WO2012009678A1 - Therapeutically active compositions and their method of use - Google Patents
Therapeutically active compositions and their method of use Download PDFInfo
- Publication number
- WO2012009678A1 WO2012009678A1 PCT/US2011/044254 US2011044254W WO2012009678A1 WO 2012009678 A1 WO2012009678 A1 WO 2012009678A1 US 2011044254 W US2011044254 W US 2011044254W WO 2012009678 A1 WO2012009678 A1 WO 2012009678A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- compound
- mhz
- nmr
- dmso
- ylmethyl
- Prior art date
Links
- 0 *C(*)(C(N(*)I*)=O)N(*)C(*)=O Chemical compound *C(*)(C(N(*)I*)=O)N(*)C(*)=O 0.000 description 10
- OLILJZGCIVMXKW-LPYMAVHISA-N C/C(/CN(C(C(NC1CCCCC1)=O)c1ccccc1C)C(C[n]1c(cccc2)c2nc1C)=O)=C\C=C Chemical compound C/C(/CN(C(C(NC1CCCCC1)=O)c1ccccc1C)C(C[n]1c(cccc2)c2nc1C)=O)=C\C=C OLILJZGCIVMXKW-LPYMAVHISA-N 0.000 description 1
- PXMIIKUDNADLAU-PGMHBOJBSA-N C/C(/F)=C(\C=C)/N(C(C(NC1CCCC1)=O)c1ccccc1F)C(Cc1ccc[s]1)=O Chemical compound C/C(/F)=C(\C=C)/N(C(C(NC1CCCC1)=O)c1ccccc1F)C(Cc1ccc[s]1)=O PXMIIKUDNADLAU-PGMHBOJBSA-N 0.000 description 1
- XMZVXXVDLZWDRI-ZXKDJJQISA-N C/C=C(\C=C)/N(C(C(NC1CCCCC1)=O)c1ccccc1C)C(OCc1ccccc1)=O Chemical compound C/C=C(\C=C)/N(C(C(NC1CCCCC1)=O)c1ccccc1C)C(OCc1ccccc1)=O XMZVXXVDLZWDRI-ZXKDJJQISA-N 0.000 description 1
- BBPJAPHIUYBHEN-WZUFQYTHSA-N C/C=C\C(CC(C)=C)N(C(C(NC1CCCCC1)=O)c1ccccc1C)C(CNCCc1ccncc1)=O Chemical compound C/C=C\C(CC(C)=C)N(C(C(NC1CCCCC1)=O)c1ccccc1C)C(CNCCc1ccncc1)=O BBPJAPHIUYBHEN-WZUFQYTHSA-N 0.000 description 1
- XDIAHFCLINWZHB-MRBKWDSJSA-N C/C=C\C(\N(C(C(NC1CCCCC1)=O)c1ccccc1)C(Cc1ccc[s]1)=O)=C/C(C)=C Chemical compound C/C=C\C(\N(C(C(NC1CCCCC1)=O)c1ccccc1)C(Cc1ccc[s]1)=O)=C/C(C)=C XDIAHFCLINWZHB-MRBKWDSJSA-N 0.000 description 1
- KSYSGUSIMXPEFV-UHFFFAOYSA-N CC(C)=C(C(C(NC1CCCCC1)=O)N(C(COc1ccccn1)=O)c1cccc(C)c1)C=C Chemical compound CC(C)=C(C(C(NC1CCCCC1)=O)N(C(COc1ccccn1)=O)c1cccc(C)c1)C=C KSYSGUSIMXPEFV-UHFFFAOYSA-N 0.000 description 1
- GPKJVRORMFJZGB-UHFFFAOYSA-N CC(C)=C(C(C(NC1CCCCC1)=O)N(C(COc1ccncc1)=O)c1cccc(C)c1)C=C Chemical compound CC(C)=C(C(C(NC1CCCCC1)=O)N(C(COc1ccncc1)=O)c1cccc(C)c1)C=C GPKJVRORMFJZGB-UHFFFAOYSA-N 0.000 description 1
- QAGKIZRRRCHJNB-VXPUYCOJSA-N CC/C(/F)=C(\C=C)/N(C(C(C=C)=C(C)C)C(NC1CCCCC1)=O)C(CNC(OC)=O)=O Chemical compound CC/C(/F)=C(\C=C)/N(C(C(C=C)=C(C)C)C(NC1CCCCC1)=O)C(CNC(OC)=O)=O QAGKIZRRRCHJNB-VXPUYCOJSA-N 0.000 description 1
- QLCIIIWKKHGWHP-UHFFFAOYSA-N CCOC(N1CCN(CC(N(C(C(NC2CCCCC2)=O)c2ccccc2C)c2cccc(F)c2)=O)CC1)=O Chemical compound CCOC(N1CCN(CC(N(C(C(NC2CCCCC2)=O)c2ccccc2C)c2cccc(F)c2)=O)CC1)=O QLCIIIWKKHGWHP-UHFFFAOYSA-N 0.000 description 1
- XREUQWFMROZSLS-UHFFFAOYSA-N CCS(NCC(N(C(C(NC1CCCCC1)=O)c1ccccc1C)c1cc(F)ccc1)=O)(=O)=O Chemical compound CCS(NCC(N(C(C(NC1CCCCC1)=O)c1ccccc1C)c1cc(F)ccc1)=O)(=O)=O XREUQWFMROZSLS-UHFFFAOYSA-N 0.000 description 1
- NLCCWANUPGEGGO-UHFFFAOYSA-N Cc1c(C(C(NC(C2)CC2(F)F)=O)N(C(CNc(nccc2)c2F)=O)c2cccc(F)c2)cccc1 Chemical compound Cc1c(C(C(NC(C2)CC2(F)F)=O)N(C(CNc(nccc2)c2F)=O)c2cccc(F)c2)cccc1 NLCCWANUPGEGGO-UHFFFAOYSA-N 0.000 description 1
- UDXSSWRZTRIJEX-UHFFFAOYSA-N Cc1c(C(C(NC2CCCCC2)=O)N(C(Cc2ccc[s]2)=O)c2ccc(C)c(Cl)c2)cccc1 Chemical compound Cc1c(C(C(NC2CCCCC2)=O)N(C(Cc2ccc[s]2)=O)c2ccc(C)c(Cl)c2)cccc1 UDXSSWRZTRIJEX-UHFFFAOYSA-N 0.000 description 1
- USEGOBKOGYJDMU-UHFFFAOYSA-N Cc1c(C(C(NC2CCCCC2)=O)N(Cc2ccc[s]2)C(C[n]2cncc2)=O)cccc1 Chemical compound Cc1c(C(C(NC2CCCCC2)=O)N(Cc2ccc[s]2)C(C[n]2cncc2)=O)cccc1 USEGOBKOGYJDMU-UHFFFAOYSA-N 0.000 description 1
- JNJKRCRGBQVPKR-UHFFFAOYSA-N Cc1cc(N(C(C(NC2CCCCC2)=O)c2c(C)cccc2)C(CNCc2c[s]cn2)=O)ccc1 Chemical compound Cc1cc(N(C(C(NC2CCCCC2)=O)c2c(C)cccc2)C(CNCc2c[s]cn2)=O)ccc1 JNJKRCRGBQVPKR-UHFFFAOYSA-N 0.000 description 1
- XNBDKVBYOJDOBA-UHFFFAOYSA-N Cc1cc(N(C(C(NC2CCCCC2)=O)c2c(C)cccc2)C(COc2ccccc2F)=O)ccc1 Chemical compound Cc1cc(N(C(C(NC2CCCCC2)=O)c2c(C)cccc2)C(COc2ccccc2F)=O)ccc1 XNBDKVBYOJDOBA-UHFFFAOYSA-N 0.000 description 1
- IKPLKUSAFBNDFA-UHFFFAOYSA-N Cc1cc(N(C(C(NC2CCCCC2)=O)c2ccccc2C)C(CN(CC2)CCN2C(OC)=O)=O)ccc1 Chemical compound Cc1cc(N(C(C(NC2CCCCC2)=O)c2ccccc2C)C(CN(CC2)CCN2C(OC)=O)=O)ccc1 IKPLKUSAFBNDFA-UHFFFAOYSA-N 0.000 description 1
- FMXBHCFSUXPKKA-UHFFFAOYSA-N Cc1ccccc1C(C(NC(CC1)CCC1(F)F)=O)N(C(CNc(nccc1)c1F)=O)c1cccc(F)c1 Chemical compound Cc1ccccc1C(C(NC(CC1)CCC1(F)F)=O)N(C(CNc(nccc1)c1F)=O)c1cccc(F)c1 FMXBHCFSUXPKKA-UHFFFAOYSA-N 0.000 description 1
- SXEARPIWGDDYLB-UHFFFAOYSA-N Cc1ccccc1C(C(NC1CCCCC1)=O)N(CC(SC=C)=C)C(CNC(OC)=O)=O Chemical compound Cc1ccccc1C(C(NC1CCCCC1)=O)N(CC(SC=C)=C)C(CNC(OC)=O)=O SXEARPIWGDDYLB-UHFFFAOYSA-N 0.000 description 1
- PSLBQAKLLCGQKW-UHFFFAOYSA-N Cc1ccccc1C(C([N](C)(C1CCCC1)C=C)=O)N(C(Cc1ccc[s]1)=O)c1cc(F)ccc1 Chemical compound Cc1ccccc1C(C([N](C)(C1CCCC1)C=C)=O)N(C(Cc1ccc[s]1)=O)c1cc(F)ccc1 PSLBQAKLLCGQKW-UHFFFAOYSA-N 0.000 description 1
- BTFQKIATRPGRBS-UHFFFAOYSA-N Cc1ccccc1C=O Chemical compound Cc1ccccc1C=O BTFQKIATRPGRBS-UHFFFAOYSA-N 0.000 description 1
- VBWIZSYFQSOUFQ-UHFFFAOYSA-N N#CC1CCCCC1 Chemical compound N#CC1CCCCC1 VBWIZSYFQSOUFQ-UHFFFAOYSA-N 0.000 description 1
- FKKJJPMGAWGYPN-UHFFFAOYSA-N NCc1ccc[s]1 Chemical compound NCc1ccc[s]1 FKKJJPMGAWGYPN-UHFFFAOYSA-N 0.000 description 1
- ZZEMYDVVPYLDBT-YFKPBYRVSA-N OC(CO[C@@H]1COCC1)=O Chemical compound OC(CO[C@@H]1COCC1)=O ZZEMYDVVPYLDBT-YFKPBYRVSA-N 0.000 description 1
- OKRROXQXGNEUSS-UHFFFAOYSA-N OC([n]1cncc1)=O Chemical compound OC([n]1cncc1)=O OKRROXQXGNEUSS-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06078—Dipeptides with the first amino acid being neutral and aromatic or cycloaliphatic
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
- C07C237/22—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
-
- 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
- C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
-
- 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
- C07C271/40—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings
- C07C271/42—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C271/44—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
-
- 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
- C07C271/40—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings
- C07C271/58—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring
-
- 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
- C07C311/03—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atoms of the sulfonamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C311/06—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atoms of the sulfonamide groups bound to hydrogen atoms or to acyclic carbon atoms to acyclic carbon atoms of hydrocarbon radicals substituted by carboxyl groups
-
- 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
- C07C311/12—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing rings
- C07C311/13—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing rings the carbon skeleton containing six-membered aromatic rings
-
- 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
- C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
- C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
- C07C311/19—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C317/00—Sulfones; Sulfoxides
- C07C317/26—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
- C07C317/32—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
- C07C317/34—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having sulfone or sulfoxide groups and amino groups bound to carbon atoms of six-membered aromatic rings being part of the same non-condensed ring or of a condensed ring system containing that ring
- C07C317/36—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having sulfone or sulfoxide groups and amino groups bound to carbon atoms of six-membered aromatic rings being part of the same non-condensed ring or of a condensed ring system containing that ring with the nitrogen atoms of the amino groups bound to hydrogen atoms or to carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C335/00—Thioureas, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C335/30—Isothioureas
- C07C335/32—Isothioureas having sulfur atoms of isothiourea groups bound to acyclic carbon atoms
-
- 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
- C07D207/04—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 no double bonds between ring members or between ring members and non-ring members
- C07D207/10—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 no 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
-
- 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
- C07D207/04—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 no double bonds between ring members or between ring members and non-ring members
- C07D207/10—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 no 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
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- 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
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
-
- 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
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/18—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
- C07D209/26—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 with an acyl radical attached to the ring nitrogen atom
-
- 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
- C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
- C07D211/14—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with 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
- C07D211/38—Halogen atoms or nitro radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with 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
- C07D211/54—Sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with 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
- C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- 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
- C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
- C07D213/30—Oxygen atoms
-
- 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
- C07D213/36—Radicals substituted by singly-bound nitrogen atoms
- C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
-
- 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
- C07D213/54—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
- C07D213/56—Amides
-
- 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
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/64—One oxygen atom attached in position 2 or 6
-
- 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
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/65—One oxygen atom attached in position 3 or 5
-
- 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
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/68—One oxygen atom attached in position 4
-
- 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
- C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
- C07D217/04—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/04—Ortho- or peri-condensed ring systems
- C07D221/18—Ring systems of four or more rings
-
- 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
-
- 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
- C07D231/14—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 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
- C07D231/38—Nitrogen atoms
- C07D231/42—Benzene-sulfonamido pyrazoles
-
- 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
-
- 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
- C07D233/56—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 only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
- C07D233/61—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 only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms not forming part of a nitro radical, attached to ring nitrogen atoms
-
- 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
- C07D233/64—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 substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
-
- 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
- C07D233/70—One oxygen atom
-
- 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
- C07D233/88—Nitrogen atoms, e.g. allantoin
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
- C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
- C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three 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
- C07D237/14—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/26—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/12—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/16—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms condensed with carbocyclic rings or ring systems
- C07D249/18—Benzotriazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D253/00—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00
- C07D253/02—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00 not condensed with other rings
- C07D253/06—1,2,4-Triazines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
- C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D257/04—Five-membered rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
- C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
- C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
- C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more 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
- C07D261/18—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
- C07D265/34—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings
- C07D265/36—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings condensed with one six-membered ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
- C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
- C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
- C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
- C07D271/10—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole 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
- C07D277/28—Radicals substituted by nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole 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
- C07D277/30—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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three 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
- C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
- C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
- C07D295/205—Radicals derived from carbonic acid
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
- C07D305/02—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings
- C07D305/04—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D305/08—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings having no 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 atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D307/18—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no 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
- C07D307/20—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D307/18—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no 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
- C07D307/22—Nitrogen atoms not forming part of a nitro radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no 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
- C07D309/10—Oxygen atoms
- C07D309/12—Oxygen atoms only hydrogen atoms and one oxygen atom directly attached to ring carbon atoms, e.g. tetrahydropyranyl ethers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no 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
- C07D309/14—Nitrogen atoms not forming part of a nitro radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
- C07D317/62—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring 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 atoms of the carbocyclic ring
- C07D317/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D319/10—1,4-Dioxanes; Hydrogenated 1,4-dioxanes
- C07D319/14—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems
- C07D319/16—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D319/20—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring with substituents attached to the hetero ring
-
- 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
- C07D333/24—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
-
- 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
- C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/04—Systems containing only non-condensed rings with a four-membered ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
- C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
Definitions
- Isocitrate dehydrogenases catalyze the oxidative decarboxylation of isocitrate to 2-oxoglutarate (i.e., a-ketoglutarate). These enzymes belong to two distinct subclasses, one of which utilizes NAD(+) as the electron acceptor and the other NADP(+).
