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, C540S487000

Reexamination Certificate

active

06323195

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
8
)alkylaminocarbonyl;
R
2
is hydrogen, (C
3
-C
12
)alkenylcarbonyloxy, (C
3
-C
12
)cycloalkylcarbonyloxy, (C
3
-C
12
)cycloalkylaminocarbonyloxy, (C
3
-C
12
)alkynylcarbonyloxy, (C
3
-C
12
)ycloalkyl(C
1
-C
12
)alkylcarbonyloxy, oxygen containing heterocyclyloxy, oxygen containing heterocyclylcarbonyloxy, sulfur containing heterocyclyloxy, sulfur containing heterocyclylcarbonyloxy, nitrogen containing heterocyclyloxy, nitrogen containing heterocyclylcarbonyloxy, haloalkylsulfonyloxy, (C
1
-C
6
)alkylsilyloxy;
R
3
is hydrogen, halo or (C
1
-C
4
)alkyl;
R
4
is hydrogen or (C
1
-C
6
)alkyl;
with the proviso that R
1
and R
2
are not both hydrogen when R
3
and R
4
are hydrogen;
all geometric, and optical and stereoisomers thereof, or a pharmaceutically acceptable addition salt thereof;
which are useful for alleviating various memory dysfunctions such as found in Alzheimer's disease.
This invention also provides a pharmaceutical composition useful for 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 dodecyl.
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.
The term “cycloalkyl” shall mean a cycloalkyl group of from 3 to 12 carbon atoms such as for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclododecyl and including multiple ring alkyls such as for example, norbornanyl, adamantyl, cis-bicyclo[3.3.0]octanyl, camphoryl, oxotricyclo[2.2.1.0
2,6
]heptane-7-yl and 3-noradamantyl.
The term “nitrogen-containing heterocycle” shall mean a 5 or 6 membered saturated or partially unsaturated ring, optionally fused to another saturated, unsaturated or aromatic ring, having at least one nitrogen atom which is also bonded to the additional portion of the molecule. Examples include morpholine, tetrahydroisoquinoline, piperidine, pyrrolidine, pyridine and the like.
The term “oxygen-containing heterocycle” shall mean a 5 or 6 membered saturated or partially unsaturated ring, optionally fused to another saturated, unsaturated or aromatic ring, having at least one oxygen atom which is also bonded to the additional portion of the molecule. Examples include furan and tetrahydrofuran and the like.
The term “sulfur-containing heterocycle” shall mean a 5 or 6 membered saturated or partially unsaturated ring, optionally fused to another saturated, unsaturated or aromatic ring, having at least one sulfur atom which is also bonded to the additional portion of the molecule. Examples include thiophene and the like.
In a preferred embodiment are compounds of the formula
wherein
R
1
is hydrogen, (C
1
-C
12
)alkylcarbonyl, (C
1
-C
12
)alkoxycarbonyl;
R
2
is hydrogen, (C
3
-C
12
)alkenylcarbonyloxy, (C
3
-C
12
)alkynylcarbonyloxy, (C
3
-C
12
)cycloalkylcarbonyloxy, (C
3
-C
12
)cycloalkyl(C
1
-C
12
)alkylcarbonyloxy, (C
3
-C
12
)cycloalkylaminocarbonyloxy, halo(C
1
-C
6
)alkylsulfonyloxyl, (C
1
-C
6
)alkylsilyloxy, pyridyloxy, thiomorpholinocarbonyloxy, furanylcarbonyloxy, thienylcarbonyloxy, tetrahydrofuranylcarbonyloxy, furanyloxy, thienyloxy, pyrrolidinylcarbonyloxy, tetrahydrofuranyloxy, piperidinylcarbonyloxy, azepincarbonyloxy, morpholinocarbonyloxy or tetrahydroisoquinolinylcarbonyloxy;
R
3
is hydrogen or halo;
R
4
is hydrogen or (C
1
-C
6
)alkyl;
with the proviso that R
1
and R
2
are not both hydrogen when R
3
and R
4
are hydrogen;
and all geometric, optical and sterioisomers and pharmaceutically acceptable addition salts thereof.
More preferably R
1
is hydrogen, (C
1
-C
12
)alkylcarbonyl or (C
1
-C
12
)alkoxycarbonyl; R
2
is (C
3
-C
12
)alkenlcarbonyloxy, (C
3
-C
12
)alkynylcarbonyloxy, (C
3
-C
12
)cycloalkylcarbonyloxy, (C
3
-C
12
)cycloalkyl(C
1
-C
12
)alkylcarbonxyloxy, pyridyloxy, furanyloxy, morpholinocarbonyloxy or tetrahydroisoquinolylcarbonyloxy; R
3
is hydrogen or bromine; and R
4
is hydrogen or methyl.
Most preferably R
1
is hydrogen, R
2
is cyclopropylcarbonyloxy, cyclobutylcarbonyloxy, cyclohexylcarbonyloxy, methylcyclohexylcarbonyloxy, adamantylcarbonyloxy, adamantylmethylcarbonyloxy, 2-methylpropenylcarbonyloxy, 2-propynylcarbonyloxy, cycloheptylaminocarbonyloxy, cyclohexylaminocarbonyloxy, morpholinocarbonyloxy or tetrahydroisoquinolylcarbonyloxy; and R
3
and R
4
are hydrogen.
The compounds of the invention are prepared from the appropriate optical isomer 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 alkylthio salt of sodium, potassium, lithium or cesium, preferably (C
1
-C
4
)alkylthio salts of sodium and lithium, most preferably EtSLi, or EtSNa. The reaction is typically carried out in a polar nonprotic solvent such as dimethylformamide (DMF) or N-methylpyrrolidone (NMP) or a protic solvent such as butanol or pentanol, preferably DMF or NMP 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
5
is (C
3
-C
12
)cycloalkylaminocarbonyl is prepared by treating the compound of Formula IV with the appropriate isocyanato compound (C
3
-C
12
)cycloalkylNCO. 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.
In the case where R
5
is cycloalkylcarbonyl, alkenylcarbonyl or alkynylcarbonyl, the compound of Formula IV is typically reacted with an appropriate carboxylic anhydride in the presence of a base such as 4-dimethylpyridine (DMAP) or carboxylic acid chloride in the presence of a base such as 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). The reactions are typically carried in a non-protic solvent such as, for example, chloroform at from about 0° C. to about 50° C., preferably from about 15° C. to about 30° C.
In the case where R
5
is pyridyl or other heterocycle, the compound of Formula IV is typically reacted with an appropriate halopyridine or other haloheterocycle in the presence of a base such as for example potassium t-butoxide. The reaction is typically carried in a non-protic polar solvent such as, for example, dimethylformamide at from about room temperature to about 150° C., preferably about 110° C.
In the case where R
5
is alkylsilyl, the compound of Formula IV is typically reacted with the appropriate alkylsilyl halide from about 0° C. to about 80° C. preferably at room temperature. The reaction is typically carried in a non-protic solvent such as dimethylformamide or terahydrofuran.
In the case where R
5
is haloalkylsulfonyl, the compound of Formula IV is typically reacted with the appropriate sulfonic acid anhydride in a solvent such as pyridine. Alternatively the reaction can be carried out at about −60° C. to about −50° C. in dichloromethane or chloroform in th

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