ES2485492T3 - Derivados de di(hetero)arilciclohexano, su preparación, su uso y composiciones farmacéuticas que los comprenden - Google Patents

Derivados de di(hetero)arilciclohexano, su preparación, su uso y composiciones farmacéuticas que los comprenden Download PDF

Info

Publication number
ES2485492T3
ES2485492T3 ES08758710.1T ES08758710T ES2485492T3 ES 2485492 T3 ES2485492 T3 ES 2485492T3 ES 08758710 T ES08758710 T ES 08758710T ES 2485492 T3 ES2485492 T3 ES 2485492T3
Authority
ES
Spain
Prior art keywords
esi
alkyl
optionally substituted
fluorophenyl
methyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
ES08758710.1T
Other languages
English (en)
Inventor
Thomas Böhme
Uwe Gerlach
Dirk Gretzke
Heinz-Werner Kleemann
Stefania Pfeiffer-Marek
Henning Vollert
Jean-Michel Altenburger
Sergio Mallart
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sanofi SA
Original Assignee
Sanofi SA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Sanofi SA filed Critical Sanofi SA
Application granted granted Critical
Publication of ES2485492T3 publication Critical patent/ES2485492T3/es
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • 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
    • 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
    • A61P9/02—Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
    • 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
    • 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
    • A61P9/06—Antiarrhythmics
    • 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
    • A61P9/08—Vasodilators for multiple indications
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/45—Carboxylic acid nitriles having cyano groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C07C255/46—Carboxylic acid nitriles having cyano groups bound to carbon atoms of rings other than six-membered aromatic rings to carbon atoms of non-condensed rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
    • C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C311/08—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/44—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
    • C07C317/46—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton the carbon skeleton being further substituted by singly-bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/62—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C62/00—Compounds having carboxyl groups bound to carbon atoms of rings other than six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C62/30—Unsaturated compounds
    • C07C62/32—Unsaturated compounds containing hydroxy or O-metal groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C62/00—Compounds having carboxyl groups bound to carbon atoms of rings other than six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C62/30—Unsaturated compounds
    • C07C62/34—Unsaturated compounds containing ether groups, groups, groups, or groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
    • C07D213/30—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
    • C07D213/46—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/55—Acids; Esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/57—Nitriles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/61—Halogen atoms or nitro radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/64—One oxygen atom attached in position 2 or 6
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D215/14—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
    • C07D217/14—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals
    • C07D217/16—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D231/16—Halogen atoms or nitro radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C07D233/60—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms with hydrocarbon radicals, substituted by oxygen or sulfur atoms, attached to ring nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/68—Halogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/84—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/16—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/24—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/30—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
    • C07D305/02—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D305/04—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
    • C07D305/02—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D305/04—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D305/06—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen 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
    • C07D405/02—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
    • 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
    • C07D417/04—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 directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Landscapes

  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Urology & Nephrology (AREA)
  • Hospice & Palliative Care (AREA)
  • Vascular Medicine (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pyridine Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Heterocyclic Compounds That Contain Two Or More Ring Oxygen Atoms (AREA)
  • Heterocyclic Compounds Containing Sulfur Atoms (AREA)
  • Thiazole And Isothizaole Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Other In-Based Heterocyclic Compounds (AREA)
  • Indole Compounds (AREA)
  • Quinoline Compounds (AREA)

Abstract

Un compuesto de la fórmula I, en la que Ar1 es fenilo o piridinilo, todos opcionalmente sustituidos con 1, 2 ó 3 sustituyentes idénticos o diferentes de la serie que consiste en halógeno, alquilo (C1-C5), cicloalquil (C3-C6)-CvH2v-, Ar3, alquil (C1-C5)-O-, -O-alquil (C1-C3)-O, cicloalquil (C3-C6)-S(O)f- y alquil (C1-C5)-S(O)k-, en donde todos los grupos alquilo y grupos cicloalquilo en Ar1 están opcionalmente sustituidos con uno o más sustituyentes flúor; Ar2 es fenilo, naftilo o heteroarilo, todos opcionalmente sustituidos con 1, 2 ó 3 sustituyentes idénticos o diferentes de la serie que consiste en halógeno, ciano, alquilo (C1-C5), cicloalquil (C3-C6)-CvH2v-, Ar3, alquil (C1-C5)-O-, -O-alquil (C1-C3)-O, cicloalquil (C3-C6)-S(O)f- y alquil (C1-C5)-S(O)k-, en donde todos los grupos alquilo y grupos cicloalquilo en Ar2 están opcionalmente sustituidos con uno o más sustituyentes flúor; Ar3 es fenilo o piridinilo, todos opcionalmente sustituidos con 1, 2 ó 3 sustituyentes idénticos o diferentes de la serie que consiste en halógeno, alquilo (C1-C5), alquil (C1-C5)-O-, -O-alquil (C1-C3)-O y alquil (C1-C5)-S(O)m-, en donde todos los grupos alquilo en Ar3 están opcionalmente sustituidos con uno o más sustituyentes flúor; Ar4 es fenilo, piridinilo o pirimidinilo, todos opcionalmente sustituidos con 1, 2 ó 3 sustituyentes idénticos o diferentes de la serie que consiste en halógeno, alquilo (C1-C5), alquil (C1-C5)-O- y alquil (C1-C5)-S(O)n-, en donde todos los grupos alquilo en Ar4 están opcionalmente sustituidos con uno o más sustituyentes flúor; R1 es R4-O- o R5R6N-; R2 es hidrógeno, alquilo (C1-C8), Ar4, R17-O-alquilo (C1-C8)-, Het-CuH2u- o cicloalquil (C3-C8)-CuH2u-, en donde todos los grupos alquilo y grupos cicloalquilo en R2 están opcionalmente sustituidos con uno o más sustituyentes flúor; R4, R5 y R6, que son todos independientes unos de otros y que pueden ser idénticos o diferentes, son hidrógeno, alquilo (C1-C5) o cicloalquil (C3-C6)-CpH2p-, en donde todos los grupos alquilo y grupos cicloalquilo en R4, R5 y R6 están opcionalmente sustituidos con uno o más sustituyentes flúor; R17 es hidrógeno, alquilo (C1-C5) o cicloalquil (C3-C6)-CqH2q-, en donde todos los grupos alquilo y grupos cicloalquilo en R17 están opcionalmente sustituidos con uno o más sustituyentes flúor; Het es un residuo de un anillo saturado de 4 miembros a 7 miembros monocíclico que contiene 1 átomo de oxígeno como heteroátomo del anillo, que está unido por un átomo de carbono de anillo que está opcionalmente sustituido con 1, 2 ó 3 sustituyentes idénticos o diferentes de la serie que consiste en fenilo y alquilo (C1-C5), en donde los grupos fenilo en Het están opcionalmente sustituidos con 1 ó 2 sustituyentes idénticos o diferentes de la serie que consiste en halógeno, alquilo (C1-C5) y alquil (C1-C5)-O-, y en donde Het y todos los grupos alquilo en Het están opcionalmente sustituidos con uno o más sustituyentes flúor; heteroarilo es un residuo de un sistema de anillo aromático de 5 miembros o 6 miembros monocíclico o de 9 miembros o 10 miembros bicíclico de la serie que consiste en tienilo, pirazolilo, imidazolilo, [1,2,4]triazolilo, tiazolilo, piridinilo, indolilo, benzodioxolilo, benzoimidazolilo, 4,5,6,7-tetrahidrobenzoimidazolilo, imidazo[4,5-b]piridinilo, quinolinilo e isoquinolinilo;

