WO2008029199A1 - Positively charged water-soluble prodrugs of n-arylanthranilic acids with very fast skin penetration rate - Google Patents

Positively charged water-soluble prodrugs of n-arylanthranilic acids with very fast skin penetration rate Download PDF

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Publication number
WO2008029199A1
WO2008029199A1 PCT/IB2006/053090 IB2006053090W WO2008029199A1 WO 2008029199 A1 WO2008029199 A1 WO 2008029199A1 IB 2006053090 W IB2006053090 W IB 2006053090W WO 2008029199 A1 WO2008029199 A1 WO 2008029199A1
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WIPO (PCT)
Prior art keywords
acid
general formula
compounds
amino
diethylaminoethyl
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PCT/IB2006/053090
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French (fr)
Inventor
Chongxi Yu
Lina Xu
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Techfields Biochem Co. Ltd
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Priority to PCT/IB2006/053090 priority Critical patent/WO2008029199A1/en
Priority to EP13153470.3A priority patent/EP2623495B1/en
Application filed by Techfields Biochem Co. Ltd filed Critical Techfields Biochem Co. Ltd
Priority to PL06795893T priority patent/PL2084132T3/en
Priority to CN200680055744.7A priority patent/CN101506168B/en
Priority to ES06795893.4T priority patent/ES2694685T3/en
Priority to PL13153470T priority patent/PL2623495T3/en
Priority to ES13153470T priority patent/ES2735287T3/en
Priority to EP06795893.4A priority patent/EP2084132B1/en
Publication of WO2008029199A1 publication Critical patent/WO2008029199A1/en
Priority to US12/351,804 priority patent/US20090238763A1/en
Priority to US12/397,308 priority patent/US20090221703A1/en
Priority to HK10100929.4A priority patent/HK1137426A1/en
Priority to US15/379,866 priority patent/US11135153B2/en
Priority to US15/402,575 priority patent/US20170209585A1/en
Priority to US15/402,618 priority patent/US9872846B2/en
Priority to US16/421,735 priority patent/US20210353579A1/en
Priority to US17/493,321 priority patent/US20220096370A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C07D213/80—Acids; Esters in position 3
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
    • C07C237/34—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having the nitrogen atom of the carboxamide group bound to an acyclic carbon atom of a hydrocarbon radical substituted by nitrogen atoms not being part of nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C327/00—Thiocarboxylic acids
    • C07C327/20—Esters of monothiocarboxylic acids
    • C07C327/30—Esters of monothiocarboxylic acids having sulfur atoms of esterified thiocarboxyl groups bound to carbon atoms of hydrocarbon radicals substituted by nitrogen atoms, not being part of nitro or nitroso groups

Definitions

  • the present invention relates to the preparations of positively charged and water- soluble pro-drugs of arylanthranilic acids and related compounds and their medicinal use in treating any nonsteroidal anti-inflammatory drugs (NSAIAs)-treatable conditions in humans or animals. More specifically, the present invention is to overcome the side effects that are associated with the use of NSAIAs. These pro-drugs can be administered orally or transdermally.
  • NSAIAs nonsteroidal anti-inflammatory drugs
  • Mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, flunixin, and related compounds have been used medicinally for many years. They are used for the relief of signs and symptoms of rheumatoid arthritis and osteoarthritis, for the treatment of dysmenorrhea.
  • This invention relates to the preparation of novel positively charged pro-drugs of arylanthranilic acids and related compounds and their use medicinally.
  • the pro-drugs of arylanthranilic acids have the general formula (1) 'Structure 1'.
  • the goal of this invention is to avoid the side effects of mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, flunixin, and related compounds by increasing the their solubility in gastric juice and their penetration rate through the membrane and skin barrier which will make it administrable transdermally (topical application).
  • These novel pro-drugs have two structural features in common: they have a lipophilic portion and a primary, secondary, or tertiary amine group that exists in the protonated form (hydrophilic part) at physiological pH. Such a hydrophilic-lipophilic balance is required for efficient passage through the membrane barrier [Susan Milosovich, et al., J. Pharm.
  • the positively charged amino groups largely increase the solubility of the drugs.
  • Mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, flunixin, and related compounds have a very low solubility in gastric juice. They stay in the GI tract for a long time and thus, may cause gastric mucosal cell damage.
  • these new pro-drugs When these new pro-drugs are administered orally in a dosage form such as a tablet, capsule, solution, or suspension, they will dissolve in the gastric juice immediately.
  • the positive charge on the amino groups of these pro-drugs will bond to the negative charge on the phosphate head group of membrane.
  • the local concentration of the outside of the membrane will be very high and will facilitate the passage of these pro-drugs from a region of high concentration to a region of low concentration.
  • pro-drugs When these pro-drugs enter the membrane, the hydrophilic part will push the pro-drug into the cytosol, a semi-liquid concentrated aqueous solution or suspension. Due to the short stay in GI tract, the pro-drugs will not cause gastric mucosal cell damage.
  • the pH of the stomach is 1-3, so the negative charge on the phosphate head group of the membrane of the gastric mucosa is bonded with proton (H + ).
  • the positive charges of these prodrugs cannot bond to phosphate head group of the gastric mucosa.
  • These prodrugs will be free both of primary insult (direct acid damage) and secondary insult (prostaglandin inhibition) to the stomach.
  • the receiving fluid consisted of 10 ml of 2% bovine serum albumin in normal saline and was stirred at 600 rpm.
  • the cumulative amounts of these prodrugs and their parent drugs penetrating the skin versus time were determined by a specific high-performance liquid chromatography method.
  • Plasma levels of mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, and flunixin were determined by a specific high-performance liquid chromatography method.
  • the results ( Figure 2) show that the peak levels of diethylaminoethyl 2-[(2,3-dimethylphenyl)amino] benzoate.
  • the peak plasma levels were -0.01 mg/ml for mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, and flunixin and ⁇ 2 mg/ml for diethylaminoethyl 2-[(2,3-dimethylphenyl)amino]benzoate.AcOH, diethylaminoethyl 2-[(2,6-dichloro-3-methylphenyl)amino]benzoate.AcOH, diethylaminoethyl 2- [ [(3-(trifluoromethyl)phenyl)amino]benzoate.
  • pro-drugs can be administered not only orally, but also transdermally for any kind of medical treatments.
  • the in vivo rates of penetration of other Pro-drugs of the general 'Structure I' are close to that of diethylaminoethyl diethylaminoethyl 2-[(2,3-dimethylphenyl)amino]benzoate.AcOH.
  • mice [11] The acute toxicity of the prodrugs was investigated.
  • the LD orally in mice are:
  • Mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, and flunixin demonstrated anti-inflammatory, analgesic, antipyretic, and antirheumatic activity.
  • a good prodrug should go back to the parent drug in plasma. Diethylaminoethyl ester group of these prodrugs can be rapidly cleaved by the enzymes in human plasma in vitro and more than 90% of the pro-drugs are changed back to their parent drugs. Due to the pro-drugs having a much better absorption rate, the prodrugs will have more strength than their parent drugs at the same dosage.
  • the analgetic, antipyretic, and antiinflammatory activities of these prodrugs were tested using mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, and flunixin as a comparison.
  • Antipyretic activity Rats received a sterilized E. coli suspension as a pyrogen.
  • the control group is group A. 2 hours later, diethylaminoethyl
  • Group A is the controlled group. 60 minutes later, a carrageenin solution was administered subcutaneously to the foot pads of the rats. The volume of the hind paw was measured at every hour after the administration of the carrageenin, and the rate of increase in the volume of the paw was calculated and designated as the rate of swelling (%). The results obtained are shown in Figure 4. The results show that these prodrugs by transdermal administration demonstrated good anti-inflammatory activity. Other compounds of the general 'Structure 1' show similar anti-inflammatory activity.
  • prodrugs can also be used to treat psoriasis, acne, sunburn or other skin disorders due to their anti-inflammatory properties and very high skin penetration rate.
  • the present invention relates to pharmaceutical preparations comprising of prodrugs of the general 'Structure 1' in addition to customary auxiliaries and excipients, e.g. in the form of tablets, capsules or solutions for administration orally and in the form of solutions, lotion, ointment, emulsion or gel for transdermal administration.
  • the new active compounds of the general 'Structure 1' can be combined with vitamins such as A, B, C or E or beta-carotene, or other pharmaceuticals, such as folic acid, etc., for treating any NSAIAs-treatable conditions in humans or animals.
  • 'Structure 1' or a composition comprising of at least one compound of the general 'Structure 1', as an active ingredient can be used for treating any NSAIAs-treatable conditions in humans or animals.
  • These systems can be a bandage or a patch comprising of one active substance-containing matrix layer and an impermeable backing layer.
