JP2024026659A - Nsaia prodrug having very fast skin- and film-infiltration rate, and new use thereof as medicine - Google Patents

Abstract

PROBLEM TO BE SOLVED: To design and synthesize a new NSAIA prodrug that is positively charged and can be administered transdermally.

SOLUTION: A positively-charged NSAIA prodrug is designed and synthesized which has a chemical structure 1, 2a, 2b, 2c, or 2d. A positively-charged amino group of the prodrug greatly increases the solubility in water of the medicine, and thus bonds to a negative charge in a phosphate head group of a film. This bonding destabilizes the film a little and can make a little room in a lipophilic moiety of the prodrug, and in some cases, a slight crack may occur by the bonding of the prodrug. As a result, the prodrug comes to enter the film inside. At pH 7.4, about 99% of the amino groups are protonated. When the amino group is not protonated, the bonding between the amino group of the prodrug and the phosphate head group of the film dissociates, and hence the prodrug enters the film completely.

SELECTED DRAWING: Figure 1

COPYRIGHT: (C)2024,JPO&INPIT

Description

The present invention relates to the design and preparation of positively charged water-soluble prodrugs of non-steroidal anti-inflammatory agents (NSAIAs) with very fast skin and blood-brain barrier penetration rates and Abnormal levels of blood lipids, heart and vascular diseases such as stroke, heart attack, Alzheimer's disease, Parkinson's disease and other neurodegenerative diseases, psoriasis, discoid lupus erythematosus, systemic lupus erythematosus (SLE), autoimmune diseases hepatitis, severe skin disease, Sjogren's syndrome, rheumatoid arthritis, polymyositis, scleroderma, Hashimoto's thyroiditis, juvenile diabetes, Addison's disease, vitiligo, pernicious anemia, glomerulonephritis, pulmonary fibrosis, multiple sclerosis (MS), Crohn's disease disease, and other autoimmune diseases, amyotrophic lateral sclerosis (ALS), oculopharyngeal 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 proctitis, chronic ulcerative colitis, cryptitis, and other anorectal Inflammatory symptoms and anal pruritus, prostatitis, prostatic cystitis, esophageal varices, autoimmune hepatitis, autoimmune nephritis, colorectitis, enteritis, phlebitis and other inflammations, skin cancer, breast cancer, colorectal cancer , oral cancer, lung and other respiratory system cancers, uterine cancer, reproductive tract cancer, urinary tract cancer, leukemia and other cancers of the blood and lymphoid tissues and other cancers, scars, abnormal vascular skin lesions, birthmarks, moles ( novel medicinal uses in the treatment and prevention of birthmarks), skin tags, age spots (melasma), and other skin diseases. These prodrugs can be administered transdermally without the aid of transdermal absorption enhancers.

NSAIAs are used to relieve the signs and symptoms of rheumatoid arthritis, osteoarthritis, and ankylosing spondylitis. NSAIAs are used alone or as an adjunct in the treatment of gallstone colic, fever, and episiotomy pain. It is also used to treat gout, acute migraine, and renal colic, as well as postoperative inflammation in patients undergoing cataract extraction surgery. Aspirin is used to prevent heart and vascular disease.

Unfortunately, a number of side effects are associated with the use of NSAIAs, including very significant gastrointestinal disturbances such as indigestion, gastroduodenal bleeding, gastric ulcers, and gastritis. Fishman (Robert, U.S. Pat. No. 7,052,715) describes the addition of oral medications that must reach significant concentration levels in the bloodstream for the purpose of effectively treating distal areas of pain or inflammation. It showed the problems. This level is often much higher than would be necessary if it were possible to precisely target a particular location of pain or wound. by Van Engelen et al., US Pat. No. 6,416,772; Macrides et al., US Pat. No. 6,346,278; Kirby et al., US Pat. No. 6,444,234, Pearson et al., US Pat. No. 6,528,040, and Botknecht et al. US Pat. No. 5,885,597), attempts have been made to develop delivery systems for transdermal application by prescription. 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 salve for topical use containing heparin and diclofenac (Donati et al., US Pat. No. 6,592,891). Kawaji et al. developed a topical oil patch containing diclofenac sodium salt (Kawaji et al., US Pat. No. 6,262,121). Effing et al. developed a device to deliver diclofenac transdermally (Effing et al., US Pat. No. 6,193,996). However, it is very difficult to deliver therapeutically effective plasma concentrations of NSAIAs in patients by prescription. Susan Milosovich et al. designed and prepared testosteronyl-4-dimethylaminobutyrate. HCl (TSBH) has a lipophilic moiety and a tertiary amine group that exists in 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).

NSAIAs have been used as medicines for over 100 years. NSAIAs are indicated for alleviation of the 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 worldwide.

Unfortunately, a number of side effects are associated with the use of NSAIAs, including very significant gastrointestinal disturbances such as indigestion, heartburn, vomiting, gastroduodenal bleeding, gastric ulcers, and gastritis. Gastroduodenal bleeding caused by NSAIAs is generally painless, but can lead to blood loss in the feces, which can lead to persistent deficiency anemia.

Transdermal delivery systems help avoid direct injury to the gastrointestinal tract and inactivation of the drug caused by "first pass metabolism" in the gastrointestinal tract and liver. Transdermal drug delivery systems using conventional transdermal absorption enhancers have limitations. First, the rate of penetration is very slow (on the scale of μg/cm ² /hour). Second, a large amount of accelerator will enter the patient's body.

Transdermal delivery systems help avoid direct injury to the gastrointestinal tract and inactivation of the drug caused by "first pass metabolism" in the gastrointestinal tract and liver. Transdermal drug delivery systems using conventional transdermal absorption enhancers have limitations. First, the rate of penetration is very slow (on the scale of μg/in ² /hour). Second, a large amount of enhancer will enter the patient's body, which may cause additional side effects. Third, in traditional transdermal drug delivery through the use of transdermal absorption enhancers, the high concentration of enhancer in the formulation can assist in drug passage through the skin, but when the enhancer and drug enter the skin, The concentration of the accelerator will be very diluted and will not help the drug molecules to pass through more biological membranes, and the drug molecules will accumulate in the subcutaneous fat layer, and the accumulated drug will be very serious and Side effects can even be fatal.

The biological activity of a drug measures the relative drug dosage that reaches the systemic circulation. However, the systemic circulation is not the "site of action" for most drugs. Even if drug molecules reach the systemic circulation, they must pass through more biological membranes, which are less permeable than the membranes of the digestive tract, and reach an elusive site called the "site of action." They interact with both intermolecular and intramolecular fluids before reaching the "site of action" and thus most drugs are metabolized by the intestinal mucosa, liver, kidneys and lungs before reaching the "site of action". This situation not only results in very low therapeutic efficacy, but also creates a toxic burden on the intestinal mucosa, liver, kidneys and lungs. If the rate of drug permeation through various membranes could be increased, the therapeutic efficacy and clinical response of the drug would be greatly improved, requiring smaller doses of the drug and reducing side effects. Transdermal prodrug delivery for prodrugs with very fast skin and membrane permeation rates would be very useful for local as well as systemic diseases. Since these prodrugs are tens to hundreds of times more effective than the parent drug, they require only a few tenths to a few hundred times the amount of normal drugs and have very few side effects. This would be useful not only for transdermal drug delivery, but also for any other drug delivery system (oral, subcutaneous, intravenous, inhalation, and nasal).

The inventors have identified lipophilic moieties and primary, secondary, and tertiary amine groups (preferably tertiary amine groups) present in protonated form (hydrophilic moieties) at physiological pH. It has been found that drugs having the following properties can penetrate the skin, blood-brain, and blood-placental barriers at very high rates (on the scale of mg/cm ² /hour). The design principles of these prodrugs are shown below.
1. The prodrug comprises a lipophilic moiety and a primary, secondary, or tertiary amine group (preferably a tertiary amine group) present in a protonated form (hydrophilic moiety) at physiological pH. and must have.
2. All NSAIA prodrugs contain one or two (preferably one) primary, secondary, or tertiary amine groups present in protonated form (hydrophilic moiety) at physiological pH. ).
3. The primary role of primary, secondary, and tertiary amine groups is to help drugs cross skin, membranes, blood-brain, blood-placenta, wounds, or other barriers. The primary, secondary, and tertiary amine groups can be any structure that is nontoxic and mediates biological activity of the parent drug.

The inventors disclosed some of all NSAIA prodrugs having "chemical structure 1" of general formula (1) as patents (International Application No. PCT/IB2006/052732, PCT/IB2006/052318) , No. PCT/IB2006/052815, No. PCT/IB2006/052563, No. PCT/IB2006/052575, No. PCT/IB2006/053741, No. PCT/IB2006/053091, No. 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。 In the formula, R represents a branched or straight chain -(CH ₂ ) _{n -} , where n=0, 1, ₂ , 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,..., and which CH ₂ is O, S, NR ₈ , CH=CH, C≡C, CHR ₈ , CR ₈ R ₉ , aryl or heteroaryl residue, or pharmacologically may be replaced with any other permissible moiety; R ₁ or R ₂ is H, an alkyl, alkyloxy, alkenyl, perfluoroalkyl, halogenated alkyl, or alkynyl residue having 1 to 12 carbon atoms; , represents any one of aryl or heteroaryl moieties, in which CH ₂ is O, S, CH=CH, C≡C, CHR ₈ , CR ₈ R ₉ , aryl or heteroaryl moiety, or pharmacologically May be replaced with any other permissible moiety; X represents O, NH, _NR8 , S, or absent; _R8 is H, OH, Cl, F, Br, I, 1 represents any one of alkyl, alkyloxy, alkenyl, perfluoroalkyl, halogenated alkyl or alkynyl residues, aryl or heteroaryl moieties having 12 carbon atoms; R ₉ is H, OH, Cl, F , Br, I represents any one of alkyl, alkyloxy, alkenyl, perfluoroalkyl, halogenated alkyl or alkynyl residues, aryl or heteroaryl moieties having from 1 to 12 carbon atoms; HA is absent , HCl, HBr, HF, HI, HOAc, citric acid, or any pharmacologically 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, may contain 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 , The R ₉ , or -(CH ₂ ) _n - group may be achiral or chiral; if the group is chiral, it may have one or more chiral centers and may be a single (R) or (S) enantiomer or It may be a mixture of (R) and (S) enantiomers; Ary- represents the following formula, 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 represents H, 1 represents any one of alkyl, alkyloxy, alkenyl, perfluoroalkyl, halogenated alkyl or alkynyl residues, aryl or heteroaryl moieties having 12 carbon atoms; X ₁ or X ₄ is 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, _Ry COO, HS, NO ₂ , CN, CH ₃ COS, NH ₂ , CH ₃ CONH, _Ry CONH _{, CH3 , CH3CH2, C3H7, C4H9 , CH3O , CH3CH2O , C3H7O ,} Cl _, F, Br, I _{, CH3S , CHF2} O, _CF3O , _{CF3CF2O , C3F7O ,} CF3 _{, CF3CF2 , C3F7 , C4F9 , CH3SO2 , RySO2 , CH3SO} , R _y SO, CH ₃ CO, CH ₃ CH ₂ CO; any Ary- is achiral or chiral; 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。 The inventors believe that the primary role of primary, secondary, and tertiary amine groups is only to help drugs cross skin, membranes, blood-brain, blood-placenta, wounds, or other barriers. Therefore, we have found that the primary, secondary, and tertiary amine groups can have any structure that is nontoxic and mediates the biological activity of the parent drug. Therefore, the inventors designed and prepared various types of amine groups for this property. Novel NSAIA prodrugs have "chemical structure 2a, 2b, 2c, or 2d" of general formula (2a, 2b, 2c, or 2d).

