JP2020147604A - Nsaia prodrug having very fast skin- and film-infiltration rate, and new use thereof as medicine - Google Patents

Abstract

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

Description

The present invention designs and prepares positively charged water-soluble prodrugs of non-steroidal anti-inflammatory agents (NSAIA) with very fast skin and blood-brain barrier penetration rates, as well as diabetes (types I and II), blood glucose and Abnormal levels of blood lipids, 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 disease hepatitis, strong Dermatomyositis, Schegren's syndrome, rheumatoid arthritis, polymyositis, proctitis, Hashimoto thyroiditis, juvenile diabetes, Addison's disease, leukoplakia, malignant anemia, glomerulonephritis, pulmonary fibrosis, multiple sclerosis (MS), clone Diseases and other autoimmune diseases, myotrophic lateral sclerosis (ALS), ocular pharyngeal muscular dystrophy (OPMD), myotonic dystrophy (MD), Duchenne muscular dystrophy (DMD), polymyositis (PM), Dermatomyositis (DM), Encapsulant Myositis (IBM), and other muscle disorders, hemorrhoids, inflammatory hemorrhoids, post-irradiation (artificial) proctitis, chronic lupus erythematosus, adenomyosis, other anal rectal Inflammatory symptoms, and anal pruritus, prostatic inflammation, prostatic cystitis, esophageal varices, autoimmune hepatitis, autoimmune nephritis, colonic proctitis, enteritis, venitis and other inflammations, dermatomyositis, breast cancer, colonic rectal cancer , Oral cancer, lung and other respiratory cancer, uterine cancer, reproductive organ cancer, urinary cancer, leukemia and other blood and lymph tissue cancer as well as other cancers, wounds, abnormal vascular skin lesions, bruise, hokuro ( With respect to new drug use in the treatment and prevention of lupus erythematosus), skin tags, aging spots (liver spots), and other skin disorders. These prodrugs can be administered transdermally without the assistance of a transdermal absorption enhancer.

NSAIA is used to relieve the signs and symptoms of rheumatoid arthritis, osteoarthritis and ankylosing spondylitis. NSAIA is used alone or as an adjunct in the treatment of biliary 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. Aspirin is used to prevent heart and vascular disease.

Unfortunately, NSAIA use has a number of side effects, including very prominent gastrointestinal disorders such as dyspepsia, gastroduodenal bleeding, gastric ulcers, and gastritis. Fishman (Robert, US Pat. No. 7,052,715) is an addition associated with oral medicine that a significant concentration level must be reached in the bloodstream for the purpose of effectively treating the distal region of pain or inflammation. Problem was shown. This level is often much higher than what is needed if it is possible to accurately target a particular site of pain or injury. By Fishman and many reporters (Van Angelen et al., U.S. Pat. No. 6416772; Maclides et al., U.S. Pat. No. 6,346,278; Kirby et al., U.S. Pat. No. 6,444,234, Pearson et al., U.S. Pat. U.S. Pat. No. 5885597) has attempted to develop a delivery system for percutaneous application by formulation. Song et al. Have developed a percutaneous drug delivery system for anti-inflammatory analgesics, including diclofenac diethylammonium salt (Song et al., US Pat. No. 6,723,337). Donati et al. Have developed a topical plaster containing heparin and diclofenac (Donati et al., US Pat. No. 6,592,891). Kawaji et al. Have developed an oil-based patch for external use containing diclofenac sodium salt (Kawaji et al., US Pat. No. 6,262,121). Effing et al. Have developed a device for percutaneously delivering diclofenac (Effing et al., US Pat. No. 6,193996). However, it is very difficult to deliver therapeutically effective plasma concentrations of NSAIA within 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 is present in a protonated form at physiological pH. They found that the prodrug (TSBH) spreads through human skin about 60 times faster than the drug (TS) itself (Susan Milosovich et al., J. Pharma. Sci., Vol. 82, 227. Page, 1993).

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

Unfortunately, NSAIA use has a number of side effects, including very prominent gastrointestinal disorders such as dyspepsia, heartburn, vomiting, gastroduodenal bleeding, gastric ulcers, and gastritis. Gastric duodenal bleeding caused by NSAIA is generally painless, but can lead to fecal loss and can lead to persistent deficiency anemia.

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

The transdermal delivery system helps avoid direct damage to the gastrointestinal tract and drug inactivation caused by "first-pass metabolism" in the gastrointestinal tract and liver. There are limitations to conventional percutaneous drug delivery systems that use percutaneous absorption enhancers. First, the permeation rate is very slow (on a μg / in ² / hour scale). Second, large amounts of accelerators can enter the patient's body, causing extra side effects. Third, in conventional percutaneous drug delivery by the use of transdermal absorption enhancers, the high concentration accelerator in the formulation can assist the drug in passing through the skin, but when the accelerator and the drug enter the skin, The concentration of the accelerator is very diluted, it does not help the drug molecule to cross the more biological membrane, the drug molecule will accumulate in the subcutaneous fat layer, the accumulated drug is very serious and Even fatal can have some side effects.

The biological activity of a drug measures the relative dose of the drug that reaches the systemic circulation. However, systemic circulation is not the "site of action" for most drugs. Drug molecules must cross more biological membranes, even if they reach the systemic circulation, which is less permeable than the membranes of the digestive tract and is often referred to as the "site of action". It interacts with intermolecular and intramolecular fluids before reaching no fluid, which results in most drugs being metabolized by the intestinal mucosa, liver, kidneys and lungs before reaching the "site of action". Not only is this situation very ineffective, but it also creates a toxic burden on the intestinal mucosa, liver, kidneys and lungs. If the rate of penetration of the drug in various membranes can be increased, the therapeutic effect and clinical response of the drug will be greatly improved, so that the required drug administration will be smaller and the side effects will be reduced. Percutaneous prodrug delivery for prodrugs with very fast skin and membrane penetration rates will be very useful not only for local diseases but also for systemic diseases. Since these prodrugs are tens to hundreds of times more effective than the parent drug, they usually require only a few tenths to a few hundredths of the drug and have very few side effects. This is useful not only for percutaneous drug delivery, but also for any other drug delivery system (oral, subcutaneous, intravenous, inhalation, and nasal).

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

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

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

In the formula, R _x represents H, CH ₃ , CH ₃ O, OH, CH ₃ CH ₂ , CF ₃ , CHF ₂ , CH ₂ F, Cl, F, Br, F; R _y is H, 1 Represents any one of an alkyl, alkyloxy, alkenyl, perfluoroalkyl, alkyl halide or alkynyl residue, aryl or heteroaryl moiety having from 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 independently H, HO, CH ₃ COO, R _y COO, HS, NO ₂ , CN, CH ₃ COS, NH ₂ , CH ₃ CONH, R _y CONH, CH ₃ , CH ₃ CH ₂ , C ₃ H ₇ , C ₄ H ₉ , CH ₃ O, CH ₃ CH ₂ O, C ₃ H ₇ O, Cl, F, Br, I, CH ₃ S, CHF ₂ O, CF ₃ O, CF ₃ CF ₂ O, C ₃ F ₇ O, CF ₃ , CF ₃ CF _2, C ₃ F ₇ , C ₄ F ₉ , CH ₃ SO ₂ , R _y SO ₂ , CH ₃ SO, Represents 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 and may have a single chiral center. It may be (R) or (S) enantiomer or a mixture of (R) and (S) enantiomer.

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 have only shown that the primary role of primary, secondary and tertiary amine groups is to help the drug pass through the skin, membrane, blood brain, blood placenta, wounds, or other barriers. Therefore, it has been found that the primary, secondary and tertiary amine groups can be of any structure that is nontoxic and mediates the biological activity of the parent drug. Therefore, the inventors have designed and prepared various types of amine groups for this property. The novel NSAIA prodrug has the general formula (2a, 2b, 2c, or 2d) "chemical structure 2a, 2b, 2c, or 2d".

In the equation, R represents a branched or linear − (CH ₂ ) _n −, and at − (CH ₂ ) _n − n = 0,1,2,3,4,5,6,7,8,9, 10 ... and any CH ₂ may be replaced with O, S, CH = CH, C≡C, CHR ₆ , CR ₆ R ₇ , aryl or heteroaryl residues, or other ring system; R ₁ represents a branched or linear − (CH ₂ ) _a −, and at − (CH ₂ ) _a −, a = 0,1,2,3,4,5,6,7,8,9,10 ... Yes, 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 system; R ₂ is branched. Or, it represents a linear − (CH ₂ ) _b −, and in − (CH ₂ ) _b −, b = 0,1,2,3,4,5,6,7,8,9,10 ... 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. Represents − (CH ₂ ) _c −, and in − (CH ₂ ) _c −, c = 0,1,2,3,4,5,6,7,8,9,10 ..., Whichever 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 ₄ is H, 1 to 12 carbons. Represents any one of alkyl, alkyloxy, alkenyl, perfluoroalkyl, alkyl halide, or alkynyl residues, aryl or heteroaryl moieties having an atom, which CH ₂ is O, S, CH = CH, C. ≡ C, CHR ₆ , CR ₆ R ₇ , may be replaced with aryl or heteroaryl moieties, or other ring moieties; R ₅ is H, alkyl, alkyloxy, alkenyl, having 1 to 12 carbon atoms. Represents any one of perfluoroalkyl, alkyl halides, or alkynyl residues, aryl or heteroaryl moieties, and any CH ₂ is O, S, CH = CH, C≡C, CHR ₆ , CR ₇ R ₆ , Aryl or heteroaryl moiety, or other ring moiety; R ₆ is H, alkyl, alkyloxy, alkenyl, perfluoroalkyl, alkyl halide, or alkyl having 1 to 12 carbon atoms. Represents any one of an enyl residue, aryl or heteroaryl moiety, which CH ₂ is O, S, CH = CH, C≡C, CHR ₆ , CR ₇ R ₅ , aryl or heteroaryl moiety, or the like. R ₇ may be replaced with the ring moiety of H, an alkyl, alkyloxy, alkenyl, perfluoroalkyl, alkyl halide, or alkynyl residue, aryl or heteroaryl moiety having 1 to 12 carbon atoms. Represents any one, and any CH ₂ may be replaced with O, S, CH = CH, C≡C, CHR ₆ , CR ₆ R ₅ , aryl or heteroaryl moiety, or other ring moiety. X represents O, NH, NR ₆ or S, which does not exist; Aryl in the "chemical structure 2a, 2b, 2c, or 2d" of the general formula (2a, 2b, 2c, or 2d) is the general formula (2a, 2b, 2c, or 2d) Defined identically to Aryl- in "Chemical Structure 1" of 1), HA represents a non-existent, 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 linear and 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 -groups may be achiral or chiral; if the groups are chiral, one or more chiral centers. May have a single (R) or (S) enantiomer or a mixture of (R) and (S) enantiomers.