  • the most preferable system is an active substance reservoir, which has a permeable bottom facing the skin. By controlling the rate of release, this system enables NSAIAs to reach constantly optimal therapeutic blood levels to increase effectiveness and reduce the side effects of NSAIAs.
  • These systems can be worn on the wrist, ankle, arm, leg, or any part of body.
  • the compounds of the general formula (1) 'Structure 1' indicated above can be prepared from mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, flunixin, and related compounds, by reaction with compounds of the general formula (2) 'Structure 2' by using coupling reagents, such as N,N'-Dicyclohexylcarbodiimide, N, N'-Diisopropylcarbodiimide, O-(Benzotriazol- 1 -yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate, O-(Benzotriazol- 1 -yl)-N,N,N',N'-tetramethyluronium hexafluo- rophosphate, Benzotriazol- 1 -yl-oxy-tris(dimethylamino)phosphonium hexafluo- rophosphate
  • R represents H, one of any alkyl, alkyloxy, alkenyl, or alkynyl residues having 1 to 12 carbon atoms, or aryl residues
  • R 4 represents H, one of any alkyl, alkyloxy, alkenyl, or alkynyl residues having 1 to 12 carbon atoms, or aryl residues
  • the compounds of the general formula (1) 'Structure 1' indicated above can be prepared from metal salts or organic base salts of mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, flunixin, and related compounds, by reaction with compounds of the general formula (3) "Structure”.
  • R represents H, one of any alkyl, alkyloxy, alkenyl, or alkynyl residues having 1 to 12 carbon atoms, or aryl residues
  • R represents H, one of any alkyl, alkyloxy, alkenyl, or alkynyl residues having 1 to 12 carbon atoms, or aryl residues
  • R 4 represents H, one of any alkyl, alkyloxy, alkenyl, or alkynyl residues having 1 to 12 carbon atoms, or aryl residues
  • Z represents halogen, or p-toluenesulphonyl
  • a " represents Cl “ , Br “ , F, I " , AcO " , citrate, or any negative ions
  • n 0, 1, 2, 3, 4, 5, 6, 7,
  • the compounds of the general formula (1) 'Structure 1' indicated above can be prepared from immobilized base salts of mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, flunixin, and related compounds of the general formula (4) 'Structure 4',
  • R represents cross-linked resin
  • Y represents H, Cl, F, CH , C H , or CF
  • Y represents H, Cl, F, CH , C H , or CF
  • Y represents H, Cl, F, CH , C H , or CF ;
  • Z represents CH or N;
  • B represents any base groups, such as pyridine, piperidine, tri- ethylamine, or other base groups, by reaction with compounds of the general formula (3) 'Structure 3' .
  • pro-drugs of mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, flunixin, and related compounds have a lipophilic portion and a hydrophilic portion (the amine groups that exist in the protonated form at physiological pH).
  • the positively charged amino groups of these pro-drugs have two major advantages. First, it largely increases the solubility of the drugs; when these new pro-drugs are administered orally in a dosage form such as a tablet, capsule, solution, or suspension, they will dissolve in gastric juice immediately. Second, the positive charge on the amino group of these pro-drugs will bond to the negative charge on the phosphate head group of membrane.
  • the local concentration outside of the membrane will be very high and will facilitate the passage of these pro-drugs from a region of high concentration to a region of low concentration.
  • the hydrophilic part will push the pro-drugs into the cytosol, a semi-liquid concentrated aqueous solution or suspension. Due to the short stay in the GI tract, the pro-drugs will not cause gastric mucosal cell damage. Experiment results show that more than 90% of the pro-drugs were changed back to the parent drugs.
  • the pro-drugs have a much better absorption rate, and thus the pro-drugs will have better strength than mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, flunixin, and related compounds at the same dosage.
  • the experiment results suggest that the pro-drugs, di- ethylaminoethyl 2-[(2,3-dimethylphenyl)amino]benzoate.AcOH, diethylaminoethyl 2-[(2,6-dichloro-3-methylphenyl)amino]benzoate.AcOH, diethylaminoethyl 2- [ [(3-(trifluoromethyl)phenyl)amino]benzoate.
  • pro-drugs can be administered not only orally, but also transdermally for any type of medical treatment and should avoid most of the side effects of mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, or flunixin, and related compounds, most notably GI disturbances such as dyspepsia, gas- troduodenal bleeding, gastric ulcerations, gastritis, and renal toxicity.
  • Another great benefit of transdermal administration of these pro-drugs is that administering medication, especially to children, will be much easier.
  • Figure 2 Total plasma levels of mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, and flunixin after topical application of 1 ml of a 20% solution of diethylaminoethyl 2-[(2,3-dimethylphenyl)amino]benzoate.AcOH (A), diethy- laminoethyl 2-[(2,6-dichloro-3-methylphenyl)amino]benzoate.AcOH (B), diethylaminoethyl 2-[[(3-(trifluoromethyl)phenyl)amino]benzoate.AcOH (C), diethylaminoethyl 2-[[3-(trifluoromethyl)phenyl]amino]-3-pyridinecarboxylate.AcOH (D), diethylaminoethyl 2-[[2-methyl-3-(trifluoromethyl)phenyl]amino
  • Figure 3 The prolongation time of the pain threshold of mice tails after 50mg/kg of diethylaminoethyl 2-[(2,3-dimethylphenyl)amino]benzoate.AcOH, diethylaminoethyl 2-[(2,6-dichloro-3-methylphenyl)amino]benzoate.AcOH, diethylaminoethyl 2- [ [(3-(trifluoromethyl)phenyl)amino]benzoate.
  • Figure 4 The rate of swelling (%) after a carrageenin injection. 1 hour before the carrageenin injection, diethylaminoethyl 2-[(2,3-dimethylphenyl)amino] benzoate.AcOH (100 mg/kg, B), diethylaminoethyl
  • R represents H, one of any alkyl, alkyloxyl, alkenyl or alkynyl residues having 1 to 12 carbon atoms, or aryl residues; R represents H, one of any alkyl, alkyloxy, alkenyl or alkynyl residues having 1 to 12 carbon atoms, or aryl residues; R represents H, one of any alkyl, alkyloxy, alkenyl or alkynyl residues having 1 to 12 carbon atoms, or aryl residues; X represents O, S, or NH; A " represents Cl “ , Br “ , F “ , I " , AcO , citrate, or any negative ions; Y represents H, Cl, F, CH , C H , or CF ; Y represents H, Cl, F, CH , C H , or CF ; Y represents H, Cl, F, CH , C H , or CF ; Y represents H, Cl, F, CH , C H
  • All R groups may include C, H, O, S, or N atoms and may have single, double, and treble bonds. Any CH groups may be replaced with O, S, or NH
  • the pro-drugs of the general formula (1) 'Structure 1' are superior to mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, flunixin, and related compounds. They can be used for treating any mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, flunixin, and related compounds-treatable conditions in humans or animals. They may be used for the relief of signs and symptoms of rheumatoid arthritis and osteoarthritis, the reduction of fever, and the treatment of dysmenorrhea. They may be also prescribed for diabetic neuropathy and acute migraine headache.
  • these pro-drugs can be used in treating asthma by inhalation to a host. They can be used to treat psoriasis, acne, sunburn or other skin disorders due to their anti-inflammatory properties. They can also be used for treating skin cancer, lung cancer, breast cancer,colon cancer, oral cancer, genital cancer, and other cancers by administering to the cancer area a very high effective amount directly.

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Abstract

The novel positively charged pro-drugs of arylanthranilic acids in the general formula (1) 'Structure 1' were designed and synthesized. The compounds of the general formula (1) 'Structure 1' indicated above can be prepared from mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, flunixin, and related compounds, by reaction with suitable alcohols, thiols, or amines and coupling reagents, such as N, N'-Dicyclohexylcarbodiimide, N, N'-Diisopropylcarbodiimide, O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate, O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, Benzotriazol-1-yl-oxy-tris (dimethylamino)phosphonium hexafluorophosphate, et al. The positively charged amino groups of these pro-drugs not only largely increases the solubility of the drugs, but also bonds to the negative charge on the phosphate head group of membranes and pushes the pro-drug into the cytosol. The results suggest that the pro-drugs diffuses through human skin ~200 times faster than does mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, flunixin, and related compounds. It takes 2-4 hours for mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, flunixin, and related compounds to reach the peak plasma level when they are taken orally, but these prodrugs only took about ~50 minutes to reach the peak plasma level when they are taken transdermally. In plasma, more than 90% of these pro-drugs can change back to the parent drugs in a few minutes. The prodrugs can be used medicinally in treating any NSAIAs-treatable conditions in humans or animals. The prodrugs can be administered not only orally, but also transdermally for any kind of medical treatments and thus avoid most of the side effects of NSAIAs, most notably GI disturbances such as dyspepsia, gastroduodenal bleeding, gastric ulcerations, and gastritis. Controlled transdermal administration systems of the prodrug enables mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, flunixin, and related compounds to reach constantly optimal therapeutic blood levels to increase effectiveness and reduce the side effects of mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, flunixin, and related compounds. Another great benefit of transdermal administration of these pro-drugs is that administering medication, especially to children, will be much easier.

