CN110627657B - 一种新的舍曲林类似物及其制备方法和应用 - Google Patents

一种新的舍曲林类似物及其制备方法和应用 Download PDF

Info

Publication number
CN110627657B
CN110627657B CN201810661677.8A CN201810661677A CN110627657B CN 110627657 B CN110627657 B CN 110627657B CN 201810661677 A CN201810661677 A CN 201810661677A CN 110627657 B CN110627657 B CN 110627657B
Authority
CN
China
Prior art keywords
alkyl
formula
radical
group
compound
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
CN201810661677.8A
Other languages
English (en)
Other versions
CN110627657A (zh
Inventor
闫京波
王刚
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.)
Beijing Anbo Ruida Pharmaceutical Technology Co ltd
Original Assignee
Beijing Anbo Ruida Pharmaceutical Technology Co ltd
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 Beijing Anbo Ruida Pharmaceutical Technology Co ltd filed Critical Beijing Anbo Ruida Pharmaceutical Technology Co ltd
Priority to CN201810661677.8A priority Critical patent/CN110627657B/zh
Publication of CN110627657A publication Critical patent/CN110627657A/zh
Application granted granted Critical
Publication of CN110627657B publication Critical patent/CN110627657B/zh
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/10—Drugs for disorders of the urinary system of the bladder
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/33—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C07C211/39—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of an unsaturated carbon skeleton
    • C07C211/41—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of an unsaturated carbon skeleton containing condensed ring systems
    • C07C211/42—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of an unsaturated carbon skeleton containing condensed ring systems with six-membered aromatic rings being part of the condensed ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C215/04—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated
    • C07C215/06—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic
    • C07C215/08—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic with only one hydroxy group and one amino group bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C217/06—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted
    • C07C217/08—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to an acyclic carbon atom
    • 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
    • C07C323/23—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 nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • 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
    • C07C323/23—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 nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C323/24—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 nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/25—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 nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/04—Heterocyclic compounds containing four-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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D215/12—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
    • 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
    • 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
    • C07D235/14—Radicals substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D237/20—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/26—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/74—Quinazolines; Hydrogenated quinazolines with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to ring carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with 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
    • C07D241/20—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
    • C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
    • C07D241/40—Benzopyrazines
    • C07D241/42—Benzopyrazines with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/32—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole 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
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
    • C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
    • C07D263/56—Benzoxazoles; Hydrogenated benzoxazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/28—Radicals substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/64—Benzothiazoles with only hydrocarbon or substituted hydrocarbon radicals attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D295/125—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 attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/13—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 attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/36—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom 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 or radicals containing only hydrogen and carbon atoms, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
    • C07D317/58—Radicals substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D319/10—1,4-Dioxanes; Hydrogenated 1,4-dioxanes
    • C07D319/14—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems
    • C07D319/16—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D319/18—Ethylenedioxybenzenes, not substituted on the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms
    • 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
    • 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
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Urology & Nephrology (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

本发明属于化合物及其制备方法和应用的技术领域，具体涉及一种舍曲林类似物或其药学上可接受的盐，其具有下述式(I)所示的结构。本发明的化合物具有优于舍曲林的药物活性。本发明还提供式(I)所示的化合物的制备方法和应用。
Figure DDA0001706930160000011

