High penetration comp1ositions (HPCs) or prodrugs (HPPs) of antimicrobials and antimicrobial-related compounds are provided. The HPCs/HPPs are capable of being converted to parent drugs or drug metabolites after crossing the biological barrier and thus can render treatments. Additionally, the HPCs/HPPs are capable of reaching areas that their parent drugs may not be able to access and rendering a sufficient concentration at the target areas and therefore render novel treatments.
C07D 205/12 - Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
C07D 277/60 - Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
C07D 211/26 - Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
C07D 211/16 - Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with acylated ring nitrogen atom
A61K 31/397 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having four-membered rings, e.g. azetidine
A61K 31/43 - Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula , e.g. penicillins, penems
A61K 31/545 - Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula , e.g. cephalosporins, cefaclor, cephalexine
A61P 31/00 - Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
Provided is a high penetration composition or high penetration prodrugs of peptide or peptide-related compound comprising functional unit, linker, and transportational unit. The functional unit is covalently linked to the transportational unit via the linker, and comprises a moiety of the peptide or the peptide-related compound. The transportational unit comprises protonatable amine group. The linker comprises chemical bond that is capable of being cleaved after the composition penetrates across a biological barrier.
The novel positively charged pro-drugs of oxicams and related compounds in the general formula (1) 'Structure 1' were designed and synthesized. 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 ~100 times faster than do oxicams and related compounds. It takes 1-2 hours for oxicams 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 oxicams-treatable conditions in humans or animals. Second, the prodrugs can be administered not only orally, but also transdermally for any kind of medical treatments and avoid most of the side effects of oxicams. Controlled transdermal administration systems of the prodrugs enable oxicams and related compounds to reach constantly optimal therapeutic blood levels to increase effectiveness and reduce the side effects of oxicams and related compounds. Another great benefit of the transdermal administration of these pro-drugs is that administering medication, especially to children, will be much easier.
C07D 417/12 - Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group containing two hetero rings linked by a chain containing hetero atoms as chain links
C07D 279/16 - 1,4-ThiazinesHydrogenated 1,4-thiazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring
4.
POSITIVELY CHARGED WATER-SOLUBLE PRODRUGS OF PROSTAGLANDINS AND RELATED COMPOUNDS WITH VERY HIGH SKIN PENETRATION RATES
The novel positively charged pro-drugs of prostaglandins, prostacyclins and related compounds in the general formula (2) 'Structure 2' were designed and synthesized. The compounds of the general formula (2) 'Structure 2' indicated above can be prepared from protected prostaglandins, prostacyclins, 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 in water, 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 diffuse through human skin ~1000 times faster than do prostaglandins, prostacyclins, and related compounds. 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 prostaglandins, prostacyclins, and related compounds-treatable conditions in humans or animals. The prodrugs can be administered transdermally for any kind of medical treatments and avoid most of the side effects of prostaglandins, prostacyclins, and related compounds. Controlled transdermal administration systems of the prodrug enable prostaglandins, prostacyclins, and related compounds to reach constantly optimal therapeutic blood levels to increase effectiveness and reduce the side effects of prostaglandins, prostacyclins, and related compounds. Another great benefit of transdermal administration of these pro-drugs is that administering medication, especially to children, will be much easier.
C07C 215/40 - Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton with quaternised nitrogen atoms bound to carbon atoms of the carbon skeleton
C07C 215/42 - Compounds containing amino and hydroxy groups bound to the same carbon skeleton having amino groups or hydroxy groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
5.
POSITIVELY CHARGED WATER-SOLUBLE PRODRUGS OF MUSTARDS AND RELATED COMPOUNDS WITH VERY HIGH SKIN PENETRATION RATES
The novel positively charged pro-drugs of mustards and related compounds 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 mustards 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 in water, 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 diffuse through human skin ~100 times faster than do mustards and related compounds. 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 mustards and related compounds-treatable conditions in humans or animals. The prodrugs can be administered transdermally for any kind of medical treatments and avoid most of the side effects of mustards and related compounds. Controlled transdermal administration systems of the prodrug enables mustards and related compounds to reach constantly optimal therapeutic blood levels to increase effectiveness and reduce the side effects of mustards and related compounds. Another great benefit of transdermal administration of these pro-drugs is that administering medication, especially to children, will be much easier.
C07C 215/40 - Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton with quaternised nitrogen atoms bound to carbon atoms of the carbon skeleton
C07C 215/42 - Compounds containing amino and hydroxy groups bound to the same carbon skeleton having amino groups or hydroxy groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
6.
POSITIVELY CHARGED WATER-SOLUBLE PRODRUGS OF N-ARYLANTHRANILIC ACIDS WITH VERY FAST SKIN PENETRATION RATE
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.