Drug absorption requires the passage of the drug in molecular form through the septum, either from the gastrointestinal tract or other sites. The drug must first dissolve and, if the drug has suitable biopharmaceutical properties, pass from the high concentration region to the low concentration region through the membrane into the blood or systemic circulation. become. All biological membranes contain lipids as the major constituents. Molecules that play a dominant role in membrane formation all have a large polar headgroup containing phosphoric acid and, in most cases, have two hydrophobic hydrocarbon tails. The membrane is bilayer and the hydrophilic headgroups are outward facing the water soluble region 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 inside. Cannot enter the cytoplasm of.

One object of the present invention is the solubility of NSAIA in gastric juice that allows oral administration and the permeation rate of NSAIA through membrane and skin barriers that allow percutaneous (local) administration. By increasing, the side effects of NSAIA are avoided. The most important goal of the present invention is to be able to penetrate the skin, cell membranes, especially the membranes of brain cells and nerve cells, staying in the systemic circulation for a very short time, which is hundreds of times more effective than the parent drug. It is the design of NSAIA prodrugs, which usually require only a few tenths to a few hundredths of the drug dose and can significantly reduce the occurrence of side effects. It is effective not only for percutaneous drug delivery, but also for other drug delivery systems (oral, subcutaneous, intravenous, inhalation, and nasal, etc.) and treats many symptoms that cannot be treated by the parent drug. be able to. These novel NSAIA prodrugs generally have two structural features. That is, it has a lipophilic moiety and a primary, secondary, or tertiary amine group that is present in a form that is protonated at physiological pH (hydrophilic moiety). Such a hydrophilic-lipophilic equilibrium is required for efficient passage through the membrane barrier (Susan Milosovich et al., J. Pharma. Sci., Vol. 82, p. 227, 1993). Positively charged amino groups greatly increase the solubility of the drug in water. The positive charge of the amino groups on these prodrugs will combine with the charge of the phosphate headgroup of the membrane. Therefore, the local concentration on the outside of the membrane or skin is very high, facilitating the passage of these prodrugs from the high concentration region to the low concentration region. This binding can slightly destabilize the membrane and leave some room for the lipophilic portion of the prodrug. As the membrane molecules move, the membrane may be slightly "cracked" due to the binding of prodrugs. 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 is completely in the membrane. When the amino group of the prodrug moves to the opposite side of the membrane and is protonated, the prodrug is then drawn into a concentrated aqueous solution of the semifluent or a cell substrate that is a suspension. Due to its short stay in the gastrointestinal tract, this prodrug does not cause damage to gastric mucosal cells. The penetration rate of the novel prodrug through human skin was measured in vitro using Franz-improved permeation cells derived from human skin tissue (thickness 360-400 μm) in the ventral and dorsal thigh regions. The receptive fluid was usually composed of 2% bovine serum albumin in 10 mL of saline and stirred at 600 rpm. The cumulative amount of prodrugs and drugs entering the skin over time was determined by selective high performance liquid chromatography. The apparent flux value of the NSAIA prodrug was 0.1 to 50 mg / cm ² / hour. This result suggests that the prodrug spreads through human skin at least hundreds of times faster than its parent drug. This result suggests that the positive charge on the dialkylaminoethyl group has an important role in the passage of the drug through the membrane and skin barrier.

The novel NSAIA prodrug can penetrate the skin barrier, blood-brain barrier, and blood-placental barrier. The in vitro penetration rates of the prodrug and its parent drug through intact rat skin were compared. A donor was constructed by applying 20% prodrug in 1 mL of ethanol or its parent drug to an area of about 5 cm ^{2 on} the back of a rat (about 200 g). After 4 hours, the rats were killed 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. The sample was then ultracentrifugated for 5 minutes and analyzed using HPLC. The results are shown in Tables 1-5.

20% aspirin, diclofenac, ketoprofen, fenoprofen, or ibuprofen in 1 mL of ethanol was applied to an area of approximately 5 cm ^{2 on} the back of the rat. After 4 hours, the rats were killed 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. No of these drugs were found in the tissues or plasma of any rat. The results show that the NSAIA prodrug can penetrate the skin barrier, blood-brain barrier, and other membrane barriers very quickly, but the parent NSAIA cannot penetrate the skin barrier in detectable amounts. It is shown that.

The prodrug of the "chemical structure 1" of the general formula (1) is obtained from the patents of the inventors (International Application Nos. PCT / IB2006 / 052732, PCT / IB2006 / 052318, PCT / IB2006 / 052815, No. PCT / IB2006 / 052563, PCT / IB2006 / 052575, PCT / IB2006 / 053741, PCT / IB2006 / 053091, PCT / IB2006 / 053090, PCT / IB2006 / 052549) It showed inflammatory, analgesic, antipyretic, and anti-rheumatic activity. The inventors have found that all of the prodrugs of the general formula (2a, 2b, 2c, or 2d) of "chemical structure 2a, 2b, 2c, or 2d" are anti-inflammatory, analgesic, antipyretic, and anti-rheumatic. It was found to show sexual activity. A main object of the present invention is a novel pharmaceutical use of NSAIA prodrugs.

The relationship between inflammation and cancer is well known. Thea D. Dr. Tlsty gave a lecture (Keystone Symposia: Inflammation and Cancer, Breckenridge, Colorado, USA, February 27-March 3, 2005) Cyclooxygenase-2 (COX-2) is aromatase activity, angiogenesis, proliferation, It states that it stimulates invasion and prostaglandin synthesis. Increased prostaglandins lead to inhibition of cell death. Aspirin and other NSAIAs inhibit COX-1 and COX-2. The overall relative risk of colorectal cancer, esophageal cancer, ovarian cancer or other cancers is reduced in people who take aspirin for a long time. However, cancer cells may change their membrane structure to prevent NSAIA from entering the cancer cells. The novel prodrugs of the present invention can penetrate any membrane barrier, can be applied topically to the outer skin area of the cancer site, extremely low systemic exposure and allow large amounts of prodrugs to enter the cancer cells. become.

To evaluate the antitumor activity of the NSAIA prodrug, we used human breast cancer cells (BCAP-37, 2-3 mm ³ tumor tissue in each mouse) in nude mice (BALB, 12 groups, 7 in each group). Mice) were subcutaneously xenografted. 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) diethylaminoethylacetylsalicylate acetylsalicylate (P-1, in acetone); 1-piperidinepropyl 2 [(2,6-dichlorophenyl) amino] benzeneace. Tart. AcOH (P-2, in water), 1-pyrrolidinepropyl 2- (3-benzoylphenyl) propionate. AcOH (P-3, in water), 4-piperidin methyl 2- (3-phenoxyphenyl) propionate. AcOH (P-4, in water), 3-piperidine methyl 2- (ρ-isobutylphenyl) propionate. AcOH (P-5, in water), diethylaminoethyl 1- (p-chlorobenzoyl) -5-methoxy-2-methylindole 3-acetate. AcOH (P-11, in water), 2- (4-morpholinyl) ethyl (Z) -5-fluoro-2-methyl-1-[(4-methylsulfinyl) phenylmethylene] -1H-indene-3-acetate. AcOH (P-12, in water), diethylaminoethyl 2- (2,4-dichlorophenoxy) benzene acetate. AcOH (P-19, in water), diethylaminoethyl 2- (8-methyl-10,11-dihydro-11-oxodibenz (b, f) oxepin-2-yl) propionate. AcOH (P-37, in water), 1-pyrrolidinepropyl 2-[[(3- (trifluoromethyl) phenyl) amino] benzoate. AcOH (P-48, in water), 4-N, N-dimethylaminobutyryloxy-2-methyl-N-2-pyridinyl-2H, 1,2-benzothiazine-3-carboxamide 1,1-dioxide. HCl (P-51, in acetone) was topically applied to the transplanted area of human breast cancer cells (near the forefoot) every 8 weeks. Tumor sizes on day 42 are shown in Tables 6 and 7.

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

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

These results also indicate that the NSAIA prodrug has very strong antitumor activity and has few or no side effects.

The hypoglycemic effect of salicylate was first observed by German doctors over 100 years ago (Edmund J. Hengesh, "Principles of medicinal chemistry", 4th edition, p. 591, Williams & Wilkins, 1995). Salicylate enhances glucose-stimulated insulin secretion and inhibits glucose production from lactic acid and alanine (HF Woods et al., Clin. Exp. Pharmacol Physiol., Vol. 1, p. 534, 1974). Certain salicylates reduce plasma levels of free fatty acids, triglycerides, and cholesterol. When the concentration of free fatty acids in plasma increases, the utilization of glucose is inhibited, and when the concentration decreases, it can contribute to hypoglycemic action. Unfortunately, large doses of salicylate (5 g daily) are required to maintain proper control of blood glucose and blood lipid levels. At this level of administration, a myriad of side effects such as stomach discomfort, nausea, vomiting and tinnitus frequently occur. The novel prodrugs of the present invention have very fast skin and membrane penetration rates. It can reach the "site of action" very quickly, and the pharmacological effects and clinical response of these prodrugs are greatly improved, so the drug dose required is much lower (hundreds of times less than the parent drug). It only takes a few tenths of the time), which will greatly reduce the occurrence of side effects.

The prodrug of the present invention lowers blood glucose levels in a rat model (SLAC / GK, type 2 diabetes, n = 7). Diethylaminoethylacetylsalicylate A 50% acetone solution of acetylsalicylate (P-1, in acetone); 4-acetamidophenylsalicyryldimethylaminobutyrate. HCl (P-6), diethylaminoethyl 5- (2,4-difluorophenyl) acetylsalicylate. 5- (2,4-difluorophenyl) acetylsalicylate (P-8), diethylaminoethyl salicyl salicylate. AcOH (P-9), diethylaminoethyl salicylate. AcOH (P-10), diethylaminoethyl 5-acetamide-acetylsalicylate (P-58), diethylaminoethylacetylsalicylic salicylate. Acetylsalicylic salicylate (P-59), diethylaminoethyl acetylsalicylic salicylate. Acetyl salicyl salicyl salicylate (P-60) (equivalent to 20 mg / kg NSAIA) once daily (8 am) for 5 weeks, rat (shaved) back (approx. 1.5 cm ² ) Was administered transdermally. Blood glucose levels were measured from week 2 to week 5 once every three days at 3:00 pm (without fasting). The results are shown in Table 10. Blood lipid levels were measured at the end of week 5. 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。

This result showed that the NSAIA prodrug lowered blood glucose levels very effectively in diabetic rat models and did not affect blood glucose levels in normal rats. Most interestingly, after 30 days of discontinuation of treatment, rat blood glucose levels remained at normal levels (7-8 mmol / L, no fasting). This means that this prodrug not only lowers blood sugar levels, but can 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。

This result showed that the NSAIA prodrug very effectively lowered blood lipid levels (total cholesterol and triglycerides) in a diabetic rat model and did not affect HDL levels.

