[go: up one dir, main page]

RU2005116846A - METHODS FOR PRODUCING PHENYLALKINE DERIVATIVES - Google Patents

METHODS FOR PRODUCING PHENYLALKINE DERIVATIVES Download PDF

Info

Publication number
RU2005116846A
RU2005116846A RU2005116846/04A RU2005116846A RU2005116846A RU 2005116846 A RU2005116846 A RU 2005116846A RU 2005116846/04 A RU2005116846/04 A RU 2005116846/04A RU 2005116846 A RU2005116846 A RU 2005116846A RU 2005116846 A RU2005116846 A RU 2005116846A
Authority
RU
Russia
Prior art keywords
membered heterocyclyl
alkylene
phenyl
independently selected
alkyl
Prior art date
Application number
RU2005116846/04A
Other languages
Russian (ru)
Inventor
Ричард АПОДАКА (US)
Ричард Аподака
С оху ДЭН (US)
Сяоху Дэн
Джилл А. ЯБЛОБНОВСКИ (US)
Джилл А. ЯБЛОБНОВСКИ
Неелакандха МАНИ (US)
Неелакандха Мани
Ченнагири Р. ПАНДИТ (US)
Ченнагири Р. Пандит
Вэй СЯО (US)
Вэй Сяо
Original Assignee
Орто-Макнейл Фармасьютикал, Инк. (Us)
Орто-Макнейл Фармасьютикал, Инк.
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
Priority claimed from PCT/US2002/038480 external-priority patent/WO2003050099A1/en
Application filed by Орто-Макнейл Фармасьютикал, Инк. (Us), Орто-Макнейл Фармасьютикал, Инк. filed Critical Орто-Макнейл Фармасьютикал, Инк. (Us)
Publication of RU2005116846A publication Critical patent/RU2005116846A/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D203/00—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D203/04—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D203/06—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D203/08—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring nitrogen atom
    • C07D203/12—Radicals substituted by nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C07D209/16—Tryptamines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
    • C07D211/14—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/26—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D215/04—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 only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms
    • C07D215/06—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 only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms having only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D225/00—Heterocyclic compounds containing rings of more than seven members having one nitrogen atom as the only ring hetero atom
    • C07D225/02—Heterocyclic compounds containing rings of more than seven members having one nitrogen atom as the only ring hetero atom not condensed with other rings
    • 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
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles 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 in position 2
    • C07D235/26—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D273/00—Heterocyclic compounds containing rings having nitrogen and oxygen atoms as the only ring hetero atoms, not provided for by groups C07D261/00 - C07D271/00
    • 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
    • C07D277/04—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings 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
    • C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D279/10—1,4-Thiazines; Hydrogenated 1,4-thiazines
    • C07D279/12—1,4-Thiazines; Hydrogenated 1,4-thiazines not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
    • C07D295/027—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring
    • C07D295/03—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring with the ring nitrogen atoms directly attached to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/06—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by halogen atoms or nitro radicals
    • C07D295/073—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by halogen atoms or nitro radicals with the ring nitrogen atoms and the substituents separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/10—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms
    • C07D295/112—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms with the ring nitrogen atoms and the doubly bound oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/135—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • 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
    • C07D401/04—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 directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D401/10—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 carbon chain containing aromatic rings
    • 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
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 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
    • C07D471/10—Spiro-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

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pyridine Compounds (AREA)
  • Indole Compounds (AREA)
  • Other In-Based Heterocyclic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Quinoline Compounds (AREA)

Claims (44)

