CN103772258B - There is positively charged aryl and the heteroaryl acetic acid class prodrug of rapid skin penetration speed - Google Patents
There is positively charged aryl and the heteroaryl acetic acid class prodrug of rapid skin penetration speed Download PDFInfo
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- CN103772258B CN103772258B CN201310648057.8A CN201310648057A CN103772258B CN 103772258 B CN103772258 B CN 103772258B CN 201310648057 A CN201310648057 A CN 201310648057A CN 103772258 B CN103772258 B CN 103772258B
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- ethyl ester
- lignocaine ethyl
- acetic acid
- ester acetate
- acid
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- -1 heteroaryl acetic acid class Chemical class 0.000 title claims description 52
- 229940002612 prodrug Drugs 0.000 title abstract description 54
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- 125000004494 ethyl ester group Chemical group 0.000 claims description 258
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 claims description 53
- 239000000243 solution Substances 0.000 claims description 52
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- 230000003203 everyday effect Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 229960000304 folic acid Drugs 0.000 description 1
- 235000019152 folic acid Nutrition 0.000 description 1
- 239000011724 folic acid Substances 0.000 description 1
- 210000001156 gastric mucosa Anatomy 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000003617 indole-3-acetic acid Substances 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 231100000636 lethal dose Toxicity 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 210000003141 lower extremity Anatomy 0.000 description 1
- 239000002075 main ingredient Substances 0.000 description 1
- 235000013372 meat Nutrition 0.000 description 1
- 210000004379 membrane Anatomy 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000011580 nude mouse model Methods 0.000 description 1
- 229940126701 oral medication Drugs 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 230000000149 penetrating effect Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000002510 pyrogen Substances 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 239000008279 sol Substances 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 230000001839 systemic circulation Effects 0.000 description 1
- 229960003604 testosterone Drugs 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 210000000689 upper leg Anatomy 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 235000019155 vitamin A Nutrition 0.000 description 1
- 239000011719 vitamin A Substances 0.000 description 1
- 229940045997 vitamin a Drugs 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 0.000 description 1
- 238000004804 winding Methods 0.000 description 1
- 210000000707 wrist Anatomy 0.000 description 1
- OENHQHLEOONYIE-JLTXGRSLSA-N β-Carotene Chemical compound CC=1CCCC(C)(C)C=1\C=C\C(\C)=C\C=C\C(\C)=C\C=C\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C OENHQHLEOONYIE-JLTXGRSLSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/337—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C219/00—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C219/02—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C219/04—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C219/10—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having at least one of the hydroxy groups esterified by a carboxylic acid having the esterifying carboxyl group bound to an acyclic carbon atom of a carbon skeleton containing rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C317/00—Sulfones; Sulfoxides
- C07C317/44—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D209/26—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with an acyl radical attached to the ring nitrogen atom
- C07D209/28—1-(4-Chlorobenzoyl)-2-methyl-indolyl-3-acetic acid, substituted in position 5 by an oxygen or nitrogen atom; Esters thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
This application discloses a kind of prodrug compound as shown in structural formula 1, and pharmaceutical composition and preparation method, and described compound or a combination thereof thing are for preparing the purposes of the medicine of the medicable state of nonsteroidal antiinflammatory drug in treatment human or animal.Disclosed herein as well is the skin-penetrating therapeutic application system comprising described compound or its pharmaceutical composition.
Description
Division is stated
The application is the divisional application of the Chinese patent application of the Application No. 200680055559.8 submitted on August 8th, 2006, invention entitled " having positively charged aryl and the heteroaryl acetic acid class prodrug of rapid skin penetration speed ".
Technical field
The present invention relates to aryl and heteroaryl acetic acid class with positive charge and water-soluble prodrug and can application on therapeutic state at any nonsteroidal antiinflammatory drug (NSAIAs) for the treatment of human or animal.Specifically, the present invention is the side effect in order to overcome nonsteroidal antiinflammatory drug to be brought.These prodrugs can be administered orally or transdermally.
Technical background
null1-methyl-5-(4-toluyl)-1H-pyrroles's-2-acetic acid (Tolmetin)，5-(4-chlorobenzoyl)-1，4-dimethyl-1H-pyrroles's-2-acetic acid (zomepirac)，1，8-diethyl-1，3，4，9-Pentamethylene oxide .-[3，4-b] indole-1-acetic acid (etodolac)，2-amino-3-benzoylphenylacetic acids (amfenac)，2-amino-3-(the bromo-benzoyl of 4-) phenylacetic acid (bromfenac)，The chloro-4-of 3-(2-propenyloxy group) phenylacetic acid (alclofenac)，2-(2，4-dichlorophenoxy)-phenylacetic acid (fenclofenac)，1-(4-chlorobenzene formacyl)-5-methoxyl group-2-Methyl-1H-indole-3-acetic acid carboxymethyl ester (acemetacin)，4-(4-chlorphenyl)-2-phenyl-5-thiazolyl acetic acid (fentiazac)，1-(p-chlorobenzoyl)-5-methoxyl group-2-Methyl-1H-indole-3-acetic acid (indomethacin)，(Z)-5-fluoro-2-methyl isophthalic acid-[(4-first thionyl) phenylmethylene]-1H-indenes-3-acetic acid (sulindac)，3-(4-chlorphenyl)-1-phenyl-1H-pyrazoles-4-acetic acid (lonazolac)，[(1-benzyl-1H-Yin reaches azoles-3-base) oxygen] acetic acid (bendazac)，6-methoxyl group-2-naphthalene-2-acetic acid (6MNA)，P-isobutyl-benzene guanidine-acetic acid (ibufenac) and related compound thereof，It is belonging to aryl and the nonsteroidal antiinflammatory drug of heteroaryl acetic acid class.They may be used for rheumatoid arthritis, the sign of osteoarthritis and symptom, treats dysmenorrhea.They can be additionally used in treatment acute gouty arthritis, ankylosing spondylitis.They can be additionally used in treatment dementia.(McGeer；Patrick L.et al., U.S. Patent number 5,192,753)
But, the use of Tolmetin, zomepirac, etodolac, amfenac, bromfenac, alclofenac, fenclofenac, acemetacin, fentiazac, indomethacin, sulindac, lonazolac, bendazac, 6MNA (6-methoxyl group-2-naphthalene-2-acetic acid), ibufenac and related compound thereof also brings a lot of side effect, topmost have gastrointestinal upset, such as dyspepsia, stomach and duodenal hemorrhage, gastric ulcer and gastritis.Fishman(Fishman；Robert, U.S. Patent number 7,052,715) point out that in order to enable effectively to treat pain or the inflammation that remote location produces, medicine concentration in blood circulation must be the highest with another problem is that oral medication produces.These concentration are often far above assuming that medicine can be directly targeted the actually required of pain or injury.Fishman et al. (Van Engelen etc., U.S. Patent number 6,416,772；Macrides etc., U.S. Patent number 6,346,278；Kirby etc., U.S. Patent number 6,444,234, Rosentsch etc., U.S. Patent number 5,654,337；Park etc., U.S. Patent number 6,190,690；Pearson etc., U.S. Patent number 6,528,040, and Botknech etc., U.S. Patent number 5,885,597) attempted by the way of preparation, developing drug delivery system for transdermal administration.But, owing to the skin penetration speed of these medicines is very slow, it is difficult to make its plasma concentration reach effective treatment level by the way of preparation.Susan Milosovich etc. has designed and synthesized 4-dimethylaminobutyricacid acid testosterone hydrochlorate (TSBH), and it has a lipophilic portion and a tertiary amine group existed at physiological ph with protonated form.They find that this prodrug (TSBH) transdermal speed is nearly 60 times [Susan Milosovich, et al., J.Pharm.Sci., 82,227 (1993)] of female medicine (TS) itself.
Summary of the invention
Technical problem
Tolmetin, zomepirac, etodolac, amfenac, bromfenac, alclofenac, fenclofenac, acemetacin, fentiazac, indomethacin, sulindac, lonazolac, bendazac, 6-methoxyl group-2-naphthalene-2-acetic acid (6MNA), ibufenac and related compound thereof have used for many years.It can be used for rheumatoid arthritis, the sign of osteoarthritis and symptom, and treatment dysmenorrhea.
But, take Tolmetin, zomepirac, etodolac, amfenac, bromfenac, alclofenac, fenclofenac, acemetacin, fentiazac, indomethacin, sulindac, lonazolac, bendazac, 6MNA, ibufenac and related compound thereof and can produce many side effect, most importantly gastrointestinal upset such as dyspepsia, stomach and duodenal hemorrhage, gastric ulcer and gastritis.They water insoluble solution or gastric juice, can rest in gastrointestinal tract for a long time, it is possible that gastric mucosal cell damage.
Solution
The present invention relates to the prodrug synthesis of the novel Tolmetin with positive charge, zomepirac, etodolac, amfenac, bromfenac, alclofenac, fenclofenac, acemetacin, fentiazac, indomethacin, sulindac, lonazolac, bendazac, 6-methoxyl group-2-naphthalene-2-acetic acid (6MNA), ibufenac and related compound thereof and they are in the application of field of medicaments.These prodrugs have the structure of formula (1) " structural formula 1 ".
In structural formula 1, R1Represent H, the alkyl of any 1-12 carbon atom, the alkoxyl of 1-12 carbon atom, the thiazolinyl of 1-12 carbon atom, the alkynyl of 1-12 carbon atom, or aryl；R2Represent H, the alkyl of any 1-12 carbon atom, the alkoxyl of 1-12 carbon atom, the thiazolinyl of 1-12 carbon atom, the alkynyl of 1-12 carbon atom, or aryl；R3Represent H, the alkyl of any 1-12 carbon atom, the alkoxyl of 1-12 carbon atom, the thiazolinyl of 1-12 carbon atom, the alkynyl of 1-12 carbon atom, or aryl；X represents O, S, NH, OCH2COO, OCH2COS, or OCH2CONH；A-Represent Cl-, Br-, F-, I-, AcO-, citrate, or other any anion；N=0,1,2,3,4,5,6,7,8,9,10 ...；Aryl represents:
All R bases can comprise C, H, O, S, atom N, can have singly-bound, double bond, and three keys.Any one CH2Group can be replaced by O, S or NH.
Medicine either absorbs through gastrointestinal tract or other approach, and the form with molecule that is required for is through barrier film.First medicine need to dissolve, and if medicine there is preferable biopharmaceutical properties, it can stride across biomembrane enter blood or systemic circulation system from the regional diffusion of the high concentration region to low concentration.All of biomembrane all contains lipid as Main Ingredients and Appearance.In biofilm structure active molecule all have 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 structure is towards the aqueous regions of both sides.The most hydrophilic medicine cannot be stopped wherein as a biomembranous part because of the reason of similar compatibility by the most hydrophobic medicine through biomembranous hydrophobic layer, thus can not be efficiently entering the Cytoplasm of inside.