- NAD(+) the electron acceptor
- NADP(+)-dependent isocitrate dehydrogenases Five isocitrate dehydrogenases have been reported: three NAD(+)-dependent isocitrate dehydrogenases, which localize to the mitochondrial matrix, and two NADP(+)-dependent isocitrate dehydrogenases, one of which is mitochondrial and the other predominantly cytosolic. Each NADP(+)-dependent isozyme is a homodimer.
- IDH1 isocitrate dehydrogenase 1 (NADP+), cytosolic
- IDP isocitrate dehydrogenase 1
- IDCD isocitrate dehydrogenase 1
- PICD PICD
- the protein encoded by this gene is the NADP(+)-dependent isocitrate dehydrogenase found in the cytoplasm and peroxisomes. It contains the PTS-1 peroxisomal targeting signal sequence. The presence of this enzyme in peroxisomes suggests roles in the regeneration of NADPH for intraperoxisomal reductions, such as the conversion of 2, 4-dienoyl- CoAs to 3-enoyl-CoAs, as well as in peroxisomal reactions that consume 2-oxoglutarate, namely the alpha-hydroxylation of phytanic acid.
- the cytoplasmic enzyme serves a significant role in cytoplasmic NADPH production.
- the human IDH1 gene encodes a protein of 414 amino acids.
- the nucleotide and amino acid sequences for human IDH1 can be found as GenBank entries NM_005896.2 and
- NP_005887.2 respectively.
- the nucleotide and amino acid sequences for IDH1 are also described in, e.g., Nekrutenko et al., Mol. Biol. Evol. 15: 1674-1684(1998); Geisbrecht et al., J. Biol. Chem. 274:30527-30533(1999); Wiemann et al., Genome Res. 11:422-435(2001); The MGC Project Team, Genome Res.
- Non-mutant e.g., wild type, IDH1 catalyzes the oxidative decarboxylation of isocitrate to a-ketoglutarate thereby reducing NAD + (NADP + ) to NADP (NADPH), e.g., in the forward reaction:
- Described herein are methods of treating a cancer characterized by the presence of a mutant allele of IDHl .
- the methods comprise the step of administering to a subject in need thereof a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein:
- R 1 is selected from C 2 -C 6 alkyl, -(C C 3 alkylene)-0-(Ci-C 3 alkyl), carbocyclyl, -(C C 2 alkylene)-(carbocyclyl), aryl, -(CrC 2 alkylene)-(aryl), -(CrC 2 alkylene)-(heteroaryl), and -(Cr C 2 alkylene)-(heterocyclyl);
- R is selected from C 4 -Cg alkyl, carbocyclyl, aryl, heterocyclyl, heteroaryl, -(Ci-C 4 alkylene)-(aryl), and -(CrC 4 alkylene)-(heteroaryl);
- R 4 is selected from -CF 3 , -CH 2 -O-CH 3 and -R 5 -R 6 -R 7 , wherein:
- R 5 is selected from a bond; C C 3 straight or branched alkyl wherein one methylene unit in the alkyl of R 5 is optionally replaced with -O-, -S- or -S(O); and C 2 -C 3 alkenyl or alkynyl;
- R 6 is selected from a bond, -NH-C(O)-, -C(O)-NH-, -NH-S(O) 1-2 -, -S(O) 1-2 -NH-, and tetrazolyl;
- R is a carbocyclyl, aryl, heterocyclyl, or heteroaryl;
- R 8 is selected from hydrogen and CrC 4 alkyl; or R 8 and R 1 are taken together with the nitrogen atom to form a 5-12 membered heterocyclyl;
- R 9 is selected from hydrogen and C C 4 alkyl; or R 9 and R 2 are taken together to form a 6-12 membered carbocyclyl or a 5-12 membered heterocyclyl; or
- any carbocyclyl, aryl, heterocyclyl or heteroaryl is optionally substituted with one or more substituents.
- the compound of formula I inhibits mutant IDH1, particularly mutant IDH1 having alpha hydroxyl neoactivity. Also described herein are pharmaceutical compositions comprising a compound of formula I.
- halo or halogen refers to any radical of fluorine, chlorine, bromine or iodine.
- alkyl refers to a hydrocarbon chain that may be a straight chain or branched chain, containing the indicated number of carbon atoms. For example, C C 12 alkyl indicates that the group may have from 1 to 12 (inclusive) carbon atoms in it.
- haloalkyl refers to an alkyl in which one or more hydrogen atoms are replaced by halo, and includes alkyl moieties in which all hydrogens have been replaced by halo (e.g., perfluoro alkyl).
- arylalkyl or “aralkyl” refer to an alkyl moiety in which an alkyl hydrogen atom is replaced by an aryl group.
- Aralkyl includes groups in which more than one hydrogen atom has been replaced by an aryl group.
- arylalkyl or “aralkyl” include benzyl, 2-phenylethyl, 3- phenylpropyl, 9-fluorenyl, benzhydryl, and trityl groups.
- alkylene refers to a divalent alkyl, e.g., -CH 2 -, -CH 2 CH 2 -, and -CH 2 CH 2 CH 2 -.
- alkenyl refers to a straight or branched hydrocarbon chain containing 2-12 carbon atoms and having one or more double bonds.
- alkenyl groups include, but are not limited to, allyl, propenyl, 2-butenyl, 3-hexenyl and 3-octenyl groups.
- One of the double bond carbons may optionally be the point of attachment of the alkenyl substituent.
- alkynyl refers to a straight or branched hydrocarbon chain containing 2-12 carbon atoms and characterized in having one or more triple bonds. Examples of alkynyl groups include, but are not limited to, ethynyl, propargyl, and 3-hexynyl.
- One of the triple bond carbons may optionally be the point of attachment of the alkynyl substituent.
- alkoxy refers to an -O-alkyl radical.
- haloalkoxy refers to an alkoxy in which one or more hydrogen atoms are replaced by halo, and includes alkoxy moieties in which all hydrogens have been replaced by halo (e.g., perfluoroalkoxy).
- carbocyclyl refers to a monocyclic, bicyclic or tricyclic, hydrocarbon ring system that is not fully aromatic, wherein any ring atom capable of substitution can be substituted by one or more substituents.
- a carbocyclyl can be fully or partially saturated.
- a bicyclic or tricylic carbocyclyl may contain one (in the case of a bicycle) or up to two (in the case of a tricycle) aromatic rings, as long as at least one ring in the carbocyclyl is non-aromatic. Unless otherwise specified, any ring atom capable of substitution in a carbocyclyl can be substituted by one or more substituents.
- aryl refers to a fully aromatic monocyclic, bicyclic, or tricyclic hydrocarbon ring system. Examples of aryl moieties are phenyl, naphthyl, and anthracenyl. Unless otherwise specified, any ring atom in an aryl can be substituted by one or more substituents.
- cycloalkyl refers to a saturated cyclic, bicyclic, tricyclic, or polycyclic hydrocarbon group. Unless otherwise specified, any ring atom can be substituted by one or more substituents.
- the cycloalkyl groups can contain fused rings. Fused rings are rings that share a common carbon atom. Examples of cycloalkyl moieties include, but are not limited to, cyclopropyl, cyclohexyl, methylcyclohexyl, adamantyl, and norbornyl. Unless otherwise specified, any ring atom can be substituted by one or more substituents.
- heterocyclyl refers to a monocyclic, bicyclic or tricyclic, ring structure that is not fully aromatic and includes one to four heteroatoms independently selected from N, O, or S in one or more of the rings.
- a heterocyclyl can be fully or partially saturated.
- a bicyclic or tricylic heterocyclyl may contain one (in the case of a bicycle) or up to two (in the case of a tricycle) aromatic rings, as long as at least one ring in the heterocyclyl is non-aromatic. Unless otherwise specified, any ring atom capable of substitution in a heterocyclyl can be substituted by one or more substituents.
- Heterocyclyl groups include, for example, thiophene, thianthrene, furan, pyran, isobenzofuran, chromene, xanthene, phenoxathiin, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, pyrimidine, phenanthroline, phenazine, phenarsazine, phenothiazine, furazan, phenoxazine, pyrrolidine, o
- heteroaryl refers to a monocyclic, bicyclic, or tricyclic ring system having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms independently selected from O, N, or S, wherein each ring in a heteroaryl is fully aromatic. Unless otherwise specified, any ring atom capable of substitution in a heteroaryl can be substituted by one or more substituents.
- heteroalkyl and “heteroaralkyl”, as used herein, refers to an alkyl group substituted with a heteroaryl group.
- the ring heteroatoms of the compounds provided herein include N-O, S(O), and S(0) 2 .
- substituted refers to the replacement of a hydrogen atom with another moiety.
- substituents include alkyl (e.g., CI, C2, C3, C4, C5, C6, C7, C8, C9, CIO, Cl l, C12 straight or branched chain alkyl), cycloalkyl, haloalkyl (e.g., perfluoroalkyl such as CF 3 ), aryl, heteroaryl, aralkyl, heteroaralkyl, heterocyclyl, alkenyl, alkynyl, cycloalkenyl,
- the substituents on a group are independently any one single, or any subset of the aforementioned substituents.
- a substituent may itself be substituted with any one of the above substituents.
- the term “elevated levels of 2HG” means 10%, 20% 30%, 50%, 75%, 100%, 200%, 500% or more 2HG then is present in a subject that does not carry a mutant IDH1 allele.
- the term “elevated levels of 2HG” may refer to the amount of 2HG within a cell, within a tumor, within an organ comprising a tumor, or within a bodily fluid.
- the term "bodily fluid” includes one or more of amniotic fluid surrounding a fetus, aqueous humour, blood (e.g., blood plasma), serum, Cerebrospinal fluid, cerumen, chyme, Cowper's fluid, female ejaculate, interstitial fluid, lymph, breast milk, mucus (e.g., nasal drainage or phlegm), pleural fluid, pus, saliva, sebum, semen, serum, sweat, tears, urine, vaginal secretion, or vomit.
- blood e.g., blood plasma
- serum Cerebrospinal fluid
- cerumen cerumen
- chyme chyme
- Cowper's fluid female ejaculate
- interstitial fluid lymph
- breast milk mucus (e.g., nasal drainage or phlegm)
- mucus e.g., nasal drainage or phlegm
- pleural fluid pus, saliva, sebum, semen, serum
- inhibitor or “prevent” include both complete and partial inhibition and prevention.
- An inhibitor may completely or partially inhibit.
- treat means decrease, suppress, attenuate, diminish, arrest, or stabilize the development or progression of a cancer (e.g., a cancer delineated herein), lessen the severity of the cancer or improve the symptoms associated with the cancer.
- an amount of a compound effective to treat a disorder or a
- terapéuticaally effective amount refers to an amount of the compound which is effective, upon single or multiple dose administration to a subject, in treating a cell, or in curing, alleviating, relieving or improving a subject with a disorder beyond that expected in the absence of such treatment.
- the term "subject” is intended to include human and non-human animals.
- exemplary human subjects include a human patient having a disorder, e.g., a disorder described herein or a normal subject.
- non-human animals of the invention includes all vertebrates, e.g., non-mammals (such as chickens, amphibians, reptiles) and mammals, such as non-human primates, domesticated and/or agriculturally useful animals, e.g., sheep, dog, cat, cow, pig, etc.