In the formula, R represents a branched or straight chain -(CH ₂ ) _{n -} , where n=0, 1, ₂ , 3, 4, 5, 6, 7, 8, 9, _{R _ _ _ 1} represents a branched or straight chain -(CH ₂ ) _a -, and in -(CH ₂ ) _a -, a=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 ₂ is branched or straight chain -(CH ₂ ) _b -, where b=0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10... in -(CH ₂ ) _b -; 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 ₃ is branched or linear -(CH ₂ ) _c - represents c=0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10... in -(CH ₂ ) _c -, and any CH ₂ may be replaced by O, S, CH═CH, C≡C, CHR ₆ , CR ₆ R ₇ , aryl or heteroaryl residues, or other ring systems; R ₄ is H, 1 to 12 carbons Represents any alkyl, alkyloxy, alkenyl, perfluoroalkyl, halogenated alkyl, or alkynyl residue, aryl or heteroaryl moiety having an atom, in which CH ₂ is O, S, CH=CH, C ≡C, CHR ₆ , CR ₆ R ₇ , aryl or heteroaryl moieties, or may be replaced by other ring moieties; R ₅ is H, alkyl having 1 to 12 carbon atoms, alkyloxy, alkenyl, Represents any one of perfluoroalkyl, halogenated alkyl, or alkynyl residue, aryl or heteroaryl moiety, in which 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 alkynyl represents any one of the residues, aryl or heteroaryl moieties, in which CH ₂ is O, S, CH═CH, C≡C, CHR ₆ , CR ₇ R ₅ , aryl or heteroaryl moiety, or other Optionally replaced with a ring moiety, R ₇ is H, an alkyl having 1 to 12 carbon atoms, an alkyloxy, an alkenyl, a perfluoroalkyl, a halogenated alkyl, or an alkynyl residue, any aryl or heteroaryl moiety. 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; represents O, NH, NR ₆ or S, which does not exist; ) and HA represents HCl, HBr, HF, HI, HOAc, citric acid, or any pharmacologically acceptable acid. 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, The 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 the group is chiral, one or more chiral centers It 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 across the septum, whether from the gastrointestinal tract or other sites. The drug must first dissolve and, if the drug has suitable biopharmaceutical properties, pass through the membrane from an area of high concentration to an area of low concentration into the blood or systemic circulation. become. All biological membranes contain lipids as their major constituents. The molecules that play a dominant role in membrane formation all have a large polar head group containing phosphate and in most cases two hydrophobic hydrocarbon tails. The membrane is bilayered, with hydrophilic head groups facing outward into the water-soluble regions on both sides. Highly hydrophilic drugs cannot pass through the hydrophobic layer of the membrane, and due to their similarity, highly hydrophilic drugs will remain within the hydrophobic membrane as part of the membrane, effectively internalizing the membrane. cannot enter the cytoplasm of

One object of the present invention is to improve the solubility of NSAIA in gastric fluids to allow for oral administration and the rate of penetration of NSAIA through membranes and skin barriers to allow for transdermal (topical) administration. The aim is to avoid the side effects of NSAIAs by increasing The most important goal of the present invention is to be able to penetrate the skin, cell membranes, especially those of brain cells and nerve cells, and remain in the systemic circulation for an extremely short time, thereby making it hundreds of times more effective than the parent drug. The aim is to design NSAIA prodrugs that require only a few tenths to a few hundredths of the normal drug dose and can significantly reduce the occurrence of side effects. It is effective not only for transdermal drug delivery, but also for other drug delivery systems (oral, subcutaneous, intravenous, inhalation, and nasal, etc.) to treat many conditions that cannot be treated by the parent drug. be able to. These new NSAIA prodrugs generally have two structural features. That is, it has a lipophilic part and a primary, secondary or tertiary amine group that is present in a protonated form (hydrophilic part) at physiological pH. Such a hydrophilic-lipophilic balance is necessary for efficient passage through membrane barriers (Susan Milosovich et al., J. Pharm. Sci., Vol. 82, p. 227, 1993). The positively charged amino group greatly increases the solubility of the drug in water. The positive charge of the amino group on these prodrugs will combine with the negative charge of the phosphate head group of the membrane. Therefore, the local concentration outside the membrane or skin will be very high, facilitating the passage of these prodrugs from areas of high concentration to areas of low concentration. This binding can slightly destabilize the membrane and make some room for the lipophilic moiety of the prodrug. When membrane molecules move, the membrane may become slightly "cracked" due to prodrug binding. This allows 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 head group of the membrane is dissociated and the prodrug completely enters the membrane. When the amino group of the prodrug moves to the other side of the membrane and becomes protonated, the prodrug is then drawn into the cell matrix, which is a semi-liquid concentrated aqueous solution or suspension. Due to the short residence time in the gastrointestinal tract, the prodrug does not cause damage to gastric mucosal cells. The permeation rate of the novel prodrugs through human skin was determined in vitro using a Franz modified permeation cell derived from human skin tissue (360-400 μm thick) from the ventral and dorsal thigh regions. The receiving fluid consisted of 2% bovine serum albumin in 10 mL of normal saline and was stirred at 600 revolutions per minute. The cumulative amount of prodrug and drug entering the skin over time was determined by selective high performance liquid chromatography. The apparent flux values of the NSAIA prodrugs ranged from 0.1 to 50 mg/cm ² /hr. 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 drugs through membrane and skin barriers.

Novel NSAIA prodrugs are capable of penetrating 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. Donors were constructed by applying 20% of the prodrug or its parent drug in 1 mL of ethanol to an area of approximately 5 cm ² on the back of a rat (approximately 200 g). After 4 hours, the rats were sacrificed and 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 was washed 3 times with pH 7.2 buffer) and the mixture was homogenized. Samples were then ultracentrifuged for 5 minutes and analyzed using HPLC. The results are shown in Tables 1 to 5.

20% aspirin, diclofenac, ketoprofen, fenoprofen, or ibuprofen in 1 mL of ethanol was applied to an approximately 5 cm ² area of the rat's back. After 4 hours, the rats were sacrificed, 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 was washed 3 times with pH 7.2 buffer) and the mixture was homogenized. These drugs were not found in the tissues or plasma of any rats. This result shows that NSAIA prodrugs can penetrate the skin barrier, blood-brain barrier, and other membrane barriers very rapidly, whereas the parent NSAIA cannot penetrate the skin barrier in detectable amounts. It is shown that.

The prodrug of "chemical structure 1" of general formula (1) is disclosed in the inventors' patents (International Application No. 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 exhibited inflammatory, analgesic, antipyretic, and antirheumatic activities. The inventors have demonstrated that all prodrugs of general formula (2a, 2b, 2c, or 2d) with "chemical structure 2a, 2b, 2c, or 2d" have anti-inflammatory, analgesic, antipyretic, and antirheumatic properties. It was found that this substance exhibits sexual activity. The main objective of the present invention is a new pharmaceutical use of NSAIA prodrugs.

The relationship between inflammation and cancer is well known. Thea D. In a lecture (Keystone Symposia: Inflammation and Cancer, Breckenridge, Colorado, USA, February 27-March 3, 2005), Dr. Tlsty explained that cyclooxygenase-2 (COX-2) is involved in aromatase activity, angiogenesis, proliferation, It is said 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 colon cancer, esophageal cancer, ovarian cancer or other cancers is reduced in people who take aspirin long-term. However, cancer cells may change their membrane structure to prevent NSAIA from entering the cancer cell. The novel prodrugs of the present invention can penetrate any membrane barrier and can be applied topically to skin areas outside the cancer site, allowing large amounts of the prodrug to enter cancer cells with extremely low systemic exposure. become.

To evaluate the antitumor activity of NSAIA prodrugs, human breast cancer cells (BCAP-37, 2-3 mm ³ tumor tissue was used for each mouse) were cultured in nude mice (BALB, 12 groups, 7 mice in each group). xenografted subcutaneously into 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 of prodrug) diethylaminoethyl acetylsalicylate acetylsalicylate (P-1, in acetone); 1-piperidinepropyl 2[(2,6-dichlorophenyl)amino]benzeneacetic acid Tart. AcOH (P-2, in water), 1-pyrrolidinepropyl 2-(3-benzoylphenyl)propionate. AcOH (P-3, in water), 4-piperidinemethyl 2-(3-phenoxyphenyl)propionate. AcOH (P-4, in water), 3-piperidinemethyl 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 applied topically to the area of human breast cancer cell implantation (near the paw) every 8 weeks. The tumor size on day 42 is shown in Tables 6 and 7.

