Classifications

• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

• R ⁇ _ a and R ⁇ b are independently -H or C ⁇ -C 6 alkyl;
• R 30 is selected from the group consisting of H; C ⁇ -C 6 alkyl, optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of C x -C 3 alkyl, halogen, -OH, -SH, -C ⁇ N, -CF 3 , C x -C 3 alkoxy, and -NR ⁇ _ aRi-b; - (CH 2 ) o- 4 -aryl; - (CH 2 ) 0 -4-heteroaryl ; C 2 -C 6 alkenyl; C 2 - C 6 alkynyl; -CO-NR N - 2 R N - 3 ; -S0 2 -NR N _ 2 R N _ 3 ; -C0 2 H; and - CO-O- (C ⁇ -C 4 alkyl) ; or R 20 , R 30 and
• R 2 and R 3 are independently H , phenyl , or C 1 -C 4 alkyl ; or R2 5 and R 3 and the carbons to which they are attached form a benzo ring which is optionally substituted with C ⁇ -C 4 alkyl , C 1 -C 4 alkoxy, or dialkylamino ; and s is Ci-Cg alkoxy or NR 4 R 5 ; wherein
• R x is OH , imidazolyl , halogen, -OC (0) CH 3 , -OC (0) CF 3 , or
• the invention provides methods of preparing compounds of formula III using compounds of formula II.
• the compound of formula II is prepared using solid ZnCl 2 .
• 1.1 to about 10 equivalents of ZnCl 2 based on the amount of the particular oxazole used is used to prepare the compound of formula II. More preferably, 1.1 to about 5 equivalents of ZnCl 2 is used. Even more preferably, about 2.5 to about 3.5 equivalents of ZnCl 2 is used.
• alkoxy and C ⁇ -C 6 alkoxy in the present invention is meant straight or branched chain alkyl groups having 1-6 carbon atoms , attached through at least one divalent oxygen atom, such as, for example, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentoxy, isopentoxy, neopentoxy, hexoxy, and 3-methylpentoxy.
• Alkenyl and "C 2 -C 6 alkenyl” means straight and branched hydrocarbon radicals having from 2 to 6 carbon atoms and from one to three double bonds and includes, for example, ethenyl, propenyl, l-but-3-enyl , l-pent-3-enyl , l-hex-5-enyl and the like .
• heterocycle By “heterocycle” , “heterocycloalkyl” or “heterocyclyl” is meant one or more carbocyclic ring systems of 4-, 5-, 6-, or 7- membered rings which includes fused ring systems of 9-11 atoms containing at least one and up to four heteroatoms selected from nitrogen, oxygen, or sulfur.
• Scheme A illustrates the preparation of the ZnCl 2 /oxazole adduct.
• the scheme discloses the use of solid ZnCl 2 . Solutions of ZnCl 2 can be used, but solid ZnCl 2 is preferred.
• the alkyllithium base used can be n-butyllithium t-butyllithium, sec-butyllithium, or methyllithium. N-butyl lithium is preferred.
• the lithiation of oxazoles has been described in Hodges, et al . , J “ . Org. Chem. 1991, 56, 449; and Whitney, S. E., et al . , J " . Org. Chem.
• Scheme B illustrates a reaction between a compound of formula I (wherein R 6 is di-n-propylamine, X is Br, and Rx is alkoxy) and a zinc chloride/oxazole adduct of formula II to form a coupled product of formula III.
• the ester is then hydrolyzed or otherwise cleaved to form the carboxylic acid.
• Scheme C illustrates the conversion of a carboxylic acid of formula IV into an acid halide or an imidazolide (compound of formula V wherein X x is Cl or imidazolyl, respectively) , or an acid anhydride (compound of formula VI) .
• Scheme C further illustrates the coupling of the acid (IV) , acid chloride (or bromide) (V), acid anhydride (VI) or imidazolide (V) with the amine of formula VIII to generate a compound of formula X.
• the amine and/or alcohol in compounds of formula VIII may be protected before the coupling reaction is performed.
• One of skill in the art can determine the need for the use of protecting groups.

Landscapes

• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Health & Medical Sciences (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Biomedical Technology (AREA)
• Neurology (AREA)
• Neurosurgery (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• General Health & Medical Sciences (AREA)
• General Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Psychiatry (AREA)
• Hospice & Palliative Care (AREA)
• Pharmacology & Pharmacy (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Plural Heterocyclic Compounds (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Catalysts (AREA)

Priority Applications (12)

Applications Claiming Priority (4)

Publications (1)

Family

ID=30003150

Family Applications (1)

Country Status (17)

Cited By (15)

Families Citing this family (6)

Citations (3)

Family Cites Families (1)

• 2003
  • 2003-06-20 EA EA200401510A patent/EA008389B1/ru unknown
  • 2003-06-20 MX MXPA04012630A patent/MXPA04012630A/es active IP Right Grant
  • 2003-06-20 BR BR0312439-8A patent/BR0312439A/pt not_active IP Right Cessation
  • 2003-06-20 PL PL03374999A patent/PL374999A1/xx unknown
  • 2003-06-20 WO PCT/US2003/019585 patent/WO2004000821A1/en not_active Ceased
  • 2003-06-20 NZ NZ537390A patent/NZ537390A/en unknown
  • 2003-06-20 AU AU2003249344A patent/AU2003249344A1/en not_active Abandoned
  • 2003-06-20 CN CNB038144476A patent/CN1324017C/zh not_active Expired - Fee Related
  • 2003-06-20 JP JP2004516055A patent/JP2005533811A/ja active Pending
  • 2003-06-20 EP EP03761206A patent/EP1532123B1/en not_active Expired - Lifetime
  • 2003-06-20 CA CA002489988A patent/CA2489988A1/en not_active Abandoned
  • 2003-06-20 AT AT03761206T patent/ATE370131T1/de not_active IP Right Cessation
  • 2003-06-20 US US10/600,100 patent/US7115747B2/en not_active Expired - Fee Related
  • 2003-06-20 DE DE60315664T patent/DE60315664D1/de not_active Expired - Lifetime
• 2004
  • 2004-12-14 IL IL16576304A patent/IL165763A0/xx unknown
  • 2004-12-16 NO NO20045497A patent/NO20045497L/no not_active Application Discontinuation
• 2005
  • 2005-01-20 CO CO05004558A patent/CO5670350A2/es not_active Application Discontinuation
• 2006
  • 2006-10-03 US US11/538,155 patent/US20070105921A1/en not_active Abandoned

Patent Citations (3)

Non-Patent Citations (1)

Also Published As

Similar Documents

Legal Events