U.S. patent application number 10/397682 was filed with the patent office on 2004-02-05 for compounds for the treatment of alzheimer's disease.
This patent application is currently assigned to BONNIE DAVIS. Invention is credited to Davis, Bonnie M., Joullie, Madeleine M..
Application Number | 20040023984 10/397682 |
Document ID | / |
Family ID | 27545410 |
Filed Date | 2004-02-05 |
United States Patent
Application |
20040023984 |
Kind Code |
A1 |
Davis, Bonnie M. ; et
al. |
February 5, 2004 |
Compounds for the treatment of alzheimer's disease
Abstract
The present invention is directed to analogs of galanthamine of
the structure 1 and their use in treating Alzehimer's diseases and
related dementias.
Inventors: |
Davis, Bonnie M.; (Syosset,
NY) ; Joullie, Madeleine M.; (Philadelphia,
PA) |
Correspondence
Address: |
LADAS & PARRY
26 WEST 61ST STREET
NEW YORK
NY
10023
US
|
Assignee: |
BONNIE DAVIS
|
Family ID: |
27545410 |
Appl. No.: |
10/397682 |
Filed: |
March 26, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10397682 |
Mar 26, 2003 |
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09723700 |
Nov 28, 2000 |
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6569848 |
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09723700 |
Nov 28, 2000 |
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08473712 |
Jun 7, 1995 |
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6268358 |
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08473712 |
Jun 7, 1995 |
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08139338 |
Oct 19, 1993 |
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6150354 |
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08139338 |
Oct 19, 1993 |
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07781028 |
Oct 18, 1991 |
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07781028 |
Oct 18, 1991 |
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07046522 |
May 4, 1987 |
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07781028 |
Oct 18, 1991 |
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07695949 |
May 6, 1991 |
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07695949 |
May 6, 1991 |
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07541076 |
Jun 21, 1990 |
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07541076 |
Jun 21, 1990 |
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07219914 |
Jul 15, 1988 |
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07219914 |
Jul 15, 1988 |
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07046522 |
May 4, 1987 |
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Current U.S.
Class: |
514/255.05 ;
514/256; 514/337; 514/410; 514/422; 514/438; 514/468 |
Current CPC
Class: |
A61K 31/55 20130101;
A61K 31/675 20130101; C07D 491/10 20130101; A61K 31/665
20130101 |
Class at
Publication: |
514/255.05 ;
514/256; 514/337; 514/410; 514/438; 514/468; 514/422 |
International
Class: |
A61K 031/497; A61K
031/506; A61K 031/4439; A61K 031/4433; A61K 031/403; A61K 031/4025;
A61K 031/381; A61K 031/343 |
Foreign Application Data
Date |
Code |
Application Number |
May 4, 1988 |
WO |
PCT/US88/01542 |
May 4, 1988 |
EP |
88905083.7 |
Jan 15, 1987 |
EP |
87100461.0 |
Claims
1. A method of treating Alzheimer's disease and related dementias
which comprises administering to a patient suffering from such a
disease a therapeutically effective amount of a compound of the
Formula I 51wherein the broken line represents an optionally
present double bond in one or two of the positions shown, R.sub.1
and R.sub.2 are each selected independently from the group
consisting of hydrogen, hydroxyl, amino, phenylamino or alkylamino,
cyano, sulfhydryl, alkoxy of 1-6 carbon atoms, alkylthio, aryloxy,
aralkoxy, C.sub.1-6 alkyl carbonate or R.sub.5-substituted phenyl
or benzyl carbonate, R.sub.5-substituted aryloxy,
R.sub.5-substituted arylthio, aralkoxy t an aliphatic or aryl
carbamyl group wherein the aliphatic or aryl moiety may be R.sub.5
substituted or unsubstituted, aralkylthio, R.sub.5-substituted
aryloxymethyl, alkanoyloxy, hydroxy-substituted alkanoyloxy,
benzoyloxy, aryloxy carbonyl, R.sub.1 may also be alkyl of up to 14
carbon atoms, or hydroxy methyl, R.sub.2 may also be carboxymethyl
provided that at least one of R.sub.1 and R.sub.2 is hydroxy, amino
or alkylamino unless R.sub.7 or R.sub.8 is hydroxymethyl, R.sub.3
is hydrogen, straight or branched chain alkyl of 1-6 carbon atoms,
cycloalkyl methyl, phenyl, R.sub.5 substituted phenyl, alkylphenyl,
R.sub.5 alkylphenyl, heterocyclic selected from .alpha.- or
.beta.-furyl, .alpha.- or .beta.-thienyl or thenyl, pyridyl,
pyrazinyl and pyrimidyl, alkyl heterocyclic or R'-substituted
heterocyclyl, where R' is alkyl or alkoxy and heterocyclyl is
selected from .alpha.- or .beta.-furyl, thienyl, thenyl, pyridyl,
pyrazinyl, pyrimidyl or is methylpyrryl or R.sub.3 is alkanoyl of 1
to 8 carbon atoms or aroyl wherein the aryl group is of 6 to 10
carbon atoms, the alkyl and aryl portions of said groups optionally
being substituted by R.sub.5 groups as hereinafter defined or
R.sub.3 is the residue of a compound having adrenergic or monoamino
oxidase activity and said residue being selected from the group
consisting of 52wherein Hal is a halogen, p is 0, 1 or 2, q is 0 or
1, r is 0 or 1 and Z is selected from the group consisting of
53wherein Q is hydrogen or hydroxy, L is hydrogen or C.sub.1-4
alkyl, G is hydrogen, C.sub.1-4 alkyl, alkylphenyl wherein said
phenyl group is optionally substituted by hydroxy or methylene
deoxy, or is alkylamino 54wherein G is as defined above, 55c)
CH.sub.2CH.sub.2NH--NH.sub.2 and 56each R.sub.4 is independently
selected from hydrogen, hydroxyl, sulfhydryl, alkyl, aryl, alkoxy,
mercaptoalkyl, aryloxy, mercaptoaryl, alkarloxy, mercaptoalkaryl,
nitro, amino, N-alkylamino, N-arylamino, N-alkarylamino, fluoro,
chloro, bromo iodo and trifluoromethyl, R.sub.5 is selected from
the group consisting of hydroxyl, sulfhydryl, alkyl, aryl, alkoxy,
mercaptoalkyl, aryloxy, mercaptoaryl, alkaryloxy, mercaptoalkaryl,
nitro, amino, N-alkylamino, N-arylamino, fluoro, chloro, bromo,
iodo and trifluoromethyl, R.sub.6 is hydrogen, halo,
trifluoromethyl or alkyl of 1 to 4 carbon atoms, R.sub.7 is
selected from the same groups as R.sub.4 or may be hydroxy alkyl of
1-2 carbon atoms, R.sub.8 is hydrogen or hydroxymethyl, R.sub.9 is
hydrogen or alkyl of 1 to 6 carbon atoms, or when R.sub.2 is
hydroxyl R.sub.9 may be 57or R.sub.2 and R.sub.9 may jointly form a
keto group provided that R.sub.1 is hydroxy or amino, X is oxygen
or NH Y is nitrogen with the proviso that when X is O, R.sub.3 is
not methyl when R.sub.1 is methoxy, R.sub.2 is hydroxy, all
R.sub.4's are hydrogen or a pharmaceutically acceptable acid
addition salt thereof.
2. A method according to claim 1 wherein the compounds used is on
wherein R.sub.1 and R.sub.2 are each selected from H, OR, SH,
NH.sub.2, NHR, CH.sub.2OH, CONHR 58wherein R is alkyl 1-6 carbon
atoms or phenyl or naphthyl or R.sup.5-substituted naphthyl or
R.sup.5-substituted phenyl or benzyl or R.sup.5-substituted benzyl,
wherein R.sub.5 is as defined in claim 1 and R.sub.10 is hydrogen,
alkyl or alkoxy, R.sub.3 is --H, or branched or linear alkyl or
--CH.sub.2--CH (CH.sub.2).sub.n wherein n is 3, 4 or 5, 59wherein
R.sub.11 is as defined for R.sub.10 above or is hydroxy or amino or
R.sub.3 is 60wherein Z is O, S, or NH or 61X is oxygen and Y is
nitrogen.
3. A method according to claim 1 wherein said compound is of the
formula 62wherein R.sup.1 is hydroxy, lower alkoxy, aryloxy,
R.sup.5 substituted aryloxy, benzyloxy or R.sup.5 substituted
benzyloxy, amino, alkylamino or an alkyl or aryl carbamyl
group.
4. A method according to claim 3, wherein R.sub.1 is selected from
the group consisting of hydroxy, methoxy, ethoxy, mono lower alkyl
carbamate, phenyl carbamate, naphthyl carbamate,
R.sub.5-substituted phenyl carbamate and R.sub.5-substituted
naphthyl carbamate wherein R.sub.5 is hydroxyl, sulfhydryl, alkyl,
aryl, alkoxy, mercaptoalkyl, aryloxy, mercaptoaryl, alkaryloxy,
mercaptoalkaryl, nitro, amino, N-alkylamino, N-arylamino,
N-alkarylamino, fluoro, chloro, bromo, iodo or trifluoromethyl.
5. A method according to claim 3, wherein said compound is selected
from N-desmethyl galanthamine, O-desmethyl, N-desmethyl
galanthamine; 13-O-ethyl, O-desmethyl, N-desmethyl galanthamine;
13-O-phenyl, O-desmethyl, N-desmethyl galanthamine; and
13-O-benzyl, O-desmethyl, N-desmethyl galanthamine; O-desmethyl,
N-desmethyl, N-ethyl galanthamin; O-desmethyl, N-desmethyl, N-ethyl
galanthamine, 13-O-methyl, 13-O-ethyl and 13-O-benzyl ethers;
O-desmethyl, N-desmethyl, N-ethyl galanthamine, 13-phenyl,
13-.alpha.-naphthyl, 13-dimethyl and 13-diethyl carbamates;
O-desmethyl, N-desmethyl, N-cyclopropyl methyl galanthamine;
O-desmethyl, N-desmethyl, N-cyclopropyl methyl galanthamine,
13-O-methyl, 13-O-ethyl and 13-O-benzyl ethers; O-desmethyl,
N-desmethyl, N-cyclopropylmethyl galanthamine, 13-phenyl,
13-d-.alpha.-naphthyl, 13-dimethyl and 13-diethyl carbamates;
O-desmethyl, N-desmethyl, N-benzyl galanthamine; O-desmethyl,
N-desmethyl, N-benzyl galanthamine, 13-O-methyl, 13-O-ethyl and
13-O-benzyl ethers and O-desmethyl, N-desmethyl, N-benzyl
galanthamine.
6. A method according to claim 1 wherein said compound is of the
formula: 63wherein R.sub.2 is hydroxy, lower alkoxy, aryloxy,
R.sub.5-substituted aryloxy, benzyloxy or R.sub.5-substituted
benzyloxy or is an alkyl or aryl carbamyl group and R.sub.3 is
hydrogen or alkyl of 1-6 carbon atoms, methyl cyclopropyl or benzyl
or R.sub.5-substituted benzyl wherein R.sub.5 is hydroxyl,
sulfhydryl, alkyl, aryl, alkoxy, mercaptoalkyl, aryloxy,
mercaptoaryl, alkaryloxy, mercaptoalkaryl, nitro, amino,
N-alkylamino, N-arylamino, N-alkarylamino, fluoro, chloro, bromo,
iodo or trifluoromethyl.
7. A method according to claim 6 wherein R.sub.2 is selected from
the group consisting of hydroxy, methoxy, mono lower alkyl
carbamate, phenyl carbamate, naphthyl carbamate,
R.sub.5-substituted phenyl carbamate, R.sub.5-substituted naphthyl
carbamate, lower alkanoyloxy benzoyloxy and R.sub.5-substituted
benzoyloxy wherein R.sub.5 is hydroxyl, sulfhydryl, alkyl, aryl,
-alkoxy, mercaptoalkyl, aryloxy, mercaptoaryl, alkaryl,
mercaptoalkaryl, nitro, amino, N-alkylamino, N-arylamino,
N-alkarylamino, fluoro, chloro, bromo iodo or trifluoromethyl.