It is an object of the invention to: by improving Tolmetin, zomepirac, etodolac, indomethacin, sulindac, amfenac, bromfenac, alclofenac, fenclofenac, acemetacin, fentiazac, lonazolac, bendazac, 6-methoxyl group-2-naphthalene-2-acetic acid (6MNA), ibufenac and related compound thereof the dissolubility in gastric juice and improving it through biomembrane and the speed of skin barrier so that it is their side effect can be avoided by the way of transdermal administration (external).These novel prodrugs have two structural features in common: they under physiological ph conditions can be with the one-level of protonated form with the presence of a lipophilic part (oil-soluble part) and one, two grades, or tertiary amine group (water-soluble portion).The balance of a water-soluble oil soluble is that medicine can be effectively through the condition [Susan Milosovich, et a1., J.Pharm.Sci., 82,227 (1993)] that biomembrane is required.Amino with positive charge considerably increases the dissolubility of medicine.null1-(p-chlorobenzoyl)-5-methoxyl group-2-Methvl-indole-3-acetic acid-lignocaine ethyl ester acetate，(Z)-5-fluoro-2-methyl isophthalic acid-[(4-first thionyl) phenylmethylene]-1H-indenes-3-acetic acid-lignocaine ethyl ester acetate，1-methyl-5-(4-toluyl)-1H-pyrroles-2-acetic acid-lignocaine ethyl ester acetate，5-(4-chlorobenzoyl)-1，4-dimethyl-1H-pyrroles-2-acetic acid-lignocaine ethyl ester acetate，1，8-diethyl-1，3，4，9-Pentamethylene oxide .-[3，4-b] indole-1-acetic acid-lignocaine ethyl ester acetate，2-amino-3-benzoylphenylacetic acids-lignocaine ethyl ester acetate，2-amino-3-(the bromo-benzoyl of 4-) phenylacetic acid-lignocaine ethyl ester acetate，The chloro-4-of 3-(2-propenyloxy group) phenylacetic acid-lignocaine ethyl ester acetate，2-(2，4-dichlorophenoxy)-phenylacetic acid-lignocaine ethyl ester acetate，1-(4-chlorobenzene formacyl)-5-methoxyl group-2-Methyl-1H-indole-3-acetoxy acid-lignocaine ethyl ester acetate，4-(4-chlorphenyl)-2-phenyl-5-thiazolyl acetic acid-lignocaine ethyl ester acetate，3-(4-chlorphenyl)-1-phenyl-1H-pyrazoles-4-acetic acid-lignocaine ethyl ester acetate，[(1-benzyl-1H-Yin reaches azoles-3-base) oxygen] acetic acid-lignocaine ethyl ester acetate，6-methoxyl group-2-naphthalene-2-acetic acid-lignocaine ethyl ester acetate，P-isobutyl-benzene guanidine-acetic acid-lignocaine ethyl ester acetate，1-(p-chlorobenzoyl)-5-methoxyl group-2-Methvl-indole-3-acetic acid (indomethacin)，(Z)-5-fluoro-2-methyl isophthalic acid-[(4-first thionyl) phenylmethylene]-1H-indenes-3-acetic acid (sulindac)，1-methyl-5-(4-toluyl)-1H-pyrroles's-2-acetic acid (Tolmetin)，5-(4-chlorobenzoyl)-1，4-dimethyl-1H-pyrroles's-2-acetic acid (zomepirac)，1，8-diethyl-1，3，4，9-Pentamethylene oxide .-[3，4-b] indole-1-acetic acid (etodolac)，2-amino-3-benzoylphenylacetic acids (amfenac)，2-amino-3-(the bromo-benzoyl of 4-) phenylacetic acid (bromfenac)，The chloro-4-of 3-(2-propenyloxy group) phenylacetic acid (alclofenac)，2-(2，4-dichlorophenoxy)-phenylacetic acid (fenclofenac)，1-(4-chlorobenzene formacyl)-5-methoxyl group-2-Methyl-1H-indole-3-acetic acid carboxymethyl ester (acemetacin)，4-(4-chlorphenyl)-2-phenyl-5-thiazolyl acetic acid (fentiazac)，3-(4-chlorphenyl)-1-phenyl-1H-pyrazoles-4-acetic acid (lonazolac)，[(1-benzyl-1H-Yin reaches azoles-3-base) oxygen] acetic acid (bendazac)，6-methoxyl group-2-naphthalene-2-acetic acid (6MNA)，The p-isobutyl-benzene guanidine-acetic acid (ibufenac) dissolubility in water is ＞ 450mg/ml respectively，＞ 400mg/ml，＞ 450mg/ml，＞ 450mg/ml，＞ 350mg/ml，＞ 450mg/ml，＞ 400mg/ml，＞ 450mg/ml，＞ 400mg/ml，＞ 450mg/ml，＞ 350mg/ml，＞ 400mg/ml，＞ 350mg/ml，＞ 400mg/ml，＞ 350mg/ml，0.1mg/ml，0.1mg/ml，0.2mg/ml，0.2mg/ml，0.1mg/ml，0.2mg/ml，0.1mg/ml，0.1mg/ml，0.1mg/ml，0.1mg/ml，0.1mg/ml，0.1mg/ml，0.1mg/ml，0.1mg/ml，And 0.1mg/ml.In most cases, the dissolving of medicine is the slowest in absorption process or limits the step of speed.Tolmetin, zomepirac, etodolac, amfenac, bromfenac, alclofenac, fenclofenac, indomethacin, sulindac, acemetacin, fentiazac, lonazolac, bendazac, 6-methoxyl group-2-naphthalene-2-acetic acid (6MNA), ibufenac and related compound dissolubility in gastric juice thereof are the least.They rest in intestines and stomach for a long time and gastric mucosal cell may be caused to damage.When these novel prodrugs are administered orally with the dosage form of such as tablet, capsule, solution or suspensoid, they can dissolve in gastric juice.In these prodrugs, the positive charge on amino can be bonded with the negative charge of the phosphate end group of cell membrane.Therefore, medicine local concentration outside biomembrane is the highest thus contribute to these prodrugs by area with high mercury to the region of low concentration.After these prodrugs enter into biomembrane, hydrophilic parts can promote prodrug to enter Cytoplasm, the aqueous solution of the concentration of-kind of semi liquid state or suspension.Owing to the time of staying in the gastrointestinal tract is short, gastric mucosal cell will not be caused damage by prodrug.null1-(p-chlorobenzoyl)-5-methoxyl group-2-Methvl-indole-3-acetic acid-lignocaine ethyl ester acetate，(Z)-5-fluoro-2-methyl isophthalic acid-[(4-first thionyl) phenylmethylene]-1H-indenes-3-acetic acid-lignocaine ethyl ester acetate，1-methyl-5-(4-toluyl)-1H-pyrroles-2-acetic acid-lignocaine ethyl ester acetate，5-(4-chlorobenzoyl)-1，4-dimethyl-1H-pyrroles-2-acetic acid-lignocaine ethyl ester acetate，1，8-diethyl-1，3，4，9-Pentamethylene oxide .-[3，4-b] indole-1-acetic acid-lignocaine ethyl ester acetate，[(1-benzyl-1H-Yin reaches azoles-3-base) oxygen] ethyl ester acetate，3-(4-chlorphenyl)-1-phenyl-1H-pyrazoles-4-ethyl ester acetate，[(1-benzyl-1H-Yin reaches azoles-3-base) oxygen] ethyl ester acetate，Indomethacin、Sulindac、Tolmetin、Zomepirac、Etodolac、Amfenac、Bromfenac、Alclofenac、Fenclofenac、Acemetacin、Fentiazac、Lonazolac、Bendazac and related compound thereof are passed through the speed of human body skin and are measured by the Franz pond improved in vitro，Wherein human body skin is isolatable from the human skin tissue (360-400 μ tm is thick) of thigh position above or below.The normal saline accepting the bovine serum albumin that solution is contained 2% by 10ml forms and stirs with the speed of 600 revs/min.The accumulation total amount that prodrug and female medicine pass through human body skin is to measure by specific high performance liquid chromatography the relation of time.nullTo be dissolved in the solution of 30%1-(p-the chlorobenzoyl)-5-methoxyl group-2-Methvl-indole-3-acetic acid-lignocaine ethyl ester acetate of 2ml pH7.4 phosphate buffered saline(PBS) (0.2M)，It is dissolved in 30% (the Z)-5-fluoro-2-methyl isophthalic acid-[solution of (4-first thionyl) phenylmethylene-1H-indenes-3-acetic acid-lignocaine ethyl ester acetate of 2ml pH7.4 phosphate buffered saline(PBS) (0.2M)，It is dissolved in the solution of 30%1-methyl-5-(4-the toluyl)-1H-pyrroles-2-acetic acid-lignocaine ethyl ester acetate of 2ml pH7.4 phosphate buffered saline(PBS) (0.2M)，It is dissolved in the 30%5-(4-chlorobenzoyl)-1 of 2ml pH7.4 phosphate buffered saline(PBS) (0.2M)，The solution of 4-dimethyl-1H-pyrroles-2-acetic acid-lignocaine ethyl ester acetate，It is dissolved in the 30%1 of 2ml pH7.4 phosphate buffered saline(PBS) (0.2M)，8-diethyl-1，3，4，9-Pentamethylene oxide .-[3，4-b] solution of indole-1-acetic acid-lignocaine ethyl ester acetate，It is dissolved in the solution of the 30%2-amino-3-benzoylphenylacetic acids-lignocaine ethyl ester acetate of 2ml pH7.4 phosphate buffered saline(PBS) (0.2M)，It is dissolved in the solution of 30%2-amino-3-(the bromo-benzoyl of the 4-) phenylacetic acid-lignocaine ethyl ester acetate of 2ml pH7.4 phosphate buffered saline(PBS) (0.2M)，It is dissolved in the solution of the chloro-4-of 30%3-(2-propenyloxy group) phenylacetic acid-lignocaine ethyl ester acetate of 2ml pH7.4 phosphate buffered saline(PBS) (0.2M)，It is dissolved in the 30%2-(2 of 2ml pH7.4 phosphate buffered saline(PBS) (0.2M)，4-dichlorophenoxy) solution of-phenylacetic acid-lignocaine ethyl ester acetate，It is dissolved in the solution of 30%l-(4-the chlorobenzene formacyl)-5-methoxyl group-2-Methyl-1H-indole-3-acetoxy acid-lignocaine ethyl ester acetate of 2ml pH7.4 phosphate buffered saline(PBS) (0.2M)，It is dissolved in the solution of 30%4-(4-the chlorphenyl)-2-phenyl-5-thiazolyl acetic acid-lignocaine ethyl ester acetate of 2ml pH7.4 phosphate buffered saline(PBS) (0.2M)，Or it is suspended in the suspension of 30% indomethacin of 2ml pH7.4 phosphate buffered saline(PBS) (0.2M)、It is suspended in the suspension of 30% sulindac of 2ml pH7.4 phosphate buffered saline(PBS) (0.2M)、It is suspended in the suspension of 30% Tolmetin of 2ml pH7.4 phosphate buffered saline(PBS) (0.2M)、It is suspended in the suspension of 30% zomepirac of 2ml pH7.4 phosphate buffered saline(PBS) (0.2M)、It is suspended in the suspension of 30% etodolac of 2ml pH7.4 phosphate buffered saline(PBS) (0.2M)、It is suspended in the suspension of 30% amfenac of 2ml pH7.4 phosphate buffered saline(PBS) (0.2M)、It is suspended in the suspension of 30% bromfenac of 2ml pH7.4 phosphate buffered saline(PBS) (0.2M)、It is suspended in the suspension of 30% alclofenac of 2ml pH7.4 phosphate buffered saline(PBS) (0.2M)、It is suspended in the suspension of 30% fenclofenac of 2ml pH7.4 phosphate buffered saline(PBS) (0.2M)、It is suspended in the suspension of 30% acemetacin of 2ml pH7.4 phosphate buffered saline(PBS) (0.2M)、Or it is suspended in the suspension of 30% fentiazac of 2ml pH7.4 phosphate buffered saline(PBS) (0.2M) as donor solution，Result is as depicted in figs. 1 and 2.nullRecord 1-(p-chlorobenzoyl)-5-methoxyl group-2-Methvl-indole-3-acetic acid-lignocaine ethyl ester acetate，(Z)-5-fluoro-2-methyl isophthalic acid-[(4-first thionyl) phenylmethylene-1H-indenes-3-acetic acid-lignocaine ethyl ester acetate，1-methyl-5-(4-toluyl)-1H-pyrroles-2-acetic acid-lignocaine ethyl ester acetate，5-(4-chlorobenzoyl)-1，4-dimethyl-1H-pyrroles-2-acetic acid-lignocaine ethyl ester acetate，1，8-diethyl-1，3，4，9-Pentamethylene oxide .