U.S. patent application number 10/293474 was filed with the patent office on 2003-07-31 for subtype-selective nmda receptor ligands and the use thereof.
Invention is credited to Araldi, Gian Luca, Bigge, Christopher F., Cai, Sui Xiong, Guzikowski, Anthony P., Keana, John F.W., Lamunyon, Donald, Lan, Nancy C., Zhou, Zhang-Lin.
Application Number | 20030144319 10/293474 |
Document ID | / |
Family ID | 21736083 |
Filed Date | 2003-07-31 |
United States Patent
Application |
20030144319 |
Kind Code |
A1 |
Bigge, Christopher F. ; et
al. |
July 31, 2003 |
Subtype-selective NMDA receptor ligands and the use thereof
Abstract
The invention relates to subtype-selective NMDA receptor ligands
and the use thereof for treating or preventing neuronal loss
associated with stroke, ischemia, CNS trauma, hypoglycemia and
surgery, as well as treating neurodegenerative diseases including
Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's
disease and Down's syndrome, treating or preventing the adverse
consequences of the overstimulation of the excitatory amino acids,
treating anxiety, psychosis, convulsions, aminoglycoside
antibiotics-induced hearing loss, migraine headache, chronic pain,
Parkinson's disease, glaucoma, CMV retinitis, urinary incontinence,
opioid tolerance or withdrawal, and inducing anesthesia, as well as
for enhancing cognition.
Inventors: |
Bigge, Christopher F.; (Ann
Arbor, MI) ; Araldi, Gian Luca; (Washington, DC)
; Cai, Sui Xiong; (Foothill, CA) ; Guzikowski,
Anthony P.; (Eugene, OR) ; Lamunyon, Donald;
(Junction City, OR) ; Lan, Nancy C.; (South
Pasadena, CA) ; Zhou, Zhang-Lin; (Irvine, CA)
; Keana, John F.W.; (Eugene, OR) |
Correspondence
Address: |
FITZPATRICK CELLA HARPER & SCINTO
30 ROCKEFELLER PLAZA
NEW YORK
NY
10112
US
|
Family ID: |
21736083 |
Appl. No.: |
10/293474 |
Filed: |
November 14, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10293474 |
Nov 14, 2002 |
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09779024 |
Feb 7, 2001 |
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09779024 |
Feb 7, 2001 |
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09091592 |
Sep 16, 1998 |
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6218404 |
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09091592 |
Sep 16, 1998 |
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PCT/US96/20746 |
Dec 20, 1996 |
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60009185 |
Dec 22, 1995 |
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Current U.S.
Class: |
514/307 ;
546/148; 546/150 |
Current CPC
Class: |
C07D 217/04 20130101;
C07D 239/06 20130101; C07D 471/04 20130101; C07D 211/18 20130101;
C07D 221/16 20130101; C07D 211/14 20130101; C07D 233/26 20130101;
C07D 451/06 20130101; C07D 221/28 20130101 |
Class at
Publication: |
514/307 ;
546/148; 546/150 |
International
Class: |
A61K 031/4709; C07D
41/02 |
Claims
What is claimed is:
1. A compound having the Formula (I): 122or a pharmaceutically
acceptable salt thereof; wherein R.sub.1-R.sub.4 are independently
hydrogen, halo, haloalkyl, aryl, fused aryl, a heterocyclic group,
a heteroaryl group, alkyl, alkenyl, alkynyl, arylalkyl,
arylalkenyl, arylalkynyl, hydroxyalkyl, nitro, amino, cyano,
cyanamido, N(CN).sub.2, guanidino, amidino, acylamido, hydroxy,
thiol, acyloxy, azido, alkoxy, carboxy, carbonylamido, or
alkylthiol; E is (CR.sub.aR.sub.b).sub.r--G.sub.s--(CR.-
sub.cR.sub.d).sub.t, wherein R.sub.a, R.sub.b, R.sub.c and R.sub.d
are independently selected from the group consisting of hydrogen,
alkyl, aryl, hydroxy or carboxy; G is oxygen, sulfur, sulfone,
sulfoxide, carboxy (CO.sub.2 or O.sub.2C), carbonyl (CO), or
NR.sub.e, wherein R.sub.e is hydrogen, alkyl or aryl; r and t are
independently 0, 1, 2, 3, 4, or 5; and s is 0 or 1; R.sub.5 is
hydrogen, hydroxy, alkylcarboxy, optionally substituted aryl,
optionally substituted aralkyl, optionally substituted
aryloxyalkyl, optionally substituted benzyloxyalkyl, a heterocyclic
group, a heterocyclic substituted alkyl group, heteroaryl, or a
heteroaryl substituted alkyl group; p is 0, 1, 2 or 3; Y is
hydrogen, hydroxy, CH.sub.3, CN, CO.sub.2R, sulfate, optionally
substituted aryl, optionally substituted aryloxy, optionally
substituted arylthioxy, optionally substituted aroyl,
.ident.--Y.sub.1, .dbd.--Y.sub.1, optionally substituted
heterocyclic group, optionally substituted heterocycloxy,
optionally substituted heteroaryl, optionally substituted
heteroaryloxy, optionally substituted cycloalkyl group, optionally
substituted cycloalkoxy group, amino, amido, carbonylamido,
hydrazino, oximo, amidino, ureido, or guanidino; and Y.sub.1 is
hydrogen, alkyl, hydroxyalkyl, optionally substituted aralkyl, an
optionally substituted aryl, optionally substituted cycloalkyl,
aminoalkyl, amidoalkyl, ureidoalkyl, or guanidinoalkyl.
2. A compound having the Formula (II): 123or a pharmaceutically
acceptable salt thereof; wherein R.sub.1-R.sub.4 are independently
hydrogen, halo, haloalkyl, aryl, fused aryl, a heterocyclic group,
a heteroaryl group, alkyl, alkenyl, alkynyl, arylalkyl,
arylalkenyl, arylalkynyl, hydroxyalkyl, nitro, amino, cyano,
cyanamido, N(CN).sub.2, guanidino, amidino, acylamido, hydroxy,
thiol, acyloxy, azido, alkoxy, carboxy, carbonylamido, or
alkylthiol; R.sub.5 is hydrogen, lower alkyl, acyl or aryl; E is
(CR.sub.aR.sub.b).sub.r--G.sub.s--(CR.sub.cR.sub.d).su- b.t,
wherein R.sub.a, R.sub.b, R.sub.c and R.sub.d are independently
selected from the group consisting of hydrogen, alkyl, aryl,
hydroxy or carboxy; G is oxygen, sulfur, sulfone, sulfoxide,
carboxy (CO.sub.2 or O.sub.2C), carbonyl (CO), or NR.sub.e, wherein
R.sub.e is hydrogen, alkyl or aryl; r and t are independently 0, 1,
2, 3, 4, or 5; and s is 0 or 1; R.sub.6 is hydrogen, hydroxy,
alkylcarboxy, optionally substituted aryl, optionally substituted
aralkyl, optionally substituted aryloxyalkyl, optionally
substituted benzyloxyalkyl, a heterocyclic group, a heterocyclic
substituted alkyl group, heteroaryl, or a heteroaryl substituted
alkyl group; p is 0, 1, 2 or 3; Y is hydrogen, hydroxy, CH.sub.3,
CN, CO.sub.2R, sulfate, optionally substituted aryl, optionally
substituted aryloxy, optionally substituted arylthioxy, optionally
substituted aroyl, .ident.--Y.sub.1, .dbd.--Y.sub.1, optionally
substituted heterocyclic group, optionally substituted
heterocycloxy, optionally substituted heteroaryl, optionally
substituted heteroaryloxy, optionally substituted cycloalkyl group,
optionally substituted cycloalkoxy group, amino, amido,
carbonylamido, hydrazino, oximo, amidino, ureido, or guanidino; and
Y.sub.1 is hydrogen, alkyl, hydroxyalkyl, optionally substituted
aralkyl, an optionally substituted aryl, optionally substituted
cycloalkyl, aminoalkyl, amidoalkyl, ureidoalkyl, or
guanidinoalkyl.
3. A compound having the Formula (IIa): 124or a pharmaceutically
acceptable salt thereof; wherein R.sub.1-R.sub.4 are independently
hydrogen, halo, haloalkyl, aryl, fused aryl, a heterocyclic group,
a heteroaryl group, alkyl, alkenyl, alkynyl, arylalkyl,
arylalkenyl, arylalkynyl, hydroxyalkyl, nitro, amino, cyano,
cyanamido, N(CN).sub.2, guanidino, amidino, acylamido, hydroxy,
thiol, acyloxy, azido, alkoxy, carboxy, carbonylamido, or
alkylthiol; R.sub.5 is hydrogen, lower alkyl, acyl or aryl; E is
(CR.sub.aR.sub.b).sub.r--G.sub.s--(CR.sub.cR.sub.d).su- b.t,
wherein R.sub.a, R.sub.b, R.sub.c and R.sub.d are independently
selected from the group consisting of hydrogen, alkyl, aryl,
hydroxy or carboxy; G is oxygen, sulfur, sulfone, sulfoxide,
carboxy (CO.sub.2 or O.sub.2C), carbonyl (CO), or NR.sub.e, wherein
R.sub.e is hydrogen, alkyl or aryl; r and t are independently 0, 1,
2, 3, 4, or 5; and s is 0 or 1; R.sub.6 is hydrogen, hydroxy,
alkylcarboxy, optionally substituted aryl, optionally substituted
aralkyl, optionally substituted aryloxyalkyl, optionally
substituted benzyloxyalkyl, a heterocyclic group, a heterocyclic
substituted alkyl group, heteroaryl, or a heteroaryl substituted
alkyl group; p is 0, 1, 2 or 3; Y is hydrogen, hydroxy, CH.sub.3,
CN, CO.sub.2R, sulfate, optionally substituted aryl, optionally
substituted aryloxy, optionally substituted arylthioxy, optionally
substituted aroyl, .ident.--Y.sub.1, .dbd.--Y.sub.1, optionally
substituted heterocyclic group, optionally substituted
heterocycloxy, optionally substituted heteroaryl, optionally
substituted heteroaryloxy, optionally substituted cycloalkyl group,
optionally substituted cycloalkoxy group, amino, amido,
carbonylamido, hydrazino, oximo, amidino, ureido, or guanidino; and
Y.sub.1 is hydrogen, alkyl, hydroxyalkyl, optionally substituted
aralkyl, an optionally substituted aryl, optionally substituted
cycloalkyl, aminoalkyl, amidoalkyl, ureidoalkyl, or
guanidinoalkyl.
4. A compound having the Formula (III): 125or a pharmaceutically
acceptable salt thereof; wherein W is an adamantyl group, an
optionally substituted aryl group, or an optionally substituted
heteroaryl group; X is a bond, (CH.sub.2).sub.m, carbonyl, oxygen,
or NR; E is
(CR.sub.aR.sub.b).sub.r--G.sub.s--(CR.sub.cR.sub.d).sub.t, wherein
R.sub.a, R.sub.b, R.sub.c and R.sub.d are independently selected
from the group consisting of hydrogen, alkyl, aryl, hydroxy or
carboxy; G is oxygen, sulfur, sulfone, sulfoxide, carboxy (CO.sub.2
or O.sub.2C), carbonyl (CO), or NR.sub.e, wherein R.sub.e is
hydrogen, alkyl or aryl; r and t are independently 0, 1, 2, 3, 4,
or 5; and s is 0 or 1; Y is hydrogen, hydroxy, CH.sub.3, CN,
CO.sub.2R; optionally substituted cycloalkyl, an aminoalkyl group,
an amidoalkyl group, a ureidoalkyl group, or a guanidinoalkyl
group; R is hydrogen, alkyl, aminoalkyl, amidoalkyl, ureidoalkyl,
or guanidinoalkyl; R.sub.1 is hydrogen, hydroxy, alkylcarboxy,
optionally substituted aryl, optionally substituted aralkyl,
optionally substituted aryloxyalkyl, optionally substituted
benzyloxyalkyl, a heterocyclic group, a heterocyclic substituted
alkyl group, heteroaryl, or a heteroaryl substituted alkyl group; m
is 0, 1, 2, or 3; and p is 0, 1, 2, 3 or 4. with the proviso, that
when W is adamantyl or when p is other than zero, or when the
piperidine ring is substituted in the 3-position with W--X, then Y
may also be optionally substituted aryl, optionally substituted
aryloxy, optionally substituted arylthioxy, optionally substituted
aroyl, .ident.--Y.sub.1, .dbd.--Y.sub.1, optionally substituted
heterocyclic group, optionally substituted heterocycloxy,
optionally substituted heteroaryl, optionally substituted
heteroaryloxy, optionally substituted cycloalkyl group, optionally
substituted cycloalkoxy group, amino, amido, ureido, or guanidino;
wherein Y.sub.1 is hydrogen, alkyl, hydroxyalkyl, optionally
substituted aralkyl, optionally substituted aryl, optionally
substituted cycloalkyl, aminoalkyl, amidoalkyl, ureidoalkyl, or
guanidinoalkyl.
5. A compound having Formula IIIa: 126or a pharmaceutically
acceptable salt thereof; wherein W is an adamantyl group or an
optionally substituted aryl group; Y is CH.sub.3, CN, CO.sub.2R,
carboxamido, an optionally substituted cycloalkyl group or an
optionally substituted heterocycloalkyl group; R is alkyl, an
aminoalkyl group, an amidoalkyl group, a ureidoalkyl group, or a
guanidinoalkyl group; n is 0, 1, 2, 3, 4, 5, or 6; and m is 0, 1,
2, 3; with the proviso, that when W is adamantyl, then Y may also
be optionally substituted aryl, optionally substituted aryloxy,
SAr, COAr, hydroxy, .ident.--Y.sub.1, .dbd.--Y.sub.1, a
heterocyclic group, a heteroaryl group, a cycloalkyl group, an
amino group, an amido group, a ureido group, or a guanidino group;
wherein Y.sub.1 is hydrogen, alkyl, hydroxyalkyl, an optionally
substituted aralkyl group, an optionally substituted aryl group, an
aminoalkyl group, an amidoalkyl group, a ureidoalkyl group, or a
guanidinoalkyl group.
6. A compound having the Formula IIIb: 127or a pharmaceutically
acceptable salt thereof; wherein W is an adamantyl group or an
optionally substituted aryl group; Y is CH.sub.3, CN, CO.sub.2R,
carboxamido, an optionally substituted cycloalkyl group or an
optionally substituted heterocycloalkyl group; R is alkyl, an
aminoalkyl group, an amidoalkyl group, a ureidoalkyl group, or a
guanidinoalkyl group; n is 0, 1, 2, 3, 4, 5, or 6; and m is 0, 1,
2, or 3; with the proviso, that when W is adamantyl, then Y may
also be optionally substituted aryl, optionally substituted
aryloxy, SAr, COAr, hydroxy, .ident.--Y.sub.1, .dbd.--Y.sub.1, a
heterocyclic group, a heteroaryl group, a cycloalkyl group, an
amino group, an amido group, a ureido group, or a guanidino group;
wherein Y.sub.1 is hydrogen, alkyl, hydroxyalkyl, an optionally
substituted aralkyl group, an optionally substituted aryl group, an
aminoalkyl group, an amidoalkyl group, a ureidoalkyl group, or a
guanidinoalkyl group.
7. A compound having the Formula IIIc: 128or a pharmaceutically
acceptable salt thereof; wherein W is an adamantyl group or an
optionally substituted aryl group; Y is CH.sub.3, CN, CO.sub.2R,
carboxamido, an optionally substituted cycloalkyl group, an
optionally substituted heterocycloalkyl group, optionally
substituted aryl, optionally substituted aryloxy, SAr, COAr,
hydroxy, .ident.--Y.sub.1, .dbd.--Y.sub.1, a heterocyclic group, a
heteroaryl group, an amino group, an amido group, a ureidoalkyl
group, a guanidinoalkyl group, or O--N.dbd.CR.sub.1R.sub.2, where
R.sub.1 and R.sub.2 are independently aryl or lower alkyl; R is
alkyl, an aminoalkyl group, an amidoalkyl group, a ureidoalkyl
group, or a guanidinoalkyl group; Y.sub.1 is hydrogen, alkyl,
hydroxyalkyl, an optionally substituted aralkyl group, an
optionally substituted aryl group, an aminoalkyl group, an
amidoalkyl group, a ureidoalkyl group, or a guanidinoalkyl group; n
is 0, 1, 2, 3, 4, 5, or 6; and m is 0, 1, 2, or 3; with the
proviso, that when W is adamantyl, then Y may also be optionally
substituted aryl, optionally substituted aryloxy, SAr, COAr,
hydroxy, .ident.--Y.sub.1, .dbd.--Y.sub.1, a heterocyclic group, a
heteroaryl group, a cycloalkyl group, an amino group, an amido
group, a ureido group, or a guanidino group; wherein Y.sub.1 is
hydrogen, alkyl, hydroxyalkyl, an optionally substituted aralkyl
group, an optionally substituted aryl group, an aminoalkyl group,
an amidoalkyl group, a ureidoalkyl group, or a guanidinoalkyl
group.
