CN105669531A

CN105669531A - Prodrug of non-steroidal anti-inflammatory drug having high skin and biological membrane penetration speed and novel medical application thereof

Info

Publication number: CN105669531A
Application number: CN201610081197.5A
Authority: CN
Inventors: 于崇曦; 徐丽娜
Original assignee: SERTHEL CORP
Current assignee: Techfields Inc.
Priority date: 2007-06-04
Filing date: 2007-06-04
Publication date: 2016-06-15
Anticipated expiration: 2027-06-04
Also published as: CN105669531B; HK1221467A1

Abstract

The novel positively charged non-steroidal anti-inflammatory drugs shown in general formulas (1, 2a, 2b, 2c or 2d), namely 'structural formulas 1, 2a, 2b, 2c or 2d', have been designed and synthesized. The compounds represented by the general formulas (1, 2a, 2b, 2c or 2d), namely 'structural formulas 1, 2a, 2b, 2c or 2d', can be prepared through reaction between the metal salts, organic alkali salts or immobilized alkali salts of the non-steroidal anti-inflammatory drugs and appropriate halides. The positively charged amino in a prodrug of the invention greatly improves the solubility of the drugs in water and can further combine with negative charges on the phosphate terminal groups of a biological membrane. Thus, the local concentrations of the drugs on the biological membrane or the outer side of the skin are very high so as to facilitate the diffusion of the prodrugs from high-concentration areas to low-concentration areas. The biological membrane can be slightly disturbed through the combination so as to allow parts of space for the fat soluble parts of the prodrugs. When molecules of the biological membrane move, the biological membrane is slightly squeezed due to the combination effects of the prodrugs, and when the amino is not protonized, the amino in the prodrugs is separated from the phosphate terminal groups of the biological membrane, and the prodrugs completely penetrate into the biological membrane. When the amino in the prodrugs moves to the other side of the biological membrane and therefore the amino is protonized, the prodrugs are drawn into the cytoplasm, a half-liquid-state aqueous solution or a suspension solution. The prodrugs can be used for the treatment and prevention of diabetes mellitus (type I and/or type II), pathoglycemia and dyslipidemia, apoplexia, myocardial infarction and other cardiac and cardiovascular diseases, an Alzheimer's disease, a Parkinson's disease and other neurodegenerative diseases, psoriasis, discoid lupus erythematosus, systemic lupus erythematosus (SLE), autoimmune hepatitis, multiple sclerosis (MS) and other autoimmune diseases, amyotrophic lateral sclerosis (ALS), oculopharyngeal muscular dystrophy (OPMD) and other muscle abnormalities, inflamed hemorrhoids, cryptitis and other anorectal inflammatory conditions, pruritus ani, prostatitis, prostatocystitis, varicose veins, autoimmune hepatitis, autoimmune nephritis, phlebitis and other inflammations, skin cancers, breast cancers, colon-rectal cancers, oral cancers and other cancers, scars, abnormal cutaneous vascular lesions, birthmarks and pigmented naevus (pigment), and the prodrugs can directly perform cutaneous penetration without skin permeation promoters.

Description

There is the prodrug of the NSAID (non-steroidal anti-inflammatory drug) of fast skin and membranes penetration speed and new medical usage thereof

The application is the divisional application of 200780053229.X Chinese invention patent application.

Technical field

The present invention relates to the design with positive charge and water miscible NSAID (non-steroidal anti-inflammatory drug) (NSAIAs) prodrug and preparation, these prodrugs can fast skin penetration, cicatrix, rate of blood-milk barrier, and blood brain barrier, the invention still further relates to the new application of these prodrugs, be used for treating and preventing diabetes (I type and II type), pathoglycemia and dyslipidemia, apoplexy, myocardial infarction and other heart and angiopathy, alzheimer's disease, parkinson and other neurodegenerative diseases, psoriasis, discoid lupus erythematosus, systemic lupus erythematosus (sle) (SLE), autoimmune hepatitis, scleroderma, desolate lattice logical sequence syndrome, rheumatoid arthritis, polymyositis, scleroderma, struma lymphomatosa, juvenile diabetes, Addison disease (Addisondisease), vitiligo, pernicious anemia, glomerulonephritis, and pulmonary fibrosis, multiple sclerosis (MS), Crohn disease (Crohn ' sdisease), and its own immune disease, amyotrophic lateral sclerosis (ALS), oculopharyngeal muscular dystrophy (OPMD), myotonia atrophica (MD), Du's Xin Shi muscular dystrophy (DMD), polymyositis (PM), dermatomyositis (DM), inclusion body myositis (IBM), and other muscle disease, hemorrhoid, the hemorrhoid of inflammation, (artificial property) proctitis after irradiation, chronic ulcerative colitis, cryptitis, and other anorectal inflammatory conditions, and pruritus ani, prostatitis, prostatocystitis, varicosis, autoimmune hepatitis, autoimmune nephritis, colorectum inflammation, intestinal is scorching, phlebitis, vascular inflammation and other inflammation, skin carcinoma, breast carcinoma, colorectal carcinoma, oral cancer, lung and other respiratory system carcinoma disease, uterus carcinoma, reproduction cancer, urinary organs cancer, leukemia and other blood and lymphoid tissue cancer and other cancer, cicatrix, abnormal vascular dermatosis, birthmark, melanotic nevus (nevus cell nevus), skin sagging, senile plaque (moth patch), and other dermatosis.These prodrugs can get final product direct transdermal administration without any dermal osmosis accelerator.

Technical background

NSAID (non-steroidal anti-inflammatory drug) is used for sign and the symptom of rheumatoid arthritis, osteoarthritis and ankylosing spondylitis. NSAID (non-steroidal anti-inflammatory drug) is used for treating biliary colic, the pain after fever and episiotomy either individually or as ancillary drug. It is also used to treatment gout, acute migraine and renal colic, and for treating patient in the postoperative inflammation of cataract extraction. Aspirin can be used for preventing heart and angiopathy.

But, use NSAID (non-steroidal anti-inflammatory drug) can produce many side reactions, most importantly gastro-intestinal tract not just as dyspepsia, stomach and duodenal hemorrhage, gastric ulcer and gastritis. Fishman (Fishman; Robert, U.S.Pat.No.7,052,715) point out with another problem is that oral medication produces, in order to enable effectively to treat pain or the inflammation that remote location produces, the drug level in blood circulation must reach significantly high. These concentration often act on the actually required of pain or injury far above assuming that medicine can be directly targeted. Fishman and other people (VanEngelen etc., U.S. Patent numbers 6,416,772 many; Macrides etc., U.S. Patent number 6,346'278; Kirby etc., U.S. Patent number 6,444,234, Pearson etc., U.S. Patent number 6,528,040 and Botknecht etc., U.S. Patent number 5,885,597) attempted developing a kind of transdermal administration transmission system by the method for preparation. Song et al. develops a kind of ataractic transdermal drug delivery system of the antiinflammatory containing diclofenac diethylammonium salt (Song etc., U.S. Patent number 6,723,337). Donati et al. develops the ointment (Donati etc., U.S. Patent number 6,592,891) containing heparin and diclofenac that a kind of local uses. Kawaji et al. develops a kind of external oily paster (Kawaji etc., U.S. Patent number 6,262,121) containing diclofenac sodium. Effing etc. develop the equipment (Effing etc., U.S. Patent number 6,193,996) of transdermal delivery diclofenac. But, it is difficult to be transmitted in host by NSAID (non-steroidal anti-inflammatory drug) and reach therapeutically effective plasma concentration by the method for preparation. SusanMilosovich etc. have designed and synthesized 4-dimethylaminobutyricacid acid testosterone ester hydrochloride (TSBH), and it has a fat-soluble part and a tertiary amine group existed at physiological ph with protonated form. They find this prodrug (TSBH) through the speed of human body skin is female medicine (TS) nearly 60 times [SusanMilosovich, etal., J.Pharm.Sci., 82,227 (1993).

Technical problem

Some NSAID (non-steroidal anti-inflammatory drug) was as medicinal more than 100 year. NSAID (non-steroidal anti-inflammatory drug) is used for sign and the symptom of rheumatoid arthritis and osteoarthritis, alleviates mild or moderate pain, brings down a fever and treat menstrual pain. They are most popular medicines in the world.

But, use NSAID (non-steroidal anti-inflammatory drug) can produce many side effect, most importantly gastrointestinal upset such as dyspepsia, heartburn, vomiting, stomach and duodenal hemorrhage, gastric ulcer and gastritis. The stomach that NSAID (non-steroidal anti-inflammatory drug) causes and duodenal hemorrhage are often painless, but can cause fecal blood and lasting iron deficiency anemia.

Transdermal drug delivery system can help prevent medicine coup injury gastrointestinal tract and the drug inactivation avoiding medicine in gastrointestinal tract and liver owing to " head crosses " effect causes. By using the Traditional transdermal form of administration of dermal osmosis accelerator to there is many limitation. First, medicine penetrates the speed of skin very slowly (with μ g/cm²/ h is measurement unit).Secondly, substantial amounts of dermal osmosis accelerator enters in host and may result in very serious side effect.