The pH of gastric juice is 1 to 3. Prodrugs can pass through the stomach wall because the phosphate headgroups are neutralized by hydrogen ions and the positive charges of the amino groups of these prodrugs cannot bind to the phosphate headgroups of the membrane. You can't, and you won't hurt or hurt your stomach. The pH of the duodenum is about 5-7 and the prodrug can pass through the mucosa of the duodenum. Since the pancreas is in the vicinity and most of the prodrugs enter it before reaching the liver, kidneys, and systemic circulation, where the drug is metabolized, very few doses of these prodrugs are taken. Only the amount is needed and the incidence of side effects is very small and low. Diethylaminoethylacetylsalicylate. 20% acetone solution of acetylsalicylate (P-1, in acetone); 4-acetamidophenylsalicyryldimethylaminobutyrate. HCl (P-6), diethylaminoethyl 5- (2,4-difluorophenyl) acetylsalicylate. 5- (2,4-difluorophenyl) acetylsalicylate (P-8), diethylaminoethyl salicyl salicylate. AcOH (P-9), diethylaminoethyl salicylate. AcOH (P-10), diethylaminoethyl 5-acetamide-acetylsalicylate (P-58), diethylaminoethylacetylsalicylic salicylate. Acetylsalityl salicylate (P-59), diethylaminoethyl acetylsalicylic salicylate. Acetylsalityl salicyl salicylate (P-60) (equivalent to 20 mg / kg NSAIA) was orally administered to rats (SLAC / GK, type 2 diabetes, n = 7) daily with food for 5 weeks. Blood glucose levels were measured from week 2 to week 5 once every three days at 3:00 pm (no fasting). The results are shown in Table 12. Blood lipid levels were measured at the end of week 5. 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。

The results show that when the prodrug is taken orally and the dose is much lower than the parent drug, the NSAIA prodrug very effectively lowers blood glucose levels in a diabetic rat model and blood glucose levels in normal rats. It was shown that it does not affect.

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 the NSAIA prodrug reduced blood lipid levels very effectively in a diabetic rat model when the prodrug was taken orally and the dose was much lower than the parent drug. ..

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

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

This result showed that the NSAIA prodrug lowered blood glucose levels very effectively 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 prior to the experiment, a thrombus was made by aspirating venous blood (1 mL) into a sterile bottle and coagulating it. To avoid fracture and slow lysis, autologous blood coagulations were stabilized in temperature controlled (70 ° C.) distilled water for 10 minutes. After anesthesia, the femoral circumflex vein was exposed and distally isolated, and an autologous thrombus (0.05 g / kg) was injected through an indwelling catheter (20GA) placed within the earlier isolated femoral circumflex vein. Diethylaminoethylacetylsalicylate. Acetylsalicylate (P-1, in acetone, 20 mg / kg) and diethylaminoethyl acetylsalicylic salicylate. A 50% acetone solution of acetylsalicylic salicylate (P-59, 20 mg / kg) was topically applied to the back of the rabbit. Two days later, the rabbits were euthanized by hyperintravenous injection of sodium amobarbital (60 mg / kg). The lungs and heart were isolated and the presence of thrombi in the pulmonary arteries was observed. Lungs were immersed in 10% formalin for 24 hours. A continuous cross section along the embolized pulmonary artery was paraffin-embedded and stained with hematoxylin-eosin. In the control group, platelet thrombi and mixed thrombi surrounded the infused blood clots and were present in both proximal and distal directions in large vessels as well as dilated vessel walls. There was an overgrowth of endothelial and fibrous cells in these vessels. In addition, there was acute pulmonary congestion. In the P-1 and P-59 groups, the lung tissue and blood vessel wall of both were normal. This result showed that the thrombotic action and the progression of the thrombus associated with the embolus could be prevented by these NSAIA prodrugs. These prodrugs can be very useful in the prevention and treatment of blood coagulation, which is a major cause of stroke, heart attack and organ transplant rejection.

The prodrugs of the present invention can help heal trauma and soften and shrink cuts and burn scars in rabbit models. The average wound area of rabbits treated with this prodrug is only one-third that of control rabbits derived from the same cut in the Chinese white rabbit model, and the wounds are similar to normal intact tissue. Flexibility.

COX-1 and COX-2 play a very important role in the immune response of animals. NSAIA inhibits COX-1 and COX-2. The NSAIA prodrugs of the present invention can be very useful in the treatment of psoriasis, discoid lupus erythematosus, systemic lupus erythematosus (SLE), and other autoimmune diseases. High-concentration Malassezia suspension (Rosenberg, EW et al., Mycopatology, Vol. 72, pp. 147-154, 1980) on shaved skin on the back of a Chinese white rabbit (n = 4 × 6) for 2 weeks. It was applied twice daily (7 am and 7 pm) to cause psoriasis-like lesions. Then 3-piperidine methyl 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), diethylaminoethyl 3- (4-chlorophenyl) -1-phenyl-1H-pyrazole-4-acetate. AcOH (P-22) 5% The aqueous solution was applied to the same area 3 hours (10 am and 10 pm) after application of the high concentration maracedia suspension (7 am and 7 pm), 10 days after application of these prodrugs. , The lesion was isolated.

To assess anti-lupus erythematosus activity, 5% diethylaminoethylacetylsalicylate acetylsalicylate (P-1, in acetone, 30 mg / kg), or 3-piperidinemethyl 2- (ρ-isobutylphenyl) propionate. AcOH (P-5, water, 30 mg / kg) was topically applied to the skin on the back of mice having discoid lupus erythematosus, systemic lupus erythematosus (MRL / LPR, n = 5 × 3) twice a day. After 6 weeks, all skin lesions and lupus nephritis were resolved in the prodrug-treated mice, but the symptoms in the control mice were exacerbated.

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

The development of cell death in amyotrophic lateral sclerosis (ALS) may include glutamate-mediated excitotoxicity, oxidative damage, and apoptosis. Cyclooxygenase-2 is present in spinal cord neurons and astrocytes and catalyzes the synthesis of prostaglandin E2. While prostaglandin E2 stimulates glutamate release from astrocytes, cyclooxygenase-2 also plays an important role in the production of pro-inflammatory cytokines, reactive oxygen species, and free radicals. Treatment with the selective cyclooxygenase-2 inhibitor celecoxib markedly inhibited the production of prostaglandin E2 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 cord of treated ALS mice showed marked conservation of spinal cord neurons and reduced astrocyte proliferation and microglial activation (Merit. E. Cudkowicz et al., Anals of neurology, 52nd). Volume 771-778, 2002). These results suggest that inhibition of cyclooxygenase-2 may be beneficial to ALS patients. The NSAIA prodrugs of the present invention can penetrate the skin and nerve cell membrane barriers at a very high rate (most NSAIAs cannot effectively penetrate nerve cells) and can be administered transdermally without damaging the digestive tract. Therefore, these prodrugs include multiple sclerosis (MS), Crohn's disease, and other autoimmune diseases, myotonic lateral sclerosis (ALS), myotonic dystrophy (OPMD), and myotonic dystrophy ( It is a very useful drug for the treatment of MD), Duchenne muscular dystrophy (DMD), polymyositis (PM), dermatomyositis (DM), inclusion myotitis (IBM), and other myopathies.

The mechanism of inflammation has been proposed as an important mediator in the pathogenic cascade of Alzheimer's disease (McGeer PL, McGeer EG, "The inflammatory response system of brain implications for the heroes , 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 suggest that NSAIA can reduce the relative risk to those who have had cumulative use of NSAIA prior to the onset of dementia for at least 2 years, or 2 years or more. When the neuroprotective capacity of NSAIA ceased in the year immediately prior to the onset of dementia, these compounds lost protection against progression in most people with prodromes of the disease. The inventors believe that the reason for this is that the tissue around the damaged nerve cell forms a scar to protect the nerve cell from further damage. Most NSAIAs have a very slow penetration rate of the cerebral blood and neuronal barriers and are unable to penetrate the scar barrier. These prodrugs of the invention have very fast penetration rates into the skin, blood brain, nerve cell membranes, and scar barriers for the treatment of Alzheimer's disease, Parkinson's disease and other progressive neurodegenerative diseases. It is a very promising drug.

These prodrugs can help patients with spinal cord injuries whose healing has been stopped by a protected scar around the injured spinal cord. While most NSAIAs are unable to penetrate the scar barrier in therapeutically effective amounts, the prodrugs of the invention can penetrate the scar barrier, have anti-inflammatory activity and aid in wound healing. Can be done.

NSAIA is not very effective in treating the above-mentioned symptoms, has serious side effects due to its inability to penetrate cell membranes, especially brain and nerve cells, and stays in the systemic circulation for too long. Most of the drug will be metabolized by the intestinal mucosa, liver, kidneys, and lungs before reaching the "site of action." Not only does this situation produce very low pharmacological effects, but it also causes 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, are hundreds of times more capable than the parent drug, and are only dozens of normal drug doses. It requires one-third or one-hundredth, and the occurrence of side effects is very low. This is beneficial not only for percutaneous drug delivery, but also for any drug delivery system (oral, subcutaneous, intravenous, inhalation, and nasal, etc.), better than being treatable by the respective parent drug. Many symptoms can be treated, and even some symptoms that cannot be treated with their respective parent drugs.

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

The compounds of the "chemical structures 1, 2a, 2b, 2c, or 2d" of the general formulas 1, 2a, 2b, 2c, or 2d described above are metal salts of NSAIA, organic basic salts, using appropriate halides. , Or it can be prepared from an immobilized basic salt.

It comprises at least one compound having a general "chemical structure 1, 2a, 2b, 2c, or 2d" or a general "chemical structure 1, 2a, 2b, 2c, or 2d" as an active ingredient. The percutaneous therapeutic application system of the composition can be used to treat any symptom that can be treated with NSAIA in humans or animals, as well as the novel symptom described in the present invention. These systems can be bandages or patches that include a matrix layer containing one active ingredient and an impermeable lining layer. The most suitable system is the active ingredient container, which has an osmotic bottom facing the skin. By controlling the release rate, the system can allow NSAIA to reach a constant therapeutic blood concentration, increase its effectiveness, and reduce the side effects of NSAIA. These systems can be worn on the wrist, ankle, arm, leg, or any part of the body.

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

In the figure, R, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , in "Chemical structure 1, 2a, 2b, 2c, or 2d" of the general formula (1, 2a, 2b, 2c, or 2d). 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 , and R in claims 1 and 2. Defined to be identical to ₇ , R ₈ , R ₉ , X, HA, and Ary-.

(Best form)
Diethylaminoethylacetylsalicylate. Preparation of Acetylsalicylate 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. Solid waste was filtered off and washed with chloroform (3 x 300 ml). 59 g of diethylaminoethanol was added to the reaction mixture. The mixture was stirred at room temperature for 3 hours. The organic solution was evaporated. After drying, 220 g of the desired product was obtained (96%). Elemental analysis: C ₂₄ H ₂₉ NO ₈ , molecular weight: 459.18. Calculated% C: 62.73, H: 6.36, N: 3.05, O: 27.86, measured% C: 62.70, H: 6.40, Cl: N: 3.01, O: 27.90.