Description

imagen1
imagen2
imagen3
imagen4
imagen5
imagen6
imagen7
imagen8
imagen9
imagen10
imagen11
imagen12
imagen13
imagen14
imagen15
imagen16
imagen17
imagen18
imagen19
imagen20
imagen21
imagen22
imagen23
imagen24
imagen25
imagen26
E08758710
25-07-2014
Tabla 1. Compuestos de ejemplo de la fórmula VIIIa.
Ejemplo
Ar2 Preparación (1) MS HPLC (Rt [min], Método)
3
3-fluorofenilo a 296 ESI+
4
2,3-difluorofenilo a 313 EI+
5
2,4-difluorofenilo a 313 EI+
6
3,4-difluorofenilo a 313 EI+
7
3,5-difluorofenilo a 313 ESI+ 2,34 LC2
8
2,4,6-trifluorofenilo a 332 ESI+ 1,84 LC1
9
2,3,4-trifluorofenilo a 332 ESI+ 1,89 LC1
10
3-fluoro-4-metilfenilo a 310 ESI+ 2,38 LC1
11
4-trifluorometilfenilo a 346 ESI+ 2,59 LC1
12
3-trifluorometilfenilo a 346 DCI
13
2-fluoro-4-trifluorometilfenilo a 364 ESI+ 2,38 LC1
14
4-cloro-3-trifluorometilfenilo a 378 ESI 2,32 LC3
15
4-fluoronaftalen-1-ilo a 346 ESI+ 2,90 LC1
16
2,2-difluorobenzo[1,3]dioxol-4-ilo a 356 EI+
17
4-bromofenilo a 356 EI+
18
4-clorofenilo a 311 ESI 2,16 LC4
19
3-clorofenilo a 312 ESI+
20
3,4-diclorofenilo a 345 ESI 2,29 LC3
21
4-metoxifenilo a 308 ESI+
22
3-metoxifenilo a 308 ESI 2,04 LC3
23
2-metoxifenilo a 308 ESI 2,10 LC3
24
fenilo a 276 ESI 2,02 LC3
26
naftalen-2-ilo a 328 ESI+ 2,58 LC1
27
quinolin-6-ilo a 329 ESI+ 1,10 LC1
28
isoquinolin-4-ilo a 329 ESI+ 1,19 LC1
29
isoquinolin-5-ilo a 329 ESI+ 1,18 LC1
30
quinolin-3-ilo a 329 ESI+ 1,33 LC1
31
6-fluoropiridin-3-ilo a 296 ESI+ 1,78 LC1
28
imagen27
E08758710
25-07-2014
Se disolvieron 500 mg de 4-(4-fluorofenil)-4-hidroxi-1-fenilciclohexanocarbonitrilo en 10 ml de sulfóxido de dimetilo seco, se trató con 190 mg de hidróxido de potasio y se agitó durante 30 min a temperatura ambiente. Posteriormente, se añadieron lentamente y gota a gota 0,17 ml de bromometilciclopropano. La mezcla de reacción se agitó durante 24 h, se trató con agua y se extrajo con EA. Las fases orgánicas combinadas se secaron sobre
5 sulfato de magnesio, y el disolvente se separó a vacío. El producto bruto, un aceite claro, se purificó por cromatografía sobre gel de sílice, usando HEP/EA (2:1). Se obtuvieron 510 mg del compuesto del título como un sólido blanco.
MS(ESI+): 350
Según los procedimientos de preparación descritos en los Ejemplos 40 y 41, los 4-(hetero)aril-4-(alcoxi pcionalmente
10 sustituido)-1-fenilciclohexanocarbonitrilos de la fórmula Xa mencionados en la Tabla 2 se prepararon por reacción de los correspondientes 4-(hetero)aril-4-hidroxi-1-fenilciclohexanocarbonitrilos con el correspondiente alquilhaluro opcionalmente sustituido de hidruro de sodio o de hidróxido de potasio.
imagen28
imagen29
Ar2
imagen30
Xa
R2O imagen31 imagen32CN
Tabla 2. Compuestos de ejemplo de la fórmula Xa.
Ejemplo
Ar2 R2 Preparación (1) MS HPLC (Rt [min], Método)
42
3-fluorofenilo metilo a 310 DCI
43
2,3-difluorofenilo metilo a 328 ESI+ 2,46 LC1
44
2,4-difluorofenilo metilo a 328 ESI+
45
3,4-difluorofenilo metilo a 328 EI+
46
3,5-difluorofenilo metilo a 328 ESI+ 2,54 LC1
47
2,4,6-trifluorofenilo metilo a 346 ESI+
48
2,3,4-trifluorofenilo metilo a 346 ESI+ 2,54 LC1
49
4-trifluorometilfenilo metilo a 360 ESI+ 2,60 LC1
50
3-trifluorometilfenilo metilo a 360 EI+
51
4-fluoronaftalen-1-ilo metilo a 360 ESI+ 2,43 LC1
52
2,2-difluorobenzo[1,3]dioxol-4-ilo metilo a 372 ESI+ 2,03 LC1
53
4-metoxifenilo metilo a 321 ESI 2,27 LC5
54
3-metoxifenilo metilo a 321 ESI 2,28 LC6
55
2-metoxifenilo metilo a 321 ESI 2,29 LC3
56
3-fluoro-4-metoxifenilo metilo a 340 ESI+
57
2,4-dimetoxifenilo metilo a 352 ESI+ 2,48 LC1
30
E08758710
25-07-2014
Ejemplo
Ar2 R2 Preparación (1) MS HPLC (Rt [min], Método)
58
benzo[1,3]dioxol-5-ilo metilo a 336 ESI+ 2,13 LC1
59
fenilo metilo a 290 ESI 2,31 LC3
61
6-fluoropiridin-3-ilo metilo a 311 ESI+ 2,33 LC1
62
2-bromo-5-fluoropiridin-4-ilo metilo a 389 ESI+ 1,97 LC1
63
3-fluoropiridin-4-ilo metilo a 311 ESI+ 1,60 LC1
64
6-metoxipiridin-3-ilo metilo a 323 ESI+ 2,22 LC1
65
tiofen-2-ilo metilo a 298 EI+
66
4-fluorofenilo etilo a 324 ESI+ 2,62 LC1
67
2-bromo-5-fluoropiridin-4-ilo etilo a 403 ESI+ 2,12 LC1
68
3-fluoropiridin-4-ilo etilo a 325 ESI+ 1,86 LC1
69
6-fluoropiridin-3-ilo etilo a 325 ESI+ 1,86 LC1
70
6-metoxipiridin-3-ilo etilo a 337 ESI+
71
4-fluorofenilo alilo a 336 DCI
72
4-fluorofenilo n-butilo b 352 ESI+ 2,92 LC1
73
4-fluorofenilo 3-metilbutilo b 366 ESI+ 3,08 LC1
75
4-fluorofenilo 4,4,4trifluorobutilo b 406 ESI+ 2,56 LC1
76
4-fluorofenilo 2,2,2trifluoroetilo b 378 ESI+
77
4-fluorofenilo n-propilo b 338 EI+
78
4-bromofenilo n-propilo b 399 ESI+ 2,58 LC1
79
2,3,4-trifluorofenilo n-propilo b 374 ESI+ 2,41 LC1
80
2,4,6-trifluorofenilo n-propilo b 374 EI+
81
4-bromofenilo ciclopropilmeti lo b 410 ESI+ 1,97 LC1
82
2,3,4-trifluorofenilo ciclopropilmeti lo b 386 ESI+ 2,72 LC1
83
quinolin-3-ilo ciclopropilmeti lo b 383 ESI+ 1,56 LC1
31
E08758710
25-07-2014
Ejemplo
Ar2 R2 Preparación (1) MS HPLC (Rt [min], Método)
84
isoquinolin-4-ilo ciclopropilmeti lo b 383 ESI+ 1,49 LC1
85
isoquinolin-5-ilo ciclopropilmeti lo b 383 ESI+ 1,46 LC1
86
quinolin-6-ilo ciclopropilmeti lo b 383 ESI+ 2,05 LC1
87
6-metoxipiridin-3-ilo ciclopropilmeti lo b 363 ESI+ 2,01 LC1
88
5-cloropiridin-2-ilo ciclopropilmeti lo b 366 ESI+ 2,39 LC1
89
2-bromo-5-fluoropiridin-4-ilo ciclopropilmeti lo b 429 ESI+ 2,19 LC1
90
3-fluoropiridin-4-ilo ciclopropilmeti lo b 351 ESI+ 1,84 LC1
91
6-fluoropiridin-3-ilo ciclopropilmeti lo b 351 ESI+ 1,97 LC1
(1) a = preparación según el Ejemplo 40
b = preparación según el Ejemplo 41 Se emplearon como agentes alquilantes los siguientes haluros de alquilo: R2 = metilo: yodometano
5 R2 = etilo: bromoetano R2 = alilo: 1-bromoprop-2-eno R2 = n-butilo: 1-bromobutano R2 = 3-metilbutilo: 1-bromo-3-metilbutano R2 = 4,4,4-trifluorobutilo: 1-bromo-4,4,4-trifluorobutano
10 R2 = 2,2,2-trifluoroetilo: 1-bromo-2,2,2-trifluoroetano R2 = n-propilo: 1-bromopropano R2 = ciclopropilmetilo-: bromometilciclopropano Ejemplo 92 Ácido 4-(4-fluorofenil)-4-metoxi-1-fenilciclohexanocarboxílico
F
imagen33
imagen34
imagen35
imagen36
O imagen37 imagen38COOH
32
E08758710
25-07-2014
Se disolvieron 500 mg de 4-(4-fluorofenil)-4-metoxi-1-fenilciclohexanocarbonitrilo en 30 ml de etilenglicol y se añadieron 272 mg de hidróxido de potasio. La mezcla de reacción se agitó luego a 200°C durante 5 h. Después de enfriar, la mezcla de reacción se vertió en una mezcla de hielo/agua y se extrajo tres veces con MTB. La fase acuosa se acidificó hasta pH = 1 con ácido clorhídrico 2 N. El producto bruto precipitado se separó por filtración con
5 succión y se disolvió en un poco de tolueno caliente. Los cristales depositados durante el enfriamiento se separaron por filtración con succión y se secaron. Se obtuvieron 450 mg del compuesto del título como un sólido blanco.
MS (ESI-): 327
HPLC (Método LC9): Rt 2,22 min
Según el procedimiento de preparación descrito en el Ejemplo 92, los ácidos 4-(hetero)aril-4-hidroxi-110 fenilciclohexanocarboxílicos de la fórmula Ic mencionada en la Tabla 3 se prepararon a partir del correspondiente 4(hetero)aril-4-hidroxi-1-fenilciclo-hexanocarbonitrilo por reacción con hidróxido de potasio.
imagen39
imagen40
Ar2
imagen41Ic
imagen42
imagen43
HO
COOH
Tabla 3. Compuestos de ejemplo de la fórmula Ic.
Ejemplo
Ar2 MS HPLC (Rt [min], Método)
93
4-fluorofenilo 313 ESI 1,70 LC3
94
2,3-difluorofenilo 331 ESI 1,96 LC6
95
2,4-difluorofenilo 331 ESI 1,97 LC6
96
3,4-difluorofenilo 331 ESI 1,94 LC6
97
3,5-difluorofenilo 331 ESI 1,97 LC6
98
2,4,6-trifluorofenilo 349 ESI 2,32 LC6
99
2,3,4-trifluorofenilo 351 ESI+ 2,06 LC1
100
3-fluoro-4-metilfenilo 329 ESI+ 2,42 LC1
101
4-trifluorometilfenilo 363 ESI 2,14 LC6
102
3-trifluorometilfenilo 363 ESI 2,17 LC6
103
2-fluoro-4-trifluorometilfenilo 383 ESI+ 2,34 LC1
104
4-cloro-3-trifluorometilfenilo 397 ESI 2,29 LC6
105
4-bromofenilo 373 ESI 2,12 LC6
106
4-clorofenilo 329 ESI 2,11 LC3
107
3,4-diclorofenilo 364 ESI 1,92 LC3
108
2,2-difluorobenzo[1,3]dioxol-4-ilo 375 ESI 2,11 LC6
109
benzo[1,3]dioxol-5-ilo 339 ESI 1,84 LC6
33
E08758710
25-07-2014
Ejemplo
Ar2 MS HPLC (Rt [min], Método)
110
4-metoxifenilo 325 ESI 1,81 LC3
111
3-metoxifenilo 325 ESI 1,89 LC6
112
2-metoxifenilo 327 ESI+ 3,50 LC7
113
2,4-dimetoxifenilo 355 ESI 2,16 LC6
114
3-fluoro-4-metoxifenilo 379 DCI, M+Cl
115
fenilo 295 ESI 1,92 LC6
116
naftalen-1-ilo 345 ESI 2,26 LC3
117
tiofen-3-ilo 303 ESI+ 2,42 LC1
118
6-metoxipiridin-3-ilo 328 ESI+ 1,34 LC1
Según el procedimiento de preparación descrito en el Ejemplo 92, los ácidos 4-(hetero)aril-4-(alcoxi opcionalmente sustituido)-1-fenilciclohexanocarboxílicos de la fórmula Id enumerada en la Tabla 4 se prepararon a partir del correspondiente 4-(hetero)aril-4-(alcoxi opcionalmente sustituido)-1-fenilciclohexanocarbonitrilo por reacción con hidróxido de potasio.
