WO2018053587A1 - Compositions pour le traitement de l'hypertension et/ou de la fibrose - Google Patents
Compositions pour le traitement de l'hypertension et/ou de la fibrose Download PDFInfo
- Publication number
- WO2018053587A1 WO2018053587A1 PCT/AU2017/051026 AU2017051026W WO2018053587A1 WO 2018053587 A1 WO2018053587 A1 WO 2018053587A1 AU 2017051026 W AU2017051026 W AU 2017051026W WO 2018053587 A1 WO2018053587 A1 WO 2018053587A1
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- WO
- WIPO (PCT)
- Prior art keywords
- compound
- stereoisomer
- pharmaceutically acceptable
- acceptable salt
- alkyl
- Prior art date
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- ZDQATZYVVPEOSP-YBFXNURJSA-N NC(C/C(/c1ccccc1)=N\Oc(c(F)c1O)ccc1F)=O Chemical compound NC(C/C(/c1ccccc1)=N\Oc(c(F)c1O)ccc1F)=O ZDQATZYVVPEOSP-YBFXNURJSA-N 0.000 description 2
- FVESWLCEMQYRAX-QGOAFFKASA-N NC(C/C(/c1ccccc1)=N\Oc(cc1)cc(O)c1F)=O Chemical compound NC(C/C(/c1ccccc1)=N\Oc(cc1)cc(O)c1F)=O FVESWLCEMQYRAX-QGOAFFKASA-N 0.000 description 2
- XSTZPHBAZPPKME-CPNJWEJPSA-N NC(C/C(/c1ccccc1)=N\Oc(cc1)cc2c1[nH]nn2)=O Chemical compound NC(C/C(/c1ccccc1)=N\Oc(cc1)cc2c1[nH]nn2)=O XSTZPHBAZPPKME-CPNJWEJPSA-N 0.000 description 2
- BLKZMGMGCHCATK-NBVRZTHBSA-N NC(C/C(/c1ccccc1)=N\Oc1cc(F)cc(O)c1)=O Chemical compound NC(C/C(/c1ccccc1)=N\Oc1cc(F)cc(O)c1)=O BLKZMGMGCHCATK-NBVRZTHBSA-N 0.000 description 2
- UQSVDJQYIIMGHM-LTGZKZEYSA-N NC(C/C(/c1ccccc1)=N\Oc1cc(NC(CC2)=O)c2cc1)=O Chemical compound NC(C/C(/c1ccccc1)=N\Oc1cc(NC(CC2)=O)c2cc1)=O UQSVDJQYIIMGHM-LTGZKZEYSA-N 0.000 description 2
- ZGWVANGPTBZZHN-WOJGMQOQSA-N NC(C/C(/c1ccccc1)=N\Oc1cccc(O)c1F)=O Chemical compound NC(C/C(/c1ccccc1)=N\Oc1cccc(O)c1F)=O ZGWVANGPTBZZHN-WOJGMQOQSA-N 0.000 description 2
- GGJVDFQOOVXWOB-XDHOZWIPSA-N NC(C/C(/c1ccccc1)=N\Oc1cccc2c1nn[nH]2)=O Chemical compound NC(C/C(/c1ccccc1)=N\Oc1cccc2c1nn[nH]2)=O GGJVDFQOOVXWOB-XDHOZWIPSA-N 0.000 description 2
- SAYWLXPHVWZIFX-LDADJPATSA-N NC(C/C(/c1ccccc1)=N\Oc1ccnc(N)c1)=O Chemical compound NC(C/C(/c1ccccc1)=N\Oc1ccnc(N)c1)=O SAYWLXPHVWZIFX-LDADJPATSA-N 0.000 description 2
- NPVDWFXOOOTIEP-KNTRCKAVSA-N CS(Nc1cc(NS(C)(=O)=O)cc(O/N=C(\CC(N)=O)/c2ccccc2)c1)(=O)=O Chemical compound CS(Nc1cc(NS(C)(=O)=O)cc(O/N=C(\CC(N)=O)/c2ccccc2)c1)(=O)=O NPVDWFXOOOTIEP-KNTRCKAVSA-N 0.000 description 1
- MTVQUFBUBGZSAA-QGOAFFKASA-N Cc(c(O)cc(O/N=C(\CC(N)=O)/c1ccccc1)c1)c1O Chemical compound Cc(c(O)cc(O/N=C(\CC(N)=O)/c1ccccc1)c1)c1O MTVQUFBUBGZSAA-QGOAFFKASA-N 0.000 description 1
- YJVFJHSEURYEFB-QGOAFFKASA-N NC(C/C(/c1ccccc1)=N\Oc(cc(cc1)O)c1F)=O Chemical compound NC(C/C(/c1ccccc1)=N\Oc(cc(cc1)O)c1F)=O YJVFJHSEURYEFB-QGOAFFKASA-N 0.000 description 1
- CDTZBKCCXLEUQQ-HMMYKYKNSA-N NC(C/C(/c1ccccc1)=N\Oc(cc1)cc2c1[nH]nc2)=O Chemical compound NC(C/C(/c1ccccc1)=N\Oc(cc1)cc2c1[nH]nc2)=O CDTZBKCCXLEUQQ-HMMYKYKNSA-N 0.000 description 1
- IUSCEPROSYXFDW-WOJGMQOQSA-N NC(C/C(/c1ccccc1)=N\Oc(cc1O)cc(O)c1Cl)=O Chemical compound NC(C/C(/c1ccccc1)=N\Oc(cc1O)cc(O)c1Cl)=O IUSCEPROSYXFDW-WOJGMQOQSA-N 0.000 description 1
- IDHPZYQJHPWZHB-WOJGMQOQSA-N NC(C/C(/c1ccccc1)=N\Oc(cc1O)cc(O)c1F)=O Chemical compound NC(C/C(/c1ccccc1)=N\Oc(cc1O)cc(O)c1F)=O IDHPZYQJHPWZHB-WOJGMQOQSA-N 0.000 description 1
- DJBALYJKQNOBES-XSFVSMFZSA-N NC(C/C(/c1ccccc1)=N\Oc1c(cn[nH]2)c2ccc1)=O Chemical compound NC(C/C(/c1ccccc1)=N\Oc1c(cn[nH]2)c2ccc1)=O DJBALYJKQNOBES-XSFVSMFZSA-N 0.000 description 1
- RRNSCDIKYBZYCJ-HMMYKYKNSA-N NC(C/C(/c1ccccc1)=N\Oc1cc([nH]nc2)c2cc1)=O Chemical compound NC(C/C(/c1ccccc1)=N\Oc1cc([nH]nc2)c2cc1)=O RRNSCDIKYBZYCJ-HMMYKYKNSA-N 0.000 description 1
