkyloxy, alkenyl, perfluoroalkyl, alkyl halide, or alkynyl residue, aryl or Represents any one of the heteroaryl moieties, any CH ₂ being O, S, CH═CH, C≡C, CHR ₈ , CR ₈ R ₉ , an aryl or heteroaryl moiety, or any pharmacologically acceptable R ₂ may be replaced with any other moiety of H; an alkyl, alkyloxy, alkenyl, perfluoroalkyl, halogenated alkyl or alkynyl residue, aryl or heteroaryl moiety having 1 to 12 carbon atoms. Represents any one and any CH ₂ is replaced with O, S, CH═CH, C≡C, CHR ₈ , CR ₈ R ₉ , an aryl or heteroaryl moiety, or another pharmacologically acceptable moiety. X is O, NH, NR ₈ , S, or absent; R ₈ is H, OH, Cl, F, Br, I, an alkyl having 1 to 12 carbon atoms, Represents any one of alkyloxy, alkenyl, perfluoroalkyl, halogenated alkyl or alkynyl residues, aryl or heteroaryl moieties; R ₉ is H, OH, Cl, F, Br, I, 1-12 Represents any one of alkyl, alkyloxy, alkenyl, perfluoroalkyl, alkyl halide or alkynyl residue having carbon atom, aryl or heteroaryl moiety; Ary in "Chemical structure 1" of the general formula (1) -Is defined as Ary- identical to the "chemical structure 2a, 2b, 2c, or 2d" of the general formula (2a, 2b, 2c, or 2d) of claim 1; HA is absent. Represents HCl, HBr, HF, HI, HOAc, citric acid or any pharmaceutically acceptable acid; all R, R ₁ , R ₂ , R ₈ , R ₉ or -(CH ₂ ) _n- The group may be branched or straight chain, and may be C, H, O, Cl, Br, It may contain F, I, P, S, N or any other pharmacologically acceptable atom and may contain single, double and/or triple bonds; all R, R ₁ , _{R 2, R 8, R 9} , or - (CH _{2) n} - group may be achiral or chiral, if groups chiral, may have one or more chiral centers, alone (R) Alternatively, the compound, which may be the (S) enantiomer or a mixture of the (R) and (S) enantiomers.

3. The compound having the “chemical structure 1, 2a, 2b, 2c, or 2d” of the general formula 1, 2a, 2b, 2c, or 2d described in 1 or 2 above is converted into N,N′-dicyclohexylcarbodiimide, N, Aspects 1 and 2 above, which can be prepared from NSAIA by reaction to form an anhydride with N'-diisopropylcarbodiimide or other coupling reagent, followed by reaction with a suitable alcohol, thiol, or amine. A method for preparing a compound of "Chemical structure 1, 2a, 2b, 2c, or 2d" of the above general formula (1, 2a, 2b, 2c, or 2d).
4. The compound of "Chemical structure 1, 2a, 2b, 2c, or 2d" of the general formula 1, 2a, 2b, 2c, or 2d described in 1 or 2 above is converted into NSAIA by using an appropriate halide. The “chemical structure of the general formula (1, 2a, 2b, 2c, or 2d) described in 1 or 2 above, which can be prepared from a metal salt, an organic basic salt, or an immobilized basic salt. 1, 2a, 2b, 2c, or 2d".
5. As an active ingredient according to the above 1 and 2, which can be administered transdermally, orally, subcutaneously, intravenously or nasally for treating any condition treatable by NSAIA in humans or animals. A compound of the general “Chemical Structure 1, 2a, 2b, 2c, or 2d”, or a “Chemical Structure 1, 2a, 2b, 2c, or 2d” of the general formula (1, 2a, 2b, 2c, or 2d), or 2d" at least one compound, wherein the symptoms treatable by NSAIA are pain, fever, cancer, dysmenorrhea, acute pain resulting from toothache, headache, arthritis and other inflammatory pain. Includes, but is not limited to, migraine, acute gouty arthritis, ankylosing spondylitis, rheumatoid arthritis, osteoarthritis, dysmenorrhea, and dementia.
6. The compound of “Chemical Structure 1, 2a, 2b, 2c, or 2d” of the general formula (1, 2a, 2b, 2c, or 2d) as the active ingredient described in 1 or 2 above, or the general formula To deliver a therapeutically effective plasma concentration of a composition comprising at least one compound of (Chemical Structure 1, 2a, 2b, 2c, or 2d) of (1, 2a, 2b, 2c, or 2d): A method of treating any NSAIA treatable condition in a human or animal by transdermal administration (in the form of a solution, spray, lotion, ointment, emulsion or gel) to any part of the body.

7. The compound of the above-mentioned 1 or 2 having the “chemical structure 1, 2a, 2b, 2c, or 2d” of the general formula (1, 2a, 2b, 2c, or 2d) as an active ingredient, or the general formula Topically administering a therapeutically effective amount of a composition comprising at least one compound of "Chemical Structure 1, 2a, 2b, 2c, or 2d" of formula (1, 2a, 2b, 2c, or 2d) to the area of inflammation. By locally treating headache, toothache, myalgia, and arthritis and other inflammatory pain in humans or animals.
8. For the treatment and prevention of diabetes (types I and II), dysglycemia, abnormal blood lipid levels, and other metabolic disorders in humans or animals, to deliver therapeutically effective plasma concentrations, any of the body's The general formula (1, 2a, 2b, 2c) as an active ingredient according to 1 and 2 above, which can be transdermally administered to a part (in the form of solution, spray, lotion, ointment, emulsion or gel). , Or 2d) the compound of “Chemical Structure 1, 2a, 2b, 2c, or 2d”, or the above-mentioned General Formula (1, 2a, 2b, 2c, or 2d) “Chemical Structure 1, 2a, 2b, 2c, Or 2d" at least one compound.
9. Oral, subcutaneous, intravenous, or nasal for the treatment and prevention of diabetes (types I and II), abnormal blood glucose levels, abnormal blood lipid levels, and other metabolic disorders in humans or animals Can be administered (in the form of solutions, sprays, emulsions, pills, tablets, or any other formulation), as described in 1 and 2 above, as an active ingredient, the compound of the general formula (1, 2a) 2b, 2c, or 2d) “chemical structure 1, 2a, 2b, 2c, or 2d” compound, or the above-mentioned general formula (1, 2a, 2b, 2c, or 2d) “chemical structure 1, 2a, 2b, 2c, or 2d" at least one compound.
10. For the treatment and prevention of abnormal blood pressure and abnormal blood lipid levels in humans or animals, in order to deliver therapeutically effective plasma concentrations, to any part of the body (solutions, sprays, lotions, ointments, emulsions or gels) “Chemical structure 1, 2a, 2b, 2c” of the above general formula (1, 2a, 2b, 2c, or 2d) as an active ingredient according to the above 1 or 2, which can be transdermally administered. , Or 2d", or a composition containing at least one compound of the "chemical structure 1, 2a, 2b, 2c, or 2d" of the above general formula (1, 2a, 2b, 2c, or 2d).

11. Oral, subcutaneous, intravenous, or nasal (solution, spray, emulsion, pill, tablet, or any) for the treatment and prevention of abnormal blood pressure and abnormal blood lipid levels in humans or animals. (Form of other formulation), the “chemical structure 1, 2a, of the general formula (1, 2a, 2b, 2c, or 2d) of the above-mentioned general formula (1, 2a, 2b, 2c, or 2d) as the active ingredient described in 1 and 2 above. 2b, 2c, or 2d", or a composition containing at least one compound of "Chemical Structure 1, 2a, 2b, 2c, or 2d" of the above general formula (1, 2a, 2b, 2c, or 2d). ..
12. For the treatment and prevention of stroke, heart attack, and other heart and vascular diseases in humans or animals, to deliver therapeutically effective plasma concentrations, to any part of the body (solutions, sprays, lotions, ointments). , In the form of an emulsion or gel), the “chemical structure 1, 2a, of the general formula (1, 2a, 2b, 2c, or 2d) as the active ingredient according to 1 and 2 above, which can be administered transdermally. 2b, 2c, or 2d", or a composition containing at least one compound of "Chemical Structure 1, 2a, 2b, 2c, or 2d" of the above general formula (1, 2a, 2b, 2c, or 2d). ..
13. Administer a therapeutically effective amount topically (in the form of a solution, spray, lotion, ointment, emulsion or gel) to the infected area (such as the neck, head, chest, legs, and/or any other part of the body) Accordingly, for the treatment and prevention of stroke, heart attack, and other heart and vascular diseases in humans or animals, the above-mentioned general formula (1, 2a, 2b) as an active ingredient according to 1 and 2 above is used. 2c, or 2d) the compound of “Chemical Structure 1, 2a, 2b, 2c, or 2d”, or the “Chemical Structure 1, 2a, 2c, or 2d) of the above general formula (1, 2a, 2b, 2c, or 2d). 2c, or 2d" at least one compound.
14. Oral, subcutaneous, intravenous or nasal (solutions, sprays, emulsions, pills) for the treatment and prevention of stroke, heart attack and other heart and vascular diseases in humans or animals. , Tablet, or any other formulation), as the active ingredient of the above formulas (1, 2a, 2b, 2c, or 2d) of the above general formula (1, 2a, 2b, 2c, or 2d). A compound of structures 1, 2a, 2b, 2c, or 2d", or at least one of the "chemical structures 1, 2a, 2b, 2c, or 2d" of the general formula (1, 2a, 2b, 2c, or 2d) A composition comprising a compound.

