WO2007132280A1 - Isatin and its derivatives for use as a medicament - Google Patents
Isatin and its derivatives for use as a medicament Download PDFInfo
- Publication number
- WO2007132280A1 WO2007132280A1 PCT/HU2007/000042 HU2007000042W WO2007132280A1 WO 2007132280 A1 WO2007132280 A1 WO 2007132280A1 HU 2007000042 W HU2007000042 W HU 2007000042W WO 2007132280 A1 WO2007132280 A1 WO 2007132280A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- group
- general formula
- fever
- linear
- branched alkyl
- Prior art date
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- JXDYKVIHCLTXOP-UHFFFAOYSA-N isatin Chemical compound C1=CC=C2C(=O)C(=O)NC2=C1 JXDYKVIHCLTXOP-UHFFFAOYSA-N 0.000 title claims abstract description 39
- 239000003814 drug Substances 0.000 title claims abstract description 11
- 206010037660 Pyrexia Diseases 0.000 claims abstract description 34
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 18
- 239000001257 hydrogen Substances 0.000 claims abstract description 18
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 17
- 239000004480 active ingredient Substances 0.000 claims abstract description 16
- 150000002431 hydrogen Chemical group 0.000 claims abstract description 15
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 13
- 150000002367 halogens Chemical class 0.000 claims abstract description 13
- 230000002265 prevention Effects 0.000 claims abstract description 12
- 238000000034 method Methods 0.000 claims abstract description 11
- 206010061218 Inflammation Diseases 0.000 claims abstract description 9
- 208000002193 Pain Diseases 0.000 claims abstract description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 9
- 230000004054 inflammatory process Effects 0.000 claims abstract description 9
- 125000002252 acyl group Chemical group 0.000 claims abstract description 7
- 125000003277 amino group Chemical group 0.000 claims abstract description 7
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims abstract description 7
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 7
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims abstract 2
- 150000001875 compounds Chemical class 0.000 claims description 17
- 238000004519 manufacturing process Methods 0.000 claims description 8
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 7
- 125000003545 alkoxy group Chemical group 0.000 claims description 5
- VAJCSPZKMVQIAP-UHFFFAOYSA-N 5-methyl-1h-indole-2,3-dione Chemical compound CC1=CC=C2NC(=O)C(=O)C2=C1 VAJCSPZKMVQIAP-UHFFFAOYSA-N 0.000 claims description 4
- OPHRQXIPRXFPJF-UHFFFAOYSA-N 6-hydroxy-1h-indole-2,3-dione Chemical compound OC1=CC=C2C(=O)C(=O)NC2=C1 OPHRQXIPRXFPJF-UHFFFAOYSA-N 0.000 claims description 4
- YMZGAPGIOFRUFU-UHFFFAOYSA-N 7-ethyl-1h-indole-2,3-dione Chemical compound CCC1=CC=CC2=C1NC(=O)C2=O YMZGAPGIOFRUFU-UHFFFAOYSA-N 0.000 claims description 4
- LPGDEHBASRKTDG-UHFFFAOYSA-N N-acetylisatin Chemical compound C1=CC=C2N(C(=O)C)C(=O)C(=O)C2=C1 LPGDEHBASRKTDG-UHFFFAOYSA-N 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 125000006527 (C1-C5) alkyl group Chemical group 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000000027 (C1-C10) alkoxy group Chemical group 0.000 abstract 1
- 238000002360 preparation method Methods 0.000 description 12
- 241000699670 Mus sp. Species 0.000 description 8
- 241000700159 Rattus Species 0.000 description 7
- -1 4-trifluoroisatin Chemical compound 0.000 description 6
- 230000001754 anti-pyretic effect Effects 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 239000003826 tablet Substances 0.000 description 6
- 239000002221 antipyretic Substances 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 241001465754 Metazoa Species 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000000730 antalgic agent Substances 0.000 description 3
- 230000003110 anti-inflammatory effect Effects 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 239000008187 granular material Substances 0.000 description 3
- 230000007246 mechanism Effects 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- MOJHIZLOKWRPIS-UHFFFAOYSA-N 6-methoxy-1h-indole-2,3-dione Chemical compound COC1=CC=C2C(=O)C(=O)NC2=C1 MOJHIZLOKWRPIS-UHFFFAOYSA-N 0.000 description 2
