WO2008020270A1 - Positively charged water-soluble prodrugs of aryl- and heteroarylpropionic acids with very fast skin penetration rate - Google Patents
Positively charged water-soluble prodrugs of aryl- and heteroarylpropionic acids with very fast skin penetration rate Download PDFInfo
- Publication number
- WO2008020270A1 WO2008020270A1 PCT/IB2006/052815 IB2006052815W WO2008020270A1 WO 2008020270 A1 WO2008020270 A1 WO 2008020270A1 IB 2006052815 W IB2006052815 W IB 2006052815W WO 2008020270 A1 WO2008020270 A1 WO 2008020270A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- acoh
- general formula
- diethylaminoethyl
- methyl
- compounds
- Prior art date
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- 239000002253 acid Substances 0.000 title claims abstract description 24
- 229940002612 prodrug Drugs 0.000 title abstract description 71
- 239000000651 prodrug Substances 0.000 title abstract description 71
- 150000007513 acids Chemical class 0.000 title abstract description 15
- 230000035515 penetration Effects 0.000 title description 11
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims abstract description 726
- MITFXPHMIHQXPI-UHFFFAOYSA-N Oraflex Chemical compound N=1C2=CC(C(C(O)=O)C)=CC=C2OC=1C1=CC=C(Cl)C=C1 MITFXPHMIHQXPI-UHFFFAOYSA-N 0.000 claims abstract description 86
- 150000001875 compounds Chemical class 0.000 claims abstract description 68
- OIRAEJWYWSAQNG-UHFFFAOYSA-N Clidanac Chemical compound ClC=1C=C2C(C(=O)O)CCC2=CC=1C1CCCCC1 OIRAEJWYWSAQNG-UHFFFAOYSA-N 0.000 claims abstract description 46
- GXEUNRBWEAIPCN-UHFFFAOYSA-N 2-chloro-2-(3-chloro-4-cyclohexylphenyl)acetic acid Chemical compound ClC1=CC(C(Cl)C(=O)O)=CC=C1C1CCCCC1 GXEUNRBWEAIPCN-UHFFFAOYSA-N 0.000 claims abstract description 41
- YLJRTDTWWRXOFG-UHFFFAOYSA-N 3-[5-(4-chlorophenyl)furan-2-yl]-3-hydroxypropanoic acid Chemical compound O1C(C(CC(O)=O)O)=CC=C1C1=CC=C(Cl)C=C1 YLJRTDTWWRXOFG-UHFFFAOYSA-N 0.000 claims abstract description 41
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- MUXFZBHBYYYLTH-UHFFFAOYSA-N Zaltoprofen Chemical compound O=C1CC2=CC(C(C(O)=O)C)=CC=C2SC2=CC=CC=C21 MUXFZBHBYYYLTH-UHFFFAOYSA-N 0.000 claims abstract description 40
- SYTBZMRGLBWNTM-UHFFFAOYSA-N flurbiprofen Chemical compound FC1=CC(C(C(O)=O)C)=CC=C1C1=CC=CC=C1 SYTBZMRGLBWNTM-UHFFFAOYSA-N 0.000 claims abstract description 40
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- RJMIEHBSYVWVIN-LLVKDONJSA-N (2r)-2-[4-(3-oxo-1h-isoindol-2-yl)phenyl]propanoic acid Chemical compound C1=CC([C@H](C(O)=O)C)=CC=C1N1C(=O)C2=CC=CC=C2C1 RJMIEHBSYVWVIN-LLVKDONJSA-N 0.000 claims abstract description 39
- MDKGKXOCJGEUJW-VIFPVBQESA-N (2s)-2-[4-(thiophene-2-carbonyl)phenyl]propanoic acid Chemical compound C1=CC([C@@H](C(O)=O)C)=CC=C1C(=O)C1=CC=CS1 MDKGKXOCJGEUJW-VIFPVBQESA-N 0.000 claims abstract description 39
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- GUHPRPJDBZHYCJ-SECBINFHSA-N (2s)-2-(5-benzoylthiophen-2-yl)propanoic acid Chemical compound S1C([C@H](C(O)=O)C)=CC=C1C(=O)C1=CC=CC=C1 GUHPRPJDBZHYCJ-SECBINFHSA-N 0.000 claims abstract description 38
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- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 4
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- BFSVOASYOCHEOV-UHFFFAOYSA-N 2-diethylaminoethanol Chemical compound CCN(CC)CCO BFSVOASYOCHEOV-UHFFFAOYSA-N 0.000 description 2
- KMGCUUQPTHDNAI-UHFFFAOYSA-N CC[n]1c(C(c2ccccc2)=O)ccc1C Chemical compound CC[n]1c(C(c2ccccc2)=O)ccc1C KMGCUUQPTHDNAI-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
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- 239000002221 antipyretic Substances 0.000 description 2
- 239000007900 aqueous suspension Substances 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
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- 238000000338 in vitro Methods 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
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- UDGSVBYJWHOHNN-UHFFFAOYSA-N n',n'-diethylethane-1,2-diamine Chemical compound CCN(CC)CCN UDGSVBYJWHOHNN-UHFFFAOYSA-N 0.000 description 2
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- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 2
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- 150000003512 tertiary amines Chemical group 0.000 description 2
- 125000004325 thiepin-2-yl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C(*)S1 0.000 description 2
- GUHPRPJDBZHYCJ-UHFFFAOYSA-N tiaprofenic acid Chemical compound S1C(C(C(O)=O)C)=CC=C1C(=O)C1=CC=CC=C1 GUHPRPJDBZHYCJ-UHFFFAOYSA-N 0.000 description 2
- UNOPUGNFTOQUIZ-VTSYCQLTSA-N (8s,9s,10r,13s,14s,17s)-17-[4-(dimethylamino)butanoyl]-10,13-dimethyl-1,2,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-3-one Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)CCCN(C)C)[C@@]1(C)CC2 UNOPUGNFTOQUIZ-VTSYCQLTSA-N 0.000 description 1
- MLSJPUAYWASKDY-UHFFFAOYSA-N 2-(3-fluoro-4-phenylphenyl)propanoyl chloride Chemical compound FC1=CC(C(C(Cl)=O)C)=CC=C1C1=CC=CC=C1 MLSJPUAYWASKDY-UHFFFAOYSA-N 0.000 description 1
- UODROGXCIVAQDJ-UHFFFAOYSA-N 2-(6-methoxynaphthalen-2-yl)propanoyl chloride Chemical compound C1=C(C(C)C(Cl)=O)C=CC2=CC(OC)=CC=C21 UODROGXCIVAQDJ-UHFFFAOYSA-N 0.000 description 1
- YBDSNEVSFQMCTL-UHFFFAOYSA-N 2-(diethylamino)ethanethiol Chemical compound CCN(CC)CCS YBDSNEVSFQMCTL-UHFFFAOYSA-N 0.000 description 1
- BSBIHHJBVMSYAP-UHFFFAOYSA-N 2-[4-(4-chlorobenzoyl)-5-methoxy-2-methyl-1h-indol-3-yl]propanoic acid Chemical compound COC1=CC=C2NC(C)=C(C(C)C(O)=O)C2=C1C(=O)C1=CC=C(Cl)C=C1 BSBIHHJBVMSYAP-UHFFFAOYSA-N 0.000 description 1
- ZFSIEKBHGRDVTA-UHFFFAOYSA-N 2-[4-(thiophene-2-carbonyl)phenyl]propanoyl chloride Chemical compound C1=CC(C(C(Cl)=O)C)=CC=C1C(=O)C1=CC=CS1 ZFSIEKBHGRDVTA-UHFFFAOYSA-N 0.000 description 1
- WRYDGMWSKBGVHS-UHFFFAOYSA-N 2-bromo-n,n-diethylethanamine Chemical compound CCN(CC)CCBr WRYDGMWSKBGVHS-UHFFFAOYSA-N 0.000 description 1
- GFJOQNDSJLCSNM-UHFFFAOYSA-N 3-(4,5-diphenyl-1,3-oxazol-2-yl)propanamide Chemical compound O1C(CCC(=O)N)=NC(C=2C=CC=CC=2)=C1C1=CC=CC=C1 GFJOQNDSJLCSNM-UHFFFAOYSA-N 0.000 description 1
- 206010002556 Ankylosing Spondylitis Diseases 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- IKWYWMSVSMGHEU-UHFFFAOYSA-N Cc(cc1)ccc1C(c1ccc[s]1)=O Chemical compound Cc(cc1)ccc1C(c1ccc[s]1)=O IKWYWMSVSMGHEU-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 206010012289 Dementia Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 201000005569 Gout Diseases 0.000 description 1
- 206010018634 Gouty Arthritis Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 241000581650 Ivesia Species 0.000 description 1
- OVBPIULPVIDEAO-UHFFFAOYSA-N N-Pteroyl-L-glutaminsaeure Natural products C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 102000004005 Prostaglandin-endoperoxide synthases Human genes 0.000 description 1
- 108090000459 Prostaglandin-endoperoxide synthases Proteins 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- CLZISMQKJZCZDN-UHFFFAOYSA-N [benzotriazol-1-yloxy(dimethylamino)methylidene]-dimethylazanium Chemical compound C1=CC=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 CLZISMQKJZCZDN-UHFFFAOYSA-N 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- OENHQHLEOONYIE-UKMVMLAPSA-N all-trans beta-carotene Natural products CC=1CCCC(C)(C)C=1/C=C/C(/C)=C/C=C/C(/C)=C/C=C/C=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C OENHQHLEOONYIE-UKMVMLAPSA-N 0.000 description 1
- 230000036592 analgesia Effects 0.000 description 1
- 210000003423 ankle Anatomy 0.000 description 1
- 230000003356 anti-rheumatic effect Effects 0.000 description 1
- 239000000924 antiasthmatic agent Substances 0.000 description 1
- 125000005200 aryloxy carbonyloxy group Chemical group 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 235000013734 beta-carotene Nutrition 0.000 description 1
- TUPZEYHYWIEDIH-WAIFQNFQSA-N beta-carotene Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)CCCC1(C)C)C=CC=C(/C)C=CC2=CCCCC2(C)C TUPZEYHYWIEDIH-WAIFQNFQSA-N 0.000 description 1
- 239000011648 beta-carotene Substances 0.000 description 1
- 229960002747 betacarotene Drugs 0.000 description 1
- 229960000074 biopharmaceutical Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000036760 body temperature Effects 0.000 description 1
- 229940098773 bovine serum albumin Drugs 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 230000002550 fecal effect Effects 0.000 description 1
- 210000003608 fece Anatomy 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 230000004907 flux Effects 0.000 description 1
- 229960000304 folic acid Drugs 0.000 description 1
- 235000019152 folic acid Nutrition 0.000 description 1
- 239000011724 folic acid Substances 0.000 description 1
- 210000001156 gastric mucosa Anatomy 0.000 description 1
- 210000000548 hind-foot Anatomy 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 210000002414 leg Anatomy 0.000 description 1
- 231100001231 less toxic Toxicity 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 231100000417 nephrotoxicity Toxicity 0.000 description 1
- 229940126701 oral medication Drugs 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 230000000149 penetrating effect Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000002510 pyrogen Substances 0.000 description 1
- 238000009790 rate-determining step (RDS) Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 210000000689 upper leg Anatomy 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 210000000707 wrist Anatomy 0.000 description 1
- OENHQHLEOONYIE-JLTXGRSLSA-N β-Carotene Chemical compound CC=1CCCC(C)(C)C=1\C=C\C(\C)=C\C=C\C(\C)=C\C=C\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C OENHQHLEOONYIE-JLTXGRSLSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/22—Radicals substituted by doubly bound hetero atoms, or by two hetero atoms other than halogen singly bound to the same carbon atom
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/06—Antimigraine agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P27/02—Ophthalmic agents
- A61P27/06—Antiglaucoma agents or miotics
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- A—HUMAN NECESSITIES
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- 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]
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
- C07D209/46—Iso-indoles; Hydrogenated iso-indoles with an oxygen atom in position 1
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/56—Ring systems containing three or more rings
- C07D209/80—[b, c]- or [b, d]-condensed
- C07D209/82—Carbazoles; Hydrogenated carbazoles
- C07D209/88—Carbazoles; Hydrogenated carbazoles 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 carbon atoms of the ring system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
- C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
- C07D263/56—Benzoxazoles; Hydrogenated benzoxazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
- C07D263/57—Aryl or substituted aryl radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur 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
- C07D333/30—Hetero atoms other than halogen
- C07D333/32—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
Definitions
- the present invention relates to the preparations of positively charged and water- soluble pro-drugs of aryl- and heteroarylpropionic 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
- 2-aryl- and heteroarylpropionic acids there are 2-aryl- and heteroarylpropionic acids, 3-aryl- and heteroarylpropionic acids and cyclized aryl- and heteroarylpropionic acids.
- 5-(4-chlorophenyl)-beta-hydroxy-2-furanpropionic acid (orpanoxin), and related compounds are members of 3-aryl and heteroarylpropionic acid group of nonsteroidal anti-inflammatory drugs.
- 5-benzoyl-2,3-dihydro-lH-pyrrolizine-l-carboxylic acid (ketorolac), 6-chloro-5-cyclohexyl-2,3-dihydro-lH-indene-l-carboxylic acid (clidanac), and related compounds are members of cyclized aryl- and heteroaryl- propionic acid group of nonsteroidal anti-inflammatory drugs.
- 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.