- XPGJCLZBFCIICY-KGENOOAVSA-N NC(C/C(/c1ccccc1)=N\Oc1cccc(CC2)c1NC2=O)=O Chemical compound NC(C/C(/c1ccccc1)=N\Oc1cccc(CC2)c1NC2=O)=O XPGJCLZBFCIICY-KGENOOAVSA-N 0.000 description 1
- LNPKUJQSZADCQG-SAPNQHFASA-N NC(C/C(/c1ccccc1)=N\Oc1cccc(O)c1)=O Chemical compound NC(C/C(/c1ccccc1)=N\Oc1cccc(O)c1)=O LNPKUJQSZADCQG-SAPNQHFASA-N 0.000 description 1
- LDBKYBTVUFRQIN-DEDYPNTBSA-N NC(C/C(/c1ccccc1)=N\Oc1cccc2c1[nH]nc2)=O Chemical compound NC(C/C(/c1ccccc1)=N\Oc1cccc2c1[nH]nc2)=O LDBKYBTVUFRQIN-DEDYPNTBSA-N 0.000 description 1
- RYPZCQBPHSVETO-GHRIWEEISA-N NC(C/C(/c1ccccn1)=N\Oc1cccc(O)c1)=O Chemical compound NC(C/C(/c1ccccn1)=N\Oc1cccc(O)c1)=O RYPZCQBPHSVETO-GHRIWEEISA-N 0.000 description 1
- IALBMKRQZMVFQH-GHRIWEEISA-N NC(C/C(/c1ccncc1)=N\Oc1cccc(O)c1)=O Chemical compound NC(C/C(/c1ccncc1)=N\Oc1cccc(O)c1)=O IALBMKRQZMVFQH-GHRIWEEISA-N 0.000 description 1
- YIJLJNROGXEFCF-GHRIWEEISA-N NC(C/C(/c1cnccc1)=N\Oc1cccc(O)c1)=O Chemical compound NC(C/C(/c1cnccc1)=N\Oc1cccc(O)c1)=O YIJLJNROGXEFCF-GHRIWEEISA-N 0.000 description 1
- IHVYIBQDBTYSEJ-SFQUDFHCSA-N NC(C/C(/c1cncnc1)=N\Oc1cccc(O)c1)=O Chemical compound NC(C/C(/c1cncnc1)=N\Oc1cccc(O)c1)=O IHVYIBQDBTYSEJ-SFQUDFHCSA-N 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
- C07C251/32—Oximes
- C07C251/50—Oximes having oxygen atoms of oxyimino groups bound to carbon atoms of substituted hydrocarbon radicals
- C07C251/54—Oximes having oxygen atoms of oxyimino groups bound to carbon atoms of substituted hydrocarbon radicals of hydrocarbon radicals substituted by singly-bound oxygen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
- C07C251/32—Oximes
- C07C251/50—Oximes having oxygen atoms of oxyimino groups bound to carbon atoms of substituted hydrocarbon radicals
- C07C251/58—Oximes having oxygen atoms of oxyimino groups bound to carbon atoms of substituted hydrocarbon radicals of hydrocarbon radicals substituted by nitrogen atoms not being part of nitro or nitroso groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C261/00—Derivatives of cyanic acid
- C07C261/04—Cyanamides
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C271/06—Esters of carbamic acids
- C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
- C07C271/26—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring
- C07C271/28—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring to a carbon atom of a non-condensed six-membered aromatic ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C275/32—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by singly-bound oxygen atoms
- C07C275/34—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by singly-bound oxygen atoms having nitrogen atoms of urea groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C307/00—Amides of sulfuric acids, i.e. compounds having singly-bound oxygen atoms of sulfate groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C307/04—Diamides of sulfuric acids
- C07C307/10—Diamides of sulfuric acids having nitrogen atoms of the sulfamide groups bound to carbon atoms of six-membered aromatic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
- C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
- C07C311/08—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member 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
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
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- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/325—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
- C07D207/327—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members 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