Description

一种新的舍曲林类似物及其制备方法和应用
技术领域
本发明涉及一种新的舍曲林类似物及其制备方法和应用，属于化合物及其制备方法和应用的技术领域。
背景技术
舍曲林【化学名(1S-顺式)-4-(3,4-二氯苯基)-1,2,3,4-四氢-N-甲基-1-萘啶胺(结构式如式(I-M)所示)】或盐酸舍曲林(也简称为舍曲林)【化学名(1S-顺式)-4-(3,4-二氯苯基)-1,2,3,4-四氢-N-甲基-1-萘啶胺盐酸盐(结构式如式(II-M)所示)】：
Figure GDA0003596153930000011
舍曲林用于治疗治疗抑郁症的相关症状，包括伴随焦虑、有或无躁狂史的抑郁症；也用于治疗强迫症。
然而舍曲林的活性仍有待进一步改善。
发明内容
本发明的目的在于克服上述现有技术中的不足，提供一种新型的舍曲林类似物，其具有优于舍曲林的药物活性。
本发明的另一个目的在于提供一种上述新型的舍曲林类似物的制备方法。
本发明的再一个目的在于提供一种上述新型的舍曲林类似物在制备治疗抑郁、强迫症的药物中的应用。
基于此，本发明提供一种新型的舍曲林类似物或其药学上可接受的盐，其具有下述式(I)所示的结构：
Figure GDA0003596153930000021
其中：
R1和R2分别独立地选自H、卤素、C1-6烷基，C3-8环烷基，羟基，C1-6烷氧基，C1-6卤代烷基；
R3选自C3-8环烷基；
R4选自未取代或任选被Rs取代的下列基团：C1-6烷基，羟基C1-6烷基，C3-10环烷基，C1-6烷基C3-10环烷基，羟基，巯基，C1-6烷氧基，羟基C1-6烷氧基，C1-6烷氧基C1-6烷氧基，C1-6烷硫基，巯基C1-6烷硫基，C1-6烷硫基C1-6烷硫基，氨基，C1-6烷基氨基，二(C1-6烷基)氨基，C3-8环烷基氨基，二(C3-8环烷基)氨基，羟基C1-6烷基氨基，3-10元杂环烷基，C1-6烷基3-10元杂环烷基，C1-6烷氧基C1-6烷基，羟基C1-6烷氧基C1-6烷基，巯基C1-6烷基，C1-6烷硫基C1-6烷基，氨基C1-6烷基，C1-6烷基氨基C1-6烷基，二(C1-6烷基)氨基C1-6烷基，羟基C1-6烷基氨基C1-6烷基、C6-14芳基、5-14元杂芳基；
Rs选自卤素、C1-6烷基或C3-10环烷基；
n为0-4的整数；
m为0-5的整数；
q为0-3的整数。
根据本发明，优选地R1和R2分别独立地选自H、卤素、C1-6烷基，C1-6烷氧基，C1-6卤代烷基。
根据本发明，优选地R3选自环丙烷基。
根据本发明，优选地R4选自H、C1-6烷基，羟基C1-6烷基，C3-8环烷基，羟基，巯基，C1-6烷氧基，羟基C1-6烷氧基，C1-6烷氧基C1-6烷氧基，C1-6烷硫基，氨基，C1-6烷基氨基，二(C1-6烷基)氨基，C3-8环烷基氨基，羟基C1-6烷基氨基，C1-6烷氧基C1-6烷基，羟基C1-6烷氧基C1-6烷基，巯基C1-6烷基，C1-6烷硫基C1-6烷基，氨基C1-6烷基，C1-6烷基氨基C1-6烷基，二(C1-6烷基)氨基C1-6烷基，羟基C1-6烷基氨基C1-6烷基，以及未取代或被卤素、C1-6烷基，取代的C3-8杂环基、C6-14芳基、C6-14杂芳基；
其中C3-8杂环基更优选为吗啉基、哌啶基、哌嗪基、吡咯烷基、氮杂环丁烷基；C6-14杂芳基更优选为吡啶基、吡嗪基、嘧啶基、哒嗪基、吡咯基、噻吩基、呋喃基、噻唑基、咪唑基、恶唑基、苯并噻唑基、苯并咪唑基、苯并恶唑基、吲哚基、喹啉基、异喹啉基、苯并吡嗪基、苯并嘧啶基、苯并二氧六环基、1,3-苯并间二氧杂环戊烯基以及
Figure GDA0003596153930000031
根据本发明，优选地n为0，1或2；更优选n为1。
根据本发明，优选地m为1，2或3；更优选m为2。
根据本发明，优选地q为0，1或2；更优选q为1。
根据本发明的优选技术方案，所述舍曲林类似物选自如下化合物：
Figure GDA0003596153930000041
Figure GDA0003596153930000051
Figure GDA0003596153930000061
Figure GDA0003596153930000071
Figure GDA0003596153930000081