Description

Description
POSITIVELY CHARGED WATER-SOLUBLE PRODRUGS OF N-ARYLANTHRANILIC ACIDS WITH VERY FAST SKIN
PENETRATION RATE
Technical Field
[1] The present invention relates to the preparations of positively charged and water- soluble pro-drugs of arylanthranilic acids and related compounds and their medicinal use in treating any nonsteroidal anti-inflammatory drugs (NSAIAs)-treatable conditions in humans or animals. More specifically, the present invention is to overcome the side effects that are associated with the use of NSAIAs. These pro-drugs can be administered orally or transdermally.
Background Art
[2] 2-[(2,3-Dimethylphenyl)amino]benzoic acid (mefenamic acid),
2-[(2,6-dichloro-3-methylphenyl)amino]benzoic acid (meclofenamic acid), 2-[[(3-trifluoromethyl)phenyl]amino]benzoic acid (flufenamic acid), 2-[[3-(trifluoromethyl)phenyl]amino]-3-pyridinecarboxylic acid (niflumic acid), 2-[[2-methyl-3-(trifluoromethyl)phenyl]amino]-3-pyridinecarboxylic acid (flunixin) and related compounds are members of arylanthranilic acid group of nonsteroidal antiinflammatory drugs. They are used for the relief of signs and symptoms of rheumatoid arthritis and osteoarthritis and for the treatment of dysmenorrhea. They are also used for the treatment of acute gouty arthritis and ankylosing spondylitis.
[3] Unfortunately, a number of side effects are associated with the use of mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, flunixin, and related compounds, most notably GI disturbances such as dyspepsia, gastroduodenal bleeding, gastric ulcerations, and gastritis. Fishman (Fishman; Robert, U.S. Pat. No. 7,052,715) indicated that an additional problem associated with oral medications, is that the concentration levels which must be achieved in the bloodstream must be significant in order to effectively treat distal areas of pain or inflammation. These levels are often much higher than would be necessary if it were possible to accurately target the particular site of pain or injury. Fishman and many others (Van Engelen et al. U.S. Pat. No. 6,416,772; Macrides et al. U.S. Pat. No. 6,346,278; Kirby et al. U.S. Pat. No. 6,444,234, Roentsch, et al., U.S. Pat. No. 5,654,337, Park, et al., U.S. Pat. No. 6,190,690, Pearson et al. U.S. Pat. No. 6,528,040, and Botknecht et al. U.S. Pat. No. 5,885,597) have tried to develop a delivery system for transdermal application by formulation. It is very difficult, however, to deliver therapeutically effective plasma levels of these kind drugs into the host by formulation, due to the slow skin penetration rate. Susan Milosovich, et al. designed and prepared testosteronyl- 4-dimethylaminobutyrate.HCl (TSBH), which has a lipophilic portion and a tertiary amine groups that exists in the protonated form at physiological pH. They found that the prodrug (TSBH) diffuses through human skin -60 times faster than does the drug (TS) itself [Susan Milosovich, et al., J. Pharm. ScL, 82, 227(1993)]. Disclosure of Invention
Technical Problem
[4] Mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, flunixin, and related compounds have been used medicinally for many years. They are used for the relief of signs and symptoms of rheumatoid arthritis and osteoarthritis, for the treatment of dysmenorrhea.
[5] Unfortunately, a number of side effects are associated with the use of mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, flunixin, and related compounds, most notably GI disturbances such as dyspepsia, gastroduodenal bleeding, gastric ulcerations, and gastritis. They are not soluble in aqueous solution and gastric juice. They stay in the GI tract for a long time and thus, may cause gastric mucosal cell damage.
Technical Solution
[6] This invention relates to the preparation of novel positively charged pro-drugs of arylanthranilic acids and related compounds and their use medicinally. The pro-drugs of arylanthranilic acids have the general formula (1) 'Structure 1'.
Figure imgf000004_0001
Structure 1
In structure 1, R represents H, one of any alkyl, alkyloxyl, alkenyl or alkynyl residues having 1 to 12 carbon atoms, or aryl residues; R represents H, one of any alkyl, alkyloxy, alkenyl or alkynyl residues having 1 to 12 carbon atoms, or aryl residues; R represents H, one of any alkyl, alkyloxy, alkenyl or alkynyl residues having 1 to 12 carbon atoms, or aryl residues; X represents O, S, or NH; A" represents Cl", Br", F", I", AcO", citrate, or any negative ions; Y represents H, Cl, F, CH , C H , or CF ; Y represents H, Cl, F, CH , C H , or CF ; Y represents H, Cl, F, CH , C H , or CF ; Z represents CH or N; and n=0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 All R groups may include
C, H, O, S, or N atoms and may have single, double, and treble bonds. Any CH groups may be replaced with O, S, or NH.
[7] Drug absorption, whether from the gastrointestinal tract or other sites, requires the passage of the drug in a molecular form across the barrier membrane. The drug must first dissolve, and if the drug possesses the desirable biopharmaceutical properties, it will pass from a region of high concentration to a region of low concentration across the membrane into the blood or general circulation. All biological membranes contain lipids as major constituents. The molecules that play the dominant roles in membrane formation all have phosphate-containing highly polar head groups, and, in most cases, two highly hydrophobic hydrocarbon tails. Membranes are bilayers, with the hy- drophilic head groups facing outward into the aqueous regions on either side. Very hy- drophilic drugs cannot pass the hydrophobic layer of membrane and very hydrophobic drugs will stay in the hydrophobic layer as part of the membrane due to their similarities and cannot enter the cytosol on the inside efficiently.
[8] The goal of this invention is to avoid the side effects of mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, flunixin, and related compounds by increasing the their solubility in gastric juice and their penetration rate through the membrane and skin barrier which will make it administrable transdermally (topical application). These novel pro-drugs have two structural features in common: they have a lipophilic portion and a primary, secondary, or tertiary amine group that exists in the protonated form (hydrophilic part) at physiological pH. Such a hydrophilic-lipophilic balance is required for efficient passage through the membrane barrier [Susan Milosovich, et al., J. Pharm. ScL, 82, 227(1993)]. The positively charged amino groups largely increase the solubility of the drugs. The solubility of diethylaminoethyl 2-[(2,3-dimethylphenyl)amino]benzoate.AcOH, diethylaminoethyl 2-[(2,6-dichloro-3-methylphenyl)amino]benzoate.AcOH, diethylaminoethyl 2- [ [(3-(trifluoromethyl)phenyl)amino]benzoate. AcOH, diethylaminoethyl 2-[[3-(trifluoromethyl)phenyl]amino]-3-pyridinecarboxylate.AcOH, diethylaminoethyl 2-[[2-methyl-3-(trifluoromethyl)phenyl]amino]-3-pyridinecarboxylate.AcOH, mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, and flunixin in water are >400 mg, >400 mg, >400 mg, >450 mg, >450 mg, <0.1 mg, <0.1 mg, <0.1 mg, <0.1 mg, <0.1 mg/ml, In many instances, the lowest or rate-limiting step in the sequence is the dissolution of the drug. Mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, flunixin, and related compounds have a very low solubility in gastric juice. They stay in the GI tract for a long time and thus, may cause gastric mucosal cell damage. When these new pro-drugs are administered orally in a dosage form such as a tablet, capsule, solution, or suspension, they will dissolve in the gastric juice immediately. The positive charge on the amino groups of these pro-drugs will bond to the negative charge on the phosphate head group of membrane. Thus, the local concentration of the