- This invention relates to the preparation of novel positively charged pro-drugs of aryl- and heteroarylpropionic acids and related compounds and their use medicinally.
- R represents CH , OH, Cl, F, or Br;
- 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, NH, OCH 2 COO, OCH 2 COS, or OCH 2 CONH;
- Aryl represents :
- X represents CH 3 O, Cl, F, CH 3 S, CHF 2 O
- Y represents CH 3 O, F, CH 3 CO
- X represents Cl, Br, F, CH 3
- X represents Cl, Br, F, CH 3
- X represents CO or O
- X represents Cl, Br, F, or CH 3 O
- X represents O or S
- Y represents CH 2 and CO
- Z represents, CO and CH 2
- R represents H, CH 3 , C 2 H 5
- AU 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.
- 4,5-Diphenyl-2-oxazole propionic acid (oxaprozin), 3-(4-biphenylylcarbonyl)propionic acid (fenbufen), 5-(4-chlorophenyl)-beta-hydroxy-2-furanpropanoic acid (orpanoxin), and related compounds are members of 3-aryl and heteroarylpropionic acid group of nonsteroidal anti-inflammatory drugs.
- the pro-drugs of 3-aryl- and heteroarylpropionic acids have the general formula (2) 'Structure 2'.
- W represents H, OH, Cl, F, or Br
- 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, NH, OCH 2 COO, OCH 2 COS, or OCH 2 CONH
- A represents Cl , Br , F , I , AcO , citrate, or any negative ions
- n 0,l,2,3,4,5,6,7,8,9,10
- W represents OH, Cl, or F
- Y represents H, Cl, OH, or CH
- Z
- X represents Cl, F, or Br
- AU R, R , R , R , and 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 Cl, F, or Br
- the cyclized aryl- and heteroarylpropionic acid are formed. They are 5-benzoyl-2,3-dihydro-lH-pyrrolizine-l-carboxylic acid (ketorolac), 6-chloro-5-cyclohexyl-2,3-dihydro-lH-indene-l-carboxylic acid (clidanac) and related compounds.
- the goal of this invention is to avoid the side effects of naproxen, suprofen, ⁇ - 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 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).
- 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.
- 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.
- pro-drugs 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 membrane is bonded with proton (H + ).
- the positive charges of prodrugs cannot bond to the negative charge on the 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 aryl- and heteroarylpropionic acids and their positively charged prodrugs and related compounds through human skin were measured in vitro by using modified Franz cells, which were isolated from human skin tissue (360-400 ⁇ m 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.
- Apparent flux values of 3.5 mg, 3.0 mg, 4.0 mg, 3.5 mg, 4.0 mg, 3.8 mg, 4.0 mg, 3.5 mg, 4.2 mg, 3.5 mg, 3.7 mg, 4.1 mg, 3.4 mg, 4.2 mg, 3.8 mg, 4.0 mg, 3.6 mg, 4.1 mg, 3.8 mg, 4.0 mg, 0.03 mg, 0.03 mg, 0.03 mg, 0.04 mg, 0.03 mg, 0.03 mg, 0.03 mg, 0.03 mg, 0.04 mg, 0.03 mg, 0.03 mg, 0.03 mg, 0.03 mg, 0.04 mg, 0.03 mg, 0.03 mg, 0.04 mg, 0.03 mg, 0.03 mg, 0.04 mg, 0.03 mg, 0.03 mg, 0.03 mg, 0.03 mg, and 0.04 mg/cm 2 /h were calculated for diethylaminoethyl 2-(6-methoxy-2-naphthyl)propionate.AcOH, di- ethylaminoethyl ⁇ -methyl-4-(2-thieny
- 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 naproxen, suprofen, ⁇ -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 were determined by a specific high-performance liquid chromatography method.
- the peak plasma levels were -0.01 mg/ml for naproxen, suprofen, ⁇ - 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 -2 mg/ml for diethylaminoethyl 2-(6-methoxy-2-naphthyl)propionate.AcOH, diethylaminoethyl ⁇ - methyl-4-(2-thienylcarbonyl)benzeneacetate.AcOH, dieth
- 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' or general 'Structure 2' are close to that of diethylaminoethyl 2-(6-methoxy-2-naphthyl)propionate.AcOH.
- 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 anti-inflammatory activities of these prodrugs were tested using naproxen, suprofen, ⁇ - 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, or clidanac 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 2-(6-methoxy-2-naphthyl)propionate.AcOH (100 mg/kg, B), diethylaminoethyl ⁇ - methyl-4-(2-thienylcarbonyl)benzeneacetate.AcOH (100 mg/kg, C), diethylaminoethyl ⁇ -methyl-(p-chlorobenzoyl)-5-methoxy-2-methylindole 3-acetate.AcOH (100 mg/kg, D), diethylaminoethyl 2-(2-fluoro-4-biphenylyl)propionate.AcOH (100 mg/kg, E), diethylaminoethyl 6-chloro- ⁇ -methyl-9H-carbazole-2-acetate.AcOH (100 mg/kg
- 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' or general '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.
- the new active compounds of the general 'Structure 1' or general '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 NSAIAs- treatable conditions in humans or animals.
- Structure 1' or general 'Structure 2' or a composition comprising of at least one compound of the general 'Structure 1' or general 'Structure 2' 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.
- 'Structure 2' indicated above can be prepared from functional derivatives of aryl- and heteroarylpropionic acids, for example, acid halides or mixed anhydrides of the general formula (3) 'Structure 3' and general formula (4) 'Structure 4'.
- X represents halogen, alkoxycarbonyl or substituted aryloxy- carbonyloxy
- Aryl, R, Y, Z, or W represent same groups as that are listed in 'structure I' or 'structure 2', 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 4 represents H, one of any alkyl, alkyloxy, alkenyl, or alkynyl residues having 1 to 12 carbon atoms, or aryl residues
- 'Structure 2' indicated above can be prepared from naproxen, suprofen, ⁇ - 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, by reaction with compounds of the general formula (5) 'Structure 5' by using coupling reagents, such as N,N'-Dicyclohexylcarbodiimide, N, N'-Diisopropylcarbodiimide, O- (Benzotriazol- 1
- the compounds of the general formula (1) 'Structure 1' or general formula (2) 'Structure 2' indicated above can be prepared from metal salts or organic base salts of naproxen, suprofen, ⁇ - 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, by reaction with compounds of the general formula (6) 'Structure 6'.
- 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,
- the compounds of the general formula (1) 'Structure 1' or general formula (2) 'Structure 2' indicated above can be prepared from immobilized base salts of naproxen, suprofen, ⁇ - 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 of the general formula (7) 'Structure 7',
- P represents cross-linked resin
- Aryl represents aryl- and heteroaryl groups that are listed in 'structure 1' and 'structure 2'
- B represents any base groups, such as pyridine, piperidine, triethylamine, or other base groups, by reaction with compounds of the general formula (6) 'Structure 6'.
- 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 prodrugs 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.
- pro-drugs 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 drugs itself.
- the pro-drugs have a much better absorption rate, and thus the pro-drugs will have better strength than naproxen, suprofen, ⁇ - 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 at the same dosage.
- the prodrugs can be administered not only orally, but also transdermally for any type of medical treatment and should avoid most of the side effects of naproxen, suprofen, ⁇ - 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, or clidanac, and related compounds, most notably GI disturbances such as dyspepsia, gastroduodenal bleeding, gastric ulcerations, gastritis, and renal toxicity.
- Another great benefit of transdermal administration of these pro-drugs is notably
- Figure 2 Cumulative amounts of diethylaminoethyl ⁇ -methyl-5H-[l] benzopyrano[2,3-b]pyridine-7-acetate.AcOH (A, 30% solution), diethylaminoethyl 2-(4-chlorophenyl)- ⁇ -methyl-5-benzoxazoleacetate.AcOH (B, 30% solution), diethylaminoethyl ⁇ -methyl-4-[(2-methyl-2-propenyl)amino]benzeneacetate.AcOH (C, 30% solution), diethylaminoethyl 5-benzoyl- ⁇ -methyl-2-thiopheneacetate.AcOH (D, 30% solution), diethylaminoethyl 3-chloro-4-(2,5-dihydro-lH-pyrrol-l-yl)- ⁇ -methyl benze- neacetate.AcOH (E, 30% solution), pranoprofen (F, 30% suspension
- Figure 3 Cumulative amounts of diethylaminoethyl 2-(10, ll-dihydro-10-oxodibenzo(b,f)thiepin-2-yl)propionate.AcOH (A, 30% solution), diethylaminoethyl 2-(8-methyl-10, ll-dihydro-ll-oxodibenz(b,f)oxepin-2-yl)propionate.AcOH (B, 30% solution), diethylaminoethyl 2-[4-(2-oxocyclopentyl-methyl)phenyl]propionate.AcOH (C, 30% solution), diethylaminoethyl
- Figure 5 Total plasma levels of naproxen, suprofen, ⁇ - methyl-(p-chlorobenzoyl)-5-methoxy-2-methylindole 3-acetic acid, flurbiprofen, carprofen after topical application of 1 ml of a 20% solution of diethylaminoethyl 2-(6-methoxy-2-naphthyl)propionate.AcOH (A), diethylaminoethyl ⁇ - methyl-4-(2-thienylcarbonyl)benzeneacetate.AcOH (B), diethylaminoethyl ⁇ - methyl-(p-chlorobenzoyl)-5-methoxy-2-methylindole 3-acetate.AcOH (C), diethylaminoethyl 2-(2-fluoro-4-biphenylyl)propionate.AcOH (D), diethylaminoethyl 6-chloro-
- Figure 6 Total plasma levels of pranoprofen, benoxaprofen, alminoprofen, tiaprofenic acid, or pirprofen after topical application of diethylaminoethyl ⁇ - methyl-5H-[l]benzopyrano[2,3-b]pyridine-7-acetate.
- AcOH diethylaminoethyl 2-(4-chlorophenyl)- ⁇ -methyl-5-benzoxazoleacetate.
- AcOH (B) diethylaminoethyl ⁇ - methyl-4- [(2-methyl-2-propenyl)amino]benzeneacetate.
- Figure 7 Total plasma levels of zaltoprofen, bermoprofen, loxoprofen, indoprofen, fenclorac after topical application of diethylaminoethyl 2-(10,
- Figure 8 Total plasma levels of oxaprozin, fenbufen, orpanoxin, ketorolac, and clidanac after topical application of diethylaminoethyl 4,5-Diphenyl-2-oxazole propionate.
- AcOH A
- B diethylaminoethyl 3-(4-biphenylylcarbonyl)propionate.
- AcOH B
- AcOH (C) diethylaminoethyl 5-benzoyl-2,3-dihydro-lH-pyrrolizine-l-carboxylate.
- AcOH (D) diethylaminoethyl 6-chloro-5-cyclohexyl-2,3-dihydro-lH-indene-l-carboxylate.
- E o
- Figure 9 The prolongation time of the pain threshold of mice tails after 50mg/kg of diethylaminoethyl 2-(6-methoxy-2-naphthyl)propionate.
- AcOH (B) diethylaminoethyl ⁇ -methyl-4-(2-thienylcarbonyl)benzeneacetate.
- AcOH (C) diethylaminoethyl ⁇ - methyl-(p-chlorobenzoyl)-5-methoxy-2-methylindole 3-acetate.
- AcOH (D) diethylaminoethyl 2-(2-fluoro-4-biphenylyl)propionate.
- AcOH (E) diethylaminoethyl 6-chloro- ⁇ -methyl-9H-carbazole-2-acetate.
- AcOH (F) were administered transdermally.
- Group A is the control group.
- Figure 10 The prolongation time of the pain threshold of mice tails after 50mg/kg of diethylaminoethyl ⁇ -methyl-5H-[l]benzopyrano[2,3-b]pyridine-7-acetate.
- AcOH (G) diethylaminoethyl 2-(4-chlorophenyl)- ⁇ -methyl-5-benzoxazoleacetate.
- AcOH (H) diethylaminoethyl ⁇ -methyl-4- [(2-methyl-2-propenyl)amino]benzeneacetate.
- Figure 12 The prolongation time of the pain threshold of mice tails after 50mg/kg of diethylaminoethyl 4,5-Diphenyl-2-oxazole propionate.AcOH (Q), diethylaminoethyl 3-(4-biphenylylcarbonyl)propionate.AcOH (R), diethylaminoethyl 5-(4-chlorophenyl)-beta-hydroxy-2-furanpropionate.AcOH (S), diethylaminoethyl 5-benzoyl-2,3-dihydro-lH-pyrrolizine-l-carboxylate.AcOH (T), diethylaminoethyl 6-chloro-5-cyclohexyl-2,3-dihydro-lH-indene-l-carboxylate.AcOH (U) were administered transdermally.
- Q diethylaminoethyl 3-(4-bipheny
- Group A is the control group.
