Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
  • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
  • A61K31/36—Compounds containing methylenedioxyphenyl groups, e.g. sesamin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/397—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having four-membered rings, e.g. azetidine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
  • A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/415—1,2-Diazoles
  • A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/42—Oxazoles
  • A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/42—Oxazoles
  • A61K31/423—Oxazoles condensed with carbocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/42—Oxazoles
  • A61K31/424—Oxazoles condensed with heterocyclic ring systems, e.g. clavulanic acid
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/4245—Oxadiazoles
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/425—Thiazoles
  • A61K31/428—Thiazoles condensed with carbocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
  • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
  • A61K31/443—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
  • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
  • A61K31/4525—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/47—Quinolines; Isoquinolines
  • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
  • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5375—1,4-Oxazines, e.g. morpholine
  • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/66—Phosphorus compounds
  • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
  • C07D261/20—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings condensed with carbocyclic rings or ring systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
  • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
  • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
  • C07D277/62—Benzothiazoles
  • C07D277/64—Benzothiazoles with only hydrocarbon or substituted hydrocarbon radicals attached in position 2
• • 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
• • 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
• • 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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
  • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen 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
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
  • C07D487/04—Ortho-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
  • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
  • C07D491/10—Spiro-condensed systems
  • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
  • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
  • C07D495/04—Ortho-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
  • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
  • C07D495/10—Spiro-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
  • C07D498/04—Ortho-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
  • C07D498/10—Spiro-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
  • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
  • C07D513/04—Ortho-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
  • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
  • C07F9/02—Phosphorus compounds
  • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
  • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
  • C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom

Definitions

• the present disclosure relates to novel compounds which are relaxin family peptide receptor 1 (RXFP1) agonists, compositions containing them, and methods of using them, for example in the treatment of heart failure, fibrotic diseases, and related diseases such as lung disease (e.g., idiopathic pulmonary fibrosis), kidney disease (e.g., chronic kidney disease), and hepatic disease (e.g., non-alcoholic steatohepatitis and portal hypertension).
• RXFP1 relaxin family peptide receptor 1
• the human relaxin hormone (also called relaxin or H2 relaxin) is a 6-kDa peptide composed of 53 amino acids whose activity was initially discovered when Frederick Hisaw in 1926 injected crude extracts from swine corpus luteum into virgin guinea pigs and observed a relaxation of the fibrocartilaginous pubic symphysis joint (Hisaw FL., Proc. Soc. Exp. Biol. Med., 1926, 23, 661-663).
• the relaxin receptor was previously known as Lgr7 but is now officially termed the relaxin family peptide receptor 1 (RXFP1) and was deorphanized as a receptor for relaxin in 2002 (Hsu SY., et al., Science, 2002, 295, 671-674).
• RXFP1 is reasonably well conserved between mouse and human with 85% amino acid identity and is essentially ubiquitously expressed in humans and in other species (Halls ML., et al., Br. J. Pharmacol., 2007, 150, 677-691).
• the cell signaling pathways for relaxin and RXFP1 are cell type dependent and quite complex (Halls ML., et al., Br. J.
• Additional vascular adaptations include an ⁇ 30% increase in global arterial compliance that is important for maintaining efficient ventricular-arterial coupling, as well as an ⁇ 50% increase in both renal blood flow (RBF) and glomerular filtration rate (GFR), important for metabolic waste elimination (Jeyabalan AC., K.P., Reanl and Electolyte Disorders.2010, 462-518), (Poppas A., et al., Circ., 1997, 95, 2407-2415). Both pre-clinical studies in rodents as well as clinical studies performed in a variety of patient settings, provide evidence that relaxin is involved, at least to some extent, in mediating these adaptive physiological changes (Conrad KP., Regul. Integr. Comp.
• Heart failure defined hemodynamically as “systemic perfusion inadequate to meet the body's metabolic demands as a result of impaired cardiac pump function”, represents a tremendous burden on today’s health care system with an estimated United States prevalence of 5.8 million and greater than 23 million worldwide (Roger VL., et al., Circ. Res., 2013, 113, 646-659). It is estimated that by 2030, an additional 3 million people in the United States alone will have HF, a 25% increase from 2010. The estimated direct costs (2008 dollars) associated with HF for 2010 was $25 billion, projected to grow to $78 B by 2030 (Heidenreich PA., et al., Circ., 2011, 123, 933-944).
• HF HF-related diseases
• Major symptoms and signs of HF include: 1) dyspnea (difficulty in breathing) resulting from pulmonary edema due to ineffective forward flow from the left ventricle and increased pressure in the pulmonary capillary bed; 2) lower extremity edema occurs when the right ventricle is unable to accommodate systemic venous return; and 3) fatigue due to the failing heart’s inability to sustain sufficient cardiac output (CO) to meet the body's metabolic needs (Kemp CD., & Conte JV., Cardiovasc. Pathol., 2011, 21, 365-371).
• HF patients are often described as “compensated” or “decompensated”.
• symptoms are stable, and many overt features of fluid retention and pulmonary edema are absent.
• Decompensated heart failure refers to a deterioration, which may present as an acute episode of pulmonary edema, a reduction in exercise tolerance, and increasing breathlessness upon exertion (Millane T., et al., BMJ, 2000, 320, 559-562).
• Millane T., et al., BMJ, 2000, 320, 559-562 In contrast to the simplistic definition of poor cardiac performance not being able to meet metabolic demands, the large number of contributory diseases, multitude of risk factors, and the many pathological changes that ultimately lead to heart failure make this disease exceedingly complex (Jessup M.
• HF left-ventricular
• EF stroke volume/end diastolic volume
• diastolic HF active relaxation is decreased and passive stiffness is increased limiting LV filling during diastole, however overall EF is maintained
• HFrEF heart failure with reduced ejection fraction
• HFpEF heart failure with preserved ejection fraction
• Serelaxin an intravenous (IV) formulation of the recombinant human relaxin peptide with a relatively short first-phase pharmacokinetic half-life of 0.09 hours, is currently being developed for the treatment of HF (Novartis, 2014). Serelaxin has been given to normal healthy volunteers (NHV) and demonstrated to increase RBF (Smith MC., et al., J. Am. Soc.
• ADHF acute decompensated HF
• chronic relaxin administration could be of benefit to patients suffering from lung disease (e.g., idiopathic pulmonary fibrosis), kidney disease (e.g., chronic kidney disease), or hepatic disease (e.g., non- alcoholic steatohepatitis and portal hypertension).
• lung disease e.g., idiopathic pulmonary fibrosis
• kidney disease e.g., chronic kidney disease
• hepatic disease e.g., non- alcoholic steatohepatitis and portal hypertension.
• present invention provides novel benzothiazole analogs, including stereoisomers, tautomers, pharmaceutically acceptable salts, or solvates thereof, which are useful as RXFP1 receptor agonists.
• the present invention also provides processes and intermediates for making the compounds of the present invention.
• the present invention also provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and at least one of the compounds of the present invention or stereoisomers, tautomers, pharmaceutically acceptable salts, or solvates thereof.
• the compounds of the invention may be used, for example, in the treatment and/or prophylaxis of heart failure, fibrotic diseases, and related diseases, such as; lung disease (e.g., idiopathic pulmonary fibrosis), kidney disease (e.g., chronic kidney disease), or hepatic disease (e.g., non-alcoholic steatohepatitis and portal hypertension).
• lung disease e.g., idiopathic pulmonary fibrosis
• kidney disease e.g., chronic kidney disease
• hepatic disease e.g., non-alcoholic steatohepatitis and portal hypertension.
• the compounds of the present invention may be used in therapy.
• the compounds of the present invention may be used for the manufacture of a medicament for the treatment and/or prophy
• the compounds of the invention can be used alone, in combination with other compounds of the present invention, or in combination with one or more, preferably one to two other agent(s). These and other features of the invention will be set forth in expanded form as the disclosure continues. DESCRIPTION OF THE INVENTION
• the invention encompasses compounds of Formula (I), which are RXFP1 receptor agonists, compositions containing them, and methods of using them.
• the present invention provides compounds of Formula (III), or pharmaceutically acceptable salts thereof, wherein: R 1 is –CH3; R 3 is -OCH3; R 4a is F; R 4b is CF3;
• R 6 is halo, C 1-4 alkyl, -OH, or -OC 1-4 alkyl
• R 11 is -OH
• the present invention provides compounds of Formula (V), or pharmaceutically acceptable salts thereof, wherein: R 1 is F; R 3 is -OCH3; R 4a is F; R 4b is CF 3 ; R 5 is
• R 6 is halo, -OH, or C1-4 alkyl substituted with 0-1 OH
• R a is H or C1-3 alkyl; or R a and R a together with the nitrogen atom to which they are both attached form a heterocyclyl
• R b is H or C 1-3 alkyl.
• the present invention provides compounds of Formula (V), or pharmaceutically acceptable salts thereof, wherein: R 1 is F; R 3 is -OCH3; R 4a is F; R 4b is CF3; R 5 is
• R 9 is OH;
• the present invention provides compounds of Formula (V), or pharmaceutically acceptable salts thereof, wherein: R 1 is F; R 3 is -OCH 3 ; R 4a is F; R 4b is CF 3 ; R 5 is C2-6 alkenyl substituted with 0-3 R 6 and 0-2 R 7 , C2-6 alkynyl substituted with 0-3 R 6 and 0-2 R 7 ; R 6 is halo, -OH, or C1-4 alkyl substituted with 0-1 OH; R 7 is -OR b or -NR a R a ; R a is H or C1-3 alkyl; or R a and R a together with the nitrogen atom to which they are both attached form a heterocyclyl; and R b is H, C1-3 alkyl, or heterocyclyl.
• R 1 is F
• R 3 is -OCH 3
• R 4a is F
• R 4b is CF 3
• R 5 is C2-6 alkenyl substituted with 0
• any instance of a variable substituent including R 1 , R 2 , R 3 , R 4 (R 4a , R 4b ), R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R a , R b , R c , R d , R e , R f , and R g can be used independently with the scope of any other instance of a variable substituent.
• the invention includes combinations of the different aspects.
• R 4a is F.
• R 4b is CF3.
• R 3 is F or –OCH3
• R 4a is F
• R 4b is CF3
• R 13 is H or C 1-5 alkyl substituted with 0-1 R 7 ; or R 13 and R 13 together with the nitrogen atom to which they are both attached form 6 7
• R is -OH or C 1-3 alkyl
• R 9 is –OH
• R 3 is F or –OCH3;
• R 4a is F;
• R 4b is CF3;
• R 5 is ;
• R a and R a together with the nitrogen atom to which they are both attached form
• R e is C 1-3 alkyl substituted with 0-2 R g ;
• R g is-OH alkyl.
• R 3 is F or –OCH3;
• R 4a is F;
• R 4b is CF3;
• R 5 is or ;
• R 7 is C alkyl substit 9 9 10 b b 1-4 uted with 0-1 R ;
• R is –OH;
• R is H or C 1-3 alkyl substituted with 0-4 R e ;
• R e is -(CH 2 ) 0-1 OR f ;