1. Способ получения соединения формулы (I)1. The method of obtaining the compounds of formula (I)
Figure 00000001
Figure 00000001
 где n равно целому числу от 0 до 1;where n is an integer from 0 to 1; R1 и R2 независимо выбраны из С1-3алкила, аллила и С3-8циклоалкила, или взятые вместе с азотом, к которому они присоединены, образуют неароматический 4-7-членный гетероциклил, необязательно включающий до двух дополнительных гетероатомов, независимо выбранных из O, S и N;R 1 and R 2 are independently selected from C 1-3 alkyl, allyl and C 3-8 cycloalkyl, or taken together with the nitrogen to which they are attached form a non-aromatic 4-7 membered heterocyclyl, optionally including up to two additional heteroatoms, independently selected from O, S and N; один из R3, R4 и R5 является G, один из оставшихся двух является водородом, и другой выбирают из водорода, фтора и хлора;one of R 3 , R 4 and R 5 is G, one of the remaining two is hydrogen, and the other is selected from hydrogen, fluorine and chlorine; G является L2Q;G is L 2 Q; L2 является метиленом;L 2 is methylene; Q является NR8R9,, где R8 независимо выбран из водорода, С1-6алкила, С3-6алкенила, 6-9-членного карбоциклила, 3-12-членного гетероциклила, фенила, (5-9-членный гетероциклил)C1-6алкилена и (фенил)C1-6алкилена; и R9 независимо выбран из С1-6алкила, С3-6алкенила, 6-9-членного карбоциклила, 3-12-членного гетероциклила, фенила, (5-9-членный гетероциклил)C1-6алкилена и (фенил)C1-6алкилена;Q is NR 8 R 9, where R 8 is independently selected from hydrogen, C 1-6 alkyl, C 3-6 alkenyl, 6-9 membered carbocyclyl, 3-12 membered heterocyclyl, phenyl, (5-9 membered heterocyclyl) C 1-6 alkylene and (phenyl) C 1-6 alkylene; and R 9 is independently selected from C 1-6 alkyl, C 3-6 alkenyl, 6-9 membered carbocyclyl, 3-12 membered heterocyclyl, phenyl, (5-9 membered heterocyclyl) C 1-6 alkylene and (phenyl ) C 1-6 alkylene; илиor Q является насыщенным 3-13-членным N-связанным гетероциклилом, где, в дополнение к N-связывающему азоту, указанный 3-13-членный гетероциклил может необязательно содержать от 1 до 3 дополнительных гетероатомов, независимо выбранных из О, S и N;Q is a saturated 3-13 membered N-linked heterocyclyl, wherein, in addition to the N-binding nitrogen, said 3-13 membered heterocyclyl may optionally contain from 1 to 3 additional heteroatoms independently selected from O, S and N; где каждая из вышеуказанных алкильных, алкиленовых, алкенильных, гетероциклических, циклоалкильных, карбоциклических и арильных групп в формуле (I) может независимо и необязательно иметь от 1 до 3 заместителей, выбранных из метокси, галогена, амино, нитро, гидроксила и С1-3алкила;where each of the above alkyl, alkylene, alkenyl, heterocyclic, cycloalkyl, carbocyclic and aryl groups in formula (I) may independently and optionally have from 1 to 3 substituents selected from methoxy, halogen, amino, nitro, hydroxyl and C 1-3 alkyl; и где 1-3 заместителя Q могут быть далее независимо выбраны (в дополнение к предшествующему разделу) из трет-бутилоксикарбонила, карбоксамида, C1-6алкила, 5-9-членного гетероциклила, N(C1-6алкил)(5-9-членного гетероциклила), NH(5-9-членного гетероциклила), О(5-9-членного гетероциклила), (5-9-членный гетероциклил)С1-3алкилена, фенила, C1-2гидроксиалкилена, C2-6алкокси, (C3-6циклоалкил)-O-, фенила, (фенил)C1-3алкилена и (фенил)C1-3алкилен-O-, и где указанные замещающие группы Q могут необязательно иметь от 1 до 3 заместителей, независимо выбранных из трифторметила, галогена, нитро, циано и гидрокси; его фармацевтически приемлемой соли, сложного эфира или амида, включающий, по меньшей мере, одну из следующих стадий: взаимодействие соединения формулы (VI) с соединением формулы (V)and where 1-3 substituents Q can be further independently selected (in addition to the previous section) from tert-butyloxycarbonyl, carboxamide, C 1-6 alkyl, 5-9 membered heterocyclyl, N (C 1-6 alkyl) (5- 9 membered heterocyclyl), NH (5-9 membered heterocyclyl), O (5-9 membered heterocyclyl), (5-9 membered heterocyclyl) C 1-3 alkylene, phenyl, C 1-2 hydroxyalkylene, C 2 -6 alkoxy, (C 3-6 cycloalkyl) -O-, phenyl, (phenyl) C 1-3 alkylene and (phenyl) C 1-3 alkylene-O-, and wherein said substituent groups Q may optionally have from 1 to 3 substituents independently selected from trifluoromethyl, ALOGIA, nitro, cyano, and hydroxy; a pharmaceutically acceptable salt, ester or amide thereof, comprising at least one of the following steps: reacting a compound of formula (VI) with a compound of formula (V)
Figure 00000002
Figure 00000002
 иand
Figure 00000003
Figure 00000003
 проведение нуклеофильного замещения X1 в соединении формулы (VIII) органическим основанием R1R2NH, где X2 является подходящей уходящей группой в реакции сочетания с алкином, и X1 является подходящей уходящей группой в нуклеофильном замещении амином.carrying out a nucleophilic substitution of X 1 in the compound of formula (VIII) with an organic base R 1 R 2 NH, where X 2 is a suitable leaving group in a coupling reaction with alkyne, and X 1 is a suitable leaving group in a nucleophilic substitution with an amine. 2. Способ по п.1, где Q является замещенным или незамещенным N-морфолинилом.2. The method according to claim 1, where Q is substituted or unsubstituted N-morpholinyl. 3. Способ по п.1, где указанным органическим основанием R1R2NH является пиперидин, и указанное нуклеофильное замещение проводят при комнатной температуре.3. The method according to claim 1, where the specified organic base R 1 R 2 NH is piperidine, and the specified nucleophilic substitution is carried out at room temperature. 