8. A compound having the Formula IIId: 129or a pharmaceutically
acceptable salt thereof; wherein W is an adamantyl group or an
optionally substituted aryl group; X is a bond, (CH.sub.2).sub.m,
oxygen, or NR; Y.sub.1 is hydrogen, alkyl, hydroxyalkyl, an
aminoalkyl group, an amidoalkyl group, a ureidoalkyl group, or a
guanidinoalkyl group; R.sub.1 is hydrogen, hydroxy, halo,
alkylcarboxy, optionally substituted aryl, optionally substituted
aralkyl, optionally substituted aryloxyalkyl, optionally
substituted benzyloxyalkyl, a heterocyclic group, a heterocyclic
substituted alkyl group, heteroaryl, or a heteroaryl substituted
alkyl group; n is 0, 1, 2, 3, 4, 5, or 6; and m is 0, 1, 2, or 3;
with the proviso that when W is an adamantyl group, then Y may
further be an optionally substituted aralkyl group, or an
optionally substituted aryl group.
9. A compound having the Formula IIIe: 130or a pharmaceutically
acceptable salt thereof; wherein W is an adamantyl group or an
optionally substituted aryl group; Y.sub.1 is hydrogen, alkyl,
hydroxyalkyl, an aminoalkyl group, an amidoalkyl group, a
ureidoalkyl group, or a guanidinoalkyl group; R.sub.1 is hydrogen,
hydroxy, halo, alkylcarboxy, optionally substituted aryl,
optionally substituted aralkyl, optionally substituted
aryloxyalkyl, optionally substituted benzyloxyalkyl, a heterocyclic
group, a heterocyclic substituted alkyl group, heteroaryl, or a
heteroaryl substituted alkyl group; n is 0, 1, 2, 3, 4, 5, or 6;
and m is 0, 1, 2, or 3; with the proviso that when W is an
adamantyl group, then Y may further be an optionally substituted
aralkyl group, or an optionally substituted aryl group.
10. A compound having the Formula IIIf: 131or a pharmaceutically
acceptable salt thereof; wherein W is an adamantyl group or an
optionally substituted aryl group; Y.sub.1 is hydrogen, alkyl,
hydroxyalkyl, an aminoalkyl group, an amidoalkyl group, a
ureidoalkyl group, or a guanidinoalkyl group; R.sub.1 is hydrogen,
hydroxy, halo, alkylcarboxy, optionally substituted aryl,
optionally substituted aralkyl, optionally substituted
aryloxyalkyl, optionally substituted benzyloxyalkyl, a heterocyclic
group, a heterocyclic substituted alkyl group, heteroaryl, or a
heteroaryl substituted alkyl group; n is 0, 1, 2, 3, 4, 5, or 6;
and m is 0, 1, 2, or 3; with the proviso that when W is an
adamantyl group, then Y.sub.1 may further be an optionally
substituted aralkyl group, or an optionally substituted aryl
group.
11. A compound having the Formula IIIg: 132or a pharmaceutically
acceptable salt thereof; wherein W is an adamantyl group or an
optionally substituted aryl group; Y.sub.1 is hydrogen, alkyl,
hydroxyalkyl, an aminoalkyl group, an amidoalkyl group, a
ureidoalkyl group, or a guanidinoalkyl group; R.sub.1 is hydrogen,
hydroxy, halo, alkylcarboxy, optionally substituted aryl,
optionally substituted aralkyl, optionally substituted
aryloxyalkyl, optionally substituted benzyloxyalkyl, a heterocyclic
group, a heterocyclic substituted alkyl group, heteroaryl, or a
heteroaryl substituted alkyl group; n is 0, 1, 2, 3, 4, 5, or 6;
and m is 0, 1, 2, or 3; with the proviso that when W is an
adamantyl group, then Y may further be an optionally substituted
aralkyl group, or an optionally substituted aryl group.
12. A compound having the Formula IIIh: 133or a pharmaceutically
acceptable salt thereof; wherein W is an adamantyl group or an
optionally substituted aryl group; Y is optionally substituted
aryl, optionally substituted aryloxy, SAr, COAr, hydroxy,
.ident.--Y.sub.1, .dbd.--Y.sub.1, a heterocyclic group, a
heteroaryl group, a cycloalkyl group, an amino group, an amido
group, a ureido group, or a guanidino group; Y.sub.1 is hydrogen,
alkyl, hydroxyalkyl, an aminoalkyl group, an amidoalkyl group, a
ureidoalkyl group, or a guanidinoalkyl group; Z is
(CH.sub.2).sub.m, oxygen, sulfur, or NR; m is 0, 1, 2, or 3; and n
is 1, 2, 3, 4, 5, or 6.
13. A compound having the Formula (IIIi): 134or a pharmaceutically
acceptable salt thereof; wherein R.sub.1-R.sub.5 are independently
hydrogen, halo, haloalkyl, aryl, fused aryl, a heterocyclic group,
a heteroaryl group, alkyl, alkenyl, alkynyl, arylalkyl,
arylalkenyl, arylalkynyl, hydroxyalkyl, nitro, amino, cyano,
acylamido, hydroxy, thiol, acyloxy, azido, alkoxy, carboxy,
carbonylamido, or alkylthiol; n is 1, 2, 3, 4, 5, or 6; Y is
optionally substituted aryl, optionally substituted aryloxy, SAr,
COAr, hydrogen, hydroxy, .ident.--Y.sub.1, .dbd.--Y.sub.1, a
heterocyclic group, a heteroaryl group, a cycloalkyl group, an
amino group, an amido group, a ureido group, or a guanidino group;
and Y.sub.1 is hydrogen, alkyl, hydroxyalkyl, an optionally
substituted aralkyl group, an optionally substituted aryl group, an
aminoalkyl group, an amidoalkyl group, a ureidoalkyl group, or a
guanidinoalkyl group.
14. A compound having Formula (IIIj): 135or a pharmaceutically
acceptable salt thereof; wherein R.sub.1-R.sub.5 are independently
hydrogen, halo, haloalkyl, aryl, fused aryl, a heterocyclic group,
a heteroaryl group, alkyl, alkenyl, alkynyl, arylalkyl,
arylalkenyl, arylalkynyl, hydroxyalkyl, nitro, amino, cyano,
acylamido, hydroxy, thiol, acyloxy, azido, alkoxy, carboxy,
carbonylamido, or alkylthiol; n is 1, 2, 3, 4, 5, or 6; Y is
optionally substituted aryl, optionally substituted aryloxy, SAr,
COAr, hydrogen, hydroxy, .ident.--Y.sub.1, .dbd.--Y.sub.1, a
heterocyclic group, a heteroaryl group, a cycloalkyl group, an
amino group, an amido group, a ureido group, or a guanidino group;
and Y.sub.1 is hydrogen, alkyl, hydroxyalkyl, an optionally
substituted aralkyl group, an optionally substituted aryl group, an
aminoalkyl group, an amidoalkyl group, a ureidoalkyl group, or a
guanidinoalkyl group.
15. A compound having the Formula (IIIk): 136or a pharmaceutically
acceptable salt thereof; wherein R.sub.1-R.sub.5 are independently
hydrogen, halo, haloalkyl, aryl, fused aryl, a heterocyclic group,
a heteroaryl group, alkyl, alkenyl, alkynyl, arylalkyl,
arylalkenyl, arylalkynyl, hydroxyalkyl, nitro, amino, cyano,
acylamido, hydroxy, thiol, acyloxy, azido, alkoxy, carboxy,
carbonylamido, or alkylthiol; n is 1, 2, 3, 4, 5, or 6; Y is
optionally substituted aryl, optionally substituted aryloxy, SAr,
COAr, hydrogen, hydroxy, .ident.--Y.sub.1, .dbd.--Y.sub.1, a
heterocyclic group, a heteroaryl group, a cycloalkyl group, an
amino group, an amido group, a ureido group, or a guanidino group;
and Y.sub.1 is hydrogen, alkyl, hydroxyalkyl, an optionally
substituted aralkyl group, an optionally substituted aryl group, an
aminoalkyl group, an amidoalkyl group, a ureidoalkyl group, or a
guanidinoalkyl group.
16. A compound having the Formula (IIIl): 137or a pharmaceutically
acceptable salt thereof; wherein W is optionally substituted aryl;
Y is optionally substituted aryl, optionally substituted aryloxy,
an optionally substituted aryloxy group, SAr, COAr, hydrogen,
hydroxy, .ident.--Y.sub.1, .dbd.--Y.sub.1, a heterocyclic group, a
heteroaryl group, a cycloalkyl group, an amino group, an amido
group, a ureido group, or a guanidino group; Y.sub.1 is hydrogen,
alkyl, hydroxyalkyl, an optionally substituted aralkyl group, an
optionally substituted aryl group, an aminoalkyl group, an
amidoalkyl group, a ureidoalkyl group, or a guanidinoalkyl group; Q
is hydrogen, alkyl, aryl, aralkyl, a heterocyclic group, a
heterocyclic substituted alkyl group, an aryl group, or an aralkyl
group; X is a bond, (CH.sub.2).sub.m, oxygen, or sulfur; m is 0, 1,
2, or 3; n is 1, 2, 3, 4, 5, or 6; and p is 0 or 1.
17. A compound having the Formula (IIIm): 138or a pharmaceutically
acceptable salt thereof; wherein W is optionally substituted aryl;
X is a bond, (CH.sub.2).sub.m, oxygen, sulfur, or NR; R is alkyl,
hydroxy, an aminoalkyl group, an amidoalkyl group, a ureidoalkyl
group, or a guanidinoalkyl group; R.sub.1 is hydrogen, hydroxy,
aryl, or aralkyl; m is 0, 1, 2, or 3; n is 1, 2, 3, 4, 5, or 6;
=single or double bond; and =carbon ring or heterocyclic ring, with
the proviso that said carbon ring is not part of a naphthyl
group.
18. A compound having the Formula (IIIn): 139or a pharmaceutically
acceptable salt thereof; wherein W is an adamantyl group or an
optionally substituted aryl group; X is a bond, (CH.sub.2).sub.m; Y
is CH.sub.3, CN, CO.sub.2R; an optionally substituted aryl group,
an optionally substituted aryloxy group, SAr, COAr, hydroxy,
.ident.--Y.sub.1, .dbd.--Y.sub.1, a heterocyclic group, a
heteroaryl group, a cycloalkyl group, an amino group, an amido
group, a ureido group, or a guanidino group; Y.sub.1 is hydrogen,
alkyl, hydroxyalkyl, an optionally substituted aralkyl group, an
optionally substituted aryl group, an aminoalkyl group, an
amidoalkyl group, a ureidoalkyl group, or a guanidinoalkyl group R
is alkyl, hydroxy, an aminoalkyl group, an amidoalkyl group, a
ureidoalkyl group, or a guanidinoalkyl group; n is 0, 1, 2, 3, 4,
5, or 6; and m is 0, 1, 2, or 3.
19. A compound having the Formula (IIIo): 140or a pharmaceutically
acceptable salt thereof; wherein Y is hydrogen, hydroxy, CH.sub.3,
CN, CO.sub.2R, optionally substituted aryl, optionally substituted
aryloxy, optionally substituted arylthioxy, optionally substituted
aroyl, .ident.--Y.sub.1, .dbd.--Y.sub.1, optionally substituted
heterocyclic group, optionally substituted heterocycloxy,
optionally substituted heteroaryl, optionally substituted
heteroaryloxy, optionally substituted cycloalkyl group, optionally
substituted cycloalkoxy group, amino, amido, ureido, or guanidino;
Y.sub.1 is hydrogen, alkyl, hydroxyalkyl, optionally substituted
aralkyl, an optionally substituted aryl, aminoalkyl, amidoalkyl,
ureidoalkyl, or guanidinoalkyl; and n is 0, 1, 2, 3, 4, 5 or 6.
20. A compound having the Formula (IV): 141or a pharmaceutically
acceptable salt thereof; wherein R.sub.1-R.sub.5 are independently
hydrogen, halo, haloalkyl, aryl, fused aryl, a heterocyclic group,
a heteroaryl group, alkyl, alkenyl, alkynyl, arylalkyl,
arylalkenyl, arylalkynyl, hydroxyalkyl, nitro, amino, cyano,
acylamido, hydroxy, thiol, acyloxy, azido, alkoxy, carboxy,
carbonylamido, or alkylthiol; E is
(CR.sub.aR.sub.b).sub.r--G.sub.s--(CR.sub.cR.sub.d).sub.t, wherein
R.sub.a, R.sub.b, R.sub.c and R.sub.d are independently selected
from the group consisting of hydrogen, alkyl, aryl, hydroxy or
carboxy; G is oxygen, sulfur, sulfone, sulfoxide, carboxy (CO.sub.2
or O.sub.2C), carbonyl (CO), or NR.sub.e, wherein R.sub.e is
hydrogen, alkyl or aryl; r and t are independently 0, 1, 2, 3, 4,
or 5; and s is 0 or 1; Y is hydrogen, hydroxy, CH.sub.3, CN,
CO.sub.2R, sulfate, optionally substituted aryl, optionally
substituted aryloxy, optionally substituted arylthioxy, optionally
substituted aroyl, .ident.--Y.sub.1, .dbd.--Y.sub.1, optionally
substituted heterocyclic group, optionally substituted
heterocycloxy, optionally substituted heteroaryl, optionally
substituted heteroaryloxy, optionally substituted cycloalkyl group,
optionally substituted cycloalkoxy group, amino, amido, ureido, or
guanidino; and Y.sub.1 is hydrogen, alkyl, hydroxyalkyl, optionally
substituted aralkyl, an optionally substituted aryl, optionally
substituted cycloalkyl, aminoalkyl, amidoalkyl, ureidoalkyl, or
guanidinoalkyl.
21. A compound having the Formula (V): 142or a pharmaceutically
acceptable salt thereof; wherein R.sub.1-R.sub.4 are independently
hydrogen, halo, haloalkyl, aryl, fused aryl, a heterocyclic group,
a heteroaryl group, alkyl, alkenyl, alkynyl, arylalkyl,
arylalkenyl, arylalkynyl, hydroxyalkyl, nitro, amino, cyano,
acylamido, hydroxy, thiol, acyloxy, azido, alkoxy, carboxy,
carbonylamido, or alkylthiol; E is
(CR.sub.aR.sub.b).sub.r--G.sub.s--(CR.sub.cR.sub.d).sub.t, wherein
R.sub.a, R.sub.b, R.sub.c and R.sub.d are independently selected
from the group consisting of hydrogen, alkyl, aryl, hydroxy or
carboxy; G is oxygen, sulfur, sulfone, sulfoxide, carboxy (CO.sub.2
or O.sub.2C), carbonyl (CO), or NR.sub.e, wherein R.sub.e is
hydrogen, alkyl or aryl; r and t are independently 0, 1, 2, 3, 4,
or 5; and s is 0 or 1; Y is hydrogen, hydroxy, CH.sub.3, CN,
CO.sub.2R, sulfate, optionally substituted aryl, optionally
substituted aryloxy, optionally substituted arylthioxy, optionally
substituted aroyl, .ident.--Y.sub.1, .dbd.--Y.sub.1, optionally
substituted heterocyclic group, optionally substituted
heterocycloxy, optionally substituted heteroaryl, optionally
substituted heteroaryloxy, optionally substituted cycloalkyl group,
optionally substituted cycloalkoxy group, amino, amido, ureido, or
guanidino; and Y.sub.1 is hydrogen, alkyl, hydroxyalkyl, optionally
substituted aralkyl, an optionally substituted aryl, optionally
substituted cycloalkyl, aminoalkyl, amidoalkyl, ureidoalkyl, or
guanidinoalkyl.
22. A compound having the Formula (VI): 143or a pharmaceutically
acceptable salt thereof; wherein W is an adamantyl group, an
optionally substituted aryl group, or an optionally substituted
heteroaryl group; X is a bond, (CH.sub.2).sub.m, oxygen, or NR; E
is (CR.sub.aR.sub.b).sub.r-- -G.sub.s--(CR.sub.cR.sub.d).sub.t,
wherein R.sub.a, R.sub.b, R.sub.c and R.sub.d are independently
selected from the group consisting of hydrogen, alkyl, aryl,
hydroxy or carboxy; G is oxygen, sulfur, sulfone, sulfoxide,
carboxy (CO.sub.2 or O.sub.2C), carbonyl (CO), or NR.sub.e, wherein
R.sub.e is hydrogen, alkyl or aryl; r and t are independently 0, 1,
2, 3, 4, or 5; and s is 0 or 1; Y is hydrogen, hydroxy, CH.sub.3,
CN, CO.sub.2R, sulfate, optionally substituted aryl, optionally
substituted aryloxy, optionally substituted arylthioxy, optionally
substituted aroyl, .ident.--Y.sub.1, .dbd.--Y.sub.1, optionally
substituted heterocyclic group, optionally substituted
heterocycloxy, optionally substituted heteroaryl, optionally
substituted heteroaryloxy, optionally substituted cycloalkyl group,
optionally substituted cycloalkoxy group, amino, amido, ureido, or
guanidino; Y.sub.1 is hydrogen, alkyl, hydroxyalkyl, optionally
substituted aralkyl, an optionally substituted aryl, optionally
substituted cycloalkyl, aminoalkyl, amidoalkyl, ureidoalkyl, or
guanidinoalkyl; R is alkyl, hydroxy, an aminoalkyl group, an
amidoalkyl group, a ureidoalkyl group, or a guanidinoalkyl group;
R.sub.1 is hydrogen, hydroxy, alkylcarboxy, optionally substituted
aryl, optionally substituted aralkyl, optionally substituted
aryloxyalkyl, optionally substituted benzyloxyalkyl, a heterocyclic
group, a heterocyclic substituted alkyl group, heteroaryl, or a
heteroaryl substituted alkyl group; m is 0, 1, 2, or 3; and p is 0,
1 or 2.