8. A method according to claim 7 wherein R.sub.3 is selected from
the group consisting of hydrogen, methyl and ethyl.
9. A method according to claim 6, wherein said compound is selected
from O-desmethyl galanthamine; O-demethyl galanthamine, O-methyl
ether; O-desmethyl galanthamine, O-ethyl ether; O-desmethyl
galanthamine, O-benzyl ether; O-desmethyl galanthamine, phenyl and
O-desmethyl N-desmethyl galanthamine, .alpha.-naphthyl carbamates;
O-desmethyl galanthamine dimethyl carbamate and O-desmethyl
galanthamine diethyl carbamate wherein the carbamyl group is bonded
to the oxygen of the cyclohexene ring, O-desmethyl N-desmethyl
galanthamine; O-desmethyl N-desmethyl galanthamine, O-methyl,
O-ethyl and O-benzyl ethers wherein etherification is at the
2-position; O-desmethyl N-desmethyl galanthamine phenyl,
.alpha.-naphthyl, dimethyl and diethyl carbamates wherein the
carbamate substitution is at the 2-position,
O-desmethyl-N-desmethyl-N-et- hyl galanthamine;
O-desmethyl-N-desmethyl-N-ethyl galanthamine, O-methyl, O-ethyl or
O-benzyl ether wherein said etherification is in the 2-position;
O-desmethyl-N-desmethyl-N-ethyl galanthamine phenyl,
.alpha.-naphthyl, dimethyl or diethyl carbamate wherein said
carbamate substitution is in the 2-position;
O-desmethyl-N-desmethyl-N-cyclopropyl methyl galanthamine,
O-methyl, O-ethyl or O-benzyl ether wherein said etherification is
in the 2-position; O-desmethyl-N-desmethyl-N-cyclopropy- lmethyl
galanthamine, O-desmethyl-N-desmethyl-N-cyclopropylmethyl
galanthamine, O-methyl, O-ethyl or O-benzyl ether wherein said
etherification is in the 2-position;
O-desmethyl-N-desmethyl-N-cyclopropy- lmethyl galanthamine phenyl,
.alpha.-naphthyl, dimethyl or diethyl carbamate wherein said
carbamate substitution is in the 2-position;
O-desmethyl-N-desmethyl-N-benzyl galanthamine;
O-desmethyl-N-desmethyl-N-- benzyl galanthamine, O-methyl, O-ethyl
or O-benzyl ether wherein said etherification is in the 2-position,
O-desmethyl-N-desmethyl-N-benzyl galanthamine phenyl,
.alpha.-naphthyl, dimethyl or diethyl carbamate wherein the
carbamate substitution is in the 2-position.
10. A method according to claim 1, wherein said compound is of the
formula: 64wherein R.sup.1, R.sup.2 and R.sup.3 are as defined in
claim 1.
11. A method according to claim 10, wherein the compound employed
is one wherein R.sup.1 is hydroxy, lower alkoxy, benzyloxy or
R.sup.5 substituted benzyloxy, amino alkylamino or alkyl or aryl
carbamyl, R.sup.2 is hydroxy, lower alkoxy, aryloxy, benzyloxy or
an alkyl or aryl carbamyl group and R.sup.3 is hydrogen, methyl,
ethyl, cyclopropyl methyl or benzyl.
12. A method according to claim 11, wherein said compound is
selected from O-desmethyl lycoramine; N-desmethyl, O-desmethyl
lycoramine; N-desmethyl N-ethyl lycoramine; N-desmethyl
N-cyclopropylmethyl lycoramine; N-desmethyl N-benzyl lycoramine;
O-desmethyl lycoramine ethyl ether; 2-deoxy-13-O-desmethyl
lycoramine; 2-O-deoxy-13-O-desmethyl lycoramine, benzyl ether
O-desmethyl lycoramine-dimethyl carbamate, O-desmethyl lycoramine
phenyl carbamate, -2-O-deoxy-13-desmethyl lycoramine dimethyl
carbamate and 2-O-deoxy-13-desmethyl lycoramine dimethyl
carbamate.
13. A method according to claim 1, wherein said compound is of the
formula: 65wherein R.sup.3 is selected from hydrogen, lower alkyl,
cycloalkyl methyl or benzyl.
14. A method according to claim 1 wherein said compound of formula
I is one wherein R.sub.1 is hydroxy, methoxy, ethoxy, acetyloxy or
carbamoyl of the formula CONHR.sub.11 wherein R.sub.11 is selected
from the group consisting of methyl, ethyl, n-propyl, n-butyl,
n-valeryl, phenyl, naphthyl, and fluoro- or nitro-substituted
phenyl or naphthyl, R.sub.2 is hydroxy, methoxy, ethoxy, acetyloxy,
propionyloxy, n-valeroyloxy, i-valeroyloxy or CONHR.sub.11 wherein
R.sub.11 is as defined above and R.sub.3 is hydrogen, methyl or
ethyl.
15. A method according to claim 14, wherein in the compound
employed, the ring to which R.sub.2 is bonded is a cyclohexane
ring.
16. A method according to claim 1 wherein the compound employed is
selected from the group consisting of galanthamine n-butyl
carbamate, galanthamine acetate, O-demethyl
galanthamine-13-methylcarbamate, N-demethyl galanthamine and
childanthine.
17. A method according to claim 1, wherein the administration is
parenteral at a daily dosage of 0.5-1,000 mg of a compound of
formula 1 as specified in claim 1 or a pharmaceutically-acceptable
acid addition salt thereof.
18. A method according to claim 3, wherein the administration is
parenteral at a daily dosage of 0.5-1,000 mg of a compound of as
specified in claim 3 or a pharmaceutically-acceptable acid addition
salt thereof.
19. A method according to claim 10, wherein the administration is
parenteral at a daily dosage of 0.5-1,000 mg of said compound.
20. A method according to claim 13, wherein the administration is
parenteral at a daily dosage of 0.5-1,000 mg of said compound.
21. A method according to claim 1, wherein a compound of Formula I
is administered at a dosage rate of 0.1-300 mg per day.
22. A method according to claims 1, wherein said compound is
administered orally at a dosage in the range 0.1-2000 mg per
day.
23. A method according to claim 3, wherein said compound is
administered orally at a dosage in the range 0.1-2000 mg per
day.
24. A method according to claim 13, wherein said compound is
administered orally at a dosage in the range 0.1-200 per day.
25. A method according to claim 24, wherein said dosage rate of
0.1-200 mg per day.
26. A method according to claim 1, wherein said compound is
administered at a dosage rate of 0.001 to 4 mg/kg body weight of a
patient, parenterally.
27. A method according to claims 1, wherein a compound is
administered intracerebroventricularly via an implanted reservoir
at a dosage rate of 0.0001 to 5.0 mg/kg per day.
28. A method according to any one of claim 1, wherein a compound is
administered in a sustained release formulation.
29. A compound of the formula 66wherein the broken line represents
an optionally present double bond in one of the two positions
shown, R.sub.1 and R.sub.2 are each selected independently from the
group consisting of hydrogen, hydroxyl, amino or alkylamino, cyano,
sulfhydryl, alkoxy preferably of 1-6 carbon atoms, alkylthio,
aryloxy, arylthio, R.sub.5-substituted aryloxy, R.sub.5-substituted
arylthio, aralkoxy, an aliphatic or aryl carbamyl group wherein the
aliphatic or aryl moiety may be R.sub.5 substituted or
unsubstituted, aralkylthio, R.sub.5-substituted aralkoxy,
R.sub.5-substituted aralkylthio, aryloxymethyl, R.sub.5 substituted
aryloxymethyl, alkanoyloxy, hydroxy-substituted alkanoyloxy,
benzoyloxy, R.sub.5-substituted benzoyloxy, aryloxy carbonyl and
R.sub.5-substituted aryloxy carbonyl, R.sub.1 may also by alkyl of
up to 14 carbon atoms, or hydroxy methyl, R.sub.2 may also be keto;
R.sub.2 may also be carboxymethyl provided that at least one of
R.sub.1 and R.sub.2 is hydroxy amino or alkylamino unless R.sub.7
or R.sub.8 is hydroxymethyl, R.sub.3 is hydrogen, straight or
branched chain alkyl, preferably of 1-6 carbon atoms, cycloalkyl
methyl, alkylphenyl, R.sub.5-substituted alkylphenyl, heterocyclic
selected from the group consisting of .alpha.- or .beta.-furyl,
.alpha.- or .beta.-thienyl or thenyl, pyridyl, pyrazinyl or
pyrimidyl groups or R.sub.3 is an alkyl or alkoxy substituted
derivative of said heterocyclic groups or R.sub.3 is alkanoyl of 1
to 8 carbon atoms or aroyl wherein the aryl group is of 6 to 10
carbon atoms, the alkyl and aryl portions of said groups optionally
being substituted by R.sub.5 groups as hereinafter defined or
R.sub.3 is the residue of a compound having adrenergic or monoamino
oxidase activity and is selected from the group consisting of
67wherein Hal is a halogen, preferably chloro, p is 0, 1 or 2, q is
0 or 1, r is 0 or 1 and Z is selected from the group consisting of
68wherein Q is hydrogen or hydroxy, L is hydrogen or C.sub.1-4
alkyl, G is hydrogen, C.sub.1-4 alkyl, alkylphenyl wherein said
phenyl group is optionally substituted by hydroxy or methylene
deoxy, or is alkyl alkanylamino 69wherein G is as defined above,
70c) --CH.sub.2--CH.sub.2NH--NH.sub.2 and 71each R.sub.4 is
independently selected from hydrogen, hydroxyl, sulfhydryl, alkyl,
aryl, aralkyl, alkoxy, mercaptoalkyl, aryloxy, mercaptoaryl,
alkaryloxy, mercaptoalkylaryl, nitro, amino, N-alkylamino,
N-arylamino, N-alkarylamino, fluoro, chloro, bromo, iodo, and
trifluoromethyl, and R.sub.5 is selected from the groups consisting
of hydroxyl, sulfhydryl, alkyl, aryl, alkoxy, mercaptoalkyl,
aryloxy, mercaptoaryl, alkaryloxy, mercaptoalkaryl, nitro, amino,
N-alkylamino, N-arylamino, N-alkarylamino, fluoro, chloro, bromo,
iodo and trifluoromethyl, R.sub.6 is hydrogen, halo,
trifluoromethyl or alkyl of 1 to 4 carbon atoms, R.sub.7 is
selected from the same groups as R.sub.4 or may be hydroxy or
mercapto alkyl of 1-2 carbon atoms, R.sub.8 is hydrogen or
hydroxymethyl, R.sub.9 is hydrogen or alkyl of 1 to 6 carbon atoms,
or when R.sub.2 is hydroxyl R.sub.9 may be 72R.sub.2 and R.sub.9
may jointly form a semi carbazone, oxime, phenyl hydrazone or keto
group, and pharmaceutically-acceptable acid addition salts thereof
with the provisoes that 1) is not methyl when R.sub.1 is methoxy,
R.sub.2 is hydroxy, and all R.sub.4's are hydrogen, 2) that when
the 3-4 bond is saturated that R.sub.1 is not hydrogen when R.sub.2
is methoxy or hydrogen, R.sub.4 is hydrogen, R.sub.3 is methyl and
R.sub.7 is hydrogen or ethoxy, 3) R.sub.1 is not acetoxy when
R.sub.2 is hydroxy, R.sub.3 is methyl, R.sub.4 is hydrogen and
R.sub.7 is hydrogen, 4) when R.sub.2 is hydroxy, R.sub.3 is not
hydrogen or benzyl when R.sub.1 is methoxy and all of R.sub.4 and
R.sub.7 are hydrogen, and 5) that the compound is not leucotamine,
O-methyl leucotamine, O-methyl leucotamine acetate, sanguinine,
lycoramine, O-demethyl lycoramine, childanthine, habranthine,
N-formyl galanthamine, acetyl dihydrogalanthamine or N,O-diacetyl
N-demethyl galanthamine, deoxydemethyl lycoramine,
dihydrochildanthine, sanguinine, dihydrosanguinine lycoramine
acetate, deoxylycoramine or deoxydemethyl, lycoramine
carbamate.