- Figure 13 The rate of swelling (%) after a carrageenin injection. 1 Hour before the carrageenin injection, diethylaminoethyl 2-(6-methoxy-2-naphthyl)propionate.AcOH (100 mg/kg, B), diethylaminoethyl ⁇ - methyl-4-(2-thienylcarbonyl)benzeneacetate.AcOH (100 mg/kg, C), diethylaminoethyl ⁇ -methyl-(p-chlorobenzoyl)-5-methoxy-2-methylindole 3-acetate.AcOH (100 mg/kg, D), diethylaminoethyl 2-(2-fluoro-4-biphenylyl)propionate.AcOH (100 mg/kg, E), diethylaminoethyl 6-chloro- ⁇ -methyl-9H-carbazole-2-acetate.AcOH (100 mg/kg,
- Figure 15 The rate of swelling (%) after a carrageenin injection. 1 Hour before the carrageenin injection, diethylaminoethyl 2-(10, ll-dihydro-10-oxodibenzo(b,f)thiepin-2-yl)propionate.AcOH (100 mg/kg, L), diethylaminoethyl 2-(8-methyl-10, ll-dihydro-ll-oxodibenz(b,f)oxepin-2-yl)propionate.AcOH (100 mg/kg, M), diethylaminoethyl 2-[4-(2-oxocyclopentyl-methyl)phenyl]propionate.AcOH (100 mg/kg, N), diethylaminoethyl 4-( 1 ,3-dihydro- 1 -oxo-2H-isoindol-2-yl)- ⁇ -methylbenz eneacetate.AcOH (100 mg/kg
- Figure 16 The rate of swelling (%) after a carrageenin injection. 1 Hour before the carrageenin injection, diethylaminoethyl 4,5-Diphenyl-2-oxazole propionate.AcOH (100 mg/kg, Q), diethylaminoethyl 3-(4-biphenylylcarbonyl)propionate.AcOH (100 mg/kg, R), diethylaminoethyl
- R represents CH , OH, Cl, F, or Br
- 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, NH, OCH 2 COO, OCH 2 COS, or OCH 2 CONH
- A represents Cl , Br , F
- Aryl represents aryl- and heteroaryl groups
- W represents H, OH, Cl, F, or Br
- 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, NH, OCH 2 COO, OCH 2 COS, or OCH 2 CONH
- A represents Cl , Bf, F
- n 0,l,2,3,4,5,6,7,8,9,10 ; Y or Y and Z together represent aryl- and heteroaryl groups.
- 'Structure 2' are superior to naproxen, suprofen, ⁇ - 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, or clidanac, and related compounds.
- 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.
Abstract
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.
Description
Description
POSITIVELY CHARGED WATER-SOLUBLE PRODRUGS OF ARYL- AND HETEROARYLPROPIONIC 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 aryl- and heteroarylpropionic 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] There are 2-aryl- and heteroarylpropionic acids, 3-aryl- and heteroarylpropionic acids and cyclized aryl- and heteroarylpropionic acids. 2-(6-methoxy-2-naphthyl) propionic acid (naproxen), α-methyl-4-(2-thienylcarbonyl)benzeneacetic acid (suprofen), α-methyl-(p-chlorobenzoyl)-5-methoxy-2-methylindole-3-acetic acid, 2-(2-fluoro-4-biphenylyl)propionic acid (flurbiprofen), 6-chloro-α-methyl-9H-carbazole-2-acetic acid (carprofen), α-methyl-5H-[l] benzopyrano[2,3-b]pyridine-7-acetic acid (pranoprofen), 2-(4-chlorophenyl)-α-methyl-5-benzoxazoleacetic acid (benoxaprofen), α- methyl-4- [(2-methyl-2-propenyl)amino]benzeneacetic acid (alminoprofen), 5-benzoyl-α-methyl-2-thiopheneacetic acid (tiaprofenic acid), 3-chloro-4-(2,5-dihydro-lH-pyrrol-l-yl)-α-methylbenzeneacetic acid (pirprofen), 2-(10, ll-dihydro-10-oxodibenzo(b,f)thiepin-2-yl)propionic acid (zaltoprofen), 2-(8-methyl-10, 11-dihydro-l l-oxodibenz(b,f)oxepin-2-yl)propionic acid (bermoprofen), 2-[4-(2-oxocyclopentyl-methyl)phenyl]propionic acid (loxoprofen), 4-( 1 ,3-dihydro- 1 -oxo-2H-isoindol-2-yl)-α-methylbenzeneacetic acid (indoprofen), α,3-dichloro-4-cyclohexylbenzeneacetic acid (fenclorac), and related compounds are members of 2-aryl and heteroarylpropionic acid group of nonsteroidal antiinflammatory drugs. 4,5-Diphenyl-2-oxazole propionic acid (oxaprozin), 3-(4-biphenylylcarbonyl)propionic acid (fenbufen),
5-(4-chlorophenyl)-beta-hydroxy-2-furanpropionic acid (orpanoxin), and related compounds are members of 3-aryl and heteroarylpropionic acid group of nonsteroidal anti-inflammatory drugs. 5-benzoyl-2,3-dihydro-lH-pyrrolizine-l-carboxylic acid (ketorolac), 6-chloro-5-cyclohexyl-2,3-dihydro-lH-indene-l-carboxylic acid (clidanac), and related compounds are members of cyclized aryl- and heteroaryl-
propionic acid group of nonsteroidal anti-inflammatory 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. The may be used for the treatment of dementia (McGeer; Patrick L. et al. U.S. Pat. No. 5,192,753).
[3] Unfortunately, a number of side effects are associated with the use 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, 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] 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, 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 NSAIAs,
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 aryl- and heteroarylpropionic acids and related compounds and their use medicinally. 2-(6-methoxy-2-naphthyl)propionic acid (naproxen), α- methyl-4-(2-thienylcarbonyl)benzeneacetic acid (suprofen), α- methyl-(p-chlorobenzoyl)-5-methoxy-2-methylindole 3-acetic acid, 2-(2-fluoro-4-biphenylyl)propionic acid (flurbiprofen), 6-chloro-α-methyl-9H-carbazole-2-acetic acid (carprofen), α-methyl-5H-[l] benzopyrano[2,3-b]pyridine-7-acetic acid (pranoprofen), 2-(4-chlorophenyl)-α-methyl-5-benzoxazoleacetic acid (benoxaprofen), α- methyl-4- [(2-methyl-2-propenyl)amino]benzeneacetic acid (alminoprofen), 5-benzoyl-α-methyl-2-thiopheneacetic acid (tiaprofenic acid), 3-chloro-4-(2,5-dihydro-lH-pyrrol-l-yl)-α-methyl benzeneacetic acid (piφrofen), 2-(10, ll-dihydro-10-oxodibenzo(b,f)thiepin-2-yl)propionic acid (zaltoprofen), 2-(8-methyl-10, 11-dihydro-l l-oxodibenz(b,f)oxepin-2-yl)propionic acid (bermoprofen), 2-[4-(2-oxocyclopentyl-methyl)phenyl]propionic acid (loxoprofen), 4-( 1 ,3-dihydro- 1 -oxo-2H-isoindol-2-yl)-α-methylbenzeneacetic acid (indoprofen), α,3-dichloro-4-cyclohexylbenzeneacetic acid (fenclorac), and related compounds are member s of 2-aryl and heteroarylpropionic acid group of nonsteroidal antiinflammatory drugs. The pro-drugs of 2-aryl- and heteroarylpropionic acids have the general formula (1) "Structure 1",
Structure 1
In structure 1, R represents CH , OH, Cl, F, or Br; 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, NH,
OCH 2 COO, OCH 2 COS, or OCH 2 CONH; A represents Cl , Br , F , I , AcO , citrate, or any negative ions; and n=O,l, 2, 3, 4, 5, 6, 7, 8, 9, 10 ; Aryl represents :
In which, X represents CH3O, Cl, F, CH3S, CHF2O
In which, Y represents CH3O, F, CH3CO, In which, X represents F, Cl. H (CH3)2N, CH3, or CH2=CH-CH2 X represents Cl, F, CF3, CH3SO,or CH3S; R represents CH3, C2H5, C3H7
In which, X represents Cl, Br, F, CH3
In which, X represents Cl, Br, F, CH3
In which, X represents Cl, F, Br
In which, X represents CO or O In which, X represents Cl, Br, F, or CH3O
In which, X represents O or S, Y represents CH2 and CO, and Z represents, CO and CH2, R represents H, CH3, C2H5
AU 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] 4,5-Diphenyl-2-oxazole propionic acid (oxaprozin), 3-(4-biphenylylcarbonyl)propionic acid (fenbufen), 5-(4-chlorophenyl)-beta-hydroxy-2-furanpropanoic acid (orpanoxin), and related
compounds are members of 3-aryl and heteroarylpropionic acid group of nonsteroidal anti-inflammatory drugs. The pro-drugs of 3-aryl- and heteroarylpropionic acids have the general formula (2) 'Structure 2'.
Structure 2
In structure 2, W represents H, OH, Cl, F, or Br; 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, NH, OCH 2 COO, OCH 2 COS, or OCH 2 CONH; A represents Cl , Br , F , I , AcO , citrate, or any negative ions; and n=0,l,2,3,4,5,6,7,8,9,10 ; W represents OH, Cl, or F; Y represents H, Cl, OH, or CH ; and Z represents:
In which, X represents Cl, F, or Br
AU R, R , R , R , and 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.
[8] In the general formula (2) 'Structure 2', when W represents H, Y and Z together represent:
In which, X represents Cl, F, or Br
The cyclized aryl- and heteroarylpropionic acid are formed. They are 5-benzoyl-2,3-dihydro-lH-pyrrolizine-l-carboxylic acid (ketorolac), 6-chloro-5-cyclohexyl-2,3-dihydro-lH-indene-l-carboxylic acid (clidanac) and related compounds.
[9] 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.
[10] The goal of this invention is to avoid the side effects 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 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-(6-methoxy-2-naphthyl)propionate.AcOH, diethylaminoethyl α- methyl-4-(2-thienylcarbonyl)benzeneacetate.AcOH, diethylaminoethyl α- methyl-(p-chlorobenzoyl)-5-methoxy-2-methylindole 3-acetate.AcOH, diethylaminoethyl 2-(2-fluoro-4-biphenylyl)propionate.AcOH, diethylaminoethyl 6-chloro-α-methyl-9H-carbazole-2-acetate. AcOH, diethylaminoethyl α-methyl-5H- [ 1 ] benzopyrano[2,3-b]pyridine-7-acetate.AcOH, diethylaminoethyl 2-(4-chlorophenyl)-α-methyl-5-benzoxazoleacetate.AcOH, diethylaminoethyl α- methyl-4-[(2-methyl-2-propenyl)amino]benzeneacetate.AcOH, diethylaminoethyl 5-benzoyl-α-methyl-2-thiopheneacetate.AcOH, diethylaminoethyl 3-chloro-4-(2,5-dihydτo-lH-pyrrol-l-yl)-α-methyl benzeneacetate.AcOH, diethylaminoethyl 2-(10, ll-dihydro-10-oxodibenzo(b,f)thiepin-2-yl)propionate.AcOH, diethylaminoethyl 2-(8-methyl-10,