Solution

Transdermal drug delivery system can help prevent medicine coup injury gastrointestinal tract, and avoids medicine in gastrointestinal tract and liver owing to " head crosses " effect causes drug inactivation. By using the Traditional transdermal form of administration of dermal osmosis accelerator to there is many limitation. First, medicine penetrates the speed of skin very slowly (with μ g/in²/ h is measurement unit). Secondly, substantial amounts of dermal osmosis accelerator enters in host and may result in extra side effect. 3rd, in the Traditional transdermal form of administration passing through use dermal osmosis accelerator, although the penetration enhancer of preparation middle and high concentration can help medicine traverse skin, but after penetration enhancer and medicine enter skin, the concentration of penetration enhancer can significantly be diluted, thus drug molecule can not be helped to stride across more biomembrane, therefore drug molecule can be assembled at subcutaneous layer of fat, and the medicine assembled may result in very serious or even fatal side effect.

The bioavailability of medicine can be weighed the medicine after administration and enter the relative quantity of system circulation. But " action site " of most drug does not circulate in system. Even if drug molecule reaches system circulation, they also have to pass through more biomembrane, these biomembranes than gastrointestinal tract mucosa be more difficult to through, and medicine arrive before the unapproachable region of so-called " action site " can and iuntercellular and intracellular liquid phase mutual effect; Therefore most drug arrive " action site " is front will by intestinal mucosa, liver, blood, kidney and lung metabolism. This situation not only causes relatively low pharmacodynamics effect, and can to intestinal mucosa, blood, liver, and kidney and lung produce toxicity burden. If we can improve medicine through various biomembranous speed, the pharmacodynamics effect of medicine and clinical effectiveness can be greatly improved, and therefore required drug dose is less, and the side effect of generation is less. Owing to prodrug has the speed of skin penetration quickly and membranes penetration, therefore the transdermal drug delivery system of these prodrugs can be not only used for the disease for the treatment of local and can treat systematic disease. Because the curative effect of prodrug improves tens times or hundred times than female medicine, so having only to 1/the tens or more than percent of routine administration dosage, and the side effect produced is less. Transdermal administration is not only benefited by these, and is also beneficial to other medicines transmission system (such as oral, subcutaneous administration, intravenously administrable, inhalation and nasal-cavity administration).

We have found that have a lipophilic portion and one when physiological ph can protonated form exist primary amine, secondary amine, or the medicine of tertiary amine group (preferred tertiary amine group) (hydrophilic segment) can at a terrific speed (with mg/cm²/ h is measurement unit) penetrate skin, cicatrix, blood-brain barrier and blood-milk barrier. The principle of the prodrug designing these NSAID (non-steroidal anti-inflammatory drug) has:

1. prodrug must have a lipophilic portion and one when physiological ph can protonated form exist primary amine, secondary amine, or tertiary amine group (preferred tertiary amine group) (hydrophilic segment).

2. in the prodrug of each NSAID (non-steroidal anti-inflammatory drug) should only one of which or two (preferably one) when physiological pH can protonated form exist one-level, two grades or tertiary amine group (hydrophilic segment).

3. the Main Function of primary amine, secondary amine or tertiary amine group is to aid in drug molecule through skin, cicatrix, biomembrane, blood brain barrier, rate of blood-milk barrier and other barriers.Primary amine, secondary amine or tertiary amine group can be nontoxic and not affect bioactive any structure of female medicine.

We have had some prodrug of whole NSAID (non-steroidal anti-inflammatory drug) of formula (1) " structural formula 1 " disclosed in multiple patents (international patent application no: PCT/IB2006/052732, PCT/IB2006/052318, PCT/IB2006/052815, PCT/IB2006/052563, PCT/IB2006/052575, PCT/IB2006/053741, PCT/IB2006/053091, PCT/IB2006/053090, PCT/IB2006/052549).

[Chem1]

Wherein, R represents side chain or straight chain-(CH₂)_n-, n=0,1,2,3,4,5,6,7,8,9,10,11,12 ..., at-(CH₂)_n-in, any CH₂Can by O, S, NR₈, CH=CH, C ≡ C, CHR₈, CR₈R₉, aryl or heteroaryl, or other any pharmaceutically acceptable group; R₁Or R₂Represent H, the alkyl of any 1-12 carbon atom, alkoxyl, thiazolinyl, perfluoroalkyl, haloalkyl or alkynyl, aryl or heteroaryl, wherein, any CH₂Can by O, S, CH=CH, C ≡ C, CHR₈, CR₈R₉, aryl or heteroaryl, or other any pharmaceutically acceptable group replaces; X represents O, NH or NR₈, S or do not have atom; R₈Represent H, OH, Cl, F, Br, I, the alkyl of arbitrary 1-12 carbon atom, alkoxyl, thiazolinyl, perfluoroalkyl, haloalkyl or alkynyl, aryl or heteroaryl; R₉Represent H, OH, Cl, F, Br, I, the alkyl of arbitrary 1-12 carbon atom, alkoxyl, thiazolinyl, perfluoroalkyl, haloalkyl or alkynyl, aryl or heteroaryl; HA represents does not have atom, HCl, HBr, HF, HI, HOAc, citric acid, or any pharmaceutically acceptable acid. All of R, R₁, R₂, R₈, R₉Or-(CH₂)_n-group can be side chain or straight chain, it is possible to containing C, H, O, Cl, Br, F, I, P, S, N or any other atoms pharmaceutically acceptable, it is possible to has a singly-bound, double bond, or/and three keys; All of R, R₁, R₂, R₈, R₉Or-(CH₂)_n-group can have chirality or not have chirality, if there being chiral radicals, then it can contain one or more chiral centres, it is possible to is single (R) or the mixture of (S) enantiomer or (R) and (S) enantiomer. Ary-represents, but is not limited to:

[Chem.2]

[Chem.3]

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[Chem.36]

[Chem.37]

[Chem.38]

Wherein, Rx represents H, CH₃、CH₃O、OH、CH₃CH₂、CF₃、CHF₂、CH₂F, Cl, F, Br, F; Ry represents H, the alkyl of arbitrary 1-12 carbon atom, alkoxyl, thiazolinyl, perfluoroalkyl, haloalkyl or alkynyl, aryl or heteroaryl; X₁Or X₄Represent CH₂, S, O, NH or CO; X₂Or X₅Represent CH, CR₈Or N; X₃Represent O, S, NH or NR₈; Y, Y₁、Y₂、Y₃、Y₄、Y₅Or Y₆Each independently represent 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; Any Ary-can have chirality or not have hands; If Ary-has chirality, then can there is one or more chiral centre, it is possible to be single (R) or the mixture of (S) enantiomer or (R) and (S) enantiomer.

We have found that the Main Function of primary amine, secondary amine or tertiary amine group is only help medicine traverse skin, biomembrane, blood-brain barrier, blood-milk barrier or other barrier, therefore primary amine, secondary amine or tertiary amine group can be any nontoxic and not affect female bioactive structure of medicine. According to this characteristic, we have designed and synthesized different types of amido. The novel prodrugs of these NSAID (non-steroidal anti-inflammatory drug) has formula (2a, 2b, 2c or 2d) " structural formula 2a, 2b, 2c or 2d ".

[Chem.39]

Wherein, R represents side chain or straight chain-(CH₂)_n-, wherein, n=0,1,2,3,4,5,6,7,8,9,10..., at-(CH₂)_n-in, arbitrary CH₂Group can by O, S, CH=CH, C ≡ C, CHR₆、CR₆R₇, aryl or heteroaryl, or other loop systems replaces; R₁Represent side chain or straight chain ,-(CH₂)_a-, wherein, a=0,1,2,3,4,5,6,7,8,9,10...; At-(CH₂)_a-in, arbitrary CH₂Group can by O, S, CH=CH, C ≡ C, CHR₆、CR₆R₇, aryl or heteroaryl, or other loop systems replaces; R₂Represent side chain or straight chain-(CH₂)_b-, wherein, b=0,1,2,3,4,5,6,7,8,9,10..., at-(CH₂)_b-in, arbitrary CH₂Group can by O, S, CH=CH, C ≡ C, CHR₆、CR₆R₇, aryl or heteroaryl, or other loop systems replaces; R₃Represent side chain or straight chain ,-(CH₂)_c-, wherein, c=0,1,2,3,4,5,6,7,8,9,10..., at-(CH₂)_c-in, arbitrary CH₂Group can by O, S, CH=CH, C ≡ C, CHR₆、CR₆R₇, aryl or heteroaryl, or other loop systems replaces; R₄Represent H, the alkyl of arbitrary 1-12 carbon atom, alkoxyl, thiazolinyl, perfluoroalkyl, haloalkyl or alkynyl, aryl or heteroaryl, wherein, arbitrary CH₂Can by O, S, CH=CH, C ≡ C, CHR₆、CR₆R₇, aryl or heteroaryl, or other loop systems replaces; R₅Represent H, the alkyl of arbitrary 1-12 carbon atom, alkoxyl, thiazolinyl, perfluoroalkyl, haloalkyl or alkynyl, aryl or heteroaryl, wherein, arbitrary CH₂Can by O, S, CH=CH, C ≡ C, CHR₆、CR₇R₆, aryl or heteroaryl, or other loop systems replaces; R₆Represent H, the alkyl of arbitrary 1-12 carbon atom, alkoxyl, thiazolinyl, perfluoroalkyl, haloalkyl or alkynyl, aryl or heteroaryl, wherein, arbitrary CH₂Can by O, S, CH=CH, C ≡ C, CHR₇、CR₇R₅, aryl or heteroaryl, or other ring base replaces; R7 represents H, the alkyl of arbitrary 1-12 carbon atom, alkoxyl, thiazolinyl, perfluoroalkyl, haloalkyl or alkynyl, aryl or heteroaryl, wherein, and arbitrary CH₂Can by O, S, CH=CH, C ≡ C, CHR₆、CR₆R₅, aryl or heteroaryl, or other ring base replaces; X represents does not have atom, O, NH, NR₆Or S; Ary-in formula (2a, 2b, 2c or 2d) " structural formula 2a, 2b, 2c or 2d " is defined as consistent with the Ary-in formula (1) " structural formula 1 "; HA represents without atom, HCl, HBr, HF, HI, HAcO, citric acid or other pharmaceutically acceptable acids. All of R, R₁、R₂、R₃、R₄、R₅、R₆、R₇, or-(CH₂)_n-group can be side chain or straight chain, it is possible to containing C, H, O, Cl, Br, F, I, P, S, N or any pharmaceutically acceptable atom, it is possible to has singly-bound, double bond or/and three keys; All of R, R₁、R₂、R₃、R₄、R₅、R₆、R₇, or-(CH₂)_n-group can be with or without chirality, if there being chiral radicals, then can have one or more chiral centre, it is possible to is single (R) or the mixture of (S) enantiomer or (R) and (S) enantiomer.