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

3-Piperidin 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 (3 x 50 ml). 300 ml of 5% Na ₂ CO ₃ was added to the solution with stirring. The mixture was stirred for 30 minutes. The chloroform solution was washed with water (3 x 100 ml) and dried over Na ₂ SO ₄ . Copper sulphate was filtered off and washed with chloroform (3 x 100 ml). 6 g of acetic acid was added to the mixture. The solution was concentrated to 100 ml in vacuo. 300 ml of hexane was added to the solution. The solid product was collected by filtration and washed with hexane (3 x 100 ml). After drying, 35 g of the desired product was obtained (96%). Elemental analysis: C ₂₁ H ₃₃ NO ₄ , molecular weight: 363.49, calculated% C: 69.39, H: 9.15, N: 3.85, O: 17.61, measured% C: 69.35, H: 9.18, N: 3.83, O: 17.64.

The prodrug of the general formula (1, 2a, 2b, 2c, or 2d) of "chemical structure 1, 2a, 2b, 2c, or 2d" is superior to NSAIA. These can be used as pharmaceuticals in the treatment of any human or animal symptom that can be treated with NSAIA. These include diabetes (types I and II), abnormal levels of blood glucose and blood lipids, heart and vascular diseases such as stroke and heart attack, Alzheimer's disease, Parkinson's disease and other neurodegenerative diseases, psoriasis, discoid erythematosus. , Systemic erythematosus (SLE), autoimmune disease hepatitis, strong skin disease, Schegren syndrome, rheumatoid arthritis, polymyositis, strong skin disease, Hashimoto thyroiditis, juvenile diabetes, azison disease, white spots, malignant anemia, glomerulonephritis , Pulmonary fibrosis, multiple sclerosis (MS), Crohn's disease, and other autoimmune diseases, myotrophic lateral sclerosis (ALS), ocular pharyngeal muscular dystrophy (OPMD), myotonic dystrophy (MD), Duchenne muscular dystrophy (DMD), polymyositis (PM), dermatomyositis (DM), inclusion myositis (IBM), and other myopathy, hemorrhoids, inflammatory hemorrhoids, post-irradiation (artificial) rectalitis, chronic Ulcerative colitis, adenomyosis, other anal-rectal inflammatory symptoms and anal pruritus, prostatic inflammation, prostatic dermatomyositis, autoimmune hepatitis, autoimmune nephritis, venitis and other inflammation, spinal cord injury, wounds, Breast cancer, colorectal cancer, oral cancer, lung and other respiratory cancers, skin cancer, uterine cancer, genital cancer, urinary cancer, leukemia and other blood and lymph tissue cancers 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 assistance of a transdermal absorption enhancer.

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

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

In the equation, R represents a branched or linear − (CH ₂ ) _n −, and at − (CH ₂ ) _n − n = 0,1,2,3,4,5,6,7,8,9, 10 ... and any CH ₂ may be replaced with O, S, CH = CH, C≡C, CHR ₆ , CR ₆ R ₇ , aryl or heteroaryl residues, or other ring system; R ₁ represents a branched or linear − (CH ₂ ) _a −, and at − (CH ₂ ) _a −, a = 0,1,2,3,4,5,6,7,8,9,10 ... Yes, 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 system; R ₂ is branched. Or, it represents a linear − (CH ₂ ) _b −, and in − (CH ₂ ) _b −, b = 0,1,2,3,4,5,6,7,8,9,10 ... 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. Represents − (CH ₂ ) _c −, and in − (CH ₂ ) _c −, c = 0,1,2,3,4,5,6,7,8,9,10 ..., Whichever 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 ₄ is H, 1 to 12 carbons. Represents any one of alkyl, alkyloxy, alkenyl, perfluoroalkyl, alkyl halide, or alkynyl residues, aryl or heteroaryl moieties having an atom, which CH ₂ is O, S, CH = CH, C. ≡ C, CHR ₆ , CR ₆ R ₇ , may be replaced with aryl or heteroaryl moieties, or other ring moieties; R ₅ is H, alkyl, alkyloxy, alkenyl, having 1 to 12 carbon atoms. Represents any one of perfluoroalkyl, alkyl halides, or alkynyl residues, aryl or heteroaryl moieties, and any CH ₂ is O, S, CH = CH, C≡C, CHR ₆ , CR ₇ R ₆ , Aryl or heteroaryl moiety, or other ring moiety; R ₆ is H, alkyl, alkyloxy, alkenyl, perfluoroalkyl, alkyl halide, or alkyl having 1 to 12 carbon atoms. Represents any one of an nylic residue, aryl or heteroaryl moiety, which CH ₂ is O, S, CH = CH, C≡C, CHR ₆ , CR ₇ R ₅ , aryl or heteroaryl moiety, or the like. R ₇ may be replaced with the ring moiety of H, an alkyl, alkyloxy, alkenyl, perfluoroalkyl, alkyl halide, or alkynyl residue, aryl or heteroaryl moiety having 1 to 12 carbon atoms. Represents any one, and any CH ₂ may be replaced with O, S, CH = CH, C≡C, CHR ₆ , CR ₇ R ₅ , aryl or heteroaryl moiety, or other ring moiety; X represents absent, O, NH, NR ₆ or S; HA represents absent, HCl, HBr, HF, HI, HOAc, citric acid, or any other pharmacologically acceptable acid. , All R, R ₁ , R ₂ , R ₈ , R ₉ , or-(CH ₂ ) _n -groups are branched or linear and C, H, O, Cl, Br, F, I, P , S, N or any other pharmacologically acceptable atom, including single, double, and / or triple bonds; all R, R ₁ , R ₂ , R ₈ , R ₉ , or-(CH ₂ ) _n -groups may be achirals or chirals; if the groups are chirals, they may have one or more chiral centers and are single (R) or (S) enantiomers. Alternatively, it may be a mixture of (R) and (S) enantiomers, and Aryl- represents, but is not limited to, the following equation.

In the formula, R _x represents H, CH ₃ , CH ₃ O, HO, CH ₃ CH ₂ , CF ₃ , CHF ₂ , CH ₂ F, Cl, F, Br, F; R _y is H, 1 Represents any one of an alkyl, alkyloxy, alkenyl, perfluoroalkyl, alkyl halide or alkynyl residue, aryl or heteroaryl moiety having from 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 independently H, HO, CH ₃ COO, R _y COO, HS, NO ₂ , CN, CH ₃ COS, NH ₂ , CH ₃ CONH, R _y CONH, CH ₃ , CH ₃ CH ₂ , C ₃ H ₇ , C ₄ H ₉ , CH ₃ O, CH ₃ CH ₂ O, C ₃ H ₇ O, Cl, F, Br, I, CH ₃ S, CHF ₂ O, CF ₃ O, CF ₃ CF ₂ O, C ₃ F ₇ O, CF ₃ , CF ₃ CF ₂ , C ₃ F ₇ , C ₄ F ₉ , CH ₃ SO ₂ , R _y SO ₂ , CH ₃ SO, Represents 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 and may have a single chiral center. A compound which may be (R) or (S) enantiomer or a mixture of (R) and (S) enantiomer.

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. 2. It is a compound of "chemical structure 1" of the general formula (1).

In the equation, R represents a branched or linear − (CH ₂ ) _n −, and at − (CH ₂ ) _n − n = 0,1,2,3,4,5,6,7,8,9, 10, 11, 12, ..., Which CH ₂ is O, S, NR ₈ , CH = CH, C≡C, CHR ₈ , CR ₈ R ₉ , aryl or heteroaryl residue, or pharmacologically It may be replaced with any other acceptable moiety; R ₁ may be an alkyl, alkyloxy, alkenyl, perfluoroalkyl, alkyl halide, or alkynyl residue, aryl or or having H, 1 to 12 carbon atoms. Represents any one of the heteroaryl moieties, which CH ₂ is O, S, CH = CH, C≡C, CHR ₈ , CR ₈ R ₉ , aryl or heteroaryl moiety, or any pharmacologically acceptable R ₂ may be replaced with other moieties of H, alkyl, alkyloxy, alkenyl, perfluoroalkyl, alkyl halide or alkynyl residues, aryl or heteroaryl moieties having 1 to 12 carbon atoms. Represents any one and replaces any CH ₂ with an O, S, CH = CH, C≡C, CHR ₈ , CR ₈ R ₉ , aryl or heteroaryl moiety, or other pharmacologically acceptable moiety. May be; X represents O, NH, NR ₈ , S, or absent; R ₈ is an alkyl having H, OH, Cl, F, Br, I, 1 to 12 carbon atoms, Represents any one of alkyloxy, alkenyl, perfluoroalkyl, alkyl halide or alkynyl residues, aryl or heteroaryl moieties; R ₉ is H, OH, Cl, F, Br, I, 1-12. Represents any one of alkyl, alkyloxy, alkenyl, perfluoroalkyl, alkyl halide or alkynyl residues, aryl or heteroaryl moieties having a carbon atom; Ary in "Chemical Structure 1" of the general formula (1). − Is defined as the same Any− as “chemical structure 2a, 2b, 2c, or 2d” of the general formula (2a, 2b, 2c, or 2d) according to claim 1; HA does not exist. 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 is branched or linear and C, H, O, Cl, Br, It may contain F, I, P, S, N or any other pharmacologically acceptable atom and may contain single, double and / or triple bonds; all R, R ₁ , The R ₂ , R ₈ , 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 a single (R). Alternatively, the compound may be (S) enantiomer or a mixture of (R) and (S) enantiomer.