Figure GDA0003596153930000091
Figure GDA0003596153930000101
Figure GDA0003596153930000111
Figure GDA0003596153930000121
本发明的化合物的药学上可接受的盐包括常规无机酸、羧酸和磺酸的酸加成盐，例如盐酸、氢溴酸、硫酸、磷酸、甲烷磺酸、乙烷磺酸、苯磺酸、甲苯磺酸、萘二磺酸、乙酸、三氟乙酸、丙酸、乳酸、酒石酸、苹果酸、柠檬酸、富马酸、马来酸和苯甲酸的盐。
本发明的化合物的药学上可接受的盐的也包括常规的碱的盐，例如和优选，碱金属盐(例如钠和钾盐)，碱土金属盐(例如钙和镁盐)和衍生自氨或具有1-16个碳原子的有机胺，例如和优选乙胺、二乙胺、三乙胺、N,N-二异丙基乙胺、一乙醇胺、二乙醇胺、三乙醇胺、二甲氨基乙醇、二乙氨基乙醇、普鲁卡因、二环己胺、二苄胺、N-甲基哌啶、N-甲基吗啉、精氨酸、赖氨酸和1,2-乙二胺的铵盐。
根据本发明的化合物取决于它们的结构可以以不同的立体异构的形式，即以构型异构体的形式，或任选地作为构象异构体(对映异构体和/或非对映异构体，包括在阻转同分异构体情况下的那些非对映异构体)存在。本发明因此包括对映异构体和非对映异构体和它们各自的混合物。立体异构一致的组分可以由这种对映异构体和/或非对映异构体的混合物以已知的方式分离；对于这优选使用层析法，特别是在非手性或手性相上的HPLC层析。
如果根据本发明的化合物可以以互变异构形式存在，本发明包括所有的互变异构形式。
在本发明的上下文中，除非另外具体说明，所述取代基如下定义：
根据本发明，“烷基”(其本身或作为化学基团的一部分)是直链烃或支链烃，优选具有1至6个碳原子，例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、戊基、1-甲基丁基、2-甲基丁基、3-甲基丁基、1，2-二甲基丙基、1，1-二甲基丙基、2，2-二甲基丙基、1-乙基丙基、己基、1-甲基戊基、2-甲基戊基、3-甲基戊基、4-甲基戊基、1，2-二甲基丙基、1，3-二甲基丁基、1，4-二甲基丁基、2，3-二甲基丁基、1，1-二甲基丁基、2，2-二甲基丁基、3，3-二甲基丁基、1，1，2-三甲基丙基、1，2，2-三甲基丙基、1-乙基丁基和2-乙基丁基。还优选具有1至4个碳原子的烷基，例如尤其是甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基。
根据本发明，“环烷基”(其本身或作为化学基团的一部分)是单环的烃，优选具有3至8个碳原子，例如环丙基、环丁基、环戊基、环己基、环庚基、环辛基。还优选具有3、4、5、6或7个碳原子的环烷基，例如尤其是环丙基或环丁基。
根据本发明，“卤素”为氟、氯、溴或碘，特别是氟、氯或溴。
根据本发明，“卤代烷基”为卤素取代的烷基，其优选具有1至9个相同或不同的卤素原子。卤代烷基的实例为三氯甲基、氯代二氟甲基、二氯氟甲基、氯甲基、溴甲基、1-氟乙基、2-氟乙基、2，2-二氟乙基、2，2，2-三氟乙基、2，2，2-三氯乙基、2-氯-2，2-二氟乙基、五氟乙基和五氟-叔丁基。优选具有1至4个碳原子以及1至9个、优选1至5个相同或不同的选自氟、氯或溴的卤素原子的卤代烷基。特别优选具有1或2个碳原子且具有1至5个相同或不同的选自氟或氯的卤素原子的卤代烷基，例如尤其是二氟甲基、三氟甲基或2，2-二氟乙基。
根据本发明，“烷氧基”为直链或支链的O-烷基，优选具有1至6个碳原子，例如甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基和叔丁氧基。还优选具有1至4个碳原子的烷氧基。
根据本发明，“烷硫基”为直链或支链的S-烷基，优选具有1至6个碳原子，例如甲硫基、乙硫基、正丙硫基、异丙硫基、正丁硫基、异丁硫基、仲丁硫基和叔丁硫基。还优选具有1至4个碳原子的烷硫基。
根据本发明，“烷基氨基”是指氨基中的一个氢原子被烷基取代，为NH-烷基。其中的烷基优选具有1至6个碳原子，例如甲氨基、乙氨基、正丙氨基、异丙氨基、正丁氨基、异丁氨基、仲丁氨基和叔丁氨基。还优选具有1至4个碳原子的烷氨基。
