WO2008012603A1 - Promédicaments hydrosolubles à charge positive du diflunisal et composés associés présentant une vitesse de pénétration cutanée très rapide - Google Patents

Promédicaments hydrosolubles à charge positive du diflunisal et composés associés présentant une vitesse de pénétration cutanée très rapide Download PDF

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WO2008012603A1
WO2008012603A1 PCT/IB2006/052563 IB2006052563W WO2008012603A1 WO 2008012603 A1 WO2008012603 A1 WO 2008012603A1 IB 2006052563 W IB2006052563 W IB 2006052563W WO 2008012603 A1 WO2008012603 A1 WO 2008012603A1
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Prior art keywords
general formula
diflunisal
acid
salicylic acid
compounds
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PCT/IB2006/052563
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English (en)
Inventor
Chongxi Yu
Lina Xu
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Techfields Biochem Co. Ltd
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Priority to PCT/IB2006/052563 priority Critical patent/WO2008012603A1/fr
Priority to CN200680055458.0A priority patent/CN101500983B/zh
Application filed by Techfields Biochem Co. Ltd filed Critical Techfields Biochem Co. Ltd
Publication of WO2008012603A1 publication Critical patent/WO2008012603A1/fr
Priority to US12/351,804 priority patent/US20090238763A1/en
Priority to US12/397,308 priority patent/US20090221703A1/en
Priority to HK10100503.8A priority patent/HK1136814A1/xx
Priority to HK16105026.9A priority patent/HK1217015A1/zh
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
    • 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
    • C07C219/14—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 a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
    • C07C229/10—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings
    • C07C229/12—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings to carbon atoms of acyclic carbon skeletons
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/58—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/60—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C53/00—Saturated compounds having only one carboxyl group bound to an acyclic carbon atom or hydrogen
    • C07C53/08—Acetic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/235—Saturated compounds containing more than one carboxyl group
    • C07C59/245—Saturated compounds containing more than one carboxyl group containing hydroxy or O-metal groups
    • C07C59/265—Citric acid