C07D 213/74 - Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
C07C 209/10 - Preparation of compounds containing amino groups bound to a carbon skeleton by substitution of functional groups by amino groups by substitution of halogen atoms with formation of amino groups bound to carbon atoms of six-membered aromatic rings or from amines having nitrogen atoms bound to carbon atoms of six-membered aromatic rings
A61P 29/00 - Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agentsNon-steroidal antiinflammatory drugs [NSAID]
C07D 215/02 - Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
C07D 217/12 - Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
C07D 239/02 - Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
7.
POSITIVELY CHARGED WATER-SOLUBLE PRODRUGS OF ACETAMINOPHEN AND RELATED COMPOUNDS WITH VERY FAST SKIN PENETRATION RATE
The novel positively charged pro-drugs of acetaminophen, acetaminosalol, and related compounds in the general formula (1) 'Structure 1' were designed and synthesized. 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 ~150 times faster than does acetaminophen, acetaminosalol, and related compounds. It takes 1-2 hours for acetaminophen and acetaminosalol, 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 be changed back to the parent drugs in a few minutes. The prodrugs can be used medicinally for 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 avoid most of the side effects of NSAIAs. Controlled transdermal administration systems of the prodrugs enables acetaminophen, acetaminosalol, and related compounds to reach constantly optimal therapeutic blood levels to increase effectiveness and reduce the side effects of acetaminophen, acetaminosalol, and related compounds. Another great benefit of transdermal administration of these pro-drugs is that administering medication, especially to children, will be much easier.
C07C 211/64 - Quaternary ammonium compounds having quaternised nitrogen atoms bound to carbon atoms of six-membered aromatic rings
C07C 215/42 - Compounds containing amino and hydroxy groups bound to the same carbon skeleton having amino groups or hydroxy groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
C07C 233/07 - Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with carbon atoms of carboxamide groups bound to carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
8.
POSITIVELY CHARGED WATER-SOLUBLE PRODRUGS OF ARYL- AND HETEROARYLPROPIONIC ACIDS WITH VERY FAST SKIN PENETRATION RATE
The novel positively charged pro-drugs of aryl- and heteroarylpropionic acids in the general formula (1) 'Structure 1' and general formula (2) 'Structure 2' were designed and synthesized. The compounds of the general formula (1) 'Structure 1' and general formula (2) 'Structure 2' indicated above can be prepared from functional derivatives of naproxen, suprofen, α- methyl-(p-chlorobenzoyl)-5-methoxy-2-methylindole 3-acetic acid, flurbiprofen, carprofen, pranoprofen, benoxaprofen, alminoprofen, tiaprofenic acid, pirprofen, zaltoprofen, bermoprofen, loxoprofen, indoprofen, fenclorac, oxaprozin, fenbufen, orpanoxin, ketorolac, clidanac, and related compounds, (for example acid halides or mixed anhydrides), by reaction with suitable alcohols, thiols, or amines. 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 -100-130 times faster than do their parent drugs. It takes 2-4 hours for naproxen, suprofen, α- methyl-(p-chlorobenzoyl)-5-methoxy-2-methylindole 3-acetic acid, flurbiprofen, carprofen, pranoprofen, benoxaprofen, alminoprofen, tiaprofenic acid, pirprofen, zaltoprofen, bermoprofen, loxoprofen, indoprofen, fenclorac, oxaprozin, fenbufen, orpanoxin, ketorolac, clidanac, and related compounds to reach the peak plasma level when they are taken orally, but these prodrugs only took about 40-50 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 drug in a few minutes. The prodrugs can be used medicinally in treating any NS AIAs-treatable conditions in humans or animals. The prodrugs can be administered not only orally, but also transdermally for any kind of medical treatments and 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 prodrugs enable naproxen, suprofen, α- methyl-(p-chlorobenzoyl)-5-methoxy-2-methylindole 3-acetic acid, flurbiprofen, carprofen, pranoprofen, benoxaprofen, alminoprofen, tiaprofenic acid, pirprofen, zaltoprofen, bermoprofen, loxoprofen, indoprofen, fenclorac, oxaprozin, fenbufen, orpanoxin, ketorolac, clidanac, and related compounds to reach constantly optimal therapeutic blood levels to increase effectiveness and reduce the side effects of NSAIAs. Another great benefit of transdermal administration of these pro-drugs is that administering medication, especially to children, will be much easier.