No matter medicine is absorb through gastrointestinal tract or other approach, is required for medicine and strides across barrier film with monomolecular form. First medicine must dissolve, and if its there is desirable biopharmaceutical properties, it can be diffused into low concentration region from area with high mercury, stride across biomembrane enter blood or system circulation. All of biomembrane contains lipid as Main Ingredients and Appearance. In biofilm structure, active molecule all has containing phosphatic highly polar head construction, and, in most of the cases, the hydrocarbon tails of two very hydrophobic. Biomembrane has double-decker, and hydrophilic head construction is towards the aqueous regions of both sides. Very hydrophilic medicine cannot by the very hydrophobic medicine through biomembranous lipid layer because of similar compatibility reason as biomembranous a part stop wherein, thus can not be efficiently entering inside Cytoplasm.

An object of the present invention is the side effect in order to avoid NSAID (non-steroidal anti-inflammatory drug), by improving NSAID (non-steroidal anti-inflammatory drug) dissolubility in gastric juice so that it can pass through oral, and improve the NSAID (non-steroidal anti-inflammatory drug) penetration speed to biomembrane and skin barrier so that it can pass through transdermal administration (external).The most important purpose of the present invention is the prodrug of design NSAID (non-steroidal anti-inflammatory drug), these prodrugs can effectively pass the cell membrane of skin, cell membrane, particularly brain cell and neurocyte, and residence time is shorter in system circulates, therefore they are than female medicine activity decades of times or hundreds times by force, and having only to 1/the tens or more than one percent of normal dose, produced side effect is less. This not only contributes to transdermal administration, but also can be used for any other form of administration (such as oral, subcutaneous administration, intravenously administrable, inhalation and nasal-cavity administration) and can treat many female irremediable states of medicine. The novel prodrugs of these NSAID (non-steroidal anti-inflammatory drug) has two structural features in common: they have a lipophilic part and one under physiological ph conditions can the one-level that exists of protonated form, two grades, or tertiary amine group (water-soluble portion). The balance of such water-soluble oil soluble is that medicine can effectively through the condition [SusanMilosovich, etal., J.Pharm.Sci., 82,227 (1993)] that biomembrane is required. The amino of positively charged greatly increases these medicines dissolubility in water. Positive charge on these prodrug amino can be combined by the negative charge on biomembranous phosphate end group. Thus, medicine local concentration outside biomembrane or skin can be significantly high thus being conducive to these prodrugs to be diffused into low concentration region from area with high mercury. This combination slightly can upset biomembrane thus the fatty contents for prodrug concedes segment space. When biomembranous molecule moves, due to the combination of prodrug, biomembrane can slightly be squeezed some gaps. And this can make prodrug be inserted in biomembrane. When pH value is 7.4, only about the amino of 99% is protonated. When amino is not protonated, the amino in prodrug can separate with biomembranous phosphate end group, and prodrug will completely in biomembrane. When the amino in prodrug moves to biomembranous opposite side and is therefore protonated, prodrug can be drawn into Cytoplasm, in the concentrated aqueous solution of a kind of semi liquid state or suspension. Owing to prodrug time of staying in the gastrointestinal tract is very short, prodrug will not gastric mucosal cell damage. These novel prodrugs are penetrated the speed of human body skin and are measured by the Franz pond improved in vitro, and wherein human body skin is isolatable from the human skin tissue (360-400 micron is thick) of thigh position above or below. Accept solution be made up of 10 milliliters of normal saline containing the bovine serum albumin of 2% and stir with the speed of 600 revs/min. The relation of time is measure by specific high performance liquid chromatography by the accumulation total amount of the medicine of prodrug and traverse skin. The apparent penetrating value of the prodrug of NSAID (non-steroidal anti-inflammatory drug) is 0.1-50mg/cm²/ h. Result illustrates that prodrug diffusion velocity in human body skin is faster at least 100 times than female medicine itself. Result illustrates that the positive charge on dialkylaminoethyl is extremely important through biomembrane and skin barrier to medicine.

The prodrug of these novel NSAID (non-steroidal anti-inflammatory drug) can through skin barrier, blood-brain barrier and blood-milk barrier. Experiment compares prodrug and their the female medicine internal penetration speed through the rat skin lived. Donor solution by be dissolved in 1 milliliter of ethanol 20% prodrug or its female drug solns form, be coated in the area at about 5 square centimeters of rat (about 200 grams) back. After 4 hours, putting to death rat, add 5 ml methanol (buffer solution of liver, kidney or cerebral tissue pH7.2 washes three times) respectively in 1 milliliter of blood, 1 gram of liver, 1 gram of kidney or 1 Borneo camphor tissue, mixture homogenizer beats.Then sample is centrifuged 5 minutes, analyzes with HPLC. Result is in shown in Table 1-5.

Table 1. diethylin ethyl salicylate acetylsalicylate (P-1) and metabolite distribution in rat body tissue and blood plasma thereof

Prodrug or metabolite	Blood plasma	Liver	Kidney	Brain
					P-1	30±10μg/ml	15±8μg/g	25±6μg/g	15±6μg/g
Aspirin	25±8μg/ml	13±8μg/g	20±6μg/g	15±5μg/g
					Salicylic acid	80±10μg/ml	30±8μg/g	45±6μg/g	30±6μg/g

Table 2.1-piperidines propyl group 2-[(2,6-Dichlorobenzene base) amino]-phenylacetate acetate (P-2) and metabolite distribution in rat body tissue and blood plasma thereof

Table 3.1-pyrrolidine propyl group 2-(3-Phenoxyphenyl) propionate. AcOH (P-3) and metabolite distribution in rat body tissue and blood plasma thereof

Prodrug or metabolite	Blood plasma	Liver	Kidney	Brain
					P-3	35±8μg/ml	22±8μg/g	25±6μg/g	20±6μg/g
Ketoprofen	70±8μg/ml	32±8μg/g	45±6μg/g	35±5μg/g

Table 4.4-piperidino methyl 2-(3-Phenoxyphenyl) propionate. AcOH (P-4) and metabolite distribution in rat body tissue and blood plasma thereof

Prodrug or metabolite	Blood plasma	Liver	Kidney	Brain
					P-4	32±8μg/ml	30±8μg/g	20±6μg/g	20±6μg/g
Fenoprofen	80±8μg/ml	38±8μg/g	48±6μg/g	45±5μg/g

Table 5.4-piperidine methyl 2-(ρ-isobutyl group propyl group) propionate. AcOH (P-5) and metabolite distribution in rat body tissue and blood plasma thereof

Prodrug or metabolite	Blood plasma	Liver	Kidney	Brain
					P-5	40±8μg/ml	25±8μg/g	30±6μg/g	25±6μg/g
Ibuprofen	70±8μg/ml	35±8μg/g	45±6μg/g	35±5μg/g

Aspirin by be dissolved in 1 milliliter of ethanol 20%, diclofenac, ketoprofen, fenoprofen or ibuprofen are coated in the area of rat back about 5 square centimeters. After 4 hours, putting to death rat, respectively at 1 milliliter of blood plasma, 1 gram of liver, 1 gram of kidney, or add 5 ml methanol in 1 Borneo camphor tissue (buffer solution of liver, kidney or cerebral tissue pH7.2 washes three times), mixture homogenizer beats. The tissue or blood plasma of rat are not detected by these medicines. Result illustrates that the prodrug of these NSAID (non-steroidal anti-inflammatory drug) can pass skin barrier, blood-brain barrier and other membranes barriers rapidly, and the amount of female medicine of NSAID (non-steroidal anti-inflammatory drug) traverse skin can't detect.