11-dihydro-l l-oxodibenz(b,f)oxepin-2-yl)propionate.AcOH, diethylaminoethyl 2-[4-(2-oxocyclopentyl-methyl)phenyl]propionate.AcOH, diethylaminoethyl 4-( 1 ,3-dihydro- 1 -oxo-2H-isoindol-2-yl)-α-methylbenzeneacetate. AcOH, diethylaminoethyl α,3-dichloro-4-cyclohexylbenzeneacetate.AcOH, diethylaminoethyl 4,5-Diphenyl-2-oxazole propionate.AcOH, diethylaminoethyl 3-(4-biphenylylcarbonyl)propionate.AcOH, diethylaminoethyl 5-(4-chlorophenyl)-beta-hydroxy-2-furanpropionate.AcOH, diethylaminoethyl 5-benzoyl-2,3-dihydro-lH-pyrrolizine-l-carboxylate.AcOH, diethylaminoethyl 6-chloro-5-cyclohexyl-2,3-dihydro-lH-indene-l-carboxylate.AcOH, 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 in water are >450 mg, >400 mg, >450 mg, > 450 mg, >350 mg, >450 mg, >400 mg, >450 mg, >400 mg, >450 mg, >350 mg, >400 mg, >350 mg, >400 mg, >350 mg, >400 mg, >400 mg, >350 mg, >450 mg, >350 mg, <0.1 mg, <0.1 mg, <0.1 mg, <0.1 mg, <0.1 mg, <0.1 mg, <0.1 mg, <0.1 mg, <0.1 mg, <0.1 mg, <0.1 mg, <0.1 mg, <0.1 mg, <0.1 mg, <0.1 mg, <0.1 mg, <0.1 mg, <0.1 mg, <0.1 mg, and <0.1 mg/ml, In many instances, the lowest or rate-limiting step in the sequence is the dissolution of the drug. 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 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 membrane is bonded with proton (H+). The positive charges of prodrugs cannot bond to the negative charge on the 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. [11] The penetration rates of aryl- and heteroarylpropionic acids and their positively charged prodrugs 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 these prodrugs or a 30% suspension 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 in 2mL of pH 7.4 phosphate buffer (0.2M) are shown in Figure 1, Figure 2, Figure 3, or Figure 4. Apparent flux values of 3.5 mg, 3.0 mg, 4.0 mg, 3.5 mg, 4.0 mg, 3.8 mg, 4.0 mg, 3.5 mg, 4.2 mg, 3.5 mg, 3.7 mg, 4.1 mg, 3.4 mg, 4.2 mg, 3.8 mg, 4.0 mg, 3.6 mg, 4.1 mg, 3.8 mg, 4.0 mg, 0.03 mg, 0.03 mg, 0.03 mg, 0.03 mg, 0.04 mg, 0.03 mg, 0.04 mg, 0.03 mg, 0.03 mg, 0.03 mg, 0.03 mg, 0.04 mg, 0.03 mg, 0.03 mg, 0.04 mg, 0.03 mg, 0.04 mg, 0.03 mg, 0.03 mg, and 0.04 mg/cm2/h were calculated for diethylaminoethyl 2-(6-methoxy-2-naphthyl)propionate.AcOH, di- ethylaminoethyl α-methyl-4-(2-thienylcarbonyl)benzeneacetate.AcOH, diethylaminoethyl α-methyl-(p-chlorobenzoyl)-5-methoxy-2-methylindole 3-acetate.AcOH, diethylaminoethyl 2-(2-fluoro-4-biphenylyl)propionate.AcOH, diethylaminoethyl 6-chloro-α-methyl-9H-carbazole-2-acetate. AcOH, diethylaminoethyl α-methyl-5H- [ 1 ] benzopyrano[2,3-b]pyridine-7-acetate.AcOH, diethylaminoethyl 2-(4-chlorophenyl)-α-methyl-5-benzoxazoleacetate.AcOH, diethylaminoethyl α-
methyl-4-[(2-methyl-2-propenyl)amino]benzeneacetate.AcOH, diethylaminoethyl 5-benzoyl-α-methyl-2-thiopheneacetate.AcOH, diethylaminoethyl 3-chloro-4-(2,5-dihydro-lH-pyrrol-l-yl)-α-methyl benzeneacetate.AcOH, diethylaminoethyl 2-(10, ll-dihydro-10-oxodibenzo(b,f)thiepin-2-yl)propionate.AcOH, diethylaminoethyl 2-(8-methyl-10,
11-dihydro-l l-oxodibenz(b,f)oxepin-2-yl)propionate.AcOH, diethylaminoethyl 2-[4-(2-oxocyclopentyl-methyl)phenyl]propionate.AcOH, diethylaminoethyl 4-( 1 ,3-dihydro- 1 -oxo-2H-isoindol-2-yl)-α-methylbenzeneacetate. AcOH, diethylaminoethyl α,3-dichloro-4-cyclohexylbenzeneacetate.AcOH, diethylaminoethyl 4,5-Diphenyl-2-oxazole propionate.AcOH, diethylaminoethyl 3-(4-biphenylylcarbonyl)propionate.AcOH, diethylaminoethyl 5-(4-chlorophenyl)-beta-hydroxy-2-furanpropionate.AcOH, diethylaminoethyl 5-benzoyl-2,3-dihydro-lH-pyrrolizine-l-carboxylate.AcOH, diethylaminoethyl 6-chloro-5-cyclohexyl-2,3-dihydro-lH-indene-l-carboxylate.AcOH, 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, and clidanac diffuses through human skin. The results suggest that the pro-drug, diethylaminoethyl 2-(6-methoxy-2-naphthyl)propionate.AcOH, diethylaminoethyl α- methyl-4-(2-thienylcarbonyl)benzeneacetate.AcOH, diethylaminoethyl α- methyl-(p-chlorobenzoyl)-5-methoxy-2-methylindole 3-acetate.AcOH, diethylaminoethyl 2-(2-fluoro-4-biphenylyl)propionate.AcOH, diethylaminoethyl 6-chloro-α-methyl-9H-carbazole-2-acetate. AcOH, diethylaminoethyl α-methyl-5H- [ 1 ] benzopyrano[2,3-b]pyridine-7-acetate.AcOH, diethylaminoethyl 2-(4-chlorophenyl)-α-methyl-5-benzoxazoleacetate.AcOH, diethylaminoethyl α- methyl-4-[(2-methyl-2-propenyl)amino]benzeneacetate.AcOH, diethylaminoethyl 5-benzoyl-α-methyl-2-thiopheneacetate.AcOH, diethylaminoethyl 3-chloro-4-(2,5-dihydro-lH-pyrrol-l-yl)-α-methyl benzeneacetate.AcOH, diethylaminoethyl 2-(10, ll-dihydro-10-oxodibenzo(b,f)thiepin-2-yl)propionate.AcOH, diethylaminoethyl 2-(8-methyl-10,
11-dihydro-l l-oxodibenz(b,f)oxepin-2-yl)propionate.AcOH, diethylaminoethyl 2-[4-(2-oxocyclopentyl-methyl)phenyl]propionate.AcOH, diethylaminoethyl 4-( 1 ,3-dihydro- 1 -oxo-2H-isoindol-2-yl)-α-methylbenzeneacetate. AcOH, diethylaminoethyl α,3-dichloro-4-cyclohexylbenzeneacetate.AcOH, diethylaminoethyl 4,5-Diphenyl-2-oxazole propionate.AcOH, diethylaminoethyl 3-(4-biphenylylcarbonyl)propionate.AcOH, diethylaminoethyl 5-(4-chlorophenyl)-beta-hydroxy-2-furanpropionate.AcOH, diethylaminoethyl
5-benzoyl-2,3-dihydro-lH-pyrrolizine-l-carboxylate.AcOH, or diethylaminoethyl 6-chloro-5-cyclohexyl-2,3-dihydro-lH-indene-l-carboxylate.AcOH diffuses through human skin -100-130 times faster than does 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, or clidanac . 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' or general 'St ructure 2' have very high penetration rates and are very close to that of diethylaminoethyl 2-(6-methoxy-2-naphthyl)propionate.AcOH. [12] The in vivo rates of penetration of aryl- and heteroarylpropionic acids and their positively charged prodrugs and related compounds 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 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 were determined by a specific high-performance liquid chromatography method. The results (Figure 5, Figure 6, Figure 7, Figure 8) show that the peak levels of diethylaminoethyl 2-(6-methoxy-2-naphthyl)propionate.AcOH, diethylaminoethyl α-methyl-4-(2-thien ylcarbonyl)benzeneacetate.AcOH, diethylaminoethyl α- methyl-(p-chlorobenzoyl)-5-methoxy-2-methylindole 3-acetate.AcOH, diethylaminoethyl 2-(2-fluoro-4-biphenylyl)propionate.AcOH, diethylaminoethyl 6-chloro-α-methyl-9H-carbazole-2-acetate. AcOH, diethylaminoethyl α-methyl-5H- [ 1 ] benzopyrano[2,3-b]pyridine-7-acetate.AcOH, diethylaminoethyl 2-(4-chlorophenyl)-α-methyl-5-benzoxazoleacetate.AcOH, diethylaminoethyl α- methyl-4-[(2-methyl-2-propenyl)amino]benzeneacetate.AcOH, diethylaminoethyl 5-benzoyl-α-methyl-2-thiopheneacetate.AcOH, diethylaminoethyl 3-chloro-4-(2,5-dihydro-lH-pyrrol-l-yl)-α-methyl benzeneacetate.AcOH, diethylaminoethyl 2-(10, ll-dihydro-10-oxodibenzo(b,f)thiepin-2-yl)propionate.AcOH, diethylaminoethyl 2-(8-methyl-10,
11-dihydro-l l-oxodibenz(b,f)oxepin-2-yl)propionate.AcOH, diethylaminoethyl 2-[4-(2-oxocyclopentyl-methyl)phenyl]propionate.AcOH, diethylaminoethyl 4-( 1 ,3-dihydro- 1 -oxo-2H-isoindol-2-yl)-α-methylbenzeneacetate. AcOH, diethylaminoethyl α,3-dichloro-4-cyclohexylbenzeneacetate.AcOH, diethylaminoethyl 4,5-Diphenyl-2-oxazole propionate.AcOH, diethylaminoethyl
3-(4-biphenylylcarbonyl)propionate.AcOH, diethylaminoethyl 5-(4-chlorophenyl)-beta-hydroxy-2-furanpropionate.AcOH, diethylaminoethyl 5-benzoyl-2,3-dihydro-lH-pyrrolizine-l-carboxylate.AcOH, diethylaminoethyl 6-ch loro-5-cyclohexyl-2,3-dihydro-lH-indene-l-carboxylate.AcOH were reached -50 minutes after application of the donor systems. 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 to reach their peak plasma level when they are taken orally. The peak plasma levels were -0.01 mg/ml 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 -2 mg/ml for diethylaminoethyl 2-(6-methoxy-2-naphthyl)propionate.AcOH, diethylaminoethyl α- methyl-4-(2-thienylcarbonyl)benzeneacetate.AcOH, diethylaminoethyl α- methyl-(p-chlorobenzoyl)-5-methoxy-2-methylindole 3-acetate.AcOH, diethylaminoethyl 2-(2-fluoro-4-biphenylyl)propionate.AcOH, diethylaminoethyl 6-chloro-α-methyl-9H-carbazole-2-acetate. AcOH, diethylaminoethyl α-methyl-5H- [ 1 ] benzopyrano[2,3-b]pyridine-7-acetate.AcOH, diethylaminoethyl 2-(4-chlorophenyl)-α-methyl-5-benzoxazoleacetate.AcOH, diethylaminoethyl α- methyl-4-[(2-methyl-2-propenyl)amino]benzeneacetate.AcOH, diethylaminoethyl 5-benzoyl-α-methyl-2-thiopheneacetate.AcOH, diethylaminoethyl 3-chloro-4-(2,5-dihydro-lH-pyrrol-l-yl)-α-methyl benzeneacetate.AcOH, diethylaminoethyl 2-(10, ll-dihydro-10-oxodibenzo(b,f)thiepin-2-yl)propionate.AcOH, diethylaminoethyl 2-(8-methyl-10,
11-dihydro-l l-oxodibenz(b,f)oxepin-2-yl)propionate.AcOH, diethylaminoethyl 2-[4-(2-oxocyclopentyl-methyl)phenyl]propionate.AcOH, diethylaminoethyl 4-( 1 ,3-dihydro- 1 -oxo-2H-isoindol-2-yl)-α-methylbenzeneacetate. AcOH, diethylaminoethyl α,3-dichloro-4-cyclohexylbenzeneacetate.AcOH, diethylaminoethyl 4,5-Diphenyl-2-oxazole propionate.AcOH, diethylaminoethyl 3-(4-biphenylylcarbonyl)propionate.AcOH, diethylaminoethyl 5-(4-chlorophenyl)-beta-hydroxy-2-furanpropionate.AcOH, diethylaminoethyl 5-benzoyl-2,3-dihydro-lH-pyrrolizine-l-carboxylate.AcOH, or diethylaminoethyl 6-chloro-5-cyclohexyl-2,3-dihydro-lH-indene-l-carboxylate.AcOH (approximately 200 times difference). -2 mg/ml 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 in plasma is more than 20-100 times higher than plasma level for effective analgesia and effective anti-inflammatory activity. This is a very exciting result. It will be very easy and fast to deliver therapeutically effective plasma level 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 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' or general 'Structure 2' are close to that of diethylaminoethyl 2-(6-methoxy-2-naphthyl)propionate.AcOH.