outside of the membrane will be very high and will facilitate the passage of these pro-drugs from a region of high concentration to a region of low concentration. When these pro-drugs enter the membrane, the hydrophilic part will push the pro-drug into the cytosol, a semi-liquid concentrated aqueous solution or suspension. Due to the short stay in GI tract, the pro-drugs will not cause gastric mucosal cell damage. The pH of the stomach is 1-3, so the negative charge on the phosphate head group of the membrane of the gastric mucosa is bonded with proton (H +). The positive charges of these prodrugs cannot bond to phosphate head group of the gastric mucosa. These prodrugs will be free both of primary insult (direct acid damage) and secondary insult (prostaglandin inhibition) to the stomach. The penetration rates of diethylaminoethyl 2-[(2,3-dimethylphenyl)amino]benzoate.AcOH, diethylaminoethyl 2-[(2,6-dichloro-3-methylphenyl)amino]benzoate.AcOH, diethylaminoethyl 2- [ [(3-(trifluoromethyl)phenyl)amino]benzoate. AcOH, diethylaminoethyl 2-[[3-(trifluoromethyl)phenyl]amino]-3-pyridinecarboxylate.AcOH, diethylaminoethyl 2-[[2-methyl-3-(trifluoromethyl)phenyl]amino]-3-pyridinecarboxylate.AcOH, mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, flunixin, and related compounds through human skin were measured in vitro by using modified Franz cells, which were isolated from human skin tissue (360-400 μm thick) of the anterior and posterior thigh areas. The receiving fluid consisted of 10 ml of 2% bovine serum albumin in normal saline and was stirred at 600 rpm. The cumulative amounts of these prodrugs and their parent drugs penetrating the skin versus time were determined by a specific high-performance liquid chromatography method. The results using a donor consisting of either a 30% solution of diethylaminoethyl 2-[(2,3-dimethylphenyl)amino]benzoate.AcOH, diethylaminoethyl 2-[(2,6-dichloro-3-methylphenyl)amino]benzoate.AcOH, diethylaminoethyl 2- [ [(3-(trifluoromethyl)phenyl)amino]benzoate. AcOH, diethylaminoethyl 2-[[3-(trifluoromethyl)phenyl]amino]-3-pyridinecarboxylate.AcOH, and diethylaminoethyl 2-[[2-methyl-3-(trifluoromethyl)phenyl]amino] - 3-pyridinecarboxylate.AcOH or a 30% suspension of mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, and flunixin in 2mL of pH 7.4 phosphate buffer (0.2M) are shown in Figure 1. Apparent flux values of 2.1 mg, 2.0 mg, 2.2 mg, 1.8 mg, 1.7 mg, 0.01 mg, 0.01 mg, 0.01 mg, 0.01 mg, and 0.01 mg/cm /h were calculated for diethylaminoethyl 2-[(2,3-dimethylphenyl)amino]benzoate.AcOH, diethylaminoethyl 2-[(2,6-dichloro-3-methylphenyl)amino]benzoate.AcOH, diethylaminoethyl 2- [ [(3-(trifluoromethyl)phenyl)amino]benzoate. AcOH, diethylaminoethyl 2-[[3-(trifluoromethyl)phenyl]amino]-3-pyridinecarboxylate.AcOH, and diethylaminoethyl 2-[[2-methyl-3-(trifluoromethyl)phenyl]amino] - 3-pyridinecarboxylate.AcOH, mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, and flunixin diffuses through human skin. The results suggest that the pro-drugs, diethylaminoethyl 2-[(2,3-dimethylphenyl)amino]benzoate.AcOH, diethylaminoethyl 2-[(2,6-dichloro-3-methylphenyl)amino]benzoate.AcOH, diethylaminoethyl 2-[[(3-(trifluoromethyl)phenyl)amino]benzoate.AcOH, diethylaminoethyl 2-[[3-(trifluoromethyl)phenyl]amino]-3-pyridinecarboxylate.AcOH, or diethylaminoethyl 2-[[2-methyl-3-(trifluoromethyl)phenyl]amino] -
3-pyridinecarboxylate.AcOH diffuses through human skin -200 times faster than does mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, or flunixin. The results suggest that the positive charge on the dialkyaminoethyl group has a very important role in the passage of the drug across the membrane and skin barrier. Other prodrugs of the general 'Structure 1' have very high penetration rates and are very close to that of diethylaminoethyl 2-[(2,3-dimethylphenyl)-amino]benzoate.AcOH. [9] The in vivo rates of penetration of diethylaminoethyl
2-[(2,3-dimethylphenyl)amino]benzoate.AcOH, diethylaminoethyl 2-[(2,6-dichloro-3-methylphenyl)amino]benzoate.AcOH, diethylaminoethyl 2- [ [(3-(trifluoromethyl)phenyl)amino]benzoate. AcOH, diethylaminoethyl 2-[[3-(trifluoromethyl)phenyl]amino]-3-pyridinecarboxylate.AcOH, and diethylaminoethyl 2-[[2-methyl-3-(trifluoromethyl)phenyl]amino] - 3-pyridinecarboxylate.AcOH, mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, and flunixin through the skin of intact hairless mice were compared. The donor consisted of a 20% solution of these compounds in 1 mL of isopropanol applied to a 10 cm on the backs of the hairless mice. Plasma levels of mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, and flunixin were determined by a specific high-performance liquid chromatography method. The results (Figure 2) show that the peak levels of diethylaminoethyl 2-[(2,3-dimethylphenyl)amino] benzoate. AcOH, diethylaminoethyl 2- [(2,6-dichloro-3-methylphenyl)amino] benzoate. AcOH, diethylaminoethyl 2- [ [(3-(trifluoromethyl)phenyl)amino] benzoate. AcOH, diethylaminoethyl 2-[[3-(trifluoromethyl)phenyl]amino] - 3-pyridinecarboxylate.AcOH, and diethylaminoethyl
2-[[2-methyl-3-(trifluoromethyl)phenyl]amino]-3-pyridinecarboxylate.AcOH were reached in -50 minutes after application of the donor systems. It takes 2-4 hours for mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, flunixin, and related compounds to reach their peak plasma level when they are taken orally. The peak plasma levels were -0.01 mg/ml for mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, and flunixin and ~2 mg/ml for diethylaminoethyl 2-[(2,3-dimethylphenyl)amino]benzoate.AcOH, diethylaminoethyl 2-[(2,6-dichloro-3-methylphenyl)amino]benzoate.AcOH, diethylaminoethyl 2- [ [(3-(trifluoromethyl)phenyl)amino]benzoate. AcOH, diethylaminoethyl 2-[[3-(trifluoromethyl)phenyl]amino]-3-pyridinecarboxylate.AcOH, and diethylaminoethyl 2-[[2-methyl-3-(trifluoromethyl)phenyl]amino] - 3-pyridinecarboxylate.AcOH (approximately 200 times difference). ~2 mg/ml of mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, and flunixin in plasma is more than ~ 50 times higher than plasma level for effective analgesia and effective antiinflammatory activity. This is a very exciting result. It will be very easy and fast to deliver therapeutically effective plasma level of mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, and flunixin into the host by administration of these prodrugs transdermally. These results suggest that the pro-drugs can be administered not only orally, but also transdermally for any kind of medical treatments. The in vivo rates of penetration of other Pro-drugs of the general 'Structure I' are close to that of diethylaminoethyl diethylaminoethyl 2-[(2,3-dimethylphenyl)amino]benzoate.AcOH.
[10] To check the gastroduodenal bleeding caused by drugs, rats were orally administered with 50 mg/kg of diethylaminoethyl 2-[(2,3-dimethylphenyl)amino] benzoate. AcOH, diethylaminoethyl 2- [(2,6-dichloro-3-methylphenyl)amino] benzoate. AcOH, diethylaminoethyl 2- [ [(3-(trifluoromethyl)phenyl)amino] benzoate. AcOH, diethylaminoethyl 2-[[3-(trifluoromethyl)phenyl]amino] - 3-pyridinecarboxylate.AcOH, diethylaminoethyl
2-[[2-methyl-3-(trifluoromethyl)phenyl]amino]-3-pyridinecarboxylate.AcOH, mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, and flunixin per day for 21 days. We found an average of 2-4 mg of fecal blood per gram of feces in the mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, and flunixin groups and none in diethylaminoethyl 2-[(2,3-dimethylphenyl)amino]benzoate.AcOH, diethylaminoethyl 2-[(2,6-dichloro-3-methylphenyl)amino]benzoate.AcOH, diethylaminoethyl 2-[[(3-(trifluoromethyl)phenyl)amino]benzoate.AcOH, diethylaminoethyl 2-[[3-(trifluoromethyl)phenyl]amino]-3-pyridinecarboxylate.AcOH, diethylaminoethyl 2-[[2-methyl-3-(trifluoromethyl)phenyl]amino]-3-pyridinecarboxylate.AcOH.