23. A compound having the Formula (VII): 144or a pharmaceutically
acceptable salt thereof; wherein W is an adamantyl group, an
optionally substituted aryl group, or an optionally substituted
heteroaryl group; X is a bond, (CH.sub.2).sub.m, oxygen, or NR; E
is (CR.sub.aR.sub.b).sub.r-- -G.sub.s--(CR.sub.cR.sub.d).sub.t,
wherein R.sub.a, R.sub.b, R.sub.c and R.sub.d are independently
selected from the group consisting of hydrogen, alkyl, aryl,
hydroxy or carboxy; G is oxygen, sulfur, sulfone, sulfoxide,
carboxy (CO.sub.2 or O.sub.2C), carbonyl (CO), or NR.sub.e, wherein
R.sub.e is hydrogen, alkyl or aryl; r and t are independently 0, 1,
2, 3, 4, or 5; and s is 0 or 1; Y is hydrogen, hydroxy, CH.sub.3,
CN, CO.sub.2R, sulfate, optionally substituted aryl, optionally
substituted aryloxy, optionally substituted arylthioxy, optionally
substituted aroyl, .ident.--Y.sub.1, .dbd.--Y.sub.1, optionally
substituted heterocyclic group, optionally substituted
heterocycloxy, optionally substituted heteroaryl, optionally
substituted heteroaryloxy, optionally substituted cycloalkyl group,
optionally substituted cycloalkoxy group, amino, amido, ureido, or
guanidino; Y.sub.1 is hydrogen, alkyl, hydroxyalkyl, optionally
substituted aralkyl, an optionally substituted aryl, optionally
substituted cycloalkyl, aminoalkyl, amidoalkyl, ureidoalkyl, or
guanidinoalkyl; R is alkyl, hydroxy, an aminoalkyl group, an
amidoalkyl group, a ureidoalkyl group, or a guanidinoalkyl group;
R.sub.1 is hydrogen, hydroxy, halo, alkylcarboxy, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted aryloxyalkyl, optionally substituted benzyloxyalkyl, a
heterocyclic group, a heterocyclic substituted alkyl group,
heteroaryl, or a heteroaryl substituted alkyl group; m is 0, 1, 2,
or 3; and p is 0, 1 or 2.
24. A compound having the Formula (VIII): 145or a pharmaceutically
acceptable salt thereof; wherein W is an adamantyl group, an
optionally substituted aryl group, or an optionally substituted
heteroaryl group; X is a bond, (CH.sub.2).sub.m, oxygen, or NR; E
is (CR.sub.aR.sub.b).sub.r-- -G.sub.s--(CR.sub.cR.sub.d).sub.t,
wherein R.sub.a, R.sub.b, R.sub.c and R.sub.d are independently
selected from the group consisting of hydrogen, alkyl, aryl,
hydroxy or carboxy; G is oxygen, sulfur, sulfone, sulfoxide,
carboxy (CO.sub.2 or O.sub.2C), carbonyl (CO), or NR.sub.e, wherein
R.sub.e is hydrogen, alkyl or aryl; r and t are independently 0, 1,
2, 3, 4, or 5; and s is 0 or 1; Y is hydrogen, hydroxy, CH.sub.3,
CN, CO.sub.2R, sulfate, optionally substituted aryl, optionally
substituted aryloxy, optionally substituted arylthioxy, optionally
substituted aroyl, .ident.--Y.sub.1, .dbd.--Y.sub.1, optionally
substituted heterocyclic group, optionally substituted
heterocycloxy, optionally substituted heteroaryl, optionally
substituted heteroaryloxy, optionally substituted cycloalkyl group,
optionally substituted cycloalkoxy group, amino, amido, ureido, or
guanidino; Y.sub.1 is hydrogen, alkyl, hydroxyalkyl, optionally
substituted aralkyl, an optionally substituted aryl, optionally
substituted cycloalkyl, aminoalkyl, amidoalkyl, ureidoalkyl, or
guanidinoalkyl; R is alkyl, hydroxy, an aminoalkyl group, an
amidoalkyl group, a ureidoalkyl group, or a guanidinoalkyl group;
R.sub.1 is hydrogen, hydroxy, alkylcarboxy, optionally substituted
aryl, optionally substituted aralkyl, optionally substituted
aryloxyalkyl, optionally substituted benzyloxyalkyl, a heterocyclic
group, a heterocyclic substituted alkyl group, heteroaryl, or a
heteroaryl substituted alkyl group; m is 0, 1, 2, or 3; and p is 0,
1 or 2.
25. A compound having the Formula (IX): 146or a pharmaceutically
acceptable salt thereof; wherein one of K and L is nitrogen and the
other is CH; E is
(CR.sub.aR.sub.b).sub.r--G.sub.s--(CR.sub.cR.sub.d).sub.t, wherein
R.sub.a, R.sub.b, R.sub.c and R.sub.d are independently selected
from the group consisting of hydrogen, alkyl, aryl, hydroxy or
carboxy; G is oxygen, sulfur, sulfone, sulfoxide, carboxy (CO.sub.2
or O.sub.2C), carbonyl (CO), or NR.sub.e, wherein R.sub.e is
hydrogen, alkyl or aryl; r and t are independently 0, 1, 2, 3, 4,
or 5; and s is 0 or 1; Y is hydrogen, hydroxy, CH.sub.3, CN,
CO.sub.2R, sulfate, optionally substituted aryl, optionally
substituted aryloxy, optionally substituted arylthioxy, optionally
substituted aroyl, .ident.--Y.sub.1, .dbd.--Y.sub.1, optionally
substituted heterocyclic group, optionally substituted
heterocycloxy, optionally substituted heteroaryl, optionally
substituted heteroaryloxy, optionally substituted cycloalkyl group,
optionally substituted cycloalkoxy group, amino, amido, ureido, or
guanidino; and Y.sub.1 is hydrogen, alkyl, hydroxyalkyl, optionally
substituted aralkyl, an optionally substituted aryl, optionally
substituted cycloalkyl, aminoalkyl, amidoalkyl, ureidoalkyl, or
guanidinoalkyl.
26. A compound having the Formula (X): 147or a pharmaceutically
acceptable salt thereof; wherein E is
(CR.sub.aR.sub.b).sub.r--G.sub.s--(- CR.sub.cR.sub.d).sub.t,
wherein R.sub.a, R.sub.b, R.sub.c and R.sub.d are independently
selected from the group consisting of hydrogen, alkyl, aryl,
hydroxy or carboxy; G is oxygen, sulfur, sulfone, sulfoxide,
carboxy (CO.sub.2 or O.sub.2C), carbonyl (CO), or NR.sub.e, wherein
R.sub.e is hydrogen, alkyl or aryl; r and t are independently 0, 1,
2, 3, 4, or 5; and s is 0 or 1; Y is hydrogen, hydroxy, CH.sub.3,
CN, CO.sub.2R, sulfate, optionally substituted aryl, optionally
substituted aryloxy, optionally substituted arylthioxy, optionally
substituted aroyl, .ident.--Y.sub.1, .dbd.--Y.sub.1, optionally
substituted heterocyclic group, optionally substituted
heterocycloxy, optionally substituted heteroaryl, optionally
substituted heteroaryloxy, optionally substituted cycloalkyl group,
optionally substituted cycloalkoxy group, amino, amido, ureido, or
guanidino; and Y.sub.1 is hydrogen, alkyl, hydroxyalkyl, optionally
substituted aralkyl, an optionally substituted aryl, optionally
substituted cycloalkyl, aminoalkyl, amidoalkyl, ureidoalkyl, or
guanidinoalkyl.
27. A compound having the Formula (XI): 148or a pharmaceutically
acceptable salt thereof; wherein E is
(CR.sub.aR.sub.b).sub.r--G.sub.s--(- CR.sub.cR.sub.d).sub.t,
wherein R.sub.a, R.sub.b, R.sub.c and R.sub.d are independently
selected from the group consisting of hydrogen, alkyl, aryl,
hydroxy or carboxy; G is oxygen, sulfur, sulfone, sulfoxide,
carboxy (CO.sub.2 or O.sub.2C), carbonyl (CO), or NR.sub.e, wherein
R.sub.e is hydrogen, alkyl or aryl; r and t are independently 0, 1,
2, 3, 4, or 5; and s is 0 or 1; Y is hydrogen, hydroxy, CH.sub.3,
CN, CO.sub.2R, sulfate, optionally substituted aryl, optionally
substituted aryloxy, optionally substituted arylthioxy, optionally
substituted aroyl, .ident.--Y.sub.1, .dbd.--Y.sub.1, optionally
substituted heterocyclic group, optionally substituted
heterocycloxy, optionally substituted heteroaryl, optionally
substituted heteroaryloxy, optionally substituted cycloalkyl group,
optionally substituted cycloalkoxy group, amino, amido, ureido, or
guanidino; and Y.sub.1 is hydrogen, alkyl, hydroxyalkyl, optionally
substituted aralkyl, an optionally substituted aryl, optionally
substituted cycloalkyl, aminoalkyl, amidoalkyl, ureidoalkyl, or
guanidinoalkyl.
28. A compound having the Formula (XII): 149or a pharmaceutically
acceptable salt thereof; wherein A and B are one or more
substituents which are independently hydrogen, halo, alkoxy,
trifluoromethylthio, cyano, carboxy or hydroxy; R.sub.1 is alkyl,
alkenyl, aralkyl, cycloalkyl-alkyl, dialkylaminoalkyl, or
hydroxyalkyl; E is
(CR.sub.aR.sub.b).sub.r--G.sub.s--(CR.sub.cR.sub.d).sub.t, wherein
R.sub.a, R.sub.b, R.sub.c and R.sub.d are independently selected
from the group consisting of hydrogen, alkyl, aryl, hydroxy or
carboxy; G is oxygen, sulfur, sulfone, sulfoxide, carboxy (CO.sub.2
or O.sub.2C), carbonyl (CO), or NR.sub.e, wherein R.sub.e is
hydrogen, alkyl or aryl; r and t are independently 0, 1, 2, 3, 4,
or 5; and s is 0 or 1; Y is hydrogen, hydroxy, CH.sub.3, CN,
CO.sub.2R, sulfate, optionally substituted aryl, optionally
substituted aryloxy, optionally substituted arylthioxy, optionally
substituted aroyl, .ident.--Y.sub.1, .dbd.--Y.sub.1, optionally
substituted heterocyclic group, optionally substituted
heterocycloxy, optionally substituted heteroaryl, optionally
substituted heteroaryloxy, optionally substituted cycloalkyl group,
optionally substituted cycloalkoxy group, amino, amido, ureido, or
guanidino; and Y.sub.1 is hydrogen, alkyl, hydroxyalkyl, optionally
substituted aralkyl, an optionally substituted aryl, optionally
substituted cycloalkyl, aminoalkyl, amidoalkyl, ureidoalkyl, or
guanidinoalkyl.
29. A compound having the Formula (XIII): 150or a pharmaceutically
acceptable salt thereof; wherein R is hydrogen, C.sub.2-C.sub.6
acyl, C.sub.1-C.sub.6 alkyl, aryl, C.sub.1-C.sub.6 alkoxycarbonyl,
C.sub.7-C.sub.10 aralkyl, C.sub.2-C.sub.6 alkenyl, C.sub.3-C.sub.15
dialkylaminoalkyl, C.sub.1-C.sub.6 hydroxyalkyl, C.sub.2-C.sub.6
alkynyl, C.sub.3-C.sub.15 trialkylsilyl, C.sub.4-C.sub.10
alkylcycloalkyl, or C.sub.3-C.sub.6 cycloalkyl; A and B are
independently selected from the group consisting of a halogen such
as chloro, fluoro, bromo, iodo, trifluoromethyl, azido,
C.sub.1-C.sub.6 alkoxy, C.sub.2-C.sub.6 dialkoxymethyl,
C.sub.1-C.sub.6 alkyl, cyano, C.sub.3-C.sub.15 dialkylaminoalkyl,
carboxy, carboxamido, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6
haloalkylthio, allyl, aralkyl, C.sub.3-C.sub.6 cycloalkyl, aroyl,
aralkoxy, C.sub.2-C.sub.6 acyl, aryl, substituted aryl, heteroaryl,
substituted heteroaryl, C.sub.5-C.sub.6 heterocycloalkyl,
C.sub.1-C.sub.6 alkylthio, C.sub.1-C.sub.6 alkylsulfonyl,
C.sub.1-C.sub.6 haloalkylsulfonyl, C.sub.1-C.sub.6 alkylsulfinyl,
C.sub.1-C.sub.6 haloalkylsulfinyl, arylthio, C.sub.1-C.sub.6
haloalkoxy, amino, C.sub.1-C.sub.6 alkylamino, C.sub.2-C.sub.15
dialkylamino, hydroxy, carbamoyl, C.sub.1-C.sub.6 N-alkylcarbamoyl,
C.sub.2-C.sub.15 N,N-dialkylcarbamoyl, nitro and C.sub.2-C.sub.15
dialkylsulfamoyl; Z represents a group selected from 151wherein
R.sup.1 is hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkenyl, aralkyl, C.sub.4-C.sub.15 dialkylaminoalkyl,
heterocycloalkyl, C.sub.2-C.sub.6 acyl, aroyl, or aralkanoyl, and
R.sup.3 is C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, phenyl,
aralkyl or C.sub.3-C.sub.15 dialkylaminoalkyl; and f and g are
independently integers selected from 0 (A or B is hydrogen,
respectively), 1, 2, 3, or 4; E is
(CR.sub.aR.sub.b).sub.r--G.sub.s--(CR.sub.cR.sub.d).sub.t, wherein
R.sub.a, R.sub.b, R.sub.c and R.sub.d are independently selected
from the group consisting of hydrogen, alkyl, aryl, hydroxy or
carboxy; G is oxygen, sulfur, sulfone, sulfoxide, carboxy (CO.sub.2
or O.sub.2C), carbonyl (CO), or NR.sub.e, wherein R.sub.e is
hydrogen, alkyl or aryl; r and t are independently 0, 1, 2, 3, 4,
or 5; and s is 0 or 1; Y is hydrogen, hydroxy, CH.sub.3, CN,
CO.sub.2R, sulfate, optionally substituted aryl, optionally
substituted aryloxy, optionally substituted arylthioxy, optionally
substituted aroyl, .ident.--Y.sub.1, .dbd.--Y.sub.1, optionally
substituted heterocyclic group, optionally substituted
heterocycloxy, optionally substituted heteroaryl, optionally
substituted heteroaryloxy, optionally substituted cycloalkyl group,
optionally substituted cycloalkoxy group, amino, amido, ureido, or
guanidino; and Y.sub.1 is hydrogen, alkyl, hydroxyalkyl, optionally
substituted aralkyl, an optionally substituted aryl, optionally
substituted cycloalkyl, aminoalkyl, amidoalkyl, ureidoalkyl, or
guanidinoalkyl.
30. A compound having the Formula (XIV): 152or a pharmaceutically
acceptable salt thereof; wherein R.sub.1 is carboxy or an
alkylester or amide thereof; alkyl carboxy or an alkyl ester or
amide thereof; hydroxy or hydroxymethyl group; p is 0, 1 or 2; the
dotted line represents a single or double bond; E is
(CR.sub.aR.sub.b).sub.r--G.sub.s--(CR.sub.cR.- sub.d).sub.t,
wherein R.sub.a, R.sub.b, R.sub.c and R.sub.d are independently
selected from the group consisting of hydrogen, alkyl, aryl,
hydroxy or carboxy; G is oxygen, sulfur, sulfone, sulfoxide,
carboxy (CO.sub.2 or O.sub.2C), carbonyl (CO), or NR.sub.e, wherein
R.sub.e is hydrogen, alkyl or aryl; r and t are independently 0, 1,
2, 3, 4, or 5; and s is 0 or 1; Y is hydrogen, hydroxy, CH.sub.3,
CN, CO.sub.2R, sulfate, optionally substituted aryl, optionally
substituted aryloxy, optionally substituted arylthioxy, optionally
substituted aroyl, .ident.--Y.sub.1, .dbd.--Y.sub.1, optionally
substituted heterocyclic group, optionally substituted
heterocycloxy, optionally substituted heteroaryl, optionally
substituted heteroaryloxy, optionally substituted cycloalkyl group,
optionally substituted cycloalkoxy group, amino, amido, ureido, or
guanidino; and Y.sub.1 is hydrogen, alkyl, hydroxyalkyl, optionally
substituted aralkyl, an optionally substituted aryl, optionally
substituted cycloalkyl, aminoalkyl, amidoalkyl, ureidoalkyl, or
guanidinoalkyl.