根据本发明，“二烷基氨基”是指氨基中的两个氢原子都被烷基取代，为N-(烷基)2。其中的烷基优选具有1至6个碳原子，例如二甲氨基、二乙氨基、甲基乙基氨基、二正丙氨基等。还优选具有1至4个碳原子的二烷基氨基。
根据本发明，“烷基亚磺酰基”为直链或支链的烷基亚磺酰基，优选具有1至6个碳原子，例如甲基亚磺酰基、乙基亚磺酰基、正丙基亚磺酰基、异丙基亚磺酰基、正丁基亚磺酰基、异丁基亚磺酰基、仲丁基亚磺酰基和叔丁基亚磺酰基。还优选具有1至4个碳原子的烷基亚磺酰基。根据本发明的烷基亚磺酰基可以被一个或更多个相同或不同的基团取代。
根据本发明，“烷基磺酰基”为直链或支链的烷基磺酰基，优选具有1至6个碳原子，例如甲基磺酰基、乙基磺酰基、正丙基磺酰基、异丙基磺酰基、正丁基磺酰基、异丁基磺酰基、仲丁基磺酰基和叔丁基磺酰基。还优选具有1至4个碳原子的烷基磺酰基。根据本发明的烷基磺酰基可以被一个或更多个相同或不同的基团取代。
根据本发明，“烷基羰基”为直链或支链的烷基-C(＝O)，优选具有2至7个碳原子，例如甲基羰基、乙基羰基、正丙基羰基、异丙基羰基、仲丁基羰基和叔丁基羰基。还优选具有1至4个碳原子的烷基羰基。根据本发明的烷基羰基可以被一个或更多个相同或不同的基团取代。
根据本发明，“环烷基羰基”为直链或支链的环烷基羰基，优选在环烷基部分具有3至8个碳原子，例如环丙基羰基、环丁基羰基、环戊基羰基、环己基羰基、环庚基-羰基、环辛基羰基。还优选在环烷基部分具有3、5或7个碳原子的环烷基羰基。
根据本发明，“烷氧羰基”(其本身或作为化学基团的一部分)是直链或支链的烷氧羰基，优选在烷氧基部分具有1至6个碳原子或具有1至4个碳原子，例如甲氧基羰基、乙氧基羰基、正丙氧基羰基、异丙氧基羰基、仲丁氧基羰基和叔丁氧基羰基。
根据本发明，“烷氧羰基”为直链或支链的烷氧羰基，优选在烷基部分具有1至6个碳原子或具有1至4个碳原子，例如甲氧基羰基、乙氧基羰基、正丙氧基羰基、异丙氧基羰基、仲丁氧基羰基和叔丁氧基羰基。
根据本发明，“烷基氨基羰基”为直链或支链的烷基氨基羰基，优选在烷基部分具有1至6个碳原子或具有1至4个碳原子，例如甲基氨基羰基、乙基氨基羰基、正丙基氨基羰基、异丙基氨基羰基、仲丁基氨基羰基和叔丁基氨基羰基。
根据本发明，“芳基”为优选具有6至14个、特别是6至10个环碳原子的单环、双环或多环芳族体系，例如苯基、萘基、蒽基、菲基，优选苯基。芳基也是多环体系，例如四氢萘基、茚基、茚满基、芴基、联苯基，其中键接侧在芳族体系上。
根据本发明，“杂环基”为具有至少一个环的碳环基团，其中至少一个碳原子被杂原子、优选被选自N、O、S、P、B、Si、Se的杂原子所代替并且其为饱和的或部分不饱和。所述杂环基优选含有3至8个环原子、特别是3至6个环原子，并且杂环中一个或更多个、优选1至4个、特别是1、2或3个杂原子优选选自N、O和S，但是其中两个氧原子不应当直接相邻。杂环通常含有至多4个氮原子，和/或至多2个氧原子和/或至多2个硫原子。
杂环基的实例为哌啶基、哌嗪基、吗啉基、硫代吗啉基、二氢吡喃基、四氢吡喃基、二噁烷基、吡咯啉基、吡咯烷基、咪唑啉基、咪唑烷基、噻唑烷基、噁唑烷基、二氧戊环基、间二氧杂环戊烯基、吡唑烷基、四氢呋喃基、二氢呋喃基、氧杂环丁烷基、环氧乙烷基、氮杂环丁烷基、氮杂环丙烷基、氧氮杂环丁烷基、氧氮杂环丙烷基、氧氮杂环庚烷基、氧氮杂环己烷基、氮杂环庚烷基、氧代吡咯烷基、二氧代吡咯烷基、氧代吗啉基、氧代哌嗪基和氧杂环庚烷基。如果杂环基或杂环任选地被取代，则其可以与其他碳环或杂环稠合。在任选取代的杂环的情况下，本发明还包括多环体系，例如8-氮杂双环[3.2.1]辛基或1-氮杂双环[2.2.1]庚基。
根据本发明，“杂芳基”代表杂芳族化合物，即落在杂环的以上定义内的完全未饱和的芳族杂环化合物。优选地对于5-元到7-元环而言，具有1至3个、优选1或2个相同或不同的来自上述组的杂原子。根据本发明的杂芳基为，例如吡咯基，呋喃基，噻吩基，噻唑基，吡唑基，咪唑基，恶唑基，噻唑基，异噻唑基，吡啶基，哒嗪基，嘧啶基，吡嗪基，苯并咪唑基，苯并恶唑基，吲哚基，喹啉基，异喹啉基，苯并吡嗪基，苯并嘧啶基，苯并二氧六环基，1,3-苯并间二氧杂环戊烯基，
Figure GDA0003596153930000161
等。