Ar2 Id R2
imagen44
O
imagen45COOH
imagen46
Tabla 4. Compuestos de ejemplo de la fórmula Id.
Ejemplo
Ar2 R2 MS HPLC (Rt [min], Método)
119
3-fluorofenilo metilo 327 ESI 2,22 LC6
120
2,3-difluorofenilo metilo 345 ESI 2,29 LC6
121
3,4-difluorofenilo metilo 345 ESI 2,26 LC9
122
3,5-difluorofenilo metilo 345 ESI 2,27 LC9
123
3-fluoro-4-metilfenilo metilo 341 ESI 2,38 LC6
124
4-trifluorometilfenilo metilo 377 ESI 2,41 LC9
125
3-trifluorometilfenilo metilo 377 ESI 2,40 LC9
126
2,2-difluorobenzo[1,3]dioxol-4-ilo metilo 389 ESI 2,38 LC6
127
3-clorofenilo metilo 345 ESI+ 4,31 LC11
128
4-metoxifenilo metilo 339 ESI 2,14 LC6
129
3-metoxifenilo metilo 341 ESI+ 4,11 LC11
34
E08758710
25-07-2014
Ejemplo
Ar2 R2 MS HPLC (Rt [min], Método)
130
2-metoxifenilo metilo 341 ESI+
131
3-fluoro-4-metoxifenilo metilo 357 ESI 2,12 LC9
132
2,4-dimetoxifenilo metilo 369 ESI 1,95 LC9
133
benzo[1,3]dioxol-5-ilo metilo 353 ESI 1,84 LC9
134
fenilo metilo 309 ESI 2,45 LC9
136
quinolin-3-ilo metilo 360 ESI 1,19 LC9
137
5-cloropiridin-2-ilo metilo 346 ESI+ 1,79 LC9
138
3-fluoropiridin-4-ilo metilo 330 ESI+ 1,33 LC1
139
6-metoxipiridin-3-ilo metilo 342 ESI+ 1,63 LC9
140
tiofen-2-ilo metilo 315 ESI 1,92 LC9
141
4-fluorofenilo etilo 341 ESI 2,37 LC9
142
3-fluoropiridin-4-ilo etilo 344 ESI+ 3,01 LC1
143
6-metoxipiridin-3-ilo etilo 356 ESI+ 1,56 LC1
144
4-fluorofenilo alilo 355 DCI
145
4-fluorofenilo n-butilo 369 ESI 2,64 LC9
146
4-fluorofenilo 3-metilbutilo 385 EI+
147
4-fluorofenilo 4,4,4-trifluorobutilo 423 ESI 2,59 LC9
148
4-fluorofenilo n-propilo 355 ESI 2,57 LC9
149
4-bromofenilo n-propilo 418 ESI+ 2,14 LC6
150
4-fluorofenilo ciclopropilmetilo 367 ESI 2,50 LC9
151
4-bromofenilo ciclopropilmetilo 430 ESI+ 2,69 LC9
152
quinolin-3-ilo ciclopropilmetilo 402 ESI+ 1,13 LC1
153
isoquinolin-4-ilo ciclopropilmetilo 402 ESI+ 1,33 LC1
154
isoquinolin-5-ilo ciclopropilmetilo 402 ESI+ 1,33 LC1
155
quinolin-6-ilo ciclopropilmetilo 402 ESI+ 1,26 LC1
156
6-metoxipiridin-3-ilo ciclopropilmetilo 382 ESI+ 1,69 LC1
157
6-cloropiridin-3-ilo ciclopropilmetilo 386 ESI+ 2,01 LC1
158
3-fluoropiridin-4-ilo ciclopropilmetilo 370 ESI+ 1,53 LC1
35
imagen47
imagen48
E08758710
25-07-2014
imagen49
imagen50
Ar2 imagen51
imagen52
Id
R2
O imagen53COOH
Tabla 5. Compuestos de ejemplo de la fórmula Id.
Ejemplo
Ar2 R2 MS TLC (Rf) (1)
165
3-metilsulfanilfenilo hidrógeno 342 ESI 0,40 a
166
2-metilsulfanilfenilo hidrógeno 342 ESI 0,60 a
167
3-metanosulfonilfenilo etilo 402 ESI 0,26b
168
3-metanosulfonilfenilo n-propilo 416 ESI 0,36b
169
3-metanosulfonilfenilo ciclopropilmetilo 428 ESI 0,30b
170
4-metanosulfonilfenilo n-propilo 416 ESI 0,33b
171
4-metanosulfonilfenilo ciclopropilmetilo 428 ESI 0,27b
172
2-metanosulfonilfenilo metilo 388 ESI 0,21b
173
2-metanosulfonilfenilo etilo 402 ESI 0,37b
174
2-metanosulfonilfenilo n-propilo 416 ESI 0,43b
175
2-metanosulfonilfenilo ciclopropilmetilo 428 ESI 0,47b
176
4-metanosulfonilfenilo hidrógeno 374 ESI 0,56c
177
3-metanosulfonilfenilo hidrógeno 374 ESI 0,53c
178
2-metanosulfonilfenilo hidrógeno 374 ESI 0,26c
(1) fase móvil de la caracterización TLC: a = EA; b = DIP/ácido acético al 2%; c = EA/ácido acético al 2%
Ejemplo 179
5 4-(3-Bromofenil)-4-hidroxi-1-fenilciclohexanocarbonitrilo
Br
imagen54
imagen55
HO imagen56 imagen57CN
Se disolvieron 8,00 g de 1,3-dibromobenceno en 200 ml de éter dietílico seco y se añadieron gota a gota 22,61 ml de una disolución de n-butil-litio (1,5 M en n-hexano) a una temperatura entre 0°C y 5°C. La mezcla de reacción se agitó durante 5 min a 0ºC. Después, se inyectó una disolución de 6,76 g de 4-oxo-1-fenilciclohexanocarbonitrilo en 70 ml 10 de THF seco a 70°C. Se dejó que la mezcla de reacción se calentase hasta la temperatura ambiente y después se agitó durante 30 min. a temperatura ambiente. La mezcla de reacción se vertió luego en 200 ml de una disolución saturada acuosa de hidrógeno sulfato de sodio, y las fases se separaron y la fase acuosa se extrajo con 200 ml de EA. Las fases orgánicas combinadas se secaron sobre sulfato de magnesio, y el disolvente se separó a vacío. El
38
imagen58
imagen59
imagen60
E08758710
25-07-2014
Ejemplo
Ar1 MS HPLC (Rt [min], Método)
195
4-metilfenilo 214,15 ESI+ 1,38 LC16
196
4-metilsulfanilfenilo 246,05 ESI+ 1,40 LC16
(1) 1H-NMR (d6-DMSO; 500 MHz): 2,38 (m, 6H), 2,68 (m, 2H), 3,78 (s, 3H), 7,00 (sistema AB, 2H), 7,48 (sistema AB, 2H)
Según el procedimiento de preparación descrito en el Ejemplo 1, los 1-(fenilo sustituido)-4-hidroxi-4-(fenilo sustituido)ciclohexanocarbonitrilos de la fórmula VIII mencionados en la Tabla 7 se prepararon por reacción del
5 correspondiente bromobenceno sustituido con n-butil-litio y el correspondiente 4-oxo-1-(fenilo sustituido)ciclohexanocarbonitrilo.
Ar2 imagen61 imagen62Ar1
VIII HO CN Tabla 7. Compuestos de ejemplo de la fórmula VIII.
Ejemplo
Ar1 Ar2 MS HPLC (Rt [min], Método)
197
4-metoxifenilo 4-fluorofenilo 308,15 ESI+ 1,55 LC16
198
3-fluorofenilo 4-fluorofenilo 313,13 ESI+ 2,23 LC15
199
2-fluorofenilo 4-fluorofenilo 313,13 ESI+ 2,24 LC15
200
4-fluorofenilo 4-fluorofenilo 313,13 ESI+ 1,81 LC8
201
4-metilfenilo 4-fluorofenilo 310,10 ESI+ 1,64 LC16
202
4-metilsulfanilfenilo 4-fluorofenilo 324,10 ESI+, M-17 1,63 LC16
203
3-metilsulfanilfenilo 4-fluorofenilo 342,47 ESI+ 2,31 LC9
204
2-metilsulfanilfenilo 4-fluorofenilo 324,05 ESI+, M-17 2,03 LC16
205
4-trifluorometoxifenilo 4-fluorofenilo 362,10 ESI+, M-17 1,73 LC16
206
3-trifluorometoxifenilo 4-fluorofenilo 362,10 ESI+, M-17 1,17 LC16
207
2-trifluorometoxifenilo 4-fluorofenilo 362,10 ESI+, M-17 1,67 LC16
208
4-fluorofenilo 2-metilsulfanil-fenilo 341,13 ESI+ 1,94 LC10
209
4-fluorofenilo 4-fluoro-2-metilsulfanilfenilo
210
4-fluorofenilo 5-fluoro-2-metilsulfanilfenilo 359,12 ESI+ 2,41 LC15
10
Ejemplo 211 1-Bromo-4-fluoro-2-metilsulfanilbenceno imagen63 Br
F
imagen64 S
42
imagen65
E08758710
25-07-2014
Tabla 8. Compuestos de ejemplo de la fórmula X
Ejemplo
Ar1 Ar2 R2 MS HPLC (Rt [min], Método)
212
3-fluorofenilo 4-fluorofenilo metilo 296,15 ESI+, M31 1,81 LC16
213
2-fluorofenilo 4-fluorofenilo metilo 296,15 ESI+, M31 1,79 LC16
214
4-fluorofenilo 4-fluorofenilo ciclopropilme tilo 367,17 ESI+ 2,29 LC10
215
4-metilfenilo 4-fluorofenilo ciclopropilme tilo 292,10 ESI+, M31 1,90 LC16
216
4-metilsulfanilfenilo 4-fluorofenilo metilo 324,15 ESI+, M31 1,89 LC16
217
4-metilsulfanilfenilo 4-fluorofenilo ciclopropilme tilo 324,10 ESI+, M71 2,05 LC16
218
3-metilsulfanilfenilo 4-fluorofenilo ciclopropilme tilo 324,10 ESI+, M71 2,03 LC16
219
2-metilsulfanilfenilo 4-fluorofenilo ciclopropilme tilo 324,10 ESI+, M71 2,04 LC16
220
4-trifluorometoxifenilo 4-fluorofenilo metilo 362,10 ESI+, M31 1,95 LC16
221
3-trifluorometoxifenilo 4-fluorofenilo metilo 362,10 ESI+, M31 1,95 LC16
222
2-trifluorometoxifenilo 4-fluorofenilo metilo 362,10 ESI+, M31 1,91 LC16
223
4-fluorofenilo 4-fluoro-2metilsulfanilfenilo ciclopropilme tilo 342,05 ESI+ 1,69 LC16
224
4-fluorofenilo 4-fluoro-2metilsulfanilfenilo n-propilo
225
4-fluorofenilo 2-metilsulfanilfenilo n-propilo 383,17 ESI+ 2,87 LC9
226
4-fluorofenilo 2-metilsulfanilfenilo ciclopropilme tilo 395,17 ESI+ 244 LC10
227
4-fluorofenilo 5-fluoro-2metilsulfanilfenilo ciclopropilme tilo 413,16 ESI+ 2,46 LC10
Según el procedimiento de preparación descrito en el Ejemplo 92, los ácidos 1-(fenilo sustituido)-4-hidroxi-4-(fenilo opcionalmente sustituido)ciclohexanocarboxílicos de la fórmula Ib mencionados en la Tabla 9 se prepararon a partir del correspondiente 1-(fenilo sustituido)-4-hidroxi-4-(fenilo opcionalmente sustituido)ciclohexanocarbonitrilo por reacción con hidróxido de potasio.
Ar2 imagen66 imagen67Ar1
Ib HO COOH
44
E08758710
25-07-2014
Tabla 9. Compuestos de ejemplo de la fórmula Ib.
Ejemplo
Ar1 Ar2 MS HPLC (Rt [min], Método)
228
4-clorofenilo 4-clorofenilo 364,06 ESI+ 2,20 LC9
229
4-metoxifenilo 4-clorofenilo 360,11 ESI+ 2,04 LC9
230
4-metoxifenilo 4-fluorofenilo 344,14 ESI+ 1,91 LC9
231
3-clorofenilo 4-clorofenilo 364,06 ESI+ 2,19 LC9
232
3,4-dimetoxifenilo 4-clorofenilo 390,12 ESI+ 1,91 LC9
Según el procedimiento de preparación descrito en el Ejemplo 92, los ácidos 1-(fenilo sustituido)-4-(alcoxi opcionalmente sustituido)-4-(fenilo sustituido)ciclohexanocarboxílicos de la fórmula Ia mencionados en la Tabla 10 se prepararon a partir del correspondiente 1-(fenilo sustituido)-4-(alcoxi opcionalmente sustituido)-4-(fenilo sustituido)ciclohexanocarbonitrilo por reacción con hidróxido de potasio.
Ar2 imagen68 imagen69Ar1
Ia R2
O COOH