Definitions

  • the present invention relates to the preparations of positively charged and water- soluble pro-drugs of 5-(2,4-difluorophenyl) salicylic acid (diflunisal), salicylsalicylic acid (salsalate) and other salicylic acid analogues and their medicinal use in treating any diflunisal, salicylsalicylic acid, and salicylic acid-treatable conditions in humans or animals. More specifically, the present invention is used to overcome the side effects that are associated with the use of diflunisal, salsalate or salicylic acid. These prodrugs can be administered orally or transdermally.
  • Diflunisal and salsalate are members of the salicylic acid group of non steroidal anti-inflammatory drugs and they have been used for more than 20 years.
  • Diflunisal is one of the 200 most-used prescription drugs. It is more potent than aspirin in its antiinflammatory properties and has a biologic half-life 3 to 4 times greater than that of aspirin.
  • 'PDR Generics' (PDR Generics, 1996, second edition, Medical Economics, Mont vale, New Jersey, pg 243) has listed many medical uses of diflunisal and salsalate.
  • Diflunisal is indicated for acute or long-term use for symptomatic treatment of mild to moderate pain, osteoarthritis, and rheumatoid arthritis. Diflunisal is used alone or as an adjunct in the treatment of dysmenorrhea and gout. Diflunisal is used alone or as an adjunct in the treatment of for loss of vision due to ophthalmic surgery. (Hirsch-Kauffmann, Dan J., U.S. Patent No. 5,1 34,165). Some diflunisal esters and related compounds have anti-platelet properties and improving the vision of a warm-blooded animal impaired by cystoid macular edema (Yung- Yu Hung, et al., U.S. Patent No. 6,593,365) .
  • Diflunisal and salsalate have been used medicinally for more than 20 years and salicylic acid is used for more than 100 years.
  • Diflunisal is more potent than aspirin in anti-inflammatory and is a moderately potent inhibitor of prostaglandin biosynthesis.
  • Diflunisal is one of the 200 most-used prescription drugs.
  • Diflunisal is indicated for acute or long-term use for symptomatic treatment of mild to moderate pain, osteoarthritis, and rheumatoid arthritis. Diflunisal is used alone or as an adjunct in the treatment of dysmenorrhea and gout.
  • This invention relates to the preparation of novel positively charged pro-drugs of diflunisal, salsalate and salicylic acid and their use medicinally. These compounds have two functional groups, which can be modified to form a positively charged hy- drophilic side chain . They are shown in the general formula (1) 'Structure 1' and general formula (2) 'Structure 2'.
  • R represents OH, OCOCH , OCOC H , OCOC H , OCOC H , OCOC H , OCOC H ,
  • R 2 represents H or 2,4-difluorophenyl
  • R represents H, one of any alkyl, alkyloxy, alkenyl or alkynyl residues having 1 to 12 carbon atoms, or aryl residues
  • R represents
  • 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
  • n 0,l,2,3,4,5,6,7,8,9,10
  • All R groups may include C, H, O, S, N atoms and may have single, double, and treble bonds. Any CH groups may be replaced with O, S, or NH.
  • X represents O or 2-OCO-C H -O
  • R represents H or 2,4-difluorophenyl
  • 6 4 represents H, one of any alkyl, alkyl, 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;
  • 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
  • All R groups may include C, H, O, S, N atoms and may have single, double, and treble bonds. Any CH groups may be replaced with O, S, or NH .
  • the goal of this invention is to avoid the side effects of diflunisal, salsalate, and salicylic acid 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 hy- drophilic-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 di- ethylaminoethyl 5-(2,4-difluorophenyl) salicylate.AcOH, diethylaminoethyl salicyl- salicylate.AcOH, diethylaminoethyl salicylate.AcOH, diflunisal, salsalate, and salicylic acid in water were >400 mg, >350 mg, >400 mg, 0.05 mg, 0.07 and 0.1 mg/ml.
  • the slowest or rate-limiting step in the sequence is the dissolution of the drug.
  • Diflunisal, salsalate, and salicylic acid have a very low solubility in gastric juice.
  • 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.
  • the hydrophilic part will push the pro-drug into the cytosol, a semi-liquid concentrated aqueous solution or suspension.
  • the cumulative amounts of diethylaminoethyl 5-(2,4-difluorophenyl) salicylate.AcOH, diethylaminoethyl salicylsalicylate.AcOH, diethylaminoethyl salicylate.AcOH, diflunisal, salsalate, and salicylic acid 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 5-(2,4-difluorophenyl) salicylate.
  • the donor consisted of a 30% solution diethylaminoethyl 5-(2,4-difluorophenyl) salicylate.AcOH, diethylaminoethyl salicylsalicylate.AcOH, diethylaminoethyl salicylate.AcOH, diflunisal, salsalate, and salicylic acid in 1 mL of isopropanol applied to a 1 cm on the backs of the hairless mice. Plasma levels of diethylaminoethyl 5-(2,4-difluorophenyl) salicylate.
  • rats (six groups, each group had 10 rats) were orally administered with 100 mg/kg of diethylaminoethyl 5-(2,4-difluorophenyl) salicylate.AcOH, diethylaminoethyl salicylsalicylate.AcOH, diethylaminoethyl salicylate .AcOH, diflunisal, salsalate, and salicylic acid per day for 21 days.
  • the acute toxicity of the prodrugs was investigated.
  • the LD orally in rats are: 1.0 g/kg , 2.0 g/kg, and 1.6 g for diethylaminoethyl 5-(2,4-difluorophenyl) salicylate.AcOH, diethylaminoethyl salicylsalicylate.AcOH, diethylaminoethyl salicylate.AcOH.
  • the results show that the prodrugs are less toxic than diflunisal (LD
  • the prodrugs 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 anti-inflammatory activities of diethylaminoethyl 5-(2,4-difluorophenyl) salicylate.AcOH, diethylaminoethyl salicylsalicylate.AcOH, diethylaminoethyl salicylate.AcOH were tested using diflunisal as a comparison.
  • Analgetic activity The prolongation time of pain the threshold of a mouse tail was determined in accordance with the D'Amour-Smith Method (J. Pharmacol. Exp. Ther., 72, 74(1941)). After 200mg/kg of diflunisal, salsalate, and salicylic acid were administered orally and 200mg/kg of diethylaminoethyl 5-(2,4-difluorophenyl) salicylate. AcOH, diethylaminoethyl salicylsalicylate.AcOH, and diethylaminoethyl salicylate.AcOH were administered transdermally, the tails of mice were exposed to heat and the prolongation time of pain threshold was determined.
  • mice were divided into 9 groups (6 mice each). Diflunisal ( 50 mg/kg and 100 mg/kg) was administered to groups Bl and B2 of mice, diethylaminoethyl 5-(2,4-difluorophenyl) salicylate.AcOH (50 mg/kg and 100 mg/kg) was administered transdermally to groups Cl and C2 of mice, diethylaminoethyl salicylsalicylate.AcOH (50 mg/kg and 100 mg/kg) was administered transdermally to groups Dl and D2 of mice , and diethylaminoethyl salicylate. AcOH (50 mg and 100 mg/kg) was administered transdermally to groups El and E2. The A group is the control group. The test compounds were administered to the mice 30 minutes before the acetic acid solution was administered. The results
  • Antipyretic activity Rats received a sterilized E. coli suspension as a pyrogen. 56 rats were divided into 9 groups. The control group is group A. 2 hours later, diflunisal (Bl for lOOmg/kg and B2 for 150mg/kg) was administered orally and diethylaminoethyl 5-(2,4-difluorophenyl) salicylate.AcOH (Cl for 100mg/kg and C2 for 150 mg), diethylaminoethyl salicylsalicylate.AcOH (Dl for 100mg/kg and D2 for 150 mg), and diethylaminoethyl salicylate.AcOH (El for 100mg/kg and E2 for 150 mg) 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.