- 206010020843 Hyperthermia Diseases 0.000 description 2
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 2
- 239000002260 anti-inflammatory agent Substances 0.000 description 2
- 229940125716 antipyretic agent Drugs 0.000 description 2
- 239000000022 bacteriostatic agent Substances 0.000 description 2
- 230000036760 body temperature Effects 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 2
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 2
- 230000036031 hyperthermia Effects 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 230000010534 mechanism of action Effects 0.000 description 2
- 238000000465 moulding Methods 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 229940069328 povidone Drugs 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- HDCOHEZURASAMI-UHFFFAOYSA-N 1,4,5,6-tetramethoxyindole-2,3-dione Chemical compound C1=C(OC)C(OC)=C(OC)C2=C1N(OC)C(=O)C2=O HDCOHEZURASAMI-UHFFFAOYSA-N 0.000 description 1
- UCTOTMPSKDARJA-UHFFFAOYSA-N 1-(2-hydroxyethyl)indole-2,3-dione Chemical compound C1=CC=C2N(CCO)C(=O)C(=O)C2=C1 UCTOTMPSKDARJA-UHFFFAOYSA-N 0.000 description 1
- POEDHWVTLBLWDA-UHFFFAOYSA-N 1-butylindole-2,3-dione Chemical compound C1=CC=C2N(CCCC)C(=O)C(=O)C2=C1 POEDHWVTLBLWDA-UHFFFAOYSA-N 0.000 description 1
- ORYSFKVWQQMDAX-UHFFFAOYSA-N 1-ethylindole-2,3-dione Chemical compound C1=CC=C2N(CC)C(=O)C(=O)C2=C1 ORYSFKVWQQMDAX-UHFFFAOYSA-N 0.000 description 1
- MPJSZKJLVPUZQF-UHFFFAOYSA-N 1-hexylindole-2,3-dione Chemical compound C1=CC=C2N(CCCCCC)C(=O)C(=O)C2=C1 MPJSZKJLVPUZQF-UHFFFAOYSA-N 0.000 description 1
- VCYBVWFTGAZHGH-UHFFFAOYSA-N 1-methylindole-2,3-dione Chemical compound C1=CC=C2N(C)C(=O)C(=O)C2=C1 VCYBVWFTGAZHGH-UHFFFAOYSA-N 0.000 description 1
- UGVPQGQPUANQSX-UHFFFAOYSA-N 1-pentylindole-2,3-dione Chemical compound C1=CC=C2N(CCCCC)C(=O)C(=O)C2=C1 UGVPQGQPUANQSX-UHFFFAOYSA-N 0.000 description 1
- KYAMYNWIAQNFEG-UHFFFAOYSA-N 2-(2,3-dioxoindol-1-yl)acetic acid Chemical compound C1=CC=C2N(CC(=O)O)C(=O)C(=O)C2=C1 KYAMYNWIAQNFEG-UHFFFAOYSA-N 0.000 description 1
- WWSWHYAXEFLETD-UHFFFAOYSA-N 4,5-dichloro-1h-indole-2,3-dione Chemical compound ClC1=CC=C2NC(=O)C(=O)C2=C1Cl WWSWHYAXEFLETD-UHFFFAOYSA-N 0.000 description 1
- UZQSNRWCIFIUSJ-UHFFFAOYSA-N 4,5-dimethyl-1h-indole-2,3-dione Chemical compound CC1=CC=C2NC(=O)C(=O)C2=C1C UZQSNRWCIFIUSJ-UHFFFAOYSA-N 0.000 description 1
- CGCVHJCZBIYRQC-UHFFFAOYSA-N 4,6-dichloro-1h-indole-2,3-dione Chemical compound ClC1=CC(Cl)=CC2=C1C(=O)C(=O)N2 CGCVHJCZBIYRQC-UHFFFAOYSA-N 0.000 description 1
- SHOAYKZGNWFWSU-UHFFFAOYSA-N 4,6-dimethyl-1h-indole-2,3-dione Chemical compound CC1=CC(C)=CC2=C1C(=O)C(=O)N2 SHOAYKZGNWFWSU-UHFFFAOYSA-N 0.000 description 1
- NUXYYWOWNFEMNH-UHFFFAOYSA-N 4,7-dichloro-1h-indole-2,3-dione Chemical compound ClC1=CC=C(Cl)C2=C1NC(=O)C2=O NUXYYWOWNFEMNH-UHFFFAOYSA-N 0.000 description 1
- UODYFWCLDYDKTE-UHFFFAOYSA-N 4,7-dimethoxy-1h-indole-2,3-dione Chemical compound COC1=CC=C(OC)C2=C1NC(=O)C2=O UODYFWCLDYDKTE-UHFFFAOYSA-N 0.000 description 1
- VYRDPBOVRAVNKT-UHFFFAOYSA-N 4,7-dimethyl-1h-indole-2,3-dione Chemical compound CC1=CC=C(C)C2=C1NC(=O)C2=O VYRDPBOVRAVNKT-UHFFFAOYSA-N 0.000 description 1
- ITRAKBJPMLKWIW-UHFFFAOYSA-N 4-Bromoisatin Chemical compound BrC1=CC=CC2=C1C(=O)C(=O)N2 ITRAKBJPMLKWIW-UHFFFAOYSA-N 0.000 description 1
- UAMMYAPYQZBSSZ-UHFFFAOYSA-N 4-chloro-5-methoxy-1h-indole-2,3-dione Chemical compound COC1=CC=C2NC(=O)C(=O)C2=C1Cl UAMMYAPYQZBSSZ-UHFFFAOYSA-N 0.000 description 1
- PSRLWIVLOPJPOL-UHFFFAOYSA-N 4-chloro-5-methyl-1h-indole-2,3-dione Chemical compound CC1=CC=C2NC(=O)C(=O)C2=C1Cl PSRLWIVLOPJPOL-UHFFFAOYSA-N 0.000 description 1
- MWCJCUFHPFXQLS-UHFFFAOYSA-N 4-chloro-7-methyl-1h-indole-2,3-dione Chemical compound CC1=CC=C(Cl)C2=C1NC(=O)C2=O MWCJCUFHPFXQLS-UHFFFAOYSA-N 0.000 description 1
- CKFAWBMSCAGKKE-UHFFFAOYSA-N 4-ethyl-1h-indole-2,3-dione Chemical compound CCC1=CC=CC2=C1C(=O)C(=O)N2 CKFAWBMSCAGKKE-UHFFFAOYSA-N 0.000 description 1
- GMOIUCVMHIKMDC-UHFFFAOYSA-N 4-fluoro-7-methyl-1h-indole-2,3-dione Chemical compound CC1=CC=C(F)C2=C1NC(=O)C2=O GMOIUCVMHIKMDC-UHFFFAOYSA-N 0.000 description 1
- NYWOXCHAPWQNFC-UHFFFAOYSA-N 4-iodo-1h-indole-2,3-dione Chemical compound IC1=CC=CC2=C1C(=O)C(=O)N2 NYWOXCHAPWQNFC-UHFFFAOYSA-N 0.000 description 1