- R 1 is selected from C 2 -C 6 alkyl, -(C C 3 alkylene)-0-(Ci-C 3 alkyl), carbocyclyl, -(C C 2 alkylene)-(carbocyclyl), aryl, -(CrC 2 alkylene)-(aryl), -(CrC 2 alkylene)-(heteroaryl), and -(Cr C 2 alkylene)-(heterocyclyl);
- R is selected from C 4 -Cg alkyl, carbocyclyl, aryl, heterocyclyl, heteroaryl, -(Ci-C 4 alkylene)-(aryl), and -(Ci-C 4 alkylene)-(heteroaryl);
- R 4 is selected from -CF 3 , -CH 2 -0-CH 3 , -CH 2 C1, -C(R 11 )-N(R 11 )-C(0)-0-(C 1 -C 4 alkyl) and -R 5 -R 6 -R 7 , wherein:
- R 5 is selected from a bond; C C 3 straight or branched alkyl wherein one methylene unit in the alkyl of R 5 is optionally replaced with -0-, -S-, -S(O)- or -S(0) 2 -; and C 2 -C 3 alkenyl or alkynyl;
- R 6 is selected from a bond, -N(R u )-C(0)-, -C(0)-N(R n )-, -N(R 11 )-S(0) 1-2 -,
- R is a carbocyclyl, aryl, heterocyclyl, or heteroaryl
- R 8 is selected from hydrogen and CrC 4 alkyl; or R 8 and R 1 are taken together with the nitrogen atom to form a 5-12 membered heterocyclyl;
- R 9 is selected from hydrogen and C C 4 alkyl; or R 9 and R 2 are taken together to form a 6-12 membered carbocyclyl or a 5-12 membered heterocyclyl; and each R is independently hydrogen or methyl,
- any carbocyclyl, aryl, heterocyclyl or heteroaryl is optionally substituted with more substituents; and wherein any hydrogen atom is replaced with deuterium.
- R 1 is selected from C 2 -C 6 alkyl, -(C 1 -C3 alkylene)-0-(Ci-C 3 alkyl), carbocyclyl, -(Ci-C 2 alkylene)-(carbocyclyl), aryl, -(CrC 2 alkylene)-(aryl), -(CrC 2 alkylene)-(heteroaryl), and -(Cr C 2 alkylene)- (heterocyclyl);
- R is selected from C 4 -Cg alkyl, carbocyclyl, aryl, heterocyclyl, heteroaryl, -(Ci-C 4 alkylene)- (aryl), and -(Ci-C 4 alkylene)-(heteroaryl);
- R 4 is selected from -CF 3 , -CH 2 -0-CH 3 and -R 5 -R 6 -R 7 , wherein:
- R 5 is selected from a bond; CrC 3 straight or branched alkyl wherein one methylene unit in the alkyl of R 5 is optionally replaced with -0-, -S- or -S(O); and C 2 -C 3 alkenyl or alkynyl;
- R 6 is selected from a bond, -NH-C(O)-, -C(0)-NH-, -NH-S(0)i_ 2 -, -S(0)i_ 2 -NH-, and tetrazolyl;
- R is a carbocyclyl, aryl, heterocyclyl, or heteroaryl
- R is s CrC 4 a R and R are taken together with the nitrogen atom to form a 5-12 membered heterocyclyl;
- R 9 is selected from hydrogen and C C 4 alkyl; or R 9 and R 2 are taken together to form a 6-12 membered carbocyclyl or a 5-12 membered heterocyclyl; or
- any cycloalkyl, phenyl or piperidinyl portion of a substituent is optionally further substituted with one or more substituents independently selected from halo, Q-C3 alkyl, CF , -NH 2 , and C C alkoxy.
- any carbocyclyl, aryl, heterocyclyl or heteroaryl portion of R 1 is optionally substituted with halo, or C C 4 alkoxy;
- any cycloalkyl, phenyl or piperidinyl portion of a substituent of R is optionally further substituted with one or more substituents independently selected from halo, CrC 3 alkyl, CF 3 , -NH 2 , and CrC 4 alkoxy; and
- R 1 is piperazinyl, morpholinyl, thiomorpholinyl, tetrahydrothiopyranyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, or tetrahydrofuranyl, wherein each member of R 1 is optionally substituted.
- R is selected from carbocyclyl, aryl, heterocyclyl, and heteroaryl, wherein each member of R is optionally substituted.
- R is carbocyclyl; aryl, heterocyclyl, heteroaryl, -(C 1 -C 2 alkylene)-(carbocyclyl), -(C 1 -C 2 alkylene)-(aryl), -(C 1 -C 2 alkylene)- (heterocyclyl), and -(C 1 -C 2 alkylene)-(heteroaryl), wherein each member of R is optionally substituted.
- R is cyclopropyl, cyclopentyl, cyclohexyl or benzyl, wherein each member of R is optionally substituted.
- I, I-a or I-b, -R 5 -R 6 -R 7 is not phenyl or N- methyleneisoindoline- 1 ,3-dione.
- R 6 is not -NHC(O)-.
- I, I-a or I-b, R 8 and R 1 are taken together with the nitrogen atom to form a 5-12 membered heterocyclyl.
- R is selected from carbocyclyl, aryl, heterocyclyl, and heteroaryl.
- -R 5 -R 6 -R 7 is not phenyl or N-methyleneisoindoline-l,3-dione.
- R 6 is not -NHC(O).
- R 9 is H. In another embodiment, R 9 is methyl or ethyl.
- I, I-a or I-b, R 9 and R 2 are taken together to form a 6-12 membered carbocyclyl or a 5-12 membered heterocyclyl, wherein carbocyclyl or heterocyclyl is optionally substituted.
- a compound of Formula I-c or a pharmaceutically acceptable salt thereof.
- R is selected from a C4-C7 monocyclic or bicyclic cycloalkyl optionally substituted on a single carbon atom with 1 to 2 fluoro; tetrahydropyranyl, pyrrolidinyl, phenyl, and t-butyl, wherein the phenyl and pyrrolidinyl are optionally substituted;
- R 2 is selected from phenyl, biphenyl, thien-2-yl, and furanyl, wherein R 2 is optionally substituted;
- R is selected from phenyl, biphenyl, pyridinyl, thiazolylmethyl, thienylmethyl, cyclohexyl and pyrazolyl, wherein any phenyl, biphenyl, pyridinyl, thiazolyl, thienyl, cyclohexyl or pyrazolyl portion of R is optionally substituted; and
- R 4 is as defined in formula A.
- R 1 is selected from cyclohexyl, cyclopentyl, cycloheptyl, cyclobutyl, 3,3-difluorocyclobutyl, 4,4,-difluorocyclohexyl, bicyclo[2.2.1]heptanyl, tertahydropyran-3-yl, tertahydropyran-4-yl, l-t-butoxycarbonylpyrrolidin-3-yl, t-butyl, 2- bromophenyl, 2-methylphenyl, and bicyclo[3.1.0]hexan-3-yl.
- R is selected from phenyl, 2-methylphenyl, 2- fluorphenyl, 2-chlorophenyl, 2-bromophenyl, 2-bromo-5-fluorophenyl, 2,5-dichlorophenyl, 2- fluoro-5-methylphenyl, thien-2-yl, 4-fluorophenyl, 5-bromofuran-2-yl, 3-methylthien-2-yl, 2,4,5- trifluorophenyl, 3-fluoro-5-chlorophenyl, 2,5-difluoro-6-chlorophenyl, 3-chlorophenyl, 3- fluorophenyl, 3-methylphenyl, 2,6-dimethylphenyl, 3-bromopohenyl, 2-ethylphenyl, 2- nitrophenyl, 3'-methoxybiphenyl-3-yl, 2,5-dibromo-6-fluorophenyl, 2-trifluor
- R is selected from 3-fluorophenyl, 3- methylphenyl, 3-chlorophenyl, thien-2-ylmethyl, 3-(l-methyl-lH-pyrazol-4-yl)phenyl, 1-methyl- lH-pyrazol-3-yl, 4-chlorophenyl, 3-acetylaminophenyl, 3'-trifluoromethoxy-biphenyl-3-yl, pyridin-3-yl, 4-fluorophenyl, thiazol-2-ylmethyl, cyclohexyl, 2-methylphenyl, 3-fluoro-4- methylphenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, phenyl, 3-bromophenyl, 2- fluorophenyl, 3-chloro-4-methylphenyl, 3-(pyriminidin-5-yl)phenyl, biphenyl-3-yl, 3-
- R 4 is selected from l-(methylmethoxycarbonylamino)ethyl, 1,2,3,4-tetrahydroquinolin-l-yl, l-ethoxycarbonylpiperidin-2-yl,
- the invention provides a compound of Formula II:
- R 1 is a C4-C7 monocyclic or bicyclic cycloalkyl optionally substituted on a single carbon atom with 1 to 2 fluoro;
- R is selected from 3-fluorophenyl, 3-methylphenyl, 3-chlorophenyl, and thien-2- ylmethyl;
- R 4 is selected from saturated heterocyclyl, -CH 2 -heterocyclyl, -CH 2 -heteroaryl, benzyl, -CH(R u )-N(R n )-heteroaryl, -CH(R 11 )-N(R 1 ⁇ -phenyl, -CH(R 11 )-N(R 1 ⁇ -heterocyclyl,
- each R 11 is independently selected from hydrogen and methyl; and each saturated heterocyclyl, heterocyclyl, phenyl, benzyl and heteroaryl is optionally substituted; and
- R 10 is selected from methyl, hydrogen, fluoro, chloro, and bromo.
- R 4 is other than thien-2-ylmethyl, 1H- benizimidazol-l-ylmethyl, lH-indol-3-ylmethyl, or lH-benzotriazol-l-ylmethyl;
- R 1 when R 1 is cyclopentyl, R 10 is hydrogen, and R 3 is 3-fluorophenyl, 3-methylphenyl, or 3- chlorophenyl, then R 4 is other than thien-2-ylmethyl;
- R 1 when R 1 is cyclopentyl, R 10 is methyl and R 3 is 3-fluorophenyl, then R 4 is other than thien-2-ylmethyl or lH-benzotriazol-l-ylmethyl;
- R 1 when R 1 is cyclopentyl, R 10 is fluoro and R 3 is 3-methylphenyl, then R 4 is other than thien-2-ylmethyl or lH-benzotriazol-l-ylmethyl;
- R 1 when R 1 is cyclopentyl, R 10 is fluoro and R 3 is 3-fluorophenyl, then R 4 is other than thien-2- ylmethyl ;
- R 4 when R 1 is cyclohexyl, R 10 is hydrogen, and R 3 is 3-methylphenyl, or 3-chlorophenyl, then R 4 is other than thien-3-ylmethyl; and when R 1 is cyclohexyl, R 10 is hydrogen, and R 3 is 3-fluorophenyl, then R 4 is other than lH-benzotriazol- 1-ylmethyl.
- R is 3-fluorophenyl
- R 1 is selected from cyclohexyl, cyclopentyl, cycloheptyl, 3,3-difluorocyclobutyl, 4,4,- difluorocyclohexyl, and bicyclo[2.2.1]heptanyl;
- R 4 is selected from l-(methylmethoxycarbonylamino)ethyl
- a compound is selected from any one of the compounds set forth in Table 2, below.
- the compound is selected from any one of Compound numbers 104, 126, 135, 140, 150, 155, 160, 161, 165, 173, 185, 186, 197, 198, 201, 202, 203, 210, 212, 213, 217, 218, 227, 228, 237, 240, 247, 253, 260, 265, 271, 272, 275, 276, 287, 288, 289, 290, 291, 293, 297, 301, 306, 307, 311, 313, 314, 316, 320, 321, 322, 331, 334, 341, 344, 348, 351, 356, 359, 361, 366, 378, 381, and 385 from Table 2.
- the compounds of this invention may contain one or more asymmetric centers and thus occur as racemates, racemic mixtures, scalemic mixtures, and diastereomeric mixtures, as well as single enantiomers or individual stereoisomers that are substantially free from another possible enantiomer or stereoisomer.
- substantially free of other stereoisomers means a preparation enriched in a compound having a selected stereochemistry at one or more selected stereocenters by at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%,
- enriched means that at least the designated percentage of a preparation is the compound having a selected stereochemistry at one or more selected stereocenters.
- the compound of Formula I is enriched for a structure or structures having a selected stereochemistry at the carbon atom that is bound to
- the selected stereochemistry at that carbon atom is R. In another embodiment the selected stereochemistry at that carbon atom is S.
- the compound is enriched in the specific stereoisomer by at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%.
- the compounds of formula I may also comprise one or more isotopic substitutions.
- H may be in any isotopic form, including 1 H, 2 H (D or deuterium), and 3 H (T or tritium);
- C may be in any isotopic form, including 12 C, 13 C, and 14 C;
- O may be in any isotopic form, including 16 0 and 18 0; and the like.
- the compounds of this invention may also be represented in multiple tautomeric forms, in such instances, the invention expressly includes all tautomeric forms of the compounds described herein, even though only a single tautomeric form may be represented (e.g., alkylation of a ring system may result in alkylation at multiple sites, the invention expressly includes all such reaction products). All such isomeric forms of such compounds are expressly included in the present invention. All crystal forms of the compounds described herein are expressly included in the present invention.
- Certain compounds of the invention are available from commercial and/or public compound libraries, such as those sold by Evotec AG (Hamburg, Germany) and its affiliates, Asinex Ltd (Moscow, Russia) and its affiliates, and thorough the National Institute of Health.
- Other compounds of the invention can be synthesized by the ordinary skilled artisan using methods well known in the art, such as through Ugi chemistry.
- compounds of the invention may be prepared according to one or more of the following general schemes.
- Certain compounds of Formula A comprising an amine in R 4 were also prepared from chloroacetyl e according to Scheme 2.
- Chloroacetyl e was synthesized according to Scheme 1, using 2-chloroacetic acid (c') in place of the carboxylic acid of R 4 .
- Chloroacetyl e was then used to produce compounds of the invention containing secondary and tertiary amines in R 4 .