In a second anti-tumor experiment, human colon cancer cells (LS174J, 2-3 mm ³ of tumor tissue were 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 approximately 30 μL of 5% (equivalent to 1.5 mg of 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-piperidinemethyl 2-(3-phenoxyphenyl)propionate. AcOH (P-4, in water), 3-piperidinemethyl 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-benzoylbenzene acetate. 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 applied topically to the implantation area (near the paw) of human colon cancer cells every 8 weeks. The 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 show that NSAIA prodrugs have very strong antitumor activity and have little or no side effects.

The hypoglycemic effects of salicylates were first observed by German physicians over 100 years ago (Edmund J. Hengesh, Principles of medicinal chemistry, 4th edition, page 591, Williams & Wilkins, 1995). Salicylates increase glucose-stimulated insulin secretion and inhibit sugar production from lactate and alanine (HF Woods et al., Clin. Exp. Pharmacol Physiol., Vol. 1, p. 534, 1974). Certain salicylates reduce plasma concentrations of free fatty acids, triglycerides, and cholesterol. Elevated plasma free fatty acid concentrations inhibit glucose utilization, and reduced concentrations can contribute to hypoglycemic effects. Unfortunately, large doses of salicylates (5 g daily) are required to maintain proper control of blood sugar and blood lipid levels. At this dosage level, a myriad of side effects frequently occur, including stomach discomfort, nausea, vomiting, and ringing in the ears. The novel prodrugs of the present invention have very fast skin and membrane penetration rates. This allows them to reach the "site of action" very quickly, and the pharmacological efficacy and clinical response of these prodrugs is greatly enhanced, so much lower drug doses are required (hundreds of times less than the parent drug). (requires only a few tenths of the total amount of sterilization required), which greatly reduces the occurrence of side effects.

The prodrug of the invention lowers blood glucose levels in a rat model (SLAC/GK, type 2 diabetes, n=7). Diethylaminoethyl acetylsalicylate 50% acetone solution of acetylsalicylate (P-1, in acetone); 4-acetamidophenylsalicylyl dimethylaminobutyrate. HCl (P-6), diethylaminoethyl 5-(2,4-difluorophenyl)acetylsalicylate. 5-(2,4-difluorophenyl)acetylsalicylate (P-8), diethylaminoethylsalicylsalicylate. AcOH (P-9), diethylaminoethyl salicylate. AcOH (P-10), diethylaminoethyl 5-acetamido-acetylsalicylate (P-58), diethylaminoethyl acetylsalicylate. Acetylsalicylsalicylate (P-59), diethylaminoethyl acetylsalicylsalicylate. Acetylsalicylsalicylate (P-60) (equivalent to 20 mg/kg NSAIA) was administered once daily (8:00 a.m.) for 5 weeks to the rat (shaved) dorsal area (approximately 1.5 cm ² ). It was administered transdermally. Blood sugar levels were measured once every 3 days at 3:00 pm (no fasting) from week 2 to week 5. The results are shown in Table 10. Blood lipid concentrations were measured at the end of the fifth 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 the NSAIA prodrug very effectively lowered blood glucose levels in the diabetic rat model and had no effect on blood glucose levels in normal rats. Most interestingly, after stopping the treatment for 30 days, the blood sugar levels of the rats remained at normal levels (7-8 mmol/L, without fasting). This means that the prodrug can not only lower blood sugar levels but also 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 the NSAIA prodrug very effectively lowered blood lipid concentrations (total cholesterol and triglycerides) in a diabetic rat model, without affecting HDL levels.

The pH of gastric fluid is between 1 and 3. The negative charge of the phosphate head group is neutralized by hydrogen ions, and the positive charge of the amino group of these prodrugs cannot bind to the phosphate head group of the membrane, so the prodrugs are unable to pass through the gastric wall. It doesn't hurt your stomach or make it worse. The pH of the duodenum is approximately 5-7, and prodrugs can pass through the duodenal mucosa. Because the pancreas is nearby and most of the prodrugs enter this before reaching the liver, kidneys, and systemic circulation, where the drug is metabolized, very small doses are needed for these prodrugs. Only a small amount is required and the incidence of side effects will be very few and low. Diethylaminoethyl acetylsalicylate. 20% acetone solution of acetylsalicylate (P-1, in acetone); 4-acetamidophenylsalicylyldimethylaminobutyrate. HCl (P-6), diethylaminoethyl 5-(2,4-difluorophenyl)acetylsalicylate. 5-(2,4-difluorophenyl)acetylsalicylate (P-8), diethylaminoethylsalicylate. AcOH (P-9), diethylaminoethyl salicylate. AcOH (P-10), diethylaminoethyl 5-acetamido-acetylsalicylate (P-58), diethylaminoethyl acetylsalicylate. Acetylsalicylsalicylate (P-59), diethylaminoethyl acetylsalicylsalicylate. Acetylsalicylsalicylsalicylate (P-60) (equivalent to 20 mg/kg NSAIA) was administered orally to rats (SLAC/GK, type 2 diabetes, n=7) daily with meals for 5 weeks. Blood sugar levels were measured once every 3 days at 3:00 pm from week 2 to week 5 (no fasting). The results are shown in Table 12. Blood lipid concentrations were measured at the end of the fifth 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 shows that when the prodrug is taken orally and the dose is much smaller than the parent drug, NSAIA prodrugs are highly effective at lowering blood glucose levels in a diabetic rat model and lowering blood glucose levels in normal rats. It was shown that there was no effect on

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 were highly effective in lowering blood lipid levels in a diabetic rat model when the prodrugs were taken orally and the dose was much lower than the parent drug. .

The prodrugs of the invention lower blood glucose levels in a rat model (SLAC:NOD-IDDM, type 1 diabetes, n=7). Diethylaminoethyl acetylsalicylate. 50% acetone solution of acetylsalicylate (P-1, in acetone); 4-acetamidophenylsalicylyldimethylaminobutyrate. HCl (P-6), diethylaminoethyl 5-(2,4-difluorophenyl)acetylsalicylate. 5-(2,4-difluorophenyl)acetylsalicylate (P-8), diethylaminoethylsalicylsalicylate. AcOH (P-9), diethylaminoethyl salicylate. AcOH (P-10), diethylaminoethyl 5-acetamido-acetylsalicylate (P-58), diethylaminoethyl acetylsalicylate. Acetylsalicylsalicylate (P-59), diethylaminoethyl acetylsalicylsalicylate. Acetylsalicylsalicylsalicylate (P-60) (equivalent to 30 mg/kg NSAIA) was administered once daily (8 a.m.) for 7 weeks to the rat (shaved) dorsal region (approximately 1.5 cm ² ). It was administered transdermally. Blood sugar levels were measured once every 3 days at 3:00 pm (no fasting) from week 4 to week 7. 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 lowered 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, thrombi were created by aspirating venous blood (1 mL) into a sterile bottle and allowing it to clot. To avoid breakage and slow dissolution, autograft blood clots were stabilized in temperature-controlled (70° C.) distilled water for 10 minutes. After anesthesia, the circumflex femoral vein was exposed and isolated distally, and an autograft thrombus (0.05 g/kg) was injected through an indwelling catheter (20 GA) placed in the earlier isolated circumflex femoral vein. Diethylaminoethyl acetylsalicylate. Acetyl salicylate (P-1, in acetone, 20 mg/kg) and diethylaminoethyl acetylsalicylate. A 50% acetone solution of acetylsalicylsalicylate (P-59, 20 mg/kg) was applied topically to the rabbit's back. Two days later, the rabbits were euthanized by an intravenous overdose of sodium amobarbital (60 mg/kg). The lungs and heart were isolated and observed whether a blood clot was present in the pulmonary artery. 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 thrombus and mixed thrombus surrounded the injected clot and were present both proximally and distally in the large sized vessels and dilated vessel walls. These vessels had excessive proliferation of endothelial cells and fiber cells. In addition, there was acute pulmonary congestion. In the P-1 and P-59 groups, both lung tissues and blood vessel walls were normal. The results showed that thrombotic effects and thrombotic progression associated with embolization can be prevented by these NSAIA prodrugs. These prodrugs can be very useful in the prevention and treatment of blood clotting, which is a major cause of stroke, heart attack and organ transplant rejection.

The prodrugs of the invention can help heal wounds and soften and reduce cut and burn scars in rabbit models. The average wound area in rabbits treated with this prodrug was only one-third that of control rabbits from the same incision in the Chinese white rabbit model, and the wound resembled normal intact tissue. flexibility.

COX-1 and COX-2 play a very important role in animal immune responses. NSAIA inhibits COX-1 and COX-2. NSAIA prodrugs of the invention may be very useful for the treatment of psoriasis, discoid lupus erythematosus, systemic lupus erythematosus (SLE), and other autoimmune diseases. Highly concentrated Malassezia suspension (Rosenberg, E.W. et al., Mycopathology, Vol. 72, pp. 147-154, 1980) was applied to the shaved skin of the back of Chinese white rabbits (n = 4 x 6) for 2 weeks. , applied twice a day (7 a.m. and 7 p.m.) to develop 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)benzene acetate. 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-thiazole acetate.AcOH (P-21), 5% of diethylaminoethyl 3-(4-chlorophenyl)-1-phenyl-1H-pyrazole-4-acetate.AcOH (P-22) The aqueous solution was applied to the same area 3 hours (10 am and 10 pm) after the application of concentrated Malassezia suspension (7 am and 7 pm). 10 days after these prodrug applications. , the lesions were isolated.

For evaluation of anti-lupus erythematosus activity, 5% diethylaminoethyl acetylsalicylate acetylsalicylate (P-1, 30 mg/kg in acetone) or 3-piperidinemethyl 2-(ρ-isobutylphenyl) propionate. AcOH (P-5, 30 mg/kg in water) was applied topically to the dorsal skin of mice with discoid lupus erythematosus, systemic lupus erythematosus (MRL/LPR, n=5×3) twice a day. After 6 weeks, all skin lesions and lupus nephritis had resolved in prodrug-treated mice, whereas symptoms in control mice had worsened.

These results demonstrate 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. It suggests that.