31. A compound having the Formula (XV): 153or a pharmaceutically
acceptable salt thereof; wherein R.sub.1-R.sub.4 are independently
hydrogen, halo, haloalkyl, aryl, fused aryl, a heterocyclic group,
a heteroaryl group, alkyl, alkenyl, alkynyl, arylalkyl,
arylalkenyl, arylalkynyl, hydroxyalkyl, nitro, amino, cyano,
cyanamido, N(CN).sub.2, guanidino, amidino, acylamido, hydroxy,
thiol, acyloxy, azido, alkoxy, carboxy, carbonylamido, or
alkylthiol; E is (CR.sub.aR.sub.b).sub.r--G.su-
b.s--(CR.sub.cR.sub.d).sub.t, wherein R.sub.a, R.sub.b, R.sub.c and
R.sub.d are independently selected from the group consisting of
hydrogen, alkyl, aryl, hydroxy or carboxy; G is oxygen, sulfur,
sulfone, sulfoxide, carboxy (CO.sub.2 or O.sub.2C), carbonyl (CO),
or NR.sub.e, wherein R.sub.e is hydrogen, alkyl or aryl; r and t
are independently 0, 1, 2, 3, 4, or 5; and s is 0 or 1; R.sub.6 is
hydrogen, hydroxy, alkylcarboxy, optionally substituted aryl,
optionally substituted aralkyl, optionally substituted
aryloxyalkyl, optionally substituted benzyloxyalkyl, a heterocyclic
group, a heterocyclic substituted alkyl group, heteroaryl, or a
heteroaryl substituted alkyl group; p is 0, 1, 2, or 3; Y is
hydrogen, hydroxy, CH.sub.3, CN, CO.sub.2R, sulfate, optionally
substituted aryl, optionally substituted aryloxy, optionally
substituted arylthioxy, optionally substituted aroyl,
.ident.--Y.sub.1, .dbd.--Y.sub.1 (which may be cis or trans,
throughout) carbonylamido, hydrazino, oximo, amidino, optionally
substituted heterocyclic group, optionally substituted
heterocycloxy, optionally substituted heteroaryl, optionally
substituted heteroaryloxy, optionally substituted cycloalkyl group,
optionally substituted cycloalkoxy group, amino, amido, ureido, or
guanidino; and Y.sub.1 is hydrogen, alkyl, hydroxyalkyl, optionally
substituted aralkyl, an optionally substituted aryl, optionally
substituted cycloalkyl, aminoalkyl, amidoalkyl, ureidoalkyl, or
guanidinoalkyl.
32. A compound of the Formula XVI: 154or a pharmaceutically
acceptable salt thereof; wherein Ar.sub.1 is optionally substituted
aryl or optionally substituted heteroaryl; X is O, NR.sub.1 or
(CH.sub.2).sub.n wherein n is 0, 1, 2, 3 or 4 and R.sub.1 is
hydrogen or a lower alkyl group having 1 to 6 carbon atoms; U is
hydroxy or hydrogen; Y is (CH.sub.2).sub.m wherein m is 1, 2 or 3;
Z is (CHR.sub.2).sub.z wherein z is 0, 1, 2, 3, or 4 and R.sub.2 is
hydroxy, hydrogen or a lower alkyl group having 1 to 6 carbon
atoms; and A and B are each hydrogen or together are
(CH.sub.2).sub.w wherein w is 0, 1, 2, 3 or 4.
33. A compound of the Formula XVII: 155or a pharmaceutically
acceptable salt thereof; wherein Ar.sub.1 is optionally substituted
aryl or optionally substituted heteroaryl; X is O, NR, or
(CH.sub.2).sub.n wherein n is 0, 1, 2, 3, or 4 and R.sub.1 is
hydrogen or a lower alkyl group having 1 to 6 carbon atoms; U is
hydroxy or hydrogen; Z is (CHR.sub.2).sub.z wherein z is 0, 1, 2, 3
or 4 and R.sub.2 is hydroxy, hydrogen or a lower alkyl group having
1 to 6 carbon atoms; Q is --CH.dbd.CH.dbd. or --C.ident.C--;
R.sub.3 is hydrogen, hydroxy or hydroxy substituted lower alkyl
having 1 to 6 carbon atoms; and Y is hydrogen, hydroxy, optionally
substituted aryl or optionally substituted heteroaryl.
34. A quaternary ammonium salt of the compounds of any one of
claims 1-33, obtained by reacting the compound with a lower alkyl
halide or methyl sulfate.
35. A pharmaceutical composition comprising the compound of any one
of claims 1-33 and a pharmaceutically acceptable carrier.
36. A pharmaceutical composition comprising the compound of claim
34 and a pharmaceutically acceptable carrier.
37. A method of treating or preventing neuronal loss associated
with stroke, ischemia, CNS trauma, hypoglycemia or surgery, or
treating a neurodegenerative disease, or treating or preventing the
adverse consequences of the overstimulation of the excitatory amino
acids, or treating anxiety, psychosis, glaucoma, CMV retinitis,
urinary incontinence, migraine headache, convulsions,
aminoglycoside antibiotics-induced hearing loss, Parkinson's
disease, chronic pain or inducing anesthesia, opioid tolerance or
withdrawal, or enhancing cognition, comprising administering to an
animal in need of such treatment an effective amount of a compound
of any one of claims 1-33.
38. A method of treating or preventing neuronal loss associated
with stroke, ischemia, CNS trauma, hypoglycemia or surgery, or
treating a neurodegenerative disease, or treating or preventing the
adverse consequences of the overstimulation of the excitatory amino
acids, or treating anxiety, psychosis, glaucoma, CMV retinitis,
urinary incontinence, migraine headache, convulsions,
aminoglycoside antibiotics-induced hearing loss, Parkinson's
disease, chronic pain or inducing anesthesia, opioid tolerance or
withdrawal, or enhancing cognition, comprising administering to an
animal in need of such treatment an effective amount of a compound
of claim 34.
39. The method of claim 37, wherein said compound is administered
as part of a pharmaceutical composition comprising a
pharmaceutically acceptable carrier.
40. The method of claim 38, wherein said compound is administered
as part of a pharmaceutical composition comprising a
pharmaceutically acceptable carrier.
Description
BACKGROUND OF THE INVENTION
[0001] 1. Field of the Invention
[0002] This invention is related to 2-substituted piperidine
analogs. The analogs are selectively active as antagonists of
N-methyl-D-aspartate (NMDA) receptor subtypes. The invention is
also directed to the use of 2-substituted piperidine analogs as
neuroprotective agents for treating conditions such as stroke,
cerebral ischemia, central nervous system trauma, hypoglycemia,
anxiety, convulsions, aminoglycoside antibiotics-induced hearing
loss, migraine headaches, chronic pain, glaucoma, CMV retinitis,
psychosis, urinary incontinence, opioid tolerance or withdrawal, or
neuro-degenerative disorders such as lathyrism, Alzheimer's
Disease, Parkinsonism and Huntington's Disease.
[0003] 2. Related Background Art
[0004] Excessive excitation by neurotransmitters can cause the
degeneration and death of neurons. It is believed that this
degeneration is in part mediated by the excitotoxic actions of the
excitatory amino acids (EAA) glutamate and aspartate at the
N-methyl-D-Aspartate (NMDA) receptor. This excitotoxic action is
considered responsible for the loss of neurons in cerebrovascular
disorders such as cerebral ischemia or cerebral infarction
resulting from a range of conditions, such as thromboembolic or
hemorrhagic stroke, cerebral vasospasms, hypoglycemia, cardiac
arrest, status epilepticus, perinatal asphyxia, anoxia such as from
drowning, pulmonary surgery and cerebral trauma, as well as
lathyrism, Alzheimer's Disease, Parkinson's Disease and
Huntington's Disease.
[0005] Excitatory amino acid receptor antagonists that block NMDA
receptors are recognized for usefulness in the treatment of
disorders. NMDA receptors are intimately involved in the phenomenon
of excitotoxicity, which may be a critical determinant of outcome
of several neurological disorders. Disorders known to be responsive
to blockade of the NMDA receptor include acute cerebral ischemia
(stroke or cerebral trauma, for example), muscular spasm,
convulsive disorders, neuropathic pain and anxiety, and may be a
significant causal factor in chronic neurodegenerative disorders
such as Parkinson's disease [T. Klockgether, L. Turski, Ann.
Neurol. 34, 585-593 (1993)], human immunodeficiency virus (HIV)
related neuronal injury, amyotrophic lateral sclerosis (ALS),
Alzheimer's disease [P. T. Francis, N. R. Sims, A. W. Procter, D.
M. Bowen, J. Neurochem. 60 (5), 1589-1604 (1993)] and Huntington's
disease. [See S. Lipton, TINS 16 (12), 527-532 (1993); S. A.
Lipton, P. A. Rosenberg, New Eng. J. Med. 330 (9), 613-622 (1994);
and C. F. Bigge, Biochem. Pharmacol. 45, 1547-1561 (1993) and
references cited therein.]. NMDA receptor antagonists may also be
used to prevent tolerance to opiate analgesia or to help control
withdrawal symptoms from addictive drugs (Eur. Pat. Appl.
488,959A).
[0006] U.S. Pat. No. 5,352,683, discloses the treatment of chronic
pain with a compound with is an antagonist of the NMDA
receptor.
[0007] U.S. Pat. No. 4,902,695, discloses certain competitive NMDA
antagonists that are useful for the treatment of neurological
disorders, including epilepsy, stroke, anxiety, cerebral ischemia,
muscular spasms, and neurodegenerative diseases such as Alzheimer's
disease and Huntington's disease.
[0008] U.S. Pat. No. 5,192,751 discloses a method of treating
urinary incontinence in a mammal which comprises administering an
effective amount of a competitive NMDA antagonist.
[0009] Evidence indicates that the NMDA receptor comprises a class
of such receptors with different subunits. Molecular cloning has
revealed the existence of at least five subunits of the NMDA
receptors designated NR1 & NR2A through 2D. It has been
demonstrated that the co-expression of NR1 with one of the NR2
subunits forms a receptor with a functional ion channel. (Ann. Rev.
Neurosci. 17:31-108(1994)). It is thought that NMDA receptors with
different subunit composition generate the different NMDA receptor
subtypes found in the mammalian brain.
[0010] An object of this invention is to provide
novel-subtype-selective NMDA receptor ligands.
SUMMARY OF THE INVENTION
[0011] The invention relates to a subtype-selective NMDA receptor
ligand having the Formula (I): 1
[0012] wherein
[0013] R.sub.1-R.sub.4 are independently hydrogen, halo, haloalkyl,
aryl, fused aryl, a heterocyclic group, a heteroaryl group, alkyl,
alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl,
hydroxyalkyl, nitro, amino, cyano, cyanamido, N(CN).sub.2,
guanidino, amidino, acylamido, hydroxy, thiol, acyloxy, azido,
alkoxy, carboxy, carbonylamido, or alkylthiol;
[0014] E is
(CR.sub.aR.sub.b).sub.r--G.sub.s--(CR.sub.cR.sub.d).sub.t, wherein
R.sub.a, R.sub.b, R.sub.c and R.sub.d are independently selected
from the group consisting of hydrogen, alkyl, aryl, hydroxy or
carboxy; G is oxygen, sulfur, sulfone, sulfoxide, carboxy (CO.sub.2
or O.sub.2C), carbonyl (CO), or NR.sub.e, wherein R.sub.e is
hydrogen, alkyl or aryl; r and t are independently 0, 1, 2, 3, 4,
or 5; and s is 0 or 1;
[0015] R.sub.5 is hydrogen, hydroxy, alkylcarboxy, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted aryloxyalkyl, optionally substituted benzyloxyalkyl, a
heterocyclic group, a heterocyclic substituted alkyl group,
heteroaryl, or a heteroaryl substituted alkyl group;
[0016] p is 0, 1, 2, or 3;
[0017] Y is hydrogen, hydroxy, CH.sub.3, CN, CO.sub.2R, sulfate,
optionally substituted aryl, optionally substituted aryloxy,
optionally substituted arylthioxy, optionally substituted aroyl,
.ident.--Y.sub.1, .dbd.--Y.sub.1 (which may be cis or trans,
throughout) carbonylamido, hydrazino, oximo, amidino, optionally
substituted heterocyclic group, optionally substituted
heterocycloxy, optionally substituted heteroaryl, optionally
substituted heteroaryloxy, optionally substituted cycloalkyl group,
optionally substituted cycloalkoxy group, amino, amido, ureido, or
guanidino; and
[0018] Y.sub.1 is hydrogen, alkyl, hydroxyalkyl, optionally
substituted aralkyl, an optionally substituted aryl, optionally
substituted cycloalkyl, aminoalkyl, amidoalkyl, ureidoalkyl, or
guanidinoalkyl.
[0019] The invention also relates to a subtype-selective NMDA
receptor ligand having the Formula (II): 2
[0020] wherein
[0021] R.sub.1-R.sub.4, E, Y and Y.sub.1 are the same as described
in formula I;
[0022] R.sub.5 is hydrogen, lower alkyl, acyl or aryl;
[0023] p is 0, 1, 2 or 3; and
[0024] R.sub.6 is hydrogen, hydroxy, alkylcarboxy, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted aryloxyalkyl, optionally substituted benzyloxyalkyl, a
heterocyclic group, a heterocyclic substituted alkyl group,
heteroaryl, or a heteroaryl substituted alkyl group; and
[0025] The invention also relates to a subtype-selective NMDA
receptor ligand having the Formula (IIa): 3
[0026] wherein
[0027] R.sub.1-R.sub.4, E, Y and Y.sub.1 are the same as described
in formula I;
[0028] R.sub.5 is hydrogen, lower alkyl, acyl or aryl;
[0029] p is 0, 1, 2 or 3; and
[0030] R.sub.6 is hydrogen, hydroxy, alkylcarboxy, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted aryloxyalkyl, optionally substituted benzyloxyalkyl, a
heterocyclic group, a heterocyclic substituted alkyl group,
heteroaryl, or a heteroaryl substituted alkyl group.
[0031] The invention also relates to a subtype-selective NMDA
receptor ligand having the Formula (III): 4
[0032] wherein
[0033] W is an adamantyl group, an optionally substituted aryl
group, or an optionally substituted heteroaryl group;
[0034] X is a bond, (CH.sub.2).sub.m, carbonyl, oxygen, or NR;
[0035] E is the same as described in formula I;
[0036] Y is hydrogen, hydroxy, CH.sub.3, CN, CO.sub.2R; an
aminoalkyl group, an amidoalkyl group, a ureidoalkyl group, or a
guanidinoalkyl group;
[0037] R is hydrogen, alkyl, aminoalkyl, amidoalkyl, ureidoalkyl,
or guanidinoalkyl;
[0038] R.sub.1 is hydrogen, hydroxy, alkylcarboxy, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted aryloxyalkyl, optionally substituted benzyloxyalkyl, a
heterocyclic group, a heterocyclic substituted alkyl group,
heteroaryl, or a heteroaryl substituted alkyl group;
[0039] m is 0, 1, 2, or 3; and
[0040] p is 0, 1, 2, 3 or 4.
[0041] with the proviso, that when W is adamantyl or when p is
greater than zero, or when the piperidine is substituted in the
3-position by W--X, then Y may also be optionally substituted aryl,
optionally substituted aryloxy, optionally substituted arylthioxy,
optionally substituted aroyl, .ident.--Y.sub.1, .dbd.--Y.sub.1,
optionally substituted heterocyclic group, optionally substituted
heterocycloxy, optionally substituted heteroaryl, optionally
substituted heteroaryloxy, optionally substituted cycloalkyl group,
optionally substituted cycloalkoxy group, amino, amido, ureido, or
guanidino; wherein
[0042] Y.sub.1 is hydrogen, alkyl, hydroxyalkyl, optionally
substituted aralkyl, optionally substituted aryl, optionally
substituted cycloalkyl, aminoalkyl, amidoalkyl, ureidoalkyl, or
guanidinoalkyl.
[0043] The invention also relates to a subtype-selective NMDA
receptor ligand having the Formula (IV): 5
[0044] wherein
[0045] R.sub.1-R.sub.5 are independently hydrogen, halo, haloalkyl,
aryl, fused aryl, a heterocyclic group, a heteroaryl group, alkyl,
alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl,
hydroxyalkyl, nitro, amino, cyano, acylamido, hydroxy, thiol,
acyloxy, azido, alkoxy, carboxy, carbonylamido, or alkylthiol;
and
[0046] E, Y and Y.sup.1 are the same as described in formula I.
[0047] The invention also relates to a subtype-selective NMDA
receptor ligand having the Formula (V): 6
[0048] wherein
[0049] R.sub.1-R.sub.4, E, Y and Y.sub.1 are the same as described
in formula I.
[0050] The invention also relates to a subtype-selective NMDA
receptor ligand having the Formula (VI): 7
[0051] wherein
[0052] W is an adamantyl group, an optionally substituted aryl
group, or an optionally substituted heteroaryl group;
[0053] X is a bond, (CH.sub.2).sub.m, oxygen, or NR;
[0054] E, Y and Y.sub.1 are the same as described in formula I;
[0055] R is alkyl, hydroxy, an aminoalkyl group, an amidoalkyl
group, a ureidoalkyl group, or a guanidinoalkyl group;
[0056] R.sub.1 is hydrogen, hydroxy, alkylcarboxy, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted aryloxyalkyl, optionally substituted benzyloxyalkyl, a
heterocyclic group, a heterocyclic substituted alkyl group,
heteroaryl, or a heteroaryl substituted alkyl group;
[0057] m is 0, 1, 2, or 3; and
[0058] q is 0, 1 or 2.
[0059] The invention also relates to a subtype-selective NMDA
receptor ligand having the Formula (VII): 8
[0060] wherein
[0061] W is an adamantyl group, an optionally substituted aryl
group, or an optionally substituted heteroaryl group;
[0062] X is a bond, (CH.sub.2).sub.m, oxygen, or NR;
[0063] E, Y and Y.sub.1 are the same as described in formula I;
[0064] R is alkyl, hydroxy, an aminoalkyl group, an amidoalkyl
group, a ureidoalkyl group, or a guanidinoalkyl group;
[0065] R.sub.1 is hydrogen, hydroxy, alkylcarboxy, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted aryloxyalkyl, optionally substituted benzyloxyalkyl, a
heterocyclic group, a heterocyclic substituted alkyl group,
heteroaryl, or a heteroaryl substituted alkyl group;
[0066] m is 0, 1, 2, or 3; and
[0067] p is 0, 1 or 2.