- R a represents hydrogen or Q-C3 alkyl
- R b represents -R 6 -R 7 , as those variables are defined for Formula A; or R a and R b are taken together to form an optionally substituted heterocyclyl or heteroaryl.
- the reaction between chloroacetyl e and the amine may be achieved under several different conditions: a) in the presence of Et 3 N in DCM and TBAI; b) by refluxing in the presence of Et 3 N in toluene under an N 2 atmosphere; c) in the presence of Nal in acetone and moderate heat (e.g., 70 *C); or d) in the presence of Et 3 N in DMF.
- Certain compounds of Formula A wherein R 1 is -CH 2 -0-R 7 were prepared from chloroacetyl e and the appropriate R hydroxyl. This reaction can be carried out in the presence of KOH and DMSO, or in the presence of K 2 C0 3 in MeCN, heated to 40 ⁇ €.
- R 4 is -C(R n )-N(R u )-0-CH 3 , or 1- methyloxycarbonylpyrrolidin-2-yl
- each R 12 is independently hydrogen or methyl, or two adjacent R 12 are taken together with the carbon and nitrogen atoms to which they are respectively bound to form a pyrrolidine or piperidine ring.
- t-butyl derivative 1 is formed according to Scheme 1, using carboxylic acid k in place of carboxylic acid of R 4 (c). Treatment of 1 with acid produces amine m, which is converted to the compound of Formula A by treatment with methyl chloroformate.
- a corresponding salt of the active compound for example, a pharmaceutically-acceptable salt.
- a salt may be formed with a suitable cation.
- suitable inorganic cations include, but are not limited to, alkali metal ions such as Na + and K + , alkaline earth cations such as Ca 2+ and Mg 2+ , and other cations such as Al 3+ .
- Suitable organic cations include, but are not limited to, ammonium ion (i.e., NH 4 + ) and substituted ammonium ions (e.g., NH 3 R + , NH 2 R 2+ , NHR 3+ , NR 4+ ).
- suitable substituted ammonium ions are those derived from: ethylamine, diethylamine,
- dicyclohexylamine triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine, and tromethamine, as well as amino acids, such as lysine and arginine.
- An example of a common quaternary ammonium ion is N(CH 3 ) 4 + .
- a salt may be formed with a suitable anion.
- suitable inorganic anions include, but are not limited to, those derived from the following inorganic acids:
- hydrochloric hydrobromic, hydroiodic, sulfuric, sulfurous, nitric, nitrous, phosphoric, and phosphorous.
- Suitable organic anions include, but are not limited to, those derived from the following organic acids: 2-acetyoxybenzoic, acetic, ascorbic, aspartic, benzoic,
- glucoheptonic, gluconic, glutamic glycolic, hydroxymaleic, hydroxynaphthalene carboxylic, isethionic, lactic, lactobionic, lauric, maleic, malic, methanesulfonic, mucic, oleic, oxalic, palmitic, pamoic, pantothenic, phenylacetic, phenylsulfonic, propionic, pyruvic, salicylic, stearic, succinic, sulfanilic, tartaric, toluenesulfonic, and valeric.
- suitable polymeric organic anions include, but are not limited to, those derived from the following polymeric acids: tannic acid, carboxymethyl cellulose.
- a reference to a particular compound also includes salt forms thereof.
- compositions and routes of administration are provided.
- compositions may be formulated together with a pharmaceutically acceptable carrier or adjuvant into pharmaceutically acceptable compositions prior to be administered to a subject.
- pharmaceutically acceptable compositions further comprise additional therapeutic agents in amounts effective for achieving a modulation of disease or disease symptoms, including those described herein.
- pharmaceutically acceptable carrier or adjuvant refers to a carrier or adjuvant that may be administered to a subject, together with a compound of this invention, and which does not destroy the pharmacological activity thereof and is nontoxic when administered in doses sufficient to deliver a therapeutic amount of the compound.
- Pharmaceutically acceptable carriers, adjuvants and vehicles that may be used in the pharmaceutical compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d- cc- tocopherol polyethyleneglycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tweens or other similar polymeric delivery matrices, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, poly
- Cyclodextrins such as ⁇ -, ⁇ -, and ⁇ -cyclodextrin, or chemically modified derivatives such as hydroxyalkylcyclodextrins, including 2- and 3-hydroxypropyl-P-cyclodextrins, or other solubilized derivatives may also be advantageously used to enhance delivery of compounds of the formulae described herein.
- compositions of this invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir, preferably by oral administration or administration by injection.
- the pharmaceutical compositions of this invention may contain any conventional non-toxic pharmaceutically-acceptable carriers, adjuvants or vehicles.
- the pH of the formulation may be adjusted with pharmaceutically acceptable acids, bases or buffers to enhance the stability of the formulated compound or its delivery form.
- parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.
- the pharmaceutical compositions may be in the form of a sterile injectable preparation, for example, as a sterile injectable aqueous or oleaginous suspension.
- This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents.
- the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
- suitable vehicles and solvents that may be employed are mannitol, water, Ringer's solution and isotonic sodium chloride solution.
- sterile, fixed oils are conventionally employed as a solvent or suspending medium.
- any bland fixed oil may be employed including synthetic mono- or diglycerides.
- Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
- These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, or carboxymethyl cellulose or similar dispersing agents which are commonly used in the formulation of pharmaceutically acceptable dosage forms such as emulsions and or suspensions.
- compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, emulsions and aqueous suspensions, dispersions and solutions.
- carriers which are commonly used include lactose and corn starch.
- Lubricating agents such as magnesium stearate, are also typically added.
- useful diluents include lactose and dried corn starch.
- the active ingredient When aqueous suspensions and/or emulsions are administered orally, the active ingredient may be suspended or dissolved in an oily phase is combined with emulsifying and/or suspending agents. If desired, certain sweetening and/or flavoring and/or coloring agents may be added.
- compositions of this invention may also be administered in the form of suppositories for rectal administration.
- These compositions can be prepared by mixing a compound of this invention with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the active components.
- suitable non-irritating excipient include, but are not limited to, cocoa butter, beeswax and polyethylene glycols.
- Topical administration of the pharmaceutical compositions of this invention is useful when the desired treatment involves areas or organs readily accessible by topical application.
- the pharmaceutical composition should be formulated with a suitable ointment containing the active components suspended or dissolved in a carrier.
- Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petroleum, white petroleum, propylene glycol, polyoxyethylene
- the pharmaceutical composition can be formulated with a suitable lotion or cream containing the active compound suspended or dissolved in a carrier with suitable emulsifying agents.
- suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
- the pharmaceutical compositions of this invention may also be topically applied to the lower intestinal tract by rectal suppository formulation or in a suitable enema formulation. Topically-transdermal patches are also included in this invention.
- the pharmaceutical compositions of this invention may be administered by nasal aerosol or inhalation.
- compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art.
- compositions of this invention comprise a combination of a compound of the formulae described herein and one or more additional therapeutic or prophylactic agents
- both the compound and the additional agent should be present at dosage levels of between about 1 to 100%, and more preferably between about 5 to 95% of the dosage normally administered in a monotherapy regimen.
- the additional agents may be administered separately, as part of a multiple dose regimen, from the compounds of this invention. Alternatively, those agents may be part of a single dosage form, mixed together with the compounds of this invention in a single composition.
- the compounds described herein can, for example, be administered by injection, intravenously, intraarterially, subdermally, intraperitoneally, intramuscularly, or subcutaneously; or orally, buccally, nasally, transmucosally, topically, in an ophthalmic preparation, or by inhalation, with a dosage ranging from about 0.5 to about 100 mg/kg of body weight, alternatively dosages between 1 mg and 1000 mg/dose, every 4 to 120 hours, or according to the requirements of the particular drug.
- the methods herein contemplate administration of an effective amount of compound or compound composition to achieve the desired or stated effect.
- the pharmaceutical compositions of this invention will be administered from about 1 to about 6 times per day or alternatively, as a continuous infusion.
- Such administration can be used as a chronic or acute therapy.
- the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
- a typical preparation will contain from about 5% to about 95% active compound (w/w).
- such preparations contain from about 20% to about 80% active compound.
- a maintenance dose of a compound, composition or combination of this invention may be administered, if necessary. Subsequently, the dosage or frequency of administration, or both, may be reduced, as a function of the symptoms, to a level at which the improved condition is retained when the symptoms have been alleviated to the desired level. Subjects may, however, require intermittent treatment on a long- term basis upon any recurrence of disease symptoms.
- compositions described above comprising a compound of formula I or a compound described in any one of the embodiments herein, may further comprise another therapeutic agent useful for treating cancer.
- the mutant IDHl has an R132X mutation.
- the R132X mutation is selected from R132H, R132C, R132L, R132V, R132S and R132G. In another aspect, the R132X mutation is R132 H.
- Also provided are methods of treating a cancer characterized by the presence of a mutant allele of IDHl comprising the step of administering to subject in need thereof (a) a compound of formula I, a compound described in any one of the embodiments herein, or a pharmaceutically acceptable salt thereof, or (b) a pharmaceutical composition comprising (a) and a
- the cancer to be treated is characterized by a mutant allele of IDHl having an R132X mutation.
- the R132X mutation is selected from R132H, R132C, R132L, R132V, R132S and R132G.
- the R132X mutation is R132 H.
- a cancer can be analyzed by sequencing cell samples to determine the presence of a mutation at amino acid 132 of IDHl .
- the cancer to be treated is further characterized by elevated levels of 2HG.
- the efficacy of cancer treatment is monitored by measuring the levels of 2HG in the subject. Typically levels of 2HG are measured prior to treatment, wherein an elevated level is indicative of the use of the compound of Formula I to treat the cancer.
- the level of 2HG is determined during the course of and/or following termination of treatment to establish efficacy.
- the level of 2HG is only determined during the course of and/or following termination of treatment.
- a reduction of 2HG levels during the course of treatment and following treatment is indicative of efficacy.
- a determination that 2HG levels are not elevated during the course of or following treatment is also indicative of efficacy.
- the these 2HG measurements will be utilized together with other well-known determinations of efficacy of cancer treatment, such as reduction in number and size of tumors and/or other cancer- associated lesions, improvement in the general health of the subject, and alterations in other biomarkers that are associated with cancer treatment efficacy.
- 2HG can be detected in a sample by LC/MS.
- the sample is mixed 80:20 with methanol, and centrifuged at 3,000 rpm for 20 minutes at 4 degrees Celsius.
- the resulting supernatant can be collected and stored at -80 degrees Celsius prior to LC-MS/MS to assess 2-hydroxyglutarate levels.
- LC liquid chromatography
- Each method can be coupled by negative electrospray ionization (ESI, -3.0 kV) to triple-quadrupole mass spectrometers operating in multiple reaction monitoring (MRM) mode, with MS parameters optimized on infused metabolite standard solutions.
- ESI, -3.0 kV negative electrospray ionization
- MRM multiple reaction monitoring
- Metabolites can be separated by reversed phase chromatography using 10 mM tributyl- amine as an ion pairing agent in the aqueous mobile phase, according to a variant of a previously reported method (Luo et al. J Chromatogr A 1147, 153-64, 2007).
- Another method is specific for 2-hydroxyglutarate, running a fast linear gradient from 50% -95% B (buffers as defined above) over 5 minutes.
- a Synergi Hydro-RP, 100mm x 2 mm, 2.1 ⁇ particle size (Phenomonex) can be used as the column, as described above.
- Metabolites can be quantified by comparison of peak areas with pure metabolite standards at known concentration.
- Metabolite flux studies from C-glutamine can be performed as described, e.g., in Munger et al. Nat Biotechnol 26, 1179-86, 2008.
- 2HG is directly evaluated.
- a derivative of 2HG formed in process of performing the analytic method is evaluated.
- a derivative can be a derivative formed in MS analysis.
- Derivatives can include a salt adduct, e.g., a Na adduct, a hydration variant, or a hydration variant which is also a salt adduct, e.g., a Na adduct, e.g., as formed in MS analysis.
- a metabolic derivative of 2HG is evaluated.
- examples include species that build up or are elevated, or reduced, as a result of the presence of 2HG, such as glutarate or glutamate that will be correlated to 2HG, e.g., R-2HG.
- Exemplary 2HG derivatives include dehydrated derivatives such as the compounds provided below or a salt adduct thereof:
- the cancer is a tumor wherein at least 30, 40, 50, 60, 70, 80 or 90% of the tumor cells carry an IDH1 mutation at the time of diagnosis or treatment.
- the cancer to be treated is characterized by a mutant allele of IDH1 wherein the IDH1 mutation result in a new ability of the enzyme to catalyze the NAPH- dependent reduction of a-ketoglutarate to R(-)-2-hydroxyglutarate in a patient.
- the IDH1 mutation is an R132X mutation.
- the R132X mutation is selected from R132H, R132C, R132L, R132V, R132S and R132G.
- the R132X mutation is R132 H or R132C.
- a cancer can be analyzed by sequencing cell samples to determine the presence and specific nature of (e.g., the changed amino acid present at) a mutation at amino acid 132 of IDH1.
- mutant alleles of IDH1 wherein the IDH1 mutation result in a new ability of the enzyme to catalyze the NAPH-dependent reduction of a-ketoglutarate to R(-)-2-hydroxyglutarate, and in particular R132H mutations of IDH1, characterize a subset of all types of cancers, without regard to their cellular nature or location in the body.
- the compounds and methods of this invention are useful to treat any type of cancer that is characterized by the presence of a mutant allele of IDH1 imparting such acitivity and in particular an IDH1 R132H mutation.
- the methods described herein can be used to treat a cancer, for example those described by the National Cancer Institute.
- a cancer can be evaluated to determine whether it contains an IDH mutant using a method described herein.