  • Anti-inflammatory activity 50 mg/kg of diethylaminoethyl 5-(2,4-difluorophenyl) salicylate.AcOH was administered orally or transdermally to rats and 50 mg/kg of diflunisal was administered orally. 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 6.
  • pro-drugs are water-soluble neutral salt and can be tolerated very well by the eye. They can be used for treating eye inflammatory diseases, for treating of ocular pain after corneal surgery, for treating glaucoma or for treating ear inflammatory and/ or painful conditions (otitis).
  • the present invention relates to pharmaceutical preparations comprising of prodrugs of the general 'Structure 1' and 'Structure 2' 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 transdermally.
  • the new active compounds of the general 'Structure 1' or 'Structure 2' 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 diflunisal, salisalicylic acid, salicylic acid-treatable conditions in humans or animals.
  • 'Structure 1' or 'Structure 2' or a composition comprising of at least one compound of the general 'Structure 1' or 'Structure 2', as an active ingredient can be used for treating any diflunisal, salisalicylic acid, salicylic acid -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.
  • this system enables diflunisal, salisalicylic acid, salicylic acid to reach constantly optimal therapeutic blood levels to increase effectiveness and reduce the side effects of diflunisal, salisalicylic acid, salicylic acid.
  • 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 functional derivatives of 5-(2,4-difluorophenyl) acetylsalicylic acid, acetylsalicylsalicylic acid, or acetylsalicylic acid, for example, acid halides or mixed anhydrides of the general formula (3) 'Structure 3'.
  • R represents acetyloxyl (OCOCH ) or 2-Acetyloxylbenzoyloxyl (salicyloyloxyl, 2-OCO-C 6 H 4 -OCOCH 3 ), R 2 represents H or 2,4-difluorophenyl, Y represents halogen, alkoxycarbonyl or substituted aryloxycarbonyloxy, by reaction with compounds of the general formula (4) 'Structure 4', then the acetyl group is removed by hydrolysis. The acetyl group does not need to be removed because it can be rapidly cleaved by the enzymes in human plasma in vitro.
  • 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 5-(2,4-difluorophenyl) acetylsalicylic acid, acetylsalicylsalicylic acid, or acetylsalicylic acid, by reaction with compounds of the general formula (4) 'Structure 4' 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) phosphoric acid
  • the compounds of the general formula (1) 'Structure 1' indicated above can be prepared from metal salts or organic base salts of 5-(2,4-d iflu- orophenyl) acetylsalicylic acid, acetylsalicylsalicylic acid, or acetylsalicylic acid, by reaction with compounds of the general formula (5) 'Structure 5'.
  • 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,l,2,3,4,5
  • the compounds of the general formula (1) 'Structure 1' indicated above can be prepared from immobilized base salts of 5-(2,4-difluorophenyl) acetylsalicylic acid, acetylsalicylsalicylic acid, or acetylsalicylic acid of the general formula (6) 'Structure 6',
  • R represents cross-linked resin
  • R represents acetyloxyl (OCOCH ) or 2-Acetyloxylbenzoyloxyl (acetylsalicyloyloxyl, 2-OCO-C 6 H 4 -OCOCH 3 )
  • R 2 represents
  • B represents any base groups, such as pyridine, piperidine, triethylamine, or other base groups, by reaction with compounds of the general formula (5) 'Structure 5' .
  • the compounds of the general formula (2) 'Structure 2' indicated above can be prepared from 5-(2,4-difluorophenyl) salicylic acid, salicylsalicylic acid, or salicylic acid of the general formula (7) 'Structure 7'.
  • R represents H or 2,4-difluorophenyl and R represents H, one of any
  • 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
  • R represents H, one of any alkyl, alkyloxy, alkenyl, or alkynyl residues having 1 to 12 carbon atoms, or aryl residues
  • X represents halogen, alkoxycarbonyl or substituted aryloxycarbonyloxy,
  • pro-drugs of diflunisal, salisalicylic acid, salicylic acid 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 was changed back to the drugs itself.
  • the pro-drugs have a much better absorption rate, and thus the pro-drugs will have better strength than diflunisal, saalisalicylic acid, and salicylic acid at the same dosage.
  • 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 diflunisal, salisalicylic acid, and salicylic acid, most notably GI disturbances such as dyspepsia, gastroduodenal bleeding, gastric ulcerations, and gastritis.
  • Another great benefit of transdermal administration of these pro-drugs is that administering medication, especially to children, will be much easier.
  • Figure 5 The prolongation time of the pain threshold of mice tails after 200mg/kg of diflunisal (B) was administered orally, 200mg/kg of diethylaminoethyl 5-(2,4-difluorophenyl) salicylate.AcOH (C), diethylaminoethyl salicylsalicylate.AcOH (D), and diethylaminoethyl salicylate.AcOH (E) were administered transdermally.
  • a group is the control group.
  • FIG. 6 The rate of swelling (%) after a carrageenin injection. 1 hour before the carrageenin injection, 50 mg of 5-(2,4-difluorophenyl) salicylic acid (diflunisal, B) was administered orally, 50 mg of diethylaminoethyl 5-(2,4-difluorophenyl) salicylate.AcOH (C) was administered orally, and transdermally (D). A is the control group.
  • R represents H or 2,4-difluorophenyl
  • 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 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 "
  • R represents H, one of any alkyl, alkyl, 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
  • 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,
  • R groups may include C, H, O, S, N atoms and may have single, double, and treble bonds. Any CH groups may be replaced with O, S, or NH.
  • the mixture was cooled to 0°C. 15 ml of triethylamine and 8.9 g (0.1 mol) of dimethylaminoethanol were added into the reaction mixture. The mixture is stirred for 3 hours at RT. The solvents are evaporated off. The residue is dissolved in methanol (300ml), 5% sodium bicarbonate (200 ml) is added into the reaction mixture. The mixture is refluxed for 2 hr. The mixture is evaporated to dryness. Methanol (300 ml) is added into the residue with stirring. Solid is removed by filtration and washed with methanol. The solution is evaporated to dryness and the residue is dissolved in chloroform (200 ml). 6 g of acetic acid is added into the reaction mixture with stirring.
  • the pro-drugs of the general formula (1) 'Structure 1' and 'Structure 2' are superior to diflunisal, salicylsalicylic acid, and salicylic acid. They may be used medicinally in treating any diflunisal, salicylsalicylic acid, and salicylic acid-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 are used alone or as an adjunct in the treatment of Bartter's syndrome and chronic uveitis, both anterior and posterior.
  • IUD-associated uterine bleeding and prophylactically to reduce the severity of nausea and prevent radiation-induced vomiting in patients receiving pelvic irradiation. They are also prescribed for diabetic neuropathy and acute migraine headache and are used in hemophilic arthropathy. They are also used in treatment of bone loss, prevention or treatment of sunburn. They may be used in the prevention of cancer. 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 acne due to their anti-inflammatory properties.