• R f is H or C 1-3 alkyl. Unless specified otherwise, these terms have the following meanings.
• Halo includes fluoro, chloro, bromo, and iodo.
• Alkyl or “alkylene” is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms.
• C1 to C10 alkyl or “C1-10 alkyl” (or alkylene)
• C1 to C6 alkyl or “C1-C6 alkyl” denotes alkyl having 1 to 6 carbon atoms.
• Alkyl group can be unsubstituted or substituted with at least one hydrogen being replaced by another chemical group.
• Example alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, t-butyl), and pentyl (e.g., n-pentyl, isopentyl, neopentyl).
• C 0 alkyl or “C 0 alkylene” is used, it is intended to denote a direct bond.
• Alkyl also includes deuteroalkyl such as CD 3 .
• alkenyl or “alkenylene” is intended to include hydrocarbon chains of either straight or branched configuration having one or more, preferably one to three, carbon- carbon double bonds that may occur in any stable point along the chain.
• C2 to C6 alkenyl or “C2-6 alkenyl” (or alkenylene) is intended to include C2, C3, C4, C5, and C6 alkenyl groups; such as ethenyl, propenyl, butenyl, pentenyl, and hexenyl.
• Alkynyl or “alkynylene” is intended to include hydrocarbon chains of either straight or branched configuration having one or more, preferably one to three, carbon- carbon triple bonds that may occur in any stable point along the chain.
• C2 to C6 alkynyl or “C2-6 alkynyl” (or alkynylene) is intended to include C2, C3, C4, C5, and C6 alkynyl groups; such as ethynyl, propynyl, butynyl, pentynyl, and hexynyl.
• Carbocycle is intended to mean any stable 3-, 4-, 5-, 6-, 7-, or 8-membered monocyclic or bicyclic or 7-, 8-, 9-, 10-, 11-, 12-, or 13-membered bicyclic or tricyclic hydrocarbon ring, any of which may be saturated, partially unsaturated, unsaturated or aromatic.
• carbocyclyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptenyl, cycloheptyl, cycloheptenyl, adamantyl, cyclooctyl, cyclooctenyl, cyclooctadienyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane (decalin), [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, anthracenyl, and tetrahydronaphthyl (tetralin).
• bridged rings are also included in the definition of carbocyclyl (e.g., [2.2.2]bicyclooctane).
• a bridged ring occurs when one or more carbon atoms link two non-adjacent carbon atoms.
• Preferred bridges are one or two carbon atoms. It is noted that a bridge always converts a monocyclic ring into a tricyclic ring. When a ring is bridged, the substituents recited for the ring may also be present on the bridge.
• carbocyclyl When the term “carbocyclyl” is used, it is intended to include “aryl,” “cycloalkyl,” and “spirocycloalkyl.” Preferred carbocyclyls, unless otherwise specified, are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, and indanyl. “Cycloalkyl” is intended to mean cyclized alkyl groups, including mono-, bi- or multicyclic ring systems. "C 3 to C 7 cycloalkyl” or “C 3-7 cycloalkyl” is intended to include C 3 , C 4 , C 5 , C 6 , and C 7 cycloalkyl groups.
• Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
• Non-limiting examples of multicyclic cycloalkyls include 1-decalinyl, norbornyl and adamantyl.
• Spirocycloalkyl is intended to mean hydrocarbon bicyclic ring systems with both rings connected through a single atom. The ring can be different in size and nature, or identical in size and nature.
• Bicyclic carbocyclyl or "bicyclic carbocyclic group” is intended to mean a stable 9- or 10-membered carbocyclic ring system that contains two fused rings and consists of carbon atoms. Of the two fused rings, one ring is a benzo ring fused to a second ring; and the second ring is a 5- or 6-membered carbon ring which is saturated, partially unsaturated, or unsaturated.
• the bicyclic carbocyclic group may be attached to its pendant group at any carbon atom which results in a stable structure.
• the bicyclic carbocyclic group described herein may be substituted on any carbon if the resulting compound is stable.
• Examples of a bicyclic carbocyclic group are, but not limited to, naphthyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, and indanyl.
• “Aryl” groups refer to monocyclic or polycyclic aromatic hydrocarbons, including, for example, phenyl, naphthyl, and phenanthranyl.
• Aryl moieties are well known and described, for example, in Lewis, R.J., ed., Hawley's Condensed Chemical Dictionary, 13th Edition, John Wiley & Sons, Inc., New York (1997). “Benzyl” is intended to mean a methyl group on which one of the hydrogen atoms is replaced by a phenyl group, wherein said phenyl group may optionally be substituted with 1 to 5 groups, preferably 1 to 3 groups.
• Heterocycle is intended to mean a stable 3-, 4-, 5-, 6-, or 7-membered monocyclic or bicyclic or 7-, 8-, 9-, 10-, 11-, 12-, 13-, or 14- membered polycyclic heterocyclic ring that is saturated, partially unsaturated, or fully unsaturated, and that contains carbon atoms and 1, 2, 3 or 4 heteroatoms independently selected from the group consisting of N, O and S; and including any polycyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring.
• the nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., N ⁇ O and S(O) p , wherein p is 0, 1 or 2).
• the nitrogen atom may be substituted or unsubstituted (i.e., N or NR wherein R is H or another substituent, if defined).
• the heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure.
• the heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable.
• a nitrogen in the heterocyclyl may optionally be quaternized.
• heterocyclyl when the total number of S and O atoms in the heterocyclyl exceeds 1, then these heteroatoms are not adjacent to one another. It is preferred that the total number of S and O atoms in the heterocyclyl is not more than 1. Bridged rings are also included in the definition of heterocyclyl. When the term “heterocyclyl” is used, it is intended to include heteroaryl.
• heterocyclyls include, but are not limited to, acridinyl, azetidinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2- dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-in
• fused ring and spiro compounds containing, for example, the above heterocyclyls are fused ring and spiro compounds containing, for example, the above heterocyclyls.
• “Bicyclic heterocyclyl” "bicyclic heterocyclyl” or “bicyclic heterocyclic group” is intended to mean a stable 9- or 10-membered heterocyclic ring system which contains two fused rings and consists of carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, O and S.
• one ring is a 5- or 6-membered monocyclic aromatic ring comprising a 5-membered heteroaryl ring, a 6- membered heteroaryl ring or a benzo ring, each fused to a second ring.
• the second ring is a 5- or 6-membered monocyclic ring which is saturated, partially unsaturated, or unsaturated, and comprises a 5-membered heterocyclyl, a 6-membered heterocyclyl or a carbocyclyl (provided the first ring is not benzo when the second ring is a carbocyclyl).
• the bicyclic heterocyclic group may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure.
• the bicyclic heterocyclic group described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. It is preferred that when the total number of S and O atoms in the heterocyclyl exceeds 1, then these heteroatoms are not adjacent to one another.
• the total number of S and O atoms in the heterocyclyl is not more than 1.
• a bicyclic heterocyclic group are, but not limited to, quinolinyl, isoquinolinyl, phthalazinyl, quinazolinyl, indolyl, isoindolyl, indolinyl, 1H-indazolyl, benzimidazolyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 5,6,7,8- tetrahydroquinolinyl, 2,3-dihydrobenzofuranyl, chromanyl, 1,2,3,4- tetrahydroquinoxalinyl, and 1,2,3,4-tetrahydroquinazolinyl.
• Heteroaryl is intended to mean stable monocyclic and polycyclic aromatic hydrocarbons that include at least one heteroatom ring member such as sulfur, oxygen, or nitrogen.
• Heteroaryl groups include, without limitation, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrroyl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, purinyl, carbazolyl, benzimidazolyl, indolinyl, benzodioxolanyl, and benzodioxane.
• Heteroaryl groups are substituted or unsubstituted.
• the nitrogen atom is substituted or unsubstituted (i.e., N or NR wherein R is H or another substituent, if defined).
• the nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., N ⁇ O and S(O) p , wherein p is 0, 1 or 2).
• substituted means that at least one hydrogen atom is replaced with a non-hydrogen group, provided that normal valencies are maintained and that the substitution results in a stable compound.
• 2 hydrogens on the atom are replaced.
• Keto substituents are not present on aromatic moieties.
• nitrogen atoms e.g., amines
• these may be converted to N-oxides by treatment with an oxidizing agent (e.g., mCPBA and/or hydrogen peroxides) to afford other compounds of this invention.
• shown and claimed nitrogen atoms are considered to cover both the shown nitrogen and its N-oxide (NoO) derivative.
• NoO N-oxide
• any variable occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence.
• a group is shown to be substituted with 0-3 R groups, then said group may optionally be substituted with up to three R groups, and at each occurrence R is selected independently from the definition of R.
• combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