The onset of cell death in amyotrophic lateral sclerosis (ALS) may include glutamate-mediated excitotoxicity, oxidative damage, and apoptosis. Cyclooxygenase-2 is present in spinal 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 celecoxib, a selective cyclooxygenase-2 inhibitor, significantly inhibited prostaglandin E2 production in the spinal cord of ALS mice. Celecoxib treatment significantly delayed the onset of weakness and weight loss and prolonged survival by 25%. The spinal cords of treated ALS mice showed significant preservation of spinal neurons and decreased astrocyte proliferation and microglial activation (Merit. E. Cudkowicz et al., Annals of neurology, Vol. 52). Vol., pp. 771-778, 2002). These results suggest that inhibition of cyclooxygenase-2 may be beneficial for ALS patients. The NSAIA prodrugs of the present invention can penetrate the skin and nerve cell membrane barriers at a very rapid rate (most NSAIAs cannot effectively penetrate nerve cells) and can be administered transdermally without damaging the gastrointestinal tract. Therefore, these prodrugs are effective in treating multiple sclerosis (MS), Crohn's disease, and other autoimmune diseases, amyotrophic lateral sclerosis (ALS), oculopharyngeal muscular dystrophy (OPMD), myotonic dystrophy ( MD), Duchenne muscular dystrophy (DMD), polymyositis (PM), dermatomyositis (DM), inclusion body myositis (IBM), and other muscle diseases.

Inflammatory mechanisms have been proposed as important mediators in the pathogenesis cascade of Alzheimer's disease (McGeer PL, McGeer EG, “The inflammatory response system of brain implications for the therapy of Alzheimer's disease. Heimer and other neurodegenerative diseases.”, Brain Res. Rev. ., 1995; Vol. 21: pp. 195-218). In a study by in't Veld et al. (the New England Journal of Medicine, 2001; Vol. 345, p. 1515), they followed approximately 7,000 people at risk for Alzheimer's disease for nearly seven years. Their results suggested that NSAIAs can reduce the relative risk for those with at least 2 years of cumulative use of NSAIAs or more than 2 years before the onset of dementia. Once the neuroprotective ability of NSAIAs ceased in the year immediately before the onset of dementia, these compounds no longer conferred protection against progression in most people with prodromal symptoms of the disease. The inventors believe that the reason for this is that the tissue around the damaged nerve cells forms a scar to protect the nerve cells from further damage. Most NSAIAs have very slow permeation rates through the brain blood and nerve cell barriers and are unable to penetrate the scar barrier. These prodrugs of the invention have very fast skin, blood brain, nerve cell membrane, and scar barrier penetration rates, making them useful 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 has been arrested by a protective scar around the injured spinal cord. While most NSAIAs are unable to penetrate the scar barrier in therapeutically effective amounts, the prodrugs of the present invention can penetrate the scar barrier, have anti-inflammatory activity, and aid in wound healing. I can do it.

NSAIAs are not very effective for the treatment of the above-mentioned symptoms, have serious side effects because they cannot penetrate cell membranes very effectively, especially brain cells and nerve cells, and they stay in the systemic circulation too long. Most of the drug will be metabolized by the intestinal mucosa, liver, kidneys, and lungs before reaching the "site of action." This situation not only produces very low pharmacological efficacy, but also creates a toxic burden on the intestinal mucosa, liver, kidneys, lungs, and other body parts. These prodrugs penetrate the skin, brain blood, brain cells, nerve cells and other membrane barriers very well, have hundreds of times the potency of the parent drug, and require only a few dozen of the normal drug dose. It requires one-fold or several-hundredth of the amount required, and the occurrence of side effects is extremely low. This makes it beneficial not only for transdermal drug delivery, but also for any drug delivery system (oral, subcutaneous, intravenous, inhalation, and nasal, etc.) that is better than that treatable by the respective parent drugs. can treat many conditions and even some conditions that cannot be treated with their respective parent drugs.

The compound of "chemical structure 1, 2a, 2b, 2c, or 2d" of the above general formula 1, 2a, 2b, 2c, or 2d is N,N'-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide, or others. can be prepared from NSAIA by reaction with a coupling reagent to form the anhydride, followed by reaction with the appropriate alcohol, thiol, or amine.

The compound of "chemical structure 1, 2a, 2b, 2c, or 2d" of the above general formula 1, 2a, 2b, 2c, or 2d can be prepared by using a suitable halide, such as a metal salt, an organic basic salt of NSAIA. or from immobilized basic salts.

Contains a compound of general "chemical structure 1, 2a, 2b, 2c, or 2d" or at least one compound of general "chemical structure 1, 2a, 2b, 2c, or 2d" as an active ingredient The transdermal therapeutic application system of the composition can be used to treat any condition treatable by NSAIAs in humans or animals, and the novel conditions described in this invention. These systems can be bandages or patches comprising a matrix layer containing one active ingredient and an impermeable backing layer. The most preferred system is an active ingredient container with a permeable bottom facing the skin. By controlling the release rate, the system allows the NSAIA to consistently reach optimal therapeutic blood concentrations, increasing efficacy and reducing the side effects of the NSAIA. These systems can be worn on the wrist, ankle, arm, leg, or any part of the body.

NSAIAs are not very effective for the treatment of the above-mentioned symptoms, have serious side effects because they cannot penetrate cell membranes very effectively, especially brain cells and nerve cells, and they stay in the systemic circulation too long. Most of the drug will be metabolized by the intestinal mucosa, liver, kidneys, and lungs before reaching the "site of action." This situation not only produces very low pharmacological efficacy, but also creates a toxic burden on the intestinal mucosa, liver, kidneys, lungs, and any other body parts. These prodrugs penetrate the skin, brain blood, brain cells, nerve cells and other membrane barriers very well, have hundreds of times the potency of the parent drug, and require only a few dozen of the normal drug dose. It requires one-fold or several-hundredth of the amount required, and the occurrence of side effects is extremely low. This would be beneficial not only for transdermal drug delivery, but also for any drug delivery system (oral, subcutaneous, intravenous, inhalation, and nasal, etc.) to treat many conditions that cannot be treated with the parent drug. These prodrugs can be administered not only transdermally, but also orally (because they cannot penetrate the stomach wall and therefore do not injure the stomach) for any type of pharmaceutical treatment, and can be administered to prevent digestion, which is the majority of the side effects of NSAIAs. Very significant gastrointestinal disorders such as gastrointestinal bleeding, gastroduodenal bleeding, gastric ulcers, and gastritis should be avoided. Another great benefit of transdermal administration of these prodrugs is the great ease of drug administration, 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 general formula (1, 2a, _2b , _2c , or 2d), R ₆ , R ₇ , R ₈ , R ₉ , X, HA, and Ary- are R, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R in claims 1 and 2; ₇ , R ₈ , R ₉ , X, HA, and Ary-.

(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 (3x300ml). 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: _{C24H29NO8 ,} molecular weight _: 459.18. Calculated %C: 62.73, H: 6.36, N: 3.05, O: 27.86, Actual %C: 62.70, H: 6.40, Cl: N: 3.01, O: 27.90.

(Form 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]benzene acetate were suspended in 180 ml of chloroform. 28.6 g (0.1 mol) of 1-piperidinepropyl 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 (3x50ml). 6g of acetic acid was added to the solution. The solution was concentrated in vacuo to 100ml. Then 300ml of hexane was added to the solution. The solid product was collected by filtration and washed with hexane (3x100ml). After drying, 40 g of the desired product were obtained (86%). Elemental analysis: _{C24H30Cl2N2O4} , molecular weight: _481.43 , calculated _% C: 59.88, H: 6.28, Cl: 14.73, _N : 5.82, _O : 13. 29, actual %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) of 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 (3x50ml). 300 ml of 5% Na ₂ CO ₃ was added to the solution while stirring. The mixture was stirred for 30 minutes. The chloroform solution was washed with water (3x100ml) and dried _{over Na2SO4} . The copper sulfate was filtered off and washed with chloroform (3x100ml). 6g of acetic acid was added to the mixture. The solution was concentrated in vacuo to 100ml. 300ml of hexane was added to the solution. The solid product was collected by filtration and washed with hexane (3x100ml). After drying, 35 g of the desired product were obtained (96%). Elemental analysis: _C21H33NO4 , 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 medicinally to treat any condition in humans or animals that can be treated with NSAIAs. These include diabetes (type I and type II), abnormal levels of blood sugar and blood lipids, heart and vascular diseases such as stroke, heart attack, Alzheimer's disease, Parkinson's disease and other neurodegenerative diseases, psoriasis, and discoid lupus erythematosus. , systemic lupus erythematosus (SLE), autoimmune hepatitis, scleroderma, Sjögren's syndrome, rheumatoid arthritis, polymyositis, scleroderma, Hashimoto's 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), oculopharyngeal 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 proctitis, chronic ulcerative colitis, cryptitis, other anorectal inflammatory conditions and anal pruritus, prostatitis, prostatic cystitis, autoimmune hepatitis, autoimmune nephritis, phlebitis and other inflammations, spinal cord injuries, wounds, Breast cancer, colorectal cancer, oral cancer, lung and other respiratory cancers, skin cancer, uterine cancer, reproductive tract cancer, urinary tract cancer, leukemia and other cancers of the blood and lymphoid tissues and other cancers, and many others. It can also be used to treat and prevent the symptoms of. These prodrugs can be administered transdermally without the aid of transdermal absorption enhancers.