-[3，4-b] indole-1-acetic acid-lignocaine ethyl ester acetate，2-amino-3-benzoylphenylacetic acids-lignocaine ethyl ester acetate，2-amino-3-(the bromo-benzoyl of 4-) phenylacetic acid-lignocaine ethyl ester acetate，The chloro-4-of 3-(2-propenyloxy group) phenylacetic acid-lignocaine ethyl ester acetate，2-(2，4-dichlorophenoxy)-phenylacetic acid-lignocaine ethyl ester acetate，1-(4-chlorobenzene formacyl)-5-methoxyl group-2-Methyl-1H-indole-3-acetoxy acid-lignocaine ethyl ester acetate，4-(4-chlorphenyl)-2-phenyl-5-thiazolyl acetic acid-lignocaine ethyl ester acetate，Indomethacin、Sulindac、Tolmetin、Zomepirac、Etodolac、Amfenac、Bromfenac、Alclofenac、Fenclofenac、Acemetacin、Fentiazac、Or the apparent penetrating value through human body skin of lonazolac is respectively 4.6mg/cm2/ h, 4mg/cm2/ h, 4.2mg/cm2/ h, 5.1mg/cm2/ h, 4.2mg/cm2/ h, 3.8mg/cm2/ h, 4.0mg/cm2/ h, 3.6mg/cm2/ h, 4.5mg/cm2/ h, 3.8mg/cm2/ h, 4.5mg/cm2/ h, 0.04mg/cm2/ h, 0.04mg/cm2/ h, 0.04mg/cm2/ h, 0.05mg/cm2/ h, 0.04mg/cm2/ h, 0.04mg/cm2/ h, 0.04mg/cm2/ h, 0.03mg/cm2/ h, 0.04mg/cm2/ h, 0.03mg/cm2/ h, and 0.04mg/cm2/h.nullResult explanation，Prodrug (1-(p-chlorobenzoyl)-5-methoxyl group-2-Methvl-indole-3-acetic acid-lignocaine ethyl ester acetate，(Z)-5-fluoro-2-methyl isophthalic acid-[(4-first thionyl) phenylmethylene-1H-indenes-3-acetic acid-lignocaine ethyl ester acetate，1-methyl-5-(4-toluyl)-1H-pyrroles-2-acetic acid-lignocaine ethyl ester acetate，5-(4-chlorobenzoyl)-1，4-dimethyl-1H-pyrroles-2-acetic acid-lignocaine ethyl ester acetate，1，8-diethyl-1，3，4，9-Pentamethylene oxide .-[3，4-b] indole-1-acetic acid-lignocaine ethyl ester acetate，2-amino-3-benzoylphenylacetic acids-lignocaine ethyl ester acetate，2-amino-3-(the bromo-benzoyl of 4-) phenylacetic acid-lignocaine ethyl ester acetate，The chloro-4-of 3-(2-propenyloxy group) phenylacetic acid-lignocaine ethyl ester acetate，2-(2，4-dichlorophenoxy)-phenylacetic acid-lignocaine ethyl ester acetate，1-(4-chlorobenzene formacyl)-5-methoxyl group-2-Methyl-1H-indole-3-acetoxy acid-lignocaine ethyl ester acetate，Or 4-(4-chlorphenyl)-2-phenyl-5-thiazolyl acetic acid-lignocaine ethyl ester acetate passes through the speed of human body skin than female medicine indomethacin，Sulindac，Tolmetin，Zomepirac，Etodolac，Amfenac，Bromfenac，Alclofenac，Fenclofenac，Acemetacin or fentiazac、Or the nearlyest 100 times of lonazolac.Positive charge on result explanation dialkylaminoethyl is extremely important through biomembrane and skin barrier to medicine.Other prodrug skin penetration rate in formula " structural formula 1 " are close with 1-(p-chlorobenzoyl)-5-methoxyl group-2-Methvl-indole-3-acetic acid-lignocaine ethyl ester acetate.
nullExperiment in vivo compares 1-(p-chlorobenzoyl)-5-methoxyl group-2-Methvl-indole-3-acetic acid-lignocaine ethyl ester acetate，(Z)-5-fluoro-2-methyl isophthalic acid-[(4-first thionyl) phenylmethylene]-1H-indenes-3-acetic acid-lignocaine ethyl ester acetate，1-methyl-5-(4-toluyl)-1H-pyrroles-2-acetic acid-lignocaine ethyl ester acetate，5-(4-chlorobenzoyl)-1，4-dimethyl-1H-pyrroles-2-acetic acid-lignocaine ethyl ester acetate，1，8-diethyl-1，3,4,9-Pentamethylene oxide .-[3，4-b] indole-1-acetic acid-lignocaine ethyl ester acetate，2-amino-3-benzoylphenylacetic acids-lignocaine ethyl ester acetate，2-amino-3-(the bromo-benzoyl of 4-) phenylacetic acid-lignocaine ethyl ester acetate，The chloro-4-of 3-(2-propenyloxy group) phenylacetic acid-lignocaine ethyl ester acetate，2-(2，4-dichlorophenoxy)-phenylacetic acid-lignocaine ethyl ester acetate，1-(4-chlorobenzene formacyl)-5-methoxyl group-2-Methyl-1H-indole-3-acetoxy acid-lignocaine ethyl ester acetate，4-(4-chlorphenyl)-2-phenyl-5-thiazolyl acetic acid-lignocaine ethyl ester acetate，3-(4-chlorphenyl)-1-phenyl-1H-pyrazoles-4-acetic acid-lignocaine ethyl ester acetate，Indomethacin，Sulindac，Tolmetin，Zomepirac，Etodolac，Amfenac，Bromfenac，Alclofenac，Fenclofenac，Acemetacin，Fentiazac，Lonazolac through live without hair without hindering the speed of the skin of mice.nullDonor is by (1-(p-the chlorobenzoyl)-5-methoxyl group-2-Methvl-indole-3-acetic acid-lignocaine ethyl ester Acetate Solution of be dissolved in 1ml isopropanol 20%，Be dissolved in 1ml isopropanol 20% (Z)-5-fluoro-2-methyl isophthalic acid-[(4-first thionyl) phenylmethylene-1H-indenes-3-acetic acid-lignocaine ethyl ester Acetate Solution，Be dissolved in 1ml isopropanol 20% 1-methyl-5-(4-toluyl)-1H-pyrroles-2-acetic acid-lignocaine ethyl ester Acetate Solution，Be dissolved in 1ml isopropanol 20% 5-(4-chlorobenzoyl)-1，4-dimethyl-1H-pyrroles-2-acetic acid-lignocaine ethyl ester Acetate Solution，Be dissolved in 1ml isopropanol 20% 1，8-diethyl-1，3，4，9-Pentamethylene oxide .-[3，4-b] indole-1-acetic acid-lignocaine ethyl ester Acetate Solution，Be dissolved in 1ml isopropanol 20% 2-amino-3-benzoylphenylacetic acids-lignocaine ethyl ester Acetate Solution，Be dissolved in 1ml isopropanol 20% 2-amino-3-(the bromo-benzoyl of 4-) phenylacetic acid-lignocaine ethyl ester Acetate Solution，Be dissolved in 1ml isopropanol 20% the chloro-4-of 3-(2-propenyloxy group) phenylacetic acid-lignocaine ethyl ester Acetate Solution，Be dissolved in 1ml isopropanol 20% 2-(2，4-dichlorophenoxy)-phenylacetic acid-lignocaine ethyl ester Acetate Solution，Be dissolved in 1ml isopropanol 20% l-(4-chlorobenzene formacyl)-5-methoxyl group-2-Methyl-1H-indole-3-acetoxy acid-lignocaine ethyl ester Acetate Solution，Be dissolved in 1ml isopropanol 20% 4-(4-chlorphenyl)-2-phenyl-5-thiazolyl acetic acid-lignocaine ethyl ester Acetate Solution，Be suspended in 1ml isopropanol 20% indomethacin suspension，Be suspended in 1ml isopropanol 20% sulindac suspension，Be suspended in 1ml isopropanol 20% Tolmetin suspension，Be suspended in 1ml isopropanol 20% zomepirac suspension，Be suspended in 1ml isopropanol 20% etodolac suspension，Be suspended in 1ml isopropanol 20% amfenac suspension，Be suspended in 1ml isopropanol 20% bromfenac suspension，Be suspended in 1ml isopropanol 20% alclofenac suspension，Be suspended in 1ml isopropanol 20% fenclofenac suspension，Be suspended in 1ml isopropanol 20% acemetacin suspension，Be suspended in 1ml isopropanol 20% fentiazac suspension，Or be suspended in 1ml isopropanol 20% lonazolac suspension composition.It is coated in respectively nude mice back 10cm2Position.Indomethacin in blood plasma, sulindac, Tolmetin, zomepirac, etodolac, amfenac, bromfenac, alclofenac, fenclofenac, acemetacin, fentiazac, the concentration of lonazolac is to measure with specific efficient liquid-phase chromatography method.nullResult (Fig. 3、Fig. 4、Fig. 5) display，After using donor systems about 50 minutes，1-(p-chlorobenzoyl)-5-methoxyl group-2-Methvl-indole-3-acetic acid-lignocaine ethyl ester acetate，(Z)-5-fluoro-2-methyl isophthalic acid-[(4-first thionyl) phenylmethylene-1H-indenes-3-acetic acid-lignocaine ethyl ester acetate，1-methyl-5-(4-toluyl)-1H-pyrroles-2-acetic acid-lignocaine ethyl ester acetate，5-(4-chlorobenzoyl)-1，4-dimethyl-1H-pyrroles-2-acetic acid-lignocaine ethyl ester acetate，1，8-diethyl-1，3，4，9-Pentamethylene oxide .-[3，4-b] indole-1-acetic acid-lignocaine ethyl ester acetate，2-amino-3-benzoylphenylacetic acids-lignocaine ethyl ester acetate，2-amino-3-(the bromo-benzoyl of 4-) phenylacetic acid-lignocaine ethyl ester acetate，The chloro-4-of 3-(2-propenyloxy group) phenylacetic acid-lignocaine ethyl ester acetate，2-(2，4-dichlorophenoxy)-phenylacetic acid-lignocaine ethyl ester acetate，1-(4-chlorobenzene formacyl)-5-methoxyl group-2-Methyl-1H-indole-3-acetoxy acid-lignocaine ethyl ester acetate，4-(4-chlorphenyl)-2-phenyl-5-thiazolyl acetic acid-lignocaine ethyl ester acetate，And 3-(4-chlorphenyl)-1-phenyl-1H-pyrazoles-4-acetic acid-lignocaine ethyl ester acetate drug level in blood plasma reaches peak value.After oral indomethacin, sulindac, Tolmetin, zomepirac, etodolac, amfenac, bromfenac, alclofenac, fenclofenac, acemetacin and fentiazac, 2-4 hour blood drug level reaches peak value.nullIndomethacin、Sulindac、Tolmetin、Zomepirac、Etodolac、Amfenac、Bromfenac、Alclofenac、Fenclofenac、Acemetacin、And fentiazac、The peak plasma concentration of lonazolac and bendazac is about 0.01mg/ml，And 1-(p-chlorobenzoyl)-5-methoxyl group-2-Methvl-indole-3-acetic acid-lignocaine ethyl ester acetate，(Z)-5-fluoro-2-methyl isophthalic acid-[(4-first thionyl) phenylmethylene-1H-indenes-3-acetic acid-lignocaine ethyl ester acetate，1-methyl-5-(4-toluyl)-1H-pyrroles-2-acetic acid-lignocaine ethyl ester acetate，5-(4-chlorobenzoyl)-1，4-dimethyl-1H-pyrroles-2-acetic acid-lignocaine ethyl ester acetate，1，8-diethyl-1，3,4,9-Pentamethylene oxide .-[3，4-b] indole-1-acetic acid-lignocaine ethyl ester acetate，2-amino-3-benzoylphenylacetic acids-lignocaine ethyl ester acetate，2-amino-3-(the bromo-benzoyl of 4-) phenylacetic acid-lignocaine ethyl ester acetate，The chloro-4-of 3-(2-propenyloxy group) phenylacetic acid-lignocaine ethyl ester acetate，2-(2，4-dichlorophenoxy)-phenylacetic acid-lignocaine ethyl ester acetate，1-(4-chlorobenzene formacyl)-5-methoxyl group-2-Methyl-1H-indole-3-acetoxy acid-lignocaine ethyl ester acetate，4-(4-chlorphenyl)-2-phenyl-5-thiazolyl acetic acid-lignocaine ethyl ester acetate，The peak plasma concentration of 3-(4-chlorphenyl)-1-phenyl-1H-pyrazoles-4-acetic acid-lignocaine ethyl ester acetate is about 2mg/ml (differing nearly 200 times).The indomethacin of about 2mg/ml in blood plasma, sulindac, Tolmetin, zomepirac, etodolac, amfenac, bromfenac, alclofenac, fenclofenac, acemetacin and fentiazac concentration are than can effectively ease pain and the plasma concentration of effective antiinflammatory has exceeded 20-100 times more than.This is stem-winding result.The treatment indomethacin of valid density, sulindac, Tolmetin, zomepirac, etodolac, amfenac, bromfenac, alclofenac, fenclofenac, acemetacin or fentiazac can be fed quickly and easily by these prodrugs.These results display prodrug is possible not only to be administered orally, and can be by transdermal administration in various treatments.Other prodrug in formula " structural formula 1 " percutaneous rate in vivo is with (Z)-5-fluoro-2-methyl isophthalic acid-[(4-first thionyl) phenylmethylene-1H-indenes-3-acetic acid-lignocaine ethyl ester acetate is close.