[13] To check the gastroduodenal bleeding caused by these prodrugs, rats were orally administered with 50 mg/kg of diethylaminoethyl 2-(6-methoxy-2-naphthyl )propionate.AcOH, diethylaminoethyl α- methyl-4-(2-thienylcarbonyl)benzeneacetate.AcOH, diethylaminoethyl α- methyl-(p-chlorobenzoyl)-5-methoxy-2-methylindole 3-acetate.AcOH, diethylaminoethyl 2-(2-fluoro-4-biphenylyl)propionate.AcOH, diethylaminoethyl 6-chloro-α-methyl-9H-carbazole-2-acetate. AcOH, diethylaminoethyl α-methyl-5H- [ 1 ] benzopyrano[2,3-b]pyridine-7-acetate.AcOH, diethylaminoethyl 2-(4-chlorophenyl)-α-methyl-5-benzoxazoleacetate.AcOH, diethylaminoethyl α- methyl-4-[(2-methyl-2-propenyl)amino]benzeneacetate.AcOH, diethylaminoethyl 5-benzoyl-α-methyl-2-thiopheneacetate.AcOH, diethylaminoethyl 3-chloro-4-(2,5-dihydro-lH-pyrrol-l-yl)-α-methyl benzeneacetate.AcOH, diethylaminoethyl 2-(10, ll-dihydro-10-oxodibenzo(b,f)thiepin-2-yl)propionate.AcOH, diethylaminoethyl 2-(8-methyl-10,
11-dihydro-l l-oxodibenz(b,f)oxepin-2-yl)propionate.AcOH, diethylaminoethyl 2-[4-(2-oxocyclopentyl-methyl)phenyl]propionate.AcOH, diethylaminoethyl 4-( 1 ,3-dihydro- 1 -oxo-2H-isoindol-2-yl)-α-methylbenzeneacetate. AcOH, diethylaminoethyl α,3-dichloro-4-cyclohexylbenzeneacetate.AcOH, diethylaminoethyl 4,5-Diphenyl-2-oxazole propionate.AcOH, diethylaminoethyl 3-(4-biphenylylcarbonyl)propionate.AcOH, diethylaminoethyl 5-(4-chlorophenyl)-beta-hydroxy-2-furanpropionate.AcOH, diethylaminoethyl 5-benzoyl-2,3-dihydro-lH-pyrrolizine-l-carboxylate.AcOH, diethylaminoethyl 6-chloro-5-cyclohexyl-2,3-dihydro-lH-indene-l-carboxylate.AcOH, 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 per day for 21 days. We found an average of 1-4 mg of fecal blood per gram of feces in the 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 groups and none in diethylaminoethyl 2-(6-methoxy-2-naphthyl)propionate.AcOH, diethylaminoethyl α- methyl-4-(2-thienylcarbonyl)benzeneacetate.AcOH, diethylaminoethyl α- methyl-(p-chlorobenzoyl)-5-methoxy-2-methylindole 3-acetate.AcOH, diethylaminoethyl 2-(2-fluoro-4-biphenylyl)propionate.AcOH, diethylaminoethyl 6-chloro-α-methyl-9H-carbazole-2-acetate. AcOH, diethylaminoethyl α-methyl-5H- [ 1 ] benzopyrano[2,3-b]pyridine-7-acetate.AcOH, diethylaminoethyl 2-(4-chlorophenyl)-α-methyl-5-benzoxazoleacetate.AcOH, diethylaminoethyl α- methyl-4-[(2-methyl-2-propenyl)amino]benzeneacetate.AcOH, diethylaminoethyl 5-benzoyl-α-methyl-2-thiopheneacetate.AcOH, diethylaminoethyl 3-chloro-4-(2,5-dihydro-lH-pyrrol-l-yl)-α-methyl benzeneacetate.AcOH, diethylaminoethyl 2-(10, ll-dihydro-10-oxodibenzo(b,f)thiepin-2-yl)propionate.AcOH, diethylaminoethyl 2-(8-methyl-10,
11-dihydro-l l-oxodibenz(b,f)oxepin-2-yl)propionate.AcOH, diethylaminoethyl 2-[4-(2-oxocyclopentyl-methyl)phenyl]propionate.AcOH, diethylaminoethyl 4-( 1 ,3-dihydro- 1 -oxo-2H-isoindol-2-yl)-α-methylbenzeneacetate. AcOH, diethylaminoethyl α,3-dichloro-4-cyclohexylbenzeneacetate.AcOH, diethylaminoethyl 4,5-Diphenyl-2-oxazole propionate.AcOH, diethylaminoethyl 3-(4-biphenylylcarbonyl)propionate.AcOH, diethylaminoethyl 5-(4-chlorophenyl)-beta-hydroxy-2-furanpropionate.AcOH, diethylaminoethyl 5-benzoyl-2,3-dihydro-lH-pyrrolizine-l-carboxylate.AcOH, diethylaminoethyl 6-chloro-5-cyclohexyl-2,3-dihydro-lH-indene-l-carboxylate.AcOH groups. [14] The acute toxicity of the prodrugs was investigated. The LD orally in mice are:
2.2 g/kg, 0.8 g/kg, 0.7g/kg , 0.75 g/kg , 1.3 g/kg , 3.5 g/kg, 1.1 g/kg, 0.6 g/kg, 0.2 g/kg for diethylaminoethyl 2-(6-methoxy-2-naphthyl)propionate.AcOH, diethylaminoethyl α-methyl-4-(2-thienylcarbonyl)benzeneacetate.AcOH, diethylaminoethyl 6-chloro-α-methyl-9H-carbazole-2-acetate. AcOH, diethylaminoethyl α-methyl-5H- [ 1 ] benzopyrano[2,3-b]pyridine-7-acetate.AcOH, diethylaminoethyl 2-(4-chlorophenyl)-α-methyl-5-benzoxazoleacetate.AcOH, diethylaminoethyl 4-( 1 ,3-dihydro- 1 -oxo-2H-isoindol-2-yl)-α-methylbenzeneacetate. AcOH, diethylaminoethyl α-methyl-4- [(2-methyl-2-propenyl)amino]benzeneacetate. AcOH, diethylaminoethyl α,3-dichloro-4-cyclohexylbenzeneacetate.AcOH, diethylaminoethyl
6-chloro-5-cyclohexyl-2,3-dihydτo-lH-indene-l-carboxylate.AcOH. The results show that the prodrugs are less toxic than their parent drugs, naproxen (LD =1.234 g/kg), suprofen (LD =0.59 g/kg), carprofen (400 mg/kg), pranoprofen (447 mg/kg),
50 benoxaprofen (LD =0.8 g/kg), alminoprofen (LD =2400 mg/kg), indoprofen (LD =0.7 mg/kg), fenclorac (LD =0.43 g/kg), clidanac (LD =0.035 g/kg).
50 50
[15] 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, or clidanac have 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 anti-inflammatory activities of these prodrugs were tested using 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, or clidanac as a comparison.
[16] 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 9, Figure 10, Figure 11, and Figure 12. Diethylaminoethyl 2-(6-methoxy-2-naphthyl)propionate.AcOH, diethylaminoethyl α-methyl-4-(2-thienylcarbonyl)benzeneacetate.AcOH, diethylaminoethyl α-methyl-(p-chlorobenzoyl)-5-methoxy-2-methylindole 3-acetate.AcOH, diethylaminoethyl 2-(2-fluoro-4-biphenylyl)propionate.AcOH, diethylaminoethyl 6-chloro-α-methyl-9H-carbazole-2-acetate. AcOH, diethylaminoethyl α-methyl-5H- [ 1 ] benzopyrano[2,3-b]pyridine-7-acetate.AcOH, diethylaminoethyl 2-(4-chlorophenyl)-α-methyl-5-benzoxazoleacetate.AcOH, diethylaminoethyl α- methyl-4-[(2-methyl-2-propenyl)amino]benzeneacetate.AcOH, diethylaminoethyl 5-benzoyl-α-methyl-2-thiopheneacetate.AcOH, diethylaminoethyl 3-chloro-4-(2,5-dihydro-lH-pyrrol-l-yl)-α-methyl benzeneacetate.AcOH, diethylaminoethyl 2-(10, ll-dihydro-10-oxodibenzo(b,f)thiepin-2-yl)propionate.AcOH, diethylaminoethyl 2-(8-methyl-10, 11-dihydro-l l-oxodibenz(b,f)oxepin-2-yl)propionate.AcOH, diethylaminoethyl
2-[4-(2-oxocyclopentyl-methyl)phenyl]propionate.AcOH, diethylaminoethyl 4-( 1 ,3-dihydro- 1 -oxo-2H-isoindol-2-yl)-α-methylbenzeneacetate. AcOH, diethylaminoethyl α,3-dichloro-4-cyclohexylbenzeneacetate.AcOH, diethylaminoethyl 4,5-Diphenyl-2-oxazole propionate.AcOH, diethylaminoethyl 3-(4-biphenylylcarbonyl)propionate.AcOH, diethylaminoethyl 5-(4-chlorophenyl)-beta-hydroxy-2-furanpropionate.AcOH, diethylaminoethyl 5-benzoyl-2,3-dihydro-lH-pyrrolizine-l-carboxylate.AcOH, diethylaminoethyl 6-chloro-5-cyclohexyl-2,3-dihydro-lH-indene-l-carboxylate.AcOH have shown analgesic activity nicely.
[17] 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-(6-methoxy-2-naphthyl)propionate.AcOH (100 mg/kg, B), diethylaminoethyl α- methyl-4-(2-thienylcarbonyl)benzeneacetate.AcOH (100 mg/kg, C), diethylaminoethyl α-methyl-(p-chlorobenzoyl)-5-methoxy-2-methylindole 3-acetate.AcOH (100 mg/kg, D), diethylaminoethyl 2-(2-fluoro-4-biphenylyl)propionate.AcOH (100 mg/kg, E), diethylaminoethyl 6-chloro-α-methyl-9H-carbazole-2-acetate.AcOH (100 mg/kg, F), diethylaminoethyl α-methyl-5H-[l]benzopyrano[2,3-b]pyridine-7-acetate.AcOH (100 mg/kg, G), diethylaminoethyl
2-(4-chlorophenyl)-α-methyl-5-benzoxazoleacetate.AcOH (100 mg/kg, H), diethylaminoethyl α-methyl-4-[(2-methyl-2-propenyl)amino]benzeneacetate.AcOH (100 mg/ kg, I), diethylaminoethyl 5-benzoyl-α-methyl-2-thiopheneacetate.AcOH (100 mg/kg, J), diethylaminoethyl 3-chloro-4-(2,5-dihydro-lH-pyrrol-l-yl)-α-methyl benze- neacetate.AcOH (100 mg/kg, K), diethylaminoethyl 2-(10, ll-dihydro-10-oxodibenzo(b,f)thiepin-2-yl)propionate.AcOH (100 mg/kg, L), diethylaminoethyl 2-(8-methyl-10, ll-dihydro-ll-oxodibenz(b,f)oxepin-2-yl)propionate.AcOH (100 mg/kg, M), diethylaminoethyl 2-[4-(2-oxocyclopentyl-methyl)phenyl]propionate.AcOH (100 mg/kg, N), diethylaminoethyl
4-( 1 ,3-dihydro- 1 -oxo-2H-isoindol-2-yl)-α-methylbenzeneacetate. AcOH ( 100 mg/kg, O), diethylaminoethyl α,3-dichloro-4-cyclohexylbenzeneacetate.AcOH (100 mg/kg, P), diethylaminoethyl 4,5-Diphenyl-2-oxazole propionate.AcOH (100 mg/kg, Q), diethylaminoethyl 3-(4-biphenylylcarbonyl)propionate.AcOH (100 mg/kg, R), diethylaminoethyl 5-(4-chlorophenyl)-beta-hydroxy-2-furanpropionate.AcOH (100 mg/kg, S), diethylaminoethyl 5-benzoyl-2,3-dihydro-lH-pyrrolizine-l-carboxylate.AcOH (100 mg/kg, T), diethylaminoethyl
6-chloro-5-cyclohexyl-2,3-dihydro-lH-indene-l-carboxylate.AcOH (100 mg/kg, U) were administered transdermally the mice 30 minutes before the acetic acid solution
was administered. The A group is the control group. The results are shown in Table 1. Table 1. The rate of writhings inhibition by prodrugs of aryl- and het- eroarylpropionic acids
[18]
The results show that the prodrugs demonstrate exceptional analgetic activity. Other compounds of the general 'Structure 1' or general 'Structure 2' show similar analgetic activity.
[19] Antipyretic activity: Rats received a sterilized E. coli suspension as a pyrogen. The control group is group A. 2 hours later, diethylaminoethyl 2-(6-methoxy-2-naphthyl)propionate.AcOH (100 mg/kg, B), diethylaminoethyl α-
methyl-4-(2-thienylcarbonyl)benzeneacetate.AcOH (100 mg/kg, C), diethylaminoethyl α-methyl-(p-chlorobenzoyl)-5-methoxy-2-methylindole 3-acetate.AcOH (100 mg/kg, D), diethylaminoethyl 2-(2-fluoro-4-biphenylyl)propionate.AcOH (100 mg/kg, E), diethylaminoethyl 6-chloro-α-methyl-9H-carbazole-2-acetate.AcOH (100 mg/kg, F), diethylaminoethyl α-methyl-5H-[l]benzopyrano[2,3-b]pyridine-7-acetate.AcOH (100 mg/kg, G), diethylaminoethyl
2-(4-chlorophenyl)-α-methyl-5-benzoxazoleacetate.AcOH (100 mg/kg, H), diethylaminoethyl α-methyl-4-[(2-methyl-2-propenyl)amino]benzeneacetate.AcOH (100 mg/ kg, I), diethylaminoethyl 5-benzoyl-α-methyl-2-thiopheneacetate.AcOH (100 mg/kg, J), diethylaminoethyl 3-chloro-4-(2,5-dihydro-lH-pyrrol-l-yl)-α-methyl benze- neacetate.AcOH (100 mg/kg, K), diethylaminoethyl 2-(10, ll-dihydro-10-oxodibenzo(b,f)thiepin-2-yl)propionate.AcOH (100 mg/kg, L), diethylaminoethyl 2-(8-methyl-10, ll-dihydro-ll-oxodibenz(b,f)oxepin-2-yl)propionate.AcOH (100 mg/kg, M), diethylaminoethyl 2-[4-(2-oxocyclopentyl-methyl)phenyl]propionate.AcOH (100 mg/kg, N), diethylaminoethyl
4-( 1 ,3-dihydro- 1 -oxo-2H-isoindol-2-yl)-α-methylbenzeneacetate. AcOH ( 100 mg/kg, O), diethylaminoethyl α,3-dichloro-4-cyclohexylbenzeneacetate.AcOH (100 mg/kg, P), diethylaminoethyl 4,5-Diphenyl-2-oxazole propionate.AcOH (100 mg/kg, Q), diethylaminoethyl 3-(4-biphenylylcarbonyl)propionate.AcOH (100 mg/kg, R), diethylaminoethyl 5-(4-chlorophenyl)-beta-hydroxy-2-furanpropionate.AcOH (100 mg/kg, S), diethylaminoethyl 5-benzoyl-2,3-dihydro-lH-pyrrolizine-l-carboxylate.AcOH (100 mg/kg, T), diethylaminoethyl
6-chloro-5-cyclohexyl-2,3-dihydro-lH-indene-l-carboxylate.AcOH (100 mg/kg, U) 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 aryl- and heteroarylpropionic acids.
