Organic compounds -- part of the class 532-570 series – Organic compounds – Silicon containing
Patent
1995-07-18
1996-06-04
Shaver, Paul F.
Organic compounds -- part of the class 532-570 series
Organic compounds
Silicon containing
556415, 556418, 556436, 556437, 556432, 556431, 556422, 556428, 556440, 556449, 522 4, C07F 708, C07F 710
Patent
active
055234429
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/US96/0672 filed Jan. 25, 1994.
This invention relates to fluorinated silylated aromatic compounds, their intermediates, methods of use 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 Formula I: ##STR1## stereoisomers or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein: or Z' is F; ##STR2## X is H, Br, Cl, F or CF.sub.3 ; Y is H, OH, (C.sub.1-6) alkyl, --(CH.sub.2).sub.m OR.sub.5, hydroxy(C.sub.1-6) alkyl, (CH.sub.2).sub.n NR.sub.6 R.sub.6 ', azido, CN, CO.sub.2 R.sub.4, COR.sub.6, SO.sub.3 H, Br, Cl, F, NO.sub.2 or --(CH.sub.2).sub.n' SiR.sub.1 'R.sub.2 'R.sub.3 ', provided that when both Z and Z' are F then Y is H or F; independently C.sub.1-10 alkyl or (CH.sub.2).sub.n" aryl;
The compounds of the present invention are used to treat patients having conditions responsive to the acetylcholin-esterase-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 terms "(CH.sub.2).sub.n " or "(CH.sub.2).sub.m " may represent alkylene chains which may be branched or straight-chained.
"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 ##STR3## Tosyl derivatives mean ##STR4## wherein R is C.sub.1-6 alkylene.
"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-phenothiazinyi, 3-isoxazolyl, 2-phenoxazinyl, 3-isochromanyl, 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 carboxamide.
R.sub.1, R.sub.2, R.sub.3, R.sub.1 ', R.sub.2 ', and R.sub.3 ' are each in
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Collard Jean-Noel
Hornsperger Jean-Marie
Merrell Pharmaceuticals Inc.
Moon Carolyn D.
Shaver Paul F.
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