15. For the treatment and prevention of organ transplant rejection in humans or animals, any part of the body (in the form of a solution, spray, lotion, ointment, emulsion or gel) is delivered to deliver a therapeutically effective plasma concentration. Compounds of "Chemical structure 1, 2a, 2b, 2c, and 2d" of the above-mentioned general formula (1, 2a, 2b, 2c, and 2d) as an active ingredient, which can be administered through the skin, as an active ingredient. Or a composition containing at least one compound of the “chemical structures 1, 2a, 2b, 2c, and 2d” of the general formula (1, 2a, 2b, 2c, and 2d).
16. 1 above for treating and preventing organ transplant rejection in humans or animals by administering a therapeutically effective amount locally (in the form of a solution, spray, lotion, ointment, emulsion or gel) to the infected area. And 2, a compound represented by the above-mentioned general formula (1, 2a, 2b, 2c, and 2d) of “chemical structure 1, 2a, 2b, 2c, and 2d” as an active ingredient, or the above-mentioned general formula (1 2a, 2b, 2c, and 2d) "Chemical structures 1, 2a, 2b, 2c, and 2d" of at least one compound.
17. Oral, subcutaneous, intravenous, or nasal (solution, spray, emulsion, pill, tablet, or any other formulation for the treatment and prevention of organ transplant rejection in humans or animals. In the above formulas (1, 2a, 2b, 2c, and 2d), the “chemical structure 1, 2a, 2b, 2c, And 2d" or at least one compound of "Chemical Structures 1, 2a, 2b, 2c, and 2d" of the above general formula (1, 2a, 2b, 2c, and 2d).
18. For the treatment and prevention of Alzheimer's disease, Parkinson's disease and other neurodegenerative diseases, to deliver a therapeutically effective plasma concentration, to any part of the body (preferably on the neck and head, solution, spray, lotion, “Chemical structure 1 of the general formula (1, 2a, 2b, 2c, or 2d) as an active ingredient according to the above 1 and 2, which can be transdermally administered (in the form of ointment, emulsion or gel). 2a, 2b, 2c, or 2d", or at least one compound of "Chemical Structure 1, 2a, 2b, 2c, or 2d" of the general formula (1, 2a, 2b, 2c, or 2d). A composition comprising.

19. For the treatment and prevention of Alzheimer's disease, Parkinson's disease and other neurodegenerative diseases, orally, subcutaneously, intravenously or nasally (solution, spray, emulsion, pill, tablet, or any “Chemical structure 1, 2a, 2b” of the general formula (1, 2a, 2b, 2c, or 2d) as the active ingredient according to 1 and 2 above, which can be administered (in the form of other formulations). 2c, or 2d", or a composition comprising at least one compound of "Chemical Structure 1, 2a, 2b, 2c, or 2d" of the above general formula (1, 2a, 2b, 2c, or 2d).
20. Transdermal administration (in the form of solutions, sprays, lotions, ointments, emulsions or gels) to any part of the body to deliver therapeutically effective plasma concentrations for the treatment and prevention of psoriasis and other skin disorders The compound of "Chemical structure 1, 2a, 2b, 2c, or 2d" of the above-mentioned general formula (1, 2a, 2b, 2c, or 2d) as the active ingredient, which is capable of being Or a composition containing at least one compound of the "chemical structure 1, 2a, 2b, 2c, or 2d" of the general formula (1, 2a, 2b, 2c, or 2d).
21. 1 for treating psoriasis and other skin disorders in humans or animals by administering a therapeutically effective amount topically (in the form of a solution, spray, lotion, ointment, emulsion or gel) to the infected area. And 2, a compound represented by the above-mentioned general formula (1, 2a, 2b, 2c, and 2d) of “chemical structure 1, 2a, 2b, 2c, and 2d” as an active ingredient, or the above-mentioned general formula (1 2a, 2b, 2c, and 2d) "Chemical structure 1, 2a, 2b, 2c, and 2d".
22. Oral, subcutaneous, intravenous, or nasal (solution, spray, emulsion, pill, tablet, or any other prescription form for the treatment and prevention of psoriasis and other skin disorders. The chemical structure 1, 2a, 2b, 2c, or 2d of the above general formula (1, 2a, 2b, 2c, or 2d) as the active ingredient according to the above 1 or 2, which can be administered. Or a compound comprising at least one compound of the chemical formula 1, 2a, 2b, 2c, or 2d of the general formula (1, 2a, 2b, 2c, or 2d).

23. Discoid lupus erythematosus in humans or animals, systemic lupus erythematosus (SLE), autoimmune disease hepatitis, scleroderma, Sjogren's syndrome, rheumatoid arthritis, polymyositis, scleroderma, Hashimoto's thyroiditis, juvenile diabetes, Addison's disease, To deliver therapeutically effective plasma concentrations for the treatment and prevention of vitiligo, pernicious anemia, glomerulonephritis, pulmonary fibrosis, multiple sclerosis (MS), Crohn's disease, and other autoimmune diseases, the body Can be transdermally administered (in the form of a solution, spray, lotion, ointment, emulsion or gel) to any part of the above formula (1, 2a, 2b, 2c, or 2d) the compound of “Chemical Structure 1, 2a, 2b, 2c, or 2d”, or the above-mentioned Chemical Formula 1, 2a, 2b, 2c, or 2d) 2c, or 2d" of at least one compound.
24. By locally (in the form of solutions, sprays, lotions, ointments, emulsions or gels) of therapeutically effective amounts administered to the infected area, discoid lupus erythematosus, systemic lupus erythematosus (SLE), autoimmunity in humans or animals. Disease hepatitis, scleroderma, Sjogren's syndrome, rheumatoid arthritis, polymyositis, scleroderma, Hashimoto thyroiditis, juvenile diabetes, Addison's disease, vitiligo, pernicious anemia, glomerulonephritis, pulmonary fibrosis, multiple sclerosis ( MS), Crohn's disease, and other autoimmune diseases, as described in 1 and 2 above, as the active ingredient, “of the general formula (1, 2a, 2b, 2c, and 2d)” A compound having the chemical structure 1, 2a, 2b, 2c, and 2d", or at least one of the "chemical structures 1, 2a, 2b, 2c, and 2d" of the general formula (1, 2a, 2b, 2c, and 2d). A composition comprising one compound.
25. Discoid lupus erythematosus in humans or animals, systemic lupus erythematosus (SLE), autoimmune disease hepatitis, scleroderma, Sjogren's syndrome, rheumatoid arthritis, polymyositis, scleroderma, Hashimoto's thyroiditis, juvenile diabetes, Addison's disease, Oral, subcutaneous, intravenous, or for the treatment and prevention of vitiligo, pernicious anemia, glomerulonephritis, pulmonary fibrosis, multiple sclerosis (MS), Crohn's disease, and other autoimmune diseases Said general formula (1) as an active ingredient according to 1 and 2 above, which can be administered intranasally (in the form of a solution, spray, emulsion, pill, tablet or any other formulation). 2a, 2b, 2c, or 2d) "Chemical Structure 1, 2a, 2b, 2c, or 2d", or "Chemical Structure 1, 2a, 2b, 2c, or 2d)" 2a, 2b, 2c, or 2d" at least one compound.
26. Amyotrophic Lateral Sclerosis (ALS), Oropharyngeal Muscular Dystrophy (OPMD), Myotonic Dystrophy (MD), Duchenne Muscular Dystrophy (DMD), Polymyositis (PM), Dermatomyositis (DM) in Humans or Animals , Inclusion body myositis (IBM), and other muscle disorders, for the treatment and prevention of therapeutically effective plasma concentrations, to deliver a therapeutically effective plasma concentration to any part of the body (solution, spray, lotion, ointment, emulsion or gel). In the form of (1), the “chemical structure 1, 2a, 2b, or 2d) of the general formula (1, 2a, 2b, 2c, or 2d) as the active ingredient, which is capable of being transdermally administered. 2c, or 2d", or a composition comprising at least one compound of "Chemical Structure 1, 2a, 2b, 2c, or 2d" of the above general formula (1, 2a, 2b, 2c, or 2d).