4. Способ по п.1, где указанное нуклеофильное замещение проводят при комнатной температуре с 10 эквивалентами пиперидина в присутствии этанола.4. The method according to claim 1, where the specified nucleophilic substitution is carried out at room temperature with 10 equivalents of piperidine in the presence of ethanol. 5. Способ по п.1, где указанное нуклеофильное замещение проводят при комнатной температуре с 10 эквивалентами пиперидина в присутствии этанола и X1 является мезилатом, с получением смеси замещенного основания и продукта элиминирования.5. The method according to claim 1, where the specified nucleophilic substitution is carried out at room temperature with 10 equivalents of piperidine in the presence of ethanol and X 1 is mesylate, to obtain a mixture of a substituted base and an elimination product. 6. Способ по п.5, далее включающий воздействие на указанную смесь HCl с получением солевого раствора, селективное осаждение и кристаллизацию из указанного солевого раствора дигидрохлорида фенилалкина.6. The method according to claim 5, further comprising exposing said mixture to HCl to obtain a saline solution, selective precipitation and crystallization of said phenylalkine dihydrochloride salt solution. 7. Способ по п.6, где указанный дигидрохлорид фенилалкин представляет собой дигидрохлорид 4-[3-(4-пиперидин-1-илбут-1-инил)бензил]морфолина.7. The method according to claim 6, wherein said phenylalkine dihydrochloride is 4- [3- (4-piperidin-1-ylbut-1-ynyl) benzyl] morpholine dihydrochloride. 8. Способ по п.1, где указанным органическим основанием R1R2NH является пиперидин.8. The method according to claim 1, where the specified organic base R 1 R 2 NH is piperidine. 9. Способ по п.1, где указанное нуклеофильное замещение проводят в присутствии этанола при комнатной температуре.9. The method according to claim 1, where the specified nucleophilic substitution is carried out in the presence of ethanol at room temperature. 10. Способ по п.1, где указанное нуклеофильное замещение проводят в присутствии этанола при комнатной температуре и указанным органическим основанием R1R2NH является пиперидин.10. The method according to claim 1, where the specified nucleophilic substitution is carried out in the presence of ethanol at room temperature and the specified organic base R 1 R 2 NH is piperidine. 11. Способ по п.10, где количество указанного пиперидина составляет 10 эквивалентов.11. The method of claim 10, wherein the amount of said piperidine is 10 equivalents. 12. Способ по п.1, где n равно 1, R3 является Н, R5 является Н, R4 является L2Q, где Q является морфолинилом, L2 такой, как определено в п.1, указанным органическим основанием R1R2NH является пиперидин, и указанное нуклеофильное замещение проводят в присутствии этанола при комнатной температуре.12. The method according to claim 1, where n is 1, R 3 is H, R 5 is H, R 4 is L 2 Q, where Q is morpholinyl, L 2 is as defined in claim 1, the indicated organic base R 1 R 2 NH is piperidine, and said nucleophilic substitution is carried out in the presence of ethanol at room temperature. 13. Способ по п.1, где указанное нуклеофильное замещение дает смесь продукта замещения и продукта элиминирования и проводится в спиртовой среде при такой температуре, что указанный продукт замещения получают с выходом, по меньшей мере, 80%.13. The method according to claim 1, where the specified nucleophilic substitution gives a mixture of the substitution product and the elimination product and is carried out in an alcohol medium at such a temperature that the specified substitution product is obtained with a yield of at least 80%. 14. Способ по п.1, где указанное нуклеофильное замещение дает смесь продукта замещения и продукта элиминирования и его проводят в присутствии этанола при комнатной температуре, и указанным органическим основанием R1R2NH является пиперидин, далее включающий обработку указанной смеси кислотой с получением солевого раствора, селективное осаждение и кристаллизацию указанного солевого раствора с получением соли.14. The method according to claim 1, where the specified nucleophilic substitution gives a mixture of the substitution product and the product of elimination and it is carried out in the presence of ethanol at room temperature, and the specified organic base R 1 R 2 NH is piperidine, further comprising treating the mixture with an acid to obtain saline solution, selective precipitation and crystallization of the specified salt solution to obtain salt. 15. Способ по п.14, где указанной кислотой является HCl.15. The method according to 14, where the specified acid is HCl. 16. Способ по п.14, где диэтиловый эфир и этанол используют в указанной кристаллизации.16. The method according to 14, where diethyl ether and ethanol are used in the specified crystallization. 17. Способ по п.16, где n равно 1, R3 является Н, R5 является Н, R4 является L2Q, где Q является морфолинилом, L2 такой, как определено в п.1, и NR1R2, взятые вместе, образуют пиперидинил, указанный продукт замещения представляет собой 4-[3-(4-пиперидин-1-илбут-1-инил)бензил]морфолин и указанная соль представляет собой дигидрохлорид указанного продукта замещения.17. The method according to clause 16, where n is 1, R 3 is H, R 5 is H, R 4 is L 2 Q, where Q is morpholinyl, L 2 as defined in claim 1, and NR 1 R 2 taken together form piperidinyl, said substitution product is 4- [3- (4-piperidin-1-ylbut-1-ynyl) benzyl] morpholine, and said salt is the dihydrochloride of said substitution product. 18. Способ по п.10, далее включающий преобразование спирта формулы (VII) в указанное соединение формулы (VIII).18. The method according to claim 10, further comprising converting the alcohol of formula (VII) to said compound of formula (VIII). 19. Способ по п.18, далее включающий восстановительное аминирование соединения формулы (VIIa) амином R8R9NH, где один из R3', R4' и R5' является C(O)Н и другие два выбирают из Н, хлора и брома, с получением соединения формулы (VII), где один из R3, R4 и R5 является NR8R9, и другие два выбирают из Н, хлора и брома,19. The method according to p. 18, further comprising reductive amination of the compounds of formula (VIIa) with an amine R 8 R 9 NH, where one of R 3 ' , R 4' and R 5 ' is C (O) H and the other two are selected from H chlorine and bromine to give a compound of formula (VII), wherein one of R 3 , R 4 and R 5 is NR 8 R 9 , and the other two are selected from H, chlorine and bromine,