[20]
The results shown that the prodrugs demonstrated strong antipyretic activity at 100 mg/kg dose. Other compounds of the general 'Structure 1' and general 'Structure 2' show similar antipyretic activity. [21] Anti-inflammatory activity: diethylaminoethyl
2-(6-methoxy-2-naphthyl)propionate.AcOH (100 mg/kg, B), diethylaminoethyl α- methyl-4-(2-thienylcarbonyl)benzeneacetate.AcOH (100 mg/kg, C), diethylaminoethyl α-methyl-(p-chlorobenzoyl)-5-methoxy-2-methylindole 3-acetate.AcOH (100 mg/kg, D), diethylaminoethyl 2-(2-fluoro-4-biphenylyl)propionate.AcOH (100 mg/kg, E), diethylaminoethyl 6-chloro-α-methyl-9H-carbazole-2-acetate.AcOH (100 mg/kg, F), diethylaminoethyl α-methyl-5H-[l]benzopyrano[2,3-b]pyridine-7-acetate.AcOH (100 mg/kg, G), diethylaminoethyl
2-(4-chlorophenyl)-α-methyl-5-benzoxazoleacetate.AcOH (100 mg/kg, H), diethylaminoethyl α-methyl-4-[(2-methyl-2-propenyl)amino]benzeneacetate.AcOH (100 mg/ kg, I), diethylaminoethyl 5-benzoyl-α-methyl-2-thiopheneacetate.AcOH (100 mg/kg, J), diethylaminoethyl 3-chloro-4-(2,5-dihydro-lH-pyrrol-l-yl)-α-methyl benze- neacetate.AcOH (100 mg/kg, K), diethylaminoethyl 2-(10, ll-dihydro-10-oxodibenzo(b,f)thiepin-2-yl)propionate.AcOH (100 mg/kg, L), diethylaminoethyl 2-(8-methyl-10,
ll-dihydro-ll-oxodibenz(b,f)oxepin-2-yl)propionate.AcOH (100 mg/kg, M), diethy- laminoethyl 2-[4-(2-oxocyclopentyl-methyl)phenyl]propionate.AcOH (100 mg/kg, N), diethylaminoethyl
4-( 1 ,3-dihydro- 1 -oxo-2H-isoindol-2-yl)-α-methylbenzeneacetate. AcOH ( 100 mg/kg, O), diethylaminoethyl α,3-dichloro-4-cyclohexylbenzeneacetate.AcOH (100 mg/kg, P), diethylaminoethyl 4,5-Diphenyl-2-oxazole propionate.AcOH (100 mg/kg, Q), diethylaminoethyl 3-(4-biphenylylcarbonyl)propionate.AcOH (100 mg/kg, R), diethylaminoethyl 5-(4-chlorophenyl)-beta-hydroxy-2-furanpropionate.AcOH (100 mg/kg, S), diethylaminoethyl 5-benzoyl-2,3-dihydro-lH-pyrrolizine-l-carboxylate.AcOH (100 mg/kg, T), diethylaminoethyl
6-chloro-5-cyclohexyl-2,3-dihydro-lH-indene-l-carboxylate.AcOH (100 mg/kg, U) 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 13, Figure 14, Figure 15, and Figure 16. The results show that these prodrugs by transdermal administration demonstrated good anti-inflammatory activity. Other compounds of the general 'Structure 1' or general 'Structure 2' show similar antiinflammatory activity.
[22] 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.
[23] 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.
[24] The present invention relates to pharmaceutical preparations comprising of prodrugs of the general 'Structure 1' or general '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. The new active compounds of the general 'Structure 1' or general '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 NSAIAs- treatable conditions in humans or animals.
[25] Transdermal therapeutic application systems of compounds of the general '
Structure 1' or general 'Structure 2' or a composition comprising of at least one compound of the general 'Structure 1' or general 'Structure 2' 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. [26] The compounds of the general formula (1) 'Structure 1' or general formula (2)
'Structure 2' indicated above can be prepared from functional derivatives of aryl- and heteroarylpropionic acids, for example, acid halides or mixed anhydrides of the general formula (3) 'Structure 3' and general formula (4) 'Structure 4'.
Structure 4 Structure 3
In structure 3 & 4, X represents halogen, alkoxycarbonyl or substituted aryloxy- carbonyloxy, Aryl, R, Y, Z, or W represent same groups as that are listed in 'structure I' or 'structure 2', by reaction with compounds of the general formula (5) 'Structure 5',
Structure 5
In structure 5, 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
[27] The compounds of the general formula (1) 'Structure 1' or general formula (2)
'Structure 2' indicated above can be prepared from 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, by reaction with compounds of
the general formula (5) 'Structure 5' 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 hexafluorophosphate, Benzotriazol- 1-yl-oxy-tris (dimethylamino)phosphonium hexafluorophosphate, et al. [28] When X represents O, the compounds of the general formula (1) 'Structure 1' or general formula (2) 'Structure 2' indicated above can be prepared from metal salts or organic base salts 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, by reaction with compounds of the general formula (6) 'Structure 6'.
Structure 6
In structure 6, 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,l,2,3,4,5
[29] When X represents O, the compounds of the general formula (1) 'Structure 1' or general formula (2) 'Structure 2' indicated above can be prepared from immobilized base salts 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 of the general formula (7) 'Structure 7',
Structure 7
In structure 7, P represents cross-linked resin; Aryl represents aryl- and heteroaryl groups that are listed in 'structure 1' and 'structure 2', B represents any base groups, such as pyridine, piperidine, triethylamine, or other base groups, by reaction with compounds of the general formula (6) 'Structure 6'.
Advantageous Effects [30] These pro-drugs 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 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 prodrugs 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 drugs itself. The pro-drugs have a much better absorption rate, and thus the pro-drugs will have better strength than 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 at the same dosage. The
experiment results suggest that the pro-drugs, diethylaminoethyl 2-(6-methoxy-2-naphthyl)propionate.AcOH, diethylaminoethyl α- methyl-4-(2-thienylcarbonyl)benzeneacetate.AcOH, diethylaminoethyl α- methyl-(p-chlorobenzoyl)-5-methoxy-2-methylindole 3-acetate.AcOH, diethylaminoethyl 2-(2-fluoro-4-biphenylyl)propionate.AcOH, diethylaminoethyl 6-chloro-α-methyl-9H-carbazole-2-acetate. AcOH, diethylaminoethyl α-methyl-5H- [ 1 ] benzopyrano[2,3-b]pyridine-7-acetate.AcOH, diethylaminoethyl 2-(4-chlorophenyl)-α-methyl-5-benzoxazoleacetate.AcOH, diethylaminoethyl α- methyl-4-[(2-methyl-2-propenyl)amino]benzeneacetate.AcOH, diethylaminoethyl 5-benzoyl-α-methyl-2-thiopheneacetate.AcOH, diethylaminoethyl 3-chloro-4-(2,5-dihydro-lH-pyrrol-l-yl)-α-methyl benzeneacetate.AcOH, diethylaminoethyl 2-(10, ll-dihydro-10-oxodibenzo(b,f)thiepin-2-yl)propionate.AcOH, diethylaminoethyl 2-(8-methyl-10,
11-dihydro-l l-oxodibenz(b,f)oxepin-2-yl)propionate.AcOH, diethylaminoethyl 2-[4-(2-oxocyclopentyl-methyl)phenyl]propionate.AcOH, diethylaminoethyl 4-( 1 ,3-dihydro- 1 -oxo-2H-isoindol-2-yl)-α-methylbenzeneacetate. AcOH, diethylaminoethyl α,3-dichloro-4-cyclohexylbenzeneacetate.AcOH, diethylaminoethyl 4,5-Diphenyl-2-oxazole propionate.AcOH, diethylaminoethyl 3-(4-biphenylylcarbonyl)propionate.AcOH, diethylaminoethyl 5-(4-chlorophenyl)-beta-hydroxy-2-furanpropionate.AcOH, diethylaminoethyl 5-benzoyl-2,3-dihydro-lH-pyrrolizine-l-carboxylate.AcOH, or diethylaminoethyl 6-chloro-5-cyclohexyl-2,3-dihydro-lH-indene-l-carboxylate.AcOH diffuses through human skin -100-130 times faster than does 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, or clidanac, and related compounds. 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, or 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. The most exciting result is that the prodrugs can be administered not only orally, but also transdermally for any type of medical treatment and should avoid most of the side effects 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, or clidanac, and related compounds, most notably GI disturbances such as dyspepsia, gastroduodenal 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
[31] Figure 1 : Cumulative amounts of diethylaminoethyl
2-(6-methoxy-2-naphthyl)propionate.AcOH (A, 30% solution), diethylaminoethyl α- methyl-4-(2-thienylcarbonyl)benzeneacetate.AcOH (B, 30% solution), diethylaminoethyl α-methyl-(p-chlorobenzoyl)-5-methoxy-2-methylindole 3-acetate.AcOH (C, 30% solution), diethylaminoethyl 2-(2-fluoro-4-biphenylyl)propionate.AcOH (D, 30% solution), diethylaminoethyl 6-chloro-α-methyl-9H-carbazole-2-acetate.AcOH (E, 30% solution), naproxen (F, 30% suspension), suprofen (G, 30% suspension), α- methyl-(p-chlorobenzoyl)-5-methoxy-2-methylindole 3-acetic acid (H, 30% suspension), flurbiprofen (I, 30% suspension), or carprofen (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).
[32] Figure 2: Cumulative amounts of diethylaminoethyl α-methyl-5H-[l] benzopyrano[2,3-b]pyridine-7-acetate.AcOH (A, 30% solution), diethylaminoethyl 2-(4-chlorophenyl)-α-methyl-5-benzoxazoleacetate.AcOH (B, 30% solution), diethylaminoethyl α-methyl-4-[(2-methyl-2-propenyl)amino]benzeneacetate.AcOH (C, 30% solution), diethylaminoethyl 5-benzoyl-α-methyl-2-thiopheneacetate.AcOH (D, 30% solution), diethylaminoethyl 3-chloro-4-(2,5-dihydro-lH-pyrrol-l-yl)-α-methyl benze- neacetate.AcOH (E, 30% solution), pranoprofen (F, 30% suspension), benoxaprofen (G, 30% suspension), alminoprofen (H, 30% suspension), tiaprofenic acid (I, 30% suspension), or pirprofen (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).
[33] Figure 3: Cumulative amounts of diethylaminoethyl 2-(10, ll-dihydro-10-oxodibenzo(b,f)thiepin-2-yl)propionate.AcOH (A, 30% solution), diethylaminoethyl 2-(8-methyl-10, ll-dihydro-ll-oxodibenz(b,f)oxepin-2-yl)propionate.AcOH (B, 30% solution), diethylaminoethyl 2-[4-(2-oxocyclopentyl-methyl)phenyl]propionate.AcOH (C, 30% solution), diethylaminoethyl
4-( 1 ,3-dihydro- 1 -oxo-2H-isoindol-2-yl)-α-methylbenzeneacetate. AcOH (D, 30% solution), diethylaminoethylα,3-dichloro-4-cyclohexylbenzeneacetate.AcOH (E, 30% solution), zaltoprofen (F, 30% suspension), bermoprofen (G, 30% suspension), loxoprofen (H, 30% suspension), indoprofen (I, 30% suspension), or fenclorac (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).
[34] Figure 4: Cumulative amounts of diethylaminoethyl 4,5-Diphenyl-2-oxazole propionate.AcOH (A, 30% solution), diethylaminoethyl
3-(4-biphenylylcarbonyl)propionate.AcOH (B, 30% solution), diethylaminoethyl 5-(4-chlorophenyl)-beta-hydroxy-2-furanpropionate.AcOH (C, 30% solution), diethylaminoethyl 5-benzoyl-2,3-dihydro-lH-pyrrolizine-l-carboxylate.AcOH (D, 30% solution), diethylaminoethyl
6-chloro-5-cyclohexyl-2,3-dihydro-lH-indene-l-carboxylate.AcOH (E, 30% solution), oxaprozin (F, 30% suspension), fenbufen (G, 30% suspension), orpanoxin (H, 30% suspension), ketorolac (I, 30% suspension), or clidanac (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).
[35] Figure 5: Total plasma levels of naproxen, suprofen, α- methyl-(p-chlorobenzoyl)-5-methoxy-2-methylindole 3-acetic acid, flurbiprofen, carprofen after topical application of 1 ml of a 20% solution of diethylaminoethyl 2-(6-methoxy-2-naphthyl)propionate.AcOH (A), diethylaminoethyl α- methyl-4-(2-thienylcarbonyl)benzeneacetate.AcOH (B), diethylaminoethyl α- methyl-(p-chlorobenzoyl)-5-methoxy-2-methylindole 3-acetate.AcOH (C), diethylaminoethyl 2-(2-fluoro-4-biphenylyl)propionate.AcOH (D), diethylaminoethyl 6-chloro-α-methyl-9H-carbazole-2-acetate.AcOH (E), naproxen (F) , suprofen (G), α- methyl-(p-chlorobenzoyl)-5-methoxy-2-methylindole 3-acetic acid (H), flurbiprofen (I), or carprofen (J) in isopropanol to the backs of hairless mice (n=5).
[36] Figure 6: Total plasma levels of pranoprofen, benoxaprofen, alminoprofen, tiaprofenic acid, or pirprofen after topical application of diethylaminoethyl α- methyl-5H-[l]benzopyrano[2,3-b]pyridine-7-acetate.AcOH (A), diethylaminoethyl 2-(4-chlorophenyl)-α-methyl-5-benzoxazoleacetate.AcOH (B), diethylaminoethyl α- methyl-4- [(2-methyl-2-propenyl)amino]benzeneacetate. AcOH (C), diethylaminoethyl 5-benzoyl-α-methyl-2-thiopheneacetate.AcOH (D), diethylaminoethyl 3-chloro-4-(2,5-dihydro-lH-pyrrol-l-yl)-α-methyl benzeneacetate.AcOH (E), pranoprofen (F), benoxaprofen (G), alminoprofen (H), tiaprofenic acid (I), or pirprofen (J) 1 ml of a 20% solution of in isopropanol to the backs of hairless mice (n=5).