本发明还涉及包含本发明化合物和药学上可接受的赋形剂的药物组合物。
适宜的赋形剂一般包括粘合剂、抗粘剂、崩解剂、填充剂、稀释剂、矫味剂、着色剂、助流剂、润滑剂、防腐剂、吸附剂和甜味剂或其组合。
典型的制剂是通过本发明的化合物与载体、稀释剂或赋形剂混合制备的。适宜的载体、稀释剂和赋形剂是本领域技术人员公知的，并且包括例如碳水化合物、蜡类、水溶性和/可溶胀聚合物、亲水性或疏水性材料、明胶、油类、溶剂、水等材料。使用的具体载体、稀释剂或赋形剂将取决于本发明化合物被应用的手段和目的。溶剂一般基于本领域技术人员认为给哺乳动物施用安全(GRAS)的溶剂进行选择。一般，安全的溶剂是非毒性水性溶剂例如水和在水中溶解或混溶的其他非毒性溶剂。适宜的水性溶剂包括水、乙醇、丙二醇、聚乙二醇(例如，PEG400、PEG300)等及其混合物。所述制剂还可包括一种或多种缓冲剂、稳定剂、表面活性剂、润湿剂、润滑剂、乳化剂、助悬剂、防腐剂、抗氧剂、遮光剂、助流剂、加工助剂、着色剂、甜味剂、芳香剂、矫味剂和其他已知添加剂，以提供药物的优美外观(即，本发明的化合物或其药物组合物)或在药物产品(药品)生产中的帮助。
制剂可使用传统溶解和混合的方法进行制备。例如，散装原料药(即，本发明的化合物或化合物的稳定形式(例如，与环糊精衍生物或其他复合剂)的稳定形式)在一种或多种赋形剂存在下被溶解在适宜的溶剂中。本发明的化合物一般被配制成药物剂型以提供易于控制剂量的药物，并给患者一种优美和容易处理的产品。
组合物通常被配制成选自以下的剂型：片剂、水性或油性混悬剂、软膏剂、贴剂、凝胶剂、洗剂、胶囊剂、乳剂、乳膏剂、喷雾剂、滴剂、可分散的粉末或颗粒、位于硬或软明胶胶囊中的乳剂、糖浆剂和酏剂。
用于应用的药物组合物(或制剂)可被包装成各种形式，取决于药物施用所使用的方法。一般地，用于分发的物品包括存有适当形式药物制剂的容器。适宜的容器是本领域技术人员公知的，并且包括例如瓶子(塑料和玻璃)、药袋、安瓿、塑料袋、金属圆桶等。容器还可包括防撬装置，以防不慎重地获取包装的内容物。此外，容器之上有描述容器内容物的标签。标签还可包括适当的警告。
本发明提供的新型舍曲林类似物能够治疗抑郁、焦虑、压力诱发的失禁、中枢性疼痛。
本发明还提供上述化合物的制备方法，其特征在于，所述方法包括如下步骤：
Figure GDA0003596153930000181
式(II)所示的化合物和R3-L反应得到式(I)所示化合物；
R1、R2、R3、R4、m、n、q具有上述定义，L为离去基团。
根据本发明，L为离去基团，优选为1-乙氧基-1-三甲硅氧基。
上述方法中，式(II)所示的化合物是由式(II)所示的化合物盐酸盐制得的：
Figure GDA0003596153930000182
上述步骤中，式(II)化合的盐酸盐在水做溶剂的情况下通过加入碳酸钾反应制得式(II)化合物。优选的，反应是常温下搅拌1-2h。更优选的，反应产物用EA萃取，无水硫酸镁干燥，抽滤浓缩后得纯品。
优选地，式(II)化合物通过如下方法制备：
Figure GDA0003596153930000191
式(III)所示的化合物与式(IV)所示的化合物在碱的存在下反应得到式(II)所示化合物；
其中，R1、R2、R4、m、n、q具有上述定义，L2为离去基团。
上述方法中，式(II)化合物与1-乙氧基-1-三甲硅氧基环丙烷的摩尔比为1:1～1:2，优选1:1.1～2，更优选1:1.2。
上述方法中，反应在溶剂中进行。所述溶剂优选为醇类溶剂，如甲醇、四氢呋喃等或其混合物。优选地，所述溶剂使用前进行无水处理。
上述方法中，反应的催化剂为硼氢化钠或氰基硼氢化钠。所述催化剂与式(II)化合物的摩尔比为1:1～3:2，优选2:1。
优选地，所述催化剂分批少量加入。优选地，采用滴加方式加入。
上述方法中，反应体系中还加入醋酸。优选地，所述醋酸与式(II)化合物的摩尔比为1:1～2:1，优选2:1。
上述反应中，加入所有原料后升温至50-80℃回流反应。优选地，升温至60-70℃。
上述方法还包括下述的后处理步骤：将反应液萃取，干燥，减压蒸馏得到粗品。
所述粗品再经过柱层析纯化得到最终的产品。
上述萃取采用DCM进行萃取。
上述干燥是用干燥剂进行干燥。优选地，干燥剂为无水硫酸镁。干燥时间为0.5-2h，优选1h。