- KDICASSDSSYKMK-UHFFFAOYSA-N 4-methyl-1h-indole-2,3-dione Chemical compound CC1=CC=CC2=C1C(=O)C(=O)N2 KDICASSDSSYKMK-UHFFFAOYSA-N 0.000 description 1
- KIFKRDLEAQUAAW-UHFFFAOYSA-N 5,6-dichloro-1h-indole-2,3-dione Chemical compound C1=C(Cl)C(Cl)=CC2=C1C(=O)C(=O)N2 KIFKRDLEAQUAAW-UHFFFAOYSA-N 0.000 description 1
- HBNMEXSXIIAELS-UHFFFAOYSA-N 5,6-dimethoxy-1h-indole-2,3-dione Chemical compound C1=C(OC)C(OC)=CC2=NC(=O)C(O)=C21 HBNMEXSXIIAELS-UHFFFAOYSA-N 0.000 description 1
- BRWIXNVFRUVHEU-UHFFFAOYSA-N 5,6-dimethyl-1h-indole-2,3-dione Chemical compound C1=C(C)C(C)=CC2=C1C(=O)C(=O)N2 BRWIXNVFRUVHEU-UHFFFAOYSA-N 0.000 description 1
- BYJCGSYNQXKHKK-UHFFFAOYSA-N 5-(2-methylpropyl)-1h-indole-2,3-dione Chemical compound CC(C)CC1=CC=C2NC(=O)C(=O)C2=C1 BYJCGSYNQXKHKK-UHFFFAOYSA-N 0.000 description 1
- VZZPLEUQAGKOMD-UHFFFAOYSA-N 5-(3-methylbutyl)-1h-indole-2,3-dione Chemical compound CC(C)CCC1=CC=C2NC(=O)C(=O)C2=C1 VZZPLEUQAGKOMD-UHFFFAOYSA-N 0.000 description 1
- GKODDAXOSGGARJ-UHFFFAOYSA-N 5-Fluoroisatin Chemical compound FC1=CC=C2NC(=O)C(=O)C2=C1 GKODDAXOSGGARJ-UHFFFAOYSA-N 0.000 description 1
- DMHGXMPXHPOXBF-UHFFFAOYSA-N 5-Methoxyisatin Chemical compound COC1=CC=C2NC(=O)C(=O)C2=C1 DMHGXMPXHPOXBF-UHFFFAOYSA-N 0.000 description 1
- UNMYHYODJHKLOC-UHFFFAOYSA-N 5-Nitroisatin Chemical compound [O-][N+](=O)C1=CC=C2NC(=O)C(=O)C2=C1 UNMYHYODJHKLOC-UHFFFAOYSA-N 0.000 description 1
- NJTNUMGNMGRBNP-UHFFFAOYSA-N 5-aminoisatin Chemical compound NC1=CC=C2NC(=O)C(=O)C2=C1 NJTNUMGNMGRBNP-UHFFFAOYSA-N 0.000 description 1
- NPRAKNSGKOICIE-UHFFFAOYSA-N 5-bromo-7-methyl-1h-indole-2,3-dione Chemical compound CC1=CC(Br)=CC2=C1NC(=O)C2=O NPRAKNSGKOICIE-UHFFFAOYSA-N 0.000 description 1
- RBSPRPMOTLWFGV-UHFFFAOYSA-N 5-butan-2-yl-1h-indole-2,3-dione Chemical compound CCC(C)C1=CC=C2NC(=O)C(=O)C2=C1 RBSPRPMOTLWFGV-UHFFFAOYSA-N 0.000 description 1
- WIEJKTTWCGNQHH-UHFFFAOYSA-N 5-butyl-1h-indole-2,3-dione Chemical compound CCCCC1=CC=C2NC(=O)C(=O)C2=C1 WIEJKTTWCGNQHH-UHFFFAOYSA-N 0.000 description 1
- LDFQLYHDZZPAGN-UHFFFAOYSA-N 5-chloro-7-methyl-1h-indole-2,3-dione Chemical compound CC1=CC(Cl)=CC2=C1NC(=O)C2=O LDFQLYHDZZPAGN-UHFFFAOYSA-N 0.000 description 1
- VPBTXKVUDRKXBP-UHFFFAOYSA-N 5-ethoxy-1h-indole-2,3-dione Chemical compound CCOC1=CC=C2NC(=O)C(=O)C2=C1 VPBTXKVUDRKXBP-UHFFFAOYSA-N 0.000 description 1
- XDGNFZUIJHZHHP-UHFFFAOYSA-N 5-ethyl-1h-indole-2,3-dione Chemical compound CCC1=CC=C2NC(=O)C(=O)C2=C1 XDGNFZUIJHZHHP-UHFFFAOYSA-N 0.000 description 1
- COIBMWDLIUTNOE-UHFFFAOYSA-N 5-hexyl-1h-indole-2,3-dione Chemical compound CCCCCCC1=CC=C2NC(=O)C(=O)C2=C1 COIBMWDLIUTNOE-UHFFFAOYSA-N 0.000 description 1
- SZEUAVRUUFUMIU-UHFFFAOYSA-N 5-hydroxy-1h-indole-2,3-dione Chemical compound OC1=CC=C2NC(=O)C(=O)C2=C1 SZEUAVRUUFUMIU-UHFFFAOYSA-N 0.000 description 1
- JERLBLNXDQMBCQ-UHFFFAOYSA-N 5-pentyl-1h-indole-2,3-dione Chemical compound CCCCCC1=CC=C2NC(=O)C(=O)C2=C1 JERLBLNXDQMBCQ-UHFFFAOYSA-N 0.000 description 1
- FBYONXZHXASRNB-UHFFFAOYSA-N 5-propyl-1h-indole-2,3-dione Chemical compound CCCC1=CC=C2NC(=O)C(=O)C2=C1 FBYONXZHXASRNB-UHFFFAOYSA-N 0.000 description 1
- XTXIILHWOQZVAQ-UHFFFAOYSA-N 6,7-dichloro-1h-indole-2,3-dione Chemical compound ClC1=CC=C2C(=O)C(=O)NC2=C1Cl XTXIILHWOQZVAQ-UHFFFAOYSA-N 0.000 description 1
- GVRLEGBOODEAOX-UHFFFAOYSA-N 6,7-dimethyl-1h-indole-2,3-dione Chemical compound CC1=CC=C2C(=O)C(=O)NC2=C1C GVRLEGBOODEAOX-UHFFFAOYSA-N 0.000 description 1
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- PDNPCCKRVLBASB-UHFFFAOYSA-N 6-chloro-5-methyl-1h-indole-2,3-dione Chemical compound C1=C(Cl)C(C)=CC2=C1NC(=O)C2=O PDNPCCKRVLBASB-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- 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
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/32—Oxygen atoms
- C07D209/38—Oxygen atoms in positions 2 and 3, e.g. isatin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
Definitions
- the present invention relates to the use of isatin and the derivatives of isatin for the treatment or prevention of fever, inflammation or pain, and in particular to their use for the treatment or prevention of fever in post-PG E2 (prostaglandin E2) phase, and the use of said compounds for the production of pharmaceutical preparations for such indications.