27. By locally (in the form of a solution, spray, lotion, ointment, emulsion or gel) of a therapeutically effective amount administered to the infected area, amyotrophic lateral sclerosis (ALS) in humans or animals, oropharyngeal type Treat and prevent muscular dystrophy (OPMD), myotonic dystrophy (MD), Duchenne muscular dystrophy (DMD), polymyositis (PM), dermatomyositis (DM), inclusion body myositis (IBM), and other myopathy For the above, the compound of “Chemical structure 1, 2a, 2b, 2c, and 2d” of the general formula (1, 2a, 2b, 2c, and 2d) as an active ingredient described in 1 and 2 above, or A composition comprising at least one compound of "Chemical Structures 1, 2a, 2b, 2c, and 2d" of the general formula (1, 2a, 2b, 2c, and 2d).
28. Amyotrophic Lateral Sclerosis (ALS), Oropharyngeal Muscular Dystrophy (OPMD), Myotonic Dystrophy (MD), Duchenne Muscular Dystrophy (DMD), Polymyositis (PM), Dermatomyositis (DM) in Humans or Animals , For the treatment and prevention of inclusion body myositis (IBM) and other muscle disorders, orally, subcutaneously, intravenously or nasally (solutions, sprays, emulsions, pills, tablets, or “Chemical structure 1, 2a” of the general formula (1, 2a, 2b, 2c, or 2d) as an active ingredient according to 1 and 2 above, which can be administered (in any other formulation form). 2b, 2c, or 2d", or a composition containing at least one compound of the "chemical structure 1, 2a, 2b, 2c, or 2d" of the above general formula (1, 2a, 2b, 2c, or 2d). Stuff.
29. Prostatic inflammation (prostatitis), prostatic cystitis, hemorrhoids, inflammatory hemorrhoids, post-irradiation (artificial) proctitis, chronic ulcerative colitis, cryptitis, other anorectal inflammatory conditions, and pruritus ani. Can be administered transdermally (in the form of solutions, sprays, lotions, ointments, emulsions or gels) to any part of the body to deliver therapeutically effective plasma concentrations for the treatment and prevention of 1 and 2, as the active ingredient, the compound of the "chemical structure 1, 2a, 2b, 2c, or 2d" of the general formula (1, 2a, 2b, 2c, or 2d), or the general formula ( A composition comprising at least one compound of "Chemical Structure 1, 2a, 2b, 2c, or 2d" of 1, 2a, 2b, 2c, or 2d).
30. Prostate inflammation (prostatitis), prostatic cystitis, hemorrhoids, inflammatory hemorrhoids by topically (in the form of a solution, spray, lotion, ointment, emulsion or gel) of a therapeutically effective amount applied to the infected area. , An active ingredient according to the above 1 and 2, for treating and preventing post-irradiation (artificial formation) proctitis, chronic ulcerative colitis, cryptitis, other anorectal inflammatory symptoms, and pruritus ani. Or a compound represented by the general formula (1, 2a, 2b, 2c, and 2d) of “chemical structure 1, 2a, 2b, 2c, and 2d”, or the general formula (1, 2a, 2b, 2c, and A composition comprising at least one compound of 2d), "Chemical structures 1, 2a, 2b, 2c, and 2d".

31. Prostate inflammation (prostatitis), prostatic cystitis, hemorrhoids, inflammatory hemorrhoids, post-irradiation (artificial) proctitis, chronic ulcerative colitis, cryptitis, other anorectal inflammatory symptoms, and pruritus ani. Orally, subcutaneously, intravenously, or nasally (in the form of solutions, sprays, emulsions, pills, tablets, or any other formulation) for the treatment and prevention of A compound of “Chemical Structure 1, 2a, 2b, 2c, or 2d” of the general formula (1, 2a, 2b, 2c, or 2d) as the active ingredient described in 1 or 2 above, or A composition comprising at least one compound of the "chemical structure 1, 2a, 2b, 2c, or 2d" of the general formula (1, 2a, 2b, 2c, or 2d).
32. To deliver therapeutically effective plasma concentrations for the treatment and prevention of autoimmune hepatitis, autoimmune nephritis, colorectal inflammation, enteritis, phlebitis, vasculitis, and other inflammation in humans or animals, the body Can be transdermally administered (in the form of a solution, spray, lotion, ointment, emulsion or gel) to any part of the above formula (1, 2a, 2b, 2c, or 2d) compound of "1, 2a, 2b, 2c, or 2d", or "chemical structure 1, 2a, 2b, 2c of the general formula (1, 2a, 2b, 2c, or 2d). , Or 2d" of at least one compound.
33. Administration of a therapeutically effective amount locally (in the form of a solution, spray, lotion, ointment, emulsion or gel) to the infected area, resulting in autoimmune hepatitis, autoimmune nephritis, colorectal inflammation in humans or animals, “The above-mentioned general formula (1, 2a, 2b, 2c, or 2d)” as an active ingredient described in 1 and 2 above for treating and preventing enteritis, phlebitis, vasculitis, and other inflammations. A compound having the chemical structure 1, 2a, 2b, 2c, or 2d", or at least one of the "chemical structures 1, 2a, 2b, 2c, or 2d" of the general formula (1, 2a, 2b, 2c, or 2d). A composition comprising one compound.
34. Oral, subcutaneous, intravenous, or for the treatment and prevention of autoimmune hepatitis, autoimmune nephritis, colorectal inflammation, enteritis, phlebitis, vasculitis, and other inflammations in humans or animals, or Said general formula (1) as an active ingredient according to 1 and 2 above, which can be administered intranasally (in the form of a solution, spray, emulsion, pill, tablet or any other formulation). 2a, 2b, 2c, or 2d) "Chemical Structure 1, 2a, 2b, 2c, or 2d", or "Chemical Structure 1, 2a, 2b, 2c, or 2d)" 2a, 2b, 2c, or 2d" at least one compound.

35. For the treatment of spinal cord injuries in humans or animals, transdermal administration (in the form of solutions, sprays, lotions, ointments, emulsions or gels) to any therapeutically effective plasma concentration. The compound of "1, 2a, 2b, 2c, or 2d" of the general formula (1, 2a, 2b, 2c, and 2d) as the active ingredient described in 1 or 2 above, or the general formula A composition comprising at least one compound of "Chemical Structures 1, 2a, 2b, 2c, and 2d" of formula (1, 2a, 2b, 2c, and 2d).
36. 1 to 2 for treating spinal cord injury in a human or animal by administering a therapeutically effective amount locally (in the form of a solution, spray, lotion, ointment, emulsion or gel) to the infected area. A compound of "Chemical structure 1, 2a, 2b, 2c, and 2d" of the general formula (1, 2a, 2b, 2c, and 2d) as an active ingredient, or a compound of the general formula (1, 2a, 2b) 2c, and 2d) "Chemical Structures 1, 2a, 2b, 2c, and 2d" of at least one compound.
37. Oral, subcutaneous, intravenous, or nasal (in the form of solutions, sprays, emulsions, pills, tablets, or any other formulation) for the treatment of spinal cord injury in humans or animals The “chemical structure 1, 2a, 2b, 2c, and 2d” of the general formula (1, 2a, 2b, 2c, and 2d) of the above general formula (1, 2a, 2b, 2c, and 2d) as an active ingredient, which can be administered, is described A composition comprising a compound or at least one compound represented by the above-mentioned general formulas (1, 2a, 2b, 2c, and 2d) "chemical structure 1, 2a, 2b, 2c, and 2d".
38. Of breast cancer, colorectal cancer, oral cancer, lung and other respiratory cancer, skin cancer, uterine cancer, genital cancer, urinary cancer, leukemia and other blood and lymphoid cancer and other cancers in humans or animals 1 above, which can be administered transdermally (in the form of solutions, sprays, lotions, ointments, emulsions or gels) to any part of the body to deliver therapeutically effective plasma concentrations for therapeutic and prophylactic purposes. And 2 as the active ingredient, the compound of "Chemical structure 1, 2a, 2b, 2c, or 2d" of the general formula (1, 2a, 2b, 2c, or 2d), or the general formula (1 2a, 2b, 2c, or 2d) "Chemical Structure 1, 2a, 2b, 2c, or 2d" of at least one compound.

39. Breast cancer, colorectal cancer, oral cancer, lung and other respiratory cancers by topically (in the form of solutions, sprays, lotions, ointments, emulsions or gels) of therapeutically effective amounts administered to the infected area. , Skin cancer, uterine cancer, genital cancer, urinary organ cancer, leukemia and other cancers of blood and lymphoid tissues and other cancers, as described above in 1 and 2, as an active ingredient, the above-mentioned general Compounds of "Chemical structure 1, 2a, 2b, 2c, and 2d" of formula (1, 2a, 2b, 2c, and 2d), or "Chemistry of the general formula (1, 2a, 2b, 2c, and 2d) A composition comprising at least one compound of structures 1, 2a, 2b, 2c, and 2d".
40. Of breast cancer, colorectal cancer, oral cancer, lung and other respiratory cancer, skin cancer, uterine cancer, genital cancer, urinary cancer, leukemia and other blood and lymphoid cancer and other cancers in humans or animals It can be administered orally, subcutaneously, intravenously, or nasally (in the form of solutions, sprays, emulsions, pills, tablets, or any other formulation) for treatment and prevention. , The compound of "Chemical structure 1, 2a, 2b, 2c, or 2d" of the general formula (1, 2a, 2b, 2c, or 2d) as the active ingredient described in 1 or 2 above, or the general formula A composition comprising at least one compound of "Chemical Structure 1, 2a, 2b, 2c, or 2d" of formula (1, 2a, 2b, 2c, or 2d).
41. Of breast cancer, colorectal cancer, oral cancer, lung and other respiratory cancer, skin cancer, uterine cancer, genital cancer, urinary cancer, leukemia and other blood and lymphoid cancer and other cancers in humans or animals The above 1 and 2, which can be administered transdermally, subcutaneously, intravenously, intranasally or orally, alone or in combination with other therapeutic agents for cancer for treatment and prevention. The compound having the “chemical structure 1, 2a, 2b, 2c, or 2d” of the general formula (1, 2a, 2b, 2c, or 2d) as the active ingredient, or the general formula (1, 2a, 2b, 2c, or 2d) at least one compound of "Chemical Structure 1, 2a, 2b, 2c, or 2d".
42. Of breast cancer, colorectal cancer, oral cancer, lung and other respiratory cancer, skin cancer, uterine cancer, genital cancer, urinary cancer, leukemia and other blood and lymphoid cancer and other cancers in humans or animals Effectiveness according to the above 1 and 2, which can be administered percutaneously, orally, subcutaneously, intravenously or intranasally before or after surgery for removing cancer for treatment. As a component, a compound having the “chemical structure 1, 2a, 2b, 2c, or 2d” of the general formula (1, 2a, 2b, 2c, or 2d), or the compound of the general formula (1, 2a, 2b, 2c, Or a composition containing at least one compound of “Chemical Structure 1, 2a, 2b, 2c, or 2d” of 2d).