The novel positively charged pro-drugs of aryl- and heteroarylacetic 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 functional derivatives of tolmetin, zomepirac, etodolac, amfenac, bromofenac, alclofenac, fenclofenac, acemetacin, indomethacin, sulindac, fentiazac, lonazolac, bendazac, 6MNA, ibufenac, and related compounds, (for example acid halides or mixed anhydrides), by reaction with suitable alcohols, thiols, or amines. 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 ~100 times faster than does tolmetin, zomepirac, etodolac, amfenac, bromofenac, alclofenac, fenclofenac, acemetacin, indomethacin, sulindac, fentiazac, lonazolac, bendazac, or related compounds. It takes 2-4 hours for tolmetin, zomepirac, etodolac, amfenac, bromofenac, alclofenac, fenclofenac, acemetacin, indomethacin, sulindac, fentiazac, lonazolac, bendazac, 6MNA, ibufenac, and related compounds to reach the peak plasma level when they are taken orally, but these prodrugs only took about 40-50 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 drug 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 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 tolmetin, zomepirac, etodolac, amfenac, bromofenac, alclofenac, fenclofenac, acemetacin, indomethacin, sulindac, fentiazac, lonazolac, bendazac, 6MNA, ibufenac, and related compounds to reach constantly optimal therapeutic blood levels to increase effectiveness and reduce the side effects of NSAIAs. Another great benefit of transdermal administration of these pro-drugs is that administering medication, especially to children, will be much easier.
C07D 231/12 - Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
10.
POSITIVELY CHARGED WATER-SOLUBLE PRODRUGS OF DIFLUNISAL AND RELATED COMPOUNDS WITH VERY FAST SKIN PENETRATION RATE
The novel positively charged pro-drugs of diflunisal, salicylsalicylic acid, and salicylic acid in the general formula(1) 'Structure 1' and general formula(2) 'Structure 2' were designed and synthesized. The compounds of the general formula(1) 'Structure 1' or general formula(2) 'Structure 2' indicated above can be prepared from functional derivatives of diflunisal, salicylsalicylic acid, or salicylic acid, (for example acid halides or mixed anhydrides), by reaction with suitable alcohols, thiols, or amines. 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-drug, diethylaminoethyl 5-(2,4-difluorophenyl) salicylate. AcOH diffuses through human skin ~150 times faster than does diflunisal itself. In plasma, more than 90% of these pro-drugs can change back to the drug in a few minutes. The prodrugs can be used medicinally in treating any diflunisal, salicylsalicylic acid, or salicylic acid-treatable conditions in humans or animals and be administered not only orally, but also transdermally for any kind of medical treatments and avoid most of the side effects of diflunisal, salicylsalicylic acid, or salicylic acid, most notably GI disturbances such as dyspepsia, gastroduodenal bleeding, gastric ulcerations, and gastritis. Controlled transdermal administration systems of the prodrug enables diflunisal, salicylsalicylic acid, or salicylic acid to reach constantly optimal therapeutic blood levels to increase effectiveness and reduce the side effects of diflunisal, salicylsalicylic acid, or salicylic acid.
C07C 215/72 - Compounds containing amino and hydroxy groups bound to the same carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings and hydroxy groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with quaternised amino groups bound to the carbon skeleton
C07C 215/40 - Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton with quaternised nitrogen atoms bound to carbon atoms of the carbon skeleton
C07C 215/42 - Compounds containing amino and hydroxy groups bound to the same carbon skeleton having amino groups or hydroxy groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
C07C 225/16 - Compounds containing amino groups and doubly-bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly-bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings
11.
POSITIVELY CHARGED WATER-SOLUBLE PRODRUGS OF DICLOFENAC WITH VERY FAST SKIN PENETRATION RATE
The novel positively charged pro-drugs of diclofenac 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 functional derivatives of diclofenac (for example acid halides or mixed anhydrides), by reaction with suitable alcohols, thiols, or amines. The positively charged amino groups of these pro-drugs not only largely increases the solubility of the drugs in water, but also bonds to the negative charge on the phosphate head group of membranes and push the pro-drug into the cytosol. The experiment results suggest that the pro-drug, diethylaminoethyl 2[(2,6-dichlorophenyl)amino]benzene acetate.AcOH diffuses through human skin ~250 times faster than do 2[(2,6-dichlorophenyl)amino]benzene acetic acid (diclofenac) and ethyl 2[(2,6-dichlorophenyl)amino]benzene acetate. In plasma, more than 90% of these pro-drugs can change back to the drug in a few minutes. The prodrugs can be used medicinally in treating any diclofenac-treatable conditions in humans or animals and be administered not only orally, but also transdermally for any kind of medical treatments and avoid most of the side effects of diclofenac, most notably GI disturbances such as dyspepsia, gastroduodenal bleeding, gastric ulcerations, and gastritis. Controlled transdermal administration systems of the prodrug enables the diclofenac to reach constantly optimal therapeutic blood levels to increase effectiveness and reduce the side effects of diclofenac.
C07C 215/40 - Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton with quaternised nitrogen atoms bound to carbon atoms of the carbon skeleton
C07C 215/42 - Compounds containing amino and hydroxy groups bound to the same carbon skeleton having amino groups or hydroxy groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
12.