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

7. The compound of the "chemical structure 1, 2a, 2b, 2c, or 2d" of the general formula (1, 2a, 2b, 2c, or 2d) as an active ingredient according to the above 1 and 2, or the general. A therapeutically effective amount of a composition comprising at least one compound of "Chemical Structure 1, 2a, 2b, 2c, or 2d" of the formula (1, 2a, 2b, 2c, or 2d) is locally administered to the inflamed area. A method of locally treating headache, toothache, muscle pain, and arthritis and other inflammatory pains in humans or animals.
8. Any of the body to deliver therapeutically effective plasma concentrations for the treatment and prevention of diabetes (types I and II), abnormal blood glucose, abnormal blood lipid levels, and other metabolic disorders in humans or animals. The general formula (1, 2a, 2b, 2c) as an active ingredient according to 1 and 2 above, which can be transdermally administered to a portion (in the form of a solution, spray, lotion, ointment, emulsion or gel). , Or 2d) "Chemical structure 1, 2a, 2b, 2c, or 2d", or "Chemical structure 1, 2a, 2b, 2c," according to the general formula (1, 2a, 2b, 2c, or 2d). Or a composition comprising at least one compound of "2d".
9. Orally, subcutaneously, intravenously, or nasally for the treatment and prevention of diabetes (types I and II), abnormal blood glucose levels, abnormal blood lipid levels, and other metabolic disorders in humans or animals. The general formula (1, 2a) as an active ingredient according to 1 and 2 above, which can be administered as a solution, a spray, an emulsion, a pill, a tablet, or any other formulation. , 2b, 2c, or 2d) "Chemical structure 1, 2a, 2b, 2c, or 2d" compound, or the general formula (1, 2a, 2b, 2c, or 2d) "Chemical structure 1, 2a, A composition comprising at least one compound of "2b, 2c, or 2d".
10. For the treatment and prevention of abnormal blood pressure and abnormal blood lipid levels in humans or animals, of any part of the body (solutions, sprays, lotions, ointments, emulsions or gels) to deliver therapeutically effective plasma concentrations. The "chemical structures 1, 2a, 2b, 2c" of the general formula (1, 2a, 2b, 2c, or 2d) as the active ingredient according to 1 and 2 above, which can be administered transdermally (in form). , 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 (solutions, sprays, emulsions, pills, tablets, or optionally, for the treatment and prevention of abnormal blood pressure and abnormal blood lipid levels in humans or animals. "Chemical structures 1, 2a, of the general formula (1, 2a, 2b, 2c, or 2d), as the active ingredient according to 1 and 2 above, which can be administered (in the form of other formulations). A composition comprising a compound of "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). .. 12. For the treatment and prevention of strokes, heart attacks, and other heart and vascular diseases in humans or animals, to deliver therapeutically effective plasma concentrations to any part of the body (solutions, sprays, lotions, ointments) , In the form of an emulsion or gel, according to 1 and 2 above, as an active ingredient in the general formula (1, 2a, 2b, 2c, or 2d), "Chemical structure 1, 2a, A composition comprising a compound of "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). ..
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 general formula (1, 2a, 2b) as an active ingredient according to 1 and 2 above for treating and preventing stroke, heart attack, and other heart and vascular diseases in humans or animals. , 2c, or 2d) "Chemical structure 1, 2a, 2b, 2c, or 2d" compound, or the general formula (1, 2a, 2b, 2c, or 2d) "Chemical structure 1, 2a, 2b, A composition comprising at least one compound of "2c, or 2d".
14. Orally, subcutaneously, intravenously, or nasally (solutions, sprays, emulsions, pills) for the treatment and prevention of strokes, heart attacks, and other heart and vascular diseases in humans or animals. , Tablets, or "Chemicals" of the general formula (1, 2a, 2b, 2c, or 2d) as the active ingredient according to 1 and 2 above, which can be administered (in the form of tablets, or any other formulation). A compound of "structures 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. To treat and prevent organ transplant rejection in humans or animals, to deliver therapeutically effective plasma concentrations to any part of the body (in the form of solutions, sprays, lotions, ointments, emulsions or gels) The compound of the above general formula (1, 2a, 2b, 2c, and 2d) of the above general formula (1, 2a, 2b, 2c, and 2d) as an active ingredient, which can be administered skin, according to the above 1 and 2. , Or a composition comprising at least one compound of the "chemical structures 1, 2a, 2b, 2c, and 2d" of the general formula (1, 2a, 2b, 2c, and 2d).
16. 1 above for treating and preventing organ transplant rejection in humans or animals by topically administering a therapeutically effective amount to the infected area (in the form of a solution, spray, lotion, ointment, emulsion or gel). And 2, as the active ingredient, the compound of the "chemical structures 1, 2a, 2b, 2c, and 2d" of the general formula (1, 2a, 2b, 2c, and 2d), or the general formula (1). , 2a, 2b, 2c, and 2d) A composition comprising at least one compound of "chemical structures 1, 2a, 2b, 2c, and 2d".
17. Orally, subcutaneously, intravenously, or nasally (solutions, sprays, emulsions, pills, tablets, or any other formulation for the treatment and prevention of organ transplant rejection in humans or animals. The "chemical structures 1, 2a, 2b, 2c, of the general formula (1, 2a, 2b, 2c, and 2d), as the active ingredient according to 1 and 2 above, which can be administered (in the form of). And 2d ”, 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).
18. Solutions, sprays, lotions, on any part of the body (preferably on the neck and head, to deliver therapeutically effective plasma concentrations for the treatment and prevention of Alzheimer's disease, Parkinson's disease and other neurodegenerative diseases. The "chemical structure 1" of the general formula (1, 2a, 2b, 2c, or 2d) as an active ingredient according to 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). Composition containing.

19. Orally, subcutaneously, intravenously, or nasally (solutions, sprays, emulsions, pills, tablets, or any) for the treatment and prevention of Alzheimer's disease, Parkinson's disease and other neurodegenerative diseases. The "chemical structures 1, 2a, 2b" of the general formula (1, 2a, 2b, 2c, or 2d) as the active ingredient according to 1 and 2 above, which can be administered (in the form of other formulations). , 2c, or 2d ”, or a composition comprising at least one compound of“ chemical structure 1, 2a, 2b, 2c, or 2d ”of the general formula (1, 2a, 2b, 2c, or 2d).
20. Transdermal administration (in the form of solutions, sprays, lotions, ointments, emulsions or gels) to any part of the body to deliver therapeutically effective plasma concentrations for the treatment and prevention of psoriasis and other skin disorders The compound of the "chemical structure 1, 2a, 2b, 2c, or 2d" of the general formula (1, 2a, 2b, 2c, or 2d) as the active ingredient according to the above 1 and 2, which can be used. , Or a composition comprising at least one compound of the "chemical structure 1, 2a, 2b, 2c, or 2d" of the general formula (1, 2a, 2b, 2c, or 2d).
21. 1 above for treating psoriasis and other skin disorders in humans or animals by topically administering a therapeutically effective amount to the infected area (in the form of a solution, spray, lotion, ointment, emulsion or gel). And 2, as the active ingredient, the compound of the "chemical structures 1, 2a, 2b, 2c, and 2d" of the general formula (1, 2a, 2b, 2c, and 2d), or the general formula (1). , 2a, 2b, 2c, and 2d) A composition comprising at least one compound of "chemical structures 1, 2a, 2b, 2c, and 2d".
22. Orally, subcutaneously, intravenously, or nasally (solutions, sprays, emulsions, pills, tablets, or any other form of formulation, for the treatment and prevention of psoriasis and other skin disorders. As the active ingredient according to 1 and 2 above, which can be administered), the "chemical structure 1, 2a, 2b, 2c, or 2d" of the general formula (1, 2a, 2b, 2c, or 2d). , Or a composition comprising at least one compound of the above-mentioned general formula (1, 2a, 2b, 2c, or 2d) of "chemical structure 1, 2a, 2b, 2c, or 2d".

23. Discoid lupus erythematosus, systemic lupus erythematosus (SLE), autoimmune disease hepatitis, scleroderma, Sjogren's syndrome, rheumatoid arthritis, polymyositis, scleroderma, Hashimoto thyroiditis, juvenile diabetes, Addison's disease, in humans or animals To deliver therapeutically effective plasma concentrations for the treatment and prevention of vitiligo, malignant anemia, glomerulonephritis, pulmonary fibrosis, multiple scleroderma (MS), Crohn's disease, and other autoimmune diseases. The general formula (1, 2a, as the active ingredient according to 1 and 2 above, which can be transdermally administered (in the form of a solution, spray, lotion, ointment, emulsion or gel) to any portion of the above. 2b, 2c, or 2d) "Chemical structure 1, 2a, 2b, 2c, or 2d" compound, or the general formula (1, 2a, 2b, 2c, or 2d) "Chemical structure 1, 2a, 2b" A composition comprising at least one compound of "2c, or 2d".
24. Discoid lupus erythematosus, systemic lupus erythematosus (SLE), autoimmunity in humans or animals by topically administering a therapeutically effective amount to the infected area (in the form of a solution, spray, lotion, ointment, emulsion or gel) Diseases Hepatitis, scleroderma, Sjogren's syndrome, rheumatoid arthritis, polymyositis, scleroderma, Hashimoto thyroiditis, juvenile diabetes, Addison's disease, vitiligo, malignant anemia, glomerulonephritis, pulmonary fibrosis, multiple sclerosis ( MS), Crohn's disease, and other autoimmune diseases, according to 1 and 2 above, as an active ingredient of the general formula (1, 2a, 2b, 2c, and 2d). Compounds 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 comprising one compound.
25. Discoid lupus erythematosus, systemic lupus erythematosus (SLE), autoimmune disease hepatitis, scleroderma, Sjogren's syndrome, rheumatoid arthritis, polymyositis, scleroderma, Hashimoto thyroiditis, juvenile diabetes, Addison's disease, in humans or animals Orally, subcutaneously, intravenously, or for the treatment and prevention of vitiligo, pernicious anemia, glomerulonephritis, pulmonary fibrosis, multiple scleroderma (MS), Crohn's disease, and other autoimmune diseases. The general formula (1) as an active ingredient according to 1 and 2 above, which can be administered nasally (in the form of a solution, spray, emulsion, pill, tablet, or any other formulation). , 2a, 2b, 2c, or 2d) "Chemical structure 1, 2a, 2b, 2c, or 2d" compound, or the general formula (1, 2a, 2b, 2c, or 2d) "Chemical structure 1, A composition comprising at least one compound of "2a, 2b, 2c, or 2d".
26. Muscular atrophic lateral sclerosis (ALS), myotonic dystrophy (OPMD), myotonic dystrophy (MD), Duchenne muscular dystrophy (DMD), polymyositis (PM), dermatomyositis (DM) in humans or animals , To deliver therapeutically effective plasma concentrations for the treatment and prevention of inclusion myotonic dystrophy (IBM), and other muscular diseases, to any part of the body (solutions, sprays, lotions, ointments, emulsions or gels) The "chemical structure 1, 2a, 2b, of the above general formula (1, 2a, 2b, 2c, or 2d), as an active ingredient according to 1 and 2 above, which can be administered transdermally (in the form of). A composition comprising a compound of "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. Myotonic lateral sclerosis (ALS), ocular pharyngeal type in humans or animals by topically administering a therapeutically effective amount to the infected area (in the form of a solution, spray, lotion, ointment, emulsion or gel) Treat and prevent myotonic dystrophy (OPMD), myotonic dystrophy (MD), Duchenne muscular dystrophy (DMD), polymyositis (PM), dermatomyositis (DM), inclusion body myositis (IBM), and other muscle disorders The compound of the "chemical structure 1, 2a, 2b, 2c, and 2d" of the general formula (1, 2a, 2b, 2c, and 2d), or the compound as the active ingredient according to the above 1 and 2. A composition comprising at least one compound of the "chemical structures 1, 2a, 2b, 2c, and 2d" of the general formula (1, 2a, 2b, 2c, and 2d).
28. Myotonic lateral sclerosis (ALS), ocular pharyngeal muscular dystrophy (OPMD), myotonic dystrophy (MD), Duchenne muscular dystrophy (DMD), polymyositis (PM), dermatomyositis (DM) in humans or animals , Orally, subcutaneously, intravenously, or nasally (solutions, sprays, emulsions, pills, tablets, or) for the treatment and prevention of inclusion body myositis (IBM), and other muscle disorders. "Chemical structure 1, 2a" of the general formula (1, 2a, 2b, 2c, or 2d) as an active ingredient according to 1 and 2 above, which can be administered (in the form of any other formulation). , 2b, 2c, 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). object.
29. Inflammation of the prostate (prostatic inflammation), prostatic cystitis, hemorrhoids, inflammatory hemorrhoids, post-irradiation (artificial formation) proctitis, chronic ulcerative colitis, adenomyosis, other inflammatory symptoms of the anal rectum, and anal pruritus Can be transdermally administered to any part of the body (in the form of a solution, spray, lotion, ointment, emulsion or gel) to deliver a therapeutically effective plasma concentration for the treatment and prevention of the above. The compound of the "chemical structure 1, 2a, 2b, 2c, or 2d" of the general formula (1, 2a, 2b, 2c, or 2d) as an active ingredient according to 1 and 2, or the general formula (1 and 2d). A composition comprising at least one compound of "chemical structure 1, 2a, 2b, 2c, or 2d" of 1, 2a, 2b, 2c, or 2d).
30. Inflammation of the prostate (proctitis), proctitis cystitis, hemorrhoids, inflammatory hemorrhoids by topically administering a therapeutically effective amount to the infected area (in the form of a solution, spray, lotion, ointment, emulsion or gel) The active ingredient according to 1 and 2 above, for treating and preventing proctitis after irradiation (artificial formation), chronic ulcerative colitis, adenomyosis, other inflammatory symptoms of the anal rectum, and anal hemorrhoids. As a compound of the "chemical structures 1, 2a, 2b, 2c, and 2d" of the general formula (1, 2a, 2b, 2c, and 2d), or the general formula (1, 2a, 2b, 2c, and A composition containing at least one compound of "chemical structures 1, 2a, 2b, 2c, and 2d" of 2d).