[11] The acute toxicity of the prodrugs was investigated. The LD orally in mice are:
0.9 g/kg, 1.0 g/kg, 0.8g/kg , 0.75 g/kg , 1.1 g/kg , for diethylaminoethyl 2-[(2,3-dimethylphenyl)amino]benzoate.AcOH, diethylaminoethyl 2-[(2,6-dichloro-3-methylphenyl)amino]benzoate.AcOH, diethylaminoethyl 2- [ [(3-(trifluoromethyl)phenyl)amino]benzoate. AcOH, diethylaminoethyl 2-[[3-(trifluoromethyl)phenyl]amino]-3-pyridinecarboxylate.AcOH, diethylaminoethyl 2-[[2-methyl-3-(trifluoromethyl)phenyl]amino]-3-pyridinecarboxylate.AcOH. The results show that the prodrugs are less toxic than their parent drugs (mefenamic acid, 600 mg/kg, flufenamic acid, 715 mg/kg, and niflumic acid, 650 mg/kg ).
[12] Mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, and flunixin demonstrated anti-inflammatory, analgesic, antipyretic, and antirheumatic activity. A good prodrug should go back to the parent drug in plasma. Diethylaminoethyl ester group of these prodrugs can be rapidly cleaved by the enzymes in human plasma in vitro and more than 90% of the pro-drugs are changed back to their parent drugs. Due to the pro-drugs having a much better absorption rate, the prodrugs will have more strength than their parent drugs at the same dosage. The analgetic, antipyretic, and antiinflammatory activities of these prodrugs were tested using mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, and flunixin as a comparison.
[13] Analgetic activity: The prolongation time of the pain threshold of a mouse tail was determined in accordance with the D'Amour-Smith Method (J. Pharmacol. Exp. Ther., 72, 74(1941)). After 50mg/kg of these prodrugs were administered transdermally, the tails of mice were exposed to heat and the prolongation time of pain threshold was determined. The results obtained are shown in Figure 3. Diethylaminoethyl 2-[(2,3-dimethylphenyl)amino]benzoate.AcOH, diethylaminoethyl 2-[(2,6-dichloro-3-methylphenyl)amino]benzoate.AcOH, diethylaminoethyl 2- [ [(3-(trifluoromethyl)phenyl)amino]benzoate. AcOH, diethylaminoethyl 2-[[3-(trifluoromethyl)phenyl]amino]-3-pyridinecarboxylate.AcOH, diethylaminoethyl 2-[[2-methyl-3-(trifluoromethyl)phenyl]amino]-3-pyridinecarboxylate.AcOH have shown analgesic activity nicely.
[14] The number of writhings that occurred when mice were administered an acetic acid solution intraperitoneally were counted, and the rate of inhibition based on the control group was calculated, diethylaminoethyl 2-[(2,3-dimethylphenyl)amino] benzoate.AcOH (100 mg/kg, B), diethylaminoethyl
2-[(2,6-dichloro-3-methylphenyl)amino]benzoate.AcOH (100 mg/kg, C), diethylaminoethyl 2-[[(3-(trifluoromethyl)phenyl)amino]benzoate.AcOH (100 mg/kg, D), diethylaminoethyl 2-[[3-(trifluoromethyl)phenyl]amino]-3-pyridinecarboxylate.AcOH (100 mg/kg, E), diethylaminoethyl 2-[[2-methyl-3-(trifluoromethyl)phenyl]amino] - 3-pyridinecarboxylate.AcOH (100 mg/kg, F) were administered transdermally the mice 60 minutes before the acetic acid solution was administered. The group A is the control group. The results are shown in Table 1.
Table 1. The rate of writhings inhibition by prodrugs of arylanthranilic adds
[15]
Figure imgf000010_0001
The results show that the prodrugs demonstrate exceptional analgetic activity. Other compounds of the general 'Structure 1' show similar analgetic activity.
[16] Antipyretic activity: Rats received a sterilized E. coli suspension as a pyrogen. The control group is group A. 2 hours later, diethylaminoethyl
2-[(2,3-dimethylphenyl)amino]benzoate.AcOH (100 mg/kg, B), diethylaminoethyl 2-[(2,6-dichloro-3-methylphenyl)amino]benzoate.AcOH (100 mg/kg, C), diethylaminoethyl 2-[[(3-(trifluoromethyl)phenyl)amino]benzoate.AcOH (100 mg/kg, D), diethylaminoethyl 2-[[3-(trifluoromethyl)phenyl]amino]-3-pyridinecarboxylate.AcOH (100 mg/kg, E), diethylaminoethyl 2-[[2-methyl-3-(trifluoromethyl)phenyl]amino] - 3-pyridinecarboxylate.AcOH (100 mg/kg, F) were administered transdermally. The body temperature of rats was taken at 90 min. intervals before and after the administration of the test compounds. The results are shown in Table 2.
Table 2. Antipyretic Activity of prodrugs of arylanthranilic acids.
[17]
Figure imgf000010_0002
The results shown that the prodrugs demonstrated strong antipyretic activity at 100 mg/kg dose. Other compounds of the general 'Structure 1' show similar antipyretic activity.
[18] Anti-inflammatory activity: diethylaminoethyl 2-[(2,3-dimethylphenyl)amino] benzoate.AcOH (100 mg/kg, B), diethylaminoethyl
2-[(2,6-dichloro-3-methylphenyl)amino]benzoate.AcOH (100 mg/kg, C), diethylaminoethyl 2-[[(3-(trifluoromethyl)phenyl)amino]benzoate.AcOH (100 mg/kg, D), diethylaminoethyl 2-[[3-(trifluoromethyl)phenyl]amino]-3-pyridinecarboxylate.AcOH (100 mg/kg, E), diethylaminoethyl 2-[[2-methyl-3-(trifluoromethyl)phenyl]amino] - 3-pyridinecarboxylate.AcOH (100 mg/kg, F) were administered transdermally. Group A is the controlled group. 60 minutes later, a carrageenin solution was administered subcutaneously to the foot pads of the rats. The volume of the hind paw was measured at every hour after the administration of the carrageenin, and the rate of increase in the volume of the paw was calculated and designated as the rate of swelling (%). The results obtained are shown in Figure 4. The results show that these prodrugs by transdermal administration demonstrated good anti-inflammatory activity. Other compounds of the general 'Structure 1' show similar anti-inflammatory activity.
[19] It is also known that a high oral dose of some of NSAIAs shows an anti- reactive-antiasthmatic activity by inhibition of the cyclooxygenase activity. Due to their very high membrane penetration rate, these prodrugs can be used in treating asthma by spraying into the mouth or nose of the host.
[20] These prodrugs can also be used to treat psoriasis, acne, sunburn or other skin disorders due to their anti-inflammatory properties and very high skin penetration rate.
[21] Recent attention has been drawn to the role of cyclooxygenase (COX)-2 in the pathogenesis of cancer and it has been considered as an attractive target for strategies in cancer patients. These prodrugs can also be used to treat skin cancer, lung cancer, breast cancer,colon cancer, oral cancer, genital cancer, and other cancers by administering to the cancer area a very high effective amount directly.
[22] The present invention relates to pharmaceutical preparations comprising of prodrugs of the general 'Structure 1' in addition to customary auxiliaries and excipients, e.g. in the form of tablets, capsules or solutions for administration orally and in the form of solutions, lotion, ointment, emulsion or gel for transdermal administration. The new active compounds of the general 'Structure 1' can be combined with vitamins such as A, B, C or E or beta-carotene, or other pharmaceuticals, such as folic acid, etc., for treating any NSAIAs-treatable conditions in humans or animals.
[23] Transdermal therapeutic application systems of compounds of the general
'Structure 1' or a composition comprising of at least one compound of the general 'Structure 1', as an active ingredient, can be used for treating any NSAIAs-treatable conditions in humans or animals. These systems can be a bandage or a patch comprising of one active substance-containing matrix layer and an impermeable backing layer. The most preferable system is an active substance reservoir, which has a permeable bottom facing the skin. By controlling the rate of release, this system enables NSAIAs to reach constantly optimal therapeutic blood levels to increase effectiveness and reduce the side effects of NSAIAs. These systems can be worn on the wrist, ankle, arm, leg, or any part of body.
[24] The compounds of the general formula (1) 'Structure 1' indicated above can be prepared from mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, flunixin, and related compounds, by reaction with compounds of the general formula (2) 'Structure 2' by using coupling reagents, such as N,N'-Dicyclohexylcarbodiimide, N, N'-Diisopropylcarbodiimide, O-(Benzotriazol- 1 -yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate, O-(Benzotriazol- 1 -yl)-N,N,N',N'-tetramethyluronium hexafluo- rophosphate, Benzotriazol- 1 -yl-oxy-tris(dimethylamino)phosphonium hexafluo- rophosphate, et al.
Figure imgf000012_0001
Structure 2
In structure 2, R represents H, one of any alkyl, alkyloxy, alkenyl, or alkynyl residues having 1 to 12 carbon atoms, or aryl residues; R 4 represents H, one of any alkyl, alkyloxy, alkenyl, or alkynyl residues having 1 to 12 carbon atoms, or aryl residues; X represents O, S or NH; and n=0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10
[25] When X represents O, the compounds of the general formula (1) 'Structure 1' indicated above can be prepared from metal salts or organic base salts of mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, flunixin, and related compounds, by reaction with compounds of the general formula (3) "Structure".