30. A compound according to claim 29, wherein R.sub.1 is CONHR
wherein R is alkyl of 1-6 carbon atoms, phenyl or
R.sub.5-substituted phenyl or naphthyl or R.sub.5-substituted
naphthyl or benzyl or R.sub.5 substituted benzyl wherein R.sub.5 is
selected from hydroxy, sulfhydryl alkyl, aryl, aralkyl, alkoxy,
thioalkyl, aryloxy, thioaryl, alkaryloxy, thioalkaryl, nitro,
amino, N-alkylamino, N-arylamino, fluoro, chloro, bromo, iodo and
trifluoromethyl; R.sub.2 is hydroxy, alkoxy of 1-6 carbon atoms,
alkanoyloxy of 1-6 carbon atoms or CONHR wherein R is as defined
above, R.sub.3 is hydrogen, lower alkyl or cyclopropyl substituted
lower alkyl and R.sub.4, R.sub.6, R.sub.7, R.sub.8 and R.sub.9 are
all hydrogen.
31. A compound according to claim 29 wherein R.sub.1 is hydroxy,
alkoxy of 1-6 carbon atoms or alkanoyloxy of 1-6 carbon atoms,
R.sub.2 is CONHR wherein R is as defined in claim 32, R.sub.3 is
hydrogen, lower alkyl or cyclopropyl substituted lower alkyl and
each of R.sub.4, R.sub.6, R.sub.7, R.sub.8 and R.sub.9 are
hydrogen.
32. A compound according to claim 29: galanthamine n-butyl
carbamate.
33. A compound according to claim 29: galanthamine n-propyl
carbamate.
34. A compound according to claim 29: galanthamine phenyl
carbamate.
35. A compound according to claim 29: galanthamine naphthyl
carbamate.
36. A compound according to claim 29: O-demethyl
galanthamine-13-methyl carbamate.
37. A compound according to claim 29: galanthamine acetate.
38. A pharmaceutical composition for treatment of Alzheimer's
disease and related dementias comprising a compound of the formula
73wherein the broken line represents an optionally present double
bond in one or two of the positions shown, R.sub.1 and R.sub.2 are
each selected independently from the group consisting of hydrogen,
hydroxyl, amino, phenylamino or alkylamino, cyano, sulfhydryl,
alkoxy of 1-6 carbon atoms, alkylthio, aryloxy, aralkoxy, C.sub.1-6
alkyl carbonate or R.sub.5-substituted phenyl or benzyl carbonate,
R.sub.5-substituted aryloxy, R.sub.5-substituted arylthio,
aralkoxy, an aliphatic or aryl carbamyl group wherein the aliphatic
or aryl moiety may be R.sub.5 substituted or unsubstituted,
aralkylthio, R.sub.5-substituted aryloxymethyl, alkanoyloxy,
hydroxy-substituted alkanoyloxy, benzoyloxy, aryloxy carbonyl,
R.sub.1 may also be alkyl of up to 14 carbon atoms, or hydroxy
methyl, R.sub.2 may also be carboxymethyl provided that at least
one of R.sub.1 and R.sub.2 is hydroxy, amino or alkylamino unless
R.sub.7 or R.sub.8 is hydroxymethyl, R.sub.3 is hydrogen, straight
or branched chain alkyl of 1-6 carbon atoms, cycloalkyl methyl,
phenyl, R.sub.5 substituted phenyl, alkylphenyl, R.sub.5
alkylphenyl, heterocyclic selected from .alpha.- or .beta.-furyl,
.alpha.- or .beta.-thienyl or thenyl, pyridyl, pyrazinyl and
pyrimidyl, alkyl heterocyclic or R'-substituted heterocyclyl, where
R' is alkyl or alkoxy and heterocyclyl is selected from .alpha.- or
.beta.-furyl, thienyl, thenyl, pyridyl, pyrazinyl, pyrimidyl or is
methylpyrryl or R.sub.3 is alkanoyl of 1 to 8 carbon atoms or aroyl
wherein the aryl group is of 6 to 10 carbon atoms, the alkyl and
aryl portions of said groups optionally being substituted by
R.sub.5 groups as hereinafter defined or R.sub.3 is the residue of
a compound having adrenergic or monoamino oxidase activity and said
residue being selected from the group consisting of 74wherein Hal
is a halogen, p is 0, 1 or 2, q is 0 or 1, r is 0 or 1 and Z is
selected from the group consisting of 75wherein Q is hydrogen or
hydroxy, L is hydrogen or C.sub.1-4 alkyl, G is hydrogen, C.sub.1-4
alkyl, alkylphenyl wherein said phenyl group is optionally
substituted by hydroxy or methylene deoxy, or is alkylamino
76wherein G is as defined above, 77c) CH.sub.2CH.sub.2NH--NH.sub.2
and 78each R.sub.4 is independently selected from hydrogen,
hydroxyl, sulfhydryl, alkyl, aryl, alkoxy, mercaptoalkyl, aryloxy,
mercaptoaryl, alkarloxy, mercaptoalkaryl, nitro, amino,
N-alkylamino, N-arylamino, N-alkarylamino, fluoro, chloro, bromo
iodo and trifluoromethyl, R.sub.5 is selected from the group
consisting of hydroxyl, sulfhydryl, alkyl, aryl, alkoxy,
mercaptoalkyl, aryloxy, mercaptoaryl, alkaryloxy, mercaptoalkaryl,
nitro, amino, N-alkylamino, N-arylamino, fluoro, chloro, bromo,
iodo and trifluoromethyl, R.sub.6 is hydrogen, halo,
trifluoromethyl or alkyl of 1 to 4 carbon atoms, R.sub.7 is
selected from the same groups as R.sub.4 or may be hydroxy alkyl of
1-2 carbon atoms, R.sub.8 is hydrogen or hydroxymethyl, R.sub.9 is
hydrogen or alkyl of 1 to 6 carbon atoms, or when R.sub.2 is
hydroxyl R.sub.9 may be 79or R.sub.2 and R.sub.9 may jointly form a
keto group provided that R.sub.1 is hydroxy or amino, X is oxygen
or NH Y is nitrogen with the proviso that when X is O, R.sub.3 is
not methyl when R.sub.1 is methoxy, R.sub.2 is hydroxy, all
R.sub.4's are hydrogen and a pharmaceutically acceptable solvent
diluent or carrier.
39. A composition according to claim 38 in the form of a Sustained
release product.
40. A method of treating Alzheimer's disease and related dementias
comprising administering to a patient suffering from such a disease
a therapeutically effective amount of lycoramine.
Description
CROSS REFERENCE TO RELATED APPLICATION
[0001] This application is a continuation-in-part of application
Ser. No. 07/541,076 filed Jun. 21, 1990 which is a continuation of
application Ser. No. 07/219,914 filed on Jul. 15, 1988 which is in
turn a continuation of part of application Ser. No. 07/046,522
filed on May 4, 1987.
[0002] The present invention is directed to galanthamine-analogues
having cholinesterase inhibiting properties and their preparation
and use for treatment of Alzheimer's disease and related dementias,
some of the analogues are novel.
[0003] U.S. Pat. No. 4,663,318 issued on May 5, 1987 describes the
use of galanthamine for the treatment of Alzheimer's disease and
related dementias.
[0004] Published European Patent Application 236684 describes the
use of galanthamine and certain analogues for the treatment of
Alzheimer's disease and related dementias, such analogues are those
wherein the hydroxy group of naturally occurring galanthamine may
be replaced by methoxy, ethoxy or lower alkanoyloxy, the methoxy
group of galanthamine may be replaced by hydrogen, methoxy, ethoxy
or lower alkanoyloxy and the N-bonded methyl group may be replaced
by other straight or branched chain alkyl groups,
cyclopropylmethyl, cyclobutylmethyl or allyl groups or substituted
lower alkyl phenyl groups or wherein other hydrogen atoms are
substituted by chloro or fluoro atoms.
[0005] The literature shows the epigalanthamine wherein the hydroxy
group is in the equatorial position so that hydrogen bond
stabilization of structure is not possible has an
anti-cholinesterase activity of only 10% of galanthamine. (Chem.
Abstr., 77, 109461s)
[0006] A number of galanthamine analogs occur naturally or have
been obtained from natural products including the following
compounds described in the text book The Alkaloids (edited by R. H.
F. Manske published by Academic Press, NY, 15th Edition):
narwedine:
[0007] (also referred to sometimes as galanthaminone) 2
[0008] Narwedine has been reported to have weak anticurare activity
at 3 mg/kg (Chem. Abstr., 78, 131941r) and to have cholinergic
effects on respiration and heart activity, 50-80% lower than
galanthamine (Chem. Abstr., 80, 103864r), Schmidt et al in Acta.
Biol. Med. Ger. 7: 402-410 (1961) report that the
anticholinesterase activity of Narwedine is less than 1% of that of
galanthamine.
[0009] (-) N-demethylgalanthamine: 3
[0010] galanthamine-O-methyl ether: 4
[0011] childanthine: 5
[0012] lycoramine: 6
[0013] It has been reported that the concentration of lycoramine
required to stimulate EEG--recorded activity is about five times
that required for galanthamine (Chem. Abstr., 62, 15306e).
[0014] deoxylycoramine 7
[0015] habranthine: 8
[0016] anhydrogalanthamine: 9
[0017] anhydro-O-demethylgalanthamine: 10
[0018] and N-mesityl and N-benzyl derivatives of galanthamine.
Reference is also made to compounds of the formulae: 11
[0019] The latter compound has been reported to have activity
similar to that of galanthamine (J. Chem. Soc., (C) 1043
(1971).
[0020] An earlier edition of this book had also referred to (+)
N-demethyldihydrogalanthamine of the formula: 12
[0021] N-demethyldihydrogalanthamine is described by Kametani et al
in J. Heterocyclic Chem., 10, 35-37 (1973). The same paper also
refers to galanthamine O, N-diacetate leucotamine 13
[0022] and its O-methyl and O-methyl acetic acid ester are
described by Kobayashi et al in Chem. Pharm. Bull., 33:, 5258-5263
(1985).
[0023] O-demethyldihydrogalanthamine (also known as
O-demethyllycoramine) and O-demethylgalanthamine (sanguinine) are
also described by Kobayashi et al in Chem. Pharm. Bull., 28:,
3433-3436 (1980).
[0024] Subsequently, Kobayashi disclosed the extraction of
O-demethyl lycoramine (also known as dihydrosanguinine) from bulbs
of Lycoris radiata Herb. (Chem. Pharm. Bull., 28: 3433-6 (1980),
Chem. Abstr. 95,25351.
[0025] A bromo-narwedine of the formula: 14
[0026] is described as an intermediate in the synthesis of
galanthamine by Kametani et al in Chem. Comm., 425 (1969) and J.
Chem. Soc. (C), 2602 (1969).
[0027] Chem. Abstr. 61,14727g Chem. Pharm. Bull., 12:1012-20 (1964)
describes the production of compounds of the formula: 15
[0028] wherein R may be hydrogen, methyl or ethyl.
[0029] A dihydro derivative of childanthine obtained by
hydrogenation of the parent compound is described by Boit in Chem.
Ber, 90: 57-9 (1957): Chem. Abstr., 51,8120f.
[0030] Chemical Abstracts 81 638193 describes n.m.r. studies on
dihydrogalanthamine and its acetic acid esters.
[0031] Fales, Giuffrida and Wildman in Journal of American Chemical
Society, 78:4145 (1956) report that the bulbs of King Alfred
daffodils contain the known alkaloids galanthamine, galanthamine,
lycoramine, haemolycoramine, haemanthamine and narcissamine and a
new alkaloid pseudo lycorine. They also reported that narcissamine
has been shown to be N-demethyl galanthamine.
[0032] Latho and Fales in J. Am. Chem. Soc., 4434-4438 (1964).
report that contrary to what had previously been believed,
narcissamine was in fact a mixture of N-demethylgalanthamine and
N-demethyllycoramine.