上述柱层析是用硅胶柱层析。
本发明还提供上述新型的舍曲林类似物在制备治疗抑郁、强迫症的药物中的应用。
有益效果
本发明提供了一种新型的舍曲林类似物及其制备方法。所述类似物具有优于舍曲林的药物活性。此外，所述化合物的制备方法的操作简便，可分别以较高的产率和/或纯度，例如产率达到80％，甚至90％以上，总的产率达50％以上，制备得到所述化合物，满足药物生产的需要。
附图说明
图1是本发明实施例1制备的化合物的1H NMR(DMSO)图；
具体实施方式
下面结合附图和具体实施例对本发明作进一步描述。但是，本领域技术人员了解，下列实施例仅仅是为了示例性地描述本发明的技术方案，并不旨在对本发明的保护范围进行任何限制。
实施例1：制备化合物1
Figure GDA0003596153930000211
在250ml单口烧瓶中加入式1-S化合物(12g，0.035mol，1eq)，150ml水作溶剂，搅拌下，向其中加入过量碳酸钾，常温搅拌1-2h。
后处理：200ml*2EA萃取，无水硫酸镁干燥，抽滤浓缩，得纯品10.9g，不做后处理，直接投下一步。
Figure GDA0003596153930000212
在250ml两口烧瓶中加入上述的纯品(10.9g，0.0356mol，1eq)，甲醇和四氢呋喃混合溶剂(体积比1:1)100ml作溶剂，搅拌下，依次向其中加入1-乙氧基-1三甲硅基环丙烷(7.5g，0.0427mol，1.2eq)和乙酸(4.3g，00712mol，2eq)，最后，向其中分批加入氰基硼氢化钠(4.5g，0.0712mol，2eq)，加入完毕后，加热回流过夜。
冷却至室温，加水停止反应。200ml*2DCM萃取，饱和食盐水洗有机相两遍，无水硫酸镁干燥，抽滤，浓缩，120g硅胶装柱，湿法上样，过柱得纯品白色固体7.9g，产率：65.3％。核磁表征数据如图1所示。MS(m/z)：346.3(M+H)。
参考实施例1相同的方法制备了化合物2至103，化合物1至103的产率和表征数据如下表1所示：
表1
Figure GDA0003596153930000221
Figure GDA0003596153930000231
Figure GDA0003596153930000241
实施例2：药物活性试验
2.1小鼠悬尾实验法测定抗抑郁活性
雄性ICR小鼠(SPF级)，体重18-22g，在25×25×25cm悬尾箱顶板中心绳上连一夹子，夹小鼠尾尖1cm处使之倒悬，头部离箱底面4-5cm。将一定剂量(24mg/kg)的本发明示例性的实施例化合物、舍曲林、0.5％羧甲基纤维素钠溶液研磨，制备成混悬液备用。实验前60min口服给予不同剂量的待测样品，给药后悬尾6分钟，累计后4分钟小鼠不动时间。结果见表2。
2.2小鼠强迫游泳实验法测定抗抑郁活性
雄性ICR小鼠(SPF级)，体重18-22g，置于水温25℃、水深为10cm的玻璃缸(直径10cm，高20cm)内。将一定剂量(24mg/kg)的本发明示例性的实施例化合物、舍曲林与0.5％羧甲基纤维素钠溶液研磨，制备成混悬液备用。实验前60min口服给予不同剂量的待测样品，给药后观察6分钟，记录后4分钟内动物的累计不动时间(即动物后肢无动作或后肢微动却保持身体漂浮不动的的时间)，结果见表2。
表2
Figure GDA0003596153930000251
Figure GDA0003596153930000261
*：与溶剂对照组相比，p＜0.05。
实施例3示例性的实施例化合物的急性毒性研究
实验材料：
ICR小鼠，雌雄各半，体重18～22g，动物以颗粒饲料喂养，自由摄食和饮水。
表2中测试的化合物分别用0.5％CMC-Na分别配制成浓度为500mg/mL的混悬液。
实验方法
ICR小鼠按体重单次灌胃10ml/kg的表2中测试的化合物，观察给药后动物14天内的毒性反应及死亡情况。结果发现，小鼠单次灌胃给药后，小鼠活动滞缓，静卧少动，40-60分钟后即恢复正常。给药后14天内，小鼠未出现死亡，第15天，全部小鼠处死，解剖，肉眼检查各脏器，均未见明显病变。
上述急性毒性实验结果表明，灌胃给药最大耐受量MTD不低于7g/kg，说明本发明实施例化合物的急性毒性较低。

