Galanthamine derivatives as acetylcholinesterase inhibitors

Details Galanthamine derivatives as acetylcholinesterase inhibitors Galanthamine derivatives as acetylcholinesterase inhibitors

1993-10-15

2001-11-27

Berch, Mark L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C540S581000

Reexamination Certificate

active

06323196

ABSTRACT:

This application relates to compounds of the formula
wherein
R
1
is hydrogen, (C
1
-C
12
)alkylcarbonyl, (C
1
-C
12
)alkoxycarbonyl, mono(C
1
-C
12
)alkylaminocarbonyl or di(C
1
-C
12
)alkylaminocarbonyl;
R
2
is (C
1
-C
18
)monoalkylaminocarbonyloxy, (C
1
-C
12
)dialkylaminocarbonyloxy or aryl(C
1
-C
4
)alkylaininocarbonyloxy);
R
3
is hydrogen, halo or (C
1
-C
4
)alkyl; or a pharmaceutically acceptable addition salt thereof,
which are useful for inhibiting acetylcholinesterase and alleviating various memory dysfunctions characterized by decreased cholinergic function such as Alzheimer's disease.
This invention also provides a pharmaceutical composition useful for inhibiting acetylcholinesterase and alleviating various memory dysfunctions characterized by decreased cholinergic function which comprises a compound of the invention in an amount sufficient to affect cholinergic function and a pharmaceutically acceptable carrier. This invention further provides a method for treating the effects of Alzheimer's disease which comprises treating a patient with a pharmaceutically effective amount of a compound of the invention.
Unless otherwise stated or indicated, the following definitions shall apply throughout the specification and appended claims.
The term “alkyl” shall mean a straight or branched alkyl group of the stated number of carbon atoms. Examples include, but are not limited to methyl, ethyl, n-propyl, iso-propyl, n-butyl, isobutyl, sec-butyl, t-butyl, and straight and branched chain pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl and pentadecyl.
The term “halo” shall mean chloro, fluoro, bromo and iodo.
The term “aryl” shall mean phenyl having 0, 1, 2 or 3 substituents independently selected from the group of (C
1
-C
6
)alkyl, (C
1
-C
6
)alkoxy, (C
1
-C
6
)alkylcarbonyl, halo or trifluoromethyl.
In one embodiment of the invention are compounds of the formula
wherein
R
1
is hydrogen, (C
1
-C
12
)alkylcarbonyl, (C
1
-C
12
)alkoxycarbonyl, mono(C
1
-C
12
)alkylaminocarbonyl, or di(C
1
-C
12
)alkylaminocarbonyl;
R
2
is mono(C
1
-C
18
)alkylaminocarbonyloxy, di(C
1
-C
8
)alkylaminocarbonyloxy, or aryl(C
1
-C
4
)alkylaminocarbonyloxy;
R
3
is hydrogen or halo; and pharmaceutically acceptable addition salts.
In a preferred embodiment are compounds of Formula II wherein R
1
is hydrogen, (C
1
-C
12
)alkylaminocarbonyl, phenyl(C
1
-C
4
)alkylaminocarbonyl, (C
3
-C
12
)Cycloalkylaminocarbonyl, (C
1
-C
12
)alkylcarbonyl or (C
1
-C
12
)alkoxycarbonyl; R
2
is (C
1
-C
12
)alkylaminocarbonyloxy or phenyl(C
1
-C
3
)alkylaminocarbonyloxy; and R
3
is hydrogen or halogen.
More preferably R
1
is hydrogen, (C
1
-C
6
)alkylcarbonyl or (C
1
-C
6
)alkoxycarbonyl; R
2
is (C-C
10
)alkylaminocarbonyloxy or phenyl(C
1
-C
2
)alkylaminocarbonyloxy; and R
3
is hydrogen.
Most preferably R
1
is hydrogen, methylcarbonyl, ethylcarbonyl, isopropylcarbonyl, t-butylcarbonyl, n-heptylcarbonyl or t-butoxycarbonyl; R
2
is methylaminocarbonyloxy, isopropylaminocarbonyloxy, t-butylaminocarbonyloxy, n-pentylaminocarbonyloxy, n-hexylaminocarbonyloxy, n-heptylaminocarbonyloxy, n-octylaminocarbonyloxy or n-nonylaminocarbonyloxy; and R
3
is hydrogen.
The compounds of the invention are prepared from the appropriate derivative of galanthamine as described more fully below and shown in Scheme I.
The intermediate 6-demethylgalanthamine of Formula IV, a known compound, was prepared in a novel process by treating the galanthamine of Formula III with an alkaline salt of ethanthiol such as, for example, with EtSLi, EtSNa or EtSK. The reaction is typically carried out in a polar nonprotic solvent such as dimethylformamide (DMF) or N-methylpyrrolidone or a protic solvent such as butanol or pentanol at from about 80° C. to about 135° C., preferably from about 90° C. to about 125° C.
