Aromatic acetylcholinesterase inhibitors

Details Aromatic acetylcholinesterase inhibitors Aromatic acetylcholinesterase inhibitors

1995-11-21

1997-09-02

Ivy, C. Warren

Organic compounds -- part of the class 532-570 series

Organic compounds

Oxygen containing

560103, 564442, 568812, C07C 49283, C07C 49213, A61K 3110

Patent

active

056634480

DESCRIPTION:

BRIEF SUMMARY
This invention relates to the use of fluorinated aromatic compounds in treating diseases associated with deficiencies of cholinergic transmission in the central nervous system and methods for their preparation.
Compounds of the present invention have the following ##STR2## stereoisomers and pharmaceutically acceptable salts thereof, wherein each of Z and Z' are independently H or F; ##STR3## CH(OH), ##STR4## X is H, Br, Cl, F or CF.sub.3 ; Y is H, Br, Cl, F, OH, OR.sub.5, OC(O)R.sub.4, N.sub.3, CN, NO.sub.2, SO.sub.3 H, CO.sub.2 R.sub.4, NH.sub.2, NHR.sub.9, NR.sub.9 R'.sub.9, C(R.sub.6)(R.sub.7)(V'R.sub.8) or C(O)R.sub.7, provided that when both Z and Z' are F, then Y is H or F; R.sub.2 and V--R.sub.3 taken together with the carbon atom to which they are attached form a 3-6 membered ring; (C.sub.1-6)alkyl, or (C.sub.3-6)cycloalkyl; (C.sub.3-8)cycloalkyl; and
The present invention uses compounds of Formula I to treat patients having conditions responsive to the acetylcholinesterase-inhibiting properties of the present compounds such as in the treatment of Degenerative Dementias.
The terms "(C.sub.1-6)alkyl" and "(C.sub.1-10)alkyl" mean straight or branched chain alkyl radicals containing respectively from 1 to 6 carbon atoms and from 1 to 10 carbon atoms, including, but not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl,t-butyl, n-pentyl, 1-methylbutyl, 2,2-dimethylbutyl, 2-methylpentyl, 2,2-dimethylpropyl, n-hexyl and so on. Likewise, the term "(C.sub.0-4)alkylene aryl" can mean straight or branched chain alkylene groups up to 4 carbon atoms such as ethylethylene, 2-methyltrimethylene, and so on. C.sub.0 of course means no alkylene moiety attached to the aryl.
"Hydroxy(C.sub.1-6)alkyl" means a (C.sub.1-6)alkyl group having from 1 to 3 hydroxy substituents thereon. Preferably, there is only one hydroxy substituent at the alpha position (attached to the carbon atom which is directly attached to the phenyl).
"Ts" or "tosyl" means ##STR5## Tosyl derivatives mean ##STR6## wherein R is C.sub.1-6 alkyl.
"Aryl" includes both carbocyclic and heterocyclic moieties of which phenyl, pyridyl, indolyl, indazolyl, furyl and thienyl are of primary interest; these moieties being inclusive of their position isomers such as, for example, 2-, 3-, or 4-pyridyl, 2- or 3-furyl and thienyl, 1-, 2-, or 3-indolyl or the 1- and 3-indazolyl, as well as the dihydro and tetrahydro analogs of the furyl and thienyl moieties. Also included within the term "aryl" are such fused carbocyclic moieties as pentalenyl, indenyl, naphthalenyl, azulenyl, heptalenyl, acenaphthylenyl, fluorenyl, phenalenyl, phenanthrenyl, anthracenyl, acephenanthrylenyl, aceanthrylenyl, triphenylenyl, pyrenyl, chrysenyl and naphthacenyl. Also included within the term "aryl" are such other heterocyclic radicals as 2- or 3-benzo[b]thienyl, 2- or 3-naphtho[2,3-b]thienyl, 2- or 3-thianthrenyl, 2H-pyran-3-(or 4- or 5-)yl, 1-isobenzofuranyl, 2H-chromenyl-3-yl, 2- or 3-phenoxathiinyl, 2- or 3-pyrrolyl, 4- or 3-pyrazolyl, 2-pyrazinyl, 2-pyrimidinyl, 3-pyridazinyl, 2-indolizinyl, 1-isoindolyl, 4H-quinolizin-2-yl, 3-isoquinolyl, 2-quinolyl, 1-phthalazinyl, 1,8-naphthyridinyl, 2-quinoxalinyl, 2-quinazolinyl, 3-cinnolinyl, 2-pteridinyl, 4aH-carbazol-2-yl, 2-carbazolyl, .beta.-carbolin-3-yl, 3-phenanthridinyl, 2-acridinyl, 2-perimidinyl, 1-phenazinyl, 3-isothiazolyl, 2-phenothiazinyl, 3-isoxazolyl, 2-phenoxazinyl, 3-iso-chromanyl, 7-chromanyl, 2-pyrrolin-3-yl, 2-imidazolidinyl, 2-imidazolin-4-yl, 2-pyrazolidinyl, 3-pyrazolin-3-yl, 2-piperidyl, 2-piperazinyl, 1-indolinyl, 1-isoindolinyl, 3-morpholinyl, benzo[[h]isoquinolinyl, and benzo[b]furanyl, including the position isomers thereof except that the heterocyclic moieties cannot be attached directly through their nitrogen atoms. Aryl groups can be substituted or unsubstituted with one, two or three substituents independently selected from C.sub.1-6 alkyl, haloalkyl, alkoxy, thioalkoxy, aminoalkylamino, dialkylamino, hydroxy, halo, mercapto, nitro, carboxaldehyde, carboxy, carboalkoxy and carboxamid

REFERENCES:
patent: 4288453 (1981-09-01), Vincent et al.
patent: 4835099 (1989-05-01), Mize et al.
patent: 5017719 (1991-05-01), Kruse et al.
patent: 5132328 (1992-07-01), Girodeau et al.
patent: 5166181 (1992-11-01), Cottens
patent: 5214069 (1993-05-01), Girodeau et al.
Gelb et al., Biochemistry, vol. 24, No. 8, pp. 1813-1817 (1985).
U. Brodbeck et al., Biochimica et Biophysica Acta, 567, pp. 357-369 (1979).
K. N. Allen et al., Biochemistry 28, pp. 8466-8473 (1989).
H. K. Nair, et al., J. Am. Chem. Soc., 115, pp. 9939-9941 (1993).
R. L. Salvador et al., Tetrahedron. vol. 27, pp. 1221-1226 (1971).
R.L. Metcalf et al., J. Econ. Entomol. 58, p. 1151 (1965) (?).
A. Aberman et al., Biochimica et Biophysica Acta, 791, pp. 278-280 (1984) (?).
Bioorg. & Med. Chem Letters vol. 3 pp. 2619-2622 (1993).

Affiliated with

Also associated with

Rating

Aromatic acetylcholinesterase inhibitors does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Aromatic acetylcholinesterase inhibitors, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Aromatic acetylcholinesterase inhibitors will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-310587