- C07D207/36—Oxygen or sulfur atoms
- C07D207/40—2,5-Pyrrolidine-diones
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/44—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members
- C07D207/444—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members having two doubly-bound oxygen atoms directly attached in positions 2 and 5
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- 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
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- 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
- C07D209/34—Oxygen atoms in position 2
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- 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
- C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
- C07D213/53—Nitrogen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/73—Unsubstituted amino or imino radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
- C07D215/227—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 2
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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
- C07D215/20—Oxygen atoms
- C07D215/24—Oxygen atoms attached in position 8
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
- C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members 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
- C07D233/72—Two oxygen atoms, e.g. hydantoin
- C07D233/76—Two oxygen atoms, e.g. hydantoin with substituted hydrocarbon radicals attached to the third ring carbon atom
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- C07D277/62—Benzothiazoles
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- C07D333/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
Definitions
- the present invention relates to novel compounds and their use in the prophylactic and/or therapeutic treatment of cardiovascular disease, and in particular the treatment of prehypertension, hypertension and/or fibrotic conditions.
- the invention has been developed primarily for the prophylactic and/or therapeutic treatment of cardiovascular disease and will be described hereinafter with reference to this application. However, it will be appreciated that the invention is not limited to this particular field of use.
- Hypertension (high blood pressure) affects 26% of the adult population worldwide with an incidence of 30-33% in western countries. The world wide incidence of hypertension is expected to reach 29% by 2025 as a consequence of the
- the present invention provides a compound of the formula
- X is:
- Ri to R 9 are independently C, N, O or S;
- Rio is independently selected from Ci -6 alkyl, halo, C 0 - 6 alkyl carboxylic acid, amino, hydroxy and Ci. 6 alkoxy;
- A is selected from optionally substituted saturated, partly saturated or unsaturated 5- or 6-membered heterocyclyl; optionally substituted d_ 6 alkoxyl amine; optionally substituted C -6 alkyl amine; optionally substituted C 0 . 6 alkyl carboxylic acid; optionally substituted C -6 alkyl hydroxyl; optionally substituted saturated or unsaturated C 0 . 6 alkyl bicyclic heterocyclyl; and optionally substituted saturated or unsaturated d. 6 alkoxyl bicyclic heterocyclyl;
- Z is selected from the group consisting of:
- Rn is independently selected from halo, alkyl, hydroxy, amino and substituted amino; Ri2, Ri4 and R 15 are independently C, CH, CH 2 , O, N, NH or S;
- n 0, 1 , 2, 3, 4 or 5;
- n 0, 1 , 2, 3 or 4,
- R 10 is independently selected from -CH 3 , -C(0)OH, -F, -NH 2 , -OH and -OCH 3 .