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。 Examples of embodiments of the present invention include the following.
1. A compound of "chemical structure 2a, 2b, 2c, or 2d" of general formula (2a, 2b, 2c, or 2d),

In the formula, R represents a branched or straight chain -(CH ₂ ) _{n -} , where n=0, 1, ₂ , 3, 4, 5, 6, 7, 8, 9, _{R _ _ _ 1} represents a branched or straight chain -(CH ₂ ) _a -, and in -(CH ₂ ) _a -, a=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 ₂ is branched or straight chain -(CH ₂ ) _b -, where b=0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10... in -(CH ₂ ) _b -; 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 ₃ is branched or linear -(CH ₂ ) _c - represents c=0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10... in -(CH ₂ ) _c -, and any CH ₂ may be replaced by O, S, CH═CH, C≡C, CHR ₆ , CR ₆ R ₇ , aryl or heteroaryl residues, or other ring systems; R ₄ is H, 1 to 12 carbons Represents any alkyl, alkyloxy, alkenyl, perfluoroalkyl, halogenated alkyl, or alkynyl residue, aryl or heteroaryl moiety having an atom, in which CH ₂ is O, S, CH=CH, C ≡C, CHR ₆ , CR ₆ R ₇ , aryl or heteroaryl moieties, or may be replaced by other ring moieties; R ₅ is H, alkyl having 1 to 12 carbon atoms, alkyloxy, alkenyl, Represents any one of perfluoroalkyl, halogenated alkyl, or alkynyl residue, aryl or heteroaryl moiety, in which 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 alkynyl represents any one of the residues, aryl or heteroaryl moieties, in which CH ₂ is O, S, CH═CH, C≡C, CHR ₆ , CR ₇ R ₅ , aryl or heteroaryl moiety, or other Optionally replaced with a ring moiety, R ₇ is H, an alkyl having 1 to 12 carbon atoms, an alkyloxy, an alkenyl, a perfluoroalkyl, a halogenated alkyl, or an alkynyl residue, any aryl or heteroaryl moiety. _{X _ _ _} represents not present, O, NH, NR ₆ or S; HA represents not present, 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, C, H, O, Cl, Br, F, I, P, may contain 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 , The R ₉ , or -(CH ₂ ) _n - group may be achiral or chiral; if the group is chiral, it may have one or more chiral centers and may be a single (R) or (S) enantiomer or It may be a mixture of (R) and (S) enantiomers, and Ary- represents the following formula, but is not limited to:

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 represents H, 1 represents any one of alkyl, alkyloxy, alkenyl, perfluoroalkyl, halogenated alkyl or alkynyl residues, aryl or heteroaryl moieties having 12 carbon atoms; X ₁ or X ₄ is 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, _Ry COO, HS, NO ₂ , CN, CH ₃ COS, NH ₂ , CH ₃ CONH, _Ry CONH _{, CH3 , CH3CH2, C3H7, C4H9 , CH3O , CH3CH2O , C3H7O ,} Cl _, F, Br, I _{, CH3S , CHF2} O, _CF3O , _{CF3CF2O , C3F7O ,} CF3 _{, CF3CF2 , C3F7 , C4F9 , CH3SO2 , RySO2 , CH3SO} , R _y SO, CH ₃ CO, CH ₃ CH ₂ CO; any Ary- is achiral or chiral; if Ary- is chiral, it may have one or more chiral centers; Compounds that may be (R) or (S) enantiomers or mixtures of (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 of "chemical structure 1" of general formula (1),

In the formula, R represents a branched or straight chain -(CH ₂ ) _{n -} , where n=0, 1, ₂ , 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,..., and which CH ₂ is O, S, NR ₈ , CH=CH, C≡C, CHR ₈ , CR ₈ R ₉ , aryl or heteroaryl residue, or pharmacologically may be replaced with any other permissible moiety; R ₁ is H, alkyl having 1 to 12 carbon atoms, alkyloxy, alkenyl, perfluoroalkyl, halogenated alkyl, or alkynyl residue, aryl or represents any one of the heteroaryl moieties, in which CH ₂ is O, S, CH═CH, C≡C, CHR ₈ , CR ₈ R ₉ , aryl or heteroaryl moiety, or any pharmacologically acceptable _R2 may be replaced by other moieties of H, alkyl, alkyloxy, alkenyl, perfluoroalkyl, halogenated alkyl or alkynyl residues having 1 to 12 carbon atoms, aryl or heteroaryl moieties; represents any one, and any CH ₂ is replaced with O, S, CH=CH, C≡C, CHR ₈ , CR ₈ R ₉ , aryl or heteroaryl moiety, or other pharmacologically acceptable moiety X represents O, NH, NR ₈ , S, or absent; R ₈ is H, OH, Cl, F, Br, I, alkyl having 1 to 12 carbon atoms; Represents any one of alkyloxy, alkenyl, perfluoroalkyl, halogenated alkyl or alkynyl residue, aryl or heteroaryl moiety; R ₉ is H, OH, Cl, F, Br, I, 1 to 12 Represents any one of alkyl, alkyloxy, alkenyl, perfluoroalkyl, halogenated alkyl or alkynyl residue, aryl or heteroaryl moiety having a carbon atom; Ary in "Chemical Structure 1" of the general formula (1) - is defined as Ary-, which is the same as "chemical structure 2a, 2b, 2c, or 2d" of the general formula (2a, 2b, 2c, or 2d) according to claim 1; HA is not present, Represents HCl, HBr, HF, HI, HOAc, citric acid, or any pharmacologically 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 contain C, H, O, Cl, Br, F, I, P, S, N or any other pharmacologically acceptable atom, and may include single bonds, divalent may contain double and/or triple bonds; all R, R ₁ , R ₂ , R ₈ , R ₉ , or -(CH ₂ ) _n - groups may be achiral or chiral; Compounds which may have one or more chiral centers, if any, and may be a single (R) or (S) enantiomer or a mixture of (R) and (S) enantiomers.

3. The compound of "chemical structure 1, 2a, 2b, 2c, or 2d" of the general formula 1, 2a, 2b, 2c, or 2d described in 1 and 2 above is combined with N,N'-dicyclohexylcarbodiimide, N, As described in 1 and 2 above, which can be prepared from NSAIA by reaction with N'-diisopropylcarbodiimide or other coupling reagent to form an anhydride, 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 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 and 2 above is added to NSAIA using an appropriate halide. The chemical structure of the general formula (1, 2a, 2b, 2c, or 2d) described in 1 and 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 as described in 1 and 2 above, which can be administered transdermally, orally, subcutaneously, intravenously, or nasally to treat any NSAIA-treatable condition in humans or animals. , or the compound having the general formula (1, 2a, 2b, 2c, or 2d) having the chemical structure 1, 2a, 2b, 2c, or 2d, or the compound having the general formula (1, 2a, 2b, 2c, or 2d) 2d, wherein the conditions treatable by the NSAIA include toothache, headache, pain derived from arthritis and other inflammatory pains, fever, cancer, dysmenorrhea, acute including, but not limited to, migraine, acute gouty arthritis, ankylosing spondylitis, rheumatoid arthritis, osteoarthritis, dysmenorrhea, and dementia.
6. A compound of "chemical structure 1, 2a, 2b, 2c, or 2d" of the general formula (1, 2a, 2b, 2c, or 2d) as described in 1 and 2 above, or the general formula (1, 2a, 2b, 2c, or 2d) to deliver a therapeutically effective plasma concentration of a composition comprising at least one compound of "chemical structure 1, 2a, 2b, 2c, or 2d"; A method of treating any NSAIA-treatable condition in humans or animals 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 "Chemical structure 1, 2a, 2b, 2c, or 2d" of the general formula (1, 2a, 2b, 2c, or 2d) as described in 1 and 2 above, or the general formula Locally 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 inflamed area. A method of locally treating headaches, toothaches, muscle pains, and arthritis and other inflammatory pains in humans or animals by.
8. any part of the body to deliver therapeutically effective plasma concentrations for the treatment and prevention of diabetes (types I and II), dysglycemia, abnormal blood lipid concentrations, and other metabolic diseases in humans or animals. The above general formulas (1, 2a, 2b, 2c) as active ingredients according to 1 and 2 above, which can be administered transdermally (in the form of a solution, spray, lotion, ointment, emulsion or gel) to , or 2d) "Chemical structure 1, 2a, 2b, 2c, or 2d" or a compound of the general formula (1, 2a, 2b, 2c, or 2d) "Chemical structure 1, 2a, 2b, 2c, or 2d.
9. Orally, subcutaneously, intravenously, or intranasally for the treatment and prevention of diabetes (types I and II), abnormal blood sugar levels, abnormal blood lipid concentrations, and other metabolic diseases in humans or animals. 1 and 2 above, which can be administered separately (in the form of a solution, spray, emulsion, pill, tablet, or any other formulation), as an active ingredient of the general formula (1, 2a) , 2b, 2c, or 2d) of “Chemical Structure 1, 2a, 2b, 2c, or 2d”, or “Chemical Structure 1, 2a, 2b, 2c, or 2d.
10. For the treatment and prevention of abnormal blood pressure and abnormal blood lipid concentrations in humans or animals, it can be applied to any part of the body (in solutions, sprays, lotions, ointments, emulsions or gels) to deliver therapeutically effective plasma concentrations. "Chemical structure 1, 2a, 2b, 2c" of the general formula (1, 2a, 2b, 2c, or 2d) as an active ingredient as described in 1 and 2 above, which can be administered transdermally (in the form of , or 2d", or a composition comprising at least one compound of "chemical structure 1, 2a, 2b, 2c, or 2d" of the general formula (1, 2a, 2b, 2c, or 2d).

11. Orally, subcutaneously, intravenously, or nasally (as a solution, spray, emulsion, pill, tablet, or any "Chemical structure 1, 2a, 2a, 2b, 2c, or 2d" or a composition containing at least one compound of "chemical structure 1, 2a, 2b, 2c, or 2d" of the general formula (1, 2a, 2b, 2c, or 2d). . 12. (solutions, sprays, lotions, ointments) to any part of the body to deliver therapeutically effective plasma concentrations for the treatment and prevention of stroke, heart attack, and other heart and vascular diseases in humans or animals. "Chemical structure 1, 2a, 2a, 2b, 2c, or 2d" or a composition containing at least one compound of "chemical structure 1, 2a, 2b, 2c, or 2d" of the general formula (1, 2a, 2b, 2c, or 2d). .
13. A therapeutically effective amount is administered topically (in the form of a solution, spray, lotion, ointment, emulsion or gel) to the infected area (such as the neck, head, chest, legs, or/and any other part of the body). The above general formula (1, 2a, 2b) as an active ingredient according to 1 and 2 above for the treatment and prevention of stroke, heart attack and other heart and vascular diseases in humans or animals. , 2c, or 2d) of "chemical structure 1, 2a, 2b, 2c, or 2d", or "chemical structure 1, 2a, 2b, 2c or 2d".
14. Orally, subcutaneously, intravenously, or intranasally (solutions, sprays, emulsions, pills) for the treatment and prevention of stroke, heart attack, and other heart and vascular diseases in humans or animals. of the general formula (1, 2a, 2b, 2c, or 2d) as an active ingredient, as defined in 1 and 2 above, which can be administered in the form of a compound of "Structure 1, 2a, 2b, 2c, or 2d", or at least one of "Chemical Structures 1, 2a, 2b, 2c, or 2d" of the general formula (1, 2a, 2b, 2c, or 2d); A composition comprising a compound.