[0033] Tetsuji Kametani et al. in Yakuyaku Zasshi 12: 1353-1358
(1977) describe a synthetic route to convert 2-benzazepin-3-ones to
galanthamine analogues in anticipation of them having analgesic
activity. Among the analogues including those where the phenol ring
is substituted by bromine or hydroxy methyl on the carbon atom
adjacent to the phenolic hydroxy group.
[0034] In German OS 2945161 there is described the production of
certain narwedine type enones and their derivatives, including
those where the benzene ring is bromo-substituted and the nitrogen
containing ring contains a keto group adjacent to the nitrogen.
[0035] Shimizu et al in Heterocycles, 8: 277-282 (1977) (abstracted
in Chemical Abstracts, 88, 136821t) describe certain narwedine
derivatives used as intermediates having the following formulae:
1617
[0036] Irwin and Smith in Arch. Int. Pharmacodyn., 127:314-330
described the cholinesterase activity of galanthamine and some of
its analogues including lycoramine acetate methiodide, neopin
methiodide (both of which were ineffective) and deoxydemethyl
lycoramine methiodide (which demonstrated good activity) and
deoxylycoramine (which exhibited some activity). It was
hypothesized that the presence of a free hydroxy group in the
cyclohexane ring conferred activity on the molecule since the
acetylation of this group led to a drop in activity.
[0037] In J. Pharm. Exp. Ther., 134:53 (1961), Irwin, Smith and
Hein expanded on the work just described and reported that
replacement of the hydroxyl group of deoxydemethyl lycoramine
methiodide by a carbamate group resulted in useful pharmacological
activity.
[0038] Subsequently, Irwin and Hine, J. Pharm. Exp. Ther., 136:20
(1962) described the activity of a number of carbamates including
deoxydemethyl lycoramine carbamate on cholinesterase activity in
rat brain.
[0039] Subsequently, Somers et al. in Neurology, 13:543 (1663)
reported that some of Irwin's compounds were useful in treating
myasthenia gravis.
[0040] One of the characteristics of Alzheimer's disease and
certain other considerations is a reduction in the amount of acetyl
choline in the brain (see for example, Perry et al British Medical
Journal 2:1457-1459 (1978). Acetylcholine is a compound that is
involved in the transmission of electrical impulses between nerve
endings. Excessive amounts of acetyl choline cause undesirable side
effects so that the brain also contains a cholinesterase enzyme to
prevent build up of acetyl choline. Thus, if the production of
acetyl choline cannot be increased, one way to approach the problem
of low acetylcholine levels is to reduce the amount or activity of
the cholinesterase so that such acetyl choline is present may be
used. Unfortunately, finding a useful treatment for Alzheimer's
disease is not simply a matter of feeding a patient with a
cholinesterase inhibitor. To be effective, a compound must pass the
blood brain barrier easily and distribute itself between the
central and peripheral nervous systems in such a way that its
effect is mainly central, and it must not have significant side
effects. It must have a reasonably long half life in the brain. It
must be reversible to at least some extent (otherwise nerve gasses
would be effective treatment--which they are not) and it must be
able to be formulated in a way that makes it suitable for use by
those suffering from the disease. Loss of acetyl choline in the
brain can exist alongside other conditions where Alzheimer's
disease is not the primary indication where the same neurochemistry
exists. References herein to "related dementias" are intended to
include to such situations. Similar problems of cholinergic
deficiency and dementia accompanied by plaques and tangles in the
brain also arise in the later stages of Down's syndrome which is
similarly a "related dementia".
DETAILED DESCRIPTION OF THE INVENTION
[0041] From one aspect, the present invention-relates to the use of
compounds of the formula I to treat Alzheimer's disease and related
dementias 18
[0042] wherein the broken line represents an optionally present
double bond in one of the two portions shown, R.sub.1 and R.sub.2
are each selected independently from the group consisting of
hydrogen, hydroxyl, amino or alkylamino or phenyl amino, cyano,
sulfhydryl, alkoxy preferably of 1-6 carbon atoms, alkylthio,
aryloxy, arylthio, R.sub.5-substituted aryloxy, R.sub.5-substituted
arylthio, aralkoxy, aralkylthio, R.sub.5-substituted aralkoxy,
R.sub.5-substituted aralkylthio, aryloxymethyl, R.sub.5-substituted
aryloxymethyl, alkanoyloxy, hydroxy-substituted alkanoyloxy,
benzoyloxy, R.sub.5-substituted benzoyloxy, aryloxy carbonyl and
R.sub.5-substituted aryloxy carbonyl and corresponding carbonates,
a mono or dialkyl or aryl carbamyl group or hydroxy methyl, R.sub.1
may also by alkyl of up to 14 carbon atoms, R.sub.2 may also be
halo such as iodo or may be carboxymethyl provided that at least
one of R.sub.1 and R.sub.2 is hydroxy, amino or alkylamino unless
R.sub.7 or R.sub.8 is hydroxymethyl,
[0043] R.sub.3 is hydrogen, straight or branched chain alkyl,
preferably of 1-6 carbon atoms, cycloalkyl methyl, alkylphenyl,
R.sub.5-substituted alkylphenyl, heterocyclic such as .alpha.- or
.beta.-furyl, .alpha.- or .beta.-thienyl or thenyl, pyridyl,
pyrrolyl pyrazinyl or pyrimidyl groups, alkyl heterocyclic and
R'-substituted heterocyclic, where R' is alkyl or alkoxy or
[0044] R.sub.3 is alkanoyl of 1 to 8 carbon atoms or aroyl wherein
the aryl group is of 6 to 10 carbon atoms, the alkyl and aryl
portions of said groups optionally being substituted by R.sub.5
groups as hereinafter defined or R.sub.3 is the residue of a
compound having adrenergic or monoamino oxidase activity and is
selected from the group consisting of 19
[0045] wherein Hal is a halogen, preferably chloro, p is), 1 or 2,
q is 0 or 1, r is 0 or 1 and Z is selected from the group
consisting of 20
[0046] wherein Q is hydrogen or hydroxy, L is hydrogen or C.sub.1-4
alkyl, G is hydrogen, C.sub.1-4 alkyl, alkylphenyl wherein said
phenyl group is optionally substituted by hydroxy or methylene
deoxy, or is alkyl alkanylamino 21
[0047] wherein G is as defined above,
[0048] iii) --C--CH--N--(C.sub.1-4 alkyl) --O--CH.sub.3.(C.sub.1-4
alkyl) 22
[0049] b) --CH--CH--NH, CH.sub.2
[0050] c) --CH.sub.2--CH.sub.2NH NH.sub.2 and 23
[0051] each R.sub.4 is independently selected from hydrogen,
hydroxyl, sulfhydryl, alkyl, aryl, aralkyl, alkoxy, thioalkoxy,
aryloxy, thioaryloxy, alkylarlyoxy, alkylmercaptoaryloxy, nitro,
amino, N-alkylamino, N-arylamino, N-alkarylamino, fluoro, chloro,
bromo iodo and trifluoromethyl, and R.sub.5 is selected from the
same groups as R.sub.4,
[0052] R.sub.6 is hydrogen, halo, trifluoromethyl or alkyl of 1 to
4 carbon atoms,
[0053] R.sub.7 is selected from the same groups as R.sub.4 or may
be hydroxy alkyl of 1-2 carbon atoms,
[0054] R.sub.8 is hydrogen or hydroxymethyl,
[0055] R.sub.9 is hydrogen, alkyl of 1 to 6 carbon atoms, phenyl or
benzyl, or when R.sub.2 is hydroxyl R.sub.9 may be a moiety of
formula I wherein R.sub.9 is hydrogen and R.sub.2 is a linking
bond; or R.sub.2 and R.sub.9 may jointly form a semicarbazone,
oxime, phenylhydrazone or a keto group
[0056] X is oxygen or NR.sub.5,
[0057] Y is nitrogen,
[0058] and methylenedioxy derivatives thereof with the proviso that
when X is O, R.sub.3 is not methyl when R.sub.1 is methoxy, R.sub.2
is hydroxy, and all R.sub.4 are hydrogen or a
pharmaceutically-acceptable acid addition salt thereof. When there
is no unsaturation in the 1,2 carbon bond, R.sup.2 is preferably
oriented axially to the cyclohexane ring. When Rand R.sub.9 jointly
form a single group it is normally desirable that R.sub.1 be
hydroxy or amino.
[0059] Preferably the aryl groups are phenyl or naphthyl or in the
case of R.sup.2 when this is a carbamate group, 1-naphthyl groups,
the aryloxy groups are phenoxy groups, the aralkyl groups are
benzyl groups and the aralkyloxy groups are benzyloxy groups.
[0060] Preferred compounds include those wherein R.sup.1 and
R.sup.2 are each selected from H, OR, 24
[0061] --CH.sub.2--OH , --CONHR 25
[0062] wherein R is alkyl 1-6 carbon atoms, phenyl or naphthyl
R.sup.5-substituted phenyl naphthyl or benzyl wherein R.sub.10 is
hydrogen, alkyl or alkoxy,
[0063] R.sub.3 is --H, or branched on linear lower alkyl or
--CH.sub.2--CH (CH.sub.2).sub.n
[0064] wherein n is 3, 4 or 5 or 26
[0065] wherein R.sub.10 is as defined above.
[0066] Preferred R.sub.3 groups are normally electron-donating such
as lower alkyl groups such methyl and tertiary butyl and phenyl and
substituted phenyl groups such as hydroxy phenyl, p-alkoxy phenyl,
p-amino phenyl and p-alkyl phenyl. However, groups such as benzyl
and benzoyl may also be of use.
[0067] X is preferably oxygen and Y is nitrogen.
[0068] When used herein the term "lower alkyl" means alkyl of 1-6
carbon atoms, preferably 1-4 carbon atoms, most commonly methyl or
ethyl.
[0069] Compounds likely to be of particular use are those wherein
R.sub.3 is hydrogen, lower alkyl or cyclopropyl methyl and R.sub.1
and R.sub.2 are each independently hydroxy, lower alkoxy, lower
alkanoyl or benzoyl or carbamate groups and the analogous dihydro
compounds wherein the cyclohexene ring of galanthamine is
saturated. Thus, R.sub.1 may typically be hydroxy, methoxy, ethoxy
or carbamoyl of the formula CONHR.sub.11 wherein R.sub.11 is
methyl, ethyl, n-propyl, n-butyl, n-valeroyl, phenyl, naphthyl or
fluoro or nitro substituted phenyl or naphthyl, R.sub.2 may
typically be hydroxy, methoxy, ethoxy, acetyloxy, propionoyloxy,
n-valeroyloxy, i-valeroyloxy, or CONMR.sub.11 wherein R.sub.11 is
as defined above. R.sub.3 is typically hydrogen, methyl or
ethyl.
[0070] Particularly preferred compounds include childanthine,
lycoramine, galanthamine esters and galanthamine--and O-demethyl
galanthamine carbamates and the corresponding N-demethyl compounds.
The galanthamine and O-demethyl galanthamine carbamates are
believed to be novel compounds.
[0071] One class of compounds according to the present invention
are those of the formula: 27
[0072] wherein R.sup.1 is as defined above, preferably hydroxy,
lower alkoxy, aryloxy, substituent aryloxy, benzyloxy or R.sup.5
substituted benzyloxy, amino, alkyl amino or an alkyl or aryl
carbamyl group.
[0073] For example, such compounds include O-demethyl,
N-demethylgalanthamine; O-ethyl, O-demethyl,
N-demethylgalanthamine; O-phenyl, O-demethyl,
N-demethylgalanthamine; and O-benzyl, O-demethylgalanthamine.
Useful carbamates may include phenylcarbamyl O-demethyl,
N-demethylgalanthamine; mono .alpha.-naphthylcarbamyl O-demethyl
N-demethyl galanthamine and dimethylcarbamyl O-demethyl,
N-demethylgalanthamine.