- R 5 to R 9 are independently C or N.
- the C 0 - 6 alkyl carboxylic acid is carboxylic acid.
- the saturated, partly saturated or unsaturated 5- or 6- membered heterocyclyl contains one or more of N, S or O, optionally substituted with one or more oxo, d_ 6 alkyl, amino, hydroxyl or halo substituents.
- the saturated, partly saturated or unsaturated 5- or 6- membered heterocyclyl is selected from pyrrolyl, pyrazolyl, imidazolyl, triazolyl, imidazolidinyl, pyrrolidinyl, pyrrolidinylidene, dihydropyrrolyl, isoxazolyl dihydrooxazolyl, isoxazolidinyl, oxazolidinyl and oxazolyl, optionally substituted with one or more oxo, Ci. 6 alkyl, amino, hydroxyl or halo substituents.
- the Ci. 6 alkoxyl amine is aminooxymethyl.
- the Ci -6 alkyl amine is optionally substituted with one or more of Ci -6 alkyl, Ci_ 6 halo alkyl, hydroxyl or halo, preferably mono-, di- or tri-substituted halo alkyl, most preferably tri-fluoro methane.
- the Ci -6 alkyl hydroxyl is methyl hydroxyl.
- the C 0 - 6 alkyl bicyclic heterocyclyl is selected from indolyl, isoindolyl, insolinyl and isoindolinyl, optionally substituted with one or more oxo, preferably dioxo.
- the Ci. 6 alkoxyl bicyclic heterocyclyl is selected indolyl, isoindolyl, insolinyl and isoindolinyl, optionally substituted with one or more oxo, and wherein the Ci. 6 alkoxyl is methoxy or ethoxy.
- A is selected from:
- halo selected from the group consisting of F, CI, Br and I.
- R 16 is selected from -CN, -S0 2 (Ri 7 ) a Ri8 and -CO(Ri 7 ) a Ri 8 ,
- a is 0 or 1 ,
- Ri 7 is selected from -NH- and -0-, and
- R 18 is selected from -H, -CH 3 , -CH 2 CH 3 , -CH 2 OH and -CH 2 CH 2 OH.
- Rn is substituted amino selected from the group consisting of -NHS0 2 CH 3 , -NHCOH, -NHCONHCH3, -NHCONHCH 2 CH 3 , -NHS0 2 NHCH 3 , -NHS0 2 NHCH 2 CH 3 , -NHCOCH 3 , -NHCOOCH 3, -NHCOOCH 2 CH 2 OH, -NHCONH 2 and
- Rn is alkyl selected from the group consisting of methyl, ethyl, propyl, butyl and pentyl.
- the compound is selected from the group consisting of:
- the compound is:
- the present invention relates to a pharmaceutical composition
- a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable excipient.
- the present invention relates to a method for the therapeutic treatment of hypertension or prehypertension in a subject comprising administering to the subject a compound according to the present invention.
- the present invention relates to a method for the therapeutic treatment of fibrosis in a subject comprising administering to the subject a compound according to the present invention.
- the present invention relates to a method for the prophylactic treatment of fibrosis in a subject comprising administering to the subject a compound according to the present invention.
- the present invention relates to a method for the therapeutic treatment of hypertension and fibrosis in a subject comprising administering to the subject a compound according to the present invention.
- the present invention relates to a method for the therapeutic treatment of prehypertension and fibrosis in a subject comprising
- the present invention relates to a compound of the present invention for use in the therapeutic treatment of hypertension or
- the present invention relates to a compound of the present invention for use in the therapeutic treatment of fibrosis.
- the present invention relates to a compound of the present invention for use in the prophylactic treatment of fibrosis.
- the present invention relates to a compound of the present invention for use in the therapeutic treatment of hypertension and fibrosis.
- the present invention relates to a compound of the present invention for use in the therapeutic treatment of prehypertension and fibrosis.
- the present invention relates to use of a compound of the present invention for the manufacture of a medicament for the therapeutic treatment of hypertension or prehypertension.
- the present invention relates to use of a compound of the present invention for the manufacture of a medicament for the therapeutic treatment of fibrosis.
- the present invention relates to use of a compound of the present invention for the manufacture of a medicament for the prophylactic treatment of fibrosis.
- the present invention relates to use of a compound of the present invention for the manufacture of a medicament for the therapeutic treatment of hypertension and fibrosis.