[0068] The invention also relates to a subtype-selective NMDA
receptor ligand having the Formula (VIII): 9
[0069] wherein
[0070] W is an adamantyl group, an optionally substituted aryl
group, or an optionally substituted heteroaryl group;
[0071] X is a bond, (CH.sub.2).sub.m, oxygen, or NR;
[0072] E, Y and Y1 are the same as described in formula I;
[0073] R is alkyl, hydroxy, an aminoalkyl group, an amidoalkyl
group, a ureidoalkyl group, or a guanidinoalkyl group;
[0074] R.sub.1 is hydrogen, hydroxy, alkylcarboxy, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted aryloxyalkyl, optionally substituted benzyloxyalkyl, a
heterocyclic group, a heterocyclic substituted alkyl group,
heteroaryl, or a heteroaryl substituted alkyl group;
[0075] m is 0, 1, 2, or 3; and
[0076] p is 0, 1 or 2.
[0077] The invention also relates to a subtype-selective NMDA
receptor ligand having the Formula (IX): 10
[0078] wherein
[0079] one of K and L is nitrogen and the other is CH; and
[0080] E, Y and Y.sub.1 are the same as described in Formula I.
[0081] The invention also relates to a subtype-selective NMDA
receptor ligand having the Formula (X): 11
[0082] wherein
[0083] E, Y and Y.sub.1 are the same as described in formula I.
[0084] The invention also relates to a subtype-selective NMDA
receptor ligand having the Formula (XI): 12
[0085] wherein
[0086] E, Y and Y.sub.1 are the same as described in formula 1.
[0087] The invention also relates to a subtype-selective NMDA
receptor ligand having the Formula (XII): 13
[0088] wherein
[0089] A and B are one or more substituents which are independently
hydrogen, halo, alkoxy, trifluoromethylthio, cyano, carboxy or
hydroxy;
[0090] R.sub.1 is alkyl, alkenyl, aralkyl, cycloalkyl-alkyl,
dialkylaminoalkyl, or hydroxyalkyl; and
[0091] E, Y and Y.sub.1 are the same as described in formula I.
[0092] The invention also relates to a subtype-selective NMDA
receptor ligand having the Formula (XIII): 14
[0093] wherein
[0094] R is hydrogen, C.sub.2-C.sub.6 acyl, C.sub.1-C.sub.6 alkyl,
aryl, C.sub.1-C.sub.6 alkoxycarbonyl, C.sub.7-C.sub.10 aralkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.3-C.sub.15 dialkylaminoalkyl,
C.sub.1-C.sub.6 hydroxyalkyl, C.sub.2-C.sub.6 alkynyl,
C.sub.3-C.sub.15 trialkylsilyl, C.sub.4-C.sub.10 alkylcycloalkyl,
or C.sub.3-C.sub.6 cycloalkyl;
[0095] A and B are independently selected from the group consisting
of a halogen such as chloro, fluoro, bromo, iodo, trifluoromethyl,
azido, C.sub.1-C.sub.6 alkoxy, C.sub.2-C.sub.6 dialkoxymethyl,
C.sub.1-C.sub.6 alkyl, cyano, C.sub.3-C.sub.15 dialkylaminoalkyl,
carboxy, carboxamido, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6
haloalkylthio, allyl, aralkyl, C.sub.3-C.sub.6 cycloalkyl, aroyl,
aralkoxy, C.sub.2-C.sub.6 acyl, aryl, substituted aryl, heteroaryl,
substituted heteroaryl, C.sub.5-C.sub.6 heterocycloalkyl,
C.sub.1-C.sub.6 alkylthio, C.sub.1-C.sub.6 alkylsulfonyl,
C.sub.1-C.sub.6 haloalkylsulfonyl, C.sub.1-C.sub.6 alkylsulfinyl,
C.sub.1-C.sub.6 haloalkylsulfinyl, arylthio, C.sub.1-C.sub.6
haloalkoxy, amino, C.sub.1-C.sub.6 alkylamino, C.sub.2-C.sub.15
dialkylamino, hydroxy, carbamoyl, C.sub.1-C.sub.6 N-alkylcarbamoyl,
C.sub.2-C.sub.15 N,N-dialkylcarbamoyl, nitro and C.sub.2-C.sub.15
dialkylsulfamoyl;
[0096] Z represents a group selected from 15
[0097] wherein R.sup.1 is hydrogen, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, aralkyl, C.sub.4-C.sub.15
dialkylaminoalkyl, heterocycloalkyl, C.sub.2-C.sub.6 acyl, aroyl,
or aralkanoyl, and R.sup.3 is C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, phenyl, aralkyl or C.sub.3-C.sub.15
dialkylaminoalkyl; and
[0098] f and g are independently integers selected from 0 (X or Y
is hydrogen, respectively), 1, 2, 3, or 4; and
[0099] E, Y and Y.sub.1 are the same as described in formual I.
[0100] The invention also relates to a subtype-selective NMDA
receptor ligand having the Formula (XIV): 16
[0101] wherein
[0102] R.sub.1 is carboxy or an alkylester or amide thereof; alkyl
carboxy or an alkyl ester or amide thereof; hydroxy or
hydroxymethyl group;
[0103] p is 0, 1 or 2;
[0104] the dotted line represents a single or double bond;
[0105] E, Y and Y.sub.1 are the same as described in formula I.
[0106] The invention relates to a subtype-selective NMDA receptor
ligand having the Formula (XV): 17
[0107] wherein
[0108] R.sub.1-R.sub.4, E, Y and Y.sub.1 are the same as described
in formula I;
[0109] R.sub.6 is hydrogen, hydroxy, alkylcarboxy, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted aryloxyalkyl, optionally substituted benzyloxyalkyl, a
heterocyclic group, a heterocyclic substituted alkyl group,
heteroaryl, or a heteroaryl substituted alkyl group; and
[0110] p is 0, 1, 2, or 3.
[0111] The invention relates to a subtype-selective NMDA receptor
ligand having the Formula (XVI): 18
[0112] wherein
[0113] Ar.sub.1 is optionally substituted aryl or optionally
substituted heteroaryl;
[0114] X is O, NR.sub.1 or (CH.sub.2).sub.n wherein n is O, 1, 2, 3
or 4 and R.sub.1 is hydrogen or a lower alkyl group having 1 to 6
carbon atoms;
[0115] U is hydroxy or hydrogen;
[0116] Y is (CH.sub.2).sub.m wherein m is 1, 2 or 3;
[0117] Z is (CHR.sub.2).sub.z wherein z is 0, 1, 2, 3 or 4 and
R.sub.2 is hydroxy, hydrogen or a lower alkyl group having 1 to 6
carbon atoms; and
[0118] A and B are each hydrogen or together are (CH.sub.2).sub.w
wherein w is 0, 1, 2, 3 or 4.
[0119] Preferred substituents of Ar.sub.1 include, for example,
hydrogen, alkyl, a halogenated alkyl group such as a
trifluoromethyl group, halogen, nitro, aryl, aralkyl, amino, a
lower alkyl amino group or a lower alkoxy group.
[0120] The invention relates to a subtype-selective NMDA receptor
ligand having the Formula (XVII): 19
[0121] wherein
[0122] Ar.sub.1 is optionally substituted aryl or optionally.
substituted heteroaryl;
[0123] X is O, NR.sub.1 or (CH.sub.2).sub.n wherein n is 0, 1, 2, 3
or 4 and R.sub.1 is hydrogen or a lower alkyl group having 1 to 6
carbon atoms;
[0124] U is hydroxy or hydrogen;
[0125] Z is (CHR.sub.2).sub.z wherein z is 0, 1, 2, 3 or 4 and
R.sub.2 is hydroxy, hydrogen or a lower alkyl group having 1 to 6
carbon atoms;
[0126] Q is --CH.dbd.CH-- or --C.ident.C--;
[0127] R.sub.3 is hydrogen, hydroxy or hydroxy substituted lower
alkyl having 1 to 6 carbon atoms; and
[0128] Y is hydrogen, hydroxy, optionally substituted aryl or
optionally substituted heteroaryl.
[0129] Preferred substituents of the aryl and heteroaryl groups
include, for example, hydrogen, alkyl, a halogenated alkyl group
such as a trifluoromethyl group, halogen, nitro, aryl, aralkyl,
amino, a lower alkyl amino group or a lower alkoxy group.
[0130] The invention also relates to the quaternary ammonium salts
of any one of the compounds above obtained by reacting the compound
with a lower alkyl halide, preferable, methyl iodide or methyl
sulfate.
[0131] The invention also relates to a method of treating or
preventing neuronal loss associated with stroke, ischemia, CNS
trauma, hypoglycemia and surgery, as well as treating
neurodegenerative diseases including Alzheimer's disease,
amyotrophic lateral sclerosis, Huntington's disease, Parkinson's
disease and Down's syndrome, treating or preventing the adverse
consequences of the overstimulation of the excitatory amino acids,
treating anxiety, psychosis, convulsions, chronic pain, glaucoma,
CMV retinitis, urinary incontinence, and inducing anesthesia, as
well as enhancing cognition, and preventing opiate tolerance and
withdrawal symptoms, comprising administering to an animal in need
of such treatment an effective amount of any one of the
subtype-selective NMDA receptor ligands of the present invention,
or a pharmaceutically acceptable salt thereof.
DETAILED DESCRIPTION OF THE INVENTION
[0132] The present invention relates to the discovery of new
compounds which are subtype-selective ligands of the NMDA receptor.
There are a number of subtypes of the NMDA receptor including
NR1A/2A, NR1A/2B, NR1A/2C and NR1A/2D. The discovery of ligands
which are selective for one or more of these subtypes allows for
the treatment of various conditions mediated through binding to the
NMDA receptor, while minimizing unwanted side effects.
[0133] Electrophysiological assays may be utilized to characterize
the actions of potential subtype-selective ligands at NMDA
receptors expressed in Xenopus oocytes. The ligand may be assayed
at the different subunit combinations of cloned rat NMDA receptors
corresponding to the four putative NMDA receptor subtypes
(Moriyoshi et al., Nature (Lond.) 354:31-37 (1991); Monyer et al.,
Science (Washington, D.C.) 256:1217-1221 (1992); Kutsuwada et al.,
Nature (Lond.) 358:36-41 (1992); Sugihara et al., Biochem. Biophys.
Res. Comm. 185:826-832 (1992)).
[0134] Using fixed saturating concentrations of agonists (glutamate
100 .mu.M, glycine 1-10 .mu.M depending on subunit combination),
the inhibitory potency of a putative subtype-selective ligand may
be assayed at the NMDA receptors assembled from NR1A/2A, NR1A/2B,
NR1A/2C and NR1A/2D subunit combinations.
[0135] Preferably, the subtype selective NMDA receptor ligands are
limited efficacy NMDA receptor antagonists. Such limited efficacy
antagonists are attractive because such drugs have built-in safety
margins; no matter how high the dosage only a certain fraction of
the response can be blocked. This could be particularly important
for analgesic, anticonvulsant, anti-psychotic, antimigraine
headache, antiparkinson's disease and antiglaucoma indications,
where overdosage of full antagonists may result in sedation. It is
also likely that limited efficacy NMDA receptor antagonists,
particularly those showing subtype-selectivity, will not induce
such profound memory deficits as full antagonists.
[0136] Certain of the subtype-selective NMDA receptor ligands are
expected to be able to mediate either inhibition or potentiation of
membrane current response. Which type of effect predominates
appears to be dependent upon the subunit composition of the
receptors and on the structure of the molecule. The 1A/2A and 1A/2B
subtypes are mainly in the forebrain. The 1A/2C and 1A/2D are
mainly in the cerebellum. In addition to the potential of
developing subtype-selective drugs for the treatment of diseases
associated with the overstimulation of the NMDA receptor with few
side effects, it is also possible to develop drugs that selectively
potentiate particular subtypes of NMDA receptors present in
particular parts of the brain. Such drugs could show therapeutic
potential as cognitive-enhancers in treatments of neurodegenerative
conditions such as Alzheimer's disease. In addition, there is a
potential for developing drugs that selectively potentiate some
subtypes of NMDA receptors while simultaneously having inhibitory
effects at other subtypes. Such compounds could be important for
adjusting imbalances in subtype activity and may have therapeutic
potential as psychotropic agents.
[0137] Compounds that are useful for treating or preventing the
adverse consequences of stroke, hypoglycemia, neurodegenerative
disorders, anxiety, epilepsy or psychosis, or that induce
analgesia, will inhibit the currents across the membranes of the
oocyte expressing various subtype NMDA receptors. However, if the
compound potentiates currents across the oocyte membrane, then the
compound is expected to be useful in enhancing cognition.
[0138] With respect to Formulae I-XVII, above:
[0139] Typical C.sub.6-14 aryl groups include phenyl, naphthyl,
phenanthryl, anthracyl, indenyl, azulenyl, biphenyl, biphenylenyl
and fluorenyl groups.
[0140] Typical halo groups include fluorine, chlorine, bromine and
iodine.
[0141] Typical C.sub.1-4 alkyl groups include methyl, ethyl,
propyl, isopropyl, butyl, sec.-butyl, and tert.-butyl groups. Also
contemplated is a trimethylene group substituted on two adjoining
positions on any benzene ring of the compounds of the
invention.
[0142] Typical C.sub.2-4 alkenyl groups include ethenyl, propenyl,
isopropenyl, butenyl, and sec.-butenyl.
[0143] Typical C.sub.2-4 alkynyl groups include ethynyl, propynyl,
butynyl, and 2-butnyyl groups.
[0144] Typical arylalkyl groups include any of the above-mentioned
C.sub.1-4 alkyl groups substituted by any of the above-mentioned
C.sub.6-14 aryl groups.
[0145] Typical arylalkenyl groups include any of the
above-mentioned C.sub.2-4 alkenyl groups substituted by any of the
above-mentioned C.sub.6-14 aryl groups.
[0146] Typical arylalkynyl groups include any of the
above-mentioned C.sub.2-4 alkynyl groups substituted by any of the
above-mentioned C.sub.6-14 aryl groups.
[0147] Typical haloalkyl groups include C.sub.1-4 alkyl groups
substituted by one or more fluorine, chlorine, bromine or iodine
atoms, e.g., fluoromethyl, difluoromethyl, trifluoromethyl,
pentafluoroethyl, 1,1-difluoroethyl and trichloromethyl groups.
[0148] Typical hydroxyalkyl groups include C.sub.1-4 alkyl groups
substituted by hydroxy, e.g., hydroxymethyl, hydroxyethyl,
hydroxypropyl and hydroxybutyl groups.
[0149] Typical alkoxy groups include oxygen substituted by one of
the C.sub.1-4 alkyl groups mentioned above.
[0150] Typical alkylthio groups include sulphur substituted by one
of the C.sub.1-4 alkyl groups mentioned above.
[0151] Typical acylamino groups include any C.sub.1-6 acyl
(alkanoyl) substituted nitrogen, e.g., acetamido, propionamido,
butanoylamido, pentanoylamido, hexanoylamido as well as
aryl-substituted C.sub.2-6 substituted acyl groups.
[0152] Typical acyloxy groups include any C.sub.1-6 acyloxy groups,
e.g., acetoxy, propionoyloxy, butanoyloxy, pentanoyloxy,
hexanoyloxy and the like.
[0153] Typical heterocyclic groups include tetrahydrofuranyl,
pyranyl, piperidinyl, piperizinyl, pyrrolidinyl, imidazolindinyl,
imidazolinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl,
isochromanyl, chromanyl, pyrazolidinyl and pyrazolinyl groups.
[0154] Typical heteroaryl groups include any one of the following
which may be optionally substituted with one or more alkyl, halo,
or hydroxy groups: thienyl, benzo[b]thienyl, naphtho[2,3-b]thienyl,
thianthrenyl, furyl, pyranyl, isobenzofuranyl, chromenyl,
xanthenyl, phenoxathiinyl, 2H-pyrrolyl, pyrrolyl, imidazolyl,
pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl,
indolizinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl,
4H-quinolizinyl, isoquinolyl, quinolyl, phthalazinyl,
naphthyridinyl, quinazolinyl, cinnolinyl, pteridinyl,
4aH-carbazolyl, carbazolyl, .beta.-carbolinyl, phenanthridinyl,
acridinyl, perimidinyl, phenanthrolinyl, phenazinyl, isothiazolyl,
phenothiazinyl, isoxazolyl, furazanyl phenoxazinyl groups,
1,4-dihydroquinoxaline-2,3-dione, 7-amino isocoumarin,
pyrido[1,2-a]pyrimidin-4-one, 1,2-benzoisoxazol-3-yl,
benzimidazolyl, 2-oxobenzimidazolyl, 2-oxindolyl and
4-nitrobenzofurazan.
[0155] Where the heteroaryl group contains a nitrogen atom in a
ring, such nitrogen atom may be in the form of an N-oxide, e.g., a
pyridyl N-oxide, pyrazinyl N-oxide, pyrimidinyl N-oxide and the
like.
[0156] Typical amino groups include --NH.sub.2, --NHR.sup.14, and
--NR.sup.14R.sup.15, wherein R.sup.14 and R.sup.15 are C.sub.1-4
alkyl groups as defined above.