[0074] A second class are those of the formula: 28
[0075] wherein R.sup.2 is hydroxy, lower alkoxy, aryloxy, mono or
di alkyl or aryl carbamates R.sup.5 substituted aryloxy benzyloxy
or R.sup.5 substituted benzyloxy or an alkyl or aryl carbamyl group
and R.sup.3 is hydrogen or alkyl of 1-6 carbon atoms such as methyl
ethyl, methyl cyclopropyl, benzyl or benzoyl or R.sup.5-substituted
benzyl or benzoyl. Suitable R.sub.3 groups are as described above.
Such compounds include O-demethylgalanthamine childanthine;
O-demethylgalanthamine; 2-O-methyl ether; O-demethyl
galanthamine-2-O-ethyl ether, O-demethylgalanthamine-2-- O-benzyl
ether; O-demethylgalanthamine-2-O-phenyl ether and O-demethyl
N-demethylgalanthamine, 2-naphthyl carbamate;
O-demethylgalanthamine-2-(l- ower alkyl) carbamates such as n-butyl
carbamate, O-demethylgalanthamine-2- -dimethyl carbamate and
O-dimethylgalanthamine-2-diethyl carbamate wherein the carbamyl
group is bonded to the oxygen of the cyclohexene ring, and the
corresponding N-demethyl and N-demethyl N-ethyl and N-demethyl
N-cyclopropyl methyl and N-demethyl N-benzyl compounds.
[0076] O-Demethyl-N-demethyl-N-ethyl galanthamine;
O-demethyl-N-demethyl-N- -ethyl galanthamine, O-methyl, O-ethyl or
O-benzyl ether wherein said etherification is in the 2-position;
O-demethyl-N-demethyl-N-ethyl galanthamine phenyl,
.alpha.-naphthyl, dimethyl or diethyl carbamate wherein said
carbamate substitution is in the 2-position;
O-demethyl-N-demethyl-N-cyclopropyl methyl galanthamine, O-methyl,
O-ethyl or O-benzyl ether wherein said etherification is in the
2-position; O-demethyl-N-demethyl-N-cyclopropylmethyl galanthamine,
O-demethyl-N-demethyl-N-cyclopropylmethyl galanthamine, O-methyl,
O-ethyl or O-benzyl ether wherein said etherification is in the
2-position; O-demethyl-N-demethyl-N-cyclo-propylmethyl galanthamine
phenyl, .alpha.-naphthyl, dimethyl or diethyl carbamate wherein
said carbamate substitution is in the 2-position;
O-demethyl-N-demethyl-N-benzyl galanthamine;
O-demethyl-N-demethyl-N-benzyl galanthamine, O-methyl, O-ethyl or
O-benzyl ether wherein said etherification is in the 2-position,
O-demethyl-N-demethyl-N-benzyl galanthamine phenyl,
.alpha.-naphthyl, dimethyl or diethyl carbamate wherein the
carbamate substitution is in the 2-position.
[0077] A third class of compounds comprises those of the formula:
29
[0078] wherein R.sup.1, R.sup.2 and R.sup.3 are as defined above,
R.sup.1 typically being hydroxy, amino lower alkoxy, benzyloxy or
R.sup.5 substituted benzyloxy, amino alkylamino or alkyl or aryl
carbamyl, R.sup.2 is hydroxy, lower alkoxy, aryloxy, benzyloxy or
an alkyl or aryl carbamyl group but is preferably hydroxy and
R.sup.3 is typically hydrogen, methyl, ethyl, cyclopropylmethyl,
phenyl, p-hydroxy phenyl, p-aminophenyl, p-alkoxyphenyl or
p-alkylphenyl or benzyl.
[0079] Such compounds include, for example, O-demethyl lycoramine;
N-demethyl, O-demethyl lycoramine; N-demethyl N-ethyl lycoramine;
N-demethyl-N-cyclopropylmethyl lycoramine; N-demethyl N-benzyl
lycoramine; O-demethyl lycoramine ethyl ether; deoxy O-demethyl
lycoramine; O-deoxy demethyl lycoramine, benzyl ether and dimethyl
and phenyl carbamyl analogs of such compounds.
[0080] A further class comprising compounds of the formula: 30
[0081] wherein R.sup.3 is selected from hydrogen, lower alkyl,
cycloalkyl methyl or benzyl.
[0082] A further class of compounds are narwedine derivatives where
R.sub.1 is hydroxy and R.sub.3 as defined above, typically
hydrogen, lower alkyl, cycloalkyl methyl or benzyl. Such compounds
many contain R.sub.4 and R.sub.6 substituents as noted above.
[0083] Compounds of the above formula I where R.sub.2 is hydroxyl
and R.sub.9 is a moiety of formula I wherein R.sub.9 is hydrogen
and R.sub.2 is a linking bond are compounds in which the structure
of formula I has linked at ring position 2 a hydroxyl group and a
second formula I structure wherein R.sub.2 is a bond linking the
second formula I structure to said position 2 of the first and in
said second formula I structure, R.sub.9 is hydrogen. Such
compounds may be made by reacting a compound of formula I wherein
R.sub.2 is hydroxyl to convert the hydroxyl to a halide, reacting
the halide to form a Grignard compound, and reacting the latter
with a galanthamine ketone.
[0084] Useful compounds may include the following: 313233
[0085] The novel compounds of the present invention in addition to
their use for treatment of Alzheimer's disease can find use in a
variety of other circumstances where cholinesterase inhibition is
desired.
[0086] Many compounds of the present invention may be obtained by
effecting suitable conversions of galanthamine. Galanthamine has
the structure: 34
[0087] Compounds wherein R.sub.1 is other than methoxy can be
obtained from galanthamine by demethylation to the corresponding
phenol and, if desired, effecting subsequent conversion thereon.
Demethylation may be effected with iodotrimethylsilane in
accordance with the method described by M. E. Jung and M. A. Lyster
in J. Org. Chem. 42 3761 (1977). Reaction with iodotrimethylsilane
way be effected in any convenient solvent, for example, chloroform
at moderate temperatures (typically 25-40.degree. C.) for several
hours (e.g. 12-20 hours) to cleave the methyl group.
[0088] The phenol obtained by this reaction may be employed itself
or used as an intermediate for the production of other active
compounds. If it is desired to avoid effecting the same reactions
at the allylic hydroxy group in the C ring as are to take place at
the phenol group, that is produced by demethylation of the A ring,
it is desirable to protect the allylic hydroxyl group when carrying
out further interconversions. Suitable protection can be effected
by converting the allylic hydroxyl group to its tetrahydropyranyl
ether or 4-methoxytetra-hydropyranyl ether. Such ethers can be
formed by reaction with dihydropyran or 4-methoxytetra-hydropyran
in a solvent such as dichloromethane at room temperature, and in
the presence of a strong organic acid such as p-toluenesulfonic
acid. When desired, the protective groups can be removed, the
tetrahydropyranyl group, for example, by treatment with methanol
and Dowex-50 WX8 and the 4-methoxytetrahydropyranyl group by
reaction with very dilute (e.g., 0.01N) hydrochloric acid.
[0089] The phenolic group obtained by demethylation of the methoxy
group of galanthamine may readily be converted into an alkali metal
salt by reaction with sodium or potassium hydroxide or reaction
with sodium hydride in tetrahydrofuran. The salt so obtained may be
"alkylated" by reaction with an appropriate alkyl, aryl, alkaryl or
R.sub.5-substituted aryl or alkaryl or heterocyclic or
R.sub.5-substituted heterocyclic halide to produce a compound
wherein R.sub.1 is alkoxy (other than methoxy), aryloxy,
alkaryloxy, R.sub.5-substituted aryloxy, R.sub.5-substituted alkoxy
or heterocyclic or R.sub.5-substituted heterocyclic. The reaction
with the halide is typically run with excess halide in the absence
of solvent or in a solvent such as dimethyl formamide or
dimethylsulfoxide. For less reactive halides, the presence of a
silver oxide catalyst may be desirable.
[0090] Reaction of the phenolic group with an isocyanate can be
used to introduce a monoalkyl or monoaryl carbamyl group.
[0091] Dialkyl or diaryl carbamates may be obtained [by] from the
mono alkyl or aryl carbamates by reaction with sodium hydride and
an alkyl or aryl iodide. For example, the dimethyl carbamate can be
obtained by reaction of the hydroxy group with methyl isocyanate
followed by reaction with sodium hydride and methyl iodide.
[0092] Conversion of the phenolic group to an amino group, which
can subsequently be alkylated by conventional means to produce a
secondary amine if desired, can be effected by the Bucherer
reaction using sodium bisulfite and ammonia.
[0093] The phenol group may be esterified, for example, with an
acid anhydride or acid halide to produce an alkanoyloxy or
aralkanoyloxy, R.sub.1 group.
[0094] Production of compounds wherein R.sub.1 is sulfhydryl or an
alkyl-, aryl-, aralkylthio group can be effected by first
converting the phenolic hydroxyl group obtained by demethylation of
galanthamine to a thiol group. This can be effected, for example,
by the Newman-Kwart rearrangement described, for example, in S.
Patai ed "The Chemistry of the Thiol Group" Part 1 John Wiley &
Sons, New York 1974 pages 201-206. This rearrangement is effected
in three steps:
[0095] (1) conversion of the hydroxyl group to the O-aryl
dialkylthiocarbamate by treatment with dialkylthiocarbonyl
chloride;
[0096] (2) pyrolysis of the O-aryl dialkylthio-carbamate to the
S-aryl dialkylthiocarbamate; and
[0097] (3) hydrolysis of this product to the aryl mercaptan.
[0098] The first stage reaction wish dimethylthio-carbamyl chloride
may be effected by dissolving the phenol obtained by demethylation
of galanthamine in aqueous potassium hydroxide at 10.degree. C. or
below and then reacting this with dimethylthiocarbamyl chloride in
tetrahydrofuran at temperatures not exceeding 12.degree. C. The
solution is made alkaline and the O-aryl dimethyl-thiocarbamate is
separated. This compound is pyrolyzed at 270-275.degree. C. for
about 45 minutes in a salt bath, and treated with potassium
hydroxide in ethylene glycol. The reaction is cooled, the product
extracted and worked up.
[0099] The thiol group can be converted to an alkali metal salt if
desired by reaction with sodium or potassium hydroxide or sodium
hydride. This salt may be alkylated to produce compounds wherein
R.sub.1 is alkylthio, arylthio, aralkylthio or alkarylthio by any
one of a wide variety of alkylating agents, for example, as
described by P. D. Boyer in J. Amer. Chem. Soc., 76:4331
(1954).
[0100] The production of the thiol group also provides a convenient
route for the production of compounds wherein R.sub.1 is hydrogen.
The thiol may be desulfurized, for example, by refluxing with Raney
nickel in absolute alcohol or dioxane, for example, as described by
R. L. Augustine "Catalytic Hydrogenation" Marcel Dekker Inc., New
York 1965 pp 131-133.
[0101] Production of a galanthamine analogue where R.sub.2 is an
alkanoyloxy or benzoyl group can be obtained by a simple
esterification reaction. Compounds wherein R.sub.2 is alkyloxy,
aryloxy, aralkyloxy or alkaryloxy may be formed by forming a salt
of the alcohol by reaction with sodium and thereafter reacting the
salt with alkyl or other halide as described above for alkylating a
phenol salt to produce R.sub.1 as other than methyl.
[0102] Similarly, reaction of the hydroxy group with an aryl or
alkyl isocyanate will produce compounds wherein R.sub.2 is a
monoaryl or monbalkyl carbamate.
[0103] In other transformations of the R.sub.2 group, the first
step in modification will normally be conversion of the allylic
alcohol into an allylic bromide by reaction with bromine or an
alkyl bromide. This may be effected by reaction with a slight
excess of carbon tetrachloride and triphenylphosphine in a solvent
such as methylene chloride at reduced temperature, for example,
around 0.degree. C. The bromide may then be reacted with magnesium
in a Grignard reaction and the Grignard reagent obtained reacted
with water to produce a compound wherein R.sub.2 is hydrogen.
Alternatively, reaction of the allylic bromide with lithium
aluminum hydride may achieve the same product.