- Exemplary cancers described by the National Cancer Institute include: Acute Lymphoblastic Leukemia, Adult; Acute Lymphoblastic
- Adrenocortical Carcinoma Childhood; AIDS-Related Lymphoma; AIDS-Related Malignancies; Anal Cancer; Astrocytoma, Childhood Cerebellar; Astrocytoma, Childhood Cerebral; Bile Duct Cancer, Extrahepatic; Bladder Cancer; Bladder Cancer, Childhood; Bone Cancer,
- Osteosarcoma/Malignant Fibrous Histiocytoma Brain Stem Glioma, Childhood; Brain Tumor, Adult; Brain Tumor, Brain Stem Glioma, Childhood; Brain Tumor, Cerebellar Astrocytoma, Childhood; Brain Tumor, Cerebral Astrocytoma/Malignant Glioma, Childhood; Brain Tumor, Ependymoma, Childhood; Brain Tumor, Medulloblastoma, Childhood; Brain Tumor,
- Retinoblastoma Gallbladder Cancer; Gastric (Stomach) Cancer; Gastric (Stomach) Cancer, Childhood; Gastrointestinal Carcinoid Tumor; Germ Cell Tumor, Extracranial, Childhood; Germ Cell Tumor, Extragonadal; Germ Cell Tumor, Ovarian; Gestational Trophoblastic Tumor; Glioma, Childhood Brain Stem; Glioma, Childhood Visual Pathway and Hypothalamic; Hairy Cell Leukemia; Head and Neck Cancer; Hepatocellular (Liver) Cancer, Adult (Primary);
- Laryngeal Cancer Childhood; Leukemia, Acute Lymphoblastic, Adult; Leukemia, Acute Lymphoblastic, Childhood; Leukemia, Acute Myeloid, Adult; Leukemia, Acute Myeloid, Childhood; Leukemia, Chronic Lymphocytic; Leukemia, Chronic Myelogenous; Leukemia, Hairy Cell; Lip and Oral Cavity Cancer; Liver Cancer, Adult (Primary); Liver Cancer,
- Lung Cancer Non-Small Cell
- Lung Cancer Small Cell
- Lymphoblastic Leukemia Adult Acute
- Lymphoblastic Leukemia Childhood Acute
- Lymphocytic Leukemia Chronic
- Lymphoma AIDS- Related
- Lymphoma Central Nervous System
- Lymphoma Cutaneous T-Cell; Lymphoma, Hodgkin's, Adult; Lymphoma, Hodgkin's,
- Lymphoma Hodgkin's During Pregnancy; Lymphoma, Non-Hodgkin's, Adult;
- Lymphoma Non- Hodgkin's, Childhood; Lymphoma, Non-Hodgkin's During Pregnancy;
- Lymphoma Primary Central Nervous System; Macroglobulinemia, Waldenstrom's; Male Breast Cancer; Malignant Mesothelioma, Adult; Malignant Mesothelioma, Childhood; Malignant Thymoma; Medulloblastoma, Childhood; Melanoma; Melanoma, Intraocular; Merkel Cell Carcinoma; Mesothelioma, Malignant; Metastatic Squamous Neck Cancer with Occult Primary; Multiple Endocrine Neoplasia Syndrome, Childhood; Multiple Myeloma/Plasma Cell Neoplasm; Mycosis Fungoides; Myelodysplasia Syndromes; Myelogenous Leukemia, Chronic; Myeloid Leukemia, Childhood Acute; Myeloma, Multiple; Myeloproliferative Disorders, Chronic; Nasal Cavity and Paranasal Sinus Cancer; Nasopharyngeal Cancer; Nasopharyngeal Cancer,
- Pancreatic Cancer Pancreatic Cancer; Pancreatic Cancer, Childhood; Pancreatic Cancer, Islet Cell; Paranasal Sinus and Nasal Cavity Cancer; Parathyroid Cancer; Penile Cancer; Pheochromocytoma; Pineal and Supratentorial Primitive Neuroectodermal Tumors, Childhood; Pituitary Tumor; Plasma Cell Neoplasm/Multiple Myeloma; Pleuropulmonary Blastoma; Pregnancy and Breast Cancer;
- Pregnancy and Hodgkin's Lymphoma Pregnancy and Non-Hodgkin's Lymphoma; Primary Central Nervous System Lymphoma; Primary Liver Cancer, Adult; Primary Liver Cancer, Childhood; Prostate Cancer; Rectal Cancer; Renal Cell (Kidney) Cancer; Renal Cell Cancer, Childhood; Renal Pelvis and Ureter, Transitional Cell Cancer; Retinoblastoma;
- Thyroid Cancer Thyroid Cancer
- Thyroid Cancer Childhood
- Transitional Cell Cancer of the Renal Pelvis and Ureter Trophoblastic Tumor, Gestational; Unknown Primary Site, Cancer of, Childhood;
- Metastases of the aforementioned cancers can also be treated or prevented in accordance with the methods described herein.
- Gliomas a type of brain tumors, can be classified as grade I to grade IV on the basis of histopathological and clinical criteria established by the World Health Organization (WHO). WHO grade I gliomas are often considered benign. Gliomas of WHO grade II or III are invasive, progress to higher-grade lesions. WHO grade IV tumors (glioblastomas) are the most invasive form.
- WHO World Health Organization
- Exemplary brain tumors include, e.g., astrocytic tumor (e.g., pilocytic astrocytoma, subependymal giant-cell astrocytoma, diffuse astrocytoma, pleomorphic xanthoastrocytoma, anaplastic astrocytoma, astrocytoma, giant cell glioblastoma, glioblastoma, secondary glioblastoma, primary adult glioblastoma, and primary pediatric glioblastoma); oligodendroglial tumor (e.g., pilocytic astrocytoma, subependymal giant-cell astrocytoma, diffuse astrocytoma, pleomorphic xanthoastrocytoma, anaplastic astrocytoma, astrocytoma, giant cell glioblastoma, glioblastoma, secondary glioblastoma, primary adult gli
- oligodendroglioma oligodendroglioma, and anaplastic oligodendroglioma
- oligoastrocytic tumor e.g.,
- oligoastrocytoma oligoastrocytoma, and anaplastic oligoastrocytoma
- ependymoma e.g., myxopapillary ependymoma, and anaplastic ependymoma
- medulloblastoma primitive neuroectodermal tumor, schwannoma, meningioma, metatypical meningioma, anaplastic meningioma
- Exemplary cancers are described in Acta Neuropathol (2008) 116:597-602 and N Engl J Med. 2009 Feb 19; 360(8):765-73, the contents of which are each incorporated herein by reference.
- the cancer is glioblastoma.
- the cancer is paragangliomas.
- the cancer is fibrosarcoma.
- the cancer is prostate cancer, e.g., stage Tl (e.g., Tla, Tib and Tic), T2 (e.g., T2a, T2b and T2c), T3 (e.g., T3a and T3b) and T4, on the TNM staging system.
- the prostate cancer is grade Gl, G2, G3 or G4 (where a higher number indicates greater difference from normal tissue).
- Types of prostate cancer include, e.g., prostate adenocarcinoma, small cell carcinoma, squamous carcinoma, sarcomas, and transitional cell carcinoma.
- the disorder is localized or metastatic prostate cancer, e.g., prostate adenocarcinoma.
- the disorder is a hematological cancer, e.g., a leukemia, e.g., AML, or acute lymphoblastic leukemia ("ALL").
- a leukemia e.g., AML
- ALL acute lymphoblastic leukemia
- the cancer is ALL (e.g., an adult or pediatric form).
- the cancer is B-ALL or T- ALL
- IDH1 R132X mutations are known to occur in certain types of cancers as indicated in Table 3, below.
- the cancer is a cancer selected from any one of the cancer types listed in Table 3, and the IDH R132X mutation is one or more of the IDHl R132X mutations listed in Table 3 for that particular cancer type.
- Treatment methods described herein can additionally comprise various evaluation steps prior to and/or following treatment with a compound of formula I or a compound described in any one of the embodiments described herein.
- the method further comprises the step of evaluating the growth, size, weight, invasiveness, stage and/or other phenotype of the cancer.
- the method further comprises the step of evaluating the IDH1 genotype of the cancer. This may be achieved by ordinary methods in the art, such as DNA sequencing, immuno analysis, and/or evaluation of the presence, distribution or level of 2HG.
- the method further comprises the step of determining the 2HG level in the subject.
- This may be achieved by spectroscopic analysis, e.g., magnetic resonance-based analysis, e.g., MRI and/or MRS measurement, sample analysis of bodily fluid, such as serum or spinal cord fluid analysis, or by analysis of surgical material, e.g., by mass-spectroscopy.
- the methods described herein comprise the additional step of coadministering to a subject in need thereof a second therapy e.g., an additional cancer therapeutic agent or an additional cancer treatment.
- additional cancer therapeutic agents include for example, chemotherapy, targeted therapy, antibody therapies, immunotherapy, and hormonal therapy.
- Additional cancer treatments include, for example: surgery, and radiation therapy. Examples of each of these treatments are provided below.
- co-administering means that the additional cancer therapeutic agent may be administered together with a compound of this invention as part of a single dosage form (such as a
- composition of this invention comprising a compound of the invention and an second therapeutic agent as described above) or as separate, multiple dosage forms.
- the additional cancer therapeutic agent may be administered prior to, consecutively with, or following the administration of a compound of this invention.
- both the compounds of this invention and the second therapeutic agent(s) are administered by
- composition of this invention comprising both a compound of the invention and a second therapeutic agent
- administration of a composition of this invention does not preclude the separate administration of that same therapeutic agent, any other second therapeutic agent or any compound of this invention to said subject at another time during a course of treatment.
- co-administering as used herein with respect to an additional cancer treatment means that the additional cancer treatment may occur prior to, consecutively with, concurrently with or following the administration of a compound of this invention.
- the additional cancer therapeutic agent is a chemotherapy agent.
- chemotherapeutic agents used in cancer therapy include, for example,
- antimetabolites e.g., folic acid, purine, and pyrimidine derivatives
- alkylating agents e.g., nitrogen mustards, nitrosoureas, platinum, alkyl sulfonates, hydrazines, triazenes, aziridines, spindle poison, cytotoxic agents, topoisomerase inhibitors and others.
- agents include Aclarubicin, Actinomycin, Alitretinoin, Altretamine, Aminopterin, Aminolevulinic acid, Amrubicin, Amsacrine, Anagrelide, Arsenic trioxide, Asparaginase, Atrasentan, Belotecan, Bexarotene, bendamustine, Bleomycin, Bortezomib, Busulfan, Camptothecin, Capecitabine, Carboplatin, Carboquone, Carmofur, Carmustine, Celecoxib, Chlorambucil, Chlormethine, Cisplatin, Cladribine, Clofarabine, Crisantaspase, Cyclophosphamide, Cytarabine, dacarbazine, Dactinomycin, Daunorubicin, Decitabine, Demecolcine, Docetaxel, Doxorubicin, Efaproxiral, Elesclomol, Elsamitrucin, Eno
- Floxuridine Fludarabine, Fluorouracil (5FU), Fotemustine, Gemcitabine, Gliadel implants, Hydroxycarbamide, Hydroxyurea, Idarubicin, Ifosfamide, Irinotecan, Irofulven, Ixabepilone, Larotaxel, Leucovorin, Liposomal doxorubicin, Liposomal daunorubicin, Lonidamine,
- two or more drugs are often given at the same time.
- two or more chemotherapy agents are used as combination chemotherapy.
- the additional cancer therapeutic agent is a targeted therapy agent.
- Targeted therapy constitutes the use of agents specific for the deregulated proteins of cancer cells.
- Small molecule targeted therapy drugs are generally inhibitors of enzymatic domains on mutated, overexpressed, or otherwise critical proteins within the cancer cell.
- Prominent examples are the tyrosine kinase inhibitors such as Axitinib, Bosutinib, Cediranib, dasatinib, erlotinib, imatinib, gefitinib, lapatinib, Lestaurtinib, Nilotinib, Semaxanib, Sorafenib, Sunitinib, and Vandetanib, and also cyclin-dependent kinase inhibitors such as Alvocidib and Seliciclib.
- Monoclonal antibody therapy is another strategy in which the therapeutic agent is an antibody which specifically binds to a protein on the surface of the cancer cells. Examples include the anti-HER2/neu antibody trastuzumab (HERCEPTIN®) typically used in breast cancer, and the anti-CD20 antibody rituximab and Tositumomab typically used in a variety of B-cell
- exemplary antibodies include Cetuximab, Panitumumab, Trastuzumab, Alemtuzumab, Bevacizumab, Edrecolomab, and Gemtuzumab.
- exemplary fusion proteins include Aflibercept and Denileukin diftitox.
- the targeted therapy can be used in combination with a compound described herein, e.g., a biguanide such as metformin or phenformin, preferably phenformin.
- Targeted therapy can also involve small peptides as "homing devices” which can bind to cell surface receptors or affected extracellular matrix surrounding the tumor. Radionuclides which are attached to these peptides (e.g., RGDs) eventually kill the cancer cell if the nuclide decays in the vicinity of the cell.
- RGDs Radionuclides which are attached to these peptides
- An example of such therapy includes BEXXAR®.
- the additional cancer therapeutic agent is an immunotherapy agent.
- Cancer immunotherapy refers to a diverse set of therapeutic strategies designed to induce the subject's own immune system to fight the tumor. Contemporary methods for generating an immune response against tumors include intravesicular BCG immunotherapy for superficial bladder cancer, and use of interferons and other cytokines to induce an immune response in renal cell carcinoma and melanoma subjects. Allogeneic hematopoietic stem cell transplantation can be considered a form of immunotherapy, since the donor's immune cells will often attack the tumor in a graft- versus- tumor effect.