- Fever is one of the defensive reactions of the body which is induced by infections or injuries, hence, to some extent, it is considered as a normal self-protection mechanism.
- Triggering stimuli of fever include, for example, bacterial or viral infections, malignant tumors, allergic reactions, hormonal disturbances, autoimmune diseases, and the overdose of certain drugs (e.g. analgesics, antipsychotics).
- the elevated body temperature significantly slows down the proliferation of certain bacteria and viruses and thereby may decrease their health damaging effects.
- the production of immune mediators which provide protection of the body, is also increased.
- antipyretic treatment is justifiable particularly in elderly and chronic patients, and in children.
- Regularly administered antipyretics include e.g. aspirin, aminophenazone and paracetamol.
- Indole derivatives substituted with aromatic monocyclic or bicyclic heterocycles inhibit lipoxygenase and thus possess antiallergenic and antiinflammatory activities [EP0544821].
- patent application No. US20030040518A1 the neurotrophic effects of isatin derivatives substituted with benzyl group, 5- or 6-membered monocyclic heterocycles etc. are described.
- the present invention relates to isatin derivatives of the general formula (I) for use as a medicament, and particularly for use in the prevention or treatment of fever, inflammation or pain, wherein in the general formula (I)
- Ri is hydrogen, or (Cj-Cio) linear or branched alkyl or hydroxyalkyl group or acyl group containing (Ci-Cio) linear or branched alkyl group,
- ⁇ R 2 -R 5 are independently hydrogen, halogen, amino group, nitro group, optionally halogen substituted (Ci -C 10 ) alkyl group, (Ci-C 10 ) alkoxy group or hydroxyl group.
- Ri is hydrogen or (C 1 -C 5 ) linear or branched alkyl or hydroxyalkyl group or acyl group containing a (Ci -C 5 ) linear or branched alkyl group
- R 2 -R 5 are independently hydrogen, halogen, amino group, nitro group, (C 1 -C 5 ) alkyl group or hydroxyl group.
- Rj is hydrogen or acetyl group
- R 2 -R 5 are independently hydrogen, methyl group or ethyl group or hydroxyl group.
- Suitable active ingredients are the following compounds, e.g.: (3-methyl)-N- butylisatin, 1 -butylisatin, 1-carboxymethylisatin ethyl ester, 1 -carboxymethylisatin, 4,5- dichloroisatin, 4,5-dimethylisatin, 4,6-dichloroisatin, 4,6-dimethylisatin, 4,7-dichloroisatin, 4,7-dimethylisatin, 4,7-dimethoxyisatin, 4-bromoisatin, 4-ethylisatin, 4-fluoro-7- methylisatin, 4-iodoisatin, 4-chloro-5-methylisatin, 4-chloro-5-methoxyisatin, 4-chloro-7- methylisatin,
- the desired effect according to the invention can be achieved particularly by the following compounds: isatin, 5 -methylisatin, 6-hydroxyisatin, 7-ethylisatin or N- acetylisatin.
- the present invention relates to the use of compounds of the general formula (I) for the manufacture of a medicament for the treatment or prevention of fever, inflammation or pain, particularly for the treatment or prevention of fever.
- the present invention also relates to methods for the prevention or treatment of fever, inflammation or pain, wherein a pharmaceutical preparation incorporating a pharmacologically effective dose of the above described active ingredient is administered to patients in need of such treatment. Description of test methods
- Treatment with PG E2 was carried out though a cannula inserted into the lateral cerebral ventricles of the conscious animals. In the case of mice, a dose of 1 ⁇ g, whereas in the case of rats a dose of 2 ⁇ g was administered in 2 ⁇ l volume. Treatment with isatin and its derivatives was carried out intraperitoneally in various doses. Measurement of the core temperature of the animals was performed using a digital thermometer (Cole-Parmer 8402- 10) inserted 5 cm deep and 2.5 cm deep into the colon of rats and mice, respectively. Isatin and PG E2 was supplied by Sigma Chemical Co. (St.
- Example 1 In the case of isatin, the inhibition of the onset of fever was achieved by a dose of 12.5 mg/kg, whereas the reduction of the developed fever was achieved by a dose of 25.0 mg/kg in rats. In mice the same values were 3.12 mg/kg and 12.5 mg/kg, respectively.
- Example 2 In the case of isatin, the inhibition of the onset of fever was achieved by a dose of 12.5 mg/kg, whereas the reduction of the developed fever was achieved by a dose of 25.0 mg/kg in rats. In mice the same values were 3.12 mg/kg and 12.5 mg/kg, respectively.
- 6-Hydroxyisatin in a dose of 10.40 mg/kg inhibited the onset of fever and reduced the already developed febrile state.
- N-Acetylisatin inhibited the PG E2 induced hyperhermia in a dose of 0.096 mg/kg, and reduced the developed fever in a dose of 0.384 mg/kg in rats.
- the dose that was effective against the development of fever was 0.00504 mg/kg, whereas for the alleviation of the developed fever, a dose of 1.24 mg/kg was effective.
- Isatin and its derivatives exert their activity post-PG E2 and thus they provide antipyretic, antiinflammatory or analgesic agents with a novel mechanism of action.
- the amount of the active ingredient of the formula (I) required to achieve the desired therapeutical effect is dependent of a number of factors, such as, for example, the nature of the compound used, the method of administration and the condition of the patient.
- the compound of formula (I) or its physiologically functional derivative (hereinafter as the active ingredient) is combined with, among others, one or more pharmaceutically acceptable carrier substances or other excipients and optionally with other active ingredients.
- the pharmaceutical preparations can be preparations suitable for administration via, for example, oral, rectal, nasal, topical (such as transdermal, buccal and sublingual), parenteral (such as subcutaneous, intramuscular, intravenous or intradermal) route.
- the preparations are suitably prepared in unit dose form, by methods conventionally used in the manufacture of pharmaceuticals.
- the active ingredient is blended with a carrier substance containing one or more additional components.