[0157] Typical carbonylamido groups are carbonyl groups substituted
by --NH.sub.2, --NHR.sup.14, and --NR.sup.14R.sup.15 groups as
defined above.
[0158] When the group is an amidino or guanidino group, any one of
the nitrogen atoms may be substituted, e.g., 20
[0159] where each R is independently hydrogen, alkyl, or aryl.
[0160] Optional substituents on the aryl, aryloxy, arylthioxy,
aroyl, heterocyclic, heterocycloxy, heteroaryl, heteroaryloxy,
cycloalkyl, and cycloalkoxy groups listed above include any one of
the typical halo, haloalkyl, aryl, fused aryl, heterocyclic,
heteroaryl, alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl,
arylalkynyl, hydroxyalkyl, nitro, amino, cyano, acylamido, hydroxy,
thiol, acyloxy, azido, alkoxy, carboxy, carbonylamido, and
alkylthiol groups mentioned above.
[0161] In the compounds having the above formulae, the group E is a
linker group between the nitrogen, e.g., piperidine nitrogen, and
the terminal group Y. Excluded from such Formulae are where two
heteroatoms are adjacent to one another such that an unstable
compound would be produced. Such adjacent heteroatoms include
--O--O--, --O--S-(divalent sulfur), --N--S-(divalent sulfur),
--S--O-(divalent sulfur), and --S--N-(divalent sulfur). Hydrazine
groups (--N--N--) are contemplated as possible linkers. Preferably,
the group E is an optionally substituted methylene linker. Most
preferably, the group E is a methylene linker (CH.sub.2).sub.n,
wherein n is 1, 2, 3, 4, 5 or 6.
[0162] Preferably, the group Y is an N-hydroxyalkylpiperidinyl
(e.g., hydroxypropyl) group, which is expected to provide a
reduction in affinity to the .alpha..sub.1 receptor, thereby
resulting in less hypotension when the compounds are administered
to animals. See, Gifford, R. W. et al., Arch. Intern. Med.
153:154-183 (1993). Alternatively, a halo group such as a
p-chlorophenyl group may be employed to give compounds having a
prolonged in vivo activity.
[0163] Compounds having Formula I may be prepared by reaction of an
appropriately substituted 1,2,3,4-tetrahydroisoquinoline with a
suitable electrophile in an aprotic solvent such as toluene or
acetonitrile. The starting 1,2,3,4-tetrahydroisoquinoline may be
prepared by the Pictet-Spenger method described in Org. Reactions
6:151-206 (1951). Optionally, a base such as potassium carbonate or
pyridine may be added. Examples of suitable electrophiles include,
for example, an alkyl, alkenyl, alkynyl, aralkyl, aryloxyalkyl, or
heteroaralkyl halide, sulfate, sulfonate, or isocyanate. Specific
examples of such electrophiles include ethyl 3-bromoethoxyphenyl
acetate, methyl 5-bromovalerate, ethyl 4-bromobutyrate,
3-butyn-1-methanesulfate, ethyl crotonate, 1-chloro-4-phenylbutane,
3-phenoxypropyl bromide, 4-chloro-4'-fluorobutyrophenone,
4-chlorobutyrophenone, 2-phenylethyl bromide,
1-bromo-3-phenylpropane, 3-phenoxypropyl bromide,
.beta.-bromo-phenetole, 3-phenoxypropyl bromide, 3-phenylpropyl
bromide, 1,3-propanesulfone, phenylisocyanate,
4-nitrophenylisocyanate, allyl iodide, bromomethylcyclopropane,
3-bromo-1-propanol, and 5-bromovaleronitrile.
[0164] A general procedure for reaction of the
piperidine-containing compound with an alkyl chloride, bromide,
tosylate or mesylate involves forming a mixture of a free base of
the amino derivative and an alkyl chloride or bromide in toluene,
acetonitrile, DMF, acetone or ethanol, in the presence of NaI. The
reaction may be refluxed for 1-10 h then cooled to room
temperature, filtered and washed with hexane. The filtrate is
evaporated, and the residue chromatographed over silica gel to give
the product. If the product is a solid, it may be crystallized, for
example, from hexane or hexane-ethyl acetate. If the product is an
oil, it may be dissolved in acetone and 4N HCl solution in
1,4-dioxane or concentrated HCl may be added until the mixture
becomes strongly acidic (pH<2). It may then be rota-evaporated,
and co-evaporated until a solid residue is obtained. The solid may
then be recrystallized from acetone to give the hydrochloride.
Alternatively, the hydrobromide or other acid addition salts may be
prepared by substitution of, for example, HBr or maleic acid for
HCl.
[0165] Examples of compounds having Formula I include those having
the Formula (Ia): 21
[0166] wherein
[0167] R.sub.1-R.sub.4 and R.sub.6-R.sub.10 are independently
hydrogen, halo, haloalkyl, aryl, fused aryl, a heterocyclic group,
a heteroaryl group, alkyl, alkenyl, alkynyl, arylalkyl,
arylalkenyl, arylalkynyl, hydroxyalkyl, nitro, amino, cyano,
acylamido, hydroxy, thiol, acyloxy, azido, alkoxy, carboxy,
carbonylamido, or alkylthiol;
[0168] n is 1, 2, 3, or 4; and
[0169] V is CH.sub.2, oxygen, sulfur, or carbonyl (CO).
[0170] Other examples include those having the Formula (Ib): 22
[0171] wherein
[0172] R.sub.1-R.sub.4 are the same as described for formula Ia;
and
[0173] n is 1, 2, 3, 4, 5, or 6.
[0174] Other examples include those having the Formula (Ic): 23
[0175] wherein
[0176] R.sub.1-R.sub.4 are the same as described for formula Ia;
and
[0177] Y.sub.1 is alkyl, optionally substituted aryl, hydroxyalkyl,
or optionally substituted alkaryl.
[0178] Other examples include those having the Formula (Id): 24
[0179] wherein
[0180] R.sub.1-R.sub.4 are the same as described for formula Ia;
and
[0181] n is 1, 2, 3, 4, 5, or 6.
[0182] Particular examples of compounds having Formula I include
25
[0183] Compounds having Formula II may be prepared by reaction of
an appropriately substituted
1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole with an electrophilic
reagent as mentioned above. The starting
1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indoles may be prepared
according to Abou-Gharbia et al., J. Med. Chem., 30:1818-1823
(1987) and Habert et al., J. Med. Chem., 23:635-643 (1980).
[0184] Particular examples of compounds having Formula II include
2-(2-phenoxyethyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole,
2-(3-phenoxypropyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole,
2-(3-phenylpropyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole and
2-(3-hydroxypropy)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b)indole.
[0185] Compounds having Formula IIa can be prepared similar to II.
Particular examples of compounds having Formula IIa are 26
[0186] With regard to Formula III when p is >0, then the
compounds may exist as a mixture of cis and trans isomers. The
invention is directed to such cis and trans isomers as well as the
individual enantiomers and diastereomeric mixtures.
[0187] When r is zero, G is NH and s is one, the N-amino piperidine
compounds may be prepared according to Scheme 1: 27
[0188] The N-amino piperidines may then be N-alkylated with one of
the electrophiles listed above to give the compound of Formula
III.
[0189] Also with regard to Formula III, when R.sub.1 is an
optionally substituted 2-aryloxyalkyl or an optionally substituted
2-benzyloxyalkyl-piperidine, the compounds may be prepared
according to Scheme 2: 2829
[0190] Scheme 2 may be generalized so that malonate A might be any
of a variety of aryl or substituted benzyl malonates, for example,
those shown below, leading to the corresponding derivatives in the
scheme. Each of those piperidines may be alkylated with one or the
other of the electrophilic reagents mentioned above. 30
[0191] Scheme 3 depicts a route to some 2-substituted and
2,3-disubstituted-4-benzyl-4-hydroxypiperidines. A variety of
electrophilic acylating agents may be used such that the final
product 6 may have different substituents on the nitrogen atom.
Also note that a variety of Grignard reagents or other nucleophiles
can be used in the step 2.fwdarw.3 so that the final product 6 may
contain various substituents at the 2-position. Also note that a
variety of alkylating agents can be used in the step 3.fwdarw.4 so
that the final product 6 will contain various substituents at the
3-position. Finally, the Grignard reagent in the step 4.fwdarw.5
can be used. Also note that a variety of Grignard reagents can be
used so that the final product 6 will contain various substituents
at the 4-position. Alkylating agents may also include PhOCH.sub.2Br
and PhCH.sub.2OCH.sub.2Br, for example. These would introduce
oxygen atoms in the substituents at the various positions.
Additionally, a high degree of stereocontrol can be achieved with
the likely relative stereochemical outcomes shown. 31
[0192] Other variations of this versatile synthetic approach are
also possible (See, Scheme 4). Again, the benzyl group was
originally introduced as a Grignard reagent so that can be varied
(see 2.fwdarw.3 above). The cuprate reagent can be varied as well
as the final benzyl Grignard reagent. The net result of this
chemistry is the preparation of 2,4,4,6-tetrasubstituted
N-alkylpiperidines. 32
[0193] One can also take advantage of the ortho lithiation of
methoxy pyridines described by Comins, D. L., et al., Tetrahedron
Lett. 29 (1988). Routes to novel piperidines are illustrated in
Scheme 5 below. 33
[0194] By choosing benzyl chloroformate as the initial
electrophilic N-acylating agent, one can prepare a family of
piperidines without a substituent on the nitrogen atom (Scheme 6).
N-Phenoxycarbamates can be removed by catalytic hydrogenation with
PtO.sub.2 in ethanol (see Comins, D. L. et al., Tet. Lett. 32:5697
(1991)).
[0195] Carbamates formed from other chloroformates can be removed
from 2,3-dihydro-4-pyridones by treatment with bases such as sodium
methoxide in methanol under reflux. Then, the electrophilic
reagents mentioned above may be used to alkylate these piperidine
nitrogens. Also note that a variety of electrophilic reagents can
be used so that the final products 13 will contain various
substituents at the 5-position. 3435
[0196] All of the above combinations can be readily made without
the hydroxy substituent at C-4 of the piperidine as shown below via
Wittig olefination of the piperidone followed by reduction (Scheme
7). 36373839
[0197] In the transformations of 20 to 21 and 22 to 23,
stereocontrol of the hydride reductions may be achieved by
substituting other hydride reagents in place of LAH.
[0198] See, Comins, D. L., et al., J. Org. Chem. 55:2574 (1990),
Comins, D. L., et al., Tetrahedron Lett. 29 (1988), and Comins, D.
L., et al., J. Am. Chem. Soc. 116:4719 (1994).
[0199] An example of compounds having Formula III include those
having Formula IIIa: 40
[0200] wherein
[0201] W is an adamantyl group or an optionally substituted aryl
group;
[0202] Y is CH.sub.3, CN, CO.sub.2R, carboxamido, an optionally
substituted cycloalkyl group or an optionally substituted
heterocycloalkyl group;
[0203] R is alkyl, an aminoalkyl group, an amidoalkyl group, a
ureidoalkyl group, or a guanidinoalkyl group;
[0204] n is 0, 1, 2, 3, 4, 5, or 6; and
[0205] m is 0, 1, 2, 3;
[0206] with the proviso, that when W is adamantyl, then Y may also
be optionally substituted aryl, optionally substituted aryloxy,
SAr, COAr, hydroxy, .ident.--Y.sub.1, .dbd.--Y.sub.1, a
heterocyclic group, a heteroaryl group, a cycloalkyl group, an
amino group, an amido group, a ureido group, or a guanidino group;
wherein
[0207] Y.sub.1 is hydrogen, alkyl, hydroxyalkyl, an optionally
substituted aralkyl group, an optionally substituted aryl group, an
aminoalkyl group, an amidoalkyl group, a ureidoalkyl group, or a
guanidinoalkyl group.
[0208] Generally, when Y is an aminoalkyl or guanidinoalkyl, n must
be greater than 1.
[0209] In general, compounds having Formula III may be prepared by
reaction of an appropriately substituted piperidine with one of the
electrophilic reagents mentioned above. Where W is an adamantyl
group, the compounds may be prepared as shown in Scheme 8.
Preferably, such adamantyl groups are 1-adamantyl. 41
[0210] Where W is a heteroaryl group, the compounds may be prepared
using an aryl lithium or grignard reagent as shown in Scheme 9.
42
[0211] Where Y is a 7-substituted isocoumarin, the compounds may be
prepared as set forth in Scheme 10. 43
[0212] See, Kerrigan et al., J. Med. Chem. 38:544 (1995) for
methods of making such 7-substituted isocoumarins wherein the
7-substituent may be an amino group, a nitro group, or amido
group.
[0213] Where Y is an optionally substituted cycloalkyl group or
optionally substituted heterocycloalkyl group, and r, s and t are
0, the compounds may be prepared as shown in Scheme 11. 44
[0214] Other cyclized analogs include compounds such as 33-36.
45
[0215] Another example of compounds within the scope of Formula III
includes compounds having the Formula IIIb: 46
[0216] wherein
[0217] W is an adamantyl group or an optionally substituted aryl
group;
[0218] Y is CH.sub.3, CN, CO.sub.2R, carboxamido, an optionally
substituted cycloalkyl group or an optionally substituted
heterocycloalkyl group;
[0219] R is alkyl, an aminoalkyl group, an amidoalkyl group, a
ureidoalkyl group, or a guanidinoalkyl group;
[0220] n is 0, 1, 2, 3, 4, 5, or 6; and
[0221] m is 0, 1, 2, or 3;
[0222] with the proviso, that when W is adamantyl, then Y may also
be optionally substituted aryl, optionally substituted aryloxy,
SAr, COAr, hydroxy, .ident.--Y.sub.1, .dbd.--Y.sub.1, a
heterocyclic group, a heteroaryl group, a cycloalkyl group, an
amino group, an amido group, a ureido group, or a guanidino group;
wherein
[0223] Y.sub.1 is hydrogen, alkyl, hydroxyalkyl, an optionally
substituted aralkyl group, an optionally substituted aryl group, an
aminoalkyl group, an amidoalkyl group, a ureidoalkyl group, or a
guanidinoalkyl group.
[0224] Another example includes compounds having the Formula IIIc:
47
[0225] wherein
[0226] W is an adamantyl group or an optionally substituted aryl
group;
[0227] Y is CH.sub.3, CN, CO.sub.2R, carboxamido, an optionally
substituted cycloalkyl group, an optionally substituted
heterocycloalkyl group, optionally substituted aryl, optionally
substituted aryloxy, SAr, COAr, hydroxy, .ident.--Y.sub.1,
.dbd.--Y.sub.1, a heterocyclic group, a heteroaryl group, an amino
group, an amido group, a ureidoalkyl group, a guanidinoalkyl group,
or O--N.dbd.CR.sub.1R.sub.2, where R.sub.1 and R.sub.2 are
independently aryl or lower alkyl;
[0228] R is alkyl, an aminoalkyl group, an amidoalkyl group, a
ureidoalkyl group, or a guanidinoalkyl group;
[0229] Y.sub.1 is hydrogen, alkyl, hydroxyalkyl, an optionally
substituted aralkyl group, an optionally substituted aryl group, an
aminoalkyl group, an amidoalkyl group, a ureidoalkyl group, or a
guinidinoalkyl group;
[0230] n is 0, 1, 2, 3, 4, 5, or 6; and
[0231] m is 0, 1, 2, or 3;
[0232] with the proviso, that when W is adamantyl, then Y may also
be optionally substituted aryl, optionally substituted aryloxy,
SAr, COAr, hydroxy, .ident.--Y.sub.1, .dbd.--Y.sub.1, a
heterocyclic group, a heteroaryl group, a cycloalkyl group, an
amino group, an amido group, a ureido group, or a guanidino group;
wherein
[0233] Y.sub.1 is hydrogen, alkyl, hydroxyalkyl, an optionally
substituted aralkyl group, an optionally substituted aryl group, an
aminoalkyl group, an amidoalkyl group, a ureidoalkyl group, or a
guanidinoalkyl group.
[0234] Another example includes compounds having the Formula IIId:
48
[0235] wherein
[0236] W is an adamantyl group or an optionally substituted aryl
group;
[0237] X is a bond, (CH.sub.2).sub.m, oxygen, or NR;
[0238] Y.sub.1 is hydrogen, alkyl, hydroxyalkyl, an aminoalkyl
group, an amidoalkyl group, a ureidoalkyl group, or a
guanidinoalkyl group;
[0239] R.sub.1 is hydrogen, hydroxy, halo, alkylcarboxy, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted aryloxyalkyl, optionally substituted benzyloxyalkyl, a
heterocyclic group, a heterocyclic substituted alkyl group,
heteroaryl, or a heteroaryl substituted alkyl group;
[0240] n is 0, 1, 2, 3, 4, 5, or 6; and
[0241] m is 0, 1, 2, or 3;
[0242] with the proviso that when W is an adamantyl group, then
Y.sub.1 may further be an optionally substituted aralkyl group, or
an optionally substituted aryl group.