Claims (8)

1.一种舍曲林类似物或其药学上可接受的盐，其特征在于，具有下述式(I)所示的结构：
Figure FDA0003614290940000011
其中：
R1选自3位和4位氯取代基；
R2选自H；
R3选自环丙烷基；
R4选自C1-6烷基，羟基C1-6烷基，C3-8环烷基，羟基，巯基，C1-6烷氧基，羟基C1-6烷氧基，C1-6烷硫基，氨基，C1-6烷基氨基，二(C1-6烷基)氨基，C3-8环烷基氨基，羟基C1-6烷基氨基，C1-6烷氧基C1-6烷基，羟基C1-6烷氧基C1-6烷基，巯基C1-6烷基，C1-6烷硫基C1-6烷基，氨基C1-6烷基，C1-6烷基氨基C1-6烷基，二(C1-6烷基)氨基C1-6烷基，羟基C1-6烷基氨基C1-6烷基，以及未取代或被C1-6烷基取代的如下基团：C3-8杂环基、C6-14芳基、C6-14杂芳基；
n为4；
m为2；
q为1或2。
2.根据权利要求1所述的类似物，其特征在于，所述舍曲林类似物选自如下化合物：
Figure FDA0003614290940000021
Figure FDA0003614290940000031
Figure FDA0003614290940000041
Figure FDA0003614290940000051
Figure FDA0003614290940000061
Figure FDA0003614290940000071
Figure FDA0003614290940000081
Figure FDA0003614290940000091
Figure FDA0003614290940000101
3.权利要求1或2所述类似物的制备方法，其特征在于，包括如下步骤：
Figure FDA0003614290940000102
式(II)所示的化合物和R3-L反应得到式(I)所示化合物；
R1、R2、R3、R4、m、n、q具有权利要求1或2所述定义，L为离去基团。
4.根据权利要求3所述的制备方法，其特征在于，L为1-乙氧基-1-三甲硅氧基。
5.根据权利要求3或4所述的制备方法，其特征在于，式(II)化合物通过如下方法制备：
Figure FDA0003614290940000111
式(III)所示的化合物与式(IV)所示的化合物在碱的存在下反应得到式(II)所示化合物；
其中，R1、R2、R4、m、n、q具有权利要求1或2所述定义，L2为离去基团。
6.权利要求1或2所述的类似物或其药学上可接受的盐在制备治疗抑郁、焦虑、压力诱发的失禁、中枢性疼痛的药物中的应用。
7.一种药物组合物，包含权利要求1或2所述的式(I)所示的类似物或其药学上可接受的盐。
8.根据权利要求7所述的药物组合物，其特征在于，还包含治疗有效量的药学上可接受的载体。
CN201810661677.8A 2018-06-25 2018-06-25 一种新的舍曲林类似物及其制备方法和应用 Active CN110627657B (zh)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201810661677.8A CN110627657B (zh) 2018-06-25 2018-06-25 一种新的舍曲林类似物及其制备方法和应用