Our patent (international patent application no: PCT/IB2006/052732, PCT/IB2006/052318, PCT/IB2006/052815, PCT/IB2006/052563, PCT/IB2006/052575, PCT/IB2006/053741, PCT/IB2006/053091, PCT/IB2006/053090, PCT/IB2006/052549) having shown that, the prodrug represented by formula (1) " structural formula 1 " has antiinflammatory, eases pain, brings down a fever and antirheumatic activity. We have found that the prodrug represented by formula (2a, 2b, 2c or 2d) " structural formula 2a, 2b, 2c or 2d " has all been proved to have antiinflammatory, eases pain, has brought down a fever and antirheumatic activity. The present invention focuses principally on the prodrug of NSAID (non-steroidal anti-inflammatory drug) new application medically.

It is known that cancer and inflammation have certain relation. Doctor TheaD.Tlsty mentions (KeystoneSymposia:InflammationandCancer in his report, Breckenridge, Colorado, the U.S., 27-March 3 February, 2005) COX-2 (COX-2) stimulates the activity of aromatase, Angiogensis, stimulate proliferation, the synthesis of infiltration and prostaglandin. The increase of prostaglandin can inhibited apoptosis. Aspirin and other NSAID (non-steroidal anti-inflammatory drug) can suppress cyclooxygenase-1 and COX-2. The people of long-term taking aspirin occurs the chance of colorectal carcinoma, esophageal carcinoma, ovarian cancer or other cancer generally speaking to decrease. But, cancerous cell can stop NSAID (non-steroidal anti-inflammatory drug) to enter cancerous cell by the structure of change cell membrane. In the present invention, these novel prodrugs can through any biomembrane, it is possible to directly at the skin surface topical of cancer location, substantial amounts of prodrug can enter into cancerous cell and amount that system exposes is non-normally low.

In order to evaluate the anti-tumor activity of NSAID (non-steroidal anti-inflammatory drug) prodrug, human breast cancer cell (BCAP-37, the tumor tissues of every mice 2-3 cubic millimeter) is transplanted to nude mice by subcutaneous (BALB, often organizes 7 mices by 12 groups).After 14 days, gross tumor volume grows to 50 ± 10 cubic millimeters (0.05 milliliters). then by (being equivalent to 1.5 milligrams of prodrugs) diethyllaminoethyl acetylsalicylate acetylsalicylate (P-1, acetone soln) of 30 microlitres 5%, 1-piperidines propyl group 2 [(2, 6-Dichlorobenzene base) amino] phenethyl ester acetate (P-2, aqueous solution), 1-pyrrolidinylpropyl 2-(3-Phenoxyphenyl) propionate. AcOH (P-3, aqueous solution), 4-piperidine methyl 2-(3-Phenoxyphenyl) propionate. AcOH (P-4, aqueous solution), 3-piperidine methyl 2-(ρ-isobutyl phenenyl) propionate. AcOH (P-5, aqueous solution), diethyllaminoethyl 1-(p-chlorobenzene formacyl)-5-methoxyl group-2 methyl indole base 3-acetas acetate (P-11, aqueous solution), the fluoro-2-methyl isophthalic acid of 2-(4-morpholinyl) ethyl (Z)-5--[(4-methylsulfinyl) phenylmethylene]-1H-indenyl-3-ethyl ester acetate (P-12, aqueous solution), diethyllaminoethyl 2-(2, 4-dichlorophenoxy) phenylacetate acetate (P-19, aqueous solution), diethyllaminoethyl 2-(8-methyl isophthalic acid 0, 11-dihydro-11-oxygen hexichol (b, f) oxa-Zhuo-2-base) propionate. AcOH (P-37, aqueous solution), 1-pyrrolidinylpropyl 2-[[(3-(trifluoromethyl) phenyl) amino] benzoate acetate (P-48, aqueous solution), 4-N, N-dimethylaminobutyryloxy-2-methyl-N-2-pyridyl-2H, 1, 2-benzothiazine base-3-amide 1, 1-dioxide. HCl (P-51, acetone soln) local application is in the position (near foreleg) implanting human breast cancer cell, every 8 hours with once. after 42 days, the size of tumor is in shown in Table 6 and table 7.

The gross tumor volume of table blank group and medication therapy groups nude mice after 6.42 days and weight

Prodrug

Blank group

P-1

P-2

P-3

P-4

P-5

Volume (mm³)

800±100

150±50

180±50

200±50

180±50

190±50

Weight

22±2

22±3

22±2

21±3

22±3

23±2

The gross tumor volume of table medication therapy groups nude mice after 7.42 days and weight

Prodrug

P-11

P-12

P-19

P-37

P-48

P-51

Volume (mm³)

210±100

250±50

280±50

250±50

290±50

390±50

Weight

21±2

23±3

21±2

23±3

22±3

23±2

In second group of anti-tumor experiment, by colon cancer cell (LS174J, every the mice 2-3 cubic millimeter tumor tissues) heteroplastic transplantation of people to nude mice by subcutaneous (BALB). after seven days, tumor grows to 55 ± 10 cubic millimeters of volumes (0.055 milliliter). then about 30 microlitres are contained 5% (being equivalent to the prodrug of 1.5 milligrams) diethyllaminoethyl acetylsalicylate acetylsalicylate (P-1, acetone soln), 1-piperidines propyl group 2 [(2, 6-Dichlorobenzene base) amino] phenylacetate acetate (P-2, aqueous solution), 1-pyrrolidinylpropyl 2-(3-benzyloxy phenyl) propyl ester acetate (P-3, aqueous solution), 4-piperidine methyl 2-(3-Phenoxyphenyl) propionate. AcOH (P-4, aqueous solution), 3-piperidine methyl 2-(ρ-isobutyl phenenyl) propionate. AcOH (P-5, aqueous solution), diethyllaminoethyl 1-methyl-5-(4-methyl benzoyl)-1H-pyrroles-2-ethyl ester acetate (P-13, aqueous solution), 2-(4-morpholinyl) ethyl 2-amino-benzoyl phenylacetate acetate (P-16, aqueous solution), diethyllaminoethyl 2-(10, 11-dihydro-10-oxygen hexichol (b, f) thiotropilium-2-yl) propionate. AcOH (P-36), diethyllaminoethyl 2-[(2, 3-3,5-dimethylphenyl) amino] benzoate acetate (P-46, aqueous solution), diethyllaminoethyl 2-[(2, the chloro-3-aminomethyl phenyl of 6-bis-) amino] benzoate acetate (P-47, aqueous solution), N-(2-thiazolyl)-4-N, N-dimethylamino butyryl acyloxy-2-methyl-2H, 1, 2-benzothiazine base-3-amide 1, 1-dioxide. HCl (P-52, acetone soln) topical is in the implant site (near the position of foreleg) of human colon cancer cell, it was administered once every 8 hours.The tumor size of the 30th day is in shown in Table 8 and 9.

The tumor size of table 8. matched group and medication therapy groups nude mice when the 30th day and weight

Prodrug

Blank group

P-1

P-2

P-3

P-4

P-5

Size (mm³)

1300±300

420±100

480±180

500±150

480±120

390±110

Weight

21±2

22±3

22±2

21±3

22±3

23±2

The size of table 9. medication therapy groups nude mouse tumor when the 30th day and weight

Prodrug

P-13

P-16

P-36

P-46

P-47

P-52

Size (mm³)

610±200

550±150

480±180

650±250

490±150

690±250

Weight

21±2

23±3

21±2

23±3

22±3

23±2

The prodrug of result display NSAID (non-steroidal anti-inflammatory drug) has a very strong anti-tumor activity, and not or only have small side effect.

Before more than 100 years, the doctor of Germany just has been found that the effect of lowering blood sugar (EdmundJ.Hengesh, Principlesofmedicinalchemistry, 4thed., pg591, Williams&Wilkins, 1995) of Salicylate. Salicylate can improve the insulin secretion that glucose stimulates, and suppress by lactic acid and alanine synthesis of glucose (H.F.Woods, etal., Clin.Exp.PharmacolPhysiol., 1,534 (1974). Some Salicylate can reduce the free fatty in blood plasma, triglyceride and cholesterol levels. Because the free fatty acid levels rising in blood plasma can suppress the utilization of glucose, therefore the reduction of its concentration has hypoglycemic effect. But, in order to blood sugar level and blood lipid level being kept (the every day 5 grams) Salicylate controlling to take heavy dose fully. Under such dosage level, often produce a lot of side effect such as gastric irritation, Nausea and vomiting and tinnitus. In the present invention, these novel prodrugs have the transdermal and membrane penetration rates that are exceedingly fast. They can arrive " action site " rapidly, it is greatly improved pharmacologic effect and the clinical response of these prodrugs, thus required drug dose lower (having only to one 1/tens to several the percent of female pharmaceutical quantities), its side effect caused is also less.