[0243] Where the compounds having Formula IIId terminate with an
alkyne (Y.sub.1=hydrogen), a propargylalcohol (Y=hydroxyalkyl), or
propargylamine (Y.sub.1=aminoalkyl) residue, they may be prepared
according to Scheme 12. 49
[0244] Another example includes compounds having the Formula IIIe:
50
[0245] wherein
[0246] W is an adamantyl group or an optionally substituted aryl
group;
[0247] Y.sub.1 is hydrogen, alkyl, hydroxyalkyl, an aminoalkyl
group, an amidoalkyl group, a ureidoalkyl group, or a
guanidinoalkyl group;
[0248] R.sub.1 is hydrogen, hydroxy, halo, alkylcarboxy, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted aryloxyalkyl, optionally substituted benzyloxyalkyl, a
heterocyclic group, a heterocyclic substituted alkyl group,
heteroaryl, or a heteroaryl substituted alkyl group;
[0249] n is 0, 1, 2, 3, 4, 5, or 6; and
[0250] m is 0, 1, 2, or 3;
[0251] with the proviso that when W is an adamantyl group, then
Y.sub.1 may further be an optionally substituted aralkyl group, or
an optionally substituted aryl group.
[0252] Another example includes compounds having the Formula IIIf:
51
[0253] wherein
[0254] W, Y.sub.1, R.sub.1, n and m are the same as described in
Formula IIIe;
[0255] with the proviso that when W is an adamantyl group, then
Y.sub.1 may further be an optionally substituted aralkyl group, or
an optionally substituted aryl group.
[0256] Another example includes compounds having the Formula IIIg:
52
[0257] wherein
[0258] W, Y.sub.1, R.sub.1, n and m are the same as described in
Formula IIIe;
[0259] with the proviso that when W is an adamantyl group, then
Y.sub.1 may further be an optionally substituted aralkyl group, or
an optionally substituted aryl group.
[0260] Another example includes compounds having the Formula IIIh:
53
[0261] wherein
[0262] W is an adamantyl group or an optionally substituted aryl
group;
[0263] Y is optionally substituted aryl, optionally substituted
aryloxy, SAr, COAr, hydroxy, .ident.--Y.sub.1, .dbd.--Y.sub.1, a
heterocyclic group, a heteroaryl group, a cycloalkyl group, an
amino group, an amido group, a ureido group, or a guanidino
group;
[0264] Y.sub.1 is hydrogen, alkyl, hydroxyalkyl, an aminoalkyl
group, an amidoalkyl group, a ureidoalkyl group, or a
guanidinoalkyl group;
[0265] Z is (CH.sub.2).sub.m, oxygen, sulfur, or NR;
[0266] m is 0, 1, 2, or 3; and
[0267] n is 1, 2, 3, 4, 5, or 6.
[0268] Examples of compounds having Formula IIIh include
3-benzyl-1-(3-phenoxypropyl)piperidine,
3-benzyl-1-(2-phenoxyethyl)piperi- dine,
3-benzyl-1-(2-phenethyl)piperidine,
3-benzyl-1-[2-(3-trifluoromethyl- )phenethyl]piperidine,
3-benzyl-1-[2-(4-aminophenyl)ethyl]piperidine,
3-benzyl-1-[2-(4-chlorophenyl)-ethyl]piperidine,
3-benzyl-1-[2-(4-fluorop- henyl)ethyl]piperidine, and
3-benzyl-1-[2-(4-methoxyphenyl)ethyl]piperidin- e.
[0269] Another example includes compounds having the Formula
(IIIi): 54
[0270] wherein
[0271] R.sub.1-R.sub.5 are independently hydrogen, halo, haloalkyl,
aryl, fused aryl, a heterocyclic group, a heteroaryl group, alkyl,
alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl,
hydroxyalkyl, nitro, amino, cyano, acylamido, hydroxy, thiol,
acyloxy, azido, alkoxy, carboxy, carbonylamido, or alkylthiol;
[0272] n is 1, 2, 3, 4, 5, or 6;
[0273] Y is optionally substituted aryl, optionally substituted
aryloxy, SAr, COAr, hydrogen, hydroxy, .ident.--Y.sub.1,
.dbd.--Y.sub.1, a heterocyclic group, a heteroaryl group, a
cycloalkyl group, an amino group, an amido group, a ureido group,
or a guanidino group; and
[0274] Y.sub.1 is hydrogen, alkyl, hydroxyalkyl, an optionally
substituted aralkyl group, an optionally substituted aryl group, an
aminoalkyl group, an amidoalkyl group, a ureidoalkyl group, or a
guanidinoalkyl group.
[0275] Compounds having Formula IIIi may be prepared by reaction of
the 4-benzoylpiperidine with one of the electrophiles listed
above.
[0276] Another example includes compounds having Formula (IIIj):
55
[0277] wherein
[0278] R.sub.1-R.sub.5, n, Y and Y.sub.1 are the same as described
for formula IIIi.
[0279] Another example includes compounds having the Formula
(IIIk): 56
[0280] wherein
[0281] R.sub.1-R.sub.5, n, Y and Y.sub.1 are the same as described
in formula IIIi.
[0282] Another example includes compounds having the Formula
(IIIl): 57
[0283] wherein
[0284] W is optionally substituted aryl;
[0285] Y is optionally substituted aryl, optionally substituted
aryloxy, an optionally substituted aryloxy group, SAr, COAr,
hydrogen, hydroxy, .ident.--Y, .dbd.--Y.sub.1, a heterocyclic
group, a heteroaryl group, a cycloalkyl group, an amino group, an
amido group, a ureido group, or a guanidino group;
[0286] Y.sub.1 is hydrogen, alkyl, hydroxyalkyl, an optionally
substituted aralkyl group, an optionally substituted aryl group, an
aminoalkyl group, an amidoalkyl group, a ureidoalkyl group, or a
guanidinoalkyl group;
[0287] Q is hydrogen, alkyl, aryl, aralkyl, a heterocyclic group, a
heterocyclic substituted alkyl group, an aryl group, or an aralkyl
group;
[0288] X is a bond, (CH.sub.2).sub.m, oxygen, or sulfur;
[0289] m is 0, 1, 2, or 3;
[0290] n is 1, 2, 3, 4, 5, or 6; and
[0291] p is 0 or 1.
[0292] Another example includes compounds having the Formula
(IIIm): 58
[0293] wherein
[0294] W is optionally substituted aryl;
[0295] X is a bond, (CH.sub.2).sub.m, oxygen, sulfur, or NR;
[0296] R is alkyl, hydroxy, an aminoalkyl group, an amidoalkyl
group, a ureidoalkyl group, or a guanidinoalkyl group;
[0297] R.sub.1 is hydrogen, hydroxy, aryl, or aralkyl;
[0298] n is 1, 2, 3, 4, 5, or 6;
[0299] =single or double bond; and
[0300] =carbon ring or heterocyclic ring, with the proviso that
said carbon ring is not part of a naphthyl group.
[0301] Compounds having Fomula IIIm may be prepared by a
Diels-Alder reaction as shown below: 59
[0302] Another example includes compounds having the Formula
(IIIn): 60
[0303] wherein
[0304] W is an adamantyl group or an optionally substituted aryl
group;
[0305] X is a bond or (CH.sub.2).sub.m;
[0306] Y is CH.sub.3, CN, CO.sub.2R; an optionally substituted aryl
group, an optionally substituted aryloxy group, SAr, COAr, hydroxy,
.ident.--Y.sub.1, .dbd.--Y.sub.1, a heterocyclic group, a
heteroaryl group, a cycloalkyl group, an amino group, an amido
group, a ureido group, or a guanidino group;
[0307] Y.sub.1 is hydrogen, alkyl, hydroxyalkyl, an optionally
substituted aralkyl group, an optionally substituted aryl group, an
aminoalkyl group, an amidoalkyl group, a ureidoalkyl group, or a
guanidinoalkyl group
[0308] R is alkyl, hydroxy, an aminoalkyl group, an amidoalkyl
group, a ureidoalkyl group, or a guanidinoalkyl group;
[0309] n is 0, 1, 2, 3, 4, 5, or 6; and
[0310] m is 0, 1, 2, or 3.
[0311] Compounds having Formula IIIn, where the group R.sub.1 is
fluoro, may be prepared by reaction of the corresponding hydroxy
piperidine with diethylaminosulfur trifluoride as shown in Scheme
13. 61
[0312] See, Sharma, R. A.; Korytnyk, W.; Tetrahedron Lett 573
(1977); and Fieser, L. F.; Fieser, M. Reagents for Organic
Synthesis 6:183 (1977). 62
[0313] An example of compounds having Formula IIIn includes: 63
[0314] Another example includes compounds having the Formula
(IIIo): 64
[0315] wherein
[0316] Y is hydrogen, hydroxy, CH.sub.3, CN, CO.sub.2R, optionally
substituted aryl, optionally substituted aryloxy, optionally
substituted arylthioxy, optionally substituted aroyl,
.ident.--Y.sub.1, .dbd.--Y.sub.1, optionally substituted
heterocyclic group, optionally substituted heterocycloxy,
optionally substituted heteroaryl, optionally substituted
heteroaryloxy, optionally substituted cycloalkyl group, optionally
substituted cycloalkoxy group, amino, amido, ureido, or
guanidino;
[0317] Y.sub.1 is hydrogen, alkyl, hydroxyalkyl, optionally
substituted aralkyl, an optionally substituted aryl, aminoalkyl,
amidoalkyl, ureidoalkyl, or guanidinoalkyl; and
[0318] n is 0, 1, 2, 3, 4, 5 or 6.
[0319] Compounds having Formula IIIo may be prepared according to
Scheme 14. 65
[0320] Particular examples of compounds having Formula III include:
66
[0321] wherein n is 0, 1, 2, 3, 4, 5 or 6; 6768 69
[0322] Method of Harper and Powers, Biochemistry 24:7200-7213
(1985).
[0323] Additional compounds having Formula III include
4-benzyl-1-(3-hydroxy-1-methylpropyl)piperidine,
4-benzyl-1-(2-hydroxyeth- yl)piperidine,
1-benzyl-3-hydroxy-3-phenylpiperidine,
3-hydroxy-3-phenyl-1-phenethylpiperi-dine,
3-hydroxy-3-phenyl-1-(phenylpr- opyl)piperidine, and
4-benzoyl-1-(3-hydroxypropyl)piperidine.
[0324] Examples of compounds having Formula IV include those having
the Formula (IVa): 70
[0325] wherein
[0326] R.sub.1-R.sub.5 are independently hydrogen, halo, haloalkyl,
aryl, fused aryl, a heterocyclic group, a heteroaryl group, alkyl,
alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl,
hydroxyalkyl, nitro, amino, cyano, acylamido, hydroxy, thiol,
acyloxy, azido, alkoxy, carboxy, carbonylamido, or alkylthiol;
[0327] n is 1, 2, 3, 4, 5, or 6;
[0328] Y is optionally substituted aryl, optionally substituted
aryloxy, SAr, COAr, hydrogen, hydroxy, .ident.--Y.sub.1,
.dbd.--Y.sub.1, a heterocyclic group, a heteroaryl group, a
cycloalkyl group, an amino group, an amido group, a ureido group,
or a guanidino group; and
[0329] Y.sub.1 is hydrogen, alkyl, hydroxyalkyl, an optionally
substituted aralkyl group, an optionally substituted aryl group, an
aminoalkyl group, an amidoalkyl group, a ureidoalkyl group, or a
guanidinoalkyl group.
[0330] Another example includes compounds having the Formula (IVb):
71
[0331] wherein
[0332] R.sub.1-R.sub.5, n, Y and Y.sub.1 are the same described in
formula IVa.
[0333] Compounds having Formula IV may be prepared by reaction of
the corresponding piperidone with a Wittig reagent derived from a
benzyl bromide. Alternatively, a benzyl grignard reagent may be
reacted with the piperidone to give the hydroxybenzyl piperidine
which may be dehydrated with sulfuric acid and heat.
[0334] Particular examples of compounds having Formula IV include
1-benzyl-4-(m-fluorobenzylidene)piperidine,
1-(3-hydroxypropyl)-4-benzyli- denepiperidine, and
1-hexyl-4-benzylidenepiperidine.
[0335] Compounds having Formula V may be prepared according to
Scheme 16 followed by reaction with one of the electrophiles
mentioned above. 72
[0336] See, Cook et al., J. Med. Chem. 38:754 (1995).
[0337] An example of compounds having Formula V include: 73
[0338] Compounds having Formula VI may be prepared according to
Scheme 17. 74
[0339] By varying the choice of the amine nucleophile, one can
synthesize a family of amidines including the following: 75
[0340] Compounds having Formula VII may be prepared according to
Scheme 18. 76
[0341] Examples of compounds having Formula VII include: 77
[0342] Compounds having Formula VIII may be prepared according to
Scheme 19. 78
[0343] Examples of compounds having Formula VIII include: 79
[0344] Compounds having Formula IX may be prepared according to
Scheme 20. 80
[0345] See, Iwasaki, N., et al., J. Med. Chem 38:496 (1995), who
describe a variety of substituents in the 7-, 8- and 9-positions
including fluoro, chloro, methoxy and nitro on the top left benzene
ring.
[0346] Compounds having Formula X may be prepared according to
Scheme 21. 81
[0347] Compounds having Formula XI may be prepared according to
Scheme 22. 82
[0348] Compounds having Formula XII may be prepared by reaction of
the corresponding
10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imines with one of
the electrophilic reagents listed above. Methods for preparing the
starting 10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imines are
disclosed in U.S. Pat. No. 4,399,141, the disclosure of which is
fully incorporated by reference herein.
[0349] Particular examples of compounds having Formula XIII include
those having the Formula (XIIIa): 83
[0350] wherein
[0351] Y is hydrogen, hydroxy, CH.sub.3, CN, CO.sub.2R, optionally
substituted aryl, optionally substituted aryloxy, optionally
substituted arylthioxy, optionally substituted aroyl,
.ident.--Y.sub.1, .dbd.--Y.sub.1, optionally substituted
heterocyclic group, optionally substituted heterocycloxy,
optionally substituted heteroaryl, optionally substituted
heteroaryloxy, optionally substituted cycloalkyl group, optionally
substituted cycloalkoxy group, amino, amido, ureido, or guanidino;
Y.sub.1 is hydrogen, alkyl, hydroxyalkyl, optionally substituted
aralkyl, an optionally substituted aryl, aminoalkyl, amidoalkyl,
ureidoalkyl, or guanidinoalkyl; and
[0352] n is 0, 1, 2, 3, 4, 5, or 6.
[0353] Compounds having Formula XIII may be prepared by reaction of
the corresponding
10,5-(iminomethano)-10,11-dihydro-5H-dibenzo[a,d]-cyclohept- enes
(IDDCS) with one of the electrophilic reagents listed above.
Methods for preparing the starting IDDCs are disclosed in U.S. Pat.
No. 5,011,834, the disclosure of which is fully incorporated by
reference herein.
[0354] Particular examples of compounds having Formula XIV include
those having the Formula (XIVa): 84
[0355] wherein
[0356] Y, Y.sub.1 and n are the same as described for formula
XIIIa.
[0357] Another example includes those having the Formula (XIVb):
85
[0358] wherein
[0359] Y, Y.sub.1 and n are the smae as described in formula
XIIIa.
[0360] Another example includes those compounds having the Formula
(XIVc): 86
[0361] wherein
[0362] Y, Y.sub.1 and n are the same as described in formula
XIIIa.
[0363] Compounds having Formula XIV may be prepared as shown in
Scheme 23. These compounds may be derived from guvacine or
4-hydroxynipecotic acid and reacted with one of the electrophiles
listed above to give the desired product. 87
[0364] RBI is Research Biochemicals International, Inc.
[0365] Compounds having Formula XV may be prepared by reaction of
an appropriate nitrogen electrophile with a suitable electrophile
XEY. Particular examples of compounds having Formula XV are 88
[0366] Examples of compounds of Formula XVI include those having
the Formula (XVIa): 89
[0367] wherein
[0368] Y.sub.1 is (CHR.sub.2).sub.n wherein n is 0, 1, 2, 3 or 4;
and
[0369] Ar.sub.1, X, U and R.sub.2 are as previously described by
Formula XVI.
[0370] Other examples include those having Formula (XVIb): 90
[0371] wherein
[0372] V is (CH.sub.2).sub.q wherein q is 1, 2 or 3 and
[0373] Ar.sub.1, X, U, Y and Z are previously described for Formula
XVI.
[0374] The N-(hydroxyalkyl)piperidines of Formula XVI are selective
antagonists of the NR1A/NR2B subtype NMDA receptors. They have good
in vivo activity and some have a long half life in vivo. These
compounds have relatively low activity at the alpha 1 receptor and
therefore potentially have an enhanced side effect profile. In
addition the compounds of Formula XVI have good water solubility
which is advantageous for formulating an aqueous solution for iv
adminstration.
[0375] Examples of compounds of Formula XVII include those having
the Formula (XVIIa): 91
[0376] wherein
[0377] Ar.sub.1, X, U, Z and Y are as previously described for
Formula XVII.
[0378] Certain of the compounds of the present invention are
expected to be potent anticonvulsants in animal models and will
prevent ischemia-induced nerve cell death in the gerbil global
ischemia model after administration.
[0379] The compounds of the present invention are active in
treating or preventing neuronal loss, neurodegenerative diseases,
chronic pain, are active as anticonvulsants and inducing
anesthesia. They are also useful for treating epilepsy and
psychosis. The therapeutic and side effect profiles of
subunit-selective NMDA receptor antagonists and agonists should be
markedly different from the more non-selective types of inhibitors.