[0104] The allyl bromide may also be used as an intermediate for
the introduction of other groups into the C ring. For example, the
bromide will react with nucleophiles such as sodium or potassium
hydrosulfide to replace the bromo group by a hydrosulfuryl group or
with sodium cyanide to introduce a cyano group. The hydrosulfuryl
group may be converted into a salt and alkylated in the same ways
as can a hydrosulfuryl group in the A ring.
[0105] The allylic hydroxyl group may also be converted into a keto
group. This can be accomplished, for example, by reaction with
Jones reagent (H.sub.2CrO.sub.4, H.sub.2SO.sub.4 water and
acetone). Proceeding via the keto group may also be an alternative
route to production of compounds wherein R.sub.2 is hydrogen. For
example, the keto compound may be reacted with ethane dithiol and
boron trifluoride etherate and the 1,3-dithiolane produced then
desulfurized by reaction with Raney nickel.
[0106] The ketone intermediate may also be used as a source for
compounds wherein R.sub.2 is amino, such compounds being obtained
by reductive amination of the keto group with ammonia and hydrogen
in the presence of a nickel catalyst.
[0107] Further analogues that can be obtained by use of the ketone
as an intermediate are those wherein R.sub.9 is other than
hydrogen. These can be obtained by reaction of the ketone with a
Grignard reagent.
[0108] The ketone may also be used as an intermediate for the
production of compounds wherein R.sub.7 is hydroxy methyl by first
effecting an .alpha.-bromination of the ketone and then converting
this to hydroxy methyl.
[0109] When R.sub.2 and R.sub.9 jointly form a semicarbazone this
can be formed from the ketone by reaction with semicarbazide.
[0110] The corresponding oxime and phenylcarbazones may also be
obtained from the keto compound by reaction with hydroxylamine and
phenylhydrazine respectively.
[0111] In order to produce compounds wherein R.sub.3 is other than
methyl, galanthamine is first demethylated to produce a compound
wherein R.sub.3 is hydrogen. Demethylation may be effected by
reaction with a chloroformate such as methyl chloroformate or
phenyl chloroformate to produce a carbamate which may then be
cleaved with hydrazine, or by reaction with
.beta.,.beta.,.beta.-trichloromethyl trichloromethyl chloroformate
followed by reaction with zinc and acetic acid. In an alternative
N-demethylation route, the hydroxy group is first protected by
acetylation and the acetyl ester then reacted with 1-chloroethyl
chloroformate in a halogenated solvent to replace the N-methyl
group by a --COOCHClCH.sub.3 group which may itself be removed by
heating in methanol. The resulting amine may then be alkylated with
other alkyl groups, branched or unbranched, alkylphenyl group or
alkylheterocyclic groups. This reaction may be carried out by
converting --NH to the corresponding sodium or potassium salt (NaH,
KH) and treating the salt with the corresponding halide, preferably
iodides, but bromides and chlorides might be used. All the halides
used are commercially available. The reaction conditions may be
modified for less reactive halides such as chlorides or aryl or
heterocyclic halides which may also be less reactive. For instance,
a special method is needed for N-phenylation as described by D. H.
R. Barton, J. P. Finet and J. Khamsi, Tetrahedron Lett., 28:887
(1987).
[0112] A chlorine atom may be introduced to the cyclohexenol ring
of galanthamine by reaction with an acid chloride of a strong
organic sulfonic acid such as p-toluene sulfonyl chloride. This
reaction proceeding with simultaneous elimination of the hydroxyl
group to produce: 35
[0113] which may itself be used as an intermediate to react with
nucleophiles such as alkoxides, azides and cyanides to introduce
such groups into the ring at the 2 or 4 positions.
[0114] It is also possible to change the degree of saturation of
the "core" structure of galanthamine. For example, if one forms an
allylic bromide in the C-ring as described above, this bromide may
be subject to catalytic hydrogenation in the presence of palladium,
for example, palladium on carbon in ethanol at room temperature and
atmospheric pressure to remove not only the bromine atom, but also
to saturate the unsaturated bond in the C ring.
[0115] The C-ring may be oxidized to produce a further unsaturated
bond by oxidation, for example, by heating with nickel, platinum or
palladium at 300-350.degree. C. or possibly under milder conditions
if acceptors such as maleic acid, cyclohexene or benzene are
present.
[0116] The oxygen of the B ring of galanthamine may be replaced by
N--R' by reaction with ammonia or an amine in the gas phase at high
temperatures in the presence of activated aluminum oxide or
aluminum silicate as described, for example, in Yu. K. Yur'ev and
E. G. Vendel'shtein, Zh. Obshch. Khim., 21: 259 (1951); Chem.
Abstr., 45:7564 (1951); Ibid. 23, 2053 (1953); Chem. Abstr., 49:
3120 (1955); H. Sugisawa and K. Aso, Tohoku J. Agr. Res., 10: 137
(1959); Chem. Abstr., 54: 11015 (1960).
[0117] R.sub.6 substituents may be introduced into the D-ring for
example by Procedure No. 4 hereinafter.
[0118] Conversion of R.sub.8 to hydroxy methyl may be effected by
photolysis in the presence of cyanogen chloride to introduce a
cyano group. This may be reduced using a Raney nickel catalyst to
produce an aldehyde group that can itself be reduced to hydroxy
methyl.
[0119] Similar conversions can be effected using lycoramine as
starting material to produce compounds wherein the C ring is
saturated.
[0120] In addition to modifying galanthamine, compounds according
to the present invention may also be produced by cyclizing an amide
of the formula: 36
[0121] R.sub.1, R.sub.3 and R.sub.4 groups may be selected as
desired in the starting material employed. Cyclization is effected
by electrochemical oxidation of the type described in U.S. Pat. No.
4,290,862 for preparing narwedine-type enones. The linear precursor
in an appropriate solvent with a conductive salt and 2% HBF, or
KC10.sub.4 or K.sub.2CO.sub.3 is added to the anode compartment of
an electrolytic cell. The cathode compartment and the electrolytic
bridge of the reference electrode contains the same anodic solvent
and the same percentage of conductive salt. The working electrode
is platinum. Oxidation is carried out at 1.3 volts at low
temperatures (below 0.degree. C.). This procedures after workup of
the product affords cyclization products.
[0122] Choice of a suitably substituted starting material permits
the production of final products where the R.sub.4 groups are other
than hydrogen.
[0123] Procedures:
[0124] 1. Conversion of Oxygen to Nitrogen in Furanoid Ring.
[0125] This transformation has been accomplished by several
authors. Passage of furan and its homologs, or reduced furans with
ammonia over alumina, at 400-450.degree. C., affords the
corresponding pyrroles. With primary, amines the N-substituted
pyrrole is obtained. A typical procedure is as follows. The furan
derivative is dissolved in liquid ammonia and passed over an
alumina catalyst (200 c.c. 4-6 mesh) which has been preheated to
400.degree. C..sup.1 Alternatively, a mixture of a furan derivative
and ammonia in aqueous-alcoholic medium may be heated at
temperature around 110-150.degree. C. The reaction proceeds more
readily under pressure and therefore can be carried out in an
autoclave..sup.2 1. C. L. Wilson, J. Chem. Soc., 63, (1945). 2. R.
C. Fuson, C. L. Fleming, R. Johnson, J. Am. Chem. Soc. 60: 1994
(1938).
[0126] 2. Introduction of --CH.sub.2OH at Position 16.
[0127] Position 16 is next to the furan ring. This position is
equivalent to the a-position of an ether and therefore prone to
radical attack by reagents such as oxygen, peroxides, and
photochemical reactions.
[0128] Irradiation of cyclic ethers in the presence of cyanogen 3.
chloride is known to produce a-cyano ethers in good yields..sup.1
Therefore, a similar reaction on galanthamine should introduce a
cyano group in this position. The cyano group is known to be
converted to an aldehyde with Raney Nickel and formic acid..sup.2
The aldehyde may in turn be reduced with any reducing agents to the
hydroxymethyl group..sup.3 1. E. Muller, H. Huber, Chem. Ber. 96,
2319 (1963). 2. T. van Es, B. Stakun, J. Chem. Soc. 5775 (1965). 3.
S. R. Sandler, W. Karo, "Organic Functional Group Preparations",
Vol. 12, 1968. Academic Press, pp. 89-90.
[0129] A typical procedure is as follows. The photolysis is carried
out using a mercury lamp S-81 in a water cooled, unfiltered quartz
immersion well. A solution of equimolar amounts of galanthamine and
cyanogen chloride, in a spectral grade solvent, is irradiated with
stirring, in a nitrogen atmosphere, and in a quartz cell. The
reaction is irradiated for 2 h in the presence of sodium
bicarbonate. The sodium bicarbonate is essential to absorb the
hydrogen chloride. Lower yields are obtained in the absence of the
reagent.
[0130] The final mixture is filtered, concentrated, washed with
appropriate reagents and dried. Removal of solvent affords the
product.
[0131] The cyano derivative obtained is dissolved in 75% (v/v) of
aqueous formic acid and treated with a 50:50 Ni--Al alloy (Raney
type). The mixture is heated for 3 h at 95C., diluted with absolute
ethanol-ethyl acetate and filtered through Celite. The filtrate is
concentrated, washed with appropriated reagents and dried. Removal
of solvent affords the product.
[0132] The aldehyde derivative is dissolved in isopropanol and
added to a solution of sodium hydroxide and sodium borohydride,
dropwise, at such rate that the reaction refluxes gently. After
standing overnight, the reaction is worked up as usual.
[0133] 3. Conversion of --OMe at Position 13 to Other
Substituents.
[0134] The reaction will require demethylation of the methoxy
group. Although demethylation of aromatic alkoxy group is
considered a standard reaction, this operation may be tricky in
polysubstituted systems. A successful approach is the reaction of
boron tribromide at 0.degree. C..sup.1 The phenol obtained may be
converted to a bromide by standard procedure..sup.2 Generation of a
lithium anion at this position.sup.3 allows a variety of reactions
such as treatment with alkyl halides to give alkyl groups, carbon
dioxide to afford acids or aldehydes and ketones to give alcohols.
1. S -Y Han, J. T. Gordon, K. Bhat, M. B. Dratman, M. M. Joullie',
Int. J. Peptide Protein Res., 30:652 (1987). 2. C. E. Kaslow and M.
M. Marsh, J. Org. Chem., 12: 456 (1947). 3. J. Chiarello and M. M.
Joullie', Tetrahedron, 44:41 (1988).
[0135] A typical procedure follows. A 1M solution of boron
tribromide is added dropwise to a solution of galanthamine in dry
methylene chloride at 0.degree. C., under nitrogen. After stirring
at 0.degree. C. for 3 h, the excess reagent and boron complexes are
hydrolyzed by water. The product is obtained by extraction of the
aqueous layer with ether. Removal of the solvent affords the
compound.
[0136] The phenol derivative is mixed thoroughly with phosphorous
pentabromide and heated at 70-80.degree. C., then at 120.degree. C.
Hydrolysis with ice and water affords the crude bromo compound
which may be recrystallized from an appropriate solvent.
[0137] A solution of n-butyl lithium was added dropwise, at
-78.degree. C., under argon, to the bromo derivative dissolved in
tetrahydrofuran and hexamethylphosphoramide to generate the
intermediate anion.
[0138] To this anion, one may add any alkyl halide to form the
corresponding derivative. Alternatively, the solution could be
poured over dry ice to afford the corresponding carboxylic acid, or
to an aldehyde or ketone to form the corresponding alcohol
derivative.
[0139] Treatment of this anion with ethyl chloracetate would give
the corresponding ethyl-carboxymethyl derivative. The above
methodology is general to introduce various groups in place of the
methoxy group in the aromatic ring (position 13).
[0140] 4. Conversions in the D Ring
[0141] Removal of the methyl group in the D ring of galanthamine
can be accomplished by the classical von Braun reaction..sup.1 The
reaction may be manipulated to give either demethylation to a
secondary amine or to open the ring. Either of these procedures
will give rise to new analogs. Ring opening would afford two
chains, one at position 10, possibly a bromoethyl groups and one at
position 5, a N-methylpropylamine. These could be used to study the
effect of disrupting ring D.