POSITIVELY CHARGED WATER-SOLUBLE PRODRUGS OF KETOPROFEN AND RELATED COMPOUNDS WITH VERY FAST SKIN PENETRATION RATE
The novel positively charged pro-drugs of ketoprofen and fenoprofen 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 functional derivatives of ketoprofen and fenoprofen, (for example acid halides or mixed anhydrides), by reaction with suitable alcohols, thiols, or amines. 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, diethylaminoethyl 2-(3-benzoylphenyl) propionate.AcOH and diethylaminoethyl 2-(3-phenoxyphenyl) propionate.AcOH diffuses through human skin ~125 times faster than does ketoprofen and fenoprofen. It takes 1-2 hours for ketoprofen or fenoprofen to reach the peak ketoprofen or fenoprofen plasma level when they are taken orally, but diethylaminoethyl 2-(3-benzoylphenyl) propionate.AcOH or diethylaminoethyl 2-(3-phenoxyphenyl) propionate.AcOH only took about 40 minutes to reach the ketoprofen or fenoprofen peak plasma level. In plasma, more than 90% of these pro-drugs can change back to the drug in a few minutes. The prodrugs can be used medicinally in treating any ketoprofen and fenoprofen-treatable conditions in humans or animals. The prodrugs can be administered not only orally, but also transdermally for any kind of medical treatments and avoid most of the side effects of ketoprofen and fenoprofen, most notably GI disturbances such as dyspepsia, gastroduodenal bleeding, gastric ulcerations, and gastritis. Controlled transdermal administration systems of the prodrug enables ketoprofen and fenoprofen to reach constantly optimal therapeutic blood levels to increase effectiveness and reduce the side effects of ketoprofen and fenoprofen. Another great benefit of transdermal administration of these pro-drugs is that administering medication, especially to children, will be much easier.
C07C 215/72 - Compounds containing amino and hydroxy groups bound to the same carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings and hydroxy groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with quaternised amino groups bound to the carbon skeleton
C07C 215/40 - Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton with quaternised nitrogen atoms bound to carbon atoms of the carbon skeleton
C07C 215/42 - Compounds containing amino and hydroxy groups bound to the same carbon skeleton having amino groups or hydroxy groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
C07C 225/16 - Compounds containing amino groups and doubly-bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly-bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings
13.
POSITIVELY CHARGED WATER-SOLUBLE PRODRUGS OF IBUPROFEN WITH VERY FAST SKIN PENETRATION RATE
The novel positively charged pro-drugs of ibuprofen in the general formula (I) 'Structure 1' were designed and synthesized. The compounds of the general formula (I) 'Structure 1' indicated above can be prepared from functional derivatives of ibuprofen, (for example acid halides or mixed anhydrides), by reaction with suitable alcohols, thiols, or amines. 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 experiment results suggest that the pro-drug, diethylaminoethyl 2-(p-isobutylphenyl) propionate.AcOH, diffuses through human skin -250 times faster than ibuprofen itself and -125 times faster than ethyl 2-(p-isobutylphenyl) propionate. In plasma, more than 90% of these pro-drugs can change back to the drug in a few minutes. The prodrugs can be used medicinally in treating any ibuprofen-treatable conditions in humans or animals and be administered not only orally, but also transdermally for any kind of medical treatments and avoid most of the side effects of ibuprofen, most notably GI disturbances such as dyspepsia, gastroduodenal bleeding, gastric ulcerations, and gastritis. Controlled transdermal administration systems of the prodrug enables the ibuprofen to reach constantly optimal therapeutic blood levels to increase effectiveness and reduce the side effects of ibuprofen.
The novel positively charged prodrugs of acetylsalicylic acid and its analogues 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 functional derivatives of ASA or its analogues,(for example acid halides or mixed anhydrides), by reaction with suitable alcohols, thiols, or amines. 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 push the pro-drug into the cytosol. The experiment results suggest that the pro-drug, diethylaminoethyl acetylsalicylate.AcOH, diffuses through human skin ~400 times faster than acetylsalicylic acid itself and ~100 times faster than ethyl acetylsalicylate. In plasma, 80% of these pro-drugs can change back to the drug in a few minutes. The pro-drugs can be used medicinally in treating any aspirin-treatable conditions in humans or animals and be administered not only orally, but also transdermally for any kind of medical treatments and avoid most of the side effects of aspirin, most notably GI disturbances such as dyspepsia, gastroduodenal bleeding, gastric ulcerations, and gastritis. Controlled transdermal administration systems of the prodrug enables the aspirin to reach constantly optimal therapeutic blood levels to increase effectiveness and reduce the side effects of aspirin.
C07C 235/42 - 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
C07C 235/16 - Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
C07C 211/64 - Quaternary ammonium compounds having quaternised nitrogen atoms bound to carbon atoms of six-membered aromatic rings
patents