[37] Figure 7: Total plasma levels of zaltoprofen, bermoprofen, loxoprofen, indoprofen, fenclorac after topical application of diethylaminoethyl 2-(10,
1 l-dihydro-10-oxodibenzo(b,f)thiepin-2-yl)propionate.AcOH (A), diethylaminoethyl 2-(8-methyl-10, ll-dihydro-ll-oxodibenz(b,f)oxepin-2-yl)propionate.AcOH (B), diethylaminoethyl 2-[4-(2-oxocyclopentyl-methyl)phenyl]propionate.AcOH (C), diethylaminoethyl 4-(l,3-dihydro-l-oxo-2H-isoindol-2-yl)-α-methylbenzeneacetate.AcOH (D), diethylaminoethylα,3-dichloro-4-cyclohexylbenzeneacetate.AcOH (E), zaltoprofen (F), bermoprofen (G), loxoprofen (H), indoprofen (I), fenclorac (J) 1 ml of
a 20% solution of in isopropanol to the backs of hairless mice (n=5).
[38] Figure 8: Total plasma levels of oxaprozin, fenbufen, orpanoxin, ketorolac, and clidanac after topical application of diethylaminoethyl 4,5-Diphenyl-2-oxazole propionate.AcOH (A), diethylaminoethyl 3-(4-biphenylylcarbonyl)propionate.AcOH (B), diethylaminoethyl 5-(4-chlorophenyl)-beta-hydroxy-2-furanpropionate.AcOH (C), diethylaminoethyl 5-benzoyl-2,3-dihydro-lH-pyrrolizine-l-carboxylate.AcOH (D), diethylaminoethyl 6-chloro-5-cyclohexyl-2,3-dihydro-lH-indene-l-carboxylate.AcOH (E), oxaprozin (F), fenbufen (G), orpanoxin (H), ketorolac (I), or clidanac (J)I ml of a 20% solution of in isopropanol to the backs of hairless mice (n=5).
[39] Figure 9: The prolongation time of the pain threshold of mice tails after 50mg/kg of diethylaminoethyl 2-(6-methoxy-2-naphthyl)propionate.AcOH (B), diethylaminoethyl α-methyl-4-(2-thienylcarbonyl)benzeneacetate.AcOH (C), diethylaminoethyl α- methyl-(p-chlorobenzoyl)-5-methoxy-2-methylindole 3-acetate.AcOH (D), diethylaminoethyl 2-(2-fluoro-4-biphenylyl)propionate.AcOH (E), diethylaminoethyl 6-chloro-α-methyl-9H-carbazole-2-acetate.AcOH (F) were administered transdermally. Group A is the control group.
[40] Figure 10: The prolongation time of the pain threshold of mice tails after 50mg/kg of diethylaminoethyl α-methyl-5H-[l]benzopyrano[2,3-b]pyridine-7-acetate.AcOH (G), diethylaminoethyl 2-(4-chlorophenyl)-α-methyl-5-benzoxazoleacetate.AcOH (H), diethylaminoethyl α-methyl-4- [(2-methyl-2-propenyl)amino]benzeneacetate. AcOH (I), diethylaminoethyl 5-benzoyl-α-methyl-2-thiopheneacetate.AcOH (J), diethylaminoethyl 3-chloro-4-(2,5-dihydro-lH-pyrrol-l-yl)-α-methyl benzeneacetate.AcOH (K) were administered transdermally. Group A is the control group.
[41] Figure 11 : The prolongation time of the pain threshold of mice tails after 50mg/kg of diethylaminoethyl 2-(10,
1 l-dihydro-10-oxodibenzo(b,f)thiepin-2-yl)propionate.AcOH (L), diethylaminoethyl 2-(8-methyl-10, ll-dihydro-ll-oxodibenz(b,f)oxepin-2-yl)propionate.AcOH (M), diethylaminoethyl 2-[4-(2-oxocyclopentyl-methyl)phenyl]propionate.AcOH (N), diethylaminoethyl 4-(l,3-dihydro-l-oxo-2H-isoindol-2-yl)-α-methylbenzeneacetate.AcOH (O), diethylaminoethyl α,3-dichloro-4-cyclohexylbenzeneacetate.AcOH (P), were administered transdermally. Group A is the control group.
[42] Figure 12: The prolongation time of the pain threshold of mice tails after 50mg/kg of diethylaminoethyl 4,5-Diphenyl-2-oxazole propionate.AcOH (Q), diethylaminoethyl 3-(4-biphenylylcarbonyl)propionate.AcOH (R), diethylaminoethyl 5-(4-chlorophenyl)-beta-hydroxy-2-furanpropionate.AcOH (S), diethylaminoethyl 5-benzoyl-2,3-dihydro-lH-pyrrolizine-l-carboxylate.AcOH (T), diethylaminoethyl 6-chloro-5-cyclohexyl-2,3-dihydro-lH-indene-l-carboxylate.AcOH (U) were administered transdermally. Group A is the control group.
[43] Figure 13. The rate of swelling (%) after a carrageenin injection. 1 Hour before the carrageenin injection, diethylaminoethyl 2-(6-methoxy-2-naphthyl)propionate.AcOH (100 mg/kg, B), diethylaminoethyl α- methyl-4-(2-thienylcarbonyl)benzeneacetate.AcOH (100 mg/kg, C), diethylaminoethyl α-methyl-(p-chlorobenzoyl)-5-methoxy-2-methylindole 3-acetate.AcOH (100 mg/kg, D), diethylaminoethyl 2-(2-fluoro-4-biphenylyl)propionate.AcOH (100 mg/kg, E), diethylaminoethyl 6-chloro-α-methyl-9H-carbazole-2-acetate.AcOH (100 mg/kg, F) were administered transdermally. A group is the control group.
[44] Figure 14. The rate of swelling (%) after a carrageenin injection. 1 Hour before the carrageenin injection, diethylaminoethyl α-methyl-5H-[l]benzopyrano[2,3-b] pyridine- 7-acetate.AcOH (100 mg/kg, G), diethylaminoethyl
2-(4-chlorophenyl)-α-methyl-5-benzoxazoleacetate.AcOH (100 mg/kg, H), diethylaminoethyl α-methyl-4-[(2-methyl-2-propenyl)amino]benzeneacetate.AcOH (100 mg/ kg, I), diethylaminoethyl 5-benzoyl-α-methyl-2-thiopheneacetate.AcOH (100 mg/kg, J), diethylaminoethyl 3-chloro-4-(2,5-dihydro-lH-pyrrol-l-yl)-α-methyl benze- neacetate.AcOH (100 mg/kg, K) were administered transdermally. Group A is the control group.
[45] Figure 15. The rate of swelling (%) after a carrageenin injection. 1 Hour before the carrageenin injection, diethylaminoethyl 2-(10, ll-dihydro-10-oxodibenzo(b,f)thiepin-2-yl)propionate.AcOH (100 mg/kg, L), diethylaminoethyl 2-(8-methyl-10, ll-dihydro-ll-oxodibenz(b,f)oxepin-2-yl)propionate.AcOH (100 mg/kg, M), diethylaminoethyl 2-[4-(2-oxocyclopentyl-methyl)phenyl]propionate.AcOH (100 mg/kg, N), diethylaminoethyl 4-( 1 ,3-dihydro- 1 -oxo-2H-isoindol-2-yl)-α-methylbenz eneacetate.AcOH (100 mg/kg, O), diethylaminoethyl α,3-dichloro-4-cyclohexylbenzeneacetate.AcOH (100 mg/kg, P) were administered transdermally. Group A is the control group.
[46] Figure 16. The rate of swelling (%) after a carrageenin injection. 1 Hour before the carrageenin injection, diethylaminoethyl 4,5-Diphenyl-2-oxazole propionate.AcOH (100 mg/kg, Q), diethylaminoethyl 3-(4-biphenylylcarbonyl)propionate.AcOH (100 mg/kg, R), diethylaminoethyl
5-(4-chlorophenyl)-beta-hydroxy-2-furanpropionate.AcOH (100 mg/kg, S), diethylaminoethyl 5-benzoyl-2,3-dihydro-lH-pyrrolizine-l-carboxylate.AcOH (100 mg/kg, T), diethylaminoethyl
6-chloro-5-cyclohexyl-2,3-dihydro-lH-indene-l-carboxylate.AcOH (100 mg/kg, U) were administered transdermally. Group A is the control group.
[47] Figure 17. In structure 1, R represents CH , OH, Cl, F, or Br; 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, NH, OCH 2 COO, OCH 2 COS, or OCH 2 CONH; A represents Cl , Br , F
, I", ACO", citrate, or any negative ions; and n=0,l,2,3,4,5,6,7,8,9,10 ; Aryl represents aryl- and heteroaryl groups
[48] Figure 18. In structure 2, W represents H, OH, Cl, F, or Br; 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, NH, OCH 2 COO, OCH 2 COS, or OCH 2 CONH; A represents Cl , Bf, F
, I , AcO , citrate, or any negative ions; and n=0,l,2,3,4,5,6,7,8,9,10 ; Y or Y and Z together represent aryl- and heteroaryl groups.
Best Mode
Preparation of diethylaminoethyl 2-(6-methoxy-2-naphthyl)propionate.AcOH
[49] 11.7 g (0.1 mol) of diethylaminoethanol was dissolved in 10% sodium bicarbonate
(200 ml) and acetone (100 ml). 24.9 g (0.1 mol) of 2-(6-methoxy-2-naphthyl) propionyl chloride was added into the reaction mixture. The mixture is stirred for 3 hours at RT. The solvents are evaporated off. The residue is suspended in ethyl acetate (500ml). 5% sodium bicarbonate (200 ml) is added into the reaction mixture with stirring. Ethyl acetate layer is collected and washed with water (3 x 500 ml). The ethyl acetate solution was dried over anhydrous sodium sulfate. Sodium sulfate is removed by filtration. 6 g of acetic acid is added into the reaction mixture with stirring. The organic solution was evaporated off. After drying, it yielded 36 g of the desired product (89.9 %). Hygroscopic product; Solubility in water: 350 mg/ml; Elementary analysis: C22H3 NO5; MW: 389.49. Calculated % C: 67.84; H: 8.02; N: 3.60; O: 20.54; Found % C: 67.82; H: 8.04; N: 3.58; O: 20.56. 1H-NMR (400 MHz, D2O): δ: 1.36 (t, 6H), 1.50 (d, 3H), 2.11 (s, 3H), 3.20 (m, 4H), 3.47(m, 2H), 3.70 (s, 3H), 3.78 (m, IH), 4.48 (t, 2H), 6.88 (b, IH), 6.98 (s, IH), 7.03 (d, IH), 7.18 (d, IH), 7.43 (s, IH), 7.50 (d, IH), 7.54 (d, IH).
Mode for Invention Preparation of diethylaminoethyl α-methyl-4-(2-thienylcarbonyl) benze- neacetate.AcOH.
[50] 28.1 g (0.1 mol) of α-methyl-4-(2-thienylcarbonyl) benzeneacetyl chloride was dissolved in 100 ml of chloroform. The mixture was cooled to 0°C. 15 ml of tri-
ethylamine and 11.7 g (0.1 mol) of diethylaminoethanol 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 stirred for 3 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. Some solid is removed by filtration. Another 6 g of acetic acid is added into the reaction mixture with stirring. The organic solution was evaporated off. After drying, it yielded 35 g of the desired product (83.2%). Hygroscopic product; Solubility in water: 400 mg/ml; Elementary analysis: C H NO S; MW: 419.53. Calculated % C: 62.68; H: 7.41; N: 3.32; O: 18.98; S: 7.61; Found % C: 62.63; H: 7.45; N: 3.31; O: 19.01; S: 7.60. 1H-NMR (400 MHz, D2O): δ: 1.36 (t, 6H), 1.45 (d, 3H), 2.11 (s, 3H), 3.20 (m, 4H), 3.47(m, 2H), 3.78 (m, IH), 4.48 (t, 2H), 6.88 (b, IH), 6.98 (s, IH), 7.31 (d, 2H), 7.05 (m, IH), 7.43 (m, 2H), 7.70 (d, 2H).
Preparation of S-diethylaminoethyl 2-(2-fluoro-4-biphenylyl)propionate.AcOH
[51] 13.2 g (0.1 mol) of diethylaminoethyl mercaptan was dissolved in 10% sodium bicarbonate (200 ml) and acetone (100 ml). 26.3 g (0.1 mol) of 2-(2-fluoro-4-biphenylyl) propionyl chloride was added into the reaction mixture. The mixture is stirred for 3 hours at RT. The solvents are evaporated off. The residue is suspended in ethyl acetate (500ml). 5% sodium bicarbonate (200 ml) is added into the reaction mixture with stirring. Ethyl acetate layer is collected and washed with water (3 x 500 ml). The ethyl acetate solution was dried over anhydrous sodium sulfate. Sodium sulfate is removed by filtration. 6 g of acetic acid is added into the reaction mixture with stirring. The organic solution was evaporated off. After drying, it yielded 36 g of the desired product (85.8%). Hygroscopic product; Solubility in water: 400 mg/ml; Elementary analysis: C23H30FNO3S; MW: 419.55. Calculated % C: 65.84; H: 7.21; F: 4.53; N: 3.34; O: 11.44; S: 7.64. Found % C: 65.80; H: 7.23; F: 4.55; N: 3.32, O: 11.47; S: 7.63. 1H-NMR (400 MHz, D2O): δ: 1.35 (t, 6H), 1.44 (d, 3H), 2.11 (s, 3H), 3.20 (m, 4H), 3.30(t, 2H), 3.80 (m, IH), 3.88 (t, 2H), 6.88 (b, IH), 6.88 (m, IH), 6.95 (m, IH), 7.22 (m, IH), 7.32 (m, 2H), 7.41 (m, IH), 7.48 (m, 2H).