nullGastroduodenal hemorrhage in order to check that these guiding drugs rise，We are to Oral Administration in Rats 50mg/kg1-(p-chlorobenzoyl)-5-methoxyl group-2-Methvl-indole-3-acetic acid-lignocaine ethyl ester acetate every day、50mg/kg (Z)-5-fluoro-2-methyl isophthalic acid-[(4-first thionyl) phenylmethylene-1H-indenes-3-acetic acid-lignocaine ethyl ester acetate、50mg/kg1-methyl-5-(4-toluyl)-1H-pyrroles-2-acetic acid-lignocaine ethyl ester acetate、50mg/kg5-(4-chlorobenzoyl)-1，4-dimethyl-1H-pyrroles-2-acetic acid-lignocaine ethyl ester acetate、50mg/kg1，8-diethyl-1，3，4，9-Pentamethylene oxide .-[3，4-b] indole-1-acetic acid-lignocaine ethyl ester acetate、50mg/kg2-amino-3-benzoylphenylacetic acids-lignocaine ethyl ester acetate、50mg/kg2-amino-3-(the bromo-benzoyl of 4-) phenylacetic acid-lignocaine ethyl ester acetate、The chloro-4-of 50mg/kg3-(2-propenyloxy group) phenylacetic acid-lignocaine ethyl ester acetate、50mg/kg2-(2，4-dichlorophenoxy)-phenylacetic acid-lignocaine ethyl ester acetate、50mg/kg1-(4-chlorobenzene formacyl)-5-methoxyl group-2-Methyl-1H-indole-3-acetoxy acid-lignocaine ethyl ester acetate、50mg/kg4-(4-chlorphenyl)-2-phenyl-5-thiazolyl acetic acid-lignocaine ethyl ester acetate、50mg/kg3-(4-chlorphenyl)-1-phenyl-1H-pyrazoles-4-acetic acid-lignocaine ethyl ester acetate、50mg/kg indomethacin、50mg/kg sulindac、50mg/kg Tolmetin、50mg/kg zomepirac、50mg/kg etodolac、50mg/kg amfenac、50mg/kg bromfenac、50mg/kg alclofenac、50mg/kg fenclofenac、50mg/kg acemetacin、50mg/kg fentiazac、Or 50mg/kg lonazolac，Continuous oral 21 days.nullAt oral indomethacin、Sulindac、Tolmetin、Zomepirac、Etodolac、Amfenac、Bromfenac、Alclofenac、Fenclofenac、Acemetacin、Fentiazac or lonazolac group we have found that in averagely every gram Oletum Ratti norvegici has 3-4mg to have blood in stool，And at oral 1-(p-chlorobenzoyl)-5-methoxyl group-2-Methvl-indole-3-acetic acid-lignocaine ethyl ester acetate、(Z)-5-fluoro-2-methyl isophthalic acid-[(4-first thionyl) phenylmethylene-1H-indenes-3-acetic acid-lignocaine ethyl ester acetate、1-methyl-5-(4-toluyl)-1H-pyrroles-2-acetic acid-lignocaine ethyl ester acetate、5-(4-chlorobenzoyl)-1，4-dimethyl-1H-pyrroles-2-acetic acid-lignocaine ethyl ester acetate、1，8-diethyl-1，3，4，9-Pentamethylene oxide .-[3，4-b] indole-1-acetic acid-lignocaine ethyl ester acetate、2-amino-3-benzoylphenylacetic acids-lignocaine ethyl ester acetate、2-amino-3-(the bromo-benzoyl of 4-) phenylacetic acid-lignocaine ethyl ester acetate、The chloro-4-of 3-(2-propenyloxy group) phenylacetic acid-lignocaine ethyl ester acetate、2-(2，4-dichlorophenoxy)-phenylacetic acid-lignocaine ethyl ester acetate、1-(4-chlorobenzene formacyl)-5-methoxyl group-2-Methyl-1H-indole-3-acetoxy acid-lignocaine ethyl ester acetate、4-(4-chlorphenyl)-2-phenyl-5-thiazolyl acetic acid-lignocaine ethyl ester acetate or 3-(4-chlorphenyl)-1-phenyl-1H-pyrazoles-4-acetic acid-lignocaine ethyl ester acetate group do not have discovery to have blood in stool.
The measuring acute toxicity of these prodrugs.Oral half lethal dose (the LD of rat50null) as follows: 1-(p-chlorobenzoyl)-5-methoxyl group-2-Methvl-indole-3-acetic acid-lignocaine ethyl ester acetate、(Z)-5-fluoro-2-methyl isophthalic acid-[(4-first thionyl) phenylmethylene-1H-indenes-3-acetic acid-lignocaine ethyl ester acetate、1-methyl-5-(4-toluyl)-1H-pyrroles-2-acetic acid-lignocaine ethyl ester acetate、5-(4-chlorobenzoyl)-1，4-dimethyl-1H-pyrroles-2-acetic acid-lignocaine ethyl ester acetate、1，8-diethyl-1，3，4，9-Pentamethylene oxide .-[3，4-b] indole-1-acetic acid-lignocaine ethyl ester acetate、2-amino-3-benzoylphenylacetic acids-lignocaine ethyl ester acetate、2-amino-3-(the bromo-benzoyl of 4-) phenylacetic acid-lignocaine ethyl ester acetate、The chloro-4-of 3-(2-propenyloxy group) phenylacetic acid-lignocaine ethyl ester acetate、2-(2，4-dichlorophenoxy)-phenylacetic acid-lignocaine ethyl ester acetate、1-(4-chlorobenzene formacyl)-5-methoxyl group-2-Methyl-1H-indole-3-acetoxy acid-lignocaine ethyl ester acetate、4-(4-chlorphenyl)-2-phenyl-5-thiazolyl acetic acid-lignocaine ethyl ester acetate、The LD50 of 3-(4-chlorphenyl)-1-phenyl-1H-pyrazoles-4-acetic acid-lignocaine ethyl ester acetate is respectively 0.1g/kg，0.5g/kg，0.6g/kg，0.2g/kg，0.6g/kg，1.0g/kg，1.6g/kg，3.0g/kg，0.2g/kg，1.2g/kg and 1.2g/kg.The acute toxicity of result display prodrug is less than female medicine indomethacin (LD50=0.013g/kg), sulindac (LD50=0.26g/kg), Tolmetin (LD50=0.35g/kg), zomepirac (LD50=0.027g/kg), etodolac (LD50=0.46g/kg), amfenac (LD50=0.31g/kg), bromfenac, alclofenac LD50=1.05g/kg), fenclofenac (LD50=2.28g/kg), acemetacin (LD50=0.024g/kg), fentiazac (LD50=0.7g/kg) or lonazolac (LD50=1.0g/kg).
Tolmetin, zomepirac, etodolac, amfenac, bromfenac, alclofenac, fenclofenac, indomethacin, sulindac, acemetacin, fentiazac and lonazolac, bendazac, 6MNA, ibufenac have been proved to antiinflammatory, have eased pain, bring down a fever and anti rheumatism action.One good prodrug must very quick return to female medicine in blood plasma.Testing in vitro proves, in the blood plasma of people, the lignocaine ethyl ester group in these prodrugs can be cut off rapidly by enzyme, and the prodrug more than 90% returns to female medicine structure.Owing to the absorbance of prodrug is higher, when same dose, the curative effect of prodrug is more higher than female medicine.We to the pain relieving of these prodrugs, bring down a fever, antiinflammatory action is tested, and contrast with female medicine Tolmetin, zomepirac, etodolac, amfenac, indomethacin, sulindac, bromfenac, alclofenac, fenclofenac, acemetacin, fentiazac, lonazolac.
Analgesic activity: measure the prolongation time of the mouse tail threshold of pain according to the method (J.Pharmacol.Exp.Ther., 72,74 (1941)) of D ' Amour-Smith.By these prodrugs respectively with the dosage of 50mg/kg to mice transdermal administration, the tail of mice is exposed in thermostimulation, measures the threshold of pain and extend the time.Result is as shown in Fig. 6 and Fig. 7.null1-(p-chlorobenzoyl)-5-methoxyl group-2-Methvl-indole-3-acetic acid-lignocaine ethyl ester acetate，(Z)-5-fluoro-2-methyl isophthalic acid-[(4-first thionyl) phenylmethylene-1H-indenes-3-acetic acid-lignocaine ethyl ester acetate，1-methyl-5-(4-toluyl)-1H-pyrroles-2-acetic acid-lignocaine ethyl ester acetate，5-(4-chlorobenzoyl)-1，4-dimethyl-1H-pyrroles-2-acetic acid-lignocaine ethyl ester acetate，1，8-diethyl-1，3，4,9-Pentamethylene oxide .-[3，4-b] indole-1-acetic acid-lignocaine ethyl ester acetate，2-amino-3-benzoylphenylacetic acids-lignocaine ethyl ester acetate，2-amino-3-(the bromo-benzoyl of 4-) phenylacetic acid-lignocaine ethyl ester acetate，The chloro-4-of 3-(2-propenyloxy group) phenylacetic acid-lignocaine ethyl ester acetate，2-(2，4-dichlorophenoxy)-phenylacetic acid-lignocaine ethyl ester acetate，1-(4-chlorobenzene formacyl)-5-methoxyl group-2-Methyl-1H-indole-3-acetoxy acid-lignocaine ethyl ester acetate，4-(4-chlorphenyl)-2-phenyl-5-thiazolyl acetic acid-lignocaine ethyl ester acetate，3-(4-chlorphenyl)-1-phenyl-1H-pyrazoles-4-acetic acid-lignocaine ethyl ester acetate shows good analgesic activities.
