Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-03-24
2001-06-19
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S297000, C546S105000, C546S106000, C546S093000, C546S079000
Reexamination Certificate
active
06248750
ABSTRACT:
This ivention relates to compounds having the formula,
wherein n is 1-4; X is hydrogen, loweralkyl, cycloalkyl, loweralkoxy, halogen, hydroxy, nitro, trifluoromethyl, formyl, loweralkylcarbonyl, arylcarbonyl, —SH, loweralkylthio, NHCOR
2
or —NR
3
R
4
where R
2
is hydrogen or loweralkyl, and R
3
and R
4
are independently hydrogen, loweralkyl or cycloalkyl; R is hydrogen, loweralkyl or loweralkylcarbonyl; and R
1
is hydrogen, loweralkyl, aryl, diloweralkylaminoloweralkyl, arylloweralkyl, furylloweralkyl, thienylloweralkyl, pyridinylloweralkyl, diarylloweralkyl, oxygen-bridged arylloweralkyl or oxygen-bridged diarylloweralkyl; stereo, optical and geometrical isomers thereof, and pharmaceutically acceptable acid addition salts thereof which are useful for enhancing memory, methods for synthesizing them, and pharmaceutical compositions comprising an effective memory enhancing amount of such a compound, and a method of increasing the cholinergic function in mammals which comprises the adminstration of an effective amount of such a compound.
Throughout the specification and the appended claims, a given chemical formula or name shall encompass all stereo, optical and tautomeric isomers thereof where such isomers exist, as well as pharmaceutically acceptable acid addition salts thereof and solvates thereof such as for instance hydrates. Thus, for instance, where the group R of Compound I is hydrogen, Formula Ia should be considered as equivalent to its tautomeric form Ib. Thus, in terms of nomenclature, N-methoxy-1,2,3,4-tetrahydro-9-acridinamine, for instance, should be considered as equivalent to N-methoxy-1,2,3,4-tetrahydroacrdin-9(10H)-imine.
The following definitions shall apply throughout the specification and the appended claims.
Unless otherwise stated or indicated, the term loweralkyl denotes a straight or branched alkyl group having from 1 to 6 carbon atoms. Examples of said alkyl include methyl, ethyl, n-propyl, iso-butyl, pentyl, and hexyl.
Unless otherwise stated or indicated, the term cycloalkyl denotes a saturated ring containing 3 to 7 carbon atoms. Examples of said cycloalkyl include cyclopropyl, cyclohexyl and cycloheptyl.
Unless otherwise stated or indicated, the term loweralkoxy denotes a straight or branched alkoxy group having 1 to 6 carbon atoms. Examples of said alkoxy include methoxy, ethoxy, iso-propoxy, sec-butoxy, and straight and branched chain hexyloxy.
Unless otherwise stated or indicated, the term halogen shall mean fluorine, chlorine, bromine or iodine.
Unless otherwise stated or indicated, the term aryl shall mean an unsubstituted phenyl group, a phenyl group substituted with 1, 2 or 3 substituents each of which being independently loweralkyl, loweralkoxy, halogen, hydroxy, trifluoromethyl, phenyl or benzyloxy.
Unless otherwise stated or indicated, the term oxygen-bridged shall signify the fact that an oxygen atom is present between aryl and ldweralkyl groups and/or an oxygen atom has replaced a methylene group in the loweralkyl group, with the proviso that said methylene group is not alpha to the amino nitrogen carrying the groups R and R
1
. Thus, for instance, examples of oxygen-bridged arylloweralkyl include 3-phenoxypropyl and 4-phenoxybutyl, and examples of oxygen-bridged diarylloweralkyl include 2-[bis(4-fluorophenyl)methoxy] ethyl and 2-[bis(3-fluorophenyl)methoxy] ethyl.
The compounds of this invention are prepared as described below. The required O-substituted hydroxylamines of formula II wherein R is hydrogen and R
1
is not hydrogen are, in some cases, commercially available and, where not, can readily be prepared by one skilled in the art by means of the alkylation and subsequent hydrolysis of N-hydroxyphthalimide as disclosed by A. Rougny and M. Daudon, Bull. Soc. Chim. France, 833 (1976). Further alkylation by methods known to one skilled in the art allows the preparation of the compounds of formula II wherein R is loweralkyl and R
1
is not hydrogen.