[0142] However, demethylation would serve to introduce
functionality in ring D via the formation of an imine. A typical
procedure for introduction of substituents in ring D follows.
Treatment of N-demethylated galanthamine with tert-butyl
hypochlorite at 0.degree. C. will afford the N-chloro derivative.
This sensitive compound is not isolated but immediately
dehalogenated with either sodium methoxide or diazabicycloundecene
to afford the highly unstable pyrroline. This intermediate can be
treated with nucleophiles.sup.3 or with benzoic and,
tert-butylisonitrile as described in reference 2. 1. H. A.
Hagerman, Org. Reactions, VII, Chap 4 (1953). 2. R. F. Nutt, M. M.
Joullie', J. Am. Chem., Soc., 104, 5852(1982). 3. J. Hausler, U.
Schmidt, Liebigs Ann. Chem. 1881 (1979).
[0143] The compounds of the present invention may be used for the
treatment of Alzheimer's disease either in free base form or as the
acid addition salts.
[0144] The compounds can be administered in any convenient chemical
or physical form. For example, they may be administered as
pharmaceutically acceptable salts, as long as these do not
quaternize the D-ring nitrogen atom. Useful salts include the
hydrobromide and hydrochloride.
[0145] The compounds or the pharmaceutically-acceptable acid
addition salts may be administered to a patient suffering from
Alzheimer's disease orally or by subcutaneous or intravenous or
injection. Sustained release delivery mechanisms are particularly
useful for administration of the compounds of the present
invention, for example, intracerebroventricularl- y by means of an
implanted reservoir by use of sustained release capsules or by
means of a trans dermal patch. It may be necessary to begin at
lower doses than are ultimately effective.
[0146] Certain of the compounds may be only sparingly soluble in
water at room temperature and so injectable compositions are
normally in the form of an aqueous suspension. If necessary,
pharmaceutically-acceptable suspension aids may be employed.
Typically, such a suspension will be employed at a concentration of
1-50 mg/ml more commonly 5-40 mg/ml, for example, 5-30 mg/ml or
10-40 mg/ml, typically 20-30 mg/ml of the compound of the present
invention. Typical dosage rates when administering compounds of the
invention will depend upon the exact nature and condition of the
patient. For example, typical dosage rates for administration by
injection are in the range 5-1,000 mg per day depending upon the
patient. In some cases, even lower dosages such as 0.5 or 1 mg per
day may be helpful. For example, divided doses in the range 0.5-5
mg/kg body weight per day may prove useful. Typically, one might
administer a dosage of 50-300 mg per day to a patient of a body
weight of 40-100 kg, although in appropriate cases such dosages may
prove useful for patients having a body weight outside this range.
In other cases, dosages as low as 0.1 mg and as high as 500 mg may
be appropriate for persons in this body weight range.
[0147] The compounds of the invention may also be administered
orally, for example, as an aqueous suspension or a solution in
aqueous ethanol or as a solid such as a tablet or capsule.
Suspensions or solutions for oral administration are typically of
about the same concentration as those used for injections. However,
it may be desirable when administering the drug orally to use a
higher dosage rate than when administering it by injection. For
example, dosages up to 200 mg per day may be used, such as dosages
in the range 10-60 mg per day. In preparing such tablets or
capsules, standard tablet or capsule-making techniques may be
employed. The dosage rate of the compound of the invention or its
pharmaceutically-acceptable salt will normally be in the same range
as for oral administration of a liquid. If desired, a
pharmaceutically-acceptable carrier such as starch or lactose may
be used in preparing tablets. Capsules may be prepared using soft
gelatine as the encapsulating agent. If desired, such capsules may
be in the form of sustained release capsules wherein the main
capsule contains microcapsules of active compound which release the
contents over a period of several hours thereby maintaining a
constant level of active compound n the patient's blood stream.
[0148] The following test provides a good animal model for
Alzheimer's disease in humans: A selective lesion is placed in a
subcortical nucleus (nucleus basalis of Meynert) with a resultant
cortical cholinergic deficiency, similar in magnitude to that seen
in early to moderate stage Alzheimer's disease. Numerous behavioral
deficits, including the inability to learn and retain new
information, characterizes this lesion. Drugs that can normalize
these abnormalities would have a reasonable expectation of efficacy
in Alzheimer's disease. Haroutunian, V, Kanof P, Davis, K L:
Pharmacological alleviations of cholinergic-lesion-induced memory
defects in rats. Life Sciences, 37:945-952 (1985).
[0149] The following specific formulations may find use in
treatment of Alzheimer's disease:
[0150] Tablets or capsules containing 0.1, 0.5, 1.0, 5, 10 and 25
mg hydrobromide of a compound according to the invention to be
taken four times a day, or a sustained-release-preparation
delivering an equivalent daily dose.
[0151] Parenteral solution containing 5 mg/ml.
[0152] Liquid formulation for oral administration available in 5
mg/5 ml and 25 mg/5 ml concentration.
[0153] There have been reports that galanthamine can cause cardiac
arrythmias. If such problems occur with the compounds of the
present invention, it may be desirable to administer compounds of
the invention in conjunction with another drug such as
propantheline bromide to control such arrythmias. As with other
drugs that act on the central nervous system, minor side effects,
such as nausea, may be noted. In this case, the compounds of the
present invention will be administered in conjunction with an agent
for control of such side effects.
[0154] A substantial proportion of patients suffering from
Alzheimer's disease exhibit not only reduced levels of acetyl
choline but also of norepinephrine in the brain. In such cases, the
compounds of the present invention may advantageously be employed
in conjunction with compounds such as clonidine desipramine,
monoamine oxidase inhibitors, methamphetamine and methyl phenidate
that stimulate the noradrenergic receptors in the brain.
[0155] The production of compounds of the present invention is
illustrated by the following Examples:
EXAMPLE 1
[0156] 37
[0157] To a solution of galanthamine (1, 0.7 g, 0.2439 mmoles) in
dry methylene chloride (4 ml), pyridinium chlorochromate (0.1577 g,
0.7317 mmoles) was added and stirred at room temperature for 8
hours. The reaction mixture was diluted with methanol and filtered.
Removal of solvent followed by purification on a silica gel column
using acetone, methanol:acetone (10:90) as eluants afforded the
desired product. (0.06 g, 86% yield).
[0158] mp. 104-186.degree.C.
EXAMPLE 2
[0159] 38
[0160] To a solution of 1 (0.07 g, 0.2439 mmoles) in methylene
chloride, acetic anhydride (0.03 ml, 0 317 mmoles) and
dimethylaminopyridine (0.0536 g, 0.439 mmoles) were added at
0.degree. C. in an ice bath. The reaction mixture was stirred at
0.degree. C. for 10 minutes and room temperature for 60 minutes.
Solvents were removed on a rotary evaporator and the residue was
diluted with ethyl acetate, washed with water, 10% Na.sub.2CO.sub.3
solution, brine, and dried (Na.sub.2SO.sub.4). Concentration of the
solvent and purification by silica gel chromatography first
acetone, then MeOH:acetone (1:10) as eluants afforded 0.0773 g of
product (96% yield).
[0161] mp. 126-128.degree. C.
EXAMPLE 3
[0162] 39
[0163] Phenylisocyanate (0.033 ml, 0.2926 mmoles) was added to a
stirred solution of 1 (0.07 g, 0.2439 mmoles) in THF (5 ml) at room
temperature, and then stirred for 30 hours under the same
conditions. The reaction mixture was concentrated, purified by
silica gel column chromatography using first acetone, then
MeOH:acetone (10:90) to give 0.0982 g (99% yield) of product.
[0164] mp 79-81.degree. C.
EXAMPLE 4
[0165] 40
[0166] 1-Naphthylisocyanate (0.042 ml, 0.2926 mmoles) was added to
a stirred solution of 1 (0.07 g, 0.2439 mmoles) in THF (5 ml) at
room temperature. The reaction mixture was stirred for 24 hours at
room temperature, and then concentrated. The crude reaction mixture
was purified by silica gel column chromatography using first
acetone, then methanol:acetone (10:90) as eluants to afford 0.11 g
of product (99%).
[0167] mp. 198-200.degree. C.
EXAMPLE 5
[0168] 41
[0169] A solution of 1 (0.1 g, 0.3484 mmoles) in 2 ml of dry
methanol, and 20% palladium on carbon (0.02 g) was hydrogenated in
a hydrogenate. The reaction mixture was shaken for 10 hours at room
temperature. The catalyst was collected on Celite, and washed
thoroughly with methanol. The solution was concentrated, and the
crude material was purified on a silica gel column using
acetone:methanol (90:10, 80:20) to afford 0.0938 g (93% yield) of
the product.
[0170] mp 110-112.degree. C.
[0171] The anticholinesterase activity of the compounds prepared in
the above examples was assayed by an assay for inhibition of
acetylcholinesterase following the procedure of G. Ellman,
Biological Pharmacology, 7:88-95 (1961) Acetylthiocholine serves as
substrate since it acts like acetylcholine. Acetylcholinesterase
cleaves it to thiocholine and acetate which react with
dithiobisnitrobenzoate to form a yellow color which is measured
photometrically.
[0172] The assay results are shown in the following table, which
also includes an assay of the activity of galanthamine.
[0173] This assay was carried out at dilution of 10.sup.-5
molar
1 TABLE PERCENT INHIBITION COMPOUND OF ACETYLCHOLINESTERASE
Galanthamine 95% Product of Example 1 10% Product of Example 2 37%
Product of Example 3 37% Product of Example 4 60% Product of
Example 5 30%
EXAMPLE 6
[0174] 42
[0175] Galanthamine (0.3 g, 1.0452 mmol) was dissolved in
CHCl.sub.3 (20 ml), and the solution cooled to 0.degree. C. in an
ice bath. A 1M solution of BBr.sub.3 in CH.sub.2Cl.sub.2 (6.2712
mmol, 6.3 ml) was added all at once. The reaction mixture was then
warmed to room temperature and stirred for 8 hours. The resulting
reaction mixture was poured into 20% solution of KH,OH mixed with
ice (v/v) and stirred for 0.5 hr. The resulting solution was
separated, dried over Na.sub.2SO.sub.4, concentrated, and then
purified by column chromatography using methanol:acetone (30:70) as
eluant to give O-demethyl galanthamine in low yield.
EXAMPLE 7
[0176] 43
[0177] Galanthamine was dissolved in CH.sub.2Cl.sub.2 (4 ml), and
the solution cooled to 0.degree. C. in an ice bath.
Triisopropylsilyl trifluoromethanesulfonate was added to the
reaction mixture, followed by 2,6-lutidine, under an argon
atmosphere. The reaction mixture was warmed to room temperature,
stirred for one hour, and then diluted five times with ether,
washed with 5% NaHCO.sub.3, and then with saturated sodium chloride
solution. The organic layer was dried over Na.sub.2SO.sub.4,
concentrated, and purified by silica gel column chromatography,
(acetone, acetone:methanol; 95:5) to give the product in
quantitative yield as a yellow oil which was soluble in
alcohols.
EXAMPLE 8
[0178] 44
[0179] Galanthamine (0.12 g, 0.4181 mmol) was dissolved in dry THF
(5 ml), and the solution cooled to 0.degree. C. in an ice bath.
Ph.sub.3P (0.1426 g, 0.5435 mmol) and diethylazodicarboxylate
(0.1092 g, 0.1 ml, 0.6271 mmol) were added to the reaction mixture,
followed by freshly distilled glacial acetic acid (0.0528 g, 0.06
ml, 0.878 mmol). The reaction mixture was warmed to room
temperature, and stirred for 24 hours at the same condition. The
resulting mixture was washed with 5% NaHCO.sub.3 solution, and then
saturated sodium chloride solution. The organic layer was dried
over Na.sub.2SO.sub.4, concentrated, and then purified by silica
gel column chromatography (acetone, and then acetone:methanol,
95:5) to give the product (0.069 g, 50% yield), which was soluble
in alcohols.