Tabla 10. Compuestos de ejemplo de la fórmula Ia.
Ejemplo
Ar1 Ar2 R2 MS HPLC (Rt [min], Método)
233
4-metoxifenilo 4-fluorofenilo metilo 281,21 ESI+, M77 2,71 LC1
234
3-fluorofenilo 4-fluorofenilo metilo 315,3 DCI
235
2-fluorofenilo 4-fluorofenilo metilo 346,14 ESI 2,22 LC17
236
4-trifluorometoxifenilo 4-fluorofenilo metilo 412,13 ESI 2,45 LC1
237
3-trifluorometoxifenilo 4-fluorofenilo metilo 335,23 ESI+, M77 2,00 LC1
238
2-trifluorometoxifenilo 4-fluorofenilo metilo 381,4 DCI, M-31
239
4-metilfenilo 4-fluorofenilo metilo 342,16 ESI 2,30 LC17
240
4-metilsulfanilfenilo 4-fluorofenilo metilo 373,14 ESI 2,38 LC17
241
4-metilsulfanilfenilo 4-fluorofenilo ciclopropilme tilo 414,20 ESI 2,58 LC17
242
4-fluorofenilo 4-fluoro-2metilsulfanilfenilo n-propilo 420,16 ESI 2,64 LC17
243
4-fluorofenilo 4-fluoro-2metilsulfanilfenilo ciclopropilme tilo
45
E08758710
25-07-2014
Ejemplo
Ar1 Ar2 R2 MS HPLC (Rt [min], Método)
244
4-fluorofenilo 2-metilsulfanilfenilo ciclopropilme tilo 414,20 ESI 2,60 LC17
245
3-metilsulfanilfenilo 4-fluorofenilo ciclopropilme tilo
246
2-metilsulfanilfenilo 4-fluorofenilo ciclopropilme tilo 343,16 ESI+, M71 2,58 LC1
247
4-fluorofenilo 5-fluoro-2metilsulfanilfenilo ciclopropilme tilo 432,16 ESI 2,62 LC17
248
4-fluorofenilo 5-fluoro-2metilsulfanilfenilo n-propilo 419,45 ESI 2,66 LC1
249
4-fluorofenilo 4-fluorofenilo ciclopropilme tilo 386,17 ESI 2,49 LC17
250
2-metilsulfanilfenilo 4-fluorofenilo etilo 297,15 ESI+, M90 2,47 LC1
Según el procedimiento de preparación descrito en el Ejemplo 164, los ácidos 1-(fenilo sustituido)-4-(alcoxi opcionalmente sustituido)-4-(fenilo sustituido)ciclohexanocarboxílicos de la fórmula Ia que comprende un sustituyente metanosulfonilo que se mencionan en la Tabla 11 se prepararon a partir del correspondiente ácido 1(fenilo sustituido)-4-(alcoxi opcionalmente sustituido)-4-(fenilo sustituido)ciclohexanocarboxílico que comprende un sustituyente metilsulfanilo por oxidación con ácido 3-cloroperbenzoico.
Ar2 imagen70 imagen71Ar1
Ia R2
O COOH