• a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring.
• substituents and/or variables are permissible only if such combinations result in stable compounds.
• the invention includes all pharmaceutically acceptable salt forms of the compounds.
• Pharmaceutically acceptable salts are those in which the counter ions do not contribute significantly to the physiological activity or toxicity of the compounds and as such function as pharmacological equivalents. These salts can be made according to common organic techniques employing commercially available reagents.
• anionic salt forms include acetate, acistrate, besylate, bromide, chloride, citrate, fumarate, glucouronate, hydrobromide, hydrochloride, hydroiodide, iodide, lactate, maleate, mesylate, nitrate, pamoate, phosphate, succinate, sulfate, tartrate, tosylate, and xinofoate.
• Some cationic salt forms include ammonium, aluminum, benzathine, bismuth, calcium, choline, diethylamine, diethanolamine, lithium, magnesium, meglumine, 4-phenylcyclohexylamine, piperazine, potassium, sodium, tromethamine, and zinc.
• a given chemical formula or name shall encompass all stereo and optical isomers and racemates thereof where such isomers exist. Unless otherwise indicated, all chiral (enantiomeric and diastereomeric) and racemic forms are within the scope of the invention. Enantiomers and diastereomers are examples of stereoisomers.
• the term "enantiomer” refers to one of a pair of molecular species that are mirror images of each other and are not superimposable.
• diastereomer refers to stereoisomers that are not mirror images.
• racemate or “racemic mixture” refers to a composition composed of equimolar quantities of two enantiomeric species, wherein the composition is devoid of optical activity.
• the invention includes all tautomeric forms of the compounds, atropisomers and rotational isomers. All processes used to prepare compounds of the present invention and intermediates made therein are considered to be part of the present invention.
• the symbols “R” and “S” represent the configuration of substituents around a chiral carbon atom(s).
• the isomeric descriptors "R” and “S” are used as described herein for indicating atom configuration(s) relative to a core molecule and are intended to be used as defined in the literature (IUPAC Recommendations 1996, Pure and Applied Chemistry, 68:2193-2222 (1996)).
• the term “chiral” refers to the structural characteristic of a molecule that makes it impossible to superimpose it on its mirror image.
• the term “homochiral” refers to a state of enantiomeric purity.
• optical activity refers to the degree to which a homochiral molecule or nonracemic mixture of chiral molecules rotates a plane of polarized light. The invention is intended to include all isotopes of atoms occurring in the compounds.
• Isotopes include those atoms having the same atomic number but different mass numbers.
• isotopes of hydrogen include deuterium and tritium.
• isotopes of carbon include 13 C and 14 C.
• Isotopically- labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwise employed. Such compounds may have a variety of potential uses, for example as standards and reagents in determining biological activity. In the case of stable isotopes, such compounds may have the potential to favorably modify biological, pharmacological, or pharmacokinetic properties.
• Optically active forms may be prepared by resolution of racemic forms or by synthesis from optically active starting materials. All processes used to prepare compounds of the present invention and intermediates made therein are considered to be part of the present invention. When enantiomeric or diastereomeric products are prepared, they may be separated by conventional methods, for example, by chromatography or fractional crystallization. Depending on the process conditions the end products of the present invention are obtained either in free (neutral) or salt form. Both the free form and the salts of these end products are within the scope of the invention. If so desired, one form of a compound may be converted into another form.
• a free base or acid may be converted into a salt; a salt may be converted into the free compound or another salt; a mixture of isomeric compounds of the present invention may be separated into the individual isomers.
• Compounds of the present invention, free form and salts thereof, may exist in multiple tautomeric forms, in which hydrogen atoms are transposed to other parts of the molecules and the chemical bonds between the atoms of the molecules are consequently rearranged. It should be understood that all tautomeric forms, insofar as they may exist, are included within the invention.
• the term "stereoisomer" refers to isomers of identical constitution that differ in the arrangement of their atoms in space. Enantiomers and diastereomers are examples of stereoisomers.
• enantiomer refers to one of a pair of molecular species that are mirror images of each other and are not superimposable.
• diastereomer refers to stereoisomers that are not mirror images.
• racemate or “racemic mixture” refers to a composition composed of equimolar quantities of two enantiomeric species, wherein the composition is devoid of optical activity.
• Human embryonic kidney cells 293 (HEK293) cells and HEK293 cells stably expressing human RXFP1 were cultured in MEM medium supplemented with 10% qualified FBS, and 300 Pg/ml hygromycin (Life Technologies). Cells were dissociated and suspended in assay buffer.
• the assay buffer was HBSS buffer (with calcium and magnesium) containing 20 mM HEPES, 0.05% BSA, and 0.5 mM IBMX. Cells (3000 cells per well, except 1500 cell per well for HEK293 cells stably expressing human RXFP1) were added to 384-well Proxiplates (Perkin-Elmer).
• time-resolved fluorescence intensity was measured using the Envision (Perkin-Elmer) at 400 nm excitation and dual emission at 590 nm and 665 nm.
• a calibration curve was constructed with an external cAMP standard at concentrations ranging from 2.7 PM to 0.1 pM by plotting the fluorescent intensity ratio from 665 nm emission to the intensity from the 590 nm emission against cAMP concentrations.
• the potency and activity of a compound to inhibit cAMP production was then determined by fitting to a 4-parametric logistic equation from a plot of cAMP level versus compound concentrations.
• the compounds of Formula (I) are RXFP1 receptor agonists and may find use in the treatment of medical indications such as heart failure, fibrotic diseases, and related diseases such as lung disease (e.g., idiopathic pulmonary fibrosis), kidney disease (e.g., chronic kidney disease), or hepatic disease (e.g., non-alcoholic steatohepatitis and portal hypertension).
• a pharmaceutical composition comprising a compound of Formula (I) and a pharmaceutically acceptable carrier.
• Another aspect of the invention is a pharmaceutical composition comprising a compound of Formula (I) for the treatment of a relaxin-associated disorder and a pharmaceutically acceptable carrier.
• Another aspect of the invention is a method of treating a disease associated with relaxin comprising administering an effective amount of a compound of Formula (I).
• Another aspect of the invention is a method of treating a cardiovascular disease comprising administering an effective amount of a compound of Formula (I) to a patient in need thereof.
• Another aspect of the invention is a method of treating heart failure comprising administering an effective amount of a compound of Formula (I) to a patient in need thereof.
• Another aspect of the invention is a method of treating fibrosis comprising administering a therapeutically effective amount of a compound of Formula (I) to a patient in need thereof.
• Another aspect of the invention is a method of treating a disease associated with fibrosis comprising administering a therapeutically effective amount of a compound of Formula (I) to a patient in need thereof.
• Another aspect of the invention is a method of treating or preventing kidney failure, comprising administering a therapeutically effective amount of a compound of Formula (I) to a patient in need thereof.
• Another aspect of the invention is a method of improving, stabilizing or restoring renal function in a patient in need thereof, comprising administering a therapeutically effective amount of a compound of Formula (I) to the patient.
• the following terms have the stated meanings.
• patient refers to any human or non-human organism that could potentially benefit from treatment with a RXFP1 agonist as understood by practioners in this field.
• exemplary subjects include human beings of any age with risk factors for cardiovascular disease. Common risk factors include, but are not limited to, age, sex, weight, family history, sleep apnea, alcohol or tobacco use, physical inactivity, arrhythmia, or signs of insulin resistance such as acanthosis nigricans, hypertension, dyslipidemia, or polycystic ovary syndrome (PCOS).
• PCOS polycystic ovary syndrome
• Treating” or “treatment” cover the treatment of a disease-state as understood by practitioners in this field and include the following: (a) inhibiting the disease-state, i.e., arresting it development; (b) relieving the disease-state, i.e., causing regression of the disease state; and/or (c) preventing the disease-state from occurring in a mammal, in particular, when such mammal is predisposed to the disease-state but has not yet been diagnosed as having it.