31. Inflammation of the prostate (prostatitis), prostatitis, hemorrhoids, inflammatory hemorrhoids, post-irradiation (artificial formation) proctitis, chronic ulcerative colitis, adenomyosis, other inflammatory symptoms of the anal rectum, and anal pruritus Orally, subcutaneously, intravenously, or nasally (in the form of solutions, sprays, emulsions, pills, tablets, or any other formulation) for the treatment and prevention of The compound of the "chemical structure 1, 2a, 2b, 2c, or 2d" of the general formula (1, 2a, 2b, 2c, or 2d) as the active ingredient according to the above 1 and 2, or the above. 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).
32. The body to deliver therapeutically effective plasma concentrations for the treatment and prevention of autoimmune hepatitis, autoimmune nephritis, colonic proctitis, enteritis, venitis, vasculitis, and other inflammations in humans or animals. The general formula (1, 2a,) as an active ingredient according to 1 and 2 above, which can be transdermally administered (in the form of a solution, spray, lotion, ointment, emulsion or gel) to any portion of the above. The compound of "1, 2a, 2b, 2c, or 2d" of 2b, 2c, or 2d), or the "chemical structure 1, 2a, 2b, 2c" of the general formula (1, 2a, 2b, 2c, or 2d). , Or a composition comprising at least one compound of "2d".
33. Autoimmune hepatitis, autoimmune nephritis, colonic proctitis, 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. The above-mentioned general formula (1, 2a, 2b, 2c, or 2d) as an active ingredient according to 1 and 2 above for treating and preventing enteritis, venous inflammation, 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 comprising one compound.
34. Orally, subcutaneously, intravenously, or for the treatment and prevention of autoimmune hepatitis, autoimmune nephritis, colonic proctitis, enteritis, venitis, vasculitis, and other inflammations in humans or animals. The general formula (1) as an active ingredient according to 1 and 2 above, which can be administered nasally (in the form of a solution, spray, emulsion, pill, tablet, or any other formulation). , 2a, 2b, 2c, or 2d) "Chemical structure 1, 2a, 2b, 2c, or 2d" compound, or the general formula (1, 2a, 2b, 2c, or 2d) "Chemical structure 1, A composition comprising at least one compound of "2a, 2b, 2c, or 2d".

35. 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 of spinal cord injuries in humans or animals. The compound of "1, 2a, 2b, 2c, or 2d" of the general formula (1, 2a, 2b, 2c, and 2d) as the active ingredient according to the above 1 and 2, or the general. A composition comprising at least one compound of the "chemical structures 1, 2a, 2b, 2c, and 2d" of the formula (1, 2a, 2b, 2c, and 2d).
36. 1 and 2 above for treating spinal cord injury in humans or animals by topically administering a therapeutically effective amount to the infected area (in the form of a solution, spray, lotion, ointment, emulsion or gel). As an active ingredient, the compound of the general formula (1, 2a, 2b, 2c, and 2d) of "chemical structures 1, 2a, 2b, 2c, and 2d", or the general formula (1, 2a, 2b). , 2c, and 2d) A composition comprising at least one compound of "chemical structures 1, 2a, 2b, 2c, and 2d".
37. Orally, subcutaneously, intravenously, or nasally (in the form of solutions, sprays, emulsions, pills, tablets, or any other formulation) for the treatment of spinal cord injuries in humans or animals. The "chemical structures 1, 2a, 2b, 2c, and 2d" of the general formula (1, 2a, 2b, 2c, and 2d) as the active ingredient according to the above 1 and 2, which can be administered. A compound or a composition comprising at least one compound of the "chemical structures 1, 2a, 2b, 2c, and 2d" of the general formula (1, 2a, 2b, 2c, and 2d).
38. Of breast cancer, colorectal cancer, oral cancer, lung and other respiratory cancers, skin cancers, uterine cancers, reproductive organ cancers, urinary cancers, leukemias and other blood and lymphoid cancers and other cancers in humans or animals 1 above, which can be transdermally administered (in the form of a solution, spray, lotion, ointment, emulsion or gel) to any part of the body to deliver a therapeutically effective plasma concentration for treatment and prevention. And 2, as the active ingredient, the compound of the "chemical structure 1, 2a, 2b, 2c, or 2d" of the general formula (1, 2a, 2b, 2c, or 2d), or the general formula (1). , 2a, 2b, 2c, or 2d) A composition comprising at least one compound of "chemical structure 1, 2a, 2b, 2c, or 2d".

39. Breast cancer, colorectal cancer, oral cancer, lung and other respiratory cancers by topically administering a therapeutically effective amount to the infected area (in the form of a solution, spray, lotion, ointment, emulsion or gel) , Skin cancer, uterine cancer, reproductive organ cancer, urinary organ cancer, leukemia and other cancers of blood and lymph tissue, as well as other cancers, as described in 1 and 2 above, as an active ingredient. Compounds of "chemical structures 1, 2a, 2b, 2c, and 2d" of formula (1, 2a, 2b, 2c, and 2d), or "chemistry" of the general formula (1, 2a, 2b, 2c, and 2d). A composition comprising at least one compound of "structures 1, 2a, 2b, 2c, and 2d".
40. Of breast cancer, colorectal cancer, oral cancer, lung and other respiratory cancers, skin cancers, uterine cancers, reproductive organ cancers, urinary cancers, leukemias and other blood and lymphoid cancers and other cancers in humans or animals It can be administered orally, subcutaneously, intravenously, or nasally (in the form of solutions, sprays, emulsions, pills, tablets, or any other formulation) for treatment and prevention. , The compound of the "chemical structure 1, 2a, 2b, 2c, or 2d" of the general formula (1, 2a, 2b, 2c, or 2d) as an active ingredient according to the above 1 and 2, or the general. A composition comprising at least one compound of the "chemical structure 1, 2a, 2b, 2c, or 2d" of the formula (1, 2a, 2b, 2c, or 2d).
41. Of breast cancer, colorectal cancer, oral cancer, lung and other respiratory cancers, skin cancers, uterine cancers, reproductive organ cancers, urinary cancers, leukemias and other blood and lymphoid cancers 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 therapeutic agents for treatment and prevention. The compound of the "chemical structure 1, 2a, 2b, 2c, or 2d" of the general formula (1, 2a, 2b, 2c, or 2d), or the compound of the general formula (1, 2a, A composition comprising at least one compound of "chemical structure 1, 2a, 2b, 2c, or 2d" of 2b, 2c, or 2d).
42. Of breast cancer, colorectal cancer, oral cancer, lung and other respiratory cancers, skin cancers, uterine cancers, reproductive organ cancers, urinary cancers, leukemias and other blood and lymphoid cancers and other cancers in humans or animals Efficacy according to 1 and 2 above, which can be administered percutaneously, orally, subcutaneously, intravenously, or nasally before or after surgery to remove the cancer for treatment. As a component, a compound of the "chemical structure 1, 2a, 2b, 2c, or 2d" of the general formula (1, 2a, 2b, 2c, or 2d), or the general formula (1, 2a, 2b, 2c, Or a composition containing at least one compound of "chemical structure 1, 2a, 2b, 2c, or 2d" of 2d).

43. 1 and 2 above, which can be administered transdermally (topically) in the form of solutions, sprays, lotions, ointments, emulsions or gels for the treatment of cuts, burns, or other trauma. , As an active ingredient, a compound of the "chemical structure 1, 2a, 2b, 2c, or 2d" of the general formula (1, 2a, 2b, 2c, or 2d), or the general formula (1, 2a, 2b, A composition comprising at least one compound of "chemical structure 1, 2a, 2b, 2c, or 2d" of 2c or 2d).
44. Percutaneous in the form of solutions, sprays, lotions, ointments, emulsions or gels for the treatment of abnormal vascular skin lesions, bruise, moles (nevus), skin tags, elderly spots (liver spots), and other skin disorders. The "chemical structures 1, 2a, 2b" of the general formula (1, 2a, 2b, 2c, or 2d) as the active ingredient according to the above 1 and 2, which can be administered (locally). , 2c, 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).
45. The general formula (1, 2a, 2b) as an active ingredient according to 1 and 2 above for treating any symptom that can be treated with NSAIA in humans or animals, and the novel symptom described in the present invention. , 2c, or 2d) "Chemical structure 1, 2a, 2b, 2c, or 2d" compound, or the general formula (1, 2a, 2b, 2c, or 2d) "Chemical structure 1, 2a, 2b, A percutaneous 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 lining layer. The most suitable system is an active ingredient container, which has a permeable bottom facing the skin, and by controlling the release rate, the NSAIA can be adjusted to the optimal therapeutic blood concentration. A system that allows you to reach a certain level, increase efficacy, and reduce the side effects of NSAIA.