These prodrugs in the present invention can reduce blood sugar level (SLAC/GK, II-patients with type Ⅰ DM, n=7) in rat model. by containing 50% diethyllaminoethyl acetylsalicylate acetylsalicylate (P-1, acetone soln), 4-acetamidophenyl salicylyl acyl group dimethylamino butyl ester hydrochlorate (P-6), diethyllaminoethyl 5-(2, 4-difluorophenyl) acetylsalicylate 5-(2, 4-difluorophenyl) acetyl salicylic salt (P-8), diethyllaminoethyl disalicylic acid ester acetate (P-9), diethylaminoethyl salicylate acetate (P-10), diethyllaminoethyl 5-acetylaminohydroxyphenylarsonic acid acetylsalicylate (P-58), diethyllaminoethyl salicylacetylsalicylic acid ester salicylacetylsalicylic acid salt (P-59), the acetone soln transdermal administration that diethyllaminoethyl salicylacetylsalicylic acid ester acetyl trimerization Salicylate (P-60) (is equivalent to the NSAID (non-steroidal anti-inflammatory drug) of 20mg/kg) is in the back (about 1.5 square centimeters) of rat (shaving), once a day (point in morning 8), continue 5 weeks. playing the 5th week from second week, within every three days, once 4 o'clock measured blood sugar level (non-fasting) in the afternoon. result is shown in Table 10. blood lipid level is measured at the 5th week end. result is shown in Table 11.

The anti-diabetic activity of the prodrug of table 10. NSAID (non-steroidal anti-inflammatory drug)

Result illustrates: the prodrug of NSAID (non-steroidal anti-inflammatory drug) effectively reduces blood sugar level in diabetes rat model, and does not affect the blood sugar level of normal rat. What is interesting is most that the blood sugar level of these rats is still stable at normal level (7-8mmol/L, non-fasting) after drug withdrawal 30 days. This means that these prodrugs are possible not only to control blood sugar level, perhaps can also cure diabetes.

The activity reducing blood fat of table 11. NSAID (non-steroidal anti-inflammatory drug) prodrug

Result illustrates that the prodrug of NSAID (non-steroidal anti-inflammatory drug) can effectively reduce blood lipid level (T-CHOL and triglyceride) in diabetes rat model, and does not affect HDL level.

The pH value of gastric acid is 1-3. negative charge on biomembranous phosphate end group is neutralized by proton, and the positive charge on these prodrugs amino not can be incorporated into biomembranous phosphate end group, and therefore these prodrugs cannot pass through coat of the stomach, from without damaging stomach or upsetting the stomach. duodenal pH value is about 5-7, so these prodrugs can pass duodenal mucosa. pancreas is near duodenum, and therefore substantial amounts of prodrug is entering and can advance to pancreas before the liver of metabolic drug, kidney and system circulation, therefore only needs the prodrug of low dosage, and the few side effects caused and low. by the diethyllaminoethyl acetylsalicylate acetylsalicylate (P-1, acetone soln) of 20%, 4-acetamidophenyl salicylyl acyl dimethylamino butyl ester hydrochlorate (P-6), diethyllaminoethyl 5-(2, 4-difluorophenyl) acetylsalicylate 5-(2, 4-difluorophenyl) acetylsalicylate (P-8), diethyllaminoethyl disalicylic acid ester acetate (P-9), diethylaminoethyl salicylate acetate (P-10), diethyllaminoethyl 5-acetylaminohydroxyphenylarsonic acid acetylsalicylate (P-58), diethyllaminoethyl salicylacetylsalicylic acid ester salicylacetylsalicylic acid salt (P-59), diethyllaminoethyl salicylacetylsalicylic acid ester acetyl trimerization Salicylate (P-60) (is equivalent to the NSAID (non-steroidal anti-inflammatory drug) of 15mg/kg) and is mixed in food, continuous 5 week every day is to rat edible (SLAC/GK together with food, II-patients with type Ⅰ DM, n=7). start by the 5th week from second week, every three days once in the afternoon 3 measure rats blood sugar level (non-fasting). result is shown in Table 12. blood lipid level is measured at the 5th week end. result is shown in Table 13.

The diabetes activity of table 12. NSAID (non-steroidal anti-inflammatory drug) prodrug

Result shows, when the prodrug of these NSAID (non-steroidal anti-inflammatory drug) is oral, can effectively reduce its blood sugar level in diabetes rat model, and without influence on the blood sugar level of normal rat, its dosage is significantly less than female pharmaceutical quantities.

The activity of the blood fat reducing of table 13. NSAID (non-steroidal anti-inflammatory drug) prodrug

It is shown that the prodrug of NSAID (non-steroidal anti-inflammatory drug) oral after the blood lipid level (T-CHOL and triglyceride) that effectively can reduce in diabetes rat model, and required dosage is well below female pharmaceutical quantities.

These prodrugs in the present invention (SLAC:NOD-IDDM, I-patients with type Ⅰ DM, n=7) can reduce blood sugar level in mouse model. by containing 20% diethyllaminoethyl acetylsalicylate acetylsalicylate (P-1, acetone soln), 4-acetamidophenyl salicylyl acyl group dimethylamino butyl ester hydrochlorate (P-6), diethyllaminoethyl 5-(2, 4-difluorophenyl) acetylsalicylate 5-(2, 4-difluorophenyl) acetylsalicylate (P-8), diethyllaminoethyl disalicylic acid ester acetate (P-9), diethylaminoethyl salicylate acetate (P-10), diethyllaminoethyl 5-acetylaminohydroxyphenylarsonic acid acetylsalicylate (P-58), diethyllaminoethyl salicylacetylsalicylic acid ester salicylacetylsalicylic acid salt (P-59), diethyllaminoethyl salicylacetylsalicylic acid ester acetyl trimerization Salicylate (P-60) (is equivalent to the NSAID (non-steroidal anti-inflammatory drug) of 20mg/kg) acetone soln transdermal administration is in the back (about 1 square centimeter) of mice (in advance shaving), (in the morning 8 point) continues seven weeks once a day. start by the 7th week from 4th week, every three days once in the afternoon 3 measure blood sugar level (non-fasting).Result is shown in Table 14.

The activity of the anti-diabetic (I-type) of the prodrug of table 14. NSAID (non-steroidal anti-inflammatory drug)

Result shows that the prodrug of these NSAID (non-steroidal anti-inflammatory drug) can effectively reduce blood sugar level in diabetic mice (I-type) model.

Select the Chinese White Rabbit (6-7 month big) that 18 body weight are at 3.0 to 3.5 kilograms, and be divided into three groups (matched group, P-1 and P-10 group, n=6). Test previous hour, extract 1 milliliter of venous blood and make its grumeleuse generate thrombosis in aseptic bottle. In order to avoid fragmentation (fragmentation) and slowly dissolving, autologous blood clots is stablized 10 minutes in the distilled water of temperature control 70 DEG C. After anesthesia, femoral vein exposed and is stripped out, with inlying catheter (20GA), autologous thrombosis (0.05g/kg) being expelled in the femoral vein being stripped out before. By the diethyllaminoethyl acetylsalicylate acetylsalicylate (P-1 of 50%, acetone soln, 15mg/kg) with the acetone soln transdermal administration of diethyllaminoethyl salicylacetylsalicylic acid ester salicylacetylsalicylic acid salt (P-59,15mg/kg) in rabbit back. After 2 days, the pentobarbital sodium (60mg/kg) excessive to rabbit intravenous injection makes its euthanasia. Take out its lung and heart, observe in pulmonary artery whether there is thrombosis. Lung tissue is soaked 24 hours in the formalin solution of 10%. Along blocked Pulmonic continuous cross section paraffin embedding, and use stained with Hematoxylin-Eosin. In matched group, platelet plug and mixed thrombus are wrapped in the coagulated mass of injection, and it exists in large-scale blood vessel and stretches blood vessel wall from inner side and outer side. In these blood vessels, endotheliocyte and the equal excessive proliferation of fibrocyte. Moreover, it has been found that there is acute pulmonary congestion. In P-1 and P-59 group, lung tissue and blood vessel wall are all normal. It is shown that the thrombus propagation that the prodrug energy antithrombotic of NSAID (non-steroidal anti-inflammatory drug) is relevant with thromboembolism. These prodrugs can be used for preventing and treating the main cause of a kind of apoplexy of thrombosis, myocardial infarction and organ-graft refection.

These prodrugs in the present invention can help wound healing in rabbit model, and can soften and reduce incised wound and the cicatrix caused of burning. In Chinese white rabbit model, the average scar size of the rabbit that prodrug was treated is only the 1/3 of the matched group rabbit of same wound size, and its cicatrix is equally soft without scar tissue place with normal.