- the active ingredient is usually blended thoroughly and uniformly with a liquid carrier or finely dispersed solid carrier substance or the mixture thereof, then optionally the blend is shaped.
- the pharmaceutical preparations suitable for oral administration produced by methods according to the invention can be presented in the form of physically separate units containing a predefined amount of the active ingredient, such as, for example, capsules, cachets or tablets; powders or granules; solutions or suspensions made with aqueous or non-aqueous liquids; or oil-in- water or water-in-oil type liquid emulsions.
- the active ingredient can also be presented in the form of bolus or ointment.
- Tablets can be prepared optionally using one or more excipients, by compression or moulding.
- Compressed tablets can be prepared by blending the active ingredient in free- flowing form such as powder or granules optionally with a binding agent (such as, e.g., povidone, gelatin, hydroxypropylmethyl cellulose), glidant, inert diluent, preservative, desintegrating agent (such as, for example, sodium starch glycolate, crosslinked povidone, crosslinked sodium carboxymethyl cellulose), surfactant or dispersing agent and compressing into tablets using an appropriate equipment.
- Moulded tablets can be prepared by moulding the powdered active ingredient moistened with an inert, liquid diluent in a form using an appropriate equipment. Tablets can be optionally provided with a coating or pattern, and additionally can be formulated as a slow or controlled release form; for example, the desired release profile can be achieved by adding hydroxypropylmethyl cellulose to the formulation in varying proportions.
- the above preparations suitable for oral administration may contain buffers for the purpose of neutralizing gastric acid.
- Said buffers can be different organic or inorganic compounds, such as, for example, the mixtures of weak acids or bases and their conjugated salts.
- preparations suitable for oral topical administration can be, for example, lozenges incorporating the active ingredient in a flavoured base, commonly in saccharose and gum arabic or tragacantha.
- compositions suitable for rectal administration can be, for example, suppositories prepared using an appropriate base containing cocoa butter or a salicylate.
- the form of the preparations suitable for parenteral administration can preferably be, for example, an aqueous (or possibly non-aqueous), isotonic, sterile solution for injection or a solution for drinking optionally containing, for example, antioxidants, buffers, bacteriostatic agents, and substances for making the preparation isotonic with the blood of the recipient.
- aqueous or possibly non-aqueous
- isotonic sterile solution for injection or a solution for drinking
- a solution for drinking optionally containing, for example, antioxidants, buffers, bacteriostatic agents, and substances for making the preparation isotonic with the blood of the recipient.
- 5 preparations can be presented in the form of sealed containers such as, for example, ampoules or vials containing unit doses or multiple doses, and can be stored in freeze-dried
- the pharmaceutical preparation according to the invention can of course contain other ingredients
- compositions for oral administration can contain sweeteners, thickeners and aromatizers as well.
- the active ingredient can be prepared by any of the known methods.
- known 20 method methods which have been published before the date of priority are meant.
Abstract
The present invention relates to 2,3-dioxoindole derivatives of the general formula (I) for use as a medicament, and particularly for use in the prevention or treatment of fever, inflammation or pain, wherein in the general formula (I); R1 is hydrogen, or (C1-C10) linear or branched alkyl or hydroxyalkyl group or acyl group containing (C1-C10) linear or branched alkyl group, R2-R5 are independently hydrogen, halogen, amino group, nitro group, optionally halogen substituted (C1-C10) alkyl group, (C1-C10) alkoxy group or hydroxyl group. The present invention also relates to methods for the prevention or treatment of fever, inflammation or pain, wherein a medicament incorporating a pharmacologically effective dose of the above described active ingredient is administered to patients in need of such treatment.
Description
Isatin and derivatives thereof for use as a medicament
The present invention relates to the use of isatin and the derivatives of isatin for the treatment or prevention of fever, inflammation or pain, and in particular to their use for the treatment or prevention of fever in post-PG E2 (prostaglandin E2) phase, and the use of said compounds for the production of pharmaceutical preparations for such indications.
Fever is one of the defensive reactions of the body which is induced by infections or injuries, hence, to some extent, it is considered as a normal self-protection mechanism. Triggering stimuli of fever include, for example, bacterial or viral infections, malignant tumors, allergic reactions, hormonal disturbances, autoimmune diseases, and the overdose of certain drugs (e.g. analgesics, antipsychotics). The elevated body temperature significantly slows down the proliferation of certain bacteria and viruses and thereby may decrease their health damaging effects. At the same time, the production of immune mediators, which provide protection of the body, is also increased.
Because of its potential benefits, fever should not be pharmacologically alleviated whenever it occurs. However, if body temperature exceeds the fever threshold (380C), antipyretic treatment is justifiable particularly in elderly and chronic patients, and in children. Regularly administered antipyretics include e.g. aspirin, aminophenazone and paracetamol.
Isatin (2,3-dioxoindole, lH-indole-2,3-dion) has been first described in 1841, and was prepared by the oxidation of indigo dye [Erdmann, J. Prakt. Chem., 1, 24, 1(1841)]. Following its establishment as a convenient starting material in synthetic chemistry, its numerous derivatives (isatin derivatives substituted on the benzene moiety with methyl group, alkoxy group or halogen are presented in patent application US 1,938,055), and uses (the application of isatin as hair colourant: US 4,750,908) and synthesis methods (EP 0028906B1, US 4,212,804; US 4,261,894; isatin, 5-methylisatin US 4,188,325) have became known since.
To the Schiff-base derivatives of isatin, activities such as, for example, anti-HIV effects [Pandeya, S. N.; Yogeeswari, P.; Sriram, D.; De Clercq, E.; Pannecouque, C; Witvrouw, M. Chemotherapy, 1999, 45, 192-196; Pandeya, S. N.; Sriram, D.; Nath, G.; De Clercq, E. Eur. J. Med. Chem. 2000, 35, 249-255], and spasmolytic effects [Sridhar, S. K.; Pandeya, S. N.; Stables, J. P.; Armes, S. K. Eur. J. Pharm. Sci. 2002, 16, 129.] are also
attributed.
Indole derivatives substituted with aromatic monocyclic or bicyclic heterocycles inhibit lipoxygenase and thus possess antiallergenic and antiinflammatory activities [EP0544821]. In patent application No. US20030040518A1, the neurotrophic effects of isatin derivatives substituted with benzyl group, 5- or 6-membered monocyclic heterocycles etc. are described.