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, which comprises a compound having a chemical structure 1.

In the equation, R represents − (CH ₂ ) _n −, where n = 0,1,2,3,4,5,6,7,8,9,10,11 or 12; R ₁ and R ₂ Independently represents any one of an alkyl, alkyloxy, alkenyl, perfluoroalkyl, alkyl halide, or alkynyl residue, aryl or heteroaryl moiety having H, 1 to 12 carbon atoms; Indicates O, NH, NR ₈ , S or absent; R ₈ is an alkyl, alkyloxy, alkenyl, perfluoro having carbon atoms of H, OH, Cl, F, Br, I, 1-12. Represents any one of an alkyl, an alkyl halide, or an alkynyl residue, an aryl or a heteroaryl moiety; HA represents an absent or pharmacologically acceptable acid; Ary- represents the chemical structure of the formula below. Represent,

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 ₃ S, CHF ₂ O, CF ₃ O, CF ₃ CF ₂ O, C ₃ F ₇ O, CF ₃ , CF ₃ CF ₂ , C ₃ F ₇ , C ₄ F ₉ , CH ₃ SO ₂ , R _y SO ₂ , CH ₃ SO, R _y SO, CH ₃ CO or CH ₃ CH ₂ CO; R _y is H, an alkyl having 1 to 12 carbon atoms, an alkyloxy, an alkenyl, a perfluoroalkyl, an alkyl halide or Represents any one of an alkynyl residue, an aryl or a heteroaryl moiety.
[2] A pharmaceutical composition for transdermal administration for lowering blood lipid levels, which comprises a compound having a chemical structure 1.

In the equation, R represents − (CH ₂ ) _n −, where n = 0,1,2,3,4,5,6,7,8,9,10,11 or 12; R ₁ and R ₂ Independently represents any one of an alkyl, alkyloxy, alkenyl, perfluoroalkyl, alkyl halide, or alkynyl residue, aryl or heteroaryl moiety having H, 1 to 12 carbon atoms; Indicates O, NH, NR ₈ , S or absent; R ₈ is an alkyl, alkyloxy, alkenyl, perfluoro having carbon atoms of H, OH, Cl, F, Br, I, 1-12. Represents any one of an alkyl, an alkyl halide, or an alkynyl residue, an aryl or a heteroaryl moiety; HA represents an absent or pharmacologically acceptable acid; Ary- represents the chemical structure of the formula below. Represent,

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 ₃ S, CHF ₂ O, CF ₃ O, CF ₃ CF ₂ O, C ₃ F ₇ O, CF ₃ , CF ₃ CF ₂ , C ₃ F ₇ , C ₄ F ₉ , CH ₃ SO ₂ , R _y SO ₂ , CH ₃ SO, R _y SO, CH ₃ CO or CH ₃ CH ₂ CO; R _y is H, an alkyl having 1 to 12 carbon atoms, an alkyloxy, an alkenyl, a perfluoroalkyl, an alkyl halide or Represents any one of an alkynyl residue, an aryl or a heteroaryl moiety.
[3] A pharmaceutical composition for transdermal administration for treating type II or type I diabetes, which comprises a compound having a chemical structure 1.

In the equation, R represents − (CH ₂ ) _n −, where n = 0,1,2,3,4,5,6,7,8,9,10,11 or 12; R ₁ and R ₂ Independently represents any one of an alkyl, alkyloxy, alkenyl, perfluoroalkyl, alkyl halide, or alkynyl residue, aryl or heteroaryl moiety having H, 1 to 12 carbon atoms; Indicates O, NH, NR ₈ , S or absent; R ₈ is an alkyl, alkyloxy, alkenyl, perfluoro having carbon atoms of H, OH, Cl, F, Br, I, 1-12. Represents any one of an alkyl, an alkyl halide, or an alkynyl residue, an aryl or a heteroaryl moiety; HA represents an absent or pharmacologically acceptable acid; Ary- represents the chemical structure of the formula below. Represent,

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 ₃ S, CHF ₂ O, CF ₃ O, CF ₃ CF ₂ O, C ₃ F ₇ O, CF ₃ , CF ₃ CF ₂ , C ₃ F ₇ , C ₄ F ₉ , CH ₃ SO ₂ , R _y SO ₂ , CH ₃ SO, R _y SO, CH ₃ CO or CH ₃ CH ₂ CO; R _y is H, an alkyl having 1 to 12 carbon atoms, an alkyloxy, an alkenyl, a perfluoroalkyl, an alkyl halide or Represents any one of an alkynyl residue, an aryl or a heteroaryl moiety.
[4] The pharmaceutical composition according to any one of [1] to [3] 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] Any of alkyl, alkyloxy, alkenyl, perfluoroalkyl, alkyl halides, or alkynyl residues, aryl or heteroaryl moieties in which R ₁ and R ₂ independently have 1 to 12 carbon atoms. The pharmaceutical composition according to any one of the above [1] to [5], which represents one.
[7] R ₁ and R ₂ independently represent any one of alkyl, alkyloxy, alkenyl, perfluoroalkyl, alkyl halide, 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 the above [1] to [7], wherein X is O or S.
[9] The pharmaceutical composition according to any one of [1] to [8] above, wherein the compound of the chemical structure 1 is diethylaminoethylacetylsalicylate HA.

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

式中、Ｒ_xは、Ｈ、ＣＨ₃、ＣＨ₃Ｏ、ＨＯ、ＣＨ₃ＣＨ₂、ＣＦ₃、ＣＨＦ₂、ＣＨ₂Ｆ、Ｃｌ、Ｆ、又はＢｒを表し；Ｒ_yは、Ｈ、１から１２の炭素原子を有するアルキル、アルキルオキシ、アルケニル、パーフルオロアルキル、ハロゲン化アルキル若しくはアルキニル残基、アリール又はヘテロアリール部分のいずれか一つを表し；Ｘ₁又はＸ₄は、ＣＨ₂、Ｓ、Ｏ、ＮＨ、又はＣＯを表し；Ｘ₂又はＸ₅は、ＣＨ、ＣＲ₈、又はＮを表し；Ｘ₃は、Ｏ、Ｓ、ＮＨ、又はＮＲ₈を表し；Ｙ、Ｙ₁、Ｙ₂、Ｙ₃、Ｙ₄、Ｙ_5、又はＹ₆は、独立してＨ、ＨＯ、ＣＨ₃ＣＯＯ、Ｒ_yＣＯＯ、ＨＳ、ＮＯ₂、ＣＮ、ＣＨ₃ＣＯＳ、ＮＨ₂、ＣＨ₃ＣＯＮＨ、Ｒ_yＣＯＮＨ、ＣＨ₃、ＣＨ₃ＣＨ₂、Ｃ₃Ｈ₇、Ｃ₄Ｈ₉、ＣＨ₃Ｏ、ＣＨ₃ＣＨ₂Ｏ_、Ｃ₃Ｈ₇Ｏ_、Ｃｌ、Ｆ、Ｂｒ、Ｉ、ＣＨ₃Ｓ、ＣＨＦ₂Ｏ、ＣＦ₃Ｏ、ＣＦ₃ＣＦ₂Ｏ、Ｃ₃Ｆ₇Ｏ、ＣＦ₃、ＣＦ₃ＣＦ_2、Ｃ₃Ｆ₇、Ｃ₄Ｆ₉、ＣＨ₃ＳＯ₂、Ｒ_yＳＯ_2、ＣＨ₃ＳＯ、Ｒ_yＳＯ、ＣＨ₃ＣＯ、又はＣＨ₃ＣＨ₂ＣＯを表す化合物。 Another aspect of the present invention may be as follows.
[1] A compound of the general formula (2a, 2b, 2c, or 2d) having a "chemical structure 2a, 2b, 2c, or 2d".

In the equation, R represents a branched or linear − (CH ₂ ) _n −, and at − (CH ₂ ) _n − n = 0,1,2,3,4,5,6,7,8,9, 10 ... a and; R ₁ is a branched or straight-chain - (CH _{2) a} - represents, - (CH _{2) a} - in a = 0,1,2,3,4,5,6,7,8 , 9, 10 ...; R ₂ represents a branched or linear − (CH ₂ ) _b −, and at − (CH ₂ ) _b −, b = 0,1,2,3,4,5,6. 7, 8, 9, 10 ... and is; R ₃ is a branched or straight-chain - (CH _{2) c} - represents a, - (CH _{2) c} - in c = 0,1,2,3,4,5 , 6, 7, 8, 9, 10 ...; R ₄ is an alkyl, alkyloxy, alkenyl, perfluoroalkyl, alkyl halide, or alkynyl residue, aryl or hetero with H, 1 to 12 carbon atoms. Represents any one of the aryl moieties; R ₅ is an alkyl, alkyloxy, alkenyl, perfluoroalkyl, alkyl halide, or alkynyl residue, aryl or heteroaryl moiety having H, 1 to 12 carbon atoms. Represents any one; R ₆ is any one of alkyl, alkyloxy, alkenyl, perfluoroalkyl, alkyl halides, or alkynyl residues, aryl or heteroaryl moieties having H, 1 to 12 carbon atoms. Represents one; R ₇ represents any one of an alkyl, alkyloxy, alkenyl, perfluoroalkyl, alkyl halide, or alkynyl residue, aryl or heteroaryl moiety having H, 1 to 12 carbon atoms. X represents non-existent, O, NH, NR ₆ or S; HA represents non-existent or pharmacologically acceptable acid, all R, R ₁ , R ₂ , R ₈ , R ₉ , Or − (CH ₂ ) _n − groups are branched or linear, and Aryl − 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 is from H, 1. Represents any one of alkyl, alkyloxy, alkenyl, perfluoroalkyl, alkyl halide 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; 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 independently H, HO, CH ₃ COO, R _y COO, HS, NO ₂ , CN, CH ₃ COS, NH ₂ , CH ₃ CONH, R _y CONH. , CH ₃ , CH ₃ CH ₂ , C ₃ H ₇ , C ₄ H ₉ , CH ₃ O, CH ₃ CH ₂ O _, C ₃ H ₇ O _, Cl, F, Br, I, CH ₃ S, CHF ₂ O , CF ₃ O, CF ₃ CF ₂ O, C ₃ F ₇ O, CF ₃ , CF ₃ CF _2, C ₃ F ₇ , C ₄ F ₉ , CH ₃ SO ₂ , R _y SO _2, CH ₃ SO, R _y 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 having the "chemical structure 1" of the general formula (1).