COX-1 and COX-2 plays very important effect in the immunoreation of animal. NSAID (non-steroidal anti-inflammatory drug) can suppress COX-1 and COX-2. in the present invention, the prodrug of NSAID (non-steroidal anti-inflammatory drug) can be used for treating psoriasis, discoid lupus erythematosus, systemic lupus erythematosus (sle) (SLE) and its own immune disease thereof. by the dense suspension of chlosma [Rosenberg, E.W., etal., Mycopatholoiga, 72,147-154 (1980)] be coated in by the back (n=4x6) of the Chinese White Rabbit of shaving, twice daily (morning 7 and point in evening 7), continue two weeks, cause being similar to psoriasic pathological changes. after smearing three hours of chlosma dense suspension (morning 7 and evening 7 point) (morning 10 and evening 10 point), 3-piperidine methyl 2-(ρ-isobutyl phenenyl) propionate. AcOH (P-5) of 5% is smeared in same position, diethyllaminoethyl 1-methyl-5-(4-methyl benzoyl)-1H-pyrroles-2-acetas acetate (P-13), diethyllaminoethyl 5-(4-chlorobenzene formacyl)-1, 4-dimethyl-1H-pyrroles-2-acetas acetate (P-14), diethyllaminoethyl-1, 8-diethyl-1, 3, 4, 9-Pentamethylene oxide .-[3, 4-b] indyl-1-acetas acetate (P-15), diethyllaminoethyl 2-amino-3-(the bromo-benzoyl of 4-) phenylacetate acetate (P-17), the chloro-4-of diethyllaminoethyl 3-(2-acrylic oxygen base) phenylacetate acetate (P-18), diethyllaminoethyl 1-(4-chlorobenzene formacyl-5-methoxyl group-2-Methyl-1H-indole base-3-acetoxy acid ester acetate (P-20), diethyllaminoethyl 4-(4-chlorphenyl)-2-phenyl-5-thiazolyl acetate acetate (P-21), the aqueous solution of diethyllaminoethyl 3-(4-chlorphenyl)-1-phenyl-1H-pyrazolyl-4-acetas acetate (P-22).After smearing prodrug ten days, diseased region obtains rehabilitation, but the state of control group mice worsens more.

In order to evaluate these prodrug against erythema lupus activity, by the diethyllaminoethyl acetylsalicylate acetylsalicylate (P-1 of 5%, acetone soln, 30mg/kg) or 3-piperidine methyl 2-(ρ-isobutyl phenenyl) propionate. AcOH (P-5, aqueous solution, 30mg/kg) partial smearing is to mice (MRL/LPR, the n=5x3) skin of back suffering from discoid lupus erythematosus and systemic lupus erythematosus (sle), every day 2 times. After six weeks, all of dermatosis of mice back and the lupus nephritis that accept prodrug treatment all rehabilitate, but the state of an illness of control group mice constantly worsens.

These are it is shown that the prodrug of these NSAID (non-steroidal anti-inflammatory drug) is expected to for treating the psoriasis of the mankind, discoid lupus erythematosus, systemic lupus erythematosus (sle) (SLE), multiple sclerosis (MS) and other autoimmune disease.

In amyotrophic lateral sclerosis (ALS), the pathogenesis of cell death may relate to the excitotoxicity of glutamate-induced, oxidative damage and apoptosis. the synthesis of the Transitional cell carcinomas catalysis PGE2 in spinal nerves unit and astrocyte. PGE2 stimulates astrocyte release glutamate, and Transitional cell carcinomas plays the effect of key in the formation of front pro-inflammatory cytokine, reactive oxygen species and free radical. Selective COX-2 inhibitor, celecoxib, the synthesis of PGE2 in ALS mouse spinal cord can be significantly inhibited. celecoxib can effectively delay the progress that mice is weak and loses weight, and life span is extended 25%. spinal neuron in the spinal cord of the ALS mice for the treatment of group is protected significantly, decrease glial cells hyperplasia and microglia activation (Merit.E.Cudkowicz, etal., Annalsofneurology, 52,771-778,2002). these are it is shown that COX-2 suppresses to potentially contribute to ALS patient. the prodrug of the NSAID (non-steroidal anti-inflammatory drug) in the present invention can penetrate skin and nerve cell membrane barriers (most of NSAID (non-steroidal anti-inflammatory drug) can not penetrate neurocyte effectively) at a terrific speed, can also under not injuring gastrointestinal situation transdermal administration, so these prodrugs are expected to for treating multiple sclerosis (MS), Crohn disease and other autoimmune diseasees, amyotrophic lateral sclerosis (ALS), oculopharyngeal muscular dystrophy disease (OPMD), myotonic dystrophy (MD), Du's Xin Shi muscular dystrophy (DMD), polymyositis (PM), dermatomyositis (DM), inclusion body myositis (IBM), and other muscle disease.

Inflammation mechanism be considered as important mediating factors in alzheimer's disease pathological process (McGeerPL, McGeerEG.Theinflammatoryresponsesystemofbrainimplication sforthetherapyofAlzheimerandotherneurodegenerativediseas es.BrainRes.Rev., 1995; 21:195-218). In the research of in ' tVeld et al. (theNewEnglandJournalofMedicine, 2001; 345,1515) tracking that the crowd that, nearly 7000 are likely to suffer from alzheimer's disease by they has carried out nearly 7 years is observed. It was found that those continued to take NSAID (non-steroidal anti-inflammatory drug) (NSAIAs) at least two years and 2 years or people more for many years before dementia occurs, the probability suffering from alzheimer's disease substantially reduces. If the effect of (NSAIAs) neuroprotective of this several years NSAID (non-steroidal anti-inflammatory drug) stopped before dementia is shown effect, then these compounds cannot provide protection for most people in the tendency phase of dementia.It is believed that this is because damaged nerve cell surrounding tissue defines cicatrix, to protect neurocyte to be not subjected to further injury. Most of NSAID (non-steroidal anti-inflammatory drug) are extremely slow through the speed of blood brain barrier and nerve cell barriers, and cannot pass through scar barrier. These prodrugs in the present invention have the ability of fast skin penetration, blood-brain barrier, neuron membrane and scar barrier, are expected to become the good medicine for the treatment of alzheimer's disease, Parkinson's disease and other neurodegenerative diseases.

These prodrugs can help the patient of those spinal cord injury, and the spinal cord that these patients are injured has wrapped up the cicatrix of protectiveness thus stopping healing. Most of NSAID (non-steroidal anti-inflammatory drug) cannot pass through scar barrier and reach therapeutically effective concentration, but these prodrugs in the present invention through scar barrier, can have anti-inflammatory activity, and can help wound healing.

Owing to NSAID (non-steroidal anti-inflammatory drug) can not effectively pass through cell membrane, particularly brain cell and neurocyte, in system circulates, the time of staying is so long that major part medicine is front just by intestinal mucosa, liver, kidney and lung metabolism in arrival " action site ", thus can not be effective to treat above-mentioned state and maybe can produce serious side effect. This situation not only causes drug effect low, and brings toxicity to bear intestinal mucosa, liver, kidney, lung and other body parts. These prodrugs in the present invention can effectively penetrate skin, blood brain barrier, brain cell, neurocyte and other membranes barriers, exceeds hundreds times than the curative effect of female medicine, it is only necessary to 1/the tens of normal drug dosage or more than one percent, and side effect greatly reduces. These prodrugs are possible not only to be applicable to transdermal administration, it is also applied for other any drug-supplying system (such as oral, subcutaneous administration, intravenously administrable, inhalation and nasal-cavity administration), they can treat its female treatable many states of medicine better, it might even be possible to treats some its corresponding female irremediable states of medicine.

Above-mentioned formula (1,2a, 2b, 2c or 2d) compound represented by " structural formula 1,2a; 2b; 2c or 2d " can prepare by NSAID (non-steroidal anti-inflammatory drug), with N, N '-Dicyclohexylcarbodiimide (DCC), N, N '-diisopropylcarbodiimide (DIC) or the reaction of other coupling agents form anhydride, then react with suitable alcohol, mercaptan or amine.

Compound represented by above-mentioned formula (1,2a, 2b, 2c or 2d) " structural formula 1,2a, 2b, 2c or 2d " can be prepared with suitable halide reaction by the slaine of NSAID (non-steroidal anti-inflammatory drug), organic alkali salt or immobilization alkali salt.

Containing formula (1,2a, 2b, 2c or 2d) the transdermal medicine for treating system of compound represented by " structural formula 1,2a, 2b; 2c or 2d ", or containing at least one formula (1,2a, 2b, 2c or 2d) compound represented by " structural formula 1,2a, 2b; 2c or 2d " as the compositions of active substance, can be used for treating any state described in the state of any NSAIAs-treatable of human or animal and the present invention. These systems can be binder or paster, and it includes the bottom containing active substance and the protective layer without infiltration. Most preferred system is a kind of active substance reservoir, and it contains the permeable bottom towards skin. By controlling rate of release, this system can make NSAID (non-steroidal anti-inflammatory drug) continually and steadily at optimal treatment haemoconcentration, thus promoting curative effect and reducing the side effect of NSAID (non-steroidal anti-inflammatory drug).These systems can be worn over any position of wrist, ankle joint, arm, lower limb or health. Advantage

Owing to NSAID (non-steroidal anti-inflammatory drug) can not effectively pass through cell membrane, particularly brain cell and neurocyte, in system circulates, the time of staying is so long that major part medicine is front just by intestinal mucosa, liver, kidney and lung metabolism in arrival " action site ", thus the state that can not be effective in the treatment present invention mention maybe can produce serious side effect. This situation not only causes drug effect low, and brings toxicity to bear intestinal mucosa, liver, kidney, lung and other body parts. These prodrugs in the present invention can effectively penetrate skin, blood brain barrier, brain cell, neurocyte and other membranes barriers, exceeds hundreds times than the curative effect of female medicine, it is only necessary to 1/the tens of normal drug dosage or more than one percent, and side effect greatly reduces. These prodrugs are possible not only to be applicable to transdermal administration, are also applied for other any drug-supplying system (such as oral, subcutaneous administration, intravenously administrable, inhalation and nasal-cavity administration), it is possible to treat many female irremediable states of medicine. These prodrugs can be used not only for transdermal administration, and (they will not injure stomach because they cannot pass through coat of the stomach) can be administered orally and be used for treating any medical application, avoid most of side effect of NSAID (non-steroidal anti-inflammatory drug), most importantly gastrointestinal upset such as dyspepsia, stomach and duodenal hemorrhage, gastric ulcer, gastritis etc. These prodrugs are that medication is convenient by another big benefit of transdermal administration, particularly for ease to children.