式中、Ｒは−（ＣＨ ₂ ） _n −を表し、ｎ＝０，１，２，３，４，５，６，７，８，９，１０，１１又は１２であり；Ｒ ₁ 及びＲ ₂ は、独立して、Ｈ、１から１２の炭素原子を有するアルキル、アルキルオキシ、アルケニル、パーフルオロアルキル、ハロゲン化アルキル、若しくはアルキニル残基、アリール又はヘテロアリール部分のいずれか一つを表し；Ｘは、Ｏ、ＮＨ、ＮＲ ₈ 、Ｓ又は存在しないことを表し；Ｒ ₈ は、Ｈ、ＯＨ、Ｃｌ、Ｆ、Ｂｒ、Ｉ、１から１２の炭素原子を有するアルキル、アルキルオキシ、アルケニル、パーフルオロアルキル、ハロゲン化アルキル、若しくはアルキニル残基、アリール又はヘテロアリール部分のいずれか一つを表し；ＨＡは、存在しない、又は薬理学的に許容できる酸を表し；Ａｒｙ−は下式の化学構造を表し、

式中、Ｙは、ＣＨ ₃ ＣＯＯを表し；Ｙ ₁ 及びＹ ₂ は、独立して、Ｈ、ＨＯ、ＣＨ ₃ ＣＯＯ、Ｒ _y ＣＯＯ、ＨＳ、ＮＯ ₂ 、ＣＮ、ＣＨ ₃ ＣＯＳ、ＮＨ ₂ 、ＣＨ ₃ ＣＯＮＨ、Ｒ _y ＣＯＮＨ、ＣＨ ₃ 、ＣＨ ₃ ＣＨ ₂ 、Ｃ ₃ Ｈ ₇ 、Ｃ ₄ Ｈ ₉ 、ＣＨ ₃ Ｏ、ＣＨ ₃ ＣＨ ₂ Ｏ、Ｃ ₃ Ｈ ₇ Ｏ、Ｃｌ、Ｆ、Ｂｒ、Ｉ、ＣＨ ₃ Ｓ、ＣＨＦ ₂ Ｏ、ＣＦ ₃ Ｏ、ＣＦ ₃ ＣＦ ₂ Ｏ、Ｃ ₃ Ｆ ₇ Ｏ、ＣＦ ₃ 、ＣＦ ₃ ＣＦ ₂ 、Ｃ ₃ Ｆ ₇ 、Ｃ ₄ Ｆ ₉ 、ＣＨ ₃ ＳＯ ₂ 、Ｒ _y ＳＯ ₂ 、ＣＨ ₃ ＳＯ、Ｒ _y ＳＯ、ＣＨ ₃ ＣＯ又はＣＨ ₃ ＣＨ ₂ ＣＯを表し；Ｒ _y は、Ｈ、１から１２の炭素原子を有するアルキル、アルキルオキシ、アルケニル、パーフルオロアルキル、ハロゲン化アルキル若しくはアルキニル残基、アリール又はヘテロアリール部分のいずれか一つを表す。
［２］化学構造１の化合物を含む、血中脂質レベルを低下させるための経皮投与用医薬組成物。

式中、Ｒは−（ＣＨ ₂ ） _n −を表し、ｎ＝０，１，２，３，４，５，６，７，８，９，１０，１１又は１２であり；Ｒ ₁ 及びＲ ₂ は、独立して、Ｈ、１から１２の炭素原子を有するアルキル、アルキルオキシ、アルケニル、パーフルオロアルキル、ハロゲン化アルキル、若しくはアルキニル残基、アリール又はヘテロアリール部分のいずれか一つを表し；Ｘは、Ｏ、ＮＨ、ＮＲ ₈ 、Ｓ又は存在しないことを表し；Ｒ ₈ は、Ｈ、ＯＨ、Ｃｌ、Ｆ、Ｂｒ、Ｉ、１から１２の炭素原子を有するアルキル、アルキルオキシ、アルケニル、パーフルオロアルキル、ハロゲン化アルキル、若しくはアルキニル残基、アリール又はヘテロアリール部分のいずれか一つを表し；ＨＡは、存在しない、又は薬理学的に許容できる酸を表し；Ａｒｙ−は下式の化学構造を表し、

式中、Ｙは、ＣＨ ₃ ＣＯＯを表し；Ｙ ₁ 及びＹ ₂ は、独立して、Ｈ、ＨＯ、ＣＨ ₃ ＣＯＯ、Ｒ _y ＣＯＯ、ＨＳ、ＮＯ ₂ 、ＣＮ、ＣＨ ₃ ＣＯＳ、ＮＨ ₂ 、ＣＨ ₃ ＣＯＮＨ、Ｒ _y ＣＯＮＨ、ＣＨ ₃ 、ＣＨ ₃ ＣＨ ₂ 、Ｃ ₃ Ｈ ₇ 、Ｃ ₄ Ｈ ₉ 、ＣＨ ₃ Ｏ、ＣＨ ₃ ＣＨ ₂ Ｏ、Ｃ ₃ Ｈ ₇ Ｏ、Ｃｌ、Ｆ、Ｂｒ、Ｉ、ＣＨ ₃ Ｓ、ＣＨＦ ₂ Ｏ、ＣＦ ₃ Ｏ、ＣＦ ₃ ＣＦ ₂ Ｏ、Ｃ ₃ Ｆ ₇ Ｏ、ＣＦ ₃ 、ＣＦ ₃ ＣＦ ₂ 、Ｃ ₃ Ｆ ₇ 、Ｃ ₄ Ｆ ₉ 、ＣＨ ₃ ＳＯ ₂ 、Ｒ _y ＳＯ ₂ 、ＣＨ ₃ ＳＯ、Ｒ _y ＳＯ、ＣＨ ₃ ＣＯ又はＣＨ ₃ ＣＨ ₂ ＣＯを表し；Ｒ _y は、Ｈ、１から１２の炭素原子を有するアルキル、アルキルオキシ、アルケニル、パーフルオロアルキル、ハロゲン化アルキル若しくはアルキニル残基、アリール又はヘテロアリール部分のいずれか一つを表す。
［３］化学構造１の化合物を含む、ＩＩ型又はＩ型糖尿病を治療するための経皮投与用医薬組成物。

式中、Ｒは−（ＣＨ ₂ ） _n −を表し、ｎ＝０，１，２，３，４，５，６，７，８，９，１０，１１又は１２であり；Ｒ ₁ 及びＲ ₂ は、独立して、Ｈ、１から１２の炭素原子を有するアルキル、アルキルオキシ、アルケニル、パーフルオロアルキル、ハロゲン化アルキル、若しくはアルキニル残基、アリール又はヘテロアリール部分のいずれか一つを表し；Ｘは、Ｏ、ＮＨ、ＮＲ ₈ 、Ｓ又は存在しないことを表し；Ｒ ₈ は、Ｈ、ＯＨ、Ｃｌ、Ｆ、Ｂｒ、Ｉ、１から１２の炭素原子を有するアルキル、アルキルオキシ、アルケニル、パーフルオロアルキル、ハロゲン化アルキル、若しくはアルキニル残基、アリール又はヘテロアリール部分のいずれか一つを表し；ＨＡは、存在しない、又は薬理学的に許容できる酸を表し；Ａｒｙ−は下式の化学構造を表し、