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201810661677.8A CN110627657B (zh) 2018-06-25 2018-06-25 一种新的舍曲林类似物及其制备方法和应用

Publications (2)

Publication Number Publication Date
CN110627657A CN110627657A (zh) 2019-12-31
CN110627657B true CN110627657B (zh) 2022-07-29

Family

ID=68967393

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201810661677.8A Active CN110627657B (zh) 2018-06-25 2018-06-25 一种新的舍曲林类似物及其制备方法和应用

Country Status (1)

Country Link
CN (1) CN110627657B (zh)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4045488A (en) * 1974-11-06 1977-08-30 Pfizer Inc. Aminophenyltetralin compounds

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010021681A2 (en) * 2008-08-18 2010-02-25 Combinatorx (Singapore) Pte. Ltd. Compositions and methods for treatment of viral diseases

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4045488A (en) * 1974-11-06 1977-08-30 Pfizer Inc. Aminophenyltetralin compounds

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
Justin M. Lopchuk等.Strain-Release Heteroatom Functionalization: Development, Scope, and Stereospecificity.《J.Am.Chem.Soc.》.2017,第139卷第3216页Figure 8，附加信息S106. *
Strain-Release Heteroatom Functionalization: Development, Scope, and Stereospecificity;Justin M. Lopchuk等;《J.Am.Chem.Soc.》;20170131;第139卷;第3216页Figure 8，附加信息S106 *

Also Published As

Publication number Publication date
CN110627657A (zh) 2019-12-31

Similar Documents

Publication Publication Date Title
TWI791511B (zh) 細胞凋亡誘導劑
AU2004213616B2 (en) A process of preparing imatinib
RU2727772C1 (ru) Производные пиримидина против вируса гриппа
TWI545124B (zh) ６，７－不飽合－７－胺甲醯基嗎啡喃衍生物之結晶及其製造方法
AU2020280699B2 (en) Compound used as RET kinase inhibitor and application thereof
WO2012149567A1 (en) Kinase inhibitors
JP6755922B2 (ja) 新規な化合物、それらの調製及びそれらの使用
CN110092787A (zh) 一种化合物或其药用盐或组合物的制备及应用
MXPA06014797A (es) Procesos para preparacion de antagonistas de receptor de hormona que libera gonadotropina.
AU2003224779A1 (en) Lansoprazole polymorphs and processes for preparation thereof
JP2022549030A (ja) 複素環アミド化合物、その薬学的に許容される塩およびその調製方法と使用
KR101827444B1 (ko) 트리사이클로 유도체 화합물의 신규한 결정형 산부가염 또는 이의 수화물 및 이의 제조방법
CN110627657B (zh) 一种新的舍曲林类似物及其制备方法和应用
DE60204582T2 (de) Neue heteroaromatische amidderivate von 3beta aminoazabicyclooctanen, verfahren zu ihrer herstellung und ihre therapeutische verwendung
AU2007259116A1 (en) Dual molecules containing a peroxide derivative, their synthesis and therapeutic uses
CA2518999A1 (en) Crystalline and amorphous solids of pantoprazole and processes for their preparation
JP2022519474A (ja) イミダゾキノリンアミン誘導体、医薬組成物、その使用
CN110627664B (zh) 一种新的氟西汀类似物及其制备方法和应用
WO2019029554A1 (zh) 磺酰胺类衍生物、其制备方法及其在医药上的用途
CN114616234A (zh) 磷咪唑并喹啉胺衍生物、及其药物组合物和应用
US20180104220A1 (en) Imidazole compound
KR102484846B1 (ko) 벤조피란 유도체의 정제방법, 이의 결정형 및 상기 결정형의 제조방법
TW483890B (en) A process for preparing naphthyridones and intermediates
CN114539283A (zh) Usp7抑制剂
TW201329033A (zh) ３－烴基－３－甲基丁酸或其鈣鹽之製備方法

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
CB02 Change of applicant information
CB02 Change of applicant information

Address after: No. 2115, floor 2, building D, building 33, No. 99, Kechuang 14th Street, Daxing District, Beijing 102600 (centralized office area) (Yizhuang group, high-end industrial area, Beijing Pilot Free Trade Zone)

Applicant after: Beijing Anbo Ruida Pharmaceutical Technology Co.,Ltd.

Address before: A4-3, 2 Dongsheng West Road, Chengdong street, Jiangyin City, Wuxi City, Jiangsu Province, 214437

Applicant before: Jiangyin Amber Biopharmaceutical Co.,Ltd.

CB03 Change of inventor or designer information
CB03 Change of inventor or designer information

Inventor after: Yan Jingbo

Inventor after: Wang Gang

Inventor before: Yan Jingbo

Inventor before: Li Song

Inventor before: Zhong Wu

Inventor before: Xiao Junhai

Inventor before: Wang Gang

GR01 Patent grant
GR01 Patent grant