Tabla 11. Compuestos de ejemplo de la fórmula Ia.
Ejemplo
Ar1 Ar2 R2 MS HPLC (Rt [min], Método)
251
4metanosulfonilfenil o 4-fluorofenilo metilo 407,50 ESI 2,03 LC17
252
4metanosulfonilfenil o 4-fluorofenilo ciclopropilme tilo 447,14 ESI 2,11 LC1
253
4-fluorofenilo 4-fluoro-2metanosulfonilfenilo ciclopropilme tilo 347,06 ESI+, M117 1,87 LC1
254
4-fluorofenilo 2-metanosulfonilfenilo ciclopropilme tilo 446,16 ESI 2,14 LC17
255
4-fluorofenilo 2-metanosulfonilfenilo n-propilo 434,10 ESI 2,16 LC17
256
2metanosulfonilfenil o 4-fluorofenilo ciclopropilme tilo 401,65 ESI-, M-45 2,16 LC17
46
imagen72
imagen73
imagen74
imagen75
imagen76
imagen77
imagen78
imagen79
imagen80
imagen81
imagen82
imagen83
imagen84
imagen85
imagen86
imagen87
imagen88
imagen89
imagen90
imagen91
imagen92
imagen93
imagen94
imagen95
imagen96
imagen97
imagen98
imagen99
imagen100
imagen101
imagen102
imagen103
imagen104
imagen105
imagen106
imagen107
imagen108
imagen109
imagen110
imagen111
imagen112
imagen113
imagen114
imagen115
imagen116
imagen117
imagen118
imagen119
imagen120
imagen121
F
F
imagen122
Arimagen1232
imagen124R2 O
R2 O
Arimagen1252 Ie If
imagen126
imagen127
imagen128