式中、Ｙは、ＣＨ ₃ ＣＯＯを表し；Ｙ ₁ 及びＹ ₂ は、独立して、Ｈ、ＨＯ、ＣＨ ₃ ＣＯＯ、Ｒ _y ＣＯＯ、ＨＳ、ＮＯ ₂ 、ＣＮ、ＣＨ ₃ ＣＯＳ、ＮＨ ₂ 、ＣＨ ₃ ＣＯＮＨ、Ｒ _y ＣＯＮＨ、ＣＨ ₃ 、ＣＨ ₃ ＣＨ ₂ 、Ｃ ₃ Ｈ ₇ 、Ｃ ₄ Ｈ ₉ 、ＣＨ ₃ Ｏ、ＣＨ ₃ ＣＨ ₂ Ｏ、Ｃ ₃ Ｈ ₇ Ｏ、Ｃｌ、Ｆ、Ｂｒ、Ｉ、ＣＨ ₃ Ｓ、ＣＨＦ ₂ Ｏ、ＣＦ ₃ Ｏ、ＣＦ ₃ ＣＦ ₂ Ｏ、Ｃ ₃ Ｆ ₇ Ｏ、ＣＦ ₃ 、ＣＦ ₃ ＣＦ ₂ 、Ｃ ₃ Ｆ ₇ 、Ｃ ₄ Ｆ ₉ 、ＣＨ ₃ ＳＯ ₂ 、Ｒ _y ＳＯ ₂ 、ＣＨ ₃ ＳＯ、Ｒ _y ＳＯ、ＣＨ ₃ ＣＯ又はＣＨ ₃ ＣＨ ₂ ＣＯを表し；Ｒ _y は、Ｈ、１から１２の炭素原子を有するアルキル、アルキルオキシ、アルケニル、パーフルオロアルキル、ハロゲン化アルキル若しくはアルキニル残基、アリール又はヘテロアリール部分のいずれか一つを表す。
［４］水及び／又はエタノールを更に含む、前記［１］〜［３］のいずれか１項に記載の医薬組成物。
［５］Ｙ ₁ 及びＹ ₂ のそれぞれがＨである、前記［１］〜［４］のいずれか１項に記載の医薬組成物。
［６］Ｒ ₁ 及びＲ ₂ が、独立して、１から１２の炭素原子を有するアルキル、アルキルオキシ、アルケニル、パーフルオロアルキル、ハロゲン化アルキル、若しくはアルキニル残基、アリール又はヘテロアリール部分のいずれか一つを表す、前記［１］〜［５］のいずれか１項に記載の医薬組成物。
［７］Ｒ ₁ 及びＲ ₂ が、独立して、１から１２の炭素原子を有するアルキル、アルキルオキシ、アルケニル、パーフルオロアルキル、ハロゲン化アルキル、若しくはアルキニル残基のいずれか一つを表す、前記［１］〜［６］のいずれか１項に記載の医薬組成物。
［８］ＸがＯ又はＳである、前記［１］〜［７］のいずれか１項に記載の医薬組成物。
［９］前記化学構造１の化合物が、ジエチルアミノエチルアセチルサリチラートＨＡである、前記［１］〜［８］のいずれか１項に記載の医薬組成物。 43. 1) and 2) above, which can be administered transdermally (topically) in the form of a solution, spray, lotion, ointment, emulsion or gel for the treatment of cuts, burns or other traumas , A compound of “Chemical structure 1, 2a, 2b, 2c, or 2d” of the general formula (1, 2a, 2b, 2c, or 2d) as an active ingredient, or the compound of the general formula (1, 2a, 2b, 2c, or 2d) a composition comprising at least one compound of "Chemical Structure 1, 2a, 2b, 2c, or 2d".
44. Transdermal in the form of solutions, sprays, lotions, ointments, emulsions or gels for the treatment of abnormal vascular skin lesions, bruises, moles (nevus), skin tags, aging spots (melasma) and other skin disorders “Chemical structure 1, 2a, 2b” of the general formula (1, 2a, 2b, 2c, or 2d) as the active ingredient according to 1 and 2 above, which can be administered (topically). 2c, or 2d", or a composition comprising at least one compound of "Chemical Structure 1, 2a, 2b, 2c, or 2d" of the above general formula (1, 2a, 2b, 2c, or 2d).
45. The above-mentioned general formula (1, 2a, 2b) as an active ingredient according to the above 1 and 2 for treating any condition treatable by NSAIA in humans or animals and the novel condition described in the present invention. 2c, or 2d) the compound of “Chemical Structure 1, 2a, 2b, 2c, or 2d”, or the “Chemical Structure 1, 2a, 2c, or 2d) of the above general formula (1, 2a, 2b, 2c, or 2d). 2c, or 2d", a transdermal therapeutic application system for a composition comprising at least one compound, comprising a matrix layer containing one active ingredient and an impermeable backing layer. The most preferable system can be the active ingredient container, which has a permeable bottom facing the skin, and controls the release rate so that the NSAIA has an optimal therapeutic blood concentration. A system that makes it possible to reach a certain level, increase efficacy and reduce the side effects of NSAIA.
Another aspect of the present invention may be as follows.
[1] A pharmaceutical composition for transdermal administration for treating cancer, heart attack or stroke, which comprises the compound of Chemical Structure 1.

Wherein, R is - (CH _{2) n} - represents, be n = 0,1,2,3,4,5,6,7,8,9,10,11 or 12; R ₁ and R ₂ Represents independently any one of H, an alkyl, alkyloxy, alkenyl, perfluoroalkyl, halogenated alkyl, or alkynyl residue having from 1 to 12 carbon atoms, an aryl or heteroaryl moiety; X Represents O, NH, NR ₈ , S or absent; R ₈ represents H, OH, Cl, F, Br, I, alkyl having 1 to 12 carbon atoms, alkyloxy, alkenyl, perfluoro. Alkyl, alkyl halide, or alkynyl residue, represents any one of aryl or heteroaryl moieties; HA represents absent or pharmacologically acceptable acid; Ary- represents a chemical structure of the formula Represents

In the formula, Y represents CH ₃ COO; Y ₁ and Y ₂ are independently H, HO, CH ₃ COO, R _y COO, HS, NO ₂ , CN, CH ₃ COS, NH ₂ , CH. ₃ CONH, R _y CONH, CH ₃ , CH ₃ CH ₂ , C ₃ H ₇ , C ₄ H ₉ , CH ₃ O, CH ₃ CH ₂ O, C ₃ H ₇ O, Cl, F, Br, I, CH ₃ S, CHF ₂ O, CF ₃ O, CF ₃ CF ₂ O, C ₃ F ₇ O, CF ₃ , CF ₃ CF ₂ , C ₃ F ₇ , C ₄ F ₉ , CH ₃ SO ₂ , R _y SO ₂ , CH ₃ SO, R _y SO, CH ₃ CO or CH ₃ CH ₂ CO; R _y is H, alkyl having 1 to 12 carbon atoms, alkyloxy, alkenyl, perfluoroalkyl, halogenated alkyl or Represents any one of an alkynyl residue, an aryl or a heteroaryl moiety.
[2] A pharmaceutical composition for transdermal administration, which comprises reducing the blood lipid level, comprising the compound of Chemical Structure 1.

Wherein, R is - (CH _{2) n} - represents, be n = 0,1,2,3,4,5,6,7,8,9,10,11 or 12; R ₁ and R ₂ Represents independently any one of H, an alkyl, alkyloxy, alkenyl, perfluoroalkyl, halogenated alkyl, or alkynyl residue having from 1 to 12 carbon atoms, an aryl or heteroaryl moiety; X Represents O, NH, NR ₈ , S or absent; R ₈ represents H, OH, Cl, F, Br, I, alkyl having 1 to 12 carbon atoms, alkyloxy, alkenyl, perfluoro. Alkyl, alkyl halide, or alkynyl residue, represents any one of aryl or heteroaryl moieties; HA represents absent or pharmacologically acceptable acid; Ary- represents a chemical structure of the formula Represents

In the formula, Y represents CH ₃ COO; Y ₁ and Y ₂ are independently H, HO, CH ₃ COO, R _y COO, HS, NO ₂ , CN, CH ₃ COS, NH ₂ , CH. ₃ CONH, R _y CONH, CH ₃ , CH ₃ CH ₂ , C ₃ H ₇ , C ₄ H ₉ , CH ₃ O, CH ₃ CH ₂ O, C ₃ H ₇ O, Cl, F, Br, I, CH ₃ S, CHF ₂ O, CF ₃ O, CF ₃ CF ₂ O, C ₃ F ₇ O, CF ₃ , CF ₃ CF ₂ , C ₃ F ₇ , C ₄ F ₉ , CH ₃ SO ₂ , R _y SO ₂ , CH ₃ SO, R _y SO, CH ₃ CO or CH ₃ CH ₂ CO; R _y is H, alkyl having 1 to 12 carbon atoms, alkyloxy, alkenyl, perfluoroalkyl, halogenated alkyl or Represents any one of an alkynyl residue, an aryl or a heteroaryl moiety.
[3] A pharmaceutical composition for transdermal administration for treating type II or type I diabetes, which comprises the compound of chemical structure 1.