- the immunotherapy agents can be used in combination with a compound or composition described herein.
- the additional cancer therapeutic agent is a hormonal therapy agent.
- the growth of some cancers can be inhibited by providing or blocking certain hormones.
- hormone- sensitive tumors include certain types of breast and prostate cancers. Removing or blocking estrogen or testosterone is often an important additional treatment.
- administration of hormone agonists, such as progestogens may be therapeutically beneficial.
- the hormonal therapy agents can be used in combination with a compound or a composition described herein.
- Other possible additional therapeutic modalities include imatinib, gene therapy, peptide and dendritic cell vaccines, synthetic chlorotoxins, and radiolabeled drugs and antibodies.
- HOBt 1 hydroxybenzotriazole HATU 0-(7-azabenzotriazol- l-yl)-N,N,N',N'-tetra-methyluronium
- the reagents were purchased from commercial sources (such as Alfa, Acros, Sigma Aldrich, TCI and Shanghai Chemical Reagent Company), and used without further purification. Flash chromatography was performed on an Ez Purifier III via column with silica gel particles of 200-300 mesh.
- Analytical and preparative thin layer chromatography plates were HSGF 254 (0.15-0.2 mm thickness, Shanghai Anbang Company, China).
- Nuclear magnetic resonance (NMR) spectra were obtained on a Brucker AMX-300 or a AMX-300 NMR (Brucker, Switzerland). Chemical shifts were reported in parts per million (ppm, ⁇ ) downfield from tetramethylsilane. Mass spectra were run with electrospray ionization (ESI) from a Waters LCT TOF Mass Spectrometer (Waters, USA).
- Step A Compound 204.
- a mixture of 2-methyl-benzaldehyde (193 mg, 1.61 mmol) and thiophen-2-yl-methylamine (182 mg, 1.61 mmol) in MeOH (4 ml) was stirred at RT for 30 minutes.
- Imidazol-l-yl-acetic acid (202 mg, 1.61 mmol) was added and the reaction mixture stirred for 10 minutes.
- Cyclohexyl isocyanide (176 mg, 1.61 mmol) was then added and the reaction mixture was stirred at RT overnight. The precipitate was filtered and washed with MeOH to afford the desired product (463 mg, 64% yield).
- Step B Compound 204 HCl Salt.
- Compound 204 (460 mg, 1.02 mmol) in HCl/Et 2 0 (5 M, 20 ml) was stirred at room temperature for 3 hours. The resulting mixture was concentrated and the solid was treated with Et 2 0 to give the HCl salt (350 mg, 70% yield).
- Example 2 Preparation of Compound 160 and its HC1 Salt.
- Compound 160 was synthesized following Scheme 2, above using the following protocol.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Epoxy Compounds (AREA)
- Pyrane Compounds (AREA)
- Pyrrole Compounds (AREA)
- Indole Compounds (AREA)
- Thiazole And Isothizaole Compounds (AREA)
- Furan Compounds (AREA)
- Heterocyclic Compounds Containing Sulfur Atoms (AREA)
- Pyridine Compounds (AREA)
- Hydrogenated Pyridines (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Other In-Based Heterocyclic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
- Heterocyclic Compounds That Contain Two Or More Ring Oxygen Atoms (AREA)
Abstract
Description
Claims
Priority Applications (10)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201180043254.6A CN103097340B (en) | 2010-07-16 | 2011-07-15 | Therapeutic activity composition and its application method |
BR112013001122-0A BR112013001122B1 (en) | 2010-07-16 | 2011-07-15 | compound of formula ii, use of the compound and pharmaceutical composition comprising said compound |
CA2805669A CA2805669C (en) | 2010-07-16 | 2011-07-15 | Therapeutically active compositions and their methods of use |
ES11738902T ES2704862T3 (en) | 2010-07-16 | 2011-07-15 | Therapeutically active compositions and their method of use |
US13/810,410 US20130184222A1 (en) | 2010-07-16 | 2011-07-15 | Therapeutically active compositions and their methods of use |
JP2013519858A JP6081354B2 (en) | 2010-07-16 | 2011-07-15 | Therapeutically active compositions and methods of their use |
EP11738902.3A EP2593425B1 (en) | 2010-07-16 | 2011-07-15 | Therapeutically active compositions and their method of use |
MX2013000614A MX342951B (en) | 2010-07-16 | 2011-07-15 | Therapeutically active compositions and their method of use. |
AU2011278998A AU2011278998B2 (en) | 2010-07-16 | 2011-07-15 | Therapeutically active compositions and their method of use |
US15/064,874 US20160264621A1 (en) | 2010-07-16 | 2016-03-09 | Therapeutically active compositions and their methods of use |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US36507210P | 2010-07-16 | 2010-07-16 | |
US61/365,072 | 2010-07-16 |
Related Child Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US13/810,410 A-371-Of-International US20130184222A1 (en) | 2010-07-16 | 2011-07-15 | Therapeutically active compositions and their methods of use |
US15/064,874 Continuation US20160264621A1 (en) | 2010-07-16 | 2016-03-09 | Therapeutically active compositions and their methods of use |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2012009678A1 true WO2012009678A1 (en) | 2012-01-19 |
WO2012009678A8 WO2012009678A8 (en) | 2012-03-29 |
Family
ID=44629416
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2011/044254 WO2012009678A1 (en) | 2010-07-16 | 2011-07-15 | Therapeutically active compositions and their method of use |
Country Status (10)
Country | Link |
---|---|
US (2) | US20130184222A1 (en) |
EP (1) | EP2593425B1 (en) |
JP (2) | JP6081354B2 (en) |
CN (1) | CN103097340B (en) |
AU (1) | AU2011278998B2 (en) |
BR (1) | BR112013001122B1 (en) |
CA (1) | CA2805669C (en) |
ES (1) | ES2704862T3 (en) |
MX (1) | MX342951B (en) |
WO (1) | WO2012009678A1 (en) |
Cited By (46)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2013098393A1 (en) * | 2011-12-30 | 2013-07-04 | Pitty, Marc-Henry | Piperazinyl derivatives for the treatment of cancer |
WO2013107405A1 (en) * | 2012-01-19 | 2013-07-25 | Agios Pharmaceuticals, Inc. | Therapeutically active compounds and their methods of use |
WO2014062511A1 (en) * | 2012-10-15 | 2014-04-24 | Agios Pharmaceuticals, Inc. | Therapeutic compounds and compositions |
WO2014128591A1 (en) | 2013-02-22 | 2014-08-28 | Pfizer Inc. | Pyrrolo [2, 3 -d]pyrimidine derivatives as inhibitors of janus- related kinases (jak) |
WO2014141104A1 (en) * | 2013-03-14 | 2014-09-18 | Novartis Ag | 3-pyrimidin-4-yl-oxazolidin-2-ones as inhibitors of mutant idh |
US8865894B2 (en) | 2012-02-24 | 2014-10-21 | Novartis Ag | Oxazolidin-2-one compounds and uses thereof |
US8883438B2 (en) | 2009-10-21 | 2014-11-11 | Agios Pharmaceuticals, Inc. | Method for diagnosing cell proliferation disorders having a neoactive mutation at residue 97 of isocitrate dehydrogenase 1 |
US20140336232A1 (en) * | 2011-11-25 | 2014-11-13 | Bayer Intellectual Property Gmbh | 2-iodo imidazole-derivatives |
US8957068B2 (en) | 2011-09-27 | 2015-02-17 | Novartis Ag | 3-pyrimidin-4-yl-oxazolidin-2-ones as inhibitors of mutant IDH |
WO2016024185A1 (en) | 2014-08-12 | 2016-02-18 | Pfizer Inc. | Pyrrolo[2,3-d]pyrimidine derivatives useful for inhibiting janus kinase |
EP2827861A4 (en) * | 2012-03-19 | 2016-03-16 | Aposignal Bioscience Llc | Composition and methods for cell modulation |
US20160074391A1 (en) * | 2013-05-14 | 2016-03-17 | Medizinische Hochschule Hannover | Means and methods for treating cancer |
WO2016062770A1 (en) * | 2014-10-23 | 2016-04-28 | Bayer Pharma Aktiengesellschaft | 1-cyclohexyl-2-phenylaminobenzimidazoles as midh1 inhibitors for the treatment of tumors |
US9434979B2 (en) | 2009-10-21 | 2016-09-06 | Shin-San Michael Su | Methods and compositions for cell-proliferation-related disorders |
US9474779B2 (en) | 2012-01-19 | 2016-10-25 | Agios Pharmaceuticals, Inc. | Therapeutically active compositions and their methods of use |
WO2017009325A1 (en) * | 2015-07-16 | 2017-01-19 | Bayer Pharma Aktiengesellschaft | 5-hydroxyalkylbenzimidazoles as midh1 inhibitors |
US9579324B2 (en) | 2013-07-11 | 2017-02-28 | Agios Pharmaceuticals, Inc | Therapeutically active compounds and their methods of use |
US9662327B2 (en) | 2011-06-17 | 2017-05-30 | Agios Pharmaceuticals, Inc | Phenyl and pyridinyl substituted piperidines and piperazines as inhibitors of IDH1 mutants and their use in treating cancer |
CN106795146A (en) * | 2014-10-01 | 2017-05-31 | 第三共株式会社 | As the inhibitor isoxazole derivativeses of saltant type isocitric dehydrogenase 1 |
US9732062B2 (en) | 2012-01-06 | 2017-08-15 | Agios Pharmaceuticals, Inc. | Therapeutically active compounds and their methods of use |
WO2017162156A1 (en) * | 2016-03-22 | 2017-09-28 | 正大天晴药业集团股份有限公司 | Iridinesulfonamide compound and use method thereof |
US9856279B2 (en) | 2011-06-17 | 2018-01-02 | Agios Pharmaceuticals, Inc. | Therapeutically active compositions and their methods of use |
US9877962B2 (en) | 2011-12-30 | 2018-01-30 | Marc Henry Pitty | Piperazinyl derivatives for the treatment of cancer |
US9968595B2 (en) | 2014-03-14 | 2018-05-15 | Agios Pharmaceuticals, Inc. | Pharmaceutical compositions of therapeutically active compounds |
US9980961B2 (en) | 2011-05-03 | 2018-05-29 | Agios Pharmaceuticals, Inc. | Pyruvate kinase activators for use in therapy |
US10017495B2 (en) | 2013-07-11 | 2018-07-10 | Agios Pharmaceuticals, Inc. | Therapeutically active compounds and their methods of use |
US10029987B2 (en) | 2009-06-29 | 2018-07-24 | Agios Pharmaceuticals, Inc. | Therapeutic compounds and compositions |
US10202371B2 (en) | 2012-11-12 | 2019-02-12 | Novartis Ag | Oxazolidin-2-one-pyrimidine derivatives and the use thereof as phosphatidylinositol-3-kinase inhibitors |
WO2019129588A1 (en) * | 2017-12-27 | 2019-07-04 | Bp Oil International Limited | Methods for preparing fuel additives |
US10376510B2 (en) | 2013-07-11 | 2019-08-13 | Agios Pharmaceuticals, Inc. | 2,4- or 4,6-diaminopyrimidine compounds as IDH2 mutants inhibitors for the treatment of cancer |
EP3434671A4 (en) * | 2016-03-22 | 2019-08-14 | Chia Tai Tianqing Pharmaceutical Group Co., Ltd. | Sultam compound and application method thereof |
US10610125B2 (en) | 2009-03-13 | 2020-04-07 | Agios Pharmaceuticals, Inc. | Methods and compositions for cell-proliferation-related disorders |
US10653710B2 (en) | 2015-10-15 | 2020-05-19 | Agios Pharmaceuticals, Inc. | Combination therapy for treating malignancies |
US10689414B2 (en) | 2013-07-25 | 2020-06-23 | Agios Pharmaceuticals, Inc. | Therapeutically active compounds and their methods of use |
US10703746B2 (en) | 2014-12-22 | 2020-07-07 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Mutant IDH1 inhibitors useful for treating cancer |
US10980788B2 (en) | 2018-06-08 | 2021-04-20 | Agios Pharmaceuticals, Inc. | Therapy for treating malignancies |
US11234976B2 (en) | 2015-06-11 | 2022-02-01 | Agios Pharmaceuticals, Inc. | Methods of using pyruvate kinase activators |
US11359151B2 (en) | 2017-12-27 | 2022-06-14 | Bp Oil International Limited | Methods for preparing fuel additives |
US11384057B2 (en) | 2017-12-27 | 2022-07-12 | Bp Oil International Limited | Methods for preparing fuel additives |
US11384302B2 (en) | 2017-12-27 | 2022-07-12 | Bp Oil International Limited | Methods for preparing fuel additives |
US11419859B2 (en) | 2015-10-15 | 2022-08-23 | Servier Pharmaceuticals Llc | Combination therapy for treating malignancies |