In studies conducted on the inhibition of the effect of certain neuropeptides on the nervous system by isatin and its derivatives, the inventors observed that, surprisingly, these compounds also prevented the occasional onset of fever as well. During further studies it was concluded that isatin and its derivatives characterized by the general formula (I) indeed possess an antipyretic activity. Furthermore, these compounds were also shown suitable for the prevention of the induction of fever (hyperthermia) in post-PG E2 phase, since these compounds do not exert their activity in a manner analogous to currently commonly used compounds acting directly on the synthesis of PG E2, but they work in post-PG E2 phase and thus they provide antipyretic, antiinflammatory and analgetic agents with a novel mechanism of action.
It is noted that according to the widely accepted mechanism of the development of fever, the different pyrogenic agents initiate a cascade in which cytokines eventually lead to the release of PG E2 which represents the final link in the development of fever. Most of the currently used antipyretics are acting primarily through the inhibition of this mechanism.
Firstly, the present invention relates to isatin derivatives of the general formula (I) for use as a medicament, and particularly for use in the prevention or treatment of fever, inflammation or pain, wherein in the general formula (I)
Ri is hydrogen, or (Cj-Cio) linear or branched alkyl or hydroxyalkyl group or acyl
group containing (Ci-Cio) linear or branched alkyl group,
■ R2-R5 are independently hydrogen, halogen, amino group, nitro group, optionally halogen substituted (Ci -C 10) alkyl group, (Ci-C10) alkoxy group or hydroxyl group.
Preferred are those compounds, wherein in the general formula (I), Ri is hydrogen or (C1-C5) linear or branched alkyl or hydroxyalkyl group or acyl group containing a (Ci -C5) linear or branched alkyl group, R2-R5 are independently hydrogen, halogen, amino group, nitro group, (C1-C5) alkyl group or hydroxyl group.
More preferred are those compounds, wherein Rj is hydrogen or acetyl group, R2-R5 are independently hydrogen, methyl group or ethyl group or hydroxyl group. Suitable active ingredients are the following compounds, e.g.: (3-methyl)-N- butylisatin, 1 -butylisatin, 1-carboxymethylisatin ethyl ester, 1 -carboxymethylisatin, 4,5- dichloroisatin, 4,5-dimethylisatin, 4,6-dichloroisatin, 4,6-dimethylisatin, 4,7-dichloroisatin, 4,7-dimethylisatin, 4,7-dimethoxyisatin, 4-bromoisatin, 4-ethylisatin, 4-fluoro-7- methylisatin, 4-iodoisatin, 4-chloro-5-methylisatin, 4-chloro-5-methoxyisatin, 4-chloro-7- methylisatin, 4-methylisatin, 4-trifluoroisatin, 5-(3-methylbutyl)isatin, 5,6-dimethylisatin, 5,6-dichloroisatin, 5,6-dimethoxyisatin, 5-aminoisatin H2SO4, 5-bromo-7-methylisatin, 5- butylisatin, 5-ethylisatin, 5-ethoxyisatin, 5-fluoroisatin, 5-hexylisatin, 5-hydroxyisatin, 5- isobutylisatin, 5-chloro-7-methylisatin, 5 -methylisatin, 5-methoxyisatin, 5-nitroisatin, 5-n- propylisatin, 5-pentylisatin, 5-sec-butylisatin, 5-succinamidoisatin, 6,7-dichloroisatin, 6,7- dimethylisatin, 6-ethylisatin, 6-ethoxyisatin, 6-fluoro-7-methylisatin, 6-fluoroisatin, 6- hydroxyisatin, 6-iodoisatin, 6-chloro-5-methylisatin, 6-chloro-5-methoxyisatm, 6-chloro-7- methylisatin, 6-chloroisatin, 6-methylisatin, 6-methoxyisatin, 6-propoxyisatin, 7- bromoisatin, 7-ethylisatin, 7-ethoxyisatin, 7-fluoro-4-methylisatin, 7-fluoro-5-methylisatin, 7-fluoroisatin, 7-hydroxyisatin, 7-isopropylisatin, 7-iodoisatin, 7-chloroisatin, 7- methylisatin, 7-methoxyisatin, 7-propylisatin, 7-trifluoro-methylisatin, methoxy-4,5,6- trimethoxyisatin, N-(2-hydroxyethyl)-isatin, N-acetylisatin, N-ethylisatin, N-hexylisatin, N-methylisatin, N-pentylisatin.
The desired effect according to the invention can be achieved particularly by the following compounds: isatin, 5 -methylisatin, 6-hydroxyisatin, 7-ethylisatin or N- acetylisatin.
Additionally, the present invention relates to the use of compounds of the general formula (I) for the manufacture of a medicament for the treatment or prevention of fever, inflammation or pain, particularly for the treatment or prevention of fever.
The present invention also relates to methods for the prevention or treatment of fever, inflammation or pain, wherein a pharmaceutical preparation incorporating a pharmacologically effective dose of the above described active ingredient is administered to patients in need of such treatment. Description of test methods
Two kinds of experimental approaches were applied. When isatin and its derivatives were co-administered with PG E2, the effect on the onset of fever was examined, and when PG E2 was administered first, then 30 minutes later isatin or its derivatives were used, the effect on the developed hyperthermia was examined. Wistar male rats and CFLP male mice were used in the experiments, under strict adherence to the rules of the University governing the employment of Laboratory Animals for Experimental Purposes which are in complete conformity with relevant international guidelines. 5 to 12 animals were used in each test group.
Treatment with PG E2 was carried out though a cannula inserted into the lateral cerebral ventricles of the conscious animals. In the case of mice, a dose of 1 μg, whereas in the case of rats a dose of 2 μg was administered in 2 μl volume. Treatment with isatin and its derivatives was carried out intraperitoneally in various doses. Measurement of the core temperature of the animals was performed using a digital thermometer (Cole-Parmer 8402- 10) inserted 5 cm deep and 2.5 cm deep into the colon of rats and mice, respectively. Isatin and PG E2 was supplied by Sigma Chemical Co. (St. Louis, Mo., USA), isatin analogues have been prepared by researchers at the Imperial College London (Hammersmith Campus du Cane Road, London, W12, United Kindgom). Syntheses were performed according to the methods of Marvel and Hiers (1941), and also Bauer and Sadler (1960), Sadler (1956), Crippenberg et al. (1957). Structural confirmation was performed by mass spectrometry analysis (Medvedev et al. 1992).