Tabla 13. Compuestos de ejemplo de las fórmulas Ie y If
Ejemplo
Ar2 R2 Fórmula, configuración MS (ESI+) HPLC (Rt [min], Método) MP
364
1-ciclopropilmetil-1H-imidazol-2ilo ciclopropilmetilo Ie cis 413 6,85 LC19 160°C
365 (1)
1-ciclopropilmetil-4,5-dimetil-1Himidazol-2-ilo ciclopropilmetilo Ie cis 441 6,7 LC19 175°C
366
1-ciclopropilmetil-1Hbenzoimidazol-2-ilo ciclopropilmetilo Ie cis 463 4,89 LC19 246°C
367
1-ciclopropilmetil-1Hbenzoimidazol-2-ilo ciclopropilmetilo If trans 463 6,9 LC19 302°C
368
1-ciclopropilmetil-4-metil-1Himidazol-2-ilo ciclopropilmetilo Ie cis 427 7,1 LC19 182 -184°C
369
5-bromo-1-ciclopropilmetil-4metil-1H-imidazol-2-ilo ciclopropilmetilo If trans 507 8,8 LC19 227°C
370
1-ciclopropilmetil-1H-imidazol-2ilo 3-metil-butilo Ie cis 429 7,0 LC19 205°C
371
1-ciclopropilmetil-1H-imidazol-2ilo 3-metil-butilo If trans 429 9,5 LC19 193°C
372
1-ciclopropilmetil-4,5-dimetil-1Himidazol-2-ilo 3-metil-butilo Ie cis 457 8,0 LC19 215°C
(1) hidrocloruro datos 1H-NMR (d6-DMSO; 400 MHz) 5 Ejemplo 364
7,4 (m, 3H), 7,1 (m, 3H), 4,1 (d, 2H), 2,8 (d, 2H), 2,2 (m, 4H), 1,9 (m, 4H), 1,1 (m, 1H), 0,8 (m, 1H), 0,5 (m, 2H), 0,4 (m, 4H), 0,0 (m, 2H) Ejemplo 365 7,5 (m, 2H), 7,2 (m, 2H), 4,3 (d, 2H), 2,9 (d, 2H), 2,4 (m, 2H), 2,28 (s, 3H), 2,25 (m, 4H), 2,2 (s, 3H), 1,8 (m, 2H), 0,95
10 (m, 2H), 0,63 (m, 2H), 0,5 (m, 4H), 0,1 (m, 2H) Ejemplo 366
97
7,6 (m, 2H), 7,45 (m, 2H), 7,15 (m, 4H), 4,48 (d, 2H), 2,85 (d, 2H), 2,4 (m, 4H), 2,1 (m, 2H), 1,9 (m, 2H), 1,1 (m, 1H), 0,85 (m, 1H), 0,7 (m, 2H), 0,6 (m, 2H), 0,35 (m, 2H), 0,0 (m, 2H) Ejemplo 367 7,6 - 7,4 (m, 4H), 7,2 - 7,0 (m, 4H), 4,45 (d, 2H), 2,8 (d, 2H), 2,35 (m, 4H), 2,2 (m, 4H), 2,0 (m, 2H), 1,1 (m, 1H), 0,9 5 (m, 1H), 0,6 (m, 2H), 0,5 (m, 2H), 0,4 (m, 2H), 0,0 (m, 2H)
Ejemplo 368 7,4 (m, 2H), 7,1 (m, 3H), 3,9 (d, 2H), 2,75 (d, 2H), 2,15 (m, 4H), 1,9 (s, 3H), 2,0 - 1,7 (m, 4H), 1,0 (m, 1H), 0,8 (m, 1H), 0,5 (m, 2H), 0,35 (m, 4H), 0,0 (m, 2H)
Ejemplo 369
10 7,45 (m, 2H), 7,15 (m, 2H), 4,15 (d, 2H), 2,8 (d, 2H), 2,35 (m, 2H), 2,25 (m, 2H), 2,0 (s, 3H), 2,0 - 1,8 (m, 4H), 1,05 (m, 1H), 0,8 (m, 1H), 0,6 (m, 2H), 0,5 (m, 2H), 0,4 (m, 2H), 0,0 (m, 2H) Análogamente a los procedimientos de preparación anteriormente descritos, se prepararon los ácidos cis-4-Ar2-4
(alcoxi opcionalmente sustituido)-1-fenilciclohexanocarboxílicos de la fórmula Ig y los ácidos trans-4-Ar2-4-(alcoxi opcionalmente sustituido)-1-fenilciclohexanocarboxílicos de la fórmula Ih enumerados en la Tabla 14.
imagen129
Ig Ih

Tabla 14. Compuestos de ejemplo de las fórmulas Ig y Ih
Ejemplo
Ar2 R2 Fórmula, configuración MS (ESI+) HPLC (Rt [min], Método) MP
373
4-bromo-1-ciclopropilmetil-5-metil1H-imidazol-2-ilo ciclopropilmetilo Ig cis 487 10 LC19 183°C
374
4-bromo-1-ciclopropilmetil-5-metil1H-imidazol-2-ilo 3-metil-butilo Ig cis 503 1,42 LC20 174°C
375
5-bromo-1-ciclopropilmetil-4-metil1H-imidazol-2-ilo 3-metil-butilo Ig cis 503 1,14 LC20 192°C
376
1-ciclopropilmetil-4,5-dimetil-1Himidazol-2-ilo 3-metil-butilo Ig cis 439 7,1 LC19 212°C
377
1-ciclopropilmetil-4,5-dimetil-1Himidazol-2-ilo ciclopropilmetilo Ig cis 423 7,9 LC19 204°C
378
1-ciclopropilmetil-5-trifluorometil1H-imidazol-2-ilo ciclopropilmetilo Ig cis 463 5,88 LC19 308°C
379
1-ciclopropilmetil-5-trifluorometil1H-imidazol-2-ilo ciclopropilmetilo Ih trans 463 6,01 LC19 192
380
1-ciclopropilmetil-4-trifluorometil1H-imidazol-2-ilo ciclopropilmetilo Ig cis 463 6,04 LC19 257°C
98
Ejemplo
Ar2 R2 Fórmula, configuración MS (ESI+) HPLC (Rt [min], Método) MP
381
1-ciclopropilmetil-4-trifluorometil1H-imidazol-2-ilo ciclopropilmetilo Ih trans 463 8,52 LC19 207°C
382
5-cloro-1-ciclopropilmetil-4-metil1H-imidazol-2-ilo ciclopropilmetilo Ig cis 443 1,03 LC20 186°C
383
4-cloro-1-ciclopropilmetil-5-metil1H-imidazol-2-ilo ciclopropilmetilo Ig cis 443 2,17 LC20 188°C
384
5-cloro-1-ciclopropilmetil-4-metil1H-imidazol-2-ilo 3-metil-butilo Ig cis 461 1,14 LC20 259°C
385
5-cloro-1-ciclopropilmetil-4-metil1H-imidazol-2-ilo 3-metiloxetan-3-ilmetil Ig cis 474 1,07 LC20 162°C
386
5-cloro-1-ciclopropilmetil-4-metil1H-imidazol-2-ilo 2-metoxi-etilo Ig cis 447 4,28 LC21 149°C
387
1-ciclopropilmetil-4,5-dicloro-1Himidazol-2-ilo ciclopropilmetilo Ig cis 463 1,50 LC20 218°C
388
5-cloro-4-metil-1-n-propil-1Himidazol-2-ilo ciclopropilmetilo Ig cis 431 1,04 LC20 130°C
389
5-cloro-4-metil-1-n-propil-1Himidazol-2-ilo 3,3-dimetilbutilo Ig cis 461 1,17 LC20 201°C
390
5-cloro-4-metil-1-n-propil-1Himidazol-2-ilo 2-metoxi-etilo Ig cis 435 0,94 LC20 152°C
391
5-cloro-1,4-dimetil-1H-imidazol-2ilo ciclopropilmetilo Ie cis 403 1,16 LC20 203°C
392
5-cloro-1,4-dimetil-1H-imidazol-2ilo 3,3-dimetilbutilo Ig cis 433 1,34 LC20 195°C
393
5-cloro-4-terc-butil-1-ciclopropilmetil-1H-imidazol-2-ilo ciclopropilmetilo Ig cis 486 5,46 LC21 204°C
394
5-cloro-1-ciclopropilmetil-4isopropil-1H-imidazol-2-ilo ciclopropilmetilo Ig cis 472 1,18 LC20 131°C