US11421168B2 (en) | 2017-12-27 | 2022-08-23 | Bp Oil International Limited | Methods for preparing fuel additives |
WO2022221686A1 (en) * | 2021-04-15 | 2022-10-20 | Pardes Biosciences, Inc. | Inhibitors of cysteine proteases and methods of use thereof |
US11731944B2 (en) | 2021-11-02 | 2023-08-22 | Insilico Medicine Ip Limited | SARS-CoV-2 inhibitors for treating coronavirus infections |
US11844758B2 (en) | 2013-07-11 | 2023-12-19 | Servier Pharmaceuticals Llc | Therapeutically active compounds and their methods of use |
EP4149535A4 (en) * | 2020-05-15 | 2024-09-11 | Purdue Research Foundation | Compounds for the treatment of sars |
Families Citing this family (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
TWI648273B (en) | 2013-02-15 | 2019-01-21 | 英商葛蘭素史克智慧財產發展有限公司 | Heterocyclic amides as kinase inhibitors (III) |
WO2015006592A1 (en) | 2013-07-11 | 2015-01-15 | Agios Pharmaceuticals, Inc. | N,6-bis(aryl or heteroaryl)-1,3,5-triazine-2,4-diamine compounds as idh2 mutants inhibitors for the treatment of cancer |
WO2015010297A1 (en) * | 2013-07-25 | 2015-01-29 | Agios Pharmaceuticals, Inc. | Therapeutically active compounds and their methods of use |
KR101861869B1 (en) * | 2013-09-10 | 2018-05-28 | 경희대학교 산학협력단 | A novel bis-amide derivatives and use thereof |
US9975885B2 (en) * | 2016-04-28 | 2018-05-22 | Purdue Research Foundation | Broad-spectrum non-covalent coronavirus protease inhibitors |
WO2019057142A1 (en) | 2017-09-22 | 2019-03-28 | 正大天晴药业集团股份有限公司 | Crystalline sulfamide compound |
EP3528460A1 (en) * | 2018-02-20 | 2019-08-21 | Darktrace Limited | Artificial intelligence privacy protection for cybersecurity analysis |
CN108484522A (en) * | 2018-04-25 | 2018-09-04 | 山东百诺医药股份有限公司 | The preparation method of 4- (1,2,4- oxadiazole -3- bases) aniline |
CN109535025B (en) * | 2018-12-18 | 2022-09-09 | 尚科生物医药(上海)有限公司 | Preparation method of Evonib intermediate 3, 3-difluorocyclobutylamine hydrochloride |
CN110283096A (en) * | 2019-07-03 | 2019-09-27 | 三峡大学 | A kind of ɑ-amino amide class compound and preparation method thereof of Cu-MOF catalysis |
CN113845440A (en) * | 2021-11-04 | 2021-12-28 | 沈阳药科大学 | Non-natural peptide IDH1 inhibitor synthesized based on UGI reaction and preparation method and application thereof |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2009150248A1 (en) * | 2008-06-13 | 2009-12-17 | Cytomics Systems | Compounds which can be used for the treatment of cancers |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ATE309207T1 (en) * | 1999-08-27 | 2005-11-15 | Sugen Inc | PHOSPHATE MIMETICS AND TREATMENT METHODS USING PHOSPHATASE INHIBITORS |
US20040067234A1 (en) * | 2002-07-11 | 2004-04-08 | Paz Einat | Isocitrate dehydrogenase and uses thereof |
CN101137414A (en) * | 2004-12-31 | 2008-03-05 | 欧兰拓制药股份有限公司 | Multicyclic bis-amide mmp inhibitors |
US8642660B2 (en) * | 2007-12-21 | 2014-02-04 | The University Of Rochester | Method for altering the lifespan of eukaryotic organisms |
PL2326735T3 (en) * | 2008-09-03 | 2017-04-28 | The Johns Hopkins University | Genetic alterations in isocitrate dehydrogenase and other genes in malignant glioma |
-
2011
- 2011-07-15 JP JP2013519858A patent/JP6081354B2/en active Active
- 2011-07-15 WO PCT/US2011/044254 patent/WO2012009678A1/en active Application Filing
- 2011-07-15 US US13/810,410 patent/US20130184222A1/en not_active Abandoned
- 2011-07-15 ES ES11738902T patent/ES2704862T3/en active Active
- 2011-07-15 MX MX2013000614A patent/MX342951B/en active IP Right Grant
- 2011-07-15 BR BR112013001122-0A patent/BR112013001122B1/en active IP Right Grant
- 2011-07-15 CA CA2805669A patent/CA2805669C/en active Active
- 2011-07-15 AU AU2011278998A patent/AU2011278998B2/en active Active
- 2011-07-15 CN CN201180043254.6A patent/CN103097340B/en active Active
- 2011-07-15 EP EP11738902.3A patent/EP2593425B1/en active Active
-
2016
- 2016-03-09 US US15/064,874 patent/US20160264621A1/en not_active Abandoned
- 2016-08-29 JP JP2016166461A patent/JP2017039725A/en not_active Withdrawn
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2009150248A1 (en) * | 2008-06-13 | 2009-12-17 | Cytomics Systems | Compounds which can be used for the treatment of cancers |
Non-Patent Citations (15)
Title |
---|
"Encyclopedia of Reagents for Organic Synthesis", 1995, JOHN WILEY AND SONS |
ACTA NEUROPATHOL, vol. 116, 2008, pages 597 - 602 |
BERGE ET AL.: "Pharmaceutically Acceptable Salts", J. PHARM. SCI., vol. 66, 1977, pages 1 - 19 |
DANG, L ET AL., NATURE, vol. 462, 2009, pages 739 - 44 |
FIESER, L ET AL.: "Fieser and Fieser's Reagents for Organic Synthesis", 1994, JOHN WILEY AND SONS |
GEISBRECHT ET AL., J. BIOL. CHEM., vol. 274, 1999, pages 30527 - 30533 |
GENOME RES., vol. 14, 2004, pages 2121 - 2127 |
GREENE, TW ET AL.: "Protective Groups in Organic Synthesis", 1999, JOHN WILEY AND SONS |
LAROCK R: "Comprehensive Organic Transformations", 1989, VCH PUBLISHERS |
LUO ET AL., J CHROMATOGRA, vol. 1147, 2007, pages 153 - 64 |
MUNGER ET AL., NAT BIOTECHNOL, vol. 26, 2008, pages 1179 - 86 |
N ENGL J MED., vol. 360, no. 8, 19 February 2009 (2009-02-19), pages 765 - 73 |
NEKRUTENKO ET AL., MOL. BIOL. EVOL., vol. 15, 1998, pages 1674 - 1684 |
SJOEBLOM ET AL., SCIENCE, vol. 314, 2006, pages 268 - 274 |
WIEMANN ET AL., GENOME RES., vol. 11, 2001, pages 422 - 435 |
Cited By (104)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10610125B2 (en) | 2009-03-13 | 2020-04-07 | Agios Pharmaceuticals, Inc. | Methods and compositions for cell-proliferation-related disorders |
US10029987B2 (en) | 2009-06-29 | 2018-07-24 | Agios Pharmaceuticals, Inc. | Therapeutic compounds and compositions |
USRE49582E1 (en) | 2009-06-29 | 2023-07-18 | Agios Pharmaceuticals, Inc. | Therapeutic compounds and compositions |
US10988448B2 (en) | 2009-06-29 | 2021-04-27 | Agios Pharmaceuticals, Inc. | Therapeutic compounds and compositions |
US11866411B2 (en) | 2009-06-29 | 2024-01-09 | Agios Pharmaceutical, Inc. | Therapeutic compounds and compositions |
US9982309B2 (en) | 2009-10-21 | 2018-05-29 | Agios Pharmaceuticals, Inc. | Method for treating cell proliferation related disorders |
US10711314B2 (en) | 2009-10-21 | 2020-07-14 | Agios Pharmaceuticals, Inc. | Methods for diagnosing IDH-mutant cell proliferation disorders |
US8883438B2 (en) | 2009-10-21 | 2014-11-11 | Agios Pharmaceuticals, Inc. | Method for diagnosing cell proliferation disorders having a neoactive mutation at residue 97 of isocitrate dehydrogenase 1 |
US9434979B2 (en) | 2009-10-21 | 2016-09-06 | Shin-San Michael Su | Methods and compositions for cell-proliferation-related disorders |
US10632114B2 (en) | 2011-05-03 | 2020-04-28 | Agios Pharmaceuticals, Inc. | Pyruvate kinase activators for use in therapy |
US11793806B2 (en) | 2011-05-03 | 2023-10-24 | Agios Pharmaceuticals, Inc. | Pyruvate kinase activators for use in therapy |
US9980961B2 (en) | 2011-05-03 | 2018-05-29 | Agios Pharmaceuticals, Inc. | Pyruvate kinase activators for use in therapy |
US9662327B2 (en) | 2011-06-17 | 2017-05-30 | Agios Pharmaceuticals, Inc | Phenyl and pyridinyl substituted piperidines and piperazines as inhibitors of IDH1 mutants and their use in treating cancer |
US9856279B2 (en) | 2011-06-17 | 2018-01-02 | Agios Pharmaceuticals, Inc. | Therapeutically active compositions and their methods of use |
US8957068B2 (en) | 2011-09-27 | 2015-02-17 | Novartis Ag | 3-pyrimidin-4-yl-oxazolidin-2-ones as inhibitors of mutant IDH |
US20140336232A1 (en) * | 2011-11-25 | 2014-11-13 | Bayer Intellectual Property Gmbh | 2-iodo imidazole-derivatives |
US9095136B2 (en) * | 2011-11-25 | 2015-08-04 | Bayer Intellectual Property Gmbh | 2-IODO imidazole-derivatives |
US9321778B2 (en) | 2011-12-30 | 2016-04-26 | Marc Henry Pitty | Piperazinyl derivatives for the treatment of cancer |
US20140356360A1 (en) * | 2011-12-30 | 2014-12-04 | Marc-Henry PITTY | Piperazinyl derivatives for the treatment of cancer |
US9877962B2 (en) | 2011-12-30 | 2018-01-30 | Marc Henry Pitty | Piperazinyl derivatives for the treatment of cancer |
FR2985256A1 (en) * | 2011-12-30 | 2013-07-05 | Pitty Marc Henry | PIPERAZINYL DERIVATIVES FOR THE TREATMENT OF CANCERS |
KR20140117456A (en) * | 2011-12-30 | 2014-10-07 | 피티, 마르크-헨리 | Piperazinyl derivatives for the treatment of cancer |
KR102086732B1 (en) | 2011-12-30 | 2020-03-09 | 피티, 마르크-헨리 | Piperazinyl derivatives for the treatment of cancer |
WO2013098393A1 (en) * | 2011-12-30 | 2013-07-04 | Pitty, Marc-Henry | Piperazinyl derivatives for the treatment of cancer |
US11505538B1 (en) | 2012-01-06 | 2022-11-22 | Servier Pharmaceuticals Llc | Therapeutically active compounds and their methods of use |
US10294215B2 (en) | 2012-01-06 | 2019-05-21 | Agios Pharmaceuticals, Inc. | Therapeutically active compounds and their methods of use |
US9732062B2 (en) | 2012-01-06 | 2017-08-15 | Agios Pharmaceuticals, Inc. | Therapeutically active compounds and their methods of use |
WO2013107405A1 (en) * | 2012-01-19 | 2013-07-25 | Agios Pharmaceuticals, Inc. | Therapeutically active compounds and their methods of use |
US9474779B2 (en) | 2012-01-19 | 2016-10-25 | Agios Pharmaceuticals, Inc. | Therapeutically active compositions and their methods of use |
US9850277B2 (en) | 2012-01-19 | 2017-12-26 | Agios Pharmaceuticals, Inc. | Therapeutically active compositions and their methods of use |
US11667673B2 (en) | 2012-01-19 | 2023-06-06 | Servier Pharmaceuticals Llc | Therapeutically active compounds and their methods of use |
US10640534B2 (en) | 2012-01-19 | 2020-05-05 | Agios Pharmaceuticals, Inc. | Therapeutically active compositions and their methods of use |
EP2804850A4 (en) * | 2012-01-19 | 2015-09-23 | Agios Pharmaceuticals Inc | Therapeutically active compounds and their methods of use |
US20150087600A1 (en) * | 2012-01-19 | 2015-03-26 | Agios Pharmaceuticals, Inc | Therapeutically active compounds and their methods of use |
US10717764B2 (en) | 2012-01-19 | 2020-07-21 | Agios Pharmaceuticals, Inc. | Therapeutically active compounds and their methods of use |
US20160304556A1 (en) * | 2012-01-19 | 2016-10-20 | Agios Pharmaceuticals, Inc | Therapeutically active compounds and their methods of use |
US9458177B2 (en) | 2012-02-24 | 2016-10-04 | Novartis Ag | Oxazolidin-2-one compounds and uses thereof |
US8865894B2 (en) | 2012-02-24 | 2014-10-21 | Novartis Ag | Oxazolidin-2-one compounds and uses thereof |
EP2827861A4 (en) * | 2012-03-19 | 2016-03-16 | Aposignal Bioscience Llc | Composition and methods for cell modulation |
WO2014062511A1 (en) * | 2012-10-15 | 2014-04-24 | Agios Pharmaceuticals, Inc. | Therapeutic compounds and compositions |
US10202339B2 (en) | 2012-10-15 | 2019-02-12 | Agios Pharmaceuticals, Inc. | Therapeutic compounds and compositions |
US10202371B2 (en) | 2012-11-12 | 2019-02-12 | Novartis Ag | Oxazolidin-2-one-pyrimidine derivatives and the use thereof as phosphatidylinositol-3-kinase inhibitors |
WO2014128591A1 (en) | 2013-02-22 | 2014-08-28 | Pfizer Inc. | Pyrrolo [2, 3 -d]pyrimidine derivatives as inhibitors of janus- related kinases (jak) |
EP3290421A1 (en) | 2013-02-22 | 2018-03-07 | Pfizer Inc | Combination of pyrrolo [2, 3 -d]pyrimidine derivatives with one or more additional agents as inhibitors of janus- related kinases (jak) |
US9035074B2 (en) | 2013-02-22 | 2015-05-19 | Pfizer Inc. | Pyrrolo[2,3-D]pyrimidine derivatives |