The writhing number of times occurred after mouse peritoneal is administered acetum counts, and calculates the suppression ratio of writhing based on matched group.nullBefore injection acetum 30 minutes，Respectively to mice transdermal administration: 1-(p-chlorobenzoyl)-5-methoxyl group-2-Methvl-indole-3-acetic acid-lignocaine ethyl ester acetate (100mg/kg，B)，(Z)-5-fluoro-2-methyl isophthalic acid-[(4-first thionyl) phenylmethylene-1H-indenes-3-acetic acid-lignocaine ethyl ester acetate (100mg/kg，C)，1-methyl-5-(4-toluyl)-1H-pyrroles-2-acetic acid-lignocaine ethyl ester acetate (100mg/kg，D)，5-(4-chlorobenzoyl)-1，4-dimethyl-1H-pyrroles-2-acetic acid-lignocaine ethyl ester acetate (100mg/kg，E)，1，8-diethyl-1，3，4,9-Pentamethylene oxide .-[3，4-b] indole-1-acetic acid-lignocaine ethyl ester acetate (100mg/kg，F)，2-amino-3-benzoylphenylacetic acids-lignocaine ethyl ester acetate (100mg/kg，G)，2-amino-3-(the bromo-benzoyl of 4-) phenylacetic acid-lignocaine ethyl ester acetate (100mg/kg，H)，The chloro-4-of 3-(2-propenyloxy group) phenylacetic acid-lignocaine ethyl ester acetate (100mg/kg，I)，2-(2，4-dichlorophenoxy)-phenylacetic acid-lignocaine ethyl ester acetate (100mg/kg，J)，1-(4-chlorobenzene formacyl)-5-methoxyl group-2-Methyl-1H-indole-3-acetoxy acid-lignocaine ethyl ester acetate (100mg/kg，K)，4-(4-chlorphenyl)-2-phenyl-5-thiazolyl acetic acid-lignocaine ethyl ester acetate (100mg/kg，L)，3-(4-chlorphenyl)-1-phenyl-1H-pyrazoles-4-acetic acid-lignocaine ethyl ester acetate (100mg/kg，M).A group is blank group.The results are shown in Table 1.
Table 1: aryl and heteroaryl acetic acid class and the related compound prodrug suppression ratio to mouse writhing thereof
| Group | Dosage (mg/kg) | Writhing number of times | Suppression ratio (%) |
| A | 0 | 35.0 | - |
| B | 100 | 15.6 | 55 |
| C | 100 | 14.2 | 59 |
| D | 100 | 17.1 | 51 |
| E | 100 | 15.6 | 55 |
| F | 100 | 14.0 | 60 |
| G | 100 | 13.8 | 61 |
| H | 100 | 13.2 | 62 |
| I | 100 | 15.7 | 55 |
| J | 100 | 14.2 | 59 |
| K | 100 | 15.6 | 55 |
| L | 100 | 16.1 | 54 |
| M | 100 | 15.2 | 57 |
Result shows that these prodrugs have outstanding analgesic effect.Other compound represented by formula " structural formula 1 " displays that close analgesic effect.
Antipyretic effect: rat accepts colibacillus deactivating suspension as pyrogen.A group is blank group.nullAfter 2 hours，Respectively to rat transdermal administration: 1-(p-chlorobenzoyl)-5-methoxyl group-2-Methvl-indole-3-acetic acid-lignocaine ethyl ester acetate (100mg/kg，B)，(Z)-5-fluoro-2-methyl isophthalic acid-[(4-first thionyl) phenylmethylene-1H-indenes-3-acetic acid-lignocaine ethyl ester acetate (100mg/kg，C)，1-methyl-5-(4-toluyl)-1H-pyrroles-2-acetic acid-lignocaine ethyl ester acetate (100mg/kg，D)，5-(4-chlorobenzoyl)-1，4-dimethyl-1H-pyrroles-2-acetic acid-lignocaine ethyl ester acetate (100mg/kg，E)，1，8-diethyl-1，3,4,9-Pentamethylene oxide .-[3，4-b] indole-1-acetic acid-lignocaine ethyl ester acetate (100mg/kg，F)，2-amino-3-benzoylphenylacetic acids-lignocaine ethyl ester acetate (100mg/kg，G)，2-amino-3-(the bromo-benzoyl of 4-) phenylacetic acid-lignocaine ethyl ester acetate (100mg/kg，H)，The chloro-4-of 3-(2-propenyloxy group) phenylacetic acid-lignocaine ethyl ester acetate (100mg/kg，I)，2-(2，4-dichlorophenoxy)-phenylacetic acid-lignocaine ethyl ester acetate (100mg/kg，J)，1-(4-chlorobenzene formacyl)-5-methoxyl group-2-Methyl-1H-indole-3-acetoxy acid-lignocaine ethyl ester acetate (100mg/kg，K)，4-(4-chlorphenyl)-2-phenyl-5-thiazolyl acetic acid-lignocaine ethyl ester acetate (100mg/kg，L)，3-(4-chlorphenyl)-1-phenyl-1H-pyrazoles-4-acetic acid-lignocaine ethyl ester acetate (100mg/kg，M).Body temperature was surveyed every 90 minutes to rat before and after medication.The results are shown in Table 2.
Table 2: aryl and heteroaryl acetic acid class and the antipyretic effect of related compound prodrug thereof
| Group | 0 minute | 90 minutes | 180 minutes | 270 minutes |
| A (blank group) | 37.33±0.05 | 37.26±0.07 | 37.32±0.05 | 37.34±0.08 |
| B(100mg/kg) | 37.35±0.06 | 36.91±0.05 | 36.85±0.08 | 36.79±0.07 |
| C(100mg/kg) | 37.28±0.06 | 36.65±0.05 | 36.62±0.08 | 36.58±0.07 |
| D(100mg/kg) | 37.27±0.06 | 36.71±0.05 | 36.65±0.08 | 36.59±0.07 |
| E(100mg/kg) | 37.21±0.07 | 36.82±0.06 | 36.70±0.05 | 36.70±0.08 |
| F(100mg/kg) | 37.23±0.06 | 36.65±0.06 | 36.58±0.08 | 36.60±0.07 |
| G(100mg/kg) | 37.22±0.06 | 36.65±0.05 | 36.62±0.08 | 36.58±0.07 |
| H(100mg/kg) | 37.25±0.06 | 36.71±0.05 | 36.65±0.08 | 36.64±0.07 |
| I(100mg/kg) | 37.23±0.07 | 36.80±0.06 | 36.70±0.05 | 36.67±0.08 |
| J(100mg/kg) | 37.22±0.06 | 36.65±0.06 | 36.58±0.08 | 36.56±0.07 |
| K(100mg/kg) | 37.21±0.06 | 36.75±0.05 | 36.62±0.08 | 36.58±0.07 |
| L(100mg/kg) | 37.23±0.06 | 36.81±0.05 | 36.75±0.08 | 36.71±0.07 |
| M(100mg/kg) | 37.22±0.07 | 36.82±0.06 | 36.80±0.05 | 36.77±0.08 |
Stronger antipyretic effect is shown when result display prodrug is by the dosed administration of 100mg/kg.Other compound represented by formula " structural formula 1 " shows similar effect of bringing down a fever.
nullAntiinflammatory action: to rat transdermal administration 100mg/kg1-(p-chlorobenzoyl)-5-methoxyl group-2-Methvl-indole-3-acetic acid-lignocaine ethyl ester acetate (B) respectively，100mg/kg (Z)-5-fluoro-2-methyl isophthalic acid-[(4-first thionyl) phenylmethylene-1H-indenes-3-acetic acid-lignocaine ethyl ester acetate (C)，100mg/kg1-methyl-5-(4-toluyl)-1H-pyrroles-2-acetic acid-lignocaine ethyl ester acetate (D)，100mg/kg5-(4-chlorobenzoyl)-1，4-dimethyl-1H-pyrroles-2-acetic acid-lignocaine ethyl ester acetate (E)，100mg/kg1，8-diethyl-1，3，4，9-Pentamethylene oxide .-[3，4-b] indole-1-acetic acid-lignocaine ethyl ester acetate (F)，100mg/kg2-amino-3-benzoylphenylacetic acids-lignocaine ethyl ester acetate (G)，100mg/kg2-amino-3-(the bromo-benzoyl of 4-) phenylacetic acid-lignocaine ethyl ester acetate (H)，The chloro-4-of 100mg/kg3-(2-propenyloxy group) phenylacetic acid-lignocaine ethyl ester acetate (I)，100mg/kg2-(2，4-dichlorophenoxy)-phenylacetic acid-lignocaine ethyl ester acetate (J)，100mg/kg1-(4-chlorobenzene formacyl)-5-methoxyl group-2-Methyl-1H-indole-3-acetoxy acid-lignocaine ethyl ester acetate (K)，100mg/kg4-(4-chlorphenyl)-2-phenyl-5-thiazolyl acetic acid-lignocaine ethyl ester acetate (L)，100mg/kg3-(4-chlorphenyl)-1-phenyl-1H-pyrazoles-4-acetic acid-lignocaine ethyl ester acetate (M).A group is blank group.Under angle dish sol solution subcutaneous administration to the meat pad of rat claw after 60 minutes.Measure the volume of a rat hind paw after being administered angle dish glue every 1 hour, calculate the rate of increase of the volume of rat hind paw, and in this, as swelling rate (%).Result is shown in Fig. 8 and Fig. 9.Result shows: these prodrugs of transdermal administration have good antiphlogistic effects.Other compound represented by formula " structural formula 1 " has close antiphlogistic effects.
When the nonsteroidal antiinflammatory drug of high oral dose, it can have anti-reactive-antasthmatic effect by the activity of suppression Cycloxygenase.Owing to these prodrugs pass through biomembranous speed quickly, thus asthma can be treated by the way of spraying into mouth and nose.Because of their antiinflammatory action and skin penetration rate faster, these prodrugs may be used for treating acne.
The present invention relates to containing the prodrug represented by formula " structural formula 1 " and typical additives, the pharmaceutical preparation of adjuvant, such as, tablet for oral administration, capsule or solution etc., or for the solution of transdermal administration, emulsion, ointment, latex or gel etc..The novel active compound of formula " structural formula 1 " can be with vitamin such as vitamin A, B, C, E, beta-carotene etc., or other medicines, such as folic acid etc., combine the treatable state of any non-steroidal anti-inflammatory drug for treating human or animal.