Wherein, R is - (CH _{2) n} - represents, be n = 0,1,2,3,4,5,6,7,8,9,10,11 or 12; R ₁ and R ₂ Represents independently any one of H, an alkyl, alkyloxy, alkenyl, perfluoroalkyl, halogenated alkyl, or alkynyl residue having from 1 to 12 carbon atoms, an aryl or heteroaryl moiety; X Represents O, NH, NR ₈ , S or absent; R ₈ represents H, OH, Cl, F, Br, I, alkyl having 1 to 12 carbon atoms, alkyloxy, alkenyl, perfluoro. Alkyl, alkyl halide, or alkynyl residue, represents any one of aryl or heteroaryl moieties; HA represents absent or pharmacologically acceptable acid; Ary- represents a chemical structure of the formula Represents

In the formula, Y represents CH ₃ COO; Y ₁ and Y ₂ are independently H, HO, CH ₃ COO, R _y COO, HS, NO ₂ , CN, CH ₃ COS, NH ₂ , CH. ₃ CONH, R _y CONH, CH ₃ , CH ₃ CH ₂ , C ₃ H ₇ , C ₄ H ₉ , CH ₃ O, CH ₃ CH ₂ O, C ₃ H ₇ O, Cl, F, Br, I, CH ₃ S, CHF ₂ O, CF ₃ O, CF ₃ CF ₂ O, C ₃ F ₇ O, CF ₃ , CF ₃ CF ₂ , C ₃ F ₇ , C ₄ F ₉ , CH ₃ SO ₂ , R _y SO ₂ , CH ₃ SO, R _y SO, CH ₃ CO or CH ₃ CH ₂ CO; R _y is H, alkyl having 1 to 12 carbon atoms, alkyloxy, alkenyl, perfluoroalkyl, halogenated alkyl or Represents any one of an alkynyl residue, an aryl or a heteroaryl moiety.
[4] The pharmaceutical composition according to any one of [1] to [3], further containing water and/or ethanol.
[5] The pharmaceutical composition according to any one of [1] to [4], wherein each of Y ₁ and Y ₂ is H.
[6] R ₁ and R ₂ are each independently an alkyl, alkyloxy, alkenyl, perfluoroalkyl, alkyl halide, or alkynyl residue having 1 to 12 carbon atoms, an aryl or heteroaryl moiety. The pharmaceutical composition according to any one of [1] to [5], which represents one.
[7] R ₁ and R ₂ independently represent any one of an alkyl, alkyloxy, alkenyl, perfluoroalkyl, halogenated alkyl, or alkynyl residue having 1 to 12 carbon atoms, The pharmaceutical composition according to any one of [1] to [6].
[8] The pharmaceutical composition according to any one of [1] to [7], wherein X is O or S.
[9] The pharmaceutical composition according to any one of [1] to [8], wherein the compound of Chemical Structure 1 is diethylaminoethylacetylsalicylate HA.

式中、Ｒは分岐又は直鎖の−（ＣＨ₂）_n−を表し、−（ＣＨ₂）_n−においてｎ＝０，１，２，３，４，５，６，７，８，９，１０…であり；Ｒ₁は分岐又は直鎖の−（ＣＨ₂）_a−を表し、−（ＣＨ₂）_a−においてａ＝０，１，２，３，４，５，６，７，８，９，１０…であり；Ｒ₂は分岐又は直鎖の−（ＣＨ₂）_b−を表し、−（ＣＨ₂）_b−においてｂ＝０，１，２，３，４，５，６，７，８，９，１０…であり；Ｒ₃は分岐又は直鎖の−（ＣＨ₂）_c−を表し、−（ＣＨ₂）_c−においてｃ＝０，１，２，３，４，５，６，７，８，９，１０…であり；Ｒ₄はＨ、１から１２の炭素原子を有するアルキル、アルキルオキシ、アルケニル、パーフルオロアルキル、ハロゲン化アルキル、若しくはアルキニル残基、アリール又はヘテロアリール部分のいずれか一つを表し；Ｒ₅は、Ｈ、１から１２の炭素原子を有するアルキル、アルキルオキシ、アルケニル、パーフルオロアルキル、ハロゲン化アルキル、若しくはアルキニル残基、アリール又はヘテロアリール部分のいずれか一つを表し；Ｒ₆は、Ｈ、１から１２の炭素原子を有するアルキル、アルキルオキシ、アルケニル、パーフルオロアルキル、ハロゲン化アルキル、若しくはアルキニル残基、アリール又はヘテロアリール部分のいずれか一つを表し；Ｒ₇は、Ｈ、１から１２の炭素原子を有するアルキル、アルキルオキシ、アルケニル、パーフルオロアルキル、ハロゲン化アルキル、若しくはアルキニル残基、アリール又はヘテロアリール部分のいずれか一つを表し；Ｘは、存在しない、Ｏ、ＮＨ、ＮＲ₆又はＳを表し；ＨＡは、存在しない、又は薬理学的に許容できる酸を表し、全てのＲ、Ｒ₁、Ｒ₂、Ｒ₈、Ｒ₉、又は−（ＣＨ₂）_n−基は、分岐又は直鎖であり、Ａｒｙ−は以下の化学構造からなる群から選択される化学構造を表し、

式中、Ｒ_xは、Ｈ、ＣＨ₃、ＣＨ₃Ｏ、ＨＯ、ＣＨ₃ＣＨ₂、ＣＦ₃、ＣＨＦ₂、ＣＨ₂Ｆ、Ｃｌ、Ｆ、又はＢｒを表し；Ｒ_yは、Ｈ、１から１２の炭素原子を有するアルキル、アルキルオキシ、アルケニル、パーフルオロアルキル、ハロゲン化アルキル若しくはアルキニル残基、アリール又はヘテロアリール部分のいずれか一つを表し；Ｘ₁又はＸ₄は、ＣＨ₂、Ｓ、Ｏ、ＮＨ、又はＣＯを表し；Ｘ₂又はＸ₅は、ＣＨ、ＣＲ₈、又はＮを表し；Ｘ₃は、Ｏ、Ｓ、ＮＨ、又はＮＲ₈を表し；Ｙ、Ｙ₁、Ｙ₂、Ｙ₃、Ｙ₄、Ｙ_5、又はＹ₆は、独立してＨ、ＨＯ、ＣＨ₃ＣＯＯ、Ｒ_yＣＯＯ、ＨＳ、ＮＯ₂、ＣＮ、ＣＨ₃ＣＯＳ、ＮＨ₂、ＣＨ₃ＣＯＮＨ、Ｒ_yＣＯＮＨ、ＣＨ₃、ＣＨ₃ＣＨ₂、Ｃ₃Ｈ₇、Ｃ₄Ｈ₉、ＣＨ₃Ｏ、ＣＨ₃ＣＨ₂Ｏ_、Ｃ₃Ｈ₇Ｏ_、Ｃｌ、Ｆ、Ｂｒ、Ｉ、ＣＨ₃Ｓ、ＣＨＦ₂Ｏ、ＣＦ₃Ｏ、ＣＦ₃ＣＦ₂Ｏ、Ｃ₃Ｆ₇Ｏ、ＣＦ₃、ＣＦ₃ＣＦ_2、Ｃ₃Ｆ₇、Ｃ₄Ｆ₉、ＣＨ₃ＳＯ₂、Ｒ_yＳＯ_2、ＣＨ₃ＳＯ、Ｒ_yＳＯ、ＣＨ₃ＣＯ、又はＣＨ₃ＣＨ₂ＣＯを表す化合物。
〔２〕一般式（１）の「化学構造１」の化合物であって、