US9549929B2 (en) | 2013-02-22 | 2017-01-24 | Pfizer Inc. | Pyrrolo[2,3-D]pyrimidine derivatives |
US9545405B2 (en) | 2013-02-22 | 2017-01-17 | Pfizer Inc. | Pyrrolo[2,3-D]pyrimidine derivatives |
US10112931B2 (en) | 2013-03-14 | 2018-10-30 | Novartis Ag | 3-pyrimidin-4-yl-oxazolidin-2-ones as inhibitors of mutant IDH |
US9688672B2 (en) | 2013-03-14 | 2017-06-27 | Novartis Ag | 3-pyrimidin-4-yl-oxazolidin-2-ones as inhibitors of mutant IDH |
EA028033B1 (en) * | 2013-03-14 | 2017-09-29 | Новартис Аг | 3-pyrimidin-4-yl-oxazolidin-2-ones as inhibitors of mutant idh |
JP2016513633A (en) * | 2013-03-14 | 2016-05-16 | ノバルティス アーゲー | 3-pyrimidin-4-yl-oxazolidine-2-one as an inhibitor of mutant IDH |
CN105263929A (en) * | 2013-03-14 | 2016-01-20 | 诺华股份有限公司 | 3-pyrimidin-4-yl-oxazolidin-2-ones as inhibitors of mutant idh |
WO2014141104A1 (en) * | 2013-03-14 | 2014-09-18 | Novartis Ag | 3-pyrimidin-4-yl-oxazolidin-2-ones as inhibitors of mutant idh |
US9434719B2 (en) | 2013-03-14 | 2016-09-06 | Novartis Ag | 3-pyrimidin-4-yl-oxazolidin-2-ones as inhibitors of mutant IDH |
US9849127B2 (en) * | 2013-05-14 | 2017-12-26 | Medizinisch Hochschule Hannover | Means and methods for treating cancer |
US20160074391A1 (en) * | 2013-05-14 | 2016-03-17 | Medizinische Hochschule Hannover | Means and methods for treating cancer |
US10017495B2 (en) | 2013-07-11 | 2018-07-10 | Agios Pharmaceuticals, Inc. | Therapeutically active compounds and their methods of use |
US11844758B2 (en) | 2013-07-11 | 2023-12-19 | Servier Pharmaceuticals Llc | Therapeutically active compounds and their methods of use |
US10376510B2 (en) | 2013-07-11 | 2019-08-13 | Agios Pharmaceuticals, Inc. | 2,4- or 4,6-diaminopyrimidine compounds as IDH2 mutants inhibitors for the treatment of cancer |
US10172864B2 (en) | 2013-07-11 | 2019-01-08 | Agios Pharmaceuticals, Inc. | Therapeutically active compounds and their methods of use |
US9579324B2 (en) | 2013-07-11 | 2017-02-28 | Agios Pharmaceuticals, Inc | Therapeutically active compounds and their methods of use |
US10028961B2 (en) | 2013-07-11 | 2018-07-24 | Agios Pharmaceuticals, Inc. | Therapeutically active compounds and their methods of use |
US10946023B2 (en) | 2013-07-11 | 2021-03-16 | Agios Pharmaceuticals, Inc. | Therapeutically active compounds and their methods of use |
US11021515B2 (en) | 2013-07-25 | 2021-06-01 | Agios Pharmaceuticals, Inc. | Therapeutically active compounds and their methods of use |
US10689414B2 (en) | 2013-07-25 | 2020-06-23 | Agios Pharmaceuticals, Inc. | Therapeutically active compounds and their methods of use |
US11504361B2 (en) | 2014-03-14 | 2022-11-22 | Servier Pharmaceuticals Llc | Pharmaceutical compositions of therapeutically active compounds |
US10799490B2 (en) | 2014-03-14 | 2020-10-13 | Agios Pharmaceuticals, Inc. | Pharmaceutical compositions of therapeutically active compounds |
US10449184B2 (en) | 2014-03-14 | 2019-10-22 | Agios Pharmaceuticals, Inc. | Pharmaceutical compositions of therapeutically active compounds |
US9968595B2 (en) | 2014-03-14 | 2018-05-15 | Agios Pharmaceuticals, Inc. | Pharmaceutical compositions of therapeutically active compounds |
WO2016024185A1 (en) | 2014-08-12 | 2016-02-18 | Pfizer Inc. | Pyrrolo[2,3-d]pyrimidine derivatives useful for inhibiting janus kinase |
US10966980B2 (en) | 2014-08-12 | 2021-04-06 | Pfizer Inc. | Pyrrolo[2,3-d]pyrimidine derivatives |
CN106795146B (en) * | 2014-10-01 | 2020-06-26 | 第一三共株式会社 | Isoxazole derivatives as inhibitors of mutant isocitrate dehydrogenase 1 |
AU2015325279B2 (en) * | 2014-10-01 | 2020-02-27 | Daiichi Sankyo Company, Limited | Isoxazole derivative as mutant isocitrate dehydrogenase 1 inhibitor |
CN106795146A (en) * | 2014-10-01 | 2017-05-31 | 第三共株式会社 | As the inhibitor isoxazole derivativeses of saltant type isocitric dehydrogenase 1 |
EP3202766A4 (en) * | 2014-10-01 | 2018-04-04 | Daiichi Sankyo Company, Limited | Isoxazole derivative as mutated isocitrate dehydrogenase 1 inhibitor |
US10137110B2 (en) | 2014-10-23 | 2018-11-27 | Bayer Pharma Aktiengesellschaft | 1-cyclohexyl-2-phenylaminobenzimidazoles as mIDH1 inhibitors for the treatment of tumors |
WO2016062770A1 (en) * | 2014-10-23 | 2016-04-28 | Bayer Pharma Aktiengesellschaft | 1-cyclohexyl-2-phenylaminobenzimidazoles as midh1 inhibitors for the treatment of tumors |
CN107108554A (en) * | 2014-10-23 | 2017-08-29 | 拜耳医药股份有限公司 | It is used for the phenyl amino benzimidazole of 1 cyclohexyl 2 for treating tumour as MIDH1 inhibitor |
CN107108554B (en) * | 2014-10-23 | 2020-11-06 | 德国癌症研究中心 | 1-cyclohexyl-2-phenylaminobenzimidazole as MIDH1 inhibitor for treating tumors |
US10703746B2 (en) | 2014-12-22 | 2020-07-07 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Mutant IDH1 inhibitors useful for treating cancer |
US11234976B2 (en) | 2015-06-11 | 2022-02-01 | Agios Pharmaceuticals, Inc. | Methods of using pyruvate kinase activators |
WO2017009325A1 (en) * | 2015-07-16 | 2017-01-19 | Bayer Pharma Aktiengesellschaft | 5-hydroxyalkylbenzimidazoles as midh1 inhibitors |
US10414734B2 (en) | 2015-07-16 | 2019-09-17 | Bayer Pharma Aktiengesellschaft | 5-hydroxyalkylbenzimidazoles as mIDH1 inhibitors |
US11419859B2 (en) | 2015-10-15 | 2022-08-23 | Servier Pharmaceuticals Llc | Combination therapy for treating malignancies |
US10653710B2 (en) | 2015-10-15 | 2020-05-19 | Agios Pharmaceuticals, Inc. | Combination therapy for treating malignancies |
CN109071429A (en) * | 2016-03-22 | 2018-12-21 | 正大天晴药业集团股份有限公司 | Third pyridine sulfamide compound and its application method |
EP3434671A4 (en) * | 2016-03-22 | 2019-08-14 | Chia Tai Tianqing Pharmaceutical Group Co., Ltd. | Sultam compound and application method thereof |
RU2741915C2 (en) * | 2016-03-22 | 2021-01-29 | Чиа Тай Тяньцин Фармасьютикал Груп Ко., Лтд. | Sultam-based compound and method of use thereof |
US11111240B2 (en) | 2016-03-22 | 2021-09-07 | Chai Tai Tianqing Pharmaceutical Group Co., Ltd. | Sultam compound and application method thereof |
AU2017239318B2 (en) * | 2016-03-22 | 2020-08-20 | Centaurus Biopharma Co., Ltd. | Sultam compound and application method thereof |
US11203586B2 (en) | 2016-03-22 | 2021-12-21 | Chia Tai Tianqing Pharmaceutical Group Co., Ltd. | Iridinesulfonamide compound and use method thereof |
RU2741915C9 (en) * | 2016-03-22 | 2021-03-31 | Чиа Тай Тяньцин Фармасьютикал Груп Ко., Лтд. | Sultam-based compound and method of use thereof |
WO2017162156A1 (en) * | 2016-03-22 | 2017-09-28 | 正大天晴药业集团股份有限公司 | Iridinesulfonamide compound and use method thereof |
CN109071429B (en) * | 2016-03-22 | 2021-04-02 | 正大天晴药业集团股份有限公司 | Prophyridine sulfonamide compounds and methods of use thereof |
US11384057B2 (en) | 2017-12-27 | 2022-07-12 | Bp Oil International Limited | Methods for preparing fuel additives |
WO2019129588A1 (en) * | 2017-12-27 | 2019-07-04 | Bp Oil International Limited | Methods for preparing fuel additives |
US11421168B2 (en) | 2017-12-27 | 2022-08-23 | Bp Oil International Limited | Methods for preparing fuel additives |
US11384302B2 (en) | 2017-12-27 | 2022-07-12 | Bp Oil International Limited | Methods for preparing fuel additives |
US11359151B2 (en) | 2017-12-27 | 2022-06-14 | Bp Oil International Limited | Methods for preparing fuel additives |
US11230680B2 (en) | 2017-12-27 | 2022-01-25 | Bp Oil International Limited | Methods for preparing fuel additives |
US10980788B2 (en) | 2018-06-08 | 2021-04-20 | Agios Pharmaceuticals, Inc. | Therapy for treating malignancies |
EP4149535A4 (en) * | 2020-05-15 | 2024-09-11 | Purdue Research Foundation | Compounds for the treatment of sars |
WO2022221686A1 (en) * | 2021-04-15 | 2022-10-20 | Pardes Biosciences, Inc. | Inhibitors of cysteine proteases and methods of use thereof |
US11731944B2 (en) | 2021-11-02 | 2023-08-22 | Insilico Medicine Ip Limited | SARS-CoV-2 inhibitors for treating coronavirus infections |
Also Published As
Publication number | Publication date |
---|---|
CN103097340B (en) | 2018-03-16 |
US20130184222A1 (en) | 2013-07-18 |
CA2805669C (en) | 2018-08-21 |
AU2011278998B2 (en) | 2016-06-09 |
JP2013536168A (en) | 2013-09-19 |
ES2704862T3 (en) | 2019-03-20 |
WO2012009678A8 (en) | 2012-03-29 |
MX2013000614A (en) | 2013-06-28 |
CN103097340A (en) | 2013-05-08 |
US20160264621A1 (en) | 2016-09-15 |
JP2017039725A (en) | 2017-02-23 |
JP6081354B2 (en) | 2017-02-15 |
AU2011278998A1 (en) | 2013-01-31 |
CA2805669A1 (en) | 2012-01-19 |
MX342951B (en) | 2016-10-18 |
EP2593425B1 (en) | 2018-10-17 |
BR112013001122A2 (en) | 2017-07-11 |
EP2593425A1 (en) | 2013-05-22 |
BR112013001122B1 (en) | 2021-06-08 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
AU2011278998B2 (en) | Therapeutically active compositions and their method of use | |
AU2017265100B2 (en) | Therapeutically active compounds and their methods of use | |
AU2012269648B2 (en) | Therapeutically active compositions and their methods of use | |
EP2804850B1 (en) | Therapeutically active compounds and their methods of use | |
AU2012269473B2 (en) | Compounds, their pharmaceutical compositions and their uses as inhibitors for treating cancers | |
CA3133753A1 (en) | Novel small molecule inhibitors of tead transcription factors | |
EP3041842B1 (en) | Spirocyclic compounds as tryptophan hydroxylase inhibitors | |
KR20140040774A (en) | Imidazopyridine compound | |
EP3024824A1 (en) | Therapeutically active compounds and use thereof | |
JP2017057221A (en) | Therapeutically active compositions and their methods of use | |
JP4069074B2 (en) | N-biphenylmethylaminocycloalkanecarboxamide derivatives | |
TW202200551A (en) | Sars-cov-2 inhibitors having covalent modifications for treating coronavirus infections | |
CA3190610A1 (en) | Nitrile derivative that acts as inhibitor of dipeptidyl peptidase 1 and use thereof | |
CA3196857A1 (en) | Pyrimidine compounds, compositions, and medicinal applications thereof | |
JP2021529772A (en) | Amino-pyrimidonyl derivative, its preparation process and pharmaceutical composition containing it | |
AU2006255642A1 (en) | 1-Hydroxycycloalkanecarboxamide derivatives as bradykinin antagonists |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
WWE | Wipo information: entry into national phase |
Ref document number: 201180043254.6 Country of ref document: CN |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 11738902 Country of ref document: EP Kind code of ref document: A1 |
|
ENP | Entry into the national phase |
Ref document number: 2013519858 Country of ref document: JP Kind code of ref document: A Ref document number: 2805669 Country of ref document: CA |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
WWE | Wipo information: entry into national phase |
Ref document number: MX/A/2013/000614 Country of ref document: MX |
|
ENP | Entry into the national phase |
Ref document number: 2011278998 Country of ref document: AU Date of ref document: 20110715 Kind code of ref document: A |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2011738902 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 13810410 Country of ref document: US |
|
REG | Reference to national code |
Ref country code: BR Ref legal event code: B01A Ref document number: 112013001122 Country of ref document: BR |
|
ENP | Entry into the national phase |
Ref document number: 112013001122 Country of ref document: BR Kind code of ref document: A2 Effective date: 20130116 |