Skin-penetrating therapeutic application system, compound that " structural formula 1 " containing formula represents or the compound that represents containing at least one formula " structural formula 1 ", as the compositions of active component, can be used for treating the medicable state of any nonsteroidal antiinflammatory drug in human or animal.These systems can be binder or paster, and it contains a hypothallus comprising active substance and the protective layer of an impermeable.Most preferably system is an active substance reservoir, containing a permeable bottom towards skin.By controlling rate of release, this system can make nonsteroidal antiinflammatory drug stable at optimal treatment blood drug level thus improves curative effect and reduce the side effect of nonsteroidal antiinflammatory drug.These systems can be worn over any position of wrist, ankle joint, arm, lower limb or health.
Compound in above-mentioned formula (1) " structural formula 1 " can be by the aryl in formula (2) " structural formula 2 " and the functional derivative of heteroaryl acetic acid, prepare as the compound in acid halide or mixed acid anhydride etc., with formula (3) " structural formula 3 " reacts.
In structural formula 2, Y represents halogen, alcoxyl carbonyl acidic group or substituted virtue oxygen carbonyl acidic group, and Aryl represents the aryl and heteroaryl groups listed in " structural formula 1 ".
In structural formula 3, R3Represent H, the alkyl of any 1-12 carbon atom, the alkoxyl of 1-12 carbon atom, the thiazolinyl of 1-12 carbon atom, the alkynyl of 1-12 carbon atom, or aryl；R4 represents H, the alkyl of any 1-12 carbon atom, the alkoxyl of 1-12 carbon atom, the thiazolinyl of 1-12 carbon atom, the alkynyl of 1-12 carbon atom, or aryl；X represents O, S or NH；N=0,1,2,3,4,5,6,7,8,9,10 ...
Compound represented by above-mentioned formula (1) " structural formula 1 " can be reacted with the compound represented by formula (3) " structural formula 3 " under the effect of coupling agent by Tolmetin, zomepirac, etodolac, amfenac, bromfenac, alclofenac, fenclofenac, acemetacin, indomethacin, sulindac, fentiazac, lonazolac, bendazac, 6-methoxyl group-2-naphthalene-2-acetic acid (6MNA), ibufenac and related compound thereof and prepare.Coupling agent has: N, N '-dicyclohexylcarbodiimide, N, N '-DIC, O-(BTA-1-base)-N, N, N ', N '-tetramethylurea Tetrafluoroboric acid ester, O-(BTA-1-base)-N, N, N ', N '-tetramethylurea hexafluorophosphoric acid ester, BTA-1-base-epoxide-three (dimethylamino) phosphorus-hexafluorophosphate etc..
When X represents O, compound represented by above-mentioned formula (1) " structural formula 1 " can be reacted with the compound represented by formula (4) " structural formula 4 " prepared by the slaine of Tolmetin, zomepirac, etodolac, amfenac, bromfenac, alclofenac, fenclofenac, acemetacin, indomethacin, sulindac, fentiazac, lonazolac, bendazac, 6MNA, ibufenac and related compound thereof or the salt of organic base.
In structural formula 4, R2Represent H, the alkyl of any 1-12 carbon atom, the alkoxyl of 1-12 carbon atom, the thiazolinyl of 1-12 carbon atom, the alkynyl of 1-12 carbon atom, or aryl；R3Represent H, the alkyl of any 1-12 carbon atom, the alkoxyl of 1-12 carbon atom, the thiazolinyl of 1-12 carbon atom, the alkynyl of 1-12 carbon atom, or aryl；R4Represent H, the alkyl of any 1-12 carbon atom, the alkoxyl of 1-12 carbon atom, the thiazolinyl of 1-12 carbon atom, the alkynyl of 1-12 carbon atom, or aryl；Z represents halogen, or p-methyl benzenesulfonic acid base；A-Represent Cl-, Br-, F-, I-, AcO-, citrate, or any anion；N=0,1,2,3,4,5 ...
When X represents O, compound represented by above-mentioned formula (1) " structural formula 1 " can be reacted with the compound represented by formula (4) " structural formula 4 " prepared by the immobilization alkali salt of Tolmetin, zomepirac, etodolac, amfenac, bromfenac, alclofenac, fenclofenac, acemetacin, indomethacin, sulindac, fentiazac, lonazolac, bendazac, 6MNA, ibufenac and related compound thereof represented by formula " structural formula 5 ".
In structural formula 5, R represents the resin of crosslinking；Aryl represents the aryl and heteroaryl groups listed in " structural formula 1 ", and B represents any basic group, such as pyridine radicals, piperidyl, triethyamino and or other basic groups.
Advantage
In the pro-drugs of these Tolmetin, zomepirac, etodolac, amfenac, bromfenac, alclofenac, fenclofenac, acemetacin, indomethacin, sulindac, fentiazac, lonazolac, bendazac, 6MNA, ibufenac and related compound thereof, some is lipophilic moieties, and another part is hydrophilic parts (amido existed with protonated form when physiological ph).The amino of positively charged has two big advantages: first, it drastically increases the dissolubility of medicine；When these new prodrugs are with when such as tablet, capsule, solution or suspensoid are administered orally, and it can dissolve in gastric juice.Second, the amino of these prodrug positively chargeds can be bonded with the negative charge of biomembranous phosphate end group.Therefore, the local concentration outside film can be the highest, thus promotes these prodrugs from area with high mercury thoroughly to low concentration region.After these prodrugs enter into biomembrane, hydrophilic parts will promote medicine to enter in Cytoplasm, and Cytoplasm is the semi liquid state aqueous solution or suspension concentrated.Owing to these prodrugs residence time in gastric juice is the shortest, damage thus without to gastric mucosa.Experimental result shows that the prodrug of 90% can become female medicine again.These prodrugs have more preferable absorbance, so under same dose, the curative effect of prodrug is better than Tolmetin, zomepirac, etodolac, amfenac, bromfenac, alclofenac, fenclofenac, acemetacin, indomethacin, sulindac, fentiazac, lonazolac, bendazac, 6MNA, ibufenac and related compound thereof.nullExperimental result display prodrug，(1-(p-chlorobenzoyl)-5-methoxyl group-2-Methvl-indole-3-acetic acid-lignocaine ethyl ester acetate，(Z)-5-fluoro-2-methyl isophthalic acid-[(4-first thionyl) phenylmethylene-1H-indenes-3-acetic acid-lignocaine ethyl ester acetate，1-methyl-5-(4-toluyl)-1H-pyrroles-2-acetic acid-lignocaine ethyl ester acetate，5-(4-chlorobenzoyl)-1，4-dimethyl-1H-pyrroles-2-acetic acid-lignocaine ethyl ester acetate，1，8-diethyl-1，3,4,9-Pentamethylene oxide .-[3，4-b] indole-1-acetic acid-lignocaine ethyl ester acetate，2-amino-3-benzoylphenylacetic acids-lignocaine ethyl ester acetate，2-amino-3-(the bromo-benzoyl of 4-) phenylacetic acid-lignocaine ethyl ester acetate，The chloro-4-of 3-(2-propenyloxy group) phenylacetic acid-lignocaine ethyl ester acetate，2-(2，4-dichlorophenoxy)-phenylacetic acid-lignocaine ethyl ester acetate，1-(4-chlorobenzene formacyl)-5-methoxyl group-2-Methyl-1H-indole-3-acetoxy acid-lignocaine ethyl ester acetate，4-(4-chlorphenyl)-2-phenyl-5-thiazolyl acetic acid-lignocaine ethyl ester acetate，Or the speed through human body skin of 3-(4-chlorphenyl)-1-phenyl-1H-pyrazoles-4-acetic acid-lignocaine ethyl ester acetate is than female medicine，Tolmetin、Zomepirac、Etodolac、Amfenac、Bromfenac、Alclofenac、Fenclofenac、Acemetacin、Indomethacin、Sulindac、Fentiazac、Lonazolac、Bendazac、6-methoxyl group-2-naphthalene-2-acetic acid (6MNA)、Ibufenac and fast about 100 times of related compound thereof.Oral Tolmetin, zomepirac, etodolac, amfenac, bromfenac, alclofenac, fenclofenac, acemetacin, indomethacin, sulindac, fentiazac, lonazolac, bendazac, 6MNA, ibufenac and related compound thereof after 2-4 hour blood drug level just reach peak value, and prodrug has only to 40-50 minute i.e. can reach peak plasma concentrations.The most exciting result is, prodrug is possible not only to be administered orally, and any Drug therapy can be used in the way of transdermal administration, thus avoid the side effect of Tolmetin, zomepirac, etodolac, amfenac, bromfenac, alclofenac, fenclofenac, acemetacin, indomethacin, sulindac, fentiazac, lonazolac, bendazac, 6MNA, ibufenac and related compound thereof, the most most importantly it is avoided that gastrointestinal upset such as dyspepsia, stomach and duodenal hemorrhage, gastric ulcer and gastritis etc..Another big benefit of transdermal administration is that medication is convenient, is particularly administered child.
Accompanying drawing explanation
nullFig. 1: 1-(p-the chlorobenzoyl)-5-methoxyl group-2-Methvl-indole-3-acetic acid-lignocaine ethyl ester acetate (A of the human skin tissue by separating in Franz pond (n=5)，The solution of 30%)，(Z)-5-fluoro-2-methyl isophthalic acid-[(4-first thionyl) phenylmethylene-1H-indenes-3-acetic acid-lignocaine ethyl ester acetate (B，The solution of 30%)，1-methyl-5-(4-toluyl)-1H-pyrroles-2-acetic acid-lignocaine ethyl ester acetate (C，The solution of 30%)，5-(4-chlorobenzoyl)-1，4-dimethyl-1H-pyrroles-2-acetic acid-lignocaine ethyl ester acetate (D，The solution of 30%)，1，8-diethyl-1，3，4，9-Pentamethylene oxide .-[3，4-b] indole-1-acetic acid-lignocaine ethyl ester acetate (E，The solution of 30%)，Indomethacin (F，The suspension of 30%)、Sulindac (G，The suspension of 30%)、Tolmetin (H，The suspension of 30%)、Zomepirac (I，The suspension of 30%)、Or etodolac (J，The suspension of 30%) accumulation total amount.Carrier solution under the conditions of various is the phosphate buffered solution (0.2M) of pH7.4.
nullFig. 2: the 2-amino-3-benzoylphenylacetic acids-lignocaine ethyl ester acetate (A of the human skin tissue by separating in Franz pond (n=5)，The solution of 30%)，2-amino-3-(the bromo-benzoyl of 4-) phenylacetic acid-lignocaine ethyl ester acetate (B，The solution of 30%)，The chloro-4-of 3-(2-propenyloxy group) phenylacetic acid-lignocaine ethyl ester acetate (C，The solution of 30%)，2-(2，4-dichlorophenoxy)-phenylacetic acid-lignocaine ethyl ester acetate (D，The solution of 30%)，1-(4-chlorobenzene formacyl)-5-methoxyl group-2-Methyl-1H-indole-3-acetoxy acid-lignocaine ethyl ester acetate (E，The solution of 30%)，4-(4-chlorphenyl)-2-phenyl-5-thiazolyl acetic acid-lignocaine ethyl ester acetate (F，The solution of 30%)，Amfenac (G，The suspension of 30%)，Bromfenac (H，The suspension of 30%)，Alclofenac (I，The suspension of 30%)，Fenclofenac (J，The suspension of 30%)，Acemetacin (K，The suspension of 30%)，Or fentiazac (L，The suspension of 30%) accumulation total amount.Carrier solution under the conditions of various is the phosphate buffered solution (0.2M) of pH7.4.
nullFig. 3: local, hairless mouse (n=5) back is used 1-(p-the chlorobenzoyl)-5-methoxyl group-2-Methyl-1H-indole-3-acetic acid-lignocaine ethyl ester acetate (A) of be dissolved in 1ml isopropanol 20%，(Z)-5-fluoro-2-methyl isophthalic acid-[(4-first thionyl) phenylmethylene-indenes-3-acetic acid-lignocaine ethyl ester acetate (B)，1-methyl-5-(4-toluyl)-1H-pyrroles-2-acetic acid-lignocaine ethyl ester acetate (C)，5-(4-chlorobenzoyl)-1，4-dimethyl-1H-pyrroles-2-acetic acid-lignocaine ethyl ester acetate (D)，Indomethacin (E)，Sulindac (F)，Tolmetin (G)，After zomepirac (H)，Indomethacin in blood plasma，Sulindac，Tolmetin，Or the total amount of zomepirac.