Figure 00000004
Figure 00000004
 20. Способ по п.19, где указанным амином является морфолин.20. The method according to claim 19, where the specified amine is morpholine. 21. Способ по п.19 далее включающий сочетание в присутствии катализатора, содержащего палладий и соли меди, соединения формулы (II) с дизамещенным бензолом, где один из указанных заместителей бензола является C(O)Н и другой из указанных заместителей бензола выбирают из хлора и брома, с получением соединения формулы (VIIa).21. The method according to claim 19 further comprising combining, in the presence of a catalyst containing palladium and a copper salt, a compound of formula (II) with disubstituted benzene, where one of these benzene substituents is C (O) H and the other of these benzene substituents is selected from chlorine and bromine to give a compound of formula (VIIa). 22. Способ получения соединения формулы (I)22. The method of obtaining the compounds of formula (I)
Figure 00000001
Figure 00000001
 где n равно целому числу от 0 до 1;where n is an integer from 0 to 1; R1 и R2 независимо выбраны из С1-3алкила, аллила и С3-8циклоалкила, или взятые вместе с азотом, к которому они присоединены, образуют неароматический 4-7-членный гетероциклил, необязательно включающий до двух дополнительных гетероатомов, независимо выбранных из O, S и N;R 1 and R 2 are independently selected from C 1-3 alkyl, allyl and C 3-8 cycloalkyl, or taken together with the nitrogen to which they are attached form a non-aromatic 4-7 membered heterocyclyl, optionally including up to two additional heteroatoms, independently selected from O, S and N; один из R3 и R5 является G, один из оставшихся и R4 является Н, и другой выбирают из водорода, фтора и хлора;one of R 3 and R 5 is G, one of the remaining and R 4 is H, and the other is selected from hydrogen, fluorine and chlorine; G является L2Q;G is L 2 Q; L2 является метиленом;L 2 is methylene; Q является NR8R9, где R8 независимо выбран из водорода, С1-6алкила, С3-6алкенила, 6-9-членного карбоциклила, 3-12-членного гетероциклила, фенила, (5-9-членный гетероциклил)C1-6алкилена и (фенил)C1-6алкилена; и R9 независимо выбран из С1-6алкила, С3-6алкенила, 6-9-членного карбоциклила, 3-12-членного гетероциклила, фенила, (5-9-членный гетероциклил)C1-6алкилена и (фенил)C1-6алкилена;Q is NR 8 R 9 , where R 8 is independently selected from hydrogen, C 1-6 alkyl, C 3-6 alkenyl, 6-9 membered carbocyclyl, 3-12 membered heterocyclyl, phenyl, (5-9 membered heterocyclyl ) C 1-6 alkylene and (phenyl) C 1-6 alkylene; and R 9 is independently selected from C 1-6 alkyl, C 3-6 alkenyl, 6-9 membered carbocyclyl, 3-12 membered heterocyclyl, phenyl, (5-9 membered heterocyclyl) C 1-6 alkylene and (phenyl ) C 1-6 alkylene; илиor Q является насыщенным 3-13-членным N-связанным гетероциклилом, где, в дополнение к N-связывающему азоту, указанный 3-13-членный гетероциклил может необязательно содержать от 1 до 3 дополнительных гетероатомов, независимо выбранных из O, S и N;Q is a saturated 3-13 membered N-linked heterocyclyl, wherein, in addition to the N-binding nitrogen, said 3-13 membered heterocyclyl may optionally contain from 1 to 3 additional heteroatoms independently selected from O, S and N; где каждая из вышеуказанных алкильных, алкиленовых, алкенильных, гетероциклических, циклоалкильных, карбоциклических и арильных групп в формуле (I) может независимо и необязательно иметь от 1 до 3 заместителей, независимо выбранных из метокси, галогена, амино, нитро, гидроксила и С1-3алкила;where each of the above alkyl, alkylene, alkenyl, heterocyclic, cycloalkyl, carbocyclic and aryl groups in formula (I) may independently and optionally have from 1 to 3 substituents independently selected from methoxy, halogen, amino, nitro, hydroxyl and C 1- 3 alkyl; и где 1-3 заместителя Q могут быть далее независимо выбраны (в дополнение к предшествующему разделу) из трет-бутилоксикарбонила, карбоксамида, C1-6алкила, 5-9-членного гетероциклила, N(C1-6алкил)(5-9-членного гетероциклила), NH(5-9-членного гетероциклила), О(5-9-членного гетероциклила), (5-9-членный гетероциклил)C1-3алкилена, фенила, C1-2гидроксиалкилена, C2-6алкокси, (C3-6циклоалкил)-O-, фенила, (фенил)C1-3алкилена и (фенил)C1-3алкилен-O-, и где указанная замещающая группа Q может необязательно иметь от 1 до 3 заместителей, независимо выбранных из трифторметила, галогена, нитро, циано и гидрокси; его фармацевтически приемлемой соли, сложного эфира или амида, включающий взаимодействие, по меньшей мере, одного из соединений формул (XXIIIw) и (XXIIIow) c соединением формулы (V)and where 1-3 substituents Q can be further independently selected (in addition to the previous section) from tert-butyloxycarbonyl, carboxamide, C 1-6 alkyl, 5-9 membered heterocyclyl, N (C 1-6 alkyl) (5- 9-membered heterocyclyl), NH (5–9-membered heterocyclyl), O (5–9-membered heterocyclyl), (5–9-membered heterocyclyl) C 1-3 alkylene, phenyl, C 1-2 hydroxyalkylene, C 2 -6 alkoxy, (C 3-6 cycloalkyl) -O-, phenyl, (phenyl) C 1-3 alkylene and (phenyl) C 1-3 alkylene-O-, and wherein said substituent group Q may optionally have from 1 to 3 substituents independently selected from trifluoromethyl, g halogen, nitro, cyano and hydroxy; a pharmaceutically acceptable salt, ester or amide thereof, comprising reacting at least one of the compounds of formulas (XXIIIw) and (XXIIIow) with a compound of formula (V)