Statistical evaluation was performed by varia analysis and paired comparison by the Tukey test. A value of P=O.05 was regarded significant. The maximum of temperature elevation induced by PG E2 was reached in 30 minutes after administration. Hence the treatment of the developed fever has been initiated at that time point. Isatin treatment was started with a dose of 50 mg/kg ip., then the subsequent doses have been halved until the smallest dose which was shown still effective was reached. Example 1 In the case of isatin, the inhibition of the onset of fever was achieved by a dose of 12.5
mg/kg, whereas the reduction of the developed fever was achieved by a dose of 25.0 mg/kg in rats. In mice the same values were 3.12 mg/kg and 12.5 mg/kg, respectively. Example 2
With 5-methylisatin, the inhibition of the onset of fever was achieved by a dose of 3.36 mg/kg, whereas the reduction of the developed fever was achieved by a dose of 13.4 mg/kg in rats. In mice, a dose of 0.21 mg/kg inhibited the onset of fever, and alleviation of the febrile state was achieved by a dose of 6.72 mg/kg. Example 3
6-Hydroxyisatin in a dose of 10.40 mg/kg inhibited the onset of fever and reduced the already developed febrile state. In mice, a dose of 5.2 mg/kg inhibited the onset of fever, and a dose of 10.4 mg/kg reduced the developed fever. Example 4
7-Ethylisatin inhibited the onset of fever in a dose of 0.122 mg/kg, and also reduced the developed fever in rats. In mice, the dose needed was 0.0288 mg/kg. Example 5
N-Acetylisatin inhibited the PG E2 induced hyperhermia in a dose of 0.096 mg/kg, and reduced the developed fever in a dose of 0.384 mg/kg in rats. In mice, the dose that was effective against the development of fever was 0.00504 mg/kg, whereas for the alleviation of the developed fever, a dose of 1.24 mg/kg was effective. Isatin and its derivatives exert their activity post-PG E2 and thus they provide antipyretic, antiinflammatory or analgesic agents with a novel mechanism of action.
The amount of the active ingredient of the formula (I) required to achieve the desired therapeutical effect is dependent of a number of factors, such as, for example, the nature of the compound used, the method of administration and the condition of the patient. For the production of the pharmaceutical preparations according to the invention, the compound of formula (I) or its physiologically functional derivative (hereinafter as the active ingredient) is combined with, among others, one or more pharmaceutically acceptable carrier substances or other excipients and optionally with other active ingredients. The pharmaceutical preparations can be preparations suitable for administration via, for example, oral, rectal, nasal, topical (such as transdermal, buccal and sublingual), parenteral (such as subcutaneous, intramuscular, intravenous or intradermal) route. The preparations are suitably prepared in unit dose form, by methods conventionally used in the
manufacture of pharmaceuticals. During the above method the active ingredient is blended with a carrier substance containing one or more additional components. For the manufacture of the preparations, the active ingredient is usually blended thoroughly and uniformly with a liquid carrier or finely dispersed solid carrier substance or the mixture thereof, then optionally the blend is shaped.
The pharmaceutical preparations suitable for oral administration produced by methods according to the invention can be presented in the form of physically separate units containing a predefined amount of the active ingredient, such as, for example, capsules, cachets or tablets; powders or granules; solutions or suspensions made with aqueous or non-aqueous liquids; or oil-in- water or water-in-oil type liquid emulsions. The active ingredient can also be presented in the form of bolus or ointment.
Tablets can be prepared optionally using one or more excipients, by compression or moulding. Compressed tablets can be prepared by blending the active ingredient in free- flowing form such as powder or granules optionally with a binding agent (such as, e.g., povidone, gelatin, hydroxypropylmethyl cellulose), glidant, inert diluent, preservative, desintegrating agent (such as, for example, sodium starch glycolate, crosslinked povidone, crosslinked sodium carboxymethyl cellulose), surfactant or dispersing agent and compressing into tablets using an appropriate equipment. Moulded tablets can be prepared by moulding the powdered active ingredient moistened with an inert, liquid diluent in a form using an appropriate equipment. Tablets can be optionally provided with a coating or pattern, and additionally can be formulated as a slow or controlled release form; for example, the desired release profile can be achieved by adding hydroxypropylmethyl cellulose to the formulation in varying proportions.
The above preparations suitable for oral administration may contain buffers for the purpose of neutralizing gastric acid. Said buffers can be different organic or inorganic compounds, such as, for example, the mixtures of weak acids or bases and their conjugated salts.
The preparations suitable for oral topical administration can be, for example, lozenges incorporating the active ingredient in a flavoured base, commonly in saccharose and gum arabic or tragacantha.
The preparations suitable for rectal administration can be, for example, suppositories prepared using an appropriate base containing cocoa butter or a salicylate.
Because the compounds of the general formula (I) are mainly water-soluble, the form
of the preparations suitable for parenteral administration can preferably be, for example, an aqueous (or possibly non-aqueous), isotonic, sterile solution for injection or a solution for drinking optionally containing, for example, antioxidants, buffers, bacteriostatic agents, and substances for making the preparation isotonic with the blood of the recipient. The
5 preparations can be presented in the form of sealed containers such as, for example, ampoules or vials containing unit doses or multiple doses, and can be stored in freeze-dried
(lyophilized) state, which can be reconstituted immediately before use by adding a suitable sterile, liquid carrier agent such as, for example, water for injections. Solutions and suspensions for injection for immediate use can be prepared from sterile powders, granules i o and the above explained tablets.
Preferred are the unit dose preparations which incorporate a daily dose or unit explained above, daily divided dose or an appropriate portion thereof of the active ingredient.