式中、Ｒは分岐又は直鎖の−（ＣＨ₂）_n−を表し、−（ＣＨ₂）_n−においてｎ＝０，１，２，３，４，５，６，７，８，９，１０，１１，１２，…であり；Ｒ₁は、Ｈ、１から１２の炭素原子を有するアルキル、アルキルオキシ、アルケニル、パーフルオロアルキル、ハロゲン化アルキル、若しくはアルキニル残基、アリール又はヘテロアリール部分のいずれか一つを表し；Ｒ₂は、Ｈ、１から１２の炭素原子を有するアルキル、アルキルオキシ、アルケニル、パーフルオロアルキル、ハロゲン化アルキル若しくはアルキニル残基、アリール又はヘテロアリール部分のいずれか一つを表し；Ｘは、Ｏ、ＮＨ、ＮＲ₈、Ｓ、又は存在しないことを表し；Ｒ₈は、Ｈ、ＯＨ、Ｃｌ、Ｆ、Ｂｒ、Ｉ、１から１２の炭素原子を有するアルキル、アルキルオキシ、アルケニル、パーフルオロアルキル、ハロゲン化アルキル若しくはアルキニル残基、アリール又はヘテロアリール部分のいずれか一つを表し；Ｒ₉は、Ｈ、ＯＨ、Ｃｌ、Ｆ、Ｂｒ、Ｉ、１から１２の炭素原子を有するアルキル、アルキルオキシ、アルケニル、パーフルオロアルキル、ハロゲン化アルキル若しくはアルキニル残基、アリール又はヘテロアリール部分のいずれか一つを表し；前記一般式（１）の「化学構造１」におけるＡｒｙ−は、前記〔１〕に記載の前記一般式（２ａ、２ｂ、２ｃ、又は２ｄ）の「化学構造２ａ、２ｂ、２ｃ、又は２ｄ」と同一のＡｒｙ−として定義され；ＨＡは、存在しない、又は薬理学的に許容できる酸を表し；全てのＲ、Ｒ₁、Ｒ₂、Ｒ₈、Ｒ₉、又は−（ＣＨ₂）_n−基は、分岐又は直鎖である化合物。
〔３〕前記〔１〕又は前記〔２〕に記載の前記一般式１、２ａ、２ｂ、２ｃ、又は２ｄの「化学構造１、２ａ、２ｂ、２ｃ、又は２ｄ」の化合物を、カップリング試薬を用いて無水物を形成する反応、次いでアルコール、チオール、又はアミンを用いる反応により、ＮＳＡＩＡから調製する、前記〔１〕又は前記〔２〕に記載の前記一般式（１、２ａ、２ｂ、２ｃ、又は２ｄ）の「化学構造１、２ａ、２ｂ、２ｃ、又は２ｄ」の化合物を調製する方法。
〔４〕前記〔１〕又は前記〔２〕に記載の前記一般式１、２ａ、２ｂ、２ｃ、又は２ｄの「化学構造１、２ａ、２ｂ、２ｃ、又は２ｄ」の化合物を、ハロゲン化物を用いて、ＮＳＡＩＡの金属塩、有機塩基性塩、又は固定化された塩基性塩から調製する、前記〔１〕又は前記〔２〕に記載の前記一般式（１、２ａ、２ｂ、２ｃ、又は２ｄ）の「化学構造１、２ａ、２ｂ、２ｃ、又は２ｄ」の化合物を調製する方法。
〔５〕代謝疾患、異常血圧、心臓及び血管疾患、臓器移植拒絶反応、神経変性疾患、皮膚疾患、自己免疫疾患、筋疾患、痛み、発熱、癌、月経困難症、急性片頭痛、急性痛風性関節炎、強直性脊椎炎、関節リウマチ、変形性関節症、認知症、炎症性症状、脊髄損傷及び傷からなる群から選択される、ヒト又は動物における疾患若しくは症状を治療又は予防するための薬剤の製造のための前記〔１〕又は〔２〕に記載の化合物の使用。
〔６〕前記薬剤が、治療上有効な血漿濃度を送達するために、ヒト又は動物において身体の部分に溶液、スプレー、ローション、軟膏、エマルジョン又はゲルの形式で経皮投与される、前記〔５〕に記載の使用。
〔７〕前記薬剤が、経口的に、皮下に、静脈内に、又は経鼻的に溶液、スプレー、エマルジョン、丸剤、錠剤の形式で投与される、前記〔５〕に記載の使用。
〔８〕前記薬剤が、治療上有効量を感染領域に局所的に溶液、スプレー、ローション、軟膏、エマルジョン又はゲルの形式で投与される、前記〔５〕に記載の使用。
〔９〕前記痛みが、歯痛、頭痛及び炎症性の痛みから選択される、前記〔５〕に記載の使用。
〔１０〕前記代謝疾患が、糖尿病（Ｉ型及び／又はＩＩ型）、異常血糖、異常血中脂質濃度からなる群から選択される、前記〔５〕に記載の使用。
〔１１〕前記心臓及び血管疾患が、脳卒中及び心臓発作からなる群から選択される、前記〔５〕に記載の使用。
〔１２〕前記神経変性疾患が、アルツハイマー病及びパーキンソン病からなる群から選択される、前記〔５〕に記載の使用。
〔１３〕前記皮膚疾患が、乾癬である、前記〔５〕に記載の使用。
〔１４〕前記自己免疫疾患が、ヒト又は動物における円板状エリテマトーデス、全身性エリテマトーデス（ＳＬＥ）、自己免疫疾患肝炎、強皮症、シェーグレン症候群、関節リウマチ、多発性筋炎、強皮症、橋本甲状腺炎、若年型糖尿病、アジソン病、白斑、悪性貧血、糸球体腎炎、肺線維症、多発性硬化症（ＭＳ）及びクローン病からなる群から選択される、前記〔５〕に記載の使用。
〔１５〕前記筋疾患が、筋萎縮性側索硬化症（ＡＬＳ）、眼球咽頭型筋ジストロフィー（ＯＰＭＤ）、筋緊張性ジストロフィー（ＭＤ）、デュシェンヌ型筋ジストロフィー（ＤＭＤ）、多発性筋炎（ＰＭ）、皮膚筋炎（ＤＭ）及び封入体筋炎（ＩＢＭ）からなる群から選択される、前記〔５〕に記載の使用。
〔１６〕前記炎症性症状が、前立腺の炎症（前立腺炎）、前立腺膀胱炎、痔、炎症性の痔、照射（人工形成）後直腸炎、慢性潰瘍性大腸炎、腺窩炎、肛門直腸の炎症性症状、肛門掻痒、自己免疫性肝炎、自己免疫性腎炎、結腸直腸炎、腸炎、静脈炎、血管炎から選択される、前記〔５〕に記載の使用。
〔１７〕前記癌が、乳癌、結腸直腸癌、口腔癌、呼吸器系の癌、皮膚癌、子宮癌、生殖器癌、泌尿器癌、白血病、並びに血液及びリンパ組織の癌から選択される、前記〔５〕に記載の使用。
〔１８〕前記傷が、切り傷及び火傷からなる群から選択される、前記〔５〕に記載の使用。
〔１９〕前記皮膚疾患が、異常血管性皮膚病変、あざ、ほくろ（母斑）、スキンタグ及び高齢スポット（肝斑）からなる群から選択される、前記〔５〕に記載の使用。
〔２０〕代謝疾患、異常血圧、心臓及び血管疾患、臓器移植拒絶反応、神経変性疾患、皮膚疾患、自己免疫疾患、筋疾患、痛み、発熱、癌、月経困難症、急性片頭痛、急性痛風性関節炎、強直性脊椎炎、関節リウマチ、変形性関節症、認知症、炎症性症状、脊髄損傷及び傷からなる群から選択される、ヒト又は動物における疾患若しくは症状を治療又は予防するための、前記〔１〕又は〔２〕に記載の化合物の経皮的治療応用システムであって、一つの有効成分を含有するマトリクス層と不浸透性の裏地層とを含むバンデージ又はパッチを含むシステム。
〔２１〕有効成分収容体を含み、皮膚に面する浸透性の底部を有し、放出率を制御することにより、ＮＳＡＩＡが至適な治療上血液濃度に一定に達し、有効性を増し、ＮＳＡＩＡの副作用を低減することを可能にする、前記〔２０〕に記載のシステム。
〔２２〕水及び前記〔１〕又は〔２〕に記載の化合物からなる組成物。 Another aspect of the present invention may be as follows.
[1] A compound of "Chemical structure 2a, 2b, 2c, or 2d" of the general formula (2a, 2b, 2c, or 2d),

Wherein, R branched or straight-chain - (CH _{2) n} - represents a, - (CH _{2) n} - in n = 0,1,2,3,4,5,6,7,8,9, 10 ... a and; R ₁ is a branched or straight-chain - (CH _{2) a} - represents, - (CH _{2) a} - in a = 0,1,2,3,4,5,6,7,8 , 9, 10,...; R ₂ represents branched or straight chain —(CH ₂ ) _b —, and in —(CH ₂ ) _b —, b=0,1,2,3,4,5,6. 7, 8, 9, 10 ... and is; R ₃ is a branched or straight-chain - (CH _{2) c} - represents a, - (CH _{2) c} - in c = 0,1,2,3,4,5 , 6,7,8,9,10...; R ₄ is H, alkyl having 1 to 12 carbon atoms, alkyloxy, alkenyl, perfluoroalkyl, halogenated alkyl, or alkynyl residue, aryl or hetero. Represents any one of aryl moieties; R ₅ is H, an alkyl, alkyloxy, alkenyl, perfluoroalkyl, halogenated alkyl, or alkynyl residue having 1 to 12 carbon atoms, an aryl or heteroaryl moiety; R ₆ represents any one of H, alkyl having 1 to 12 carbon atoms, alkyloxy, alkenyl, perfluoroalkyl, alkyl halide, or alkynyl residue, aryl or heteroaryl moiety; R ₇ represents H, any one of an alkyl, alkyloxy, alkenyl, perfluoroalkyl, halogenated alkyl, or alkynyl residue having 1 to 12 carbon atoms, an aryl or heteroaryl moiety. X represents absent, O, NH, NR ₆ or S; HA represents absent or a pharmacologically acceptable acid; all R, R ₁ , R ₂ , R ₈ , R _9; , or - (CH _{2) n} - groups are branched or straight chain, Ary- represents a chemical structure selected from the group consisting of the following chemical structure,