Figure 00000005
Figure 00000005
 где W является C(O)Н или G, и X2 является подходящей уходящей группой в реакции сочетания с алкином.where W is C (O) H or G, and X 2 is a suitable leaving group in a coupling reaction with an alkine. 23. Способ по п.22, где Q является замещенным или незамещенным N-морфолинилом.23. The method of claim 22, wherein Q is substituted or unsubstituted N-morpholinyl. 24. Способ получения соединения формулы (I)24. The method of obtaining the compounds of formula (I)
Figure 00000001
Figure 00000001
 где n равно целому числу от 0 до 1;where n is an integer from 0 to 1; R1 и R2 независимо выбраны из С1-3алкила, аллила и С3-8циклоалкила, или взятые вместе с азотом, к которому они присоединены, образуют неароматический 4-7-членный гетероциклил, необязательно включающий до двух дополнительных гетероатомов, независимо выбранных из O, S и N;R 1 and R 2 are independently selected from C 1-3 alkyl, allyl and C 3-8 cycloalkyl, or taken together with the nitrogen to which they are attached form a non-aromatic 4-7 membered heterocyclyl, optionally including up to two additional heteroatoms, independently selected from O, S and N; один из R3, R4 и R5 является G, один из оставшихся двух является водородом, и другой выбирают из водорода, фтора и хлора;one of R 3, R 4 and R 5 is G, one of the remaining two is hydrogen and the other is selected from hydrogen, fluoro and chloro; G является L2Q;G is L 2 Q; L2 является метиленом;L 2 is methylene; Q является NR8R9, где R8 независимо выбран из водорода, С1-6алкила, С3-6алкенила, 6-9-членного карбоциклила, 3-12-членного гетероциклила, фенила, (5-9-членный гетероциклил)С1-6алкилена и (фенил)C1-6алкилена; и R9 независимо выбран из С1-6алкила, С3-6алкенила, 6-9-членного карбоциклила, 3-12-членного гетероциклила, фенила, (5-9-членный гетероциклил)C1-6алкилена и (фенил)C1-6алкилена;Q is NR 8 R 9 , where R 8 is independently selected from hydrogen, C 1-6 alkyl, C 3-6 alkenyl, 6-9 membered carbocyclyl, 3-12 membered heterocyclyl, phenyl, (5-9 membered heterocyclyl ) C 1-6 alkylene and (phenyl) C 1-6 alkylene; and R 9 is independently selected from C 1-6 alkyl, C 3-6 alkenyl, 6-9 membered carbocyclyl, 3-12 membered heterocyclyl, phenyl, (5-9 membered heterocyclyl) C 1-6 alkylene and (phenyl ) C 1-6 alkylene; илиor Q является насыщенным 3-13-членным N-связанным гетероциклилом, где, в дополнение к N-связывающему азоту, указанный 3-13-членный гетероциклил может необязательно содержать от 1 до 3 дополнительных гетероатомов, независимо выбранных из O, S и N;Q is a saturated 3-13 membered N-linked heterocyclyl, wherein, in addition to the N-binding nitrogen, said 3-13 membered heterocyclyl may optionally contain from 1 to 3 additional heteroatoms independently selected from O, S and N; где каждая из вышеуказанных алкильных, алкиленовых, алкенильных, гетероциклических, циклоалкильных, карбоциклических и арильных групп в формуле (I) может независимо и необязательно иметь от 1 до 3 заместителей, независимо выбранных из метокси, галогена, амино, нитро, гидроксила и С1-3алкила;where each of the above alkyl, alkylene, alkenyl, heterocyclic, cycloalkyl, carbocyclic and aryl groups in formula (I) may independently and optionally have from 1 to 3 substituents independently selected from methoxy, halogen, amino, nitro, hydroxyl and C 1- 3 alkyl; и где 1-3 заместителя Q могут быть далее независимо выбраны (в дополнение к предшествующему разделу) из трет-бутилоксикарбонила, карбоксамида, C1-6алкила, 5-9-членного гетероциклила, N(C1-6алкил)(5-9-членного гетероциклила), NH(5-9-членного гетероциклила), О(5-9-членного гетероциклила), (5-9-членный гетероциклил)C1-3алкилена, фенила, C1-2гидроксиалкилена, C2-6алкокси, (C3-6циклоалкил)-O-, фенила, (фенил)C1-3алкилена и (фенил)С1-3алкилен-O-, и где каждая из замещающих групп Q может необязательно иметь от 1 до 3 заместителей, независимо выбранных из трифторметила, галогена, нитро, циано и гидрокси; его фармацевтически приемлемой соли, сложного эфира или амида, включающий взаимодействие соединения формулы (VII)and where 1-3 substituents Q can be further independently selected (in addition to the previous section) from tert-butyloxycarbonyl, carboxamide, C 1-6 alkyl, 5-9 membered heterocyclyl, N (C 1-6 alkyl) (5- 9-membered heterocyclyl), NH (5–9-membered heterocyclyl), O (5–9-membered heterocyclyl), (5–9-membered heterocyclyl) C 1-3 alkylene, phenyl, C 1-2 hydroxyalkylene, C 2 -6 alkoxy, (C 3-6 cycloalkyl) -O-, phenyl, (phenyl) C 1-3 alkylene and (phenyl) C 1-3 alkylene-O-, and where each of the substituent groups Q may optionally have from 1 up to 3 substituents independently selected from trifluoromethyl, ha logen, nitro, cyano and hydroxy; a pharmaceutically acceptable salt, ester or amide thereof, comprising reacting a compound of formula (VII)
Figure 00000006
Figure 00000006