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention porte sur la conception et la synthèse de nouveaux promédicaments à charge positive du diflunisal, de l'acide salicylsalicylique et de l'acide salicylique de formule générale (1) 'Structure 1' et de formule générale (2) 'Structure 2'. Les composés de formule générale (1) 'Structure 1' ou de formule générale (2) 'Structure 2' indiqués ci-dessus peuvent être préparés à partir de dérivés fonctionnels du diflunisal, de l'acide salicylsalicylique ou de l'acide salicylique (par exemple d'hydracides ou d'anhydrides mélangés) par mise en réaction avec des alcools, des thiols ou des amines appropriés. Les groupes amino à charge positive de ces promédicaments peuvent non seulement augmenter largement la solubilité de ces médicaments, mais aussi se lier à la charge négative sur le groupe de tête phosphatique de membranes et pousser le promédicament vers le cytosol. Les résultats suggèrent que ce promédicament, le salicylate de diéthylaminoéthyl 5-(2,4-difluorophényl) AcOH, se diffuse à travers la peau humaine ~150 fois plus rapidement que le diflunisal lui-même. Dans le plasma, plus de 90 % de ces promédicaments peuvent redonner le médicament en quelques minutes. Les promédicaments peuvent être utilisés médicalement dans le traitement de n'importe quel trouble pouvant être traité au diflunisal, à l'acide salicylsalicylique ou à l'acide salicylique chez l'homme ou chez l'animal et peuvent être administrés non seulement par voie orale, mais aussi par voie transdermique pour tout type de traitements médicaux. Ces promédicaments évitent également la plupart des effets secondaires du diflunisal, de l'acide salicylsalicylique ou de l'acide salicylique, plus particulièrement les troubles gastro-intestinaux tels que la dyspepsie, le saignement gastroduodénal, les ulcérations gastriques et la gastrite. Des systèmes d'administration par voie transdermique contrôlée dudit promédicament permettent au diflunisal, à l'acide salicylsalicylique ou à l'acide salicylique d'atteindre en permanence des concentrations sanguines thérapeutiques optimales pour une plus grande efficacité du diflunisal, de l'acide salicylsalicylique ou de l'acide salicylique et moins d'effets secondaires.
PCT/IB2006/052563 2006-07-09 2006-07-26 Promédicaments hydrosolubles à charge positive du diflunisal et composés associés présentant une vitesse de pénétration cutanée très rapide WO2008012603A1 (fr)