In the formula, R _x represents H, CH ₃ , CH ₃ O, HO, CH ₃ CH ₂ , CF ₃ , CHF ₂ , CH ₂ F, Cl, F, or Br; R _y is H, 1 to Represents any one of an alkyl, alkyloxy, alkenyl, perfluoroalkyl, halogenated alkyl or alkynyl residue, aryl or heteroaryl moiety having 12 carbon atoms; X ₁ or X ₄ is CH ₂ , S, Represents O, NH, or CO; X ₂ or X ₅ represents CH, CR ₈ , or N; X ₃ represents O, S, NH, or NR ₈ ; Y, Y ₁ , Y ₂ , Y ₃ , Y ₄ , Y _5, or Y ₆ are independently H, HO, CH ₃ COO, R _y COO, HS, NO ₂ , CN, CH ₃ COS, NH ₂ , CH ₃ CONH, R _y CONH. , CH ₃ , CH ₃ CH ₂ , C ₃ H ₇ , C ₄ H ₉ , CH ₃ O, CH ₃ CH ₂ O _, C ₃ H ₇ O _, Cl, F, Br, I, CH ₃ S, CHF ₂ O , CF ₃ O, CF ₃ CF ₂ O, C ₃ F ₇ O, CF ₃ , CF ₃ CF _2, C ₃ F ₇ , C ₄ F ₉ , CH ₃ SO ₂ , R _y SO _2, CH ₃ SO, R A compound representing _y SO, CH ₃ CO, or CH ₃ CH ₂ CO.
[2] A compound having the “chemical structure 1” of the general formula (1),

Wherein, R branched or straight-chain - (CH _{2) n} - represents a, - (CH _{2) n} - in n = 0,1,2,3,4,5,6,7,8,9, 10, 11, 12,...; R ₁ is H, of an alkyl, alkyloxy, alkenyl, perfluoroalkyl, halogenated alkyl, or alkynyl residue having 1 to 12 carbon atoms, an aryl or heteroaryl moiety. R ₂ represents any one of H, an alkyl having 1 to 12 carbon atoms, an alkyloxy, an alkenyl, a perfluoroalkyl, a halogenated alkyl or alkynyl residue, an aryl or a heteroaryl moiety. X is O, NH, NR ₈ , S, or absent; R ₈ is H, OH, Cl, F, Br, I, alkyl having 1 to 12 carbon atoms, alkyloxy. , Alkenyl, perfluoroalkyl, alkyl halide or alkynyl residue, aryl or heteroaryl moiety; R ₉ is H, OH, Cl, F, Br, I, 1 to 12 carbon atoms. Represents any one of an alkyl, an alkyloxy, an alkenyl, a perfluoroalkyl, a halogenated alkyl or an alkynyl residue, an aryl or a heteroaryl moiety having: Ary- in the "chemical structure 1" of the general formula (1) is , HA is absent, or is defined as Ary- which is the same as the “chemical structure 2a, 2b, 2c, or 2d” of the general formula (2a, 2b, 2c, or 2d) described in [1] above; Represents a pharmacologically acceptable acid; a compound in which all R, R ₁ , R ₂ , R ₈ , R ₉ or —(CH ₂ ) _n — groups are branched or linear.
[3] The compound of the chemical formula 1, 2a, 2b, 2c, or 2d of the general formula 1, 2a, 2b, 2c, or 2d described in [1] or [2] is a coupling reagent. Is prepared from NSAIA by a reaction to form an anhydride with an alcohol, a thiol, or an amine, and then the above-mentioned general formula (1, 2a, 2b, 2c) described in [1] or [2] above. , Or 2d) "Chemical structure 1, 2a, 2b, 2c, or 2d".
[4] A compound represented by the above-mentioned [1] or [2], represented by the general formula 1, 2a, 2b, 2c, or 2d, which has a "chemical structure 1, 2a, 2b, 2c, or 2d", is converted into a halide. Is prepared from a metal salt of NSAIA, an organic basic salt, or an immobilized basic salt, using the above-mentioned general formula (1, 2a, 2b, 2c, or the above-mentioned [1] or [2], or A method for preparing a compound having the "chemical structure 1, 2a, 2b, 2c, or 2d" of 2d).
[5] Metabolic disease, abnormal blood pressure, heart and vascular disease, organ transplant rejection, neurodegenerative disease, skin disease, autoimmune disease, muscle disease, pain, fever, cancer, dysmenorrhea, acute migraine, acute goutiness A drug for treating or preventing a disease or condition in a human or animal selected from the group consisting of arthritis, ankylosing spondylitis, rheumatoid arthritis, osteoarthritis, dementia, inflammatory condition, spinal cord injury and injury. Use of the compound according to the above [1] or [2] for production.
[6] The drug is transdermally administered to a part of the body in humans or animals in the form of a solution, spray, lotion, ointment, emulsion or gel in order to deliver a therapeutically effective plasma concentration. ] The use described in.
[7] The use according to [5] above, wherein the drug is orally, subcutaneously, intravenously, or intranasally administered in the form of a solution, spray, emulsion, pill, or tablet.
[8] The use according to [5] above, wherein the drug is administered in a therapeutically effective amount locally to the infected area in the form of a solution, spray, lotion, ointment, emulsion or gel.
[9] The use according to [5] above, wherein the pain is selected from toothache, headache and inflammatory pain.
[10] The use according to [5] above, wherein the metabolic disease is selected from the group consisting of diabetes (type I and/or type II), abnormal blood glucose, and abnormal blood lipid concentration.
[11] The use according to [5] above, wherein the heart and vascular disease is selected from the group consisting of stroke and heart attack.
[12] The use according to [5] above, wherein the neurodegenerative disease is selected from the group consisting of Alzheimer's disease and Parkinson's disease.
[13] The use according to [5] above, wherein the skin disease is psoriasis.
[14] The autoimmune disease is discoid lupus erythematosus in humans or animals, systemic lupus erythematosus (SLE), autoimmune disease hepatitis, scleroderma, Sjogren's syndrome, rheumatoid arthritis, polymyositis, scleroderma, Hashimoto thyroid gland Use according to the above [5], selected from the group consisting of inflammation, juvenile diabetes, Addison's disease, vitiligo, pernicious anemia, glomerulonephritis, pulmonary fibrosis, multiple sclerosis (MS) and Crohn's disease.
[15] The muscle disease is amyotrophic lateral sclerosis (ALS), oropharyngeal muscular dystrophy (OPMD), myotonic dystrophy (MD), Duchenne muscular dystrophy (DMD), polymyositis (PM), skin Use according to [5] above, selected from the group consisting of myositis (DM) and inclusion body myositis (IBM).
[16] The inflammatory symptoms include prostatic inflammation (prostatitis), prostatic cystitis, hemorrhoids, inflammatory hemorrhoids, post-irradiation (artificial formation) proctitis, chronic ulcerative colitis, cryptitis, and anorectal. The use according to [5] above, which is selected from inflammatory symptoms, pruritus ani, autoimmune hepatitis, autoimmune nephritis, colorectal inflammation, enteritis, phlebitis, and vasculitis.
[17] The cancer is selected from breast cancer, colorectal cancer, oral cancer, respiratory cancer, skin cancer, uterine cancer, genital cancer, urinary cancer, leukemia, and blood and lymphoid tissue cancer. The use according to 5].
[18] The use according to [5] above, wherein the scratch is selected from the group consisting of cuts and burns.
[19] The use according to [5] above, wherein the skin disease is selected from the group consisting of abnormal vascular skin lesions, bruises, moles (nevus), skin tags and aged spots (melasma).
[20] metabolic disease, abnormal blood pressure, heart and vascular disease, organ transplant rejection, neurodegenerative disease, skin disease, autoimmune disease, muscle disease, pain, fever, cancer, dysmenorrhea, acute migraine, acute goutiness For treating or preventing a disease or condition in a human or animal selected from the group consisting of arthritis, ankylosing spondylitis, rheumatoid arthritis, osteoarthritis, dementia, inflammatory condition, spinal cord injury and injury, A system for transdermal therapeutic application of a compound according to [1] or [2], which comprises a bandage or patch comprising a matrix layer containing one active ingredient and an impermeable backing layer.
[21] It contains an active ingredient container, has a permeable bottom facing the skin, and controls the release rate to reach a certain therapeutic blood concentration of NSAIA at a certain level, thereby increasing the efficacy of NSAIA. The system according to [20] above, which makes it possible to reduce the side effects of
[22] A composition comprising water and the compound according to [1] or [2].

Claims (5)

Cancer comprising at least one compound selected from diethylaminoethyl acetylsalicylate HA, diethylaminoethyl 5-acetamido-acetylsalicylate HA, and diethylaminoethylacetylsalicylsalicylate HA, and water and/or ethanol , a pharmaceutical composition for transdermal administration for treating a heart attack or stroke, H a is absent, or a pharmaceutically acceptable acid table to pharmaceutical compositions. A method for reducing blood lipid levels, comprising at least one compound selected from diethylaminoethyl acetylsalicylate HA, diethylaminoethyl 5-acetamido-acetylsalicylate HA, and diethylaminoethylacetylsalicylic salicylate HA. a peel administered pharmaceutical compositions, H a is absent, or a pharmaceutically acceptable acid table to pharmaceutical compositions. To treat type II or type I diabetes comprising at least one compound selected from diethylaminoethyl acetylsalicylate HA, diethylaminoethyl 5-acetamido-acetylsalicylate HA, and diethylaminoethylacetylsalicylic salicylate HA. a transdermal administration pharmaceutical compositions, H a is absent, or a pharmaceutically acceptable acid table to pharmaceutical compositions. The pharmaceutical composition according to claim 2 or 3 , further comprising water and/or ethanol. The reduction compound is a diethylaminoethyl acetylsalicylate HA, pharmaceutical composition according to any one of claims 1-4.

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