Preparation of N-diethylaminoethyl 5-benzoyl-2, 3-dihydro-lH-pyrrolizine-l-carboxylamide.AcOH.
[52] 11.6 g (0.1 mol) of diethylaminoethylamine was dissolved in 10% sodium bicarbonate (200 ml) and acetone (100 ml). 27.4 g (0.1 mol) of 5-benzoyl-2, 3-dihydro-lH-pyrrolizine-l-carboxylyl chloride was added into the reaction mixture.
The mixture is stirred for 3 hours at RT. The solvents are evaporated off. The residue is suspended in ethyl acetate (500ml). 5% sodium bicarbonate (200 ml) is added into the reaction mixture with stirring. Ethyl acetate layer is collected and washed with water (3 x 500 ml). The ethyl acetate solution was dried over anhydrous sodium sulfate. Sodium sulfate is removed by filtration. 6 g of acetic acid is added into the reaction mixture with stirring. The organic solution was evaporated off. After drying, it yielded 35 g of the desired product (84.8 %). Hygroscopic product; Solubility in water: 400 mg/ml; Elementary analysis: C H N O ; MW: 412.50. Calculated % C: 66.81; H: 7.56; N:
J J 23 31 3 A ' '
10.16; O: 15.48; Found % C: 66.90; H: 7.38; N: 10.18; O: 15.54. 1H-NMR (400 MHz, D2O): δ: 1.39 (t, 6H), 2.10 (s, 3H), 2.27 (m, 2H), 3.22 (m, 4H), 3.50(t, 2H), 3.60 (t, 2H), 3.80 (m, 2H), 3.71 (m, IH), 5.85 (m, IH), 6.70 (m, IH), 6.85 (b, IH), 7.32 (b, IH), 7.40 (m, IH), 7.45 (m, 2H), 7.78 (m, 2H).
Preparation of N-dimethylaminoethyl 4, 5-Diphenyl-2-oxazole pro- pionamide.AcOH amide.AcOH
[53] 29.3 g (0.1 mol) of 4, 5-Diphenyl-2-oxazole propionic acid was dissolved in 100 ml of acetonitrile. 32.1 g of O-(Benzotriazol-l-yl)-N,N,N',N'-tetramethyluronium tetraflu- oroborate and 30 ml of triethylamine were added into the reaction mixture. 11.6 g of diethylaminoethylamine 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 40 g of the desired product (88.6%). Hygroscopic product; Solubility in water: 400 mg/ml; Elementary analysis: C H N O ; MW: 451.56. Calculated % C: 69.16; H: 7.37; N: 9.31; O: 14.17; Found % C: 69.11; H: 7.40; N: 9.30; O: 14.19. 1H-NMR (400 MHz, D2O): δ: 1.41 (t, 6H), 2.10 (s, 3H), 2.45 (t, 2H), 2.76 (t, 2H), 3.22 (m, 4H), 3.49(t, 2H), 3.60 (t, 2H), 6.87 (b, IH), 7.22 (b, IH), 7.22 (m, 2H), 7.32 (m, 4H), 7.47 (m, 4H).
Preparation of diethylaminoethyl 6-chloro-α-methyl-9H-carbazole-2-acetate.AcOH.
[54] 60 g of Polymer-bound triethylamine (3 mol/g, 100-200 mesh) was suspended in
180 ml of chloroform. 27.4 g (0.1 mol) of 6-chloro-α-methyl-9H-carbazole-2-acetic 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 38 g of the desired product (87.8%). Hygroscopic product; Solubility in water: 400 mg/ml; Elementary analy Jsis: C 23 H 29 ClN 2 O 4 ;' MW: 432.94. Calculated % C: 63.81; ' H: 6.75; ' Cl: 8.19,' N:
6.47; O: 14.78; Found % C: 63.85; H: 6.78; Cl: 8.17; N: 6.44; O: 14.76. 1H-NMR (400 MHz, D2O): δ: 1.39 (t, 6H), 1.47 (d, 3H), 2.11 (s, 3H), 3.21 (m, 4H), 3.49(m, 2H), 3.77 (m, IH), 4.48 (t, 2H), 6.80 (b, IH), 6.85 (m, IH), 7.10 (m, IH), 7.05 (m, IH), 7.26 (m, IH), 7.34 (m, IH), 7.50 (m, IH), 7.52 (m, IH).
Industrial Applicability
[55] The pro-drugs of the general formula (1) 'Structure 1' and general formula (2)
'Structure 2' are superior to 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, or clidanac, and related compounds. They may be used medicinally in treating any 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-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.
Sequence List Text
[56]
Claims
[1] The compounds of the general formula (1) 'Structure 1'
Structure 1 in structure 1, R represents CH , OH, Cl, F, or Br; 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, NH, OCH 2 COO, OCH 2 COS, or OCH 2 CONH; 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 ; Aryl represents:
In which, X represents CH3O, Cl, F, CH3S,
CHF2O
In which, Y represents CH3O, F, CH3CO, In which, X represents F, Cl, H (CH3)2N, CH3, or CH2=CH-CH2. X represents Cl. F, CF3, CH3SO,or CH3S; R represents CH3, C2H5, C3H7
In which, X represents Cl, Br, F, CH3
In which, X represents Cl, Br, F, CH3
In which, X represents Cl, F, Br
In which, X represents CO or O In which, X represents Cl, Br, F, or CFL5O
In which, X represents O or S, Y represents CH2 and CO, and Z represents, CO and CH2, R represents H, CH3, C2H5
All R, R , R , 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.
[2] The compounds of the general formula (2) 'Structure 2',
Structure 2 in structure 2, W represents H, OH, Cl, F, or Br; 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, NH, OCH 2 COO, OCH 2 COS, or OCH 2 CONH; 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 ; Y represents H and Z represents:
In which, X represents Cl, F, or Br
or Wrepresents H, Z and Y togetherrepresent:
In which, X represents Cl, F, or Br
All R, R , R , 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.
[3] Processes for the preparation of compounds of the general formula (1) 'Structure I' and general formula (2) 'Structure 2' according to Claim 1 and Claim 2, wherein 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 are reacted with compounds of the general formula (5) 'Structure 5',
Structure 5
In structure 5, 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
[4] Processes for the preparation of compounds of the general formula (1) 'Structure
I' and general formula (2) 'Structure 2' according to Claim 1 and Claim 2, wherein 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, or clidanac, and related compounds are reacted with compounds of the general formula (5) 'Structure 5' 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.
[5] Processes for the preparation of compounds of the general formula (1) 'Structure
I' and general formula (2) 'Structure 2' according to Claim 1 and Claim 2, wherein metal salts, organic base salts, or immobilized base salts 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, or clidanac, and related compounds are reacted with compounds of the general formula (6) 'Structure 6',
Structure 6
In structure 6, 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
[6] Compounds of the general formula (2 ) 'Structure 1' and general formula (2)
'Structure 2' or a composition comprising of at least one compound of the general formula (1) 'Structure 1' and general formula (2) 'Structure 2', as an active ingredient, according to Claim 1 and Claim 2, 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.
[7] 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 1' and general formula (2) 'Structure 2' or a composition comprising at least one compound of the general formula (1) 'Structure 1' or general formula (2) 'Structure 2', as an active ingredient, according to Claim 1 and Claim 2.
[8] 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 to the inflamed area a therapeutically effective amount of the compounds of the general formula (1) 'Structure 1' and general formula (2) 'Structure 2' or a composition comprising at least one compound of the general formula (1) 'Structure 1' and general formula (2) 'Structure 2', as an active ingredient, according to Claim 1 and Claim 2.
[9] Compounds of the general formula (1) 'Structure 1' and general formula (2)
'Structure 2' or a composition comprising at least one compound of the general formula (1) 'Structure 1' and general formula (2) 'Structure 2', as an active ingredient, according to Claim 1 and Claim 2, 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.
[10] Compounds of the general formula (1) 'Structure 1' or general formula (2)
'Structure 2' or a composition comprising at least one compound of the general
formula (1) 'Structure 1' and general formula (2) 'Structure 2', as an active ingredient, according to Claim 1 and Claim 2, are administered by spraying to through the mouth or nose or other parts of body for treating asthma.
[11] Compounds of the general formula (1) 'Structure 1' and general formula (2)
'Structure 2' or a composition comprising at least one compound of the general formula (1) 'Structure 1' and general formula (2) 'Structure 2', as an active ingredient, according to Claim 1 and Claim 2, 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.
[12] Transdermal therapeutic application systems of Compounds of the general formula (1) 'Structure 1' and general formula (2) 'Structure 2' or a composition comprising at least one compound of the general formula (1) 'Structure 1' and general formula (2) 'Structure 2', as an active ingredient, according to Claim land Claim 2, 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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| Application Number | Priority Date | Filing Date | Title |
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| CN2006800556054A CN101506161B (en) | 2006-08-15 | 2006-08-15 | Positively charged water-soluble prodrugs of aryl and heteroaryl propionic acids with fast skin penetration rate |
| PCT/IB2006/052815 WO2008020270A1 (en) | 2006-08-15 | 2006-08-15 | Positively charged water-soluble prodrugs of aryl- and heteroarylpropionic acids with very fast skin penetration rate |
| JP2009524242A JP5424880B2 (en) | 2006-08-15 | 2006-08-15 | Positively charged water-soluble prodrugs of aryl- and heteroarylpropionic acids with very fast skin permeability |
| CA2660814A CA2660814C (en) | 2006-08-15 | 2006-08-15 | Positively charged water-soluble prodrugs of aryl- and heteroarylpropionic acids with very fast skin penetration rate |
| AU2006347391A AU2006347391B2 (en) | 2006-08-15 | 2006-08-15 | Positively charged water-soluble prodrugs of aryl- and heteroarylpropionic acids with very fast skin penetration rate |
| EP06795662A EP2054384A4 (en) | 2006-08-15 | 2006-08-15 | Positively charged water-soluble prodrugs of aryl- and heteroarylpropionic 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 |
| HK10100928.5A HK1137425A1 (en) | 2006-08-15 | 2010-01-28 | Positively charged water-soluble prodrugs of aryl- and heteroarylpropionic 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 |
| US17/493,321 US20220096370A1 (en) | 2006-07-09 | 2021-10-04 | High penetration composition and uses thereof |
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| PCT/IB2006/052815 WO2008020270A1 (en) | 2006-08-15 | 2006-08-15 | Positively charged water-soluble prodrugs of aryl- and heteroarylpropionic acids with very fast skin penetration rate |
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| PCT/IB2006/052732 Continuation-In-Part WO2008017903A1 (en) | 2006-07-09 | 2006-08-08 | Positively charged water-soluble prodrugs of aryl- and heteroarylacetic acids with very fast skin penetration rate |
| PCT/IB2006/053090 Continuation-In-Part WO2008029199A1 (en) | 2006-07-09 | 2006-09-03 | Positively charged water-soluble prodrugs of n-arylanthranilic acids with very fast skin penetration rate |
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| PCT/IB2006/052732 Continuation-In-Part WO2008017903A1 (en) | 2006-07-09 | 2006-08-08 | Positively charged water-soluble prodrugs of aryl- and heteroarylacetic acids with very fast skin penetration rate |
| PCT/IB2006/053090 Continuation-In-Part WO2008029199A1 (en) | 2006-07-09 | 2006-09-03 | Positively charged water-soluble prodrugs of n-arylanthranilic acids with very fast skin penetration rate |
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| JP (1) | JP5424880B2 (en) |
| CN (1) | CN101506161B (en) |
| AU (1) | AU2006347391B2 (en) |
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| CN115850289B (en) * | 2021-09-24 | 2023-10-24 | 石家庄迪斯凯威医药科技有限公司 | Novel pranoprofen derivative, and pharmaceutical composition and application thereof |
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- 2006-08-15 CN CN2006800556054A patent/CN101506161B/en active Active
- 2006-08-15 EP EP06795662A patent/EP2054384A4/en active Pending
- 2006-08-15 WO PCT/IB2006/052815 patent/WO2008020270A1/en active Application Filing
- 2006-08-15 JP JP2009524242A patent/JP5424880B2/en not_active Expired - Fee Related
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Also Published As
| Publication number | Publication date |
|---|---|
| AU2006347391B2 (en) | 2013-03-07 |
| CN101506161B (en) | 2013-11-13 |
| JP2010500989A (en) | 2010-01-14 |
| EP2054384A1 (en) | 2009-05-06 |
| AU2006347391A1 (en) | 2008-02-21 |
| CA2660814C (en) | 2017-07-18 |
| JP5424880B2 (en) | 2014-02-26 |
| CA2660814A1 (en) | 2008-02-21 |
| HK1137425A1 (en) | 2010-07-30 |
| CN101506161A (en) | 2009-08-12 |
| EP2054384A4 (en) | 2010-11-03 |
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