In order to simplify the description of the synthetic schemes, the description will be presented with specific reference to the situation where n=2, but it will readily be understood that the synthetic schemes can also be applied to the other situations by making obvious modifications where necessary.
Throughout the description of the synthetic steps, definitions of X, R and R
1
through R
4
are as given above unless otherwise stated or indicated.
A compound of formula IV wherein R is not loweralkylcarbonyl can be prepared by reacting a compound of formula III with a hydroxylamine of formula II. Said reaction can be conducted at a temperature of 120-220° C. in the presence of a hydroxylated aromatic compound such as phenol or cresol.
A compound of formula IVb wherein R is loweralkylcarbonyl can be prepared by reacting a compound of formula IVa with an acylating agent such as an acid halide or anhydride of formula V wherein R
5
is loweralkyl and Y is chlorine, bromine or OC(═O)R
5
. The reaction can be carried out in an inert solvent such as chloroform, methylene chloride, toluene, tetrahydrofuran or diethyl ether in the presence of a proton acceptor such as pyridine, 4-dimethylamninopyridine, triethylamine or diisopropylethylamine at a temperature of 0-100° C.
The compounds of Formula I of the present invention can be used for the treatment of various memory dysfunctions characterized by decreased cholinergic function, such as Alzheimer's disease.
This utility can be ascertained by determining the ability of these compounds to inhibit the activity of the enzyme acetylcholinesterase and thereby increase the acetylcholine levels in the brain.
CHOLINESTERASE INHIBITION ASSAY
The ability to inhibit acetylchlinesterase was determined by the photometric method of Ellman et al., Biochem. Pharmacol. 7, 88 (1961). Results of some of the compounds of this invention are presented in Table 1 below along with a result of a reference compound.
TABLE 1
Cholinesterase Inhibition
IC
50
(molar conc.)
Compound
N-methoxy-1,2,3,4-tetrahydro-9-acridinamine
5.1 × 10
−7
N-benzyloxy-1,2,3,4-tetrahydro-9-acridinamine
6.1 × 10
−6
N-propyloxy-1,2,3,4-tetrahydro-9-acridinamine
8.3 × 10
−7
N-methyl-N-methoxy-1,2,3,4-tetrahydro-9-acridinamine
2.7 × 10
−5
N-(2-fluorobenzyloxy)-1,2,3,4-tetrahydro-9-acridinamine
5.2 × 10
−6
Reference Compound
9-Amino-1,2,3,4-tetrahydroacridine
3.1 × 10
−7
This utility can also be ascertained by determining the ability of these compounds to restore cholinergically deficient memory in the Dark Avoidance Assay. In this assay mice are tested for their ability to remember an unpleasant stimulus for a period of 24 hours. A mouse is placed in a chamber that contains a dark compartment; a srong incandescent light drives it to the dark compartment, where an electric shock is administered through metal plates on the floor. The animal is removed from the testing apparatus and tested again, 24 hours later, for the ability to remember the electric shock.
If scopolamine, an anticholinergic that is known to cause memory impairment, is administered before an animal's initial exposure to the test chamber, the animal re-enters the dark compartment shortly after being placed in the test chamber 24 hours later. This effect of scopolamine is blocked by an active test compound, resulting in a greater interval before re-entry into the dark compartment.
The results for active compounds are expressed as the percent of a group of animals in which the effect of scopolamine is blocked, as manifested by an increased interval between being placed in the test chamber and re-entering the dark compartment. Results of Dark Avoidance Assay for representative compounds of this invention and a reference compound are presented in Table 2.
TABLE 2
Dark Avoidance Assay
% Animals
with
Scopolamine
Induced
Dose
memory
(mg/kg)
deficit reversed
(s.c.)
Compound
N-methoxy-1,2,3,4-tetrahydro-9-acridinamine
27%
1.0
N-methoxy-N-methyl-1,2,3,4-tetrahydro-
27%
1.0
9-acridinamine
Reference Compound
9-amino-1,2,3,4-t
Kapples Kevin James
Shutske Gregory Michael
Frommer & Lawrence & Haug LLP
Hoechst Roussel Pharmaceuticals
Patel Sudhaker B.
Raymond Richard L.
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