 с органическим основанием R1R2NH в присутствии галогенида триалкилфосфония и основания.with an organic base R 1 R 2 NH in the presence of a trialkylphosphonium halide and a base. 25. Способ по п.24, где указанный галогенид триалкилфосфония представляет собой йодид (цианометил)триметилфосфония, и указанным основанием является DIPEA.25. The method according to paragraph 24, where the specified halide trialkylphosphonium is an iodide (cyanomethyl) trimethylphosphonium, and the specified base is DIPEA. 26. Способ получения соединения формулы (I)26. A method of obtaining a compound of formula (I)
Figure 00000001
Figure 00000001
 где n равно целому числу от 0 до 1;where n is an integer from 0 to 1; R1 и R2 независимо выбраны из С1-3алкила, аллила и С3-8циклоалкила, или взятые вместе с азотом, к которому они присоединены, образуют неароматический 4-7-членный гетероциклил, необязательно включающий до двух дополнительных гетероатомов, выбранных из O, S и N;R 1 and R 2 are independently selected from C 1-3 alkyl, allyl and C 3-8 cycloalkyl, or taken together with the nitrogen to which they are attached form a non-aromatic 4-7 membered heterocyclyl, optionally including up to two additional heteroatoms selected from O, S and N; R4 является G, один из оставшихся R3 и R5 является водородом, и другой выбирают из водорода, фтора и хлора;R 4 is G, one of the remaining R 3 and R 5 is hydrogen, and the other is selected from hydrogen, fluorine and chlorine; G является L2Q;G is L 2 Q; L2 является метиленом;L 2 is methylene; Q является NR8R9, где R8 независимо выбран из водорода, С1-6алкила, С3-6алкенила, 6-9-членного карбоциклила, 3-12-членного гетероциклила, фенила, (5-9-членный гетероциклил)C1-6алкилена и (фенил)C1-6алкилена; и R9 независимо выбран из С1-6алкила, С3-6алкенила, 6-9-членного карбоциклила, 3-12-членного гетероциклила, фенила, (5-9-членный гетероциклил)C1-6алкилена и (фенил)C1-6алкилена;Q is NR 8 R 9 , where R 8 is independently selected from hydrogen, C 1-6 alkyl, C 3-6 alkenyl, 6-9 membered carbocyclyl, 3-12 membered heterocyclyl, phenyl, (5-9 membered heterocyclyl ) C 1-6 alkylene and (phenyl) C 1-6 alkylene; and R 9 is independently selected from C 1-6 alkyl, C 3-6 alkenyl, 6-9 membered carbocyclyl, 3-12 membered heterocyclyl, phenyl, (5-9 membered heterocyclyl) C 1-6 alkylene and (phenyl ) C 1-6 alkylene; илиor Q является насыщенным 3-13-членным N-связанным гетероциклилом, где, в дополнение к N-связывающему азоту, указанный 3-13-членный гетероциклил может необязательно содержать от 1 до 3 дополнительных гетероатомов, необязательно выбранных из O, S и N;Q is a saturated 3-13 membered N-linked heterocyclyl, where, in addition to the N-binding nitrogen, said 3-13 membered heterocyclyl may optionally contain from 1 to 3 additional heteroatoms optionally selected from O, S and N; где каждая из вышеуказанных алкильных, алкиленовых, алкенильных, гетероциклических, циклоалкильных, карбоциклических и арильных групп в формуле (I) может независимо и необязательно иметь 1 до 3 заместителей, независимо выбранных из метокси, галогена, амино, нитро, гидроксила и С1-3алкила;where each of the above alkyl, alkylene, alkenyl, heterocyclic, cycloalkyl, carbocyclic and aryl groups in the formula (I) may independently and optionally have 1 to 3 substituents independently selected from methoxy, halogen, amino, nitro, hydroxyl and C 1-3 alkyl; и где 1-3 заместителя Q могут быть далее независимо выбраны (в дополнение к предшествующему разделу) из трет-бутилоксикарбонила, карбоксамида, C1-6алкила, 5-9-членного гетероциклила, N(C1-6алкил)(5-9-членного гетероциклила), NH(5-9-членного гетероциклила), О(5-9-членного гетероциклила), (5-9-членный гетероциклил)C1-3алкилена, фенила, C1-2гидроксиалкилена, C2-6алкокси, (C3-6циклоалкил)-O-, фенила, (фенил)C1-3алкилена и (фенил)С1-3алкилен-O-, и где указанные замещающие группы Q могут необязательно иметь от 1 до 3 заместителей, независимо выбранных из трифторметила, галогена, нитро, циано и гидрокси; его фармацевтически приемлемой соли, сложного эфира или амида, включающий: взаимодействие соединения формулы (XXIIImw) с соединением формулы (V)and where 1-3 substituents Q can be further independently selected (in addition to the previous section) from tert-butyloxycarbonyl, carboxamide, C 1-6 alkyl, 5-9 membered heterocyclyl, N (C 1-6 alkyl) (5- 9-membered heterocyclyl), NH (5–9-membered heterocyclyl), O (5–9-membered heterocyclyl), (5–9-membered heterocyclyl) C 1-3 alkylene, phenyl, C 1-2 hydroxyalkylene, C 2 -6 alkoxy, (C 3-6 cycloalkyl) -O-, phenyl, (phenyl) C 1-3 alkylene and (phenyl) C 1-3 alkylene-O-, and wherein said substituent groups Q may optionally have from 1 to 3 substituents independently selected from trifluoromethyl, ALOGIA, nitro, cyano, and hydroxy; a pharmaceutically acceptable salt, ester or amide thereof, comprising: reacting a compound of formula (XXIIImw) with a compound of formula (V)
Figure 00000007
Figure 00000007
 где W является C(O)Н или G, и X2 является подходящей уходящей группой в реакции сочетания с алкином.wherein W is C (O) H or G, and X 2 is a suitable leaving group in the coupling reaction with an alkyne. 27. Способ по п.26, где указанный W является C(O)Н, далее включающий проведение восстановительного аминирования указанного W органическим основанием R9R8NH.27. The method of claim 26, wherein said W is C (O) H, further comprising reductive amination of said W with an organic base R 9 R 8 NH. 28. Способ по п.26, где n равно 1, R3 является H, R5 является Н, W является C(O)Н, и X2 является хлором или бромом, и соединение формулы (V) является 1-бут-3-инилпиперидином, с образованием фенилалкина.28. The method according to p. 26, where n is 1, R 3 is H, R 5 is H, W is C (O) H, and X 2 is chlorine or bromine, and the compound of formula (V) is 1-but- 3-ynylpiperidine, with the formation of phenylalkine. 