Accompanying drawing explanation

Wherein, R, R in formula (1,2a, 2b, 2c or 2d) " structural formula 1,2a, 2b, 2c or 2d "₁、R₂、R₃、R₄、R₅、R₆、R₇、R₈、R₉, X, in definition and the claim 1 of HA and Ary-and claim 2 to R, R₁、R₂、R₃、R₄、R₅、R₆、R₇、R₈、R₉, X, HA definition consistent.

Preferred forms

The preparation of diethyllaminoethyl acetylsalicylate acetylsalicylate

180 grams of 2-aspirin are dissolved in 1000 milliliters of chloroforms. Mixture is cooled to 5 DEG C. 103 gram of 1,3-Dicyclohexylcarbodiimide is joined said mixture. Mixture is stirred at room temperature 2 hours. Solids removed by filtration impurity is also washed with chloroform, washes 3 times for each 300 milliliters. 59 grams of diethylaminoethanols are joined in reactant mixture. Mixture is stirred at room temperature 3 hours. It is evaporated organic solvent. Obtain 220 grams of target products (productivity 96%) after drying. Elementary analysis: C₂₄H₂₉NO₈; Molecular weight: 459.18. Theoretical value (%) C:62.73; H:6.36; N:3.05; O:27.86; Measured value (%) C:62.70; H:6.40; Cl:N:3.01; O:27.90.

Embodiment

The preparation of 1-piperidines propyl group 2 [(2,6-Dichlorobenzene base) amino] phenylacetate acetate

31.8 the 2 of gram (0.1 mole) [(2,6-Dichlorobenzene base) amino] phenylacetic acid is received in the chloroform being suspended from 180 milliliters. Adding the 1-piperidines propyl bromide hydrogen bromide salt of 28.6 grams (0.1 moles) to mixture, mixture is stirred at room temperature 5 hours. Mixture with 5% Na₂CO₃Wash once each 300 milliliters and wash with water three times each 100 milliliters. Mixture anhydrous sodium sulfate dries. Be filtered to remove sodium sulfate, and with chloroform wash three times each 50 milliliters. 6 grams of acetic acid are added to solution. Solution for vacuum concentration is to 100 milliliters. Then 300 milliliters of hexanes are added in the solution. Solid collected by filtration product, and with hexane wash three times each 100 milliliters. After drying, 40 grams of target products (productivity 86%) are obtained.Elementary analysis: C₂₄H₃₀Cl₂N₂O₄; Molecular weight: 481.43. Theoretical value (%) C:59.88; H:6.28; Cl:14.73; N:5.82; O:13.29; Measured value (%) C:59.83; H:6.32; Cl:14.71, N:5.79; O:13.35.

The preparation of 3-piperidine methyl 2-(ρ-isobutyl phenenyl) propionate. AcOH

The triethylamine (3mmol/g, 100-200 order) of 60 grams of Polymer-bound is suspended in 500 milliliters of chloroforms. In mixture, stirring adds 20.6 grams of (0.1 mole) 2-(ρ-isobutyl phenenyl) propanoic acid. In mixture, stirring adds 39 grams of (0.15 mole) 3-piperidine methyl bromine hydrogen bromide salts, and mixture at room temperature stirs 10 hours. Be filtered to remove polymer, with acetone wash three times each 50 milliliters. Stirring adds the Na of 300 milliliter 5% in the solution₂CO₃Aqueous solution. Mixture stirs 30 minutes. Chloroformic solution wash with water three times each 100 milliliters, then use dried over sodium sulfate. Be filtered to remove sodium sulfate, and with chloroform wash three times each 100 milliliters. Mixed liquor adds 6 grams of acetic acid. Solution for vacuum concentration to 100 milliliters, is subsequently adding 300 milliliters of hexanes. Solid collected by filtration product and with hexane wash three times each 100 milliliters, obtain 35 grams of target products after drying, productivity is 96%. Elementary analysis: C₂₁H₃₃NO₄; Molecular weight: 363.49; Theoretical value (%): C:69.39; H:9.15; N:3.85; O:17.61; Measured value (%): C:69.35; H:9.18; N:3.83; O:17.64.

Industrial applicibility

Prodrug in formula (1,2a, 2b, 2c or 2d) " structural formula 1,2a, 2b, 2c or 2d " is better than NSAID (non-steroidal anti-inflammatory drug). they can be used for treating the state that any NSAID (non-steroidal anti-inflammatory drug) of human or animal can be treated. they can be additionally used in treatment and prevention diabetes (I type and II type), pathoglycemia and dyslipidemia, apoplexy, myocardial infarction and other heart and cardiovascular disease, alzheimer's disease, Parkinson's disease and other neurodegenerative diseases, psoriasis, discoid lupus erythematosus, systemic lupus erythematosus (sle) (SLE), autoimmune hepatitis, scleroderma, desolate lattice logical sequence syndrome, rheumatoid arthritis, polymyositis, scleroderma, chronic lymphocytic thyroiditis, juvenile diabetes, Addison disease, vitiligo, pernicious anemia, glomerulonephritis, pulmonary fibrosis, multiple sclerosis (MS), Crohn disease, with other autoimmune disease, amyotrophic lateral sclerosis (ALS), oculopharyngeal muscular dystrophy (OPMD), myotonia atrophica (MD), Du's Xin Shi muscular dystrophy (DMD), polymyositis (PM), dermatomyositis (DM), inclusion body myositis (IBM), and other muscle disease, hemorrhoid, inflammatory hemorrhoid, (artificial property) proctitis after irradiation, chronic ulcerative colitis, cryptitis, and other anorectal inflammatory conditions, and pruritus ani, prostatitis, prostatocystitis, autoimmune hepatitis, autoimmune nephritis, phlebitis, other inflammation, spinal injury, cicatrix, breast carcinoma, colorectal carcinoma, oral cancer, lung and other respiratory system carcinoma disease, skin carcinoma, uterus carcinoma, reproduction cancer, urinary organs cancer, leukemia and other blood and lymphoid tissue cancer and other cancer, and other states many. namely these prodrugs can be used for transdermal administration without adding dermal osmosis accelerator.

Claims

1. the compound represented by formula (2a, 2b, 2c or 2d) " structural formula 2a, 2b, 2c or 2d ":

Wherein, R represent side chain or straight chain-(CH₂)_n-, wherein, n=0,1,2,3,4,5,6,7,8,9,10..., at-(CH₂)_n-in, any CH₂Can by O, S, CH=CH, C ≡ C, CHR₆、CR₆R₇, aryl or heteroaryl, or other ring systems replace;R₁Represent side chain or straight chain-(CH₂)_a-, wherein, a=0,1,2,3,4,5,6,7,8,9,10..., at-(CH₂)_a-in, any CH₂Can by O, S, CH=CH, C ≡ C, CHR₆、CR₆R₇, aryl or heteroaryl, or other ring systems replace; R₂Represent side chain or straight chain-(CH₂)_b-, wherein, b=0,1,2,3,4,5,6,7,8,9,10..., at-(CH₂)_b-in, any CH₂Can by O, S, CH=CH, C ≡ C, CHR₆、CR₆R₇, aryl or heteroaryl, or other ring systems replace; R₃Represent side chain or straight chain-(CH₂)_c-, wherein, c=0,1,2,3,4,5,6,7,8,9,10..., at-(CH₂)_c-in, any CH₂Can by O, S, CH=CH, C ≡ C, CHR₆、CR₆R₇, aryl or heteroaryl, or other ring systems replace; R₄Represent H, the alkyl of any 1-12 carbon atom, alkoxyl, thiazolinyl, perfluoroalkyl, haloalkyl or alkynyl, aryl or heteroaryl, wherein, any CH₂Can by O, S, CH=CH, C ≡ C, CHR₆、CR₆R₇, aryl or heteroaryl, or other ring systems replace; R₅Represent H, the alkyl of any 1-12 carbon atom, alkoxyl, thiazolinyl, perfluoroalkyl, haloalkyl or alkynyl, aryl or heteroaryl, wherein, any CH₂Can by O, S, CH=CH, C ≡ C, CHR₆、CR₇R₆, aryl or heteroaryl, or other ring systems replace; R₆Represent H, the alkyl of any 1-12 carbon atom, alkoxyl, thiazolinyl, perfluoroalkyl, haloalkyl or alkynyl, aryl or heteroaryl, wherein, any CH₂Can by O, S, CH=CH, C ≡ C, CHR₆、CR₇R₅, aryl or heteroaryl, or other ring systems replace; R₇Represent H, the alkyl of any 1-12 carbon atom, alkoxyl, thiazolinyl, perfluoroalkyl, haloalkyl or alkynyl, aryl or heteroaryl, wherein, any CH₂Can by O, S, CH=CH, C ≡ C, CHR₆、CR₇R₅, aryl or heteroaryl, or other ring systems replace; X represents does not have atom, O, NH, NR₆Or S; HA represents does not have acid, HCl, HBr, HF, HI, HOAc, citric acid or other any pharmaceutically acceptable acids, all R, R₁、R₂、R₈、R₉Or-(CH₂)_n-group can be side chain or straight chain, it is possible to containing C, H, O, Cl, Br, F, I, P, S, N and other any atom pharmaceutically acceptable, it is possible to has a singly-bound, double bond, or/and three keys; All R, R₁、R₂、R₈、R₉Or-(CH₂)_n-group can have chirality or not have chirality, if there being chiral radicals, it is possible to have one or more chiral centre, can be single (R) or the mixture of (S) enantiomer or (R) and (S) enantiomer, Ary-represents, but is not limited to