EXAMPLE 9
[0180] 45
[0181] Galanthamine (0.1 g, 0.3484 mmol) was dissolved in 7 ml of
dry THF. n-Butyl isocyanate (0.0691 g, 0.08 ml, 0.6968 mmol) was
added to the reaction mixture at room temperature, under an argon
atmosphere. The reaction mixture was refluxed for 20 hours. The
solvent was concentrated, and then purified by silica gel column
chromatography using first acetone, and then acetone:methanol
(19:1) to give the product in quantitative yield as a white foam,
which was soluble in alcohols.
EXAMPLE 10
[0182] 46
[0183] Galanthamine (0.1427 g, 0.4972 mmol) was dissolved in
CH.sub.2Cl.sub.2 (5 ml), and the solution cooled to 0.degree. C. To
the solution was added para-toluenesulfonyl choride (0.2274 g,
1.1932 mmol) and pyridine (0.7866 g, 9.944 mmol, 0.8 ml). The
reaction mixture was stirred for 12 hours at room temperature,
under an argon atmosphere. The reaction mixture was then diluted
with methylene chloride and saturated sodium chloride aqueous
solution, filtered, separated. The resulting organic layer was
washed with brine, dried over Na.sub.2SO.sub.4, concentrated,
purified by silica gel column chromatography with acetone as an
eluant to afford the possible product (0.0733 g, 48% yield).
EXAMPLE 11
[0184] 47
[0185] Narwedine (0.079 g, 0.2 mmol) was dissolved in 3 ml of
ethanol, and H.sub.2O (1 ml) was added. Semicarbazide hydrochloride
(0.0587 g, 0.5262 mmol) and sodium acetate (0.0863 g, 1.0524 mmol)
Mere added to the reaction mixture. The reaction mixture was warmed
to 100.degree. C. and stirred for 5 hours. It was then concentrated
in vacuo to remove the alcohol. The aqueous reaction solution was
allowed to cool to crystallize the product. The crystals of
semicarbazone were removed by filtration and recrystallized from
methanol and diethyl ether to afford 0.061 g (64% yield) of
narwedine semicarbazone as white crystals, mp 264.degree. C.
(decomposition).
[0186] The product was soluble in alcohols
EXAMPLE 12
[0187] Galanthamine (0.25 g, 0.871 mmol) was dissolved in dry
diethyl ether (50 ml), and methyl iodide (0.1854 g, 1.3065 mmol,
0.081 mmol) was added. The reaction mixture was stirred for 5 hours
at room temperature under an argon atmosphere. The white solid
which formed was collected, washed with ether and then
recrystallized from hot water and methanol to afford white
crystals, mp 289-291.degree. C. The product was soluble in hot
water and slightly soluble in cold water. The yield of galanthamine
methiodide was 0.2904 g (78%).
EXAMPLE 13
[0188] 48
[0189] Galanthamine (1, 0.25 g, 0.871 mmol) was dissolved in 50 ml
of dry ether. Benzyl bromide (0.2235 g, 0.16 ml, 1.3065 mmol) was
added, and the reaction mixture was stirred for 20 hours at room
temperature, under an argon atmosphere. The white precipitate
formed was collected and thoroughly washed with ether. The crystals
were recrystallized from methanol and ether to give galanthamine
benzyl bromide (0.3272 g, 82% yield) as white crystals. mp
192.degree. C. (decomposition)
[0190] The product was soluble in alcohols.
[0191] The compounds were tested in the assay described after
Example 5 but at different concentrations. The results obtained
were as follows:
2 Concentration 10.sup.-5 10.sup.-6 molar 10.sup.-9 molar
galanthamine 93 68 22 O-demethyl- 100+ 89 55 galanthamine
galanthamine benzyl -- 77 40 bromide galanthamine 97 75 29
methiodidle N-demethyl 88 56 15 galanthamine galanthamine 75
n-butyl carbamate Product of 73 Example 10 epigalanthamine 21
acetate (from Example 8) Product of 17 Example 7 narwedine inactive
semicarbazone N-demethyl inactive lycoramine
[0192] Further compounds were prepared by methods analogous to
those described above and were tested in a cholinesterase assay as
described above. The results were as follows as cholinesterase
inhibition at 10.sup.-5 M:
3 N-allyl galanthamine bromide 96 lycoramine azide 25 lycoramine 30
4,5-dehydrogalanthamine 30 2-amino-2-dehydroxy lycoramine 17
2-iodo-2-dehydroxy lycoramine 15
[0193] Other cholinesterase activity tests for compounds according
to the invention produced the following results, which may,
however, be less reliable than those noted above.
4 Acetylcholinesterase Inhibition Assay Structure % Inhibition at
Name (R.sub.1 = CH.sub.3) -10.sup.-5 10.sup.-6 10.sup.-7
Galanthamine R.sub.2 = H 93 52 13 R.sub.3 = CH.sub.3 n-butyl
carbamate R.sub.2 = CONHnBu 44 37 9 R.sub.3 = CH.sub.3 n-propyl
carbamate R.sub.2 = CONHnPr 34 50 21 R.sub.3 = CH.sub.3 propyl
ester R.sub.2 = OCOCH.sub.3 51 48 40 R.sub.3 = CH.sub.3 ethyl
carbaxnate R.sub.2 = CONHEt 59 70 9 R.sub.3 = CH.sub.3 o-F-benzoic
ester R.sub.2 = O-fluoro- 27 39 37 benzoic R.sub.3 = CH.sub.3
o-F-phenoxypropionic ester 49 17 15 0 3-NO.sub.2O-4-F-phenyl
carbamate R.sub.3 = CH.sub.3 48 51 64 50 R.sub.3 = CH.sub.3
iso-valeroyl ester R.sub.2 = OCOCH.sub.2CH(CH.sub.3).sub.2 33 39 13
R.sub.3 = CH.sub.3 valeric ester R.sub.2 =
OCO(CH.sub.2).sub.3CH.sub.3 41 35 37 R.sub.3 = CH.sub.3 hexanoic
ester R.sub.2 = OCO(CH.sub.2).sub.4CH.sub.3 55 30 36 R.sub.3 =
CH.sub.3 decanoic ester R.sub.2 = OCO(CH.sub.2).sub.6CH.sub.3 30 24
6 R.sub.3 = CH3 octyl carbamate R.sub.2 =
OCONH(CH.sub.2).sub.7CH.su- b.3 55 35 16 R.sub.3 = CH.sub.3 imide
R.sub.2 = 10 29 12 R.sub.3 = CH.sub.3 cyclopropyl R.sub.2 = OCO- 40
13 0 carbinol ester cyclopropyl R.sub.3 = CH.sub.3 isopropyl
carbamate R.sub.2 = OCONHCH-- 21 0 0 (CH.sub.3).sub.2 21 0 0
R.sub.3 = CH.sub.3
[0194] Acetyl cholinesterase inhibition data was also obtained for
a compound wherein the methoxy group of galanthamine was replaced
by an N-methyl carbamate group and for childanthine. In this case,
IC.sub.50 data was obtained and compared with that for
galanthamine
5 S 5 mM 0.3 mM O-demethyl-galanthamine-13-methyl 0.002 0.002
carbamate childanthine 0.31 0.08 galanthamine 9.7 0.7
[0195] In vivo Testing
[0196] Galanthamine n-butyl carbamate was tested in the nucleus
basalis model for galanthamine discussed in the Hartounian et al
paper noted above. In the test, mice were given the drug three and
1/2 hours before two learning trials in a shuttle box. They are
placed in the lighted compartment and receive an electric footshock
when they cross into the preferred side, the dark. The next day,
they are again placed in the lighted compartment and the time to
enter the dark is noted. The latency to enter the dark compartment
is the basis for this figure. In this passive avoidance test,
results were obtained with the n-butyl carbamate that were
comparable with those obtained with galanthamine but that the best
dose with the n-butyl carbamate was 0.5 mg/kg whereas with
galanthamine the best dose was 3 mg/kg. Two mice given 100 mg/kg of
the n-butyl carbamate showed cholinergic side effects but neither
died. Below 50 mg/kg no side effects were noted.
[0197] In a similar test using normal mice, the mice remained in
the light (less preferred) side of the shuttle box for over six
minutes at the best dose (0.1 mg/kg) as compared to a best dose
result of about 90 seconds for the nucleas basalis-lesioned
animals.
[0198] In a second set of test chosen to mimic certain aspects of
Alzheimer's disease, a scopolamine dementia dark avoidance test,
three galanthamine analogs were evaluated for their ability to
antagonize a scopolamine induced memory deficit in a passive
avoidance paradigm in mice. Furnished data on the effects of these
compound on cholinesterase activity were used to determine doses
for testing. N-Demethyl galanthamine was inactive in antagonizing
the scopolamine induced memory deficit at doses of 0.3, 1.0 and 3.0
mg/kg so. The two other compounds were tested at 1,3 and 10 mg/kg
sc and did antagonize the scopolamine induced deficit. Galanthamine
acetate was active at doses of 3 and 10 mg/kg sc; lycoramine was
active at 10 mg/kg sc.
[0199] Training and testing of passive avoidance were conducted in
a two-compartment (light/dark) test cage. On the training day, mice
were individually placed in the light half of the cage and after
entering the dark compartment,, were administered a 3 sec 0.4 mA
footshock. They were then removed from the test chamber and
returned to their home cages. Twenty-four hours later, the animals
were again placed in the lighted half of the test cage and the
latency to enter the dark compartment was measured.
[0200] All animals in each group of 15 naive male CFW mice were
injected twice subcutaneously. Thirty minutes prior to training,
animals were administered 3 mg/kg scopolamine HBr or its 0.9% NaCl
vehicle. Five minutes prior to training, independent groups were
administered one of three doses of the test compounds or the
distilled water vehicle. One group in each experiment received
vehicle twice, another group received scopolamine and the dH.sub.2O
vehicle; the remaining groups received scopolamine and a test
compound.
[0201] A cutoff value (CO), defined as the second-longest latency
in the scopolamine/vehicle treated group, was used to determine
whether a compound was active. If 20% or more of the animals in a
treatment group had latencies greater than the CO value, the
compound was considered active at that dose.
[0202] Results
[0203] The three compounds were tested in two separate experiments;
the results are presented below in Tables 1 and 2. Doses considered
active are marked with an asterisk (*).
6TABLE 1 N-Demethylgalanthamine Dose Mean Treatment mg/kg sc
Latency #> CO/n % > CO saline 205 12/15 scopolamine 34
scopolamine + 0.3 21 0/15 0 N-demethyl 2.0 33 2/15 13 galanthamine
3.0 26 2/15 13 Cut-off value = 38 seconds
[0204]
7TABLE 2 Galanthamine Acetate and Lycoramine Dose Mean Treatment
mg/kg sc Latency # > CO/n % > CO saline 235 14/15 scopolamine
21 scopolamine + 1 21 1/15 7 galanthamine 3 38 4/15 27* acetate 10
31 3/15 20* Scopolamine + 1 26 1/15 7 lycoramine 3 19 0/15 0 10 48
4/15 27* Cut-off value = 41 seconds O-Demethyl
galanthamine-13-methyl carbamate and childanthine were also tested
in the same way. The carbamate showed activity at doses of
0.001-0.003 and childanthine at doses of 0.3. Lycoramine was also
found to be active in this test.
[0205] A number of compounds were also evaluated in a standardized
Profile of Observable Effects (POE) which involves administering
drug to animal in increasing amounts and observing this for up to
two hours to see whether peripheral cholinergic effects such as
tremor, lacrimation, salivation, pilo erection, defection or red
eye occur. With subcutaneous administration to mice, such effects
were not noted in any of four mice when using
O-demethyl-galanthamine-13-methylcarbamate at a dosage of 0.31
mg/kg, were noticeable in one mouse out of four at 0.63 mg/kg and
in all four mice at 1 mg/kg when using childanthine there were no
noticeable effects in four mice at 20 mg/kg but noticeable effects
in all four at 40 mg/kg (by way of comparison POE values for
galanthamine were two out of four mice showing effects at 10 mg/kg
but none showing effects at 5 mg/kg.
* * * * *