Priority Applications (11)

Application Number Priority Date Filing Date Title
PCT/IB2006/052563 WO2008012603A1 (fr) 2006-07-26 2006-07-26 Promédicaments hydrosolubles à charge positive du diflunisal et composés associés présentant une vitesse de pénétration cutanée très rapide
CN200680055458.0A CN101500983B (zh) 2006-07-26 2006-07-26 具有快速皮肤穿透速度的带正电荷的水溶性二氟尼柳及相关化合物的前药
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
HK10100503.8A HK1136814A1 (en) 2006-07-26 2010-01-18 Positively charged water-soluble prodrugs of diflunisal and related compounds with very fast skin penetration rate
HK16105026.9A HK1217015A1 (zh) 2006-07-26 2016-05-03 帶正電荷的水溶性二氟尼柳及相關化合物的前藥
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
US17/493,321 US20220096370A1 (en) 2006-07-09 2021-10-04 High penetration composition and uses thereof

Applications Claiming Priority (1)

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PCT/IB2006/052563 WO2008012603A1 (fr) 2006-07-26 2006-07-26 Promédicaments hydrosolubles à charge positive du diflunisal et composés associés présentant une vitesse de pénétration cutanée très rapide

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PCT/IB2006/052549 Continuation-In-Part WO2008012602A1 (fr) 2006-07-09 2006-07-25 Promédicaments hydrosolubles à charge positive du diclofénac présentant une vitesse de pénétration cutanée très rapide
PCT/IB2006/052575 Continuation-In-Part WO2008012605A1 (fr) 2006-07-09 2006-07-27 Promédicaments hydrosolubles à charge positive de kétoprofène et composés associés à vitesse de pénétration cutanée très rapide

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PCT/IB2006/052575 Continuation-In-Part WO2008012605A1 (fr) 2006-07-09 2006-07-27 Promédicaments hydrosolubles à charge positive de kétoprofène et composés associés à vitesse de pénétration cutanée très rapide

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