Ejemplo 395 5-Cloro-4-metil-1H-imidazol
imagen130
99
imagen131
imagen132
imagen133
imagen134
imagen135
imagen136 imagen137Arimagen1382 imagen139Ar1
imagen140In
O COOH

Tabla 16. Compuestos de ejemplo de la fórmula In.
Ejemplo
Ar1 Ar2 MS (ESI+) HPLC (Rt Método) [min], MP
407
piridin-3-ilo 5-cloro-1-ciclopropilmetil-4metil-1H-imidazol-2-ilo 444 0,8 LC20 245°C
408
4-metanosulfonilfenilo 5-cloro-1-ciclopropilmetil-4metil-1H-imidazol-2-ilo 522 0,96 LC20 156ºC.
409
3-trifluorometoxi-fenilo 5-cloro-1-ciclopropilmetil-4metil-1H-imidazol-2-ilo 527 1,18 LC20 205°C
410
4-trifluorometoxi-fenilo 5-cloro-1-ciclopropilmetil-4metil-1H-imidazol-2-ilo 527 1,16 LC20 106°C
411
6-metilpiridin-3-ilo 5-cloro-1-ciclopropilmetil-4metil-1H-imidazol-2-ilo 495 3,35 LC21 120°C
412
4-metilfenilo 1-ciclopropilmetil-1Hbenzoimidazol-2-ilo 459 1,05 LC20 163°C
413
3-metanosulfonilfenilo 1-ciclopropilmetil-1Hbenzoimidazol-2-ilo 523 0,95 LC20 229°C
414
3-trifluorometoxi-fenilo 1-ciclopropilmetil-1Hbenzoimidazol-2-ilo 529 5,26 LC21 222°C
415
6-metilpiridin-3-ilo 1-ciclopropilmetil-1Hbenzoimidazol-2-ilo 471 0,77 LC20 186°C
Ejemplo 416
5
Éster metílico del ácido fluorofenil)ciclohexanocarboxílico cis-4-(4-bromo-1-ciclopropilmetil-5-metil-1H-imidazol-2-il)-4-ciclopropilmetoxi-1-(4-
Br
F
imagen141
Se suspendieron 1,28 g (5 mmol) de ácido cis 4-(4-bromo-1-ciclopropilmetil-5-metil-1H-imidazol-2-il)-4ciclopropilmetoxi-1-(4-fluorofenil)ciclohexanocarboxílico y carbonato de potasio (0,7 g, 5 mmol) en DMF (20 ml). Se añadió yodometano (0,32 ml, 1 eq.) y la mezcla se agitó durante 18 h a 20°C. El medio de reacción se vertió en agua 10 y se extrajo con EA. Las fases orgánicas combinadas se lavaron con salmuera y se secaron sobre sulfato de sodio,
105
imagen142
imagen143
imagen144
imagen145
imagen146
imagen147
imagen148
imagen149
imagen150
imagen151
imagen152
imagen153
imagen154
imagen155
imagen156
imagen157
imagen158
imagen159
imagen160
Se disolvieron 1,7 g de 1-ciclopropilmetil-3-(3-metilsulfanilfenil)-1H-[1,2,4]triazol en 15 ml de THF anhidro y se enfrió hasta -70°C en atmósfera de nitrógeno. Se añadieron gota a gota 3,05 mL de una disolución 2,5 M de n-butil-litio en hexano. Después de 30 min, se añadió una disolución de 1,1 g de 4-oxo-1-fenilciclohexanocarbonitrilo en 5 ml de
5 THF. La mezcla de reacción se dejó calentar hasta temperatura ambiente durante 18 h. Se añadieron 50 ml de agua, y la mezcla se extrajo tres veces con 50 ml de EA cada vez. Las fases orgánicas combinadas se lavaron con salmuera y se secaron sobre sulfato sódico. El disolvente se separó a vacío. La cromatografía ultrarrápida del residuo (120 g de gel de sílice; HEP/EA, gradiente de 90:10 a 60:40) proporcionó 1,6 g del compuesto del título cis como un sólido blanco y 0,58 g del compuesto del título trans como un sólido blanco.
10 Ejemplo 460-1
cis-4-[2-Ciclopropilmetil-5-(3-metilsulfanilfenil)-2H-[1,2,4]triazol-3-il]-4-hidroxi-1-fenilciclohexanocarbonitrilo
imagen161
TLC (HEP/EA 3:2): Rf 0,58 Ejemplo 460-2 15 trans-4-[2-Ciclopropilmetil-5-(3-metilsulfanilfenil)-2H-[1,2,4]triazol-3-il]-4-hidroxi-1-fenilciclohexanocarbonitrilo
imagen162
TLC (HEP/EA 3:2): Rf 0,52 Ejemplo 461 trans-4-[2-Ciclopropilmetil-5-(3-metilsulfanil-fenil)-2H-[1,2,4]triazol-3-il]-4-fenoxi-1-fenil-ciclohexanocarbonitrilo
124
imagen163
imagen164
imagen165
imagen166
imagen167
imagen168
imagen169
imagen170
imagen171
imagen172
imagen173
imagen174
imagen175
imagen176
imagen177
imagen178

Claims (1)

  1. imagen1
    imagen2
ES08758710.1T 2007-06-05 2008-05-23 Derivados de di(hetero)arilciclohexano, su preparación, su uso y composiciones farmacéuticas que los comprenden Active ES2485492T3 (es)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
EP07290698 2007-06-05
EP07290698 2007-06-05
PCT/EP2008/004112 WO2008148468A1 (en) 2007-06-05 2008-05-23 Di(hetero)arylcyclohexane derivatives, their preparation, their use and pharmaceutical compositions comprising them

Publications (1)

Publication Number Publication Date
ES2485492T3 true ES2485492T3 (es) 2014-08-13

Family

ID=38704822

Family Applications (1)

Application Number Title Priority Date Filing Date
ES08758710.1T Active ES2485492T3 (es) 2007-06-05 2008-05-23 Derivados de di(hetero)arilciclohexano, su preparación, su uso y composiciones farmacéuticas que los comprenden

Country Status (19)