Fig. 4: local, hairless mouse (n=5) back is used the 1 of be dissolved in 1ml isopropanol 20%, 8-diethyl-1, 3, 4, 9-Pentamethylene oxide .-[3, 4-b] indole-1-acetic acid-lignocaine ethyl ester acetate (A), 2-amino-3-benzoylphenylacetic acids-lignocaine ethyl ester acetate (B), 2-amino-3-(the bromo-benzoyl of 4-) phenylacetic acid-lignocaine ethyl ester acetate (C), the chloro-4-of 3-(2-propenyloxy group) phenylacetic acid-lignocaine ethyl ester acetate (D), etodolac (E), amfenac (F), bromfenac (G), or after alclofenac (H), etodolac in blood plasma, amfenac, bromfenac, or the total amount of alclofenac.
Fig. 5: local, hairless mouse (n=5) back is used the 2-(2 of be dissolved in 1ml isopropanol 20%, 4-dichlorophenoxy)-phenylacetic acid-lignocaine ethyl ester acetate (A), 1-(4-chlorobenzene formacyl)-5-methoxyl group-2-Methyl-1H-indole-3-acetoxy acid-lignocaine ethyl ester acetate (B), 4-(4-chlorphenyl)-2-phenyl-5-thiazolyl acetic acid-lignocaine ethyl ester acetate (C), 3-(4-chlorphenyl)-1-phenyl-1H-pyrazoles-4-acetic acid-lignocaine ethyl ester acetate (D), fenclofenac (E), acemetacin (F), fentiazac (G), after lonazolac (H), fentiazac in blood plasma, acemetacin, fentiazac or the total amount of lonazolac.
nullFig. 6: at 1-(p-the chlorobenzoyl)-5-methoxyl group-2-Methvl-indole-3-acetic acid-lignocaine ethyl ester acetate (B) of transdermal administration 50mg/kg，(Z)-5-fluoro-2-methyl isophthalic acid-[(4-first thionyl) phenylmethylene-1H-indenes-3-acetic acid-lignocaine ethyl ester acetate (C)，1-methyl-5-(4-toluyl)-1H-pyrroles-2-acetic acid-lignocaine ethyl ester acetate (D)，5-(4-chlorobenzoyl)-1，4-dimethyl-1H-pyrroles-2-acetic acid-lignocaine ethyl ester acetate (E)，1，8-diethyl-1，3，4，9-Pentamethylene oxide .-[3，4-b] indole-1-acetic acid-lignocaine ethyl ester acetate (F)，After 2-amino-3-benzoylphenylacetic acids-lignocaine ethyl ester acetate (G)，The mouse tail threshold of pain extends the time.A is matched group.
Fig. 7: at 2-amino-3-(the bromo-benzoyl of the 4-) phenylacetic acid-lignocaine ethyl ester acetate (B) of transdermal administration 50mg/kg, the chloro-4-of 3-(2-propenyloxy group) phenylacetic acid-lignocaine ethyl ester acetate (C), 2-(2, 4-dichlorophenoxy)-phenylacetic acid-lignocaine ethyl ester acetate (D), 1-(4-chlorobenzene formacyl)-5-methoxyl group-2-Methyl-1H-indole-3-acetoxy acid-lignocaine ethyl ester acetate (E), 4-(4-chlorphenyl)-2-phenyl-5-thiazolyl acetic acid-lignocaine ethyl ester acetate (F), after 3-(4-chlorphenyl)-1-phenyl-1H-pyrazoles-4-acetic acid-lignocaine ethyl ester acetate (G), the mouse tail threshold of pain extends the time.A is matched group.
Fig. 8: the swelling rate (%) after the dish glue of injection angle.nullAngle dish glue first 1 hour transdermal administration 1-(p-chlorobenzoyl)-5-methoxyl group-2-Methvl-indole-3-acetic acid-lignocaine ethyl ester acetate (100mg/kg of injection，B)，(Z)-5-fluoro-2-methyl isophthalic acid-[(4-first thionyl) phenylmethylene-1H-indenes-3-acetic acid-lignocaine ethyl ester acetate (100mg/kg，C)，1-methyl-5-(4-toluyl)-1H-pyrroles-2-acetic acid-lignocaine ethyl ester acetate group (100mg/kg，D)，5-(4-chlorobenzoyl)-1,4-dimethyl-1H-pyrroles-2-acetic acid-lignocaine ethyl ester acetate (100mg/kg，E)，1，8-diethyl-1，3，4，9-Pentamethylene oxide .-[3，4-b] indole-1-acetic acid-lignocaine ethyl ester acetate (100mg/kg，F)，2-amino-3-benzoylphenylacetic acids-lignocaine ethyl ester acetate (100mg/kg，G).A is matched group.
Fig. 9: the swelling rate (%) after the dish glue of injection angle.nullAngle dish glue first 1 hour transdermal administration 2-amino-3-(the bromo-benzoyl of 4-) phenylacetic acid-lignocaine ethyl ester acetate (100mg/kg of injection，H)，The chloro-4-of 3-(2-propenyloxy group) phenylacetic acid-lignocaine ethyl ester acetate (100mg/kg，I)，2-(2，4-dichlorophenoxy)-phenylacetic acid-lignocaine ethyl ester acetate (100mg/kg，J)，1-(4-chlorobenzene formacyl)-5-methoxyl group-2-Methyl-1H-indole-3-acetoxy acid-lignocaine ethyl ester acetate (100mg/kg，K)，4-(4-chlorphenyl)-2-phenyl-5-thiazolyl acetic acid-lignocaine ethyl ester acetate (100mg/kg，L)，3-(4-chlorphenyl)-1-phenyl-1H-pyrazoles-4-acetic acid-lignocaine ethyl ester acetate (100mg/kg，M).A is matched group.
Figure 10: structural formula 1: in structural formula 1, Aryl represents the aryl and the group of heteroaryl, R listed in " structural formula 1 "1Represent H, the alkyl of any 1-12 carbon atom, the alkoxyl of 1-12 carbon atom, the thiazolinyl of 1-12 carbon atom, the alkynyl of 1-12 carbon atom, or aryl；R2Represent H, the alkyl of any 1-12 carbon atom, the alkoxyl of 1-12 carbon atom, the thiazolinyl of 1-12 carbon atom, the alkynyl of 1-12 carbon atom, or aryl；R3Represent H, the alkyl of any 1-12 carbon atom, the alkoxyl of 1-12 carbon atom, the thiazolinyl of 1-12 carbon atom, the alkynyl of 1-12 carbon atom, or aryl；X represents O, S, NH, OCH2COO, OCH2COS, or OCH2CONH；A-Represent Cl-, Br-, F-, I-, AcO-, citrate, or other any anion；N=0,1,2,3,4,5,6,7,8,9,10 ...
Preferred forms
(Z) synthesis of-5-fluoro-2-methyl isophthalic acid-[(4-first thionyl) phenylmethylene]-1H-indenes-3-acetic acid-lignocaine ethyl ester acetate
11.7g (0.1mol) N, N-diethylaminoethanol is dissolved in 10% sodium bicarbonate solution and the 100ml acetone of 200ml.Reactant mixture adds 37.5g (0.1mol) (Z)-5-fluoro-2-methyl isophthalic acid-[(4-first thionyl) phenylmethylene-1H-indenes-3-chloroacetic chloride.It is stirred at room temperature 3 hours.After solvent evaporated, residue is suspended from 500ml ethyl acetate, and stirring adds 200ml5% sodium bicarbonate solution.Collect ethyl acetate layer and wash with water 3 times, each 500ml.Ethyl acetate layer anhydrous sodium sulfate is dried.It is filtered to remove sodium sulfate.In reactant mixture, stirring adds 6g acetic acid.Boil off organic facies.Obtaining the target product of the easy moisture absorption of 42g after drying, productivity is 81.5%.Dissolubility in water: 400mg/ml；Elementary analysis: C28H34FNO5S；Molecular weight: 515.64.Theoretical value %C:65.22；H:6.65；F:3.68；N:2.72；O:15.51；S:6.22；Measured value %C:65.20；H:6.67；N:3.67；O:15.53；S:6.21.1H-NMR (400MHz, D2O): δ: 1.36 (t.6H), 1.65 (s, 3H), 2.11 (s, 3H), 2.56 (s, 3H), 2.82 (s, 2H), 3.27 (m, 4H), 3.47 (m, 2H), 4.48 (t, 2H), 6.74 (s, 1H), 6.84 (m, 1H), 6.88 (b, 1H), 7.00 (m, 1H), 7.30 (m, 1H), 7.63 (m, 2H), (7.65 m, 2H).
Embodiment
The synthesis of 1-methyl-5-(4-toluyl)-1H-pyrroles's-2-acetate. AcOH
28.6g (0.1mol) 1-methyl-5-(4-toluyl)-1H-pyrroles's-2-chloroacetic chloride is dissolved in 100ml chloroform.Mixture is cooled to 0 DEG C.Reactant mixture adds 15ml triethylamine and 8.9g (0.1mol) diethylaminoethanol, is stirred at room temperature 3 hours.Solvent evaporated.Residue is dissolved in 300ml methanol, adds 200ml5% sodium bicarbonate solution, stirs 3 hours.It is evaporated mixture.In residue, stirring adds 300ml methanol.Solids removed by filtration is also washed with methanol.Filtrate is evaporated, and residue is dissolved in 200ml chloroform.In reactant mixture, stirring adds 6g acetic acid.Solids removed by filtration.Reactant mixture is stirred for add another 6g acetic acid.Boil off organic facies.Dried the easy hygroscopic target product of 37g, productivity 88.8%.Dissolubility in water: 500mg/ml；Elementary analysis: C23H32N2O5；Molecular weight: 416.51.Theoretical value %C:66.32；H:7.74；N:6.73；O:19.21；Measured value %C:66.29；H:7.76；N:6.73；O:19.22.1H-NMR (400MHz, D2O): δ: 1.51 (t, 6H), 2.21 (s, 3H), 2.35 (s, 3H), 3.25 (m, 4H), 3.48 (s, 3H), 3.50 (m, 2H), 3.55 (s, 2H), 4.50 (t, 2H), 5.86 (m, 1H), 6.67 (m, 1H), 6.70 (b, 1H), 7.25 (m, 2H), 7.67 (m, 2H).