- the present invention relates to use of a compound of the present invention for the manufacture of a medicament for the therapeutic treatment of prehypertension and fibrosis.
- the fibrosis is myocardial fibrosis.
- the fibrosis is kidney fibrosis.
- the fibrosis is liver fibrosis.
- the fibrosis is lung fibrosis.
- the present invention relates to an alpha helix backbone having the structure:
- Figure 1 Synthesis scheme for (3E)-3-(3-hydroxyphenoxy)imino-3-phenyl- propanamide (VB0001).
- Figure 2 Synthesis scheme for 0-[3-[tert-butyl(dimethyl)silyl]oxyphenyl] hydroxylamine (compound A).
- FIG. 3 Systolic blood pressure in SHR on a 2.2% salt diet with VB0001 (in 20% DMSO) at a dose of 20 pmol/kg/min or vehicle control (20% DMSO) administered intravenously via an osmotic minipump for 4 weeks. * p ⁇ 0.0005 vs 18 week control.
- Figure 4 Myocardial fibrosis in SHR on a 2.2% salt diet with VB0001 (in 20% DMSO) at a dose of 20 pmol/kg/min or vehicle control (20% DMSO) administered intravenously via an osmotic minipump for 4 weeks. * p ⁇ 0.0005 vs 18 week control.
- the present invention relates to certain compounds that show blood pressure lowering and anti-fibrotic effects in oral dosing studies in an experimental animal model. With respect to anti-fibrotic activity, the compounds of the present invention are effective in preventing fibrosis, slowing down progression of established fibrosis and/or reducing the degree (reversal) of established fibrosis. These are important findings with respect to the range and severity of conditions which can be treated with the compounds of the present invention.
- Ri to R 9 are independently C, N, O or S;
- R 0 is independently selected from Ci -6 alkyl, halo, C 0 . 6 alkyl carboxylic acid, amino, hydroxy and d_ 6 alkoxy;
- A is selected from optionally substituted saturated, partly saturated or unsaturated 5- or 6-membered heterocyclyl; optionally substituted Ci_ 6 alkoxyl amine; optionally substituted Ci. 6 alkyl amine; optionally substituted C 0 - 6 alkyl carboxylic acid; optionally substituted Ci. 6 alkyl hydroxyl; optionally substituted saturated or unsaturated C 0 - 6 alkyl bicyclic heterocyclyl; and optionally substituted saturated or unsaturated Ci. 6 alkoxyl bicyclic heterocyclyl;
- Z is selected from the group consisting of:
- Rn is independently selected from halo, alkyl, hydroxy, amino and substituted amino; Ri2, Ri4 and R 15 are independently C, CH, CH 2 , O, N, NH or S;
- n 0, 1 , 2, 3, 4 or 5;
- n 0, 1 , 2, 3 or 4,
- halo designates -F, -CI, -Br or -I; the term “hydroxy” means -OH; the term “amino” means -NH 2 ; and the term “substituted amino” includes - NHW, wherein W is selected from -CN, -S0 2 (X) a Y and -CO(X) a Y, a is 0 or 1 , X is selected from -NH- and -0-, and Y is selected from -H, -CH 3 , -CH 2 CH 3 , -CH 2 OH and - CH 2 CH 2 OH.
- the present invention contemplates all such compounds, including cis- and trans-isomers, (R)- and (S)-enantiomers, diastereomers, (d)-isomers, (l)-isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention. All such isomers, as well as mixtures thereof, are intended to be included in this invention.
- a particular enantiomer of a compound of the present invention may be prepared by asymmetric synthesis, or by derivatization with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers.
- diastereomeric salts may be formed with an appropriate optically active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means well known in the art, and subsequent recovery of the pure enantiomers.
- the compounds of the present invention may be prepared by the methods illustrated in the general reaction schemes as, for example, described below, or by modifications thereof, using readily available starting materials, reagents and conventional synthesis procedures. In these reactions, it is also possible to make use of variants which are in themselves known, but are not mentioned here.
- the present invention also contemplates pharmaceutically acceptable salts of the compounds.
- pharmaceutically acceptable salt includes both acid and base addition salts and refers to salts which retain the biological effectiveness and properties of the free bases or acids, and which are not biologically or otherwise undesirable.
- the pharmaceutically acceptable salts are formed with inorganic or organic acids or bases, and can be prepared in situ during the final isolation and purification of the compounds, or by separately reacting a purified compound in its free base or acid form with a suitable organic or inorganic acid or base, and isolating the salt thus formed.