Figure imgf000012_0002
Structure 3
In structure 3, R represents H, one of any alkyl, alkyloxy, alkenyl, or alkynyl residues having 1 to 12 carbon atoms, or aryl residues; R represents H, one of any alkyl, alkyloxy, alkenyl, or alkynyl residues having 1 to 12 carbon atoms, or aryl residues; R 4 represents H, one of any alkyl, alkyloxy, alkenyl, or alkynyl residues having 1 to 12 carbon atoms, or aryl residues; Z represents halogen, or p-toluenesulphonyl, A" represents Cl", Br", F, I", AcO", citrate, or any negative ions; and n=0, 1, 2, 3, 4, 5, 6, 7,
8, 9, 10
[26] When X represents O, the compounds of the general formula (1) 'Structure 1' indicated above can be prepared from immobilized base salts of mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, flunixin, and related compounds of the general formula (4) 'Structure 4',
Figure imgf000013_0001
Structure 4
In structure 4, R represents cross-linked resin; Y represents H, Cl, F, CH , C H , or CF ; Y represents H, Cl, F, CH , C H , or CF ; Y represents H, Cl, F, CH , C H , or CF ;
3 2 3 2 5 3 3 3 2 5 3
Z represents CH or N; B represents any base groups, such as pyridine, piperidine, tri- ethylamine, or other base groups, by reaction with compounds of the general formula (3) 'Structure 3' .
Advantageous Effects
[27] These pro-drugs of mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, flunixin, and related compounds have a lipophilic portion and a hydrophilic portion (the amine groups that exist in the protonated form at physiological pH). The positively charged amino groups of these pro-drugs have two major advantages. First, it largely increases the solubility of the drugs; when these new pro-drugs are administered orally in a dosage form such as a tablet, capsule, solution, or suspension, they will dissolve in gastric juice immediately. Second, the positive charge on the amino group of these pro-drugs will bond to the negative charge on the phosphate head group of membrane. Thus, the local concentration outside of the membrane will be very high and will facilitate the passage of these pro-drugs from a region of high concentration to a region of low concentration. When these pro-drugs enter the membrane, the hydrophilic part will push the pro-drugs into the cytosol, a semi-liquid concentrated aqueous solution or suspension. Due to the short stay in the GI tract, the pro-drugs will not cause gastric mucosal cell damage. Experiment results show that more than 90% of the pro-drugs were changed back to the parent drugs. The pro-drugs have a much better absorption rate, and thus the pro-drugs will have better strength than mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, flunixin, and related compounds at the same dosage. The experiment results suggest that the pro-drugs, di- ethylaminoethyl 2-[(2,3-dimethylphenyl)amino]benzoate.AcOH, diethylaminoethyl 2-[(2,6-dichloro-3-methylphenyl)amino]benzoate.AcOH, diethylaminoethyl 2- [ [(3-(trifluoromethyl)phenyl)amino]benzoate. AcOH, diethylaminoethyl 2-[[3-(trifluoromethyl)phenyl]amino]-3-pyridinecarboxylate.AcOH, or diethylaminoethyl 2-[[2-methyl-3-(trifluoromethyl)phenyl]amino]-3-pyridineca rboxylate. AcOH diffuses through human skin -200 times faster than does mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, or flunixin. It takes 2-4 hours for mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, flunixin, and related compounds to reach the peak plasma level when they are taken orally, but these prodrugs only took about -50 minutes to reach the peak plasma level. The most exciting result is that the pro-drugs can be administered not only orally, but also transdermally for any type of medical treatment and should avoid most of the side effects of mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, or flunixin, and related compounds, most notably GI disturbances such as dyspepsia, gas- troduodenal bleeding, gastric ulcerations, gastritis, and renal toxicity. Another great benefit of transdermal administration of these pro-drugs is that administering medication, especially to children, will be much easier.
Description of Drawings
[28] Figure 1: Cumulative amounts of diethylaminoethyl 2-[(2,3-dimethylphenyl)amino
]benzoate.AcOH (A, 30% solution), diethylaminoethyl
2-[(2,6-dichloro-3-methylphenyl)amino]benzoate.AcOH (B, 30% solution), diethylaminoethyl 2-[[(3-(trifluoromethyl)phenyl)amino]benzoate.AcOH (C, 30% solution), diethylaminoethyl 2-[[3-(trifluoromethyl)phenyl]amino]-3-pyridinecarboxylate.AcOH (D, 30% solution), diethylaminoethyl 2-[[2-methyl-3-(trifluoromethyl)phenyl]amino] - 3-pyridinecarboxylate.AcOH (E, 30% solution), mefenamic acid (F, 30% suspension), meclofenamic acid (G, 30% suspension), flufenamic acid (H, 30% suspension), niflumic acid (I, 30% suspension), flunixin (J, 30% suspension), crossing isolated human skin tissue in Franz cells (n=5). In each case, the vehicle was pH 7.4 phosphate buffer (0.2 M).
[29] Figure 2: Total plasma levels of mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, and flunixin after topical application of 1 ml of a 20% solution of diethylaminoethyl 2-[(2,3-dimethylphenyl)amino]benzoate.AcOH (A), diethy- laminoethyl 2-[(2,6-dichloro-3-methylphenyl)amino]benzoate.AcOH (B), diethylaminoethyl 2-[[(3-(trifluoromethyl)phenyl)amino]benzoate.AcOH (C), diethylaminoethyl 2-[[3-(trifluoromethyl)phenyl]amino]-3-pyridinecarboxylate.AcOH (D), diethylaminoethyl 2-[[2-methyl-3-(trifluoromethyl)phenyl]amino] - 3-pyridinecarboxylate.AcOH (E), mefenamic acid (F), meclofenamic acid (G), flufenamic acid (H), niflumic acid (I), and flunixin (J) in isopropanol to the backs of hairless mice (n=5).
[30] Figure 3: The prolongation time of the pain threshold of mice tails after 50mg/kg of diethylaminoethyl 2-[(2,3-dimethylphenyl)amino]benzoate.AcOH, diethylaminoethyl 2-[(2,6-dichloro-3-methylphenyl)amino]benzoate.AcOH, diethylaminoethyl 2- [ [(3-(trifluoromethyl)phenyl)amino]benzoate. AcOH, diethylaminoethyl 2-[[3-(trifluoromethyl)phenyl]amino]-3-pyridinecarboxylate.AcOH, diethylaminoethyl 2-[[2-methyl-3-(trifluoromethyl)phenyl]amino]-3-pyridinecarboxylate.AcOH were administered transdermally. Group A is the control group.
[31] Figure 4. The rate of swelling (%) after a carrageenin injection. 1 hour before the carrageenin injection, diethylaminoethyl 2-[(2,3-dimethylphenyl)amino] benzoate.AcOH (100 mg/kg, B), diethylaminoethyl
2-[(2,6-dichloro-3-methylphenyl)amino]benzoate.AcOH (100 mg/kg, C), diethylaminoethyl 2-[[(3-(trifluoromethyl)phenyl)amino]benzoate.AcOH (100 mg/kg, D), diethylaminoethyl 2-[[3-(trifluoromethyl)phenyl]amino]-3-pyridinecarboxylate.AcOH (100 mg/kg, E), diethylaminoethyl 2-[[2-methyl-3-(trifluoromethyl)phenyl]amino] - 3-pyridinecarboxylate.AcOH (100 mg/kg, F) were administered transdermally. Group A is the control group.