The pharmaceutical preparation according to the invention can of course contain other
15 excipients conventionally used in the manufacture of pharmaceuticals in addition to those mentioned above, depending on the form of the preparation concerned, such as, for example, preparations for oral administration can contain sweeteners, thickeners and aromatizers as well.
The active ingredient can be prepared by any of the known methods. By known 20 method, methods which have been published before the date of priority are meant.
Claims
1. Compounds of the general formula (I) for use as a medicament, wherein in general formula (I)
■ Ri is hydrogen, or (Q-Qo) linear or branched alkyl or hydroxyalkyl group or acyl group containing (C1-Ci0) linear or branched alkyl group,
" R2-R5 are independently hydrogen, halogen, amino group, nitro group, optionally halogen substituted (C1-C10) alkyl group, (Ci-Ci0) alkoxy group or hydroxyl group.
2. Compounds of the general formula (I) for use in the treatment or prevention of fever, inflammation or pain, wherein in general formula (I)
■R] is hydrogen, or (Q -Qo) linear or branched alkyl or hydroxyalkyl group or acyl group containing (Q -Qo) linear or branched alkyl group, " R2-R5 are independently hydrogen, halogen, amino group, nitro group, optionally halogen substituted (Q-Qo) alkyl group, (Ci-Qo) alkoxy group or hydroxyl group.
3. The use of compounds of the general formula (I) for the manufacture of a medicament for the treatment or prevention of fever, inflammation or pain, wherein in general formula (I)
" R1 is hydrogen, or (C1-C10) linear or branched alkyl or hydroxyalkyl group or acyl group containing (C1-C10) linear or branched alkyl group,
" R2-R5 are independently hydrogen, halogen, amino group, nitro group, optionally halogen substituted (C1-Ci0) alkyl group, (Ci-Ci0) alkoxy group or hydroxyl group.
4. The use as according to claim 3, wherein in the general formula (I)
" R1 is hydrogen, or (Ci-C5) linear or branched alkyl or hydroxyalkyl group or acyl group containing (C1-C5) linear or branched alkyl group,
■ R2-R5 are independently hydrogen, halogen, amino group, nitro group, (C1-C5) alkyl group or hydroxyl group.
5. The use according to claim 3, wherein in the general formula (I)
■ Ri is hydrogen or acetyl group,
■ R2-R5 are independently hydrogen, methyl group or ethyl group or hydroxyl group.
6. The use according to claim 3, wherein the compound of the general formula (I) is " isatin,
■ 5-methylisatin,
■ 6-hydroxyisatin,
■ 7-ethylisatin or
■ N-acetylisatin.
7. Method for the prevention or treatment of fever, inflammation or pain, comprising of administering a pharmaceutical preparation containing an effective dose of any of the active ingredients defined in any of claims 3 to 6 to the patient in need of such treatment.
Applications Claiming Priority (2)
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HU0600409A HUP0600409A3 (en) | 2006-05-15 | 2006-05-15 | Izatin and it's derivatives for use as a medicine |
HUP0600409 | 2006-05-15 |
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WO2007132280A1 true WO2007132280A1 (en) | 2007-11-22 |
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PCT/HU2007/000042 WO2007132280A1 (en) | 2006-05-15 | 2007-05-15 | Isatin and its derivatives for use as a medicament |
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WO (1) | WO2007132280A1 (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102875445A (en) * | 2012-09-29 | 2013-01-16 | 山东鲁诺动物药业有限公司 | Synthetic method of 5-trifluoromethyl isatin |
CN109734645A (en) * | 2019-02-21 | 2019-05-10 | 南京金浩医药科技有限公司 | A kind of synthesis technology of isatin |
Citations (2)
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WO2001055110A1 (en) * | 2000-01-24 | 2001-08-02 | Neurosearch A/S | Isatine derivatives with neurotrophic activity |
WO2006044415A2 (en) * | 2004-10-12 | 2006-04-27 | Decode Genetics, Inc. | Carboxylic acid peri - substituted bicyclics for occlusive artery disease |
-
2006
- 2006-05-15 HU HU0600409A patent/HUP0600409A3/en unknown
-
2007
- 2007-05-15 WO PCT/HU2007/000042 patent/WO2007132280A1/en active Application Filing
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2001055110A1 (en) * | 2000-01-24 | 2001-08-02 | Neurosearch A/S | Isatine derivatives with neurotrophic activity |
WO2006044415A2 (en) * | 2004-10-12 | 2006-04-27 | Decode Genetics, Inc. | Carboxylic acid peri - substituted bicyclics for occlusive artery disease |
Non-Patent Citations (3)
Title |
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PATAKI I ET AL: "Isatin (Indole-2, 3-dione) inhibits natriuretic peptide-induced hyperthermia in rats", PEPTIDES 2000 UNITED STATES, vol. 21, no. 3, 2000, pages 373 - 377, XP002452295, ISSN: 0196-9781 * |
PATAKI I ET AL: "The effects of isatin (indole-2, 3-dione) on pituitary adenylate cyclase-activating polypeptide-induced hyperthermia in rats", BMC NEUROSCIENCE 20 FEB 2002 UNITED KINGDOM, vol. 3, 20 February 2002 (2002-02-20), XP002452294, ISSN: 1471-2202 * |
SRIDHAR S ET AL: "Synthesis, characterisation and pharmacological screening of some isatinoid compounds", INDIAN JOURNAL OF CHEMISTRY, SECTION B: ORGANIC, INCL. MEDICINAL, PUBLICATIONS & INFORMATIONS DIRECTORATE, NEW DELHI, IN, vol. 41B, March 2002 (2002-03-01), pages 668 - 672, XP009089842, ISSN: 0019-5103 * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102875445A (en) * | 2012-09-29 | 2013-01-16 | 山东鲁诺动物药业有限公司 | Synthetic method of 5-trifluoromethyl isatin |
CN109734645A (en) * | 2019-02-21 | 2019-05-10 | 南京金浩医药科技有限公司 | A kind of synthesis technology of isatin |
Also Published As
Publication number | Publication date |
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HU0600409D0 (en) | 2006-07-28 |
HUP0600409A2 (en) | 2008-03-28 |
HUP0600409A3 (en) | 2008-05-28 |
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