Wherein, R_xRepresent H, CH₃, CH₃O, HO, CH₃CH₂, CF₃, CHF₂, CH₂F, Cl, F, Br, F; R_yRepresent H, the alkyl of any 1-12 carbon atom, alkoxyl, thiazolinyl, perfluoroalkyl, haloalkyl or alkynyl, aryl or heteroaryl; X₁Or X₄Represent CH₂, S, O, NH or CO; X₂Or X₅Represent CH, CR₈Or N; X₃Represent O, S, NH or NR₈; Y, Y₁, Y₂, Y₃, Y₄, Y₅Or Y₆Each independently represent 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;Any Ary-can have chirality or not have hands; If Ary-has chirality, it can have one or more chiral centre, it is possible to is single (R) or the mixture of (S) enantiomer or (R) and (S) enantiomer.

2. the compound represented by formula (1) " structural formula 1 ":

Wherein, R represent side chain or straight chain-(CH₂)_n-, n=0,1,2,3,4,5,6,7,8,9,10,11,12 ..., at-(CH₂)_n-in, arbitrary CH₂Can by O, S, NR₈, CH=CH, C ≡ C, CHR₈、CR₈R₉, aryl or heteroaryl, or other pharmaceutically acceptable group any replaces; R₁Represent H, the alkyl of arbitrary 1-12 carbon atom, alkoxyl, thiazolinyl, perfluoroalkyl, haloalkyl or alkynyl, aryl or heteroaryl, wherein, arbitrary CH₂Can by O, S, CH=CH, C ≡ C, CHR₈、CR₈R₉, aryl or heteroaryl, or other pharmaceutically acceptable group any replaces; R₂Represent H, the alkyl of arbitrary 1-12 carbon atom, alkoxyl, thiazolinyl, perfluoroalkyl, haloalkyl or alkynyl, aryl or heteroaryl, wherein, arbitrary CH₂Can by O, S, CH=CH, C ≡ C, CHR₈、CR₈R₉, aryl or heteroaryl, or other pharmaceutically acceptable group any replaces; X represents O, NH, NR₈, S, or there is no atom; R₈Represent H, OH, Cl, F, Br, I, the alkyl of arbitrary 1-12 carbon atom, alkoxyl, thiazolinyl, perfluoroalkyl, haloalkyl or alkynyl, aryl or heteroaryl; R₉Represent H, OH, Cl, F, Br, I, the alkyl of arbitrary 1-12 carbon atom, alkoxyl, thiazolinyl, perfluoroalkyl, haloalkyl or alkynyl, aryl or heteroaryl; The Ary-group that Ary-group in formula (1) " structural formula 1 " is defined as in the formula (2a, 2b, 2c or 2d) " structural formula 2a, 2b, 2c or 2d " with claim 1 is consistent; HA represents does not have acid, HCl, HBr, HF, HI, HOAc, citric acid, or other any other pharmaceutically acceptable acids, all of R, R₁、R₂、R₈、R₉Or-(CH₂)_n-group can be side chain or straight chain, it is possible to comprises C, H, O, Cl, Br, F, I, P, S, N or other arbitrary pharmaceutically acceptable atom, it is possible to has singly-bound, double bond or/and three keys; All of R, R₁、R₂、R₈、R₉Or-(CH₂)_n-group can have chirality or not have hands; If there being chiral radicals, it can be a mulitiple chiral centers, and can be single (R) or the mixture of (S) isomer or (R) and (S) isomer.

3. the formula (1 as described in claim 1 and claim 2, 2a, 2b, 2c or 2d) " structural formula 1, 2a, 2b, 2c or 2d " represented by the preparation method of compound, wherein, formula (1 as described in claim 1 and claim 2, 2a, 2b, 2c or 2d) " structural formula 1, 2a, 2b, 2c or 2d " represented by compound can be prepared by NSAID (non-steroidal anti-inflammatory drug), by itself and N, N '-Dicyclohexylcarbodiimide, N, N '-diisopropylcarbodiimide or the reaction of other coupling agents form anhydride, then with suitable alcohol, mercaptan or amine reaction preparation.

4. formula as described in claim 1 and claim 2 (1,2a, 2b, 2c or 2d) preparation method of compound represented by " structural formula 1,2a, 2b; 2c or 2d ", wherein, the formula (1 as described in claim 1 and claim 2,2a, 2b, 2c or 2d) compound represented by " structural formula 1,2a; 2b, 2c or 2d " can obtain with suitable halide reaction by the slaine of NSAID (non-steroidal anti-inflammatory drug), organic alkali salt or immobilization alkali salt.

5. the formula (1 as described in claim 1 and claim 2,2a, 2b, 2c or 2d) a kind of compound or a kind of containing at least one formula (1 represented by " structural formula 1; 2a; 2b; 2c or 2d ", 2a, 2b, 2c or 2d) compound represented by " structural formula 1; 2a; 2b, 2c or 2d " is as the compositions of active component, and this compound or compositions are characterised by that the mode that can pass through transdermal, oral, subcutaneous, vein or nasal-cavity administration is for treating the treatable disease of any NSAID (non-steroidal anti-inflammatory drug) of human or animal;The treatable disease of NSAID (non-steroidal anti-inflammatory drug) includes but not limited to: pain, fever, cancer, dysmenorrhea, acute migraine, acute gouty arthritis, ankylosing spondylitis, rheumatoid arthritis, osteoarthritis, dysmenorrhea and the dementia that toothache, headache, arthritis and other inflammation cause.

6. the method treating the state of any NSAIAs-treatable of human or animal, the method by giving formula (1 as described in claim 1 and 2 at any part of health in the way of transdermal administration, 2a, 2b, 2c or 2d) " structural formula 1, 2a, 2b, 2c or 2d " represented by a kind of compound or one at least contain a kind of formula (1, 2a, 2b, 2c or 2d) " structural formula 1, 2a, 2b, 2c or 2d " represented by compound as the compositions of active component and reach therapeutically effective plasma concentration, wherein transdermal administration includes solution, spray, emulsion, ointment, latex or gel.

7. the pain of external curing human or animal such as headache, toothache, myalgia, the pain that arthritis and other any inflammation cause, or the method for the state of other any NSAIAs-treatable, by the formula (1 as described in claim 1 and 2 in areas of inflammation topical treatment effective dose, 2a, 2b, 2c or 2d) " structural formula 1, 2a, 2b, 2c or 2d " represented by a kind of compound or one at least contain a kind of formula (1, 2a, 2b, 2c or 2d) " structural formula 1, 2a, 2b, 2c or 2d " represented by compound as the compositions of active component.

8. the formula (1 as described in claim 1 and claim 2, 2a, 2b, 2c or 2d) " structural formula 1, 2a, 2b, 2c or 2d " represented by a kind of compound or a kind of containing at least one formula (1, 2a, 2b, 2c or 2d) " structural formula 1, 2a, 2b, 2c or 2d " represented by compound as the compositions of active component, this compound or compositions are characterised by pass through at health any part transdermal administration and reaching therapeutically effective plasma concentration, for treating and preventing the diabetes (I type and/or II type) of human or animal, pathoglycemia, dyslipidemia and other metabolic disease, wherein transdermal administration includes solution, spray, emulsion, ointment, latex or gel.

9. the formula (1 as described in claim 1 and claim 2, 2a, 2b, 2c or 2d) " structural formula 1, 2a, 2b, 2c or 2d " represented by a kind of compound or one at least contain a kind of formula (1, 2a, 2b, 2c or 2d) " structural formula 1, 2a, 2b, 2c or 2d " represented by compound as the compositions of active component, this compound or compositions are characterised by can passing through to be administered orally, subcutaneous, the mode of vein or nasal-cavity administration is for treating and preventing the diabetes (I type and/or II type) of human or animal, pathoglycemia, dyslipidemia and other metabolic disease, wherein form of administration includes solution, spray, latex, pill, tablet, or other dosage forms.

10. the formula (1 as described in claim 1 and claim 2, 2a, 2b, 2c or 2d) " structural formula 1, 2a, 2b, 2c or 2d " represented by a kind of compound or a kind of containing at least one formula (1, 2a, 2b, 2c or 2d) " structural formula 1, 2a, 2b, 2c or 2d " represented by compound as the compositions of active component, this compound or compositions are characterised by pass through at health any part transdermal administration and reaching therapeutically effective plasma concentration, for treating and preventing dysarteriotony and the dyslipidemia of human or animal, wherein transdermal administration includes solution, spray, emulsion, ointment, latex or gel.