Country Link
US (1) US8076324B2 (es)
EP (1) EP2164825B1 (es)
JP (1) JP5384485B2 (es)
KR (1) KR101608702B1 (es)
CN (1) CN101679191B (es)
AR (1) AR066833A1 (es)
AU (1) AU2008258871B2 (es)
BR (1) BRPI0812590A2 (es)
CA (1) CA2689985C (es)
CL (1) CL2008001615A1 (es)
DK (1) DK2164825T3 (es)
ES (1) ES2485492T3 (es)
IL (1) IL202470A (es)
MX (1) MX2009012644A (es)
MY (1) MY148903A (es)
PT (1) PT2164825E (es)
TW (1) TWI445526B (es)
UY (1) UY31118A1 (es)
WO (1) WO2008148468A1 (es)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20150166528A1 (en) 2012-06-14 2015-06-18 Basf Se Pesticidal methods using substituted 3-pyridyl thiazole compounds and derivatives for combating animal pests
KR20180094939A (ko) 2015-12-17 2018-08-24 메르크 파텐트 게엠베하 폴리시클릭 tlr7/8 안타고니스트 및 면역 질환의 치료에서 이들의 용도
SG11201900947RA (en) * 2016-08-08 2019-02-27 Merck Patent Gmbh Tlr7/8 antagonists and uses thereof
CN110483402B (zh) * 2019-08-12 2021-07-23 上海毕得医药科技股份有限公司 一种3-溴-5-苯基-1h-吡唑的合成方法

Family Cites Families (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3927930A1 (de) * 1989-08-24 1991-02-28 Bayer Ag Cyclisch substituierte (chinolin-2-yl-methoxy)phenyl-essig-saeure-derivate
US5552438A (en) 1992-04-02 1996-09-03 Smithkline Beecham Corporation Compounds useful for treating allergic and inflammatory diseases
ES2098069T3 (es) * 1993-02-23 1997-04-16 Hoechst Ag Bencenosulfonil-ureas y -tioureas sustituidas, procedimiento para su preparacion y su utilizacion como agentes farmaceuticos.
DE4341655A1 (de) * 1993-12-07 1995-06-08 Hoechst Ag Aminosubstituierte Benzolsulfonylharnstoffe und -thioharnstoffe, Verfahren zu ihrer Herstellung und ihre Verwendung als Pharmazeutika
DE19505397A1 (de) * 1995-02-17 1996-08-22 Hoechst Ag Substituierte Benzolsulfonylharnstoffe und -thioharnstoffe, Verfahren zu ihrer Herstellung, ihre Verwendung als Medikament oder Diagnostikum sowie sie enthaltendes Medikament
JP2000507558A (ja) * 1996-03-25 2000-06-20 スミスクライン・ビーチャム・コーポレイション Ｃｎｓ損傷についての新規な治療
UY25338A1 (es) 1998-01-07 2001-08-27 Smithkline Beecham Corp Método para tratar copd
CA2317548A1 (en) 1998-01-07 1999-07-15 Theodore Torphy Method for treating multiple sclerosis
DE19832009A1 (de) * 1998-07-16 2000-01-20 Hoechst Marion Roussel De Gmbh 2,5-Substituierte Benzolsulfonylharnstoffe und -thioharnstoffe, Verfahren zu ihrer Herstellung, ihre Verwendung und sie enthaltende pharamazeutische Präparate
KR100981592B1 (ko) * 1998-09-10 2010-09-13 사노피-아벤티스 도이칠란트 게엠베하 벤젠설포닐(티오)우레아 또는 베타-수용체 차단제와 배합된 벤젠설포닐(티오)우레아를 포함하는 자율신경계 기능부전의 치료 또는 예방을 위한 약제학적 조성물
US6887870B1 (en) * 1999-10-12 2005-05-03 Bristol-Myers Squibb Company Heterocyclic sodium/proton exchange inhibitors and method
CA2401489A1 (en) * 2000-03-02 2001-09-07 Ichiro Miki Oxygen-containing heterocyclic compounds
GB0012214D0 (en) * 2000-05-19 2000-07-12 Merck Sharp & Dohme Therapeutic agents
DE10135636A1 (de) * 2001-07-17 2003-02-06 Gruenenthal Gmbh Substituierte 4-Aminocyclohexanole
EP1536790A2 (en) 2002-08-09 2005-06-08 AstraZeneca AB Oxadiazoles as modulators of metabotropic glutamate receptor-5
JPWO2005037269A1 (ja) * 2003-10-21 2006-12-28 住友製薬株式会社 新規ピペリジン誘導体
WO2005097738A1 (ja) * 2004-04-06 2005-10-20 Dainippon Sumitomo Pharma Co., Ltd. 新規スルホンアミド誘導体

Also Published As

Publication number Publication date
UY31118A1 (es) 2009-01-30
BRPI0812590A2 (pt) 2015-02-18
CL2008001615A1 (es) 2008-10-10
US8076324B2 (en) 2011-12-13
KR20100017659A (ko) 2010-02-16
JP5384485B2 (ja) 2014-01-08
TW200911228A (en) 2009-03-16
AR066833A1 (es) 2009-09-16
MX2009012644A (es) 2009-12-10
WO2008148468A1 (en) 2008-12-11
IL202470A (en) 2013-08-29
JP2010529052A (ja) 2010-08-26
CN101679191B (zh) 2014-03-12
CA2689985A1 (en) 2008-12-11
US20100204206A1 (en) 2010-08-12
DK2164825T3 (da) 2014-07-14
AU2008258871B2 (en) 2013-08-15
CA2689985C (en) 2015-07-14
IL202470A0 (en) 2010-06-30
EP2164825A1 (en) 2010-03-24
EP2164825B1 (en) 2014-04-30
TWI445526B (zh) 2014-07-21
AU2008258871A1 (en) 2008-12-11
CN101679191A (zh) 2010-03-24
KR101608702B1 (ko) 2016-04-04
MY148903A (en) 2013-06-14
PT2164825E (pt) 2014-06-24

Similar Documents

Publication Publication Date Title
ES2629751T3 (es) Derivados de pirazol novedosos
ES2674813T3 (es) Compuesto heterocíclico que contiene nitrógeno parcialmente saturado
ES2524259T3 (es) Inhibidores de metaloproteinasa de matriz a base de arilsulfonamida
ES2535155T3 (es) Moduladores de receptores de estrógeno y usos de los mismos
ES2485492T3 (es) Derivados de di(hetero)arilciclohexano, su preparación, su uso y composiciones farmacéuticas que los comprenden
CN109310671B (zh) 布鲁顿酪氨酸激酶抑制剂
CN104672223A (zh) 二氢嘧啶衍生物的制备方法及其中间体
AR050364A1 (es) Derivados de sulfonamidas, su preparacion y su aplicacion en terapeutica
SK285433B6 (sk) Spôsob prípravy bifenylových derivátov vhodných na prípravu 4-aryl-1-fenylalkyl-1,2,3,6-tetrahydropyridínov
JP2005503372A5 (es)
JP2009509986A5 (es)
JP2010533715A5 (es)
JP2014520898A5 (es)
TW200536832A (en) Process for producing 5-hydroxy-4-thiomethylpyrazole compound
CN102884056A (zh) 酮基苯并呋喃衍生物、其合成方法及中间体
KR20180095564A (ko) 벤조피페리딘 유도체, 이의 제조 방법 및 이의 의학적 용도
TW201702226A (zh) 尿素衍生物或其醫藥上可接受鹽
CN106083840B (zh) 2-氨甲酰环氨基脲衍生物的合成
TWI597273B (zh) 含氮飽和雜環化合物
TW201418233A (zh) 新穎腎素抑制劑
JP2018502875A (ja) クロメノンモノカルボン酸トランスポータ阻害薬
WO2010135350A2 (en) Biphenyl intermediate compounds and methods for the preparation of a dual angiotensin ii and endothelin a receptor antagonist
JP2010526142A5 (es)
EP4206197A1 (en) Preparation method for novel rho-related protein kinase inhibitor and intermediate in preparation method
JP2018536652A5 (es)