15. Orally (in the form of a solution, spray, lotion, ointment, emulsion or gel) to any part of the body to deliver therapeutically effective plasma concentrations for the treatment and prevention of organ transplant rejection in humans or animals. Compounds of "chemical structures 1, 2a, 2b, 2c, and 2d" of the general formulas (1, 2a, 2b, 2c, and 2d) as active ingredients, as described in 1 and 2 above, which can be administered through the skin. , 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).
16. 1 above for the treatment and prevention of 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, as an active ingredient, the compound of "chemical structures 1, 2a, 2b, 2c, and 2d" of the general formula (1, 2a, 2b, 2c, and 2d), or the compound of the general formula (1 , 2a, 2b, 2c, and 2d).
17. Orally, subcutaneously, intravenously, or intranasally (as a solution, spray, emulsion, pill, tablet, or any other formulation) for the treatment and prevention of organ transplant rejection in humans or animals. "Chemical structures 1, 2a, 2b, 2c, and 2d" or at least one compound of "chemical structures 1, 2a, 2b, 2c, and 2d" of the general formulas (1, 2a, 2b, 2c, and 2d).
18. For the treatment and prevention of Alzheimer's disease, Parkinson's disease and other neurodegenerative diseases, solutions, sprays, lotions, "Chemical structure 1" of the general formula (1, 2a, 2b, 2c, or 2d) as an active ingredient as described in 1 and 2 above, which can be administered transdermally (in the form of an 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. Orally, subcutaneously, intravenously, or nasally (as a solution, spray, emulsion, pill, tablet, or any "Chemical structure 1, 2a, 2b" of the general formula (1, 2a, 2b, 2c, or 2d) as an active ingredient as described in 1 and 2 above, which can be administered (in other formulation formats). .
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 diseases. 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 as described in 1 and 2 above, which can be , or a composition comprising at least one compound of "chemical structure 1, 2a, 2b, 2c, or 2d" of the general formula (1, 2a, 2b, 2c, or 2d).
21. 1 above for treating psoriasis and other skin diseases 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, as an active ingredient, the compound of "chemical structures 1, 2a, 2b, 2c, and 2d" of the general formula (1, 2a, 2b, 2c, and 2d), or the compound of the general formula (1 , 2a, 2b, 2c, and 2d).
22. Orally, subcutaneously, intravenously, or intranasally (in the form of a solution, spray, emulsion, pill, tablet, or any other formulation) for the treatment and prevention of psoriasis and other skin diseases. "Chemical structure 1, 2a, 2b, 2c, or 2d of the general formula (1, 2a, 2b, 2c, or 2d) as an active ingredient as described in 1 and 2 above, which can be administered in or at least one compound having the chemical structure 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, Sjögren's syndrome, rheumatoid arthritis, polymyositis, scleroderma, Hashimoto's thyroiditis, juvenile diabetes, Addison's disease, to deliver therapeutically effective plasma concentrations to the body for the treatment and prevention of vitiligo, pernicious anemia, glomerulonephritis, pulmonary fibrosis, multiple sclerosis (MS), Crohn's disease, and other autoimmune diseases. 1 and 2 above, which can be administered transdermally (in the form of a solution, spray, lotion, ointment, emulsion or gel) in any part of the general formula (1, 2a, 2a, 2b, 2c, or 2d) of “Chemical Structure 1, 2a, 2b, 2c, or 2d” or “Chemical Structure 1, 2a, 2b” of the general formula (1, 2a, 2b, 2c, or 2d) , 2c, or 2d.
24. Discoid lupus erythematosus, systemic lupus erythematosus (SLE), autoimmunity 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. Diseases Hepatitis, scleroderma, Sjögren's syndrome, rheumatoid arthritis, polymyositis, scleroderma, Hashimoto's thyroiditis, juvenile diabetes, Addison's disease, vitiligo, pernicious anemia, glomerulonephritis, pulmonary fibrosis, multiple sclerosis ( of the general formulas (1, 2a, 2b, 2c, and 2d) as an active ingredient as described in 1 and 2 above for treating and preventing MS), Crohn's disease, and other autoimmune diseases. A compound of "chemical structures 1, 2a, 2b, 2c, and 2d" or at least one of "chemical structures 1, 2a, 2b, 2c, and 2d" of the general formula (1, 2a, 2b, 2c, and 2d) A composition containing two compounds.
25. Discoid lupus erythematosus in humans or animals, systemic lupus erythematosus (SLE), autoimmune disease hepatitis, scleroderma, Sjögren's syndrome, rheumatoid arthritis, polymyositis, scleroderma, Hashimoto's thyroiditis, juvenile diabetes, Addison's disease, Orally, subcutaneously, intravenously, or for the treatment and prevention of vitiligo, pernicious anemia, glomerulonephritis, pulmonary fibrosis, multiple sclerosis (MS), Crohn's disease, and other autoimmune diseases. The above general formula (1 , 2a, 2b, 2c, or 2d) of "chemical structure 1, 2a, 2b, 2c, or 2d", or "chemical structure 1," of the general formula (1, 2a, 2b, 2c, or 2d) 2a, 2b, 2c, or 2d.
26. Amyotrophic lateral sclerosis (ALS), oculopharyngeal muscular dystrophy (OPMD), myotonic dystrophy (MD), Duchenne muscular dystrophy (DMD), polymyositis (PM), dermatomyositis (DM) in humans or animals to any part of the body (solution, spray, lotion, ointment, emulsion or gel) to deliver therapeutically effective plasma concentrations for the treatment and prevention of , inclusion body myositis (IBM), and other muscle diseases. "Chemical structure 1, 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).

27. amyotrophic lateral sclerosis (ALS), oculopharyngeal type, 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. Treat and prevent muscular dystrophy (OPMD), myotonic dystrophy (MD), Duchenne muscular dystrophy (DMD), polymyositis (PM), dermatomyositis (DM), inclusion body myositis (IBM), and other muscle diseases. A compound of "chemical structures 1, 2a, 2b, 2c, and 2d" of the general formula (1, 2a, 2b, 2c, and 2d) as an active ingredient, as described in 1 and 2 above, for A composition containing at least one compound having the chemical structures 1, 2a, 2b, 2c, and 2d of the general formula (1, 2a, 2b, 2c, and 2d).
28. Amyotrophic lateral sclerosis (ALS), oculopharyngeal muscular dystrophy (OPMD), myotonic dystrophy (MD), Duchenne muscular dystrophy (DMD), polymyositis (PM), dermatomyositis (DM) in humans or animals Orally, subcutaneously, intravenously, or intranasally (as a solution, spray, emulsion, pill, tablet, or "Chemical structure 1, 2a of the general formula (1, 2a, 2b, 2c, or 2d) as an active ingredient as described in 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 "chemical structure 1, 2a, 2b, 2c, or 2d" of the general formula (1, 2a, 2b, 2c, or 2d) thing.
29. Inflammation of the prostate gland (prostatitis), prostatic cystitis, hemorrhoids, inflammatory hemorrhoids, proctitis after irradiation (prosthesis), chronic ulcerative colitis, cryptitis, other anorectal inflammatory conditions, and anal pruritus. The above-mentioned drugs can be administered transdermally (in the form of a solution, spray, lotion, ointment, emulsion or gel) to any part of the body to deliver therapeutically effective plasma concentrations for the treatment and prevention of 1 and 2, as an 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 compound of the general formula (1, 2a, 2b, 2c, or 2d), or 1, 2a, 2b, 2c, or 2d).
30. Inflammation of the prostate gland (prostatitis), prostatic cystitis, hemorrhoids, inflammatory hemorrhoids by administering therapeutically effective amounts topically (in the form of solutions, sprays, lotions, ointments, emulsions or gels) to the infected area. , post-irradiation (artificial formation) proctitis, chronic ulcerative colitis, cryptitis, other anorectal inflammatory conditions, and anal pruritus, as described in 1 and 2 above. A compound of "chemical structure 1, 2a, 2b, 2c, and 2d" of the general formula (1, 2a, 2b, 2c, and 2d), or a compound of the general formula (1, 2a, 2b, 2c, and 2d) as 2d) A composition comprising at least one compound having "chemical structures 1, 2a, 2b, 2c, and 2d".

31. Inflammation of the prostate gland (prostatitis), prostatic cystitis, hemorrhoids, inflammatory hemorrhoids, post-irradiation proctitis, chronic ulcerative colitis, cryptitis, other anorectal inflammatory conditions, and anal pruritus. For the treatment and prevention of The 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 A composition containing at least one compound of "chemical structure 1, 2a, 2b, 2c, or 2d" of general formula (1, 2a, 2b, 2c, or 2d).
32. to deliver therapeutically effective plasma concentrations to the body for the treatment and prevention of autoimmune hepatitis, autoimmune nephritis, colorectitis, enteritis, phlebitis, vasculitis, and other inflammations in humans or animals. 1 and 2 above, which can be administered transdermally (in the form of a solution, spray, lotion, ointment, emulsion or gel) in any part of the general formula (1, 2a, 2a, 2b, 2c, or 2d) 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.
33. autoimmune hepatitis, autoimmune nephritis, colorectitis, in humans or animals by administering therapeutically effective amounts topically (in the form of solutions, sprays, lotions, ointments, emulsions or gels) to the infected area; of the general formula (1, 2a, 2b, 2c, or 2d) as an active ingredient as described in 1 and 2 above for treating and preventing enteritis, phlebitis, vasculitis, and other inflammations. A compound of "Chemical structure 1, 2a, 2b, 2c, or 2d" or at least one of "Chemical structure 1, 2a, 2b, 2c, or 2d" of the general formula (1, 2a, 2b, 2c, or 2d) A composition containing two compounds.
34. Orally, subcutaneously, intravenously, or for the treatment and prevention of autoimmune hepatitis, autoimmune nephritis, colorectitis, enteritis, phlebitis, vasculitis, and other inflammations in humans or animals. The above general formula (1 , 2a, 2b, 2c, or 2d) of "chemical structure 1, 2a, 2b, 2c, or 2d", or "chemical structure 1," of the general formula (1, 2a, 2b, 2c, or 2d) 2a, 2b, 2c, or 2d.