• Preventing” or “prevention” cover the preventive treatment (i.e., prophylaxis and/or risk reduction) of a subclinical disease-state aimed at reducing the probability of the occurrence of a clinical disease-state as understood by practitioners in this field.
• Patients are selected for preventative therapy based on factors that are known to increase risk of suffering a clinical disease state compared to the general population.
• “Prophylaxis” therapies can be divided into (a) primary prevention and (b) secondary prevention.
• Primary prevention is defined as treatment in a subject that has not yet presented with a clinical disease state, whereas secondary prevention is defined as preventing a second occurrence of the same or similar clinical disease state.
• “Risk reduction” or “reducing risk” covers therapies that lower the incidence of development of a clinical disease state. As such, primary and secondary prevention therapies are examples of risk reduction.
• “Therapeutically effective amount” is intended to include an amount of a compound of the present invention that is effective when administered alone or in combination with other agents to treat disorders as understood by practitioners in this field.
• disorders of the cardiovascular system include for example the following disorders: hypertension (high blood pressure), peripheral and cardiac vascular disorders, coronary heart disease, stable and unstable angina pectoris, heart attack, myocardial insufficiency, abnormal heart rhythms (or arrhythmias), persistent ischemic dysfunction ("hibernating myocardium”), temporary postischemic dysfunction ("stunned myocardium”), heart failure, disturbances of peripheral blood flow, acute coronary syndrome, heart failure, heart muscle disease (cardiomyopathy), myocardial infarction and vascular disease (blood vessel disease).
• Heart failure includes both acute and chronic manifestations of heart failure, as well as more specific or related types of disease, such as advanced heart failure, post- acute heart failure, cardio-renal syndrome, heart failure with impaired kidney function, chronic heart failure, chronic heart failure with mid-range ejection fraction (HFmEF), compensated heart failure, decompensated heart failure, right heart failure, left heart failure, global failure, ischemic cardiomyopathy, dilated cardiomyopathy, heart failure associated with congenital heart defects, heart valve defects, heart failure associated with heart valve defects, mitral stenosis, mitral insufficiency, aortic stenosis, aortic insufficiency, tricuspid stenosis, tricuspid insufficiency, pulmonary stenosis, pulmonary valve insufficiency, heart failure associated with combined heart valve defects, myocardial inflammation (myocarditis), chronic myocarditis, acute myocarditis, viral myocarditis, diabetic heart failure, alcoholic cardio
• Fibrotic disorders encompasses diseases and disorders characterized by fibrosis, including among others the following diseases and disorders: hepatic fibrosis, cirrhosis of the liver, NASH, pulmonary fibrosis or lung fibrosis, cardiac fibrosis, endomyocardial fibrosis, nephropathy, glomerulonephritis, interstitial renal fibrosis, fibrotic damage resulting from diabetes, bone marrow fibrosis and similar fibrotic disorders, scleroderma, morphea, keloids, hypertrophic scarring (also following surgical procedures), naevi, diabetic retinopathy, proliferative vitreoretinopathy and disorders of the connective tissue (for example sarcoidosis).
• diseases and disorders including among others the following diseases and disorders: hepatic fibrosis, cirrhosis of the liver, NASH, pulmonary fibrosis or lung fibrosis, cardiac fibrosis, endomyocardial
• Relaxin-associated disorders include but are not limited to disorders of the cardiovascular system and fibrotic disorders.
• the compounds of this invention can be administered by any suitable means, for example, orally, such as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions (including nanosuspensions, microsuspensions, spray-dried dispersions), syrups, and emulsions; sublingually; bucally; parenterally, such as by subcutaneous, intravenous, intramuscular, or intrasternal injection, or infusion techniques (e.g., as sterile injectable aqueous or non-aqueous solutions or suspensions); nasally, including administration to the nasal membranes, such as by inhalation spray; topically, such as in the form of a cream or ointment; or rectally such as in the form of suppositories.
• suitable means for example, orally, such as tablets, capsules (
• “Pharmaceutical composition” means a composition comprising a compound of the invention in combination with at least one additional pharmaceutically acceptable carrier.
• a “pharmaceutically acceptable carrier” refers to media generally accepted in the art for the delivery of biologically active agents to animals, in particular, mammals, including, i.e., adjuvant, excipient or vehicle, such as diluents, preserving agents, fillers, flow regulating agents, disintegrating agents, wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents, perfuming agents, anti-bacterial agents, anti-fungal agents, lubricating agents and dispensing agents, depending on the nature of the mode of administration and dosage forms.
• Pharmaceutically acceptable carriers are formulated according to a number of factors well within the purview of those of ordinary skill in the art. These include, without limitation: the type and nature of the active agent being formulated; the subject to which the agent-containing composition is to be administered; the intended route of administration of the composition; and the therapeutic indication being targeted. Pharmaceutically acceptable carriers include both aqueous and non-aqueous liquid media, as well as a variety of solid and semi-solid dosage forms. Such carriers can include a number of different ingredients and additives in addition to the active agent, such additional ingredients being included in the formulation for a variety of reasons, e.g., stabilization of the active agent, binders, etc., well known to those of ordinary skill in the art.
• the daily oral dosage of each active ingredient when used for the indicated effects, will range between about 0.01 to about 5000 mg per day, preferably between about 0.1 to about 1000 mg per day, and most preferably between about 0.1 to about 250 mg per day.
• the most preferred doses will range from about 0.01 to about 10 mg/kg/minute during a constant rate infusion.
• Compounds of this invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three, or four times daily.
• the compounds are typically administered in admixture with suitable pharmaceutical diluents, excipients, or carriers (collectively referred to herein as pharmaceutical carriers) suitably selected with respect to the intended form of administration, e.g., oral tablets, capsules, elixirs, and syrups, and consistent with conventional pharmaceutical practices.
• Dosage forms (pharmaceutical compositions) suitable for administration may contain from about 1 milligram to about 2000 milligrams of active ingredient per dosage unit. In these pharmaceutical compositions the active ingredient will ordinarily be present in an amount of about 0.1-95% by weight based on the total weight of the composition.
• a typical capsule for oral administration contains at least one of the compounds of the present invention (250 mg), lactose (75 mg), and magnesium stearate (15 mg).
• a typical injectable preparation is produced by aseptically placing at least one of the compounds of the present invention (250 mg) into a vial, aseptically freeze-drying and sealing. For use, the contents of the vial are mixed with 2 mL of physiological saline, to produce an injectable preparation.
• the compounds may be employed in combination with other suitable therapeutic agents useful in the treatment of diseases or disorders including: anti-atherosclerotic agents, anti-dyslipidemic agents, anti-diabetic agents, anti-hyperglycemic agents, anti-hyperinsulinemic agents, anti-thrombotic agents, anti-retinopathic agents, anti-neuropathic agents, anti-nephropathic agents, anti-ischemic agents, anti-hypertensive agents, anti-obesity agents, anti-hyperlipidemic agents, anti-hypertriglyceridemic agents, anti-hypercholesterolemic agents, anti-restenotic agents, anti-pancreatic agents, lipid lowering agents, anorectic agents, memory enhancing agents, anti-dementia agents, cognition promoting agents, appetite suppressants, agents for treating heart failure, agents for treating peripheral arterial disease, agents for treating malignant tumors, and anti-inflammatory agents.
• anti-atherosclerotic agents anti-dyslipidemic agents, anti-
• the additional therapeutic agents may include ACE inhibitors, ⁇ -blockers, diuretics, mineralocorticoid receptor antagonists, ryanodine receptor modulators, SERCA2a activators, renin inhibitors, calcium channel blockers, adenosine A1 receptor agonists, partial adenosine A1 receptor, dopamine ⁇ -hydroxylase inhibitors, angiotensin II receptor antagonists, angiotensin II receptor antagonists with biased agonism for select cell signaling pathways, combinations of angiotensin II receptor antagonists and neprilysin enzyme inhibitors, neprilysin enzyme inhibitors, soluble guanylate cyclase activators, myosin ATPase activators, rho-kinase 1 inhibitors, rho-kinase 2 inhibitors, apelin receptor agonists, nitroxyl donating compounds, calcium-dependent kinase II inhibitors, antifibrotic agents, galectin-3 inhibitors, vaso