[32] Figure 5. In structure 1, R represents H, one of any alkyl, alkyloxyl, alkenyl or alkynyl residues having 1 to 12 carbon atoms, or aryl residues; R represents H, one of any alkyl, alkyloxy, alkenyl or alkynyl residues having 1 to 12 carbon atoms, or aryl residues; R represents H, one of any alkyl, alkyloxy, alkenyl or alkynyl residues having 1 to 12 carbon atoms, or aryl residues; X represents O, S, or NH; A" represents Cl", Br", F", I", AcO , citrate, or any negative ions; Y represents H, Cl, F, CH , C H , or CF ; Y represents H, Cl, F, CH , C H , or CF ; Y represents H, Cl, F, CH , C H , or
3 2 3 2 5 3 3 3 2 5
CF ; Z represents CH or N; and n=0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 ; All R groups may include C, H, O, S, or N atoms and may have single, double, and treble bonds. Any CH groups may be replaced with O, S, or NH
Best Mode
Preparation of N-diethylaminoethyl 2-[(2,3-dimethylphenyl)amino] benzoamide.AcOH. [33] 24.1 g (0.1 mol) of 2-[(2,3-dimethylphenyl)amino]benzoic acid was dissolved in
100 ml of acetonitrile. 32.1 g of O-(Benzotriazol-l-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate and 30 ml of triethylamine were added into the reaction mixture. 11.6 g of dimethylaminoethylamine was added into the reaction mixture. The mixture was stirred for 3 hours at RT. The solvents were evaporated off. 250 ml of ethyl acetate was added into the reaction mixture and the mixture was washed with water (3 x 100 ml). The organic solution was dried over anhydrous sodium sulfate. Sodium sulfate was removed by filtration. 6 g of acetic acid was added into the reaction mixture with stirring. Hexane (200 ml) was added. The solid product was collected by filtration. After drying, it yielded 37 g of the desired product (92.5%). Hygroscopic product; Solubility in water: 400 mg/ml; Elementary analysis: C H N O ; MW: 399.53. Calculated % C: 69.14; H: 8.33; N: 10.52; O: 12.01; Found % C: 69.11; H: 8.35; N: 10.51; O: 12.03. 1H-NMR (400 MHz, D2O): δ: 1.41 (t, 6H), 2.10 (s, 3H), 2.30 (s, 3H), 2.31 (s, 3H), 3.22 (m, 4H), 3.54 (m, 2H), 3.60 (m, 2H), 6.15 (m, IH), 6.30 (m, IH), 6.57 (m, IH), 6.72 (m, IH), 7.20 (m, 2H), 7.70 (m, IH), 7.80 (b, IH).
Mode for Invention
Preparation of N-diethylaminoethyl 2-[(2,6-dichloro-3-methylphenyl)amino] benzoamide.AcOH
[34] 29.6 g (0.1 mol) of 2-[(2,6-dichloro-3-methylphenyl)amino]benzoic acid was dissolved in 300 ml of chloroform. 20.6 g of N, N'-Dicyclohexylcarbodiimide was added into the reaction mixture. 11.7 g of diethylaminoethylamine was added into the reaction mixture. The mixture was stirred for 3 hours at RT. The solid is removed by filtration. The chloroform solution was washed with 5% NaHCO (2 x 100 ml) and water (3 x 100 ml). The organic solution was dried over anhydrous sodium sulfate. Sodium sulfate was removed by filtration. 6 g of acetic acid was added into the reaction mixture with stirring. Hexane (200 ml) was added. The solid product was collected by filtration. After drying, it yielded 39 g of the desired product (85.8%). Hygroscopic product; Solubility in water: 400 mg/ml; Elementary analysis: C H Cl N O ; MW: 454.39. Calculated % C: 58.15; H: 6.43; Cl: 15.60; N: 9.25, O: 10.56; Found % C: 58.10; H: 6.46; Cl: 15.62; N: 9.22, O: 10.60. 1H-NMR (400 MHz, D O): δ: 1.43 (t, 6H), 2.11 (s, 3H), 2.28 (s, 3H), 3.23 (m, 4H), 3.49 (m, 2H), 3.63 (m, 2H), 6.30 (d, IH), 6.57 (m, IH), 6.72 (d, IH), 6.80 (m, IH), 7.20 (m, IH), 7.68 (m, 1 H), 7.70 (b, IH). Preparation of S-dimethylaminoethyl 2-[[(3-trifluoromethyl)phenyl]amino] benzoate.AcOH.
[35] 28.1 g (0.1 mol) of 2-[[(3-trifluoromethyl)phenyl]amino]benzoic acid was dissolved in 300 ml of chloroform. N, N'-Dicyclohexylcarbodiimide was added into the reaction mixture. 11.7 g of dimethylaminoethyl mercaptan was added into the reaction mixture. The mixture was stirred for 3 hours at RT. The solid is removed by filtration. The chloroform solution was washed with 5% NaHCO (2 x 100 ml) and water (3 x 100 ml). The organic solution was dried over anhydrous sodium sulfate. Sodium sulfate was removed by filtration. 6 g of acetic acid was added into the reaction mixture with stirring. Hexane (200 ml) was added. The solid product was collected by filtration. After drying, it yielded 39 g of the desired product (88.5%). Hygroscopic product; Solubility in water: 400 mg/ml; Elementary analysis: C H F N O S; MW: 456.52. Calculated % C: 57.88; H: 5.96; F: 12.48; N: 6.14, O: 10.51; S: 7.02; Found % C: 57.84; H: 5.99; F: 12.45; N: 6.15, O: 10.56, S: 7.01. 1H-NMR (400 MHz, D2O): δ: 1.44 (t, 6H), 2.11 (s, 3H), 3.23 (m, 4H), 3.30 (m, 2H), 3.90 (m, 2H), 6.46 (m, IH), 6.65 (m, 2H), 6.77 (m, 2H), 6.90 (m, IH), 7.30 (m, IH), 7.78 (m, 1 H). Preparation of diethylaminoethyl 2-[[3-(trifluoromethyl)phenyl]amino] -
3-pyridinecarboxylate.AcOH
[36] 28.2 g (0.1 mol) of 2-[[3-(trifluoromethyl)phenyl]amino]-3-pyridinecarboxylic acid was dissolved in 200 ml of 10% NaHCO . 100 ml of acetone and 43 g (0.15mol) of diethylaminoethyl bromide.HBr was added into the mixture and the mixture was stirred for 5 hours at RT. The mixture is extracted with ethyl acetate (2 x 300 ml). The ethyl acetate solution is dried over anhydrous sodium sulfate. 6 g of acetic acid is added into the solution. The solution was concentrated in vacuo to 100 ml. Then 300 ml of hexane was added into the solution. The solid product was collected by filtration and washed with hexane (3 x 100 ml). After drying, it yielded 38 g of the desired product (86.1%). Hygroscopic product; Solubility in water: 400 mg/ml; Elementary analysis: C H F N
21 26 3 3
O4; MW: 441.44. Calculated % C: 57.14; H: 5.94; F: 12.91, N: 9.52; O: 14.50; Found % C: 57.11; H: 5.97; F: 12.92; N: 9.50; O: 14.50. 1H-NMR (400 MHz, D O): δ: 1.44 (t, 6H), 2.11 (s, 3H), 3.23 (m, 4H), 3.70 (m, 2H), 4.60 (m, 2H), 6.46 (m, IH), 6.65 (s, IH), 6.77 (m, IH), 6.83 (m, IH), 6.90 (m, IH), 8.00 (m, IH), 8.38 (m, 1 H). Preparation of diethylaminoethyl 2-[[2-methyl-3-(trifluoromethyl)phenyl] amino]-3-pyridinecarboxylate.AcOH
[37] 60 g of Polymer-bound triethylamine (3 mol/g, 100-200 mesh) was suspended in
180 ml of chloroform. 29.6 g (0.1 mol) of 2-[[2-methyl-3-(trifluoromethyl)phenyl] amino]-3-pyridinecarboxylic acid was added into the mixture with stirring. 43 g (0.15mol) of diethylaminoethyl bromide .HBr was added into the mixture and the mixture was stirred for 5 hours at RT. The polymer was removed by filtration and washed with tetrahydrofuran (3 x 50 ml). 8.2 g (0.1 mol) of sodium acetate was added into the reaction mixture with stirring. The mixture was stirred for 2 h. The solid was removed by filtration and washed with chloroform (3 x 50 ml). The solution was concentrated in vacuo to 100 ml. Then 300 ml of hexane was added into the solution. The solid product was collected by filtration and washed with hexane (3 x 100 ml). After drying, it yielded 40 g of the desired product (87.8%). Hygroscopic product; Solubility in water: 400 mg/ml; Elementary analysis: C 22 H 28 F 3N 3O 4; MW: 455.47. Calculated %
C: 58.01; H: 6.20; F: 12.51, N: 9.23; O: 14.05; Found % C: 57.98; H: 6.23; F: 12.50; N: 9.21; O: 14.08. 1H-NMR (400 MHz, D2O): δ: 1.45 (t, 6H), 2.11 (s, 3H), 2.35 (s, 3H), 3.23 (m, 4H), 3.70 (m, 2H), 4.60 (m, 2H), 6.36 (m, IH), 6.65 (m, IH), 6.77 (m, IH), 6.83 (m, IH), 8.00 (m, IH), 8.38 (m, 1 H).