29. Способ по п.28, где указанное взаимодействие проводят в присутствии пирролидина и при температуре около 50°C с образованием фенилалкина.29. The method according to p, where the specified interaction is carried out in the presence of pyrrolidine and at a temperature of about 50 ° C with the formation of phenylalkine. 30. Способ по п.29, где указанное взаимодействие проводят в присутствии катализатора, содержащего палладий и соли меди.30. The method according to clause 29, where the specified interaction is carried out in the presence of a catalyst containing palladium and copper salts. 31. Способ по п.28, где X2 является бромом, и указанное взаимодействие проводят в таких условиях, что выход указанного фенилалкина составляет, по меньшей мере, 80%.31. The method according to p, where X 2 is bromine, and the specified interaction is carried out under such conditions that the yield of said phenylalkine is at least 80%. 32. Способ по п.28, далее включающий восстановительное аминирование R8R9NH указанного фенилалкина с получением основания.32. The method of claim 28, further comprising reductive amination of R 8 R 9 NH of said phenylalkine to give a base. 33. Способ по п.32, где указанный R8R9NH является морфолином и указанное основание представляет собой 4-[3-(4-пиперидин-1-илбут-1-инил)бензил]морфолин.33. The method of claim 32, wherein said R 8 R 9 NH is morpholine and said base is 4- [3- (4-piperidin-1-ylbut-1-ynyl) benzyl] morpholine. 34. Способ по п.32, далее включающий образование солевого раствора с HCl.34. The method according to p, further comprising forming a saline solution with HCl. 35. Способ по п.34, далее включающий получение дигидрохлорида указанного основания путем кристаллизации.35. The method according to clause 34, further comprising obtaining the dihydrochloride of the specified base by crystallization. 36. Способ по п.35, где указанное основание представляет собой 4-[3-(4-пиперидин-1-илбут-1-инил)бензил]морфолин.36. The method of claim 35, wherein said base is 4- [3- (4-piperidin-1-ylbut-1-ynyl) benzyl] morpholine. 37. Способ по п.22, где n равно 1, R4 является Н, R3 является Н, R5 является C(O)Н, NR1R2, взятые вместе, образуют пиперидинил, где указанное взаимодействие проводят при комнатной температуре.37. The method according to item 22, where n is 1, R 4 is H, R 3 is H, R 5 is C (O) H, NR 1 R 2 taken together form piperidinyl, where the specified interaction is carried out at room temperature . 38. Способ по п.22, где n равно 1, R4 является Н, R3 является Н, R5 является C(O)Н, NR1R2, взятые вместе, образуют пиперидинил, где указанное взаимодействие проводят при комнатной температуре в присутствии катализатора, содержащего палладий и соли меди, и указанное взаимодействие дает фенилалкин.38. The method according to item 22, where n is 1, R 4 is H, R 3 is H, R 5 is C (O) H, NR 1 R 2 taken together form piperidinyl, where the specified interaction is carried out at room temperature in the presence of a catalyst containing palladium and copper salts, and this interaction gives phenylalkine. 39. Способ по п.22, где n равно 1, R4 является Н, R3 является Н, R5 является C(O)Н, NR1R2, взятые вместе, образуют пиперидинил, X2 является бромом, где указанное взаимодействие проводят при комнатной температуре в присутствии катализатора, содержащего палладий и соли меди, и указанное взаимодействие дает фенилалкин.39. The method according to item 22, where n is 1, R 4 is H, R 3 is H, R 5 is C (O) H, NR 1 R 2 taken together form piperidinyl, X 2 is bromine, where indicated the interaction is carried out at room temperature in the presence of a catalyst containing palladium and copper salts, and this interaction gives phenylalkine. 40. Способ по п.22, где n равно 1, R4 является Н, R3 является Н, R5 является C(O)Н, NR1R2, взятые вместе, образуют пиперидинил, где указанное взаимодействие проводят при комнатной температуре в присутствии катализатора, содержащего палладий и соли меди, и указанное взаимодействие дает фенилалкин, далее включающий восстановительное аминирование R8R9NH указанного фенилалкина с получением основания.40. The method according to item 22, where n is 1, R 4 is H, R 3 is H, R 5 is C (O) H, NR 1 R 2 taken together form piperidinyl, where this interaction is carried out at room temperature in the presence of a catalyst containing palladium and copper salts, and this interaction gives phenylalkin, further comprising reductive amination of R 8 R 9 NH of said phenylalkine to give a base. 41. Способ по п.40, где указанный R8R9NH является морфолином, и указанным основанием является 4-[4-(4-пиперидин-1-илбут-1-инил)бензил]морфолин.41. The method of claim 40, wherein said R 8 R 9 NH is morpholine and said base is 4- [4- (4-piperidin-1-ylbut-1-ynyl) benzyl] morpholine. 42. Способ по п.40, далее включающий образование солевого раствора с HCl.42. The method according to p, further comprising the formation of a saline solution with HCl. 43. Способ по п.42, далее включающий получение дигидрохлорида указанного основания путем кристаллизации.43. The method according to § 42, further comprising obtaining dihydrochloride of the specified base by crystallization. 44. Способ по п.43, где указанным основанием является 4-[4-(4-пиперидин-1-илбут-1-инил)бензил]морфолин.44. The method according to item 43, where the specified base is 4- [4- (4-piperidin-1-ylbut-1-ynyl) benzyl] morpholine.
RU2005116846/04A 2002-12-02 2003-06-17 METHODS FOR PRODUCING PHENYLALKINE DERIVATIVES RU2005116846A (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
USPCT/US02/38480 2002-12-02
PCT/US2002/038480 WO2003050099A1 (en) 2001-12-10 2002-12-02 Phenylalkynes