• the additional therapeutic agents may also include nintedanib, Pirfenidone, LPA1 antagonists, LPA1 receptor antagonists, GLP1 analogs, tralokinumab (IL-13, AstraZeneca), vismodegib (hedgehog antagonist, Roche), PRM-151 (pentraxin-2, TGF beta-1, Promedior), SAR-156597 (bispecific Mab IL-4&IL-13, Sanofi), pumpuzumab ((anti-lysyl oxidase-like 2 (anti-LOXL2) antibody, Gilead), CKD-942, PTL-202 (PDE inh./pentoxifylline/NAC oral control.
• omipalisib oral PI3K/mTOR inhibitor, GSK
• IW-001 oral sol. bovine type V collagen mod., ImmuneWorks
• STX-100 integrated alpha V/ beta-6 ant, Stromedix/ Biogen
• Actimmune IFN gamma
• PC-SOD midismase; inhaled, LTT Bio-Pharma / CKD Pharm
• lebrikizumab anti-IL-13 SC humanized mAb, Roche
• AQX-1125 SHIP1 activator, Aquinox), CC-539 (JNK inhibitor, Celgene), FG-3019 (FibroGen), SAR-100842 (Sanofi), and obeticholic acid (OCA or INT-747, Intercept).
• the above other therapeutic agents when employed in combination with the compounds of the present invention may be used, for example, in those amounts indicated in the Physicians' Desk Reference, as in the patents set out above, or as otherwise determined by practitioners in the art.
• the compound of the present invention and a second therapeutic agent are combined in a single dosage unit they are formulated such that although the active ingredients are combined in a single dosage unit, the physical contact between the active ingredients is minimized (that is, reduced).
• one active ingredient may be enteric coated.
• enteric coating one of the active ingredients, it is possible not only to minimize the contact between the combined active ingredients, but also, it is possible to control the release of one of these components in the gastrointestinal tract such that one of these components is not released in the stomach but rather is released in the intestines.
• One of the active ingredients may also be coated with a material that affects a sustained-release throughout the gastrointestinal tract and also serves to minimize physical contact between the combined active ingredients.
• the sustained-released component can be additionally enteric coated such that the release of this component occurs only in the intestine.
• Still another approach would involve the formulation of a combination product in which the one component is coated with a sustained and/or enteric release polymer, and the other component is also coated with a polymer such as a low viscosity grade of hydroxypropyl methylcellulose (HPMC) or other appropriate materials as known in the art, in order to further separate the active components.
• HPMC hydroxypropyl methylcellulose
• the polymer coating serves to form an additional barrier to interaction with the other component.
• the compounds of the present invention are also useful as standard or reference compounds, for example as a quality standard or control, in tests or assays involving RXFP1. Such compounds may be provided in a commercial kit, for example, for use in pharmaceutical research involving RXFP1.
• a compound of the present invention could be used as a reference in an assay to compare its known activity to a compound with an unknown activity. This would ensure the experimenter that the assay was being performed properly and provide a basis for comparison, especially if the test compound was a derivative of the reference compound.
• compounds according to the present invention could be used to test their effectiveness.
• the compounds of the present invention may also be used in diagnostic assays involving RXFP1.
• the present invention also encompasses an article of manufacture. As used herein, article of manufacture is intended to include, but not be limited to, kits and packages.
• the article of manufacture of the present invention comprises: (a) a first container; (b) a pharmaceutical composition located within the first container, wherein the composition, comprises a first therapeutic agent, comprising a compound of the present invention or a pharmaceutically acceptable salt form thereof; and, (c) a package insert stating that the pharmaceutical composition can be used for the treatment of dyslipidemias and the sequelae thereof.
• the package insert states that the pharmaceutical composition can be used in combination (as defined previously) with a second therapeutic agent for the treatment of dyslipidemias and the sequelae thereof.
• the article of manufacture can further comprise: (d) a second container, wherein components (a) and (b) are located within the second container and component (c) is located within or outside of the second container.
• the first container is a receptacle used to hold a pharmaceutical composition. This container can be for manufacturing, storing, shipping, and/or individual/bulk selling.
• First container is intended to cover a bottle, jar, vial, flask, syringe, tube (e.g., for a cream preparation), or any other container used to manufacture, hold, store, or distribute a pharmaceutical product.
• the second container is one used to hold the first container and, optionally, the package insert. Examples of the second container include, but are not limited to, boxes (e.g., cardboard or plastic), crates, cartons, bags (e.g., paper or plastic bags), pouches, and sacks.
• the package insert can be physically attached to the outside of the first container via tape, glue, staple, or another method of attachment, or it can rest inside the second container without any physical means of attachment to the first container.
• the package insert is located on the outside of the second container.
• the package insert is physically attached via tape, glue, staple, or another method of attachment.
• it can be adjacent to or touching the outside of the second container without being physically attached.
• the package insert is a label, tag, marker, etc. that recites information relating to the pharmaceutical composition located within the first container. The information recited will usually be determined by the regulatory agency governing the area in which the article of manufacture is to be sold (e.g., the United States Food and Drug Administration).
• the package insert specifically recites the indications for which the pharmaceutical composition has been approved.
• the package insert may be made of any material on which a person can read information contained therein or thereon.
• the package insert is a printable material (e.g., paper, plastic, cardboard, foil, adhesive-backed paper or plastic, etc.) on which the desired information has been formed (e.g., printed or applied).
• GENERAL METHODS OF SYNTHESIS The compounds of this invention can be made by various methods known in the art including those of the following schemes and in the specific embodiments section. The structure numbering and variable numbering shown in the synthetic schemes are distinct from, and should not be confused with, the structure or variable numbering in the claims or the rest of the specification.
• the chloro moiety of I-V can be further converted to a variety of functional groups or can be de- chlorinated under dehalogenation conditions (e.g.Pd(OAc)2, JohnPhos) to afford intermediate I-VI.
• dehalogenation conditions e.g.Pd(OAc)2, JohnPhos
• the chlorine may be removed from I-IV followed by amide formation using an appropriate amine and AlMe3, or coupling of the carboxylic acid (derived from hydrolysis of the ester) with appropriate amines of this invention via standard coupling procedures known in the art.
• the coupling of intermediate I-VI with appropriately carboxylic acids of this invention via a variety of amide bond forming conditions e.g., TCFH, 1-methyl-1H-imidazole or BOP, DIEA or other conditions known in the art
• TCFH 1-methyl-1H-imidazole or BOP, DIEA or other conditions known in the art
• Scheme II describes how benzothiazole examples of this invention may be prepared from commercially available intermediate I-VII.
• intermediate I-VII Starting from methyl 2-methylbenzo[d]thiazole-5-carboxylate intermediate I-VII, nitration (HNO 3 , H 2 SO 4 ) provides nitro intermediates I-VIIIa and I-VIIIb.
• Intermediate I-VIIIa can be hydrolyzed (e.g., LiOH, H 2 O) to the carboxylic acid derivative I-IX, which can be coupled with various amines of this invention (e.g., POCl3, or BOP, DIEA, or HATU, DIEA and or other methods known in the art) to provide intermediate I-X.
• amines of this invention e.g., POCl3, or BOP, DIEA, or HATU, DIEA and or other methods known in the art
• I-X e.g., H2, Pd/C, or Zn, NH4Cl
• I-XI a variety of amide bond forming conditions
• benzothiazoles (Scheme III) of this invention can also be synthesized via the general methods described in Schemes I and II.
• the aniline intermediate I-XV can then be coupled under conditions previously described or known in the art to with appropriately substituted benzoic acids to afford benzothiazole compounds of this invention.
• Trifluoromethylbenzothiazole intermediates I-XVI can be accessed according to the general route shown in Scheme IV (Du, G. et.al. Het.2015, 9, 1723). The intermediate I-XIII can then be converted to the trifluorobenzothiazole intermediate I- XVI as previous shown in Scheme II.