35. Transdermal administration (in the form of a solution, spray, lotion, ointment, emulsion or gel) to any part of the body to deliver therapeutically effective plasma concentrations for the treatment of spinal cord injury in humans or animals. The compound of "1, 2a, 2b, 2c, or 2d" of the general formula (1, 2a, 2b, 2c, and 2d) as described in 1 and 2 above, or the general formula A composition comprising at least one compound of formulas (1, 2a, 2b, 2c, and 2d) and having "chemical structures 1, 2a, 2b, 2c, and 2d."
36. 1 and 2 above for treating spinal cord injury 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. as an active ingredient, a compound of "chemical structure 1, 2a, 2b, 2c, and 2d" of the general formula (1, 2a, 2b, 2c, and 2d), or a compound of the general formula (1, 2a, 2b , 2c, and 2d).
37. Orally, subcutaneously, intravenously, or intranasally (in the form of a solution, spray, emulsion, pill, tablet, or any other formulation) for the treatment of spinal cord injuries in humans or animals. "Chemical structures 1, 2a, 2b, 2c, and 2d" of the general formulas (1, 2a, 2b, 2c, and 2d) as active ingredients as described in 1 and 2 above, which can be administered. A composition comprising a compound or at least one compound having "chemical structures 1, 2a, 2b, 2c, and 2d" of the general formula (1, 2a, 2b, 2c, and 2d).
38. Breast cancer, colorectal cancer, oral cancer, lung and other respiratory cancers, skin cancer, uterine cancer, reproductive tract cancer, urinary tract cancer, leukemia and other cancers of the blood and lymphoid tissues and other cancers in humans or animals. 1 above, which can be administered transdermally (in the form of a solution, spray, lotion, ointment, emulsion or gel) to any part of the body to deliver therapeutically effective plasma concentrations for treatment and prophylaxis. and 2, the 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).

39. Cancers of the breast, colorectal, oral cavity, lung and other respiratory systems by administering a therapeutically effective amount topically (in the form of a solution, spray, lotion, ointment, emulsion or gel) to the infected area. , skin cancer, uterine cancer, reproductive tract cancer, urinary tract cancer, leukemia and other cancers of the blood and lymphoid tissues, and other cancers as described in 1 and 2 above, as an active ingredient. Compounds of "chemical structures 1, 2a, 2b, 2c, and 2d" of formulas (1, 2a, 2b, 2c, and 2d), or "chemical structures 1, 2a, 2b, 2c, and 2d" of the general formulas (1, 2a, 2b, 2c, and 2d) A composition comprising at least one compound of structures 1, 2a, 2b, 2c, and 2d.
40. Breast cancer, colorectal cancer, oral cancer, lung and other respiratory cancers, skin cancer, uterine cancer, reproductive tract cancer, urinary tract cancer, leukemia and other cancers of the blood and lymphoid tissues and other cancers in humans or animals. Can be administered orally, subcutaneously, intravenously, or intranasally (in the form of solutions, sprays, emulsions, pills, tablets, or any other formulation) for treatment and prophylaxis. , the compound of "chemical structure 1, 2a, 2b, 2c, or 2d" of the general formula (1, 2a, 2b, 2c, or 2d) as described in 1 and 2 above, or the general formula A composition comprising at least one compound of formula (1, 2a, 2b, 2c, or 2d) with "chemical structure 1, 2a, 2b, 2c, or 2d".
41. Breast cancer, colorectal cancer, oral cancer, lung and other respiratory cancers, skin cancer, uterine cancer, reproductive tract cancer, urinary tract cancer, leukemia and other cancers of the blood and lymphoid tissues and other cancers in humans or animals. 1 and 2 above, which can be administered percutaneously, subcutaneously, intravenously, nasally or orally, alone or in combination with other cancer therapeutics, for treatment and prevention. 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 a compound of the general formula (1, 2a, 2b, 2c, or 2d) A composition comprising at least one compound having "chemical structure 1, 2a, 2b, 2c, or 2d".
42. Breast cancer, colorectal cancer, oral cancer, lung and other respiratory cancers, skin cancer, uterine cancer, reproductive tract cancer, urinary tract cancer, leukemia and other cancers of the blood and lymphoid tissues and other cancers in humans or animals. For treatment, the effective drug according to 1 and 2 above, which can be administered transdermally, orally, subcutaneously, intravenously, or nasally, before or after surgery to remove cancer. A compound of "chemical structure 1, 2a, 2b, 2c, or 2d" of the general formula (1, 2a, 2b, 2c, or 2d) as a component, or a compound of the general formula (1, 2a, 2b, 2c, or 2d) a composition comprising at least one compound having "chemical structure 1, 2a, 2b, 2c, or 2d".

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 trauma. , 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 a compound of the general formula (1, 2a, 2b, 2c or 2d) A composition comprising at least one compound having "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, birthmarks, moles (nevi), skin tags, age spots (melasma), and other skin diseases "Chemical structure 1, 2a, 2b" of the general formula (1, 2a, 2b, 2c, or 2d) as an active ingredient as described in 1 and 2 above, which can be administered locally (topically). , 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).
45. The above general formula (1, 2a, 2b) as an active ingredient as described in 1 and 2 above for treating any condition treatable by NSAIA in humans or animals and the novel condition described in the present invention. , 2c, or 2d) of "chemical structure 1, 2a, 2b, 2c, or 2d", or "chemical structure 1, 2a, 2b, Transdermal therapeutic application system of a composition comprising at least one compound of "2c or 2d", a bandage or patch comprising a matrix layer containing one active ingredient and an impermeable backing layer. The most preferred system is an active ingredient receptacle with a permeable bottom facing the skin and controlling the rate of release so that the NSAIA reaches optimal therapeutic blood concentrations. A system that makes it possible to reach a constant, increase the effectiveness and reduce the side effects of NSAIAs.

式中、Ｒは－（ＣＨ₂）_n－を表し、ｎ＝０，１，２，３，４，５，６，７，８，９，１０，１１又は１２であり；Ｒ₁及びＲ₂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、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；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、ＣＨ₃ＣＯＯを表し；Ｙ₁及びＹ₂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又はＣＨ₃ＣＨ₂ＣＯ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－（ＣＨ₂）_n－を表し、ｎ＝０，１，２，３，４，５，６，７，８，９，１０，１１又は１２であり；Ｒ₁及びＲ₂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、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；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、ＣＨ₃ＣＯＯを表し；Ｙ₁及びＹ₂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又はＣＨ₃ＣＨ₂ＣＯ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－（ＣＨ₂）_n－を表し、ｎ＝０，１，２，３，４，５，６，７，８，９，１０，１１又は１２であり；Ｒ₁及びＲ₂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、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；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、ＣＨ₃ＣＯＯを表し；Ｙ₁及びＹ₂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又はＣＨ₃ＣＨ₂ＣＯ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］Ｙ₁及びＹ₂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］Ｒ₁及びＲ₂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］Ｒ₁及びＲ₂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。 Another aspect of the present invention may be as follows.
[1] A pharmaceutical composition for transdermal administration for treating cancer, heart attack or stroke, comprising a compound of chemical structure 1.

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

In the formula, Y represents CH ₃ COO; Y ₁ and Y ₂ independently represent 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 _3S , _{CHF2O ,} CF3O _{, CF3CF2O , C3F7O ,} CF3 _{, CF3CF2 , C3F7 , C4F9 , CH3SO2 , RySO2} , 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, aryl or heteroaryl moiety.
[2] A pharmaceutical composition for transdermal administration, comprising a compound of chemical structure 1, for lowering blood lipid levels.

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

In the formula, Y represents CH ₃ COO; Y ₁ and Y ₂ independently represent 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 _3S , _{CHF2O ,} CF3O _{, CF3CF2O , C3F7O ,} CF3 _{, CF3CF2 , C3F7 , C4F9 , CH3SO2 , RySO2} , 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, aryl or heteroaryl moiety.
[3] A pharmaceutical composition for transdermal administration for treating type II or type I diabetes, comprising a compound of chemical structure 1.

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

In the formula, Y represents CH ₃ COO; Y ₁ and Y ₂ independently represent 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 _3S , _{CHF2O ,} CF3O _{, CF3CF2O , C3F7O ,} CF3 _{, CF3CF2 , C3F7 , C4F9 , CH3SO2 , RySO2} , 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, aryl or heteroaryl moiety.
[4] The pharmaceutical composition according to any one of [1] to [3] above, further comprising water and/or ethanol.
[5] The pharmaceutical composition according to any one of [1] to [4] above, wherein each of Y ₁ and Y ₂ is H.
[6] R ₁ and R ₂ are independently any alkyl, alkyloxy, alkenyl, perfluoroalkyl, halogenated alkyl, or alkynyl residue, aryl, or heteroaryl moiety having 1 to 12 carbon atoms. The pharmaceutical composition according to any one of [1] to [5] above.
[7] The above, wherein R ₁ and R ₂ independently represent any one of alkyl, alkyloxy, alkenyl, perfluoroalkyl, halogenated alkyl, or alkynyl residues 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] above, wherein X is O or S.
[9] The pharmaceutical composition according to any one of [1] to [8] above, wherein the compound of chemical structure 1 is diethylaminoethyl acetylsalicylate 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。 Another aspect of the present invention may be as follows.
[1] A compound of "chemical structure 2a, 2b, 2c, or 2d" of general formula (2a, 2b, 2c, or 2d),

In the formula, R represents a branched or straight chain -(CH ₂ ) _{n -} , where n=0, 1, ₂ , 3, 4, 5, 6, 7, 8, 9, 10...; R ₁ represents a branched or linear -(CH ₂ ) _a -, and in -(CH ₂ ) _a -, a=0, 1, 2, 3, 4, 5, 6, 7, 8 , 9, 10...; R ₂ represents a branched or straight chain -(CH ₂ ) _b -, and in -(CH ₂ ) _b -, b=0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10...; R ₃ represents a branched or straight chain -(CH ₂ ) _c -, and in -(CH ₂ ) _c -, 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 R 5 represents any one of the aryl moieties; R ₅ represents H, alkyl having 1 to 12 carbon atoms, alkyloxy, alkenyl, perfluoroalkyl, halogenated alkyl, or alkynyl residue, aryl or heteroaryl moiety; R ₆ represents any one of H, alkyl having 1 to 12 carbon atoms, alkyloxy, alkenyl, perfluoroalkyl, halogenated alkyl, or alkynyl residue, aryl or heteroaryl moiety; R ₇ represents any one of H, an alkyl, alkyloxy, alkenyl, perfluoroalkyl, halogenated alkyl, or alkynyl residue having 1 to 12 carbon atoms, an aryl or a heteroaryl moiety; ; X represents absent, O _, NH, _{NR 6} or _S ; HA represents absent or _a pharmacologically acceptable acid; , or -(CH ₂ ) _n - group is branched or straight chain, Ary- represents a chemical structure selected from the group consisting of the following chemical structures,