Industrial Applicability
[38] The pro-drugs of the general formula (1) 'Structure 1' are superior to mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, flunixin, and related compounds. They can be used for treating any mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, flunixin, and related compounds-treatable conditions in humans or animals. They may be used for the relief of signs and symptoms of rheumatoid arthritis and osteoarthritis, the reduction of fever, and the treatment of dysmenorrhea. They may be also prescribed for diabetic neuropathy and acute migraine headache. Due to their very high membrane penetration rate, these pro-drugs can be used in treating asthma by inhalation to a host. They can be used to treat psoriasis, acne, sunburn or other skin disorders due to their anti-inflammatory properties. They can also be used for treating skin cancer, lung cancer, breast cancer,colon cancer, oral cancer, genital cancer, and other cancers by administering to the cancer area a very high effective amount directly.
Sequence List Text
[39]

Claims

Claims
[1] The compounds of the general formula (1) 'Structure 1'
Figure imgf000019_0001
Structure 1
In structure 1, R represents H, one of any alkyl, alkyloxyl, alkenyl or alkynyl residues having 1 to 12 carbon atoms, or aryl residues; R represents H, one of any alkyl, alkyloxy, alkenyl or alkynyl residues having 1 to 12 carbon atoms, or aryl residues; R represents H, one of any alkyl, alkyloxy, alkenyl or alkynyl residues having 1 to 12 carbon atoms, or aryl residues; X represents O, S, or NH; A" represents Cl", Br", F", I", AcO", citrate, or any negative ions; Y represents H, Cl, F, CH , C H , or CF ; Y represents H, Cl, F, CH , C H , or CF ; Y
3 2 5 3 2 3 2 5 3 3 represents H, Cl, F, CH , C H , or CF ; Z represents CH or N; and n=0, 1, 2, 3, 4,
5, 6, 7, 8, 9, 10 All R groups may include C, H, O, S, or N atoms and may have single, double, and treble bonds. Any CH groups may be replaced with O, S, or NH.
[2] Processes for the preparation of compounds of the general formula (1) 'Structure I' according to Claim 1, wherein the compounds can be preparated from mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, flunixin, and related compounds, by reaction with compounds of the general formula (2) 'Structure 2' by using coupling reagents, such as N, N'-Dicyclohexylcarbodiimide, N, N'-Diisopropylcarbodiimide, O- (Benzotriazol-l-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate, O- (Benzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, Ben- zotriazol-1-yl-oxy-tris (dimethylamino)phosphonium hexafluorophosphate, et al.
Figure imgf000020_0001
Structure 2
In structure 2, R represents H, one of any alkyl, alkyloxy, alkenyl, or alkynyl residues having 1 to 12 carbon atoms, or aryl residues; R 4 represents H, one of any alkyl, alkyloxy, alkenyl, or alkynyl residues having 1 to 12 carbon atoms, or aryl residues; X represents O, S or NH; and n=0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10
[3] Processes for the preparation of compounds of the general formula (1) 'Structure
I' according to Claim 1, wherein the compounds can be preparated from metal salts, organic base salts, or immobilized base salts of mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, flunixin, and related compounds, by reaction with compounds of the general formula (3) 'Structure 3'.
Figure imgf000020_0002
Structure 3
In structure 3, R represents H, one of any alkyl, alkyloxy, alkenyl, or alkynyl residues having 1 to 12 carbon atoms, or aryl residues; R represents H, one of any alkyl, alkyloxy, alkenyl, or alkynyl residues having 1 to 12 carbon atoms, or aryl residues; R 4 represents H, one of any alkyl, alkyloxy, alkenyl, or alkynyl residues having 1 to 12 carbon atoms, or aryl residues; Z represents halogen, or p-toluenesulphonyl, A" represents Cl", Br", F, I", AcO", citrate, or any negative ions; and n=0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10
[4] Compounds of the general formula (1) 'Structure 1' or a composition comprising of at least one compound of the general formula (1) 'Structure 1', as an active ingredient, according to Claim 1, where they can be administered orally or transdermally, for treating any NS AIAs-treatable conditions in humans or animals. The NSAIAs-treatable conditions include, but are not limited to, pain from a toothache, headache, and arthritis and other inflammatory pain, fever, cancer, dysmenorrhea, radiation-induced vomiting, diabetic neuropathy and acute migraine headache, hemophilic arthropathy, bone loss, and sunburn.
[5] Methods for treating any NSAIAs-treatable conditions in humans or animals by administering transdermally to any part of body (in the from of a solution, spray, lotion, ointment, emulsion or gel) to deliver therapeutically effective plasma levels of the compounds of the general formula (1) 'Structure l' or a composition comprising at least one compound of the general formula (1) 'Structure 1', as an active ingredient, according to Claim 1.
[6] Methods for topically treating pain such as a headache, toothache, and muscle pain, and arthritis and other inflammatory pain in humans or animals by administering transdermally to the inflamed area a therapeutically effective amount of the compounds of the general formula (1) 'Structure 1' or a composition comprising at least one compound of the general formula (1) 'Structure 1', as an active ingredient, according to Claim 1.
[7] Compounds of the general formula (1) 'Structure 1' or a composition comprising at least one compound of the general formula (1) 'Structure 1', as an active ingredient, according to Claim 1, may be administered transdermally, for treating psoriasis, acne, sunburn or other skin disorders in the from of a solution, spray, lotion, ointment, emulsion or gel.
[8] Compounds of the general formula (1) 'Structure 1' or a composition comprising at least one compound of the general formula (1) 'Structure 1', as an active ingredient, according to Claim 1, may be administered transdermally, for treating skin cancer, lung cancer, breast cancer,colon cancer, oral cancer, genital cancer, and other cancers .
[9] Compounds of the general formula (1) 'Structure 1' or a composition comprising at least one compound of the general formula (1) 'Structure 1', as an active ingredient, according to Claim 1, are administered by spraying to through the mouth or nose or other parts of body for treating asthma.
[10] Compounds of the general formula (1) 'Structure 1' or a composition comprising at least one compound of the general formula (1) 'Structure 1', as an active ingredient, according to Claim 1, for treating any eye inflammatory diseases, for treating of ocular pain after corneal surgery, for treating glaucoma or for treating ear inflammatory and/or painful conditions (otitis) in humans or animals.
[11] Transdermal therapeutic application systems of Compounds of the general formula (1) 'Structure 1' or a composition comprising at least one compound of the general formula (1) 'Structure 1', as an active ingredient, according to Claim 1, for treating any NSAIAs-treatable conditions in humans or animals. These systems can be a bandage or a patch comprising of one active substance- containing matrix layer and an impermeable backing layer. The most preferable system is an active substance reservoir, which has a permeable bottom facing the skin. By controlling the rate of release, this system enables the NSAIAs to reach constantly optimal therapeutic blood levels to increase effectiveness and reduce the side effects of NSAIAs.
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EP06795893.4A EP2084132B1 (en) 2006-09-03 2006-09-03 Positively charged water-soluble prodrugs of n-arylanthranilic acids with very fast skin penetration rate
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PL06795893T PL2084132T3 (en) 2006-09-03 2006-09-03 Positively charged water-soluble prodrugs of n-arylanthranilic acids with very fast skin penetration rate
CN200680055744.7A CN101506168B (en) 2006-09-03 2006-09-03 Positively charged water-soluble prodrugs of n-arylanthranilic acids with very fast skin penetration rate
ES06795893.4T ES2694685T3 (en) 2006-09-03 2006-09-03 Water-soluble prodrugs positively charged with n-arylanthranilic acids with very rapid penetration rate into the skin
PL13153470T PL2623495T3 (en) 2006-09-03 2006-09-03 Positively charged water-soluble prodrugs of n-arylanthranilic acids with very fast skin penetration rate
ES13153470T ES2735287T3 (en) 2006-09-03 2006-09-03 Water-soluble prodrugs positively charged with n-arylantranilic acids with very fast skin penetration rate
PCT/IB2006/053090 WO2008029199A1 (en) 2006-09-03 2006-09-03 Positively charged water-soluble prodrugs of n-arylanthranilic acids with very fast skin penetration rate
US12/351,804 US20090238763A1 (en) 2006-07-09 2009-01-09 High penetration compositions and uses thereof
US12/397,308 US20090221703A1 (en) 2006-07-09 2009-03-03 High penetration composition and uses thereof
HK10100929.4A HK1137426A1 (en) 2006-09-03 2010-01-28 Positively charged water-soluble prodrugs of n-arylanthranilic acids with very fast skin penetration rate
US15/379,866 US11135153B2 (en) 2006-07-09 2016-12-15 High penetration composition and uses thereof
US15/402,575 US20170209585A1 (en) 2006-07-09 2017-01-10 High penetration compositions and uses thereof
US15/402,618 US9872846B2 (en) 2006-07-09 2017-01-10 High penetration compositions and uses thereof
US16/421,735 US20210353579A1 (en) 2006-07-09 2019-05-24 High penetration compositions and uses thereof
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