• Scheme IV Substituted benzoic acids or heterocyclic acid intermediates used in the preparation of Examples in this invention can be synthesized by the general route shown in Scheme V.
• Arylisoxazoline intermediates of this invention can be obtained from commercially available aryl or heteroaryl carboxaldehydes as shown by the general route in Scheme VI. Conversion of the aldehyde I-XX to the oxime I-XXI followed by treatment with NCS provides chlorooxime I-XXII. Treatment of IXII with an appropriate olefin affords arylisoxazoline intermediates for the general formula I-XXIII, IXXIV. Conversely treatment of I-XXII with an acetylenic intermediate affords arylisoxazole derivatives I-XXV of this invention.
• Heteroaryl carboxaldehydes can also be subjected to similar conditions to afford heteroaryl isoxazoline or isoxazole intermediates of this invention. Diastereomeric mixtures generated from the condensation can be separated via chiral SFC.
• Difluorodioxolone intermediates of this invention can be obtained from commercially available 2,2-difluorobenzo[d][1,3]dioxol-5-amine as shown in Scheme VII.
• Bromination (NBS) affords intermediate I-XXVI.
• Palladium catalysis of intermediate I-XXVI in the presence of CO in MeOH affords the methyl ester intermediate I-XXVII which can be converted to a variety of amides of this invention by treatment with XNH2 in the presence of AlMe3, or via a sequential hydrolysis (LiOH, THF/ MeOH /water), followed by peptide coupling procedures known in the art to afford intermediate I-XXVIII.
• Reverse phase preparative HPLC was carried out using C18 columns with UV 220 nm or prep LCMS detection eluting with gradients of Solvent A (90% water, 10% MeOH, 0.1% TFA) and Solvent B (10% water, 90% MeOH, 0.1% TFA) or with gradients of Solvent A (95% water, 5% ACN, 0.1% TFA) and Solvent B (5% water, 95% ACN, 0.1% TFA) or with gradients of Solvent A (95% water, 2% ACN, 0.1% HCOOH) and Solvent B (98% ACN, 2% water, 0.1% HCOOH) or with gradients of Solvent A (95% water, 5% ACN, 10 mM NH4OAc) and Solvent B (98% ACN, 2% water, 10 mM NH4OAc) or with gradients of Solvent A (98% water, 2% ACN, 0.1% NH4OH) and Solvent B (98% ACN, 2% water, 0.1% NH4OH).
• Method A Instrument: Waters Acquity coupled with a Waters MICROMASS® ZQ Mass Spectrometer Linear gradient of 2 to 98 % B over 1 min, with 0.5 min hold time at 98 % B UV visualization at 220 nm
• Method B Instrument: Shimadzu Prominence HPLC coupled with a Shimadzu LCMS-2020 Mass Spectrometer Linear gradient of 0 to 100 % B over 3 min, with 0.75 min hold time at 100 % B UV visualization at 220 nm
• reaction mixture was heated under microwave irradiation at 120 °C for 30 min.
• the cooled reaction mixture was quenched with 1N HCl (10 mL), extracted with EtOAc (3 x 30 mL).
• the combined organic portions were washed with brine (15 mL), dried (MgSO4) and concentrated under reduced pressure.
• the residue was purified via normal phase chromatography, eluted with hexanes/EtOAc to afford 1-3 (0.8 g, 2 mmol, 90 % yield) orange solid.
• Diasteromeric intermediate 4-2 Preparation of 5-(5-(hydroxymethyl)-3a,5,6,6a- tetrahydro-4H-cyclopenta[d]isoxazol-3-yl)-2-methoxybenzoic acid.
• Intermediate 4-1 (88 mg, 0.29 mmol) was dissolved in THF (1 mL)/MeOH (1 mL) and treated with LiOH monohydrate (36 mg, 0.86 mmol) in H 2 O (1 mL) at rt. After 3 h, the reaction mixture was diluted with H 2 O (5 mL) and the pH of the aq. layer was adjusted to pH 7 with 1M HCl solution and extracted with EtOAc (2 x 25 mL).
• Intermediate 5-1 Preparation of methyl 2-methoxy-5-(3a,5,6,6a-tetrahydro-4H- pyrrolo[3,4-d]isoxazol-3-yl)benzoate.
• Intermediates 5-1 and 5-2 were prepared and isolated in a similar manner as that described for intermediate 3-3 by substituting tert- butyl 2,5-dihydro-1H-pyrrole-1-carboxylate for 2,5-dihydrofuran in the cycloaddition step, followed by SFC separation of the resulting diastereomer to the isomers by the following preparative chromatographic methods: Instrument: Jasco SFC Prep Column: Regis Whelk 21 X 250 mm ID, 5 ⁇ m, Temperature: 40 °C, Flow rate: 45 mL/min, 150 Bar, Mobile Phase: gradient 80/20 CO2/MeOH, Detector Wavelength: 220 nm, Injection Volume: 0.5 mL to afford intermediate 5-1 (peak 1, 0.36 g
• Analytical Chromatographic Conditions Instrument: Shimadzu Nexera SFC, Column: Chiralcel OD-H, 4.6 X 100 mm ID, 3 ⁇ m, Temperature: 40 °C, Flow rate: 2.0 mL/min, 150 Bar, Mobile Phase: gradient 85/15 CO2/MeOH. Detector Wavelength: 220 nm.
• Analytical Chromatographic Conditions Instrument: Shimadzu Nexera SFC, Column: Chiralcel OD-H, 4.6 X 100 mm ID, 3 ⁇ m, Temperature: 40 °C, Flow rate: 2.0 mL/min, 150 Bar, Mobile Phase: gradient 93/7 CO2/MeOH. Detector Wavelength: 220 nm.
• Intermediate 11-1 Preparation of 5-(5-(2-hydroxypropan-2-yl)-4,5-dihydroisoxazol-3- yl)-2-methoxybenzoic acid.
• Intermediate 11-1 was prepared (181 mg, 100% yield) in a similar manner as intermediate 4-1 by substituting 2-(cyclopent-3-en-1-yl)propan-2-ol for cyclopent-3-en-1-ylmethanol followed by hydrolysis as that described for intermediate 3- 6.
• Intermediates 12-2 and 12-3 Preparation of 2-methoxy-5-(5-(1-(2- methoxyethoxy)cyclopropyl)-4,5-dihydroisoxazol-3-yl)benzoic acid.
• Intermediate 12-1 ( 0.27 g, 0.77 mmol, 87 % yield) was prepared in a similar manner as that described for intermediate 3-3 by substituting 1-(2-methoxyethoxy)-1- vinylcyclopropane for 2,5-dihydrofuran followed by ester hydrolysis as described for intermediate 3-6.
• Analytical Chromatographic Conditions Instrument: Shimadzu Nexera SFC, Column: Chiralpak, 4.6 x 100 mm ID, 3 ⁇ m, Temperature: 40 °C, Flow rate: 2.0 mL/min, 150 Bar, Mobile Phase: gradient 75/25 CO 2 /MeOH. Detector Wavelength: 220 nm.
• Intermediate 15-3 Preparation of 2-methyl-6-nitrobenzo[d]thiazole-5-carboxylic acid. Hydrolysis of intermediate 15-1 (46 mg, 0.18 mmol) was done in THF (2 mL)/MeOH (0.5 mL)/water (0.5 mL), and LiOH (2M, 0.5 ml, 0.5 mmol) in 24 h. The solvents were reduced in vacuo and the residue dissolved in dil. HCl (2 mL). The solution was extracted with EtOAc (2 x 10 mL) and the combined organic portions dried (MgSO4) and concentrated under reduced pressure to yield intermediate 15-3 (39 mg, 0.16 mmol, 90 % yield) as a yellow solid.
• Intermediate 16-2 Preparation of tert-butyl 2-bromo-2-(3-bromo-4- fluorophenyl)acetate. To a 20 mL reaction vial charged with intermediate 16-1 (266 mg, 0.92 mmol) was added NBS (0.2 g, 1 mmol), carbon tetrachloride (10 mL), and AIBN (15 mg, 90 mmol). The solution was stirred at 77 o C, for 3 h. The solution was concentrated under reduced pressure and purified by normal phase silica gel chromatography to afford intermediate 16-2 (0.3 g, 0.8 mmol, 91 % yield).
• Preparative chromatographic conditions Instrument: Berger MG II; Column: Chiralpak ID, 21 x 250 mm, 5 micron; Mobile phase: 20 % MeOH / 80 % CO2; Flow conditions; 45 mL/min, 120 Bar, 40 °C; Detector wavelength: 209 nm; Injection details: 49 injections in MeOH.
• Analytical chromatographic conditions Instrument: Waters UPC2 analytical SFC; Column: Chiralpak IC, 4.6 x 100 mm, 3 micron; Mobile phase: 25 % MeOH / 75 % CO2; Flow conditions: 2 mL/min, 150 Bar, 40 °C; Detector wavelength: 220 nm.
• intermediate 20-1 (0.28 g, 0.77 mmol) in toluene (4 mL), was added TFA (0.6 mL, 8 mmol), PCl3 (3.8 mL, 7.7 mmol) and the reaction mixture was heated to 100 °C for 2 h, then stirred at rt for 18 h. The solvents were removed under reduced pressure and the residue was purified via silica gel chromatography eluting with hexanes/EtOAc to afford intermediate 20-2 (0.2 g, 0.8 mmol, 100 % yield) as a white solid.
• reaction mixure was then heated to 50 o C and iron (543 mg, 9.70 mmol) was added. The reaction temperature was then increased to 80 o C and the reaction mixture stirred for 14 h. The reaction mixture was allowed to cool to rt and then filtered through Celite ® and washed with EtOAc. The solution was concentrated under reduced pressure. The resulting residue was dissolved in EtOAc (20 mL) and washed with water (20 mL). The organic layers were then dried over sodium sulfate, concentrated under reduced pressure to get a residue which was purified by silica gel column chromatography using hexane and EtOAc as eluents to yield intermediate 22-4 (400 mg, 91% yield).
• reaction mixture was degassed for 2 min with nitrogen, then heated at 80 °C for 18 h. After cooling to rt, the reaction mixture was diluted with 1N HCl (25 mL) and the solution extracted with EtOAc (3 x 25 mL). The combined organic portions were dried over Na2SO4, filtered, concentrated under reduced pressure, and the resulting residue was dissolved in DMF and purified by preparative RP-HPLC to afford intermediate 23 (586 mg, 1.69 mmol, 66 % yield).
• reaction mixture was purified by reverse phase HPLC (5:95 ACN, water with 0.05% TFA to 95:5 ACN , water with 0.05% TFA) to afford example 2 (2.6 mg, 4.2 ⁇ mol, 62 % yield).
• Example 30 Preparation of 2-(6-fluoro-3'-((5-((4-fluoro-3- (trifluoromethyl)phenyl)carbamoyl)-2-methylbenzo[d]thiazol-6-yl)carbamoyl)-4'- methoxy-[1,1'-biphenyl]-3-yl)-2-(tetrahydro-2H-pyran-4-carboxamido)acetic acid 5
• Example 30 To intermediate 15 (34 mg, 92 Pmol) and intermediate 16-6 (44 mg, 92 Pmol) in ACN (2 mL), was added DIEA (0.4 mL, 2.1 mmol) followed by HATU (42 mg, 0.11 mmol).