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 represents H, 1 to represents any one of alkyl, alkyloxy, alkenyl, perfluoroalkyl, halogenated alkyl or alkynyl residues, aryl or heteroaryl moieties having 12 carbon atoms; X ₁ or X ₄ represents CH ₂ , S, represents O, NH, or CO; _X2 or _X5 represents CH, _CR8 , or N; _X3 represents O, S, NH, or _NR8 ; Y, _Y1 , _Y2 , Y ₃ , Y ₄ , Y _{5 ,} or Y ₆ is independently H, HO, CH ₃ COO, R _y COO, HS, NO ₂ , CN, CH ₃ COS, NH ₂ , CH ₃ CONH, R _y CONH , _CH3 , _CH3CH2 , _{C3H7 , C4H9 ,} CH3O, _{CH3CH2O , C3H7O, Cl , F ,} Br _, I _{, CH3S , CHF2O} , _CF3O , _{CF3CF2O , C3F7O ,} CF3 _{, CF3CF2 , C3F7 , C4F9 , CH3SO2 , RySO2 , CH3SO} , _{R y} A compound representing SO, CH ₃ CO, or CH ₃ CH ₂ CO.

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。 [2] A compound of "chemical structure 1" of general formula (1),

In the formula, R represents a branched or straight chain -(CH ₂ ) _{n -} , where n=0, 1, ₂ , 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,...; R ₁ is H, an alkyl, alkyloxy, alkenyl, perfluoroalkyl, halogenated alkyl, or alkynyl residue having 1 to 12 carbon atoms, an aryl or heteroaryl moiety; _R2 represents any one of H, alkyl, alkyloxy, alkenyl, perfluoroalkyl, halogenated alkyl or alkynyl residue having 1 to 12 carbon atoms, aryl or heteroaryl moiety; _{represents ;} , alkenyl, perfluoroalkyl, halogenated alkyl 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 alkyl, alkyloxy, alkenyl, perfluoroalkyl, halogenated alkyl or alkynyl residue, aryl or heteroaryl moiety; Ary- in "Chemical Structure 1" of the general formula (1) is , defined as Ary-, which is the same as "chemical structure 2a, 2b, 2c, or 2d" of the general formula (2a, 2b, 2c, or 2d) described in [1] above; HA is absent, or 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 straight chain.
[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 the above [1] or [2] is combined with a coupling reagent. The general formula (1, 2a, 2b, 2c) described in [1] or [2] above is prepared from NSAIA by a reaction to form an anhydride using a , or 2d), a method for preparing a compound having "chemical structure 1, 2a, 2b, 2c, or 2d".
[4] The compound having the chemical structure 1, 2a, 2b, 2c, or 2d of the general formula 1, 2a, 2b, 2c, or 2d described in the above [1] or [2] is treated with a halide. The general formula (1, 2a, 2b, 2c, or 2d) A method for preparing a compound of "chemical structure 1, 2a, 2b, 2c, or 2d".
[5] Metabolic diseases, abnormal blood pressure, heart and vascular diseases, organ transplant rejection, neurodegenerative diseases, skin diseases, autoimmune diseases, muscle diseases, pain, fever, cancer, dysmenorrhea, acute migraine, acute gouty of drugs for the treatment or prevention of diseases or conditions in humans or animals selected from the group consisting of arthritis, ankylosing spondylitis, rheumatoid arthritis, osteoarthritis, dementia, inflammatory conditions, spinal cord injuries and wounds. Use of the compound described in [1] or [2] above for production.
[6] Said drug is administered transdermally to a body part in a human or animal in the form of a solution, spray, lotion, ointment, emulsion or gel to deliver a therapeutically effective plasma concentration. Use as described in ].
[7] The use according to [5] above, wherein the drug is administered orally, subcutaneously, intravenously, or nasally 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 sugar, and abnormal blood lipid concentration.
[11] The use according to [5] above, wherein the heart and blood vessel 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 human or animal discoid lupus erythematosus, systemic lupus erythematosus (SLE), autoimmune disease hepatitis, scleroderma, Sjögren's syndrome, rheumatoid arthritis, polymyositis, scleroderma, Hashimoto's thyroid The use according to [5] above, which is selected from the group consisting of MS, 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), oculopharyngeal muscular dystrophy (OPMD), myotonic dystrophy (MD), Duchenne muscular dystrophy (DMD), polymyositis (PM), skin The use according to [5] above, which is selected from the group consisting of myositis (DM) and inclusion body myositis (IBM).
[16] The inflammatory symptoms include prostate inflammation (prostatitis), prostatic cystitis, hemorrhoids, inflammatory hemorrhoids, post-irradiation (artificial formation) proctitis, chronic ulcerative colitis, cryptitis, and anorectal inflammation. The use according to [5] above, which is selected from inflammatory symptoms, anal pruritus, autoimmune hepatitis, autoimmune nephritis, colorectitis, enteritis, phlebitis, and vasculitis.
[17] The cancer described above is selected from breast cancer, colorectal cancer, oral cavity cancer, respiratory system cancer, skin cancer, uterine cancer, reproductive organ cancer, urinary organ cancer, leukemia, and cancer of blood and lymph tissue. Use as described in 5].
[18] The use according to [5] above, wherein the wound 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, birthmarks, moles (nevi), skin tags, and age spots (melasma).
[20] Metabolic diseases, abnormal blood pressure, heart and vascular diseases, organ transplant rejection, neurodegenerative diseases, skin diseases, autoimmune diseases, muscle diseases, pain, fever, cancer, dysmenorrhea, acute migraine, acute gouty for treating or preventing a disease or condition in humans or animals selected from the group consisting of arthritis, ankylosing spondylitis, rheumatoid arthritis, osteoarthritis, dementia, inflammatory conditions, spinal cord injuries and wounds. A system for transdermal therapeutic application of a compound according to [1] or [2], comprising a bandage or patch comprising a matrix layer containing one active ingredient and an impermeable backing layer.
[21] Contains an active ingredient receptacle, has a permeable bottom facing the skin, and controls the release rate so that the NSAIA reaches a constant optimal therapeutic blood concentration, increasing the effectiveness, and the NSAIA The system according to [20] above, which makes it possible to reduce side effects of.
[22] A composition comprising water and the compound described in [1] or [2] above.

Claims (1)

A compound of "chemical structure 2a, 2b, 2c, or 2d" of general formula (2a, 2b, 2c, or 2d),

In the formula, R represents a branched or straight chain -(CH ₂ ) _{n -} , where n=0, 1, ₂ , 3, 4, 5, 6, 7, 8, 9, _{R _ _ _ 1} represents a branched or straight chain -(CH ₂ ) _a -, and in -(CH ₂ ) _a -, a=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 ₂ is branched or straight chain -(CH ₂ ) _b -, where b=0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10... in -(CH ₂ ) _b -; 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 ₃ is branched or linear -(CH ₂ ) _c - represents c=0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10... in -(CH ₂ ) _c -, and any CH ₂ may be replaced by O, S, CH═CH, C≡C, CHR ₆ , CR ₆ R ₇ , aryl or heteroaryl residues, or other ring systems; R ₄ is H, 1 to 12 carbons Represents any alkyl, alkyloxy, alkenyl, perfluoroalkyl, halogenated alkyl, or alkynyl residue, aryl or heteroaryl moiety having an atom, in which CH ₂ is O, S, CH=CH, C ≡C, CHR ₆ , CR ₆ R ₇ , aryl or heteroaryl moieties, or may be replaced by other ring moieties; R ₅ is H, alkyl having 1 to 12 carbon atoms, alkyloxy, alkenyl, Represents any one of perfluoroalkyl, halogenated alkyl, or alkynyl residue, aryl or heteroaryl moiety, in which 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 alkynyl represents any one of the residues, aryl or heteroaryl moieties, in which CH ₂ is O, S, CH═CH, C≡C, CHR ₆ , CR ₇ R ₅ , aryl or heteroaryl moiety, or other Optionally replaced with a ring moiety, R ₇ is H, an alkyl having 1 to 12 carbon atoms, an alkyloxy, an alkenyl, a perfluoroalkyl, a halogenated alkyl, or an alkynyl residue, any aryl or heteroaryl moiety. _{X _ _ _} represents not present, O, NH, NR ₆ or S; HA represents not present, 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, C, H, O, Cl, Br, F, I, P, may contain 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 , The R ₉ , or -(CH ₂ ) _n - group may be achiral or chiral; if the group is chiral, it may have one or more chiral centers and may be a single (R) or (S) enantiomer or It may be a mixture of (R) and (S) enantiomers, and Ary- represents the following formula, but is not limited to:

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 represents H, 1 represents any one of alkyl, alkyloxy, alkenyl, perfluoroalkyl, halogenated alkyl or alkynyl residues, aryl or heteroaryl moieties having 12 carbon atoms; X ₁ or X ₄ is 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, _Ry COO, HS, NO ₂ , CN, CH ₃ COS, NH ₂ , CH ₃ CONH, _Ry CONH _{, CH3 , CH3CH2, C3H7, C4H9 , CH3O , CH3CH2O , C3H7O ,} Cl _, F, Br, I _{, CH3S , CHF2} O, _CF3O , _{CF3CF2O , C3F7O ,} CF3 _{, CF3CF2 , C3F7 , C4F9 , CH3SO2 , RySO2 , CH3SO} , R _y SO, CH ₃ CO, CH ₃ CH ₂ CO; any Ary- is achiral or chiral; if Ary- is chiral, it may have one or more chiral centers; Compounds that may be (R) or (S) enantiomers or mixtures of (R) and (S) enantiomers.

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