The synthesis of 1-(p-chlorobenzoyl)-5-methoxyl group-2 methyl indole-3-acetic acid dimethylamino second thioesters acetate
10.4g (0.1mol) N, N-dimethylamino ethyl mercaptan is dissolved in 200ml10% sodium bicarbonate solution and 100ml acetone.Reactant mixture adds 37.6g (0.1mol) 1-(p-chlorobenzoyl)-5-methoxyl group-2 methyl indole-3-chloroacetic chloride, is stirred at room temperature 3 hours.Solvent evaporated.Residue is suspended from 500ml ethyl acetate, and stirring adds 200ml5% sodium bicarbonate solution.Collect ethyl acetate layer and wash with water 3 times, each 500ml.Ethyl acetate layer anhydrous sodium sulfate is dried.It is filtered to remove sodium sulfate.In reactant mixture, stirring adds 6g acetic acid.Boil off organic facies.Obtain the target product of the easy moisture absorption of 46g, productivity 86.3% after drying.Dissolubility in water: 400mg/ml；Elementary analysis: C27H33ClN2O5S；Molecular weight: 533.08.Theoretical value %C:60.83；H:6.24；Cl；6.65；N:5.26；O:15.01；S:6.02.Measured value %C:60.80；H:6.26；Cl:6.66；N:5.25, O:15.02；S:6.01.1H-NMR (400MHz, D2O): δ: 1.47 (t, 6H), 2.20 (s, 3H), 2.28 (s, 3H), 3.28 (m, 4H), 3.31 (t, 2H), 3.54 (s, 2H), 3.73 (s, 3H), 3.91 (t, 2H), 6.70 (b, 1H), 6.24 (m, 1H), 6.68 (m, 1H), 6.75 (m, 1H), 7.46 (m, 2H), 7.75 (m, 2H).
The synthesis of N-dimethylaminoethyl 5-(4-chlorobenzoyl)-1,4-dimethyl-1H-pyrroles's-2-acetamide acetate
8.8g (0.1mol) dimethylaminoethylamine is dissolved in 200ml10% sodium bicarbonate solution and 100ml acetone.Reactant mixture adds 31g (0.1mol) 2-(3-benzoyloxy phenyl) propionyl chloride, is stirred at room temperature 3 hours.Solvent evaporated.Residue is suspended from 500ml ethyl acetate, is stirred for adding 200ml5% sodium bicarbonate solution.Collect ethyl acetate layer, and wash with water 3 times, each 500ml.Ethyl acetate layer anhydrous sodium sulfate is dried.It is filtered to remove sodium sulfate.In reactant mixture, stirring adds 6g acetic acid.It is evaporated organic facies.Obtain the target product of the easy moisture absorption of 33g, productivity 85.9% after drying.Dissolubility in water: 400mg/ml；Elementary analysis: C23H32ClN3O4；Molecular weight: 449.97.Theoretical value %C:61.39；H:7.17；Cl；7.88；N:9.34；O:14.22；Measured value %C:61.37；H:7.18；Cl；7.89；N:9.32；O:14.24.1H-NMR (400MHz, D2O): δ: 1.42 (t, 6H), 2.05 (s, 3H), 2.21 (s, 3H), 3.26 (m, 4H), 3.48 (s, 2H), 3.50 (t, 2H), 3.64 (t, 2H), 3.50 (s, 3H), 5.66 (s, 1H), 7.0 (b, 1H), 7.46 (m, 2H), 7.54 (m, 2H), 7.47 (b, 1H).
N-dimethylaminoethyl 1,8-diethyl-1, the synthesis of 3,4,9-Pentamethylene oxide .s [3,4-b] indole-1-acetamide acetate
28.9g (0.1mol) 1,8-diethyl-1,3,4,9-Pentamethylene oxide .s [3,4-b] indole-1-acetic acid is dissolved in 100ml acetonitrile.Reactant mixture adds 32.1g O-(BTA 1-yl)-N, N, N ', N '-tetramethylurea Tetrafluoroboric acid ester and 30ml triethylamine.Reactant mixture adds 11.7g dimethylaminoethylamine.It is stirred at room temperature 3 hours.Solvent evaporated.Reactant mixture adds 250ml ethyl acetate, and washes with water 3 times, each 100ml.Organic facies anhydrous sodium sulfate is dried.It is filtered to remove sodium sulfate.In reactant mixture, stirring adds 6g acetic acid.Add 200ml hexane.Solid product is collected by filtration.Obtain the target product of the easy moisture absorption of 40g, productivity 89.4% after drying.Dissolubility in water: 400mg/ml；Elementary analysis: C25H41N3O4；MW:447.61.Theoretical value %C:67.08；H:9.23；N:9.39；O:14.30；Measured value %C:67.05；H:9.25；N:9.38；O:14.32.1H-NMR (400MHz, D2O): δ: 0.95 (t, 3H), 1.20 (t, 3H), 1.24 (t, 3H), 1.40 (m, 2H), 1.50 (s, 6H), 1.87 (m, 2H), 2.21 (s, 3H), 2.25 (s, 2H), 2.56 (m, 2H), 3.08 (m, 1H), 3.11 (m, 1H), 3.28 (m, 4H), 3.50 (m, 2H), 3.64 (m, 2H), 7.0 (b, 1H), 6.43 (m, 1H), 6.70 (m, 1H), 6.72 (m, 1H), 7.6 (b, 1H).
The synthesis of the chloro-4-of 3-(2-propenyloxy group) phenylacetic acid-lignocaine ethyl ester acetate
The triethylamine (3mol/g, 100-200 mesh) of 60g Polymer-bound is suspended from 180ml chloroform.In mixture, stirring adds 22.7g (0.1mol) 3-chloro-4-(2-propenyloxy group) phenylacetic acid.Mixture adds 43g (0.15mol) diethyllaminoethyl bromine hydrogen bromide salt, is stirred at room temperature 5 hours.It is filtered to remove polymer, and washes three times with oxolane, each 50ml.In reactant mixture, stirring adds 8.2g (0.1mol) sodium acetate.Mixture stirs 2 hours.Solids removed by filtration, washes 3 times with chloroform, each 50ml.Filter vacuum is concentrated into 100ml, adds 300ml hexane.Solid product is collected by filtration, and washes 3 times with hexane, each 100ml.The dried target product obtaining the easy moisture absorption of 34g, productivity 88.3%.Dissolubility in water: 400mg/ml；Elementary analysis: C19H29ClN2O4；Molecular weight: 384.9.Theoretical value %C:59.29；H:7.59；CL；9.21, N:7.28；O:16.63；Measured value %C:59.26；H:7.61；CL；9.22；N:7.26；O:16.65.1H-NMR (400MHz, D2O: δ: 1.56 (t, 6H), 2.21 (s, 3H), 3.27 (m, 4H), 3.43 (s, 2H), 3.50 (m, 2H), 3.63 (m, 2H), 4.60 (s, 2H), 5.23 (m, 2H), 5.89 (m, 1H), 6.5 (b, 1H), 6.61 (m, 1H), 6.81 (m, 1H), 6.94 (m, 1H), 7.70 (b, 1H).
Industrial applicibility
Prodrug shown in formula (1) " structural formula 1 " is better than Tolmetin, zomepirac, etodolac, amfenac, bromfenac, alclofenac, fenclofenac, acemetacin, indomethacin, sulindac, fentiazac, lonazolac, bendazac, 6MNA, ibufenac and related compound thereof.They can be used for treating the state that any Tolmetin, zomepirac, etodolac, amfenac, bromfenac, alclofenac, fenclofenac, acemetacin, indomethacin, sulindac, fentiazac, lonazolac, bendazac, 6MNA, ibufenac and the related compound thereof of human or animal can be treated.They can be used for rheumatoid arthritis, osteoarticular sign and symptom, brings down a fever, and treatment dysmenorrhea.They can be additionally used in treatment diabetic neuropathy and acute migraine.Due to these prodrug membrane penetration rates quickly, thus can by suction by the way of treat asthma.Due to the anti-inflammatory activity of these prodrugs, they can be additionally used in treatment acne.
Claims (14)
1. selected from following compound:
1-(p-chlorobenzoyl)-5-methoxyl group-2-Methvl-indole-3-acetic acid-lignocaine ethyl ester acetate；
(Z)-5-fluoro-2-methyl isophthalic acid-[(4-first thionyl) phenylmethylene]-1H-indenes-3-acetic acid-lignocaine ethyl ester acetic acid
Salt；
1-methyl-5-(4-toluyl)-1H-pyrroles-2-acetic acid-lignocaine ethyl ester acetate；
5-(4-chlorobenzoyl)-1,4-dimethyl-1H-pyrroles-2-acetic acid-lignocaine ethyl ester acetate；
1,8-diethyl-1,3,4,9-Pentamethylene oxide .-[3,4-b] indole-1-acetic acid-lignocaine ethyl ester acetate；
2-amino-3-benzoylphenylacetic acids-lignocaine ethyl ester acetate；
2-amino-3-(the bromo-benzoyl of 4-) phenylacetic acid-lignocaine ethyl ester acetate；
The chloro-4-of 3-(2-propenyloxy group) phenylacetic acid-lignocaine ethyl ester acetate；
2-(2,4 dichloro benzene epoxide)-phenylacetic acid-lignocaine ethyl ester acetate；
L-(4-chlorobenzene formacyl)-5-methoxyl group-2-Methyl-1H-indole-3-acetoxy acid-lignocaine ethyl ester vinegar
Hydrochlorate；
4-(4-chlorphenyl)-2-phenyl-5-thiazolyl acetic acid-lignocaine ethyl ester acetate；
3-(4-chlorphenyl)-1-phenyl-1H-pyrazoles-4-acetic acid-lignocaine ethyl ester acetate；With
[(1-benzyl-1H-indazole-3-base) oxygen] acetic acid-lignocaine ethyl ester acetate.
2. compound as claimed in claim 1 is used for treating in human or animal in preparation that nonsteroidal antiinflammatory drug can
Purposes in the medicine of the state for the treatment of.
3. purposes as claimed in claim 2, the medicable state of wherein said nonsteroidal antiinflammatory drug is selected from:
Vomiting that pain, fever, cancer, radiotherapy cause, diabetic neuropathy, eye inflammation, green light
Eye, ear inflammation, hemophilic arthritis, bone run off and dermatosis.
4. purposes as claimed in claim 2, wherein said medicine be solution, suspension, spray, emulsion,
Ointment, latex or gel preparations.
5. purposes as claimed in claim 3, wherein said pain is selected from: has a headache, have a toothache, operation on cornea
After ocular pain, ear's pain, myalgia, dysmenorrhea, arthritis and other inflammatory pain.
6. purposes as claimed in claim 5, wherein said headache is acute migraine.
7. purposes as claimed in claim 3, wherein said dermatosis is selected from: acne and sunburn.
8. the purposes as according to any one of claim 5 to 7, wherein said medicine is carried out by transdermal administration
Treatment.
9. compound as claimed in claim 1 is used for the purposes treating in the medicine of asthma in preparation.
10. purposes as claimed in claim 9, wherein said medicine is by lip-syncing or nose or other portions of health
The mode of position spray delivery is treated.
11. 1 kinds of skin-penetrating therapeutic application systems, it comprises compound as claimed in claim 1, and can be used for
The medicable state of non-steroidal anti-inflammatory drug in treatment human or animal.
12. skin-penetrating therapeutic application systems as claimed in claim 11, described application system is binder or paster,
It includes a hypothallus comprising active substance and the protective layer of an impermeable.
13. skin-penetrating therapeutic application systems as claimed in claim 11, it includes an active substance reservoir, its bag
Include a permeable bottom towards skin.
Skin-penetrating therapeutic application system as described in any one in 14. such as claim 11 to 13, it is characterised in that
It makes nonsteroidal anti-inflammatory drug stable at optimal treatment blood drug level by control rate of release thus improves treatment
Imitate and reduce the side effect of nonsteroidal anti-inflammatory drug.
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