In the equation, R represents a branched or linear − (CH ₂ ) _n −, and at − (CH ₂ ) _n − n = 0,1,2,3,4,5,6,7,8,9, 10, 11, 12, ...; R ₁ is an alkyl, alkyloxy, alkenyl, perfluoroalkyl, alkyl halide, or alkynyl residue, aryl or heteroaryl moiety having H, 1 to 12 carbon atoms. Represents any one; R ₂ is any one of alkyl, alkyloxy, alkenyl, perfluoroalkyl, alkyl halide or alkynyl residues, aryl or heteroaryl moieties having H, 1 to 12 carbon atoms. Represents; X represents O, NH, NR ₈ , S, or is absent; R ₈ is an alkyl, alkyloxy with H, OH, Cl, F, Br, I, 1 to 12 carbon atoms. , Alkenyl, perfluoroalkyl, alkyl halide or alkynyl residues, aryl or heteroaryl moieties; R ₉ is the carbon atom of H, OH, Cl, F, Br, I, 1-12. Represents any one of alkyl, alkyloxy, alkenyl, perfluoroalkyl, alkyl halide or alkynyl residues, aryl or heteroaryl moieties having the above; Ary− in "Chemical Structure 1" of the general formula (1) , Defined as the same Aryl- as "chemical structure 2a, 2b, 2c, or 2d" of the general formula (2a, 2b, 2c, or 2d) described in [1] above; HA does not exist or Represents a pharmacologically acceptable acid; all R, R ₁ , R ₂ , R ₈ , R ₉ , or − (CH ₂ ) _n − groups are branched or linear compounds.
[3] A coupling reagent for the compound of the "chemical structure 1, 2a, 2b, 2c, or 2d" of the general formula 1, 2a, 2b, 2c, or 2d according to the above [1] or the above [2]. The general formula (1, 2a, 2b, 2c) according to the above [1] or the above [2], which is prepared from NSAIA by a reaction for forming an anhydride using the above, and then a reaction with an alcohol, thiol, or amine. , Or 2d), a method for preparing a compound having a “chemical structure 1, 2a, 2b, 2c, or 2d”.
[4] A halide of the compound of the "chemical structure 1, 2a, 2b, 2c, or 2d" of the general formula 1, 2a, 2b, 2c, or 2d according to the above [1] or the above [2]. The general formula (1, 2a, 2b, 2c, or) according to the above [1] or the above [2], which is prepared from a metal salt, an organic basic salt, or an immobilized basic salt of NSAIA. 2d) A method for preparing a compound having a "chemical structure 1, 2a, 2b, 2c, or 2d".
[5] Metabolic disease, abnormal blood pressure, heart and vascular disease, organ transplant rejection, neurodegenerative disease, skin disease, autoimmune disease, muscle disease, pain, fever, cancer, menstrual difficulty, acute migraine, acute gout Drugs for treating or preventing diseases or symptoms in humans or animals selected from the group consisting of arthritis, tonic spondylitis, rheumatoid arthritis, osteoarthritis, dementia, inflammatory symptoms, spinal cord injuries and injuries. Use of the compound according to the above [1] or [2] for production.
[6] The agent is transdermally administered to a body part in humans or animals in the form of a solution, spray, lotion, ointment, emulsion or gel to deliver a therapeutically effective plasma concentration. ] Use described in.
[7] The use according to [5] above, wherein the drug is orally, subcutaneously, intravenously or nasally administered in the form of a solution, spray, emulsion, pill or tablet.
[8] The use according to [5] above, wherein the agent is administered in the form of a solution, spray, lotion, ointment, emulsion or gel topically to the infected area in a therapeutically effective amount.
[9] The use according to [5] above, wherein the pain is selected from toothache, headache and inflammatory pain.
[10] The use according to [5] above, wherein the metabolic disease is selected from the group consisting of diabetes (type I and / or type II), abnormal blood glucose, and abnormal blood lipid concentration.
[11] The use according to [5] above, wherein the heart and vascular disease is selected from the group consisting of stroke and heart attack.
[12] The use according to [5] above, wherein the neurodegenerative disease is selected from the group consisting of Alzheimer's disease and Parkinson's disease.
[13] The use according to the above [5], wherein the skin disease is psoriasis.
[14] The autoimmune disease is discoid lupus erythematosus, systemic lupus erythematosus (SLE), autoimmune disease hepatitis, scleroderma, Sjogren's syndrome, rheumatoid arthritis, polymyositis, scleroderma, Hashimoto thyroid. The use according to [5] above, which is selected from the group consisting of inflammation, juvenile diabetes, Addison's disease, leukoplakia, pernicious anemia, glomerulonephritis, pulmonary fibrosis, multiple sclerosis (MS) and Crohn's disease.
[15] The muscle diseases include muscular atrophic lateral sclerosis (ALS), ocular pharyngeal muscular dystrophy (OPMD), myotonic dystrophy (MD), Duchenne muscular dystrophy (DMD), polymyositis (PM), and dermatomyositis. The use according to [5] above, which is selected from the group consisting of myotitis (DM) and inclusion body myositis (IBM).
[16] The inflammatory symptoms include inflammation of the prostate (prostatic inflammation), prostatic cystitis, hemorrhoids, inflammatory hemorrhoids, post-irradiation (artificial formation) proctitis, chronic ulcerative colitis, vasculitis, and anal rectum. The use according to [5] above, which is selected from inflammatory symptoms, hemorrhoids, autoimmune hepatitis, autoimmune nephritis, colonic proctitis, enteritis, venous inflammation, and vasculitis.
[17] The cancer is selected from breast cancer, colorectal cancer, oral cancer, respiratory cancer, skin cancer, uterine cancer, genital cancer, urinary cancer, leukemia, and cancer of blood and lymphatic tissue. 5] Use described in.
[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, bruises, moles (nevus), skin tags and elderly spots (chloasma).
[20] Metabolic disease, abnormal blood pressure, heart and vascular disease, organ transplant rejection, neurodegenerative disease, skin disease, autoimmune disease, muscle disease, pain, fever, cancer, menstrual difficulty, acute migraine, acute gout The above for treating or preventing a disease or symptom in a human or animal selected from the group consisting of arthritis, tonic spondylitis, rheumatoid arthritis, osteoarthritis, dementia, inflammatory symptoms, spinal cord injury and injury. A percutaneous therapeutic application system for the compound according to [1] or [2], the system comprising a bandage or patch containing a matrix layer containing one active ingredient and an impermeable lining layer.
[21] By containing an active ingredient container, having an osmotic bottom facing the skin, and controlling the release rate, NSAIA reaches a constant therapeutically optimal blood concentration, increases efficacy, and NSAIA. The system according to the above [20], which makes it possible to reduce the side effects of the above.
[22] A composition comprising water and the compound according to the above [1] or [2].

Claims (1)

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

In the equation, R represents a branched or linear − (CH ₂ ) _n −, and at − (CH ₂ ) _n − n = 0,1,2,3,4,5,6,7,8,9, 10 ... and any CH ₂ may be replaced with O, S, CH = CH, C≡C, CHR ₆ , CR ₆ R ₇ , aryl or heteroaryl residues, or other ring system; R ₁ represents a branched or linear − (CH ₂ ) _a −, and at − (CH ₂ ) _a −, a = 0,1,2,3,4,5,6,7,8,9,10 ... Yes, 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 system; R ₂ is branched. Or, it represents a linear − (CH ₂ ) _b −, and in − (CH ₂ ) _b −, b = 0,1,2,3,4,5,6,7,8,9,10 ... 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. Represents − (CH ₂ ) _c −, and in − (CH ₂ ) _c −, c = 0,1,2,3,4,5,6,7,8,9,10 ..., Whichever 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 ₄ is H, 1 to 12 carbons. Represents any one of alkyl, alkyloxy, alkenyl, perfluoroalkyl, alkyl halide, or alkynyl residues, aryl or heteroaryl moieties having an atom, which CH ₂ is O, S, CH = CH, C. ≡ C, CHR ₆ , CR ₆ R ₇ , may be replaced with aryl or heteroaryl moieties, or other ring moieties; R ₅ is H, alkyl, alkyloxy, alkenyl, having 1 to 12 carbon atoms. Represents any one of perfluoroalkyl, alkyl halides, or alkynyl residues, aryl or heteroaryl moieties, and any CH ₂ is O, S, CH = CH, C≡C, CHR ₆ , CR ₇ R ₆ , Aryl or heteroaryl moiety, or other ring moiety; R ₆ is H, alkyl, alkyloxy, alkenyl, perfluoroalkyl, alkyl halide, or alkyl having 1 to 12 carbon atoms. Represents any one of an nylic residue, aryl or heteroaryl moiety, which CH ₂ is O, S, CH = CH, C≡C, CHR ₆ , CR ₇ R ₅ , aryl or heteroaryl moiety, or the like. R ₇ may be replaced with the ring moiety of H, an alkyl, alkyloxy, alkenyl, perfluoroalkyl, alkyl halide, or alkynyl residue, aryl or heteroaryl moiety having 1 to 12 carbon atoms. Represents any one, and any CH ₂ may be replaced with O, S, CH = CH, C≡C, CHR ₆ , CR ₇ R ₅ , aryl or heteroaryl moiety, or other ring moiety; X represents absent, O, NH, NR ₆ or S; HA represents absent, HCl, HBr, HF, HI, HOAc, citric acid, or any other pharmacologically acceptable acid. , All R, R ₁ , R ₂ , R ₈ , R ₉ , or-(CH ₂ ) _n -groups are branched or linear and C, H, O, Cl, Br, F, I, P , S, N or any other pharmacologically acceptable atom, including single, double, and / or triple bonds; all R, R ₁ , R ₂ , R ₈ , R ₉ , or-(CH ₂ ) _n -groups may be achirals or chirals; if the groups are chirals, they may have one or more chiral centers and are single (R) or (S) enantiomers. Alternatively, it may be a mixture of (R) and (S) enantiomers, and Aryl- represents, but is not limited to, the following equation.

In the formula, R _x represents H, CH ₃ , CH ₃ O, HO, CH ₃ CH ₂ , CF ₃ , CHF ₂ , CH ₂ F, Cl, F, Br, F; R _y is H, 1 Represents any one of an alkyl, alkyloxy, alkenyl, perfluoroalkyl, alkyl halide or alkynyl residue, aryl or heteroaryl moiety having from 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 independently H, HO, CH ₃ COO, R _y COO, HS, NO ₂ , CN, CH ₃ COS, NH ₂ , CH ₃ CONH, R _y CONH, CH ₃ , CH ₃ CH ₂ , C ₃ H ₇ , C ₄ H ₉ , CH ₃ O, CH ₃ CH ₂ O, C ₃ H ₇ O, Cl, F, Br, I, CH ₃ S, CHF ₂ O, CF ₃ O, CF ₃ CF ₂ O, C ₃ F ₇ O, CF ₃ , CF ₃ CF ₂ , C ₃ F ₇ , C ₄ F ₉ , CH ₃ SO ₂ , R _y SO ₂ , CH ₃ SO, Represents 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 and may have a single chiral center. A compound which may be (R) or (S) enantiomer or a mixture of (R) and (S) enantiomer.

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