• reaction mixture was concentrated under vacuum and purified using silica gel chromatography to yield tert-butyl 6-fluoro-3'-((6-((4-fluoro- 3-(trifluoromethyl)phenyl)carbamoyl)-3-methylbenzo[d]isoxazol-5-yl)carbamoyl)-4'- methoxy-[1,1'-biphenyl]-3-carboxylate that was treated with TFA at 0 o C and the reaction mixture was stirred for 5 h at rt.
• Example 35 Preparation of N3-(2,2-difluoro-6-((4-fluoro-3- (trifluoromethyl)phenyl)carbamoyl)benzo[d][1,3]dioxol-5-yl)-4-methoxy-N1-((1- (methylsulfonyl)cyclopropyl)methyl)isophthalamide
• Example 35-1 Preparation of tert-butyl 3-((2,2-difluoro-6-((4-fluoro-3- (trifluoromethyl)phenyl)carbamoyl)benzo[d][1,3]dioxol-5-yl)carbamoyl)-4- methoxybenzoate.
• Example 35-2 Preparation of 3-((2,2-difluoro-6-((4-fluoro-3- (trifluoromethyl)phenyl)carbamoyl)benzo[d][1,3]dioxol-5-yl)carbamoyl)-4- methoxybenzoic acid.
• example 35-1 (280 mg, 0.46 mmol) in DCM (8 mL) at 0 °C was added TFA (1 mL, 10 mmol) and the reaction mixture stirred at rt for 4 h. The solution was concentrated under vacuum and the residue triturated with diethyl ether to generate a solid which was dried to yield example 35-2 (210 mg, 0.37 mmol, 83 % yield) which was used without further purification.
• Example 35 To a solution of example 35-2 (15 mg, 0.03 mmol), (1- (methylsulfonyl)cyclopropyl)methanamine hydrochloride (6 mg, 0.03 mmol) in DMF (2 mL) was added TEA (0.01 mL, 0.08 mmol) and HATU (12 mg, 0.03 mmol) at 0 o C. The reaction mixture was stirred at rt for 14 h.
• Example 43 Preparation of 2,2-difluoro-N-(4-fluoro-3-(trifluoromethyl)phenyl)-6- (2-methoxy-5-(3a,5,6,6a-tetrahydro-4H-pyrrolo[3,4-d]isoxazol-3- yl)benzamido)benzo[d][1,3]dioxole-5-carboxamide
• Example 43-1 Preparation of tert -butyl 3-(3-((2,2-difluoro-6-((4-fluoro-3- (trifluoromethyl)phenyl)carbamoyl)benzo[d][1,3]dioxol-5-yl)carbamoyl)-4- methoxyphenyl)-3a,4,6,6a-tetrahydro-5H-pyrrolo[3,4-d]isoxazole-5-carboxylate.
• Example 43 To a solution of example 43-1 peak-2 (130 mg, 0.18 mmol) in DCM (10 mL) at 0 °C was added TFA (0.28 mL, 3.6 mmol) and the reaction mixture stirred at rt for 4 h.
• reaction mixture was then concentrated under vacuum and the residue subjected to reverse phase HPLC purification using Waters XBridge C18 column, 19 x 150 mm, 5 microns; Mobile Phase A: 10-mM NH 4 OAc; Mobile Phase B: ACN; Gradient: 21-65 % B over 25 min, then a 5 minute hold at 100 % B at a flow rate of 15 mL/min to yield example 43 (15 mg, 0.020 mmol, 13 % yield).
• reaction mixture was concentrated under vacuum and the residue subjected to reverse phase HPLC purification using Waters XBridge C18 column, 19 x 150 mm, 5 microns; Mobile Phase A: 10-mM NH 4 OAc; Mobile Phase B: ACN; Gradient: 15-65 % B over 25 min, then a 5 minute hold at 100 % B at a flow rate of 15 mL/min to yield example 44 (8 mg, 0.01 mmol, 40 % yield).
• reaction mixture was then concentrated under vacuum which was then subjected to reverse phase HPLC purification using Waters XBridge C18 column, 19 x 150 mm, 5 microns; Mobile Phase A: 10-mM NH4OAc; Mobile Phase B: ACN; Gradient: 30-75 % B over 25 min, then a 5 minute hold at 100 % B at a flow rate of 15 mL/min to yield example 45 (18 mg, 0.010 mmol, 81 % yield).
• reaction mixture was then concentrated under vacuum and the residue subjected to reverse phase HPLC purification using Waters XBridge C18 column, 19 x 150 mm, 5 micron; Mobile Phase A: 10-mM NH4OAc; Mobile Phase B: ACN; Gradient: 15-55 % B over 25 min, then a 5 minute hold at 100 % B at a flow rate of 15 mL/min to yield example 46 (14 mg, 0.020 mmol, 55 % yield).
• example 57 To a solution of example 57 (130 mg, 0.2 mmol) in THF (6.0 mL) at 0 °C was added CDI (65 mg, 0.40 mmol) followed by TEA (0.14 mL, 0.99 mmol) and the reaction mixture was stirred at 80 o C for 4 h. The reaction mixture was then concentrated under vacuum and the residue (40 mg, 0.006 mmol) was dissolved in THF (2 mL) and cooled to 0 o C. To this cooled solution was added methanesulfonamide (16 mg, 0.17 mmol) followed by TEA (0.04 mL, 0.29 mmol) and the reaction mixture was heated to 80 o C and stirred at that temperature for 2 h.
• CDI 65 mg, 0.40 mmol
• TEA 0.14 mL, 0.99 mmol
• reaction mixture was then concentrated under vacuum and the residue subjected to reverse phase HPLC purification using Waters XBridge C18 column, 19 x 150 mm, 5 micron; Mobile Phase A: 10-mM NH 4 OAc; Mobile Phase B: ACN; Gradient: 15-55 % B over 25 min, then a 5 minute hold at 100 % B at a flow rate of 15 mL/min to yield example 47 (18 mg, 0.080 mmol, 41 % yield).
• reaction mixture was then concentrated under vacuum and the residue subjected to reverse phase HPLC purification using Waters XBridge C18 column, 19 x 150 mm, 5 micron; Mobile Phase A: 10-mM NH 4 OAc; Mobile Phase B: ACN; Gradient: 20-65 % B over 25 min, then a 5 minute hold at 100 % B at a flow rate of 15 mL/min to yield example 48 (6 mg, 0.01 mmol, 10 % yield).
• Example 49-1 Preparation of 6-(5-(1-benzyl-1,4,5,6-tetrahydropyridin-3-yl)-2- methoxybenzamido)-2,2-difluoro-N-(4-fluoro-3- (trifluoromethyl)phenyl)benzo[d][1,3]dioxole-5-carboxamide.
• Example 49-1 (400 mg, 0.56 mmol, 74 % yield) is prepared in the same way as example 43-1 by replacing intermediate 25 with 5-(1-benzyl-1,4,5,6-tetrahydropyridin-3-yl)-2-methoxybenzoic acid made similar to intermediate 27.
• Example 49-2 Preparation of 2,2-difluoro-N-(4-fluoro-3-(trifluoromethyl)phenyl)-6-(2- methoxy-5-(piperidin-3-yl)benzamido)benzo[d][1,3]dioxole-5-carboxamide.
• Pd-C 156 mg, 1.46 mmol
• Example 49 Preparation of 2,2-difluoro-N-(4-fluoro-3-(trifluoromethyl)phenyl)-6-(2- methoxy-5-(1-(methylsulfonyl)piperidin-3-yl)benzamido)benzo[d][1,3]dioxole-5- carboxamide: To a solution of Example 49-2 peak2 (10 mg, 0.02 mmol) and TEA (5 PL, 0.05 mmol) in DCM (2 mL) at 0 °C was added methanesulfonyl chloride (2.3 mg, 0.02 mmol) and the reaction mixture stirred at rt for 12 h.
• reaction mixture was then concentrated under vacuum and the residue subjected to reverse phase HPLC purification using Waters XBridge C18 column, 19 x 150 mm, 5 microns; Mobile Phase A: 10-mM NH 4 OAc; Mobile Phase B: ACN; Gradient: 15-65 % B over 25 min, then a 5 minute hold at 100 % B at a flow rate of 15 mL/min to yield Example 49 (2 mg, 0.003 mmol, 20 % yield).
• Example 50 Preparation of 6-(5-(5-amino-3a,5,6,6a-tetrahydro-4H- cyclopenta[d]isoxazol-3-yl)-2-methoxybenzamido)-2,2-difluoro-N-(4-fluoro-3- (trifluoromethyl)phenyl)benzo[d][1,3]dioxole-5-carboxamide
• Example 50-1 (70 mg, 0.11 mmols, 8 % yield) was prepared in the same way as example 43-1 by replacing intermediate 25 with the racemic 5-(5-((tert-butoxycarbonyl)amino)- 3a,5,6,6a-tetrahydro-4H-cyclopenta[d]isoxazol-3-yl)-2-methoxybenzoic acid prepared as intermediate 3-3.
• reaction mixture was then concentrated under vacuum and the residue subjected to reverse phase HPLC purification using Waters XBridge C18 column, 19 x 150 mm, 5 micron; Mobile Phase A: 10-mM NH4OAc; Mobile Phase B: ACN; Gradient: 18-65 % B over 25 min, then a 5 minute hold at 100 % B at a flow rate of 15 mL/min to yield example 50 (8 mg, 0.01 mmol, 9 % yield).
• Example 51 Preparation of 2,2-difluoro-N-(4-fluoro-3-(trifluoromethyl)phenyl)-6- (5-(5-(2-hydroxyacetamido)-3a,5,6,6a-tetrahydro-4H-cyclopenta[d]isoxazol-3-yl)-2- methoxybenzamido)benzo[d][1,3]dioxole-5-carboxamide
• HATU (12 mg, 0.03 mmol
• TEA 0.2 mL, 0.16 mmol
• reaction mixture was then concentrated under vacuum and the residue subjected to reverse phase HPLC purification using Waters XBridge C18 column, 19 x 150 mm, 5 microns; Mobile Phase A: 10-mM NH 4 OAc; Mobile Phase B: ACN; Gradient: 25-55 % B over 25 min, then a 5 minute hold at 100 % B at a flow rate of 15 mL/min to yield example 51 (3 mg, 0.004 mmol, 10 % yield).
• Example 52 (8 mg, 0.01 mmol, 4 % yield) was prepared in the same way as example 43-1 by replacing intermediate 25 with intermediate 28 followed by deprotection with 20% TFA in DCM.
• reaction mixture was then concentrated under vacuum and the residue subjected to reverse phase HPLC purification using Waters XBridge C18 column, 19 x 150 mm, 5 microns; Mobile Phase A: 10-mM NH4OAc; Mobile Phase B: ACN; Gradient: 15-65% B over 25 min, then a 5 minute hold at 100% B at a flow rate of 15 mL/min to yield example 53 (1.2 mg, 0.0010 mmol, 5.0 % yield).

Landscapes

• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Health & Medical Sciences (AREA)
• General Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Animal Behavior & Ethology (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Epidemiology (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Cardiology (AREA)
• Heart & Thoracic Surgery (AREA)
• Molecular Biology (AREA)
• Biochemistry (AREA)
• Hospice & Palliative Care (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Priority Applications (5)

Applications Claiming Priority (2)

Publications (1)

Family

ID=85278236

Family Applications (1)

Country Status (6)

Cited By (2)

Citations (3)

• 2022
  • 2022-12-14 WO PCT/US2022/081519 patent/WO2023114822A1/en not_active Ceased
  • 2022-12-14 JP JP2024535921A patent/JP2025501509A/ja active Pending
  • 2022-12-14 EP EP22859491.7A patent/EP4448500A1/en active Pending
  • 2022-12-14 US US18/718,477 patent/US20250066344A1/en active Pending
  • 2022-12-14 KR KR1020247023154A patent/KR20240120745A/ko active Pending
  • 2022-12-14 CN CN202280082604.8A patent/CN118401502A/zh active Pending

Patent Citations (3)

Non-Patent Citations (1)

Also Published As

Similar Documents

Legal Events