- fibrosis as used in the context of the present invention includes, but is not limited to, myocardial fibrosis, kidney fibrosis, liver fibrosis and/or lung fibrosis.
- the compounds of the present invention may be used prophylactically in subjects at risk of developing fibrosis.
- subjects in the risk category for developing fibrosis are those having hypertension, diabetes, myocarditis, ischaemic heart disease, Conn's Syndrome, pheochromocytoma, genetic predisposition high salt diet and/or receiving drugs used in cancer chemotherapy (such as daunorubicin).
- prophylactic as used in the context of the present invention is intended inter alia to encompass treatments used to prevent or slow down the development of fibrosis in the at risk group. Subjects who may be given prophylactic treatment may already have signs of early heart failure on echocardiography.
- hypertension indicates an adult blood pressure of above about 139 mmHg systolic and/or above about 89 mmHg diastolic.
- prehypertension indicates an adult blood pressure in the range about 120-139 mmHg systolic and/or about 80-89 mmHg diastolic.
- the present invention also contemplates pharmaceutical compositions which include the compounds of the present invention, in conjunction with acceptable pharmaceutical excipients.
- pharmaceutically acceptable excipient means any pharmaceutically acceptable inactive component of the composition.
- excipients include diluents, buffers, binders, lubricants, disintegrants, colorants, antioxidants/preservatives, pH- adjusters, etc.
- the excipients are selected based on the desired physical aspects of the final form: e.g. obtaining a tablet with desired hardness and friability being rapidly dispersible and easily swallowed etc.
- compositions may include any type of dosage form such as tablets, capsules, powders, liquid formulations, delayed or sustained release, patches, snuffs, nasal sprays and the like.
- dosage form such as tablets, capsules, powders, liquid formulations, delayed or sustained release, patches, snuffs, nasal sprays and the like.
- the physical form and content of the pharmaceutical compositions contemplated are conventional preparations that can be formulated by those skilled in the pharmaceutical formulation field and are based on well established principles and compositions described in, for example, Remington: The Science and Practice of Pharmacy, 19th Edition, 1995; British Pharmacopoeia 2000 and similar formulation texts and manuals.
- the compounds or compositions are to be administered orally, they may be formulated as tablets, capsules, granules, powders or syrups; or for parenteral administration, they may be formulated as injections (intravenous,
- ophthalmic mucous membrane route preparations or suppositories.
- they may be formulated as eyedrops or eye ointments.
- these formulations can be prepared by conventional means, and, if desired, the active ingredient may be mixed with any conventional additive, such as an excipient, a binder, a disintegrating agent, a lubricant, a corrigent, a solubilizing agent, a suspension aid, an emulsifying agent or a coating agent.
- composition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of active ingredient in combination with a pharmaceutically acceptable carrier.
- the dosage of a compound and frequency of administration that should be used can also be easily determined by the practicing physician in order to produce the desired response.
- a daily dosage of from 0.0001 mg to 200 mg of the compound of the present invention may be a suitable effective amount for an adult human patient, and this may be administered in a single dose or in divided doses.
- a "patient” or “subject” to be treated by the subject method can mean either a human or non-human subject.
- an "effective amount" of a subject compound refers to an amount of the therapeutic in a preparation which, when applied as part of a desired dosage regimen provides a benefit according to clinically acceptable standards for the treatment or prophylaxis of a particular disorder.
- VB0001 and vehicle control infusions were via Alzet osmotic minipump, which was inserted under general anaesthesia (Isoflurane 3% in oxygen) at 14 weeks.
- tissue slices ⁇ 3 mm thick were fixed in 10% buffered formalin for 24 hours, processed and embedded in paraffin.
- Three ⁇ transverse sections were stained using Masson's Trichrome.
- a minimum of 20 random fields at 40x magnification from transverse sections (5 at each of 2 levels) were digitized.
- the degree of fibrosis was determined as a percent of field area of each digitized image using Image-Pro Plus V.5 (Media Cybernetics, Bethesda, MD, USA), and then averaged to determine the level of fibrosis for each rat.
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Abstract
La présente invention concerne de nouveaux composés et leur utilisation dans le traitement prophylactique et/ou thérapeutique de l'hypertension et/ou de la fibrose.
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WO2023229099A1 (fr) * | 2022-05-24 | 2023-11-30 | (주)이노보테라퓨틱스 | Dérivé d'oxime de benzofuranyle hydroxyphénylméthanone et ses utilisations |
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