Publications (1)

Publication Number Publication Date
RU2005116846A true RU2005116846A (en) 2006-01-20

Family

ID=32467117

Family Applications (1)

Application Number Title Priority Date Filing Date
RU2005116846/04A RU2005116846A (en) 2002-12-02 2003-06-17 METHODS FOR PRODUCING PHENYLALKINE DERIVATIVES

Country Status (11)

Country Link
EP (1) EP1567494A1 (en)
JP (1) JP2006514939A (en)
KR (1) KR20050086801A (en)
CN (1) CN1738799A (en)
AU (1) AU2003245613A1 (en)
BR (1) BR0316971A (en)
CA (1) CA2507875A1 (en)
MX (1) MXPA05005830A (en)
RU (1) RU2005116846A (en)
WO (1) WO2004050623A1 (en)
ZA (1) ZA200505323B (en)

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU3894299A (en) * 1998-05-15 1999-12-06 American Home Products Corporation Compositions comprising 2-phenyl-indole compounds and estrogen formulations
WO2001066534A2 (en) * 2000-03-09 2001-09-13 Abbott Laboratories Cyclic and bicyclic diamino histamine-3 receptor antagonists
US20020147198A1 (en) * 2001-01-12 2002-10-10 Guoqing Chen Substituted arylamine derivatives and methods of use
CA2469893A1 (en) * 2001-12-10 2003-06-19 Ortho-Mcneil Pharmaceutical, Inc. Phenylalkynes

Also Published As

Publication number Publication date
ZA200505323B (en) 2006-09-27
CA2507875A1 (en) 2004-06-17
CN1738799A (en) 2006-02-22
MXPA05005830A (en) 2006-02-08
KR20050086801A (en) 2005-08-30
BR0316971A (en) 2005-10-25
WO2004050623A1 (en) 2004-06-17
JP2006514939A (en) 2006-05-18
AU2003245613A1 (en) 2004-06-23
EP1567494A1 (en) 2005-08-31

Similar Documents

Publication Publication Date Title
RU2167866C2 (en) Derivatives of arylglycineamides and pharmaceutical composition containing these compounds
JP2008521817A5 (en)
EP0773937A1 (en) Novel aryl piperazine-derived piperazide derivatives, methods for their preparation, their use as drugs and pharmaceutical compositions comprising same
JP2000504677A (en) Sulfonamide derivatives for 5HT7 receptor antagonists
PT96255B (en) PROCESS FOR THE PREPARATION OF NEW 1-NAFETYPIPERAZINE DERIVATIVES
CZ39396A3 (en) The use of substituted aryloxyalkyldiamines, the compounds per se, process of their preparation, pharmaceutical compositions based thereon and process of their preparation
MX2011005367A (en) Aryl piperazine and their use as alpha2c antagonists.
CZ362599A3 (en) Indazolamide compounds functioning as serotoninergic preparations
EP3023417A1 (en) Process for the preparation of an antidepressant and the intermediates thereof
WO1997041108A1 (en) Substituted piperazines and piperidines as central nervous system agents
JP5387917B2 (en) Novel carbamoyloxyarylalkanoylarylpiperazine compounds, pharmaceutical compositions containing the compounds and methods of treating pain, anxiety and depression by administration of the compounds
PL183526B1 (en) N-substituted derivatives of 3-azabicyclo [3.2.0] heptane, method of obtaining them and their application
RU2005116846A (en) METHODS FOR PRODUCING PHENYLALKINE DERIVATIVES
FR2650591A1 (en) NOVEL OXAZOLO PYRIDINE DERIVATIVES, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING SAME
FI85700C (en) FOERFARANDE FOER FRAMSTAELLNING AV ETT TERAPEUTISKT ANVAENDBART PIPERIDINDERIVAT.
CN1143950A (en) Nitroxy group-containing benzylamine derivatives and their use for treating cardiovascular diseases, as well as increased intra-ocular pressure
RU2003127397A (en) SUBSTITUTED PROPAN-1, 3-DIAMINE DERIVATIVES AND THEIR APPLICATION IN PHARMACEUTICALS
WO2016151328A1 (en) Method for making serotonin reuptake inhibitors
PL139590B1 (en) Process for preparing novel derivatives of piperidine
DK156396B (en) 2- (N-PYRROLIDINO) -3-ISOBUTOXY-N-SUBSTITUTED PHENYL-N-BENZYL-PROPYLAMINE COMPOUNDS AND PHARMACEUTICAL AGENTS CONTAINING THESE
CS241030B2 (en) Method of 1,1,2-triphenylpropane and 1,1,2-triphenylpropene's new derivatives production
EP0223124B1 (en) Substituted aminosulfonyl 6-nitrobenzoic-esters or amides, processes for their preparation and pharmaceutical compositions containing them
AU671361B2 (en) 2-aminopyrazine-5-carboxamide derivatives, their preparation and their application in therapeutics
JP2008512366A5 (en)
ES2289000T3 (en) (4-ACILAMINOPIPERIDIN-1-IL) -ATAMETERS IN THE QUALITY OF NEUROQUININE ANTAGONISTS.

Legal Events

Date Code Title Description
FA92 Acknowledgement of application withdrawn (lack of supplementary materials submitted)

Effective date: 20070911