The compound of Formula V wherein R
4
is hydrogen and R
5
is (C
1
-C
12
)alkyl, or phenyl(C
1
-C
6
)alkyl is prepared by treating the compound of Formula IV with the appropriate isocyanato compound R
5
NCO. The reaction is carried out in an aprotic solvent such as, for example, tetrahydrofuran in the presence of base such as, for example, potassium carbonate at from about −10° C. to about 30° C. for from about 0.5 hours to about 4 hours
Alternatively and in the case where R
4
and R
5
are not hydrogen, the compound of Formula V is prepared by first reacting the compound of Formula IV with carbonyldumidazole and subsequently adding the appropriate R
4
R
5
NH compound. The reaction is typically carried out in a nonprotic organic solvent such as methylene chloride, chloroform or tetrahydrofuran (THF) at from about −10° C. to about 50° C., preferably from about 0° C. to about 30° C.
The compound of Formula VI can be prepared from the compound of Formula V. In the case where R
6
is alkylamino or arylamino, a solution of the appropriate isocyanate and the compound V in a nonprotic solvent such as tetrahydrofuran in a sealed tube at from about 55° C. to about 85° C. for from about 24 hours to about 120 hours, preferably from about 60° C. to about 70° C. for from about 60 hours to about 80 hours. Alternatively, where NR
4
R
5
and R
8
are identical, the compounds are made from the compound of Formula IV using over two moles of the appropriate isocyanate in a sealed tube as described above.
In the case where R
6
is alkyl or aryl, the compound of Formula V is typically reacted with an appropriate carboxylic anhydride in the presence of a base such as 4-dimethylaminopyridine (DMAP) or pyrrolidinopyridine or carboxylic acid chloride in the presence of a base such as 1,8-diaza-bicyclo[5.4.0]undec-7-ene (DBU). The reactions are typically carried out in a non-protic solvent such as, for example, chloroform or dichloromethane at from about 0° C. to about 50° C., preferably at from about 15° C. to about 30° C.
In the case where R
6
is alkoxy or aryloxy, the compound of Formula V is typically reacted with the appropriate chloroformate in the presence of an amine such as triethylamine; or with the appropriate dicarbonate in the presence of an amine such as DMAP. The reactions are typically carried out in an inert organic solvent such as methylene chloride at from about −10° C. to about 50° C., preferably from about 0° C. to about 30° C.
In the case where X is Br, the compound of Formula IV is treated with bromine in the presence of an amine such as t-butylamine to obtain the brominated compound. The bromine is first added to the t-butylamine at from about −20° C. to about −30° C., then the reaction mixture is cooled to about −80° C. to about −70° C. and the galanthamine compound is added. The reaction is typically carried out in a nonpolar organic solvent such as for example toluene. Following addition of galanthamine the mixture is allowed to warm from about −70° C. to −80° C. to about room temperature for from about 6 hours to about 10 hours, preferably about 8 hours.
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. The compounds to of the present invention are advantageous because they are less toxic and/or more potent than the related compounds known in the art.
This utility is manifested by the ability of these compounds to inhibit the enzyme acetylcholinesterase and thereby increase acetylcholine levels in the brain.
The ability to inhibit acetylcholinesterase was determined by the photometric method of Eliman et al., Biochem. Pharmacol. 7,88 (1961). Results of acetylcholinesterase inhibition for some of the compounds of this invention are presented in Table I along with those for reference compounds.
TABLE I
Acetylcholinesterase Inhibition Assay
IC
50
&mgr;M
Compound
CHE I
6-O-Demethyl-6-O-(methylamino-carbonyl)galanthamine
0.0020
6-O-Demethyl-6-O-methylaminocarbonyl-3-O-
0.047 
(2-propylcarbonyl)galanthamine hydrochioride
Tacrine
0.32 
This utility can also be ascertained by determining the ability o

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