The subtype-selective ligands of the present invention are expected
to exhibit little or no untoward side effects caused by
non-selective binding with other receptors, particularly, the PCP
and glutamate binding sites associated with the NMDA receptor. In
addition, selectivity for different NMDA receptor subtypes will
reduce side effects such as sedation that are common to
non-subtype-selective NMDA receptor antagonists. The compounds of
the present invention are effective in treating or preventing the
adverse consequences of the hyperactivity of the excitatory amino
acids, e.g., those that are involved in the NMDA receptor system,
by preventing the ligand-gated cation channels from opening and
allowing excessive influx of Ca.sup.++ into neurons, as occurs
during ischemia.
[0380] Neurodegenerative diseases that may be treated with the
compounds of the present invention include those selected from the
group consisting of Alzheimer's disease, amyotrophic lateral
sclerosis, Huntington's disease, Parkinson's disease and Down's
syndrome.
[0381] The compounds of the present invention find particular
utility in the treatment or prevention of neuronal loss associated
with multiple strokes which give rise to dementia. After a patient
has been diagnosed as suffering from a stroke, the compounds of the
present invention may be administered to ameliorate the immediate
ischemia and prevent further neuronal damage that may occur from
recurrent strokes.
[0382] Moreover, the compounds of the present invention are able to
cross the blood/brain barrier, which makes them particularly useful
for treating or preventing conditions involving the central nervous
system.
[0383] The compounds of the invention find particular utility in
treating or preventing the adverse neurological consequences of
surgery. For example, coronary bypass surgery requires the use of
heart-lung machines, which tend to introduce air bubbles into the
circulatory system that may lodge in the brain. The presence of
such air bubbles robs neuronal tissue of oxygen, resulting in
anoxia and ischemia. Pre- or post-surgical administration of the
compounds of the present invention will treat or prevent the
resulting ischemia. In a preferred embodiment, the compounds of the
invention are administered to patients undergoing cardiopulmonary
bypass surgery or carotid endarterectomy surgery.
[0384] The compounds of the present invention also find utility in
treating or preventing chronic pain. Such chronic pain may be the
result of surgery, trauma, headache, arthritis, pain from terminal
cancer or degenerative diseases. The compounds of the present
invention also find particular utility in the treatment of phantom
pain that results from amputation of an extremity. In addition to
treatment of pain, the compounds of the invention are also expected
to be useful in inducing anesthesia, either general or local
anesthesia, for example, during surgery.
[0385] The subunit-selective NMDA receptor antagonists, agonists
and modulators may be tested for in vivo anticonvulsant activity
after iv or ip injection using a number of anticonvulsant tests in
mice (audiogenic seizure model in DBA-2 mice,
pentylenetetrazol-induced seizures in mice, maximum electroshock
seizure test (MES) or NMDA-induced death). The compounds may also
be tested in drug discrimination tests in rats trained to
discriminate PCP from saline. It is expected that most of the
compounds of the present invention will not generalize to PCP at
any dose. In addition, it is also expected that none of the
compounds will produce a behavioral excitation in locomotor
activity tests in the mouse. It is expected that such results will
suggest that the subunit-selective NMDA receptor antagonists and
agonists of the present invention do not show the PCP-like
behavioral side effects that are common to NMDA channel blockers
such as MK-801 and PCP or to competitive NMDA antagonists such as
CGS 19755.
[0386] The subunit-selective NMDA receptor antagonists and agonists
are also expected to show potent activity in vivo after
intraperitoneal injection suggesting that these compounds can
penetrate the blood/brain barrier.
[0387] Elevated levels of glutamate has been associated with
glaucoma. In addition, it has been disclosed that glaucoma
management, particularly protection of retinal ganglion cells, can
be achieved by administering to a patient a compound capable of
reducing glutamate-induced excitotoxicity in a concentration
effective to reduce the excitotoxicity. See WO94/13275. Thus, the
compounds of the present invention, which are expected to cross the
blood-retina barrier, are also expected to be useful in the
treatment of glaucoma. Preferably, the invention is directed to the
treatment of patients which have primary open-angle glaucoma,
chronic closed-angle glaucoma, pseudo doexfoliation, or other types
of glaucoma or ocular hypertension. Preferably, the compound is
administered over an extended period (e.g. at least six months and
preferably at least one year), regardless of the changes in the
patient's intraocular pressure over the period of
administration.
[0388] The compounds of the present invention are also useful in
treating CMV retinitis, particularly in combination with antiviral
agents. CMV afflicts the ganglion cell layer which may result in
higher levels of glutamate. Thus, NMDA receptor antagonists could
block retinitis by blocking the toxicity effect of high level of
glutamate.
[0389] Aminoglycoside antibiotics have been used successfully in
the treatment of serious Gram-negative bacterial infections.
However, prolonged treatment with these antibiotics will result in
the destruction of sensory hearing cells of the inner ear and
consequently, induce permanent loss of hearing. A recent study of
Basile, et al. (Nature Medicine, 2: 1338-1344, 1996) indicated that
aminoglycosides produce a polyamine-like enhancement of glutamate
excitotoxicity through their interaction with the NMDA receptor.
Thus, compounds of the present invention with NMDA receptor
antagonist activity will be useful in preventing aminoglycoside
antibiotics-induced hearing loss by antagonizing their interaction
with the receptor.
[0390] The compounds of the present invention are useful in
treating headaches, in particular, migraine headaches. During
migraine attack, a sensory disturbance with unique changes of brain
blood flow will result in the development of characteristic
migraine auras. Since this unique phenomena has been replicated in
animal experiments with cortical-spreading depression (CSD) of Lea,
A. A. P. J., Neurophysiol. 7:359-390 (1944), CSD is considered an
important phenomena in the pathophysiology of migraine with aura
(Tepley et al., In: Biomagnetism, eds. S. Williamson, L. Kaufmann,
pp. 327-330, Plenum Press, New York (1990)). The CSD is associated
with the propagation (2.about.6 mm/s) of transient changes in
electrical activity which relate to the failure of ion homoestatis
in the brain, efflux of excitatory amino acids from the neurons and
increased energy metabolism (Lauritzen, M., Acta Neurol. Scand. 76
(Suppl. 113):4-40 (1987)). It has been demonstrated that the
initiation of CSD in a variety of animals, including humans,
involved the release of glutamate and could be triggered by NMDA
(Curtis et al., Nature 191:1010-1011 (1961); and Lauritzen et al.,
Brain Res. 475:317-327 (1988)). Subtype selective NMDA antagonists
will be therapeutically useful for migraine headache because of
their expected low side effects, their ability to cross the blood
brain barrier and their systemic bioavailability.
[0391] Bladder activity is controlled by parasympathetic
preganglionic neurons in the sacral spinal cord (DeGroat et al., J.
Auton. Nerv. Sys. 3:135-160(1981)). In humans, it has been shown
that the highest density of NMDA receptors in the spinal cord are
located at the sacral level, including those areas that putatively
contain bladder parasympathetic preganglionic neurons (Shaw et al.,
Brain Research 539:164-168 (1991)). Because NMDA receptors are
excitatory in nature, pharmacological blockade of these receptors
would suppress bladder activity. It has been shown that the
noncompetitive NMDA receptor antagonist MK801 increased the
frequency of micturition in rat (Vera and Nadelhaft, Neuroscience
Letters 134:135-138(1991)). In addition, competitive NMDA receptor
antagonists have also been shown to produce a dose-dependent
inhibition of bladder and of urethral sphincter activity (U.S. Pat.
No. 5,192,751). Thus, it is anticipated that subtype-selective NMDA
receptor antagonists will be effective in the treatment of urinary
incontinence mediated by their modulation on the receptor channel
activity.
[0392] Non-competitive NMDA receptor antagonist MK801 has been
shown to be effective in a variety of animal models of anxiety
which are highly predictive of human anxiety (Clineschmidt, B. V.
et al., Drug Dev. Res. 2:147-163 (1982)). In addition, NMDA
receptor glycine site antagonists are shown to be effective in the
rat protentiated startle test (Anthony, E. W., Eur. J. Pharmacol.
250:317-324 (1993)) as well as several other animal anxiolytic
models (Winslow, J. et al, Eur. J. Pharmacol. 190:11-22 (1990);
Dunn, R. et al., Eur. J. Pharmacol. 214:207-214 (1992); and Kehne,
J. H. et al, Eur. J. Pharmacol. 193:282-292 (1981)).
[0393] Glycine site antagonists, (+) HA-966 and
5,7-dichlorokynurenic acid were found to selectively antagonize
d-amphetamine induced stimulation when injected into rat nucleus
accumbens but not in striatum (Hutson, P. H. et al., Br. J.
Pharmacol. 103:2037-2044 (1991)). Interestingly, (+) HA-966 was
also found to block PCP and MK801-induced behavioral arousal
(Bristow, L. J. et al., Br. J. Pharmacal, 108:1156-1163 (1993)).
These findings suggest that a potential use of NMDA receptor
channel modulators, but not channel blockers, as atypical
neuroleptics.
[0394] It has been shown that in an animal model of Parkinson's
disease--MPP.sup.+ or methamphetamine-induced damage to
dopaminergic neurons--can be inhibited by NMDA receptor antagonists
(Rojas et al., Drug Dev. Res. 29:222-226 (1993); and Sonsalla et
al, Science 243;398-400 (1989)). In addition, NMDA receptor
antagonists have been shown to inhibit haloperidol-induced
catalepsy (Schmidt, W. J. et al., Amino Acids 1:225-237 (1991)),
increase activity in rodents depleted of monoamines (Carlsson et
al., Trends Neurosci. 13:272-276 (1990)) and increase ipsilateral
rotation after unilateral substantia nigra lesion in rats (Snell,
L. D. et al., J. Pharmacol. Exp. Ther. 235:50-57 (1985)). These are
also experimental animal models of Parkinson's disease. In animal
studies, the antiparkinsonian agent amantadine and memantine showed
antiparkinsonian-like activity in animals at plasma levels leading
to NMDA receptor antagonism (Danysz, W. et al., J. Neural Trans.
7:155-166, (1994)). Thus, it is possible that these
antiparkinsonian agents act therapeutically through antagonism of
an NMDA receptor. Therefore, the balance of NMDA receptor activity
maybe important for the regulation of extrapyramidal function
relating to the appearance of parkinsonian symptoms.
[0395] It is well known to use opiates, e.g., morphine, in the
medical field to alleviate pain. (As used herein, the term
"opiates" is intended to mean any preparation or derivative of
opium, especially the alkaloids naturally contained therein, of
which there are about twenty, e.g., morphine, noscapine, codeine,
papaverine, and thebaine, and their derivatives.) Unfortunately,
with continued use, the body builds up a tolerance for the opiate,
and, thus, for continued relief, the patient must be subjected to
progressively larger doses. Tolerance develops after both acute and
chronic morphine administration (Kornetsky et al., Science
162:1011-1012 (1968); Way et al., J. Pharmacol. Exp Ther. 167:1-8
(1969); Huidobro et al., J. Pharmacol. Exp Ther. 198:318-329
(1976); Lutfy et al., J. Pharmacol. Exp Ther. 256:575-580 (1991)).
This, in itself, can be detrimental to the patient's health.
Furthermore, a time can come when the tolerance is substantially
complete and the pain killing properties of the drug are no longer
effective. Additionally, administration of higher doses of morphine
may lead to respiratory depression, causing the patient to stop
breathing. Seeking alternative drugs to produce analgesia without
development of tolerance or as an adjunct therapy to block
tolerance without interference with analgesia is an active area of
research.
[0396] Recent studies have suggested a modulatory role for the NMDA
receptor in morphine tolerance. (Trujillo et al., Science 251:85-87
(1991); Marek et al., Brain Res. 547:77-81 (1991); Tiseo et al., J.
Pharmacol. Exp Ther. 264:1090-1096 (1993); Lutfy et al., Brain Res.
616:83-88 (1993); Herman et al., Neuropsychopharmacology 12:269-294
(1995).) Further, it has been reported that NMDA receptor
antagonists are useful for inhibiting opioid tolerance and some of
the symptoms of opioid withdrawal. Thus, the present invention is
also directed to the administration of the compounds described
herein to inhibit opiate tolerance and to treat or ameliorate the
symptoms of opiate withdrawal by blocking the glycine co-agonist
site associated with the NMDA receptor.
[0397] Thus, the present invention is directed to compounds having
high binding to a particular NMDA receptor subunit and low binding
to other sites such as dopamine and other catecholamine receptors,
and a sites. According to the present invention, those compounds
having high binding to a particular NMDA subunit exhibit an
IC.sub.50 of about 100 .mu.M or less in an NMDA subunit binding
assay (see the Examples). Preferably, the compounds of the present
invention exhibit an IC.sub.50 of 10 .mu.M or less. Most
preferably, the compounds of the present invention exhibit an
IC.sub.50 of about 1.0 .mu.M or less.
[0398] The efficacy of the NMDA subunit selective antagonists to
inhibit glutamate neurotoxicity in rat brain cortex neuron cell
culture system may be determined as follows. An excitotoxicity
model modified after that developed by Choi (Choi, D. W., J.
Neuroscience 7:357 (1987)) may be used to test anti-excitotoxic
efficacy of the antagonists. Fetuses from rat embryonic day 19 are
removed from time-mated pregnant rats. The brains are removed from
the fetuses and the cerebral cortex is dissected. Cells from the
dissected cortex are dissociated by a combination of mechanical
agitation and enzymatic digestion according to the method of Landon
and Robbins (Methods in Enzymology 124:412 (1986)). The dissociated
cells are passed through an 80 micron nitex screen and the
viability of the cells are assessed by Trypan Blue. The cells are
plated on poly-D-lysine coated plates and incubated at 37.degree.
C. in an atmosphere containing 91% O.sub.2/9% CO.sub.2. Six days
later, fluoro-d-uracil is added for two days to suppress non-neural
cell growth. At culture day 12, the primary neuron cultures are
exposed to 100 .mu.M glutamate for 5 minutes with or without
increasing doses of antagonist or other drugs. After 5 minutes the
cultures are washed and incubated for 24 hours at 37.degree. C.
Neuronal cell damage is quantitated by measuring lactate
dehydrogenase (LDH) activity that is released into the culture
medium. The LDH activity is measured according to the method of
Decker et al. (Decker et al., J. Immunol. Methods 15:16
(1988)).
[0399] The anticonvulsant activity of the antagonists may be
assessed in the audiogenic seizure model in DBA-2 mice as follows.
DBA-2 mice may be obtained from Jackson Laboratories, Bar Harbor,
Me. These mice at an age of <27 days develop a tonic seizure
within 5-10 seconds and die when they are exposed to a sound of 14
kHz (sinus wave) at 110 dB (Lonsdale, D., Dev. Pharmacol. Ther.
4:28 (1982)). Seizure protection is defined when animals injected
with drug 30 minutes prior to sound exposure do not develop a
seizure and do not die during a 1 minute exposure to the sound. 21
day old DBA-2 mice are used for all experiments. Compounds are
given intraperitoneally in either saline, DMSO or
polyethyleneglycol-400. Appropriate solvent controls are included
in each experiment. Dose response curves are constructed by giving
increasing doses of drug from 1 mg/kg to 100 mg/kg. Each dose group
(or solvent control) consists of at least six animals.
[0400] The anticonvulsant efficacy of the antagonists may be
assessed in the pentylenetetrazol (PTZ)-induced seizure test as
follows. Swiss/Webster mice, when injected with 50 mg/kg PTZ (i.p.)
develop a minimal clonic seizure of approximately 5 seconds in
length within 5-15 minutes after drug injection. Anticonvulsant
efficacy of an antagonist (or other) drug is defined as the absence
of a seizure when a drug is given 30 minutes prior to PTZ
application and a seizure does not develop for up to 45 minutes
following PTZ administration. The antagonist or other drugs are
given intraperitoneally in either saline, DMSO or
polyethyleneglycol-400. Appropriate solvent controls are included
in each experiment. Dose response curves are constructed by giving
increasing doses of drug from 1 mg/kg to 100 mg/kg. Each dose group
(or solvent control) consists of at least six animals.
[0401] The efficacy of NMDA antagonists to protect mice from
NMDA-induced death may be assessed as follows. When mice are
injected with 200 mg/kg N-methyl-D-aspartate (NMDA) i.p., the
animals will develop seizures followed by death within 5-10
minutes. The antagonists are tested for their ability to prevent
NMDA-induced death by giving the drugs i.p. 30 minutes prior to the
NMDA application. The antagonist or other drugs are given
intraperitoneally in either saline, DMSO or polyethyleneglycol-400.
Appropriate solvent controls are included in each experiment. Dose
response curves are constructed by giving increasing doses of drug
from 1 mg/kg to 100 mg/kg. Each dose group (or solvent control)
consists of at least six animals.
[0402] The series of different evaluations may be conducted on
doses of the NMDA antagonists of the invention to determine the
biological activity of the compounds both in normal gerbils and in
animals exposed to 5 minutes of bilateral carotid occlusion. See
Scheme 24. 92
[0403] These studies are conducted in animals who are conscious and
have no other pharmacological agents administered to them. Gerbils
are preinstrumented 48-hours prior to ischemia to allow for the
complete elimination of the pentobarbital anesthetic which is
employed. When tested with drugs, animals are given IP injections
of the NMDA antagonist or vehicle. In the case of multiple
injections, animals are given IP injections 2 hours apart and the
final injection is given 30 minutes prior to the ischemic period or
in the case of post treatment, the animals are given injections at
30 minutes, 2 hours, 4 hours and 6 hours post-ischemic
reperfusion.
[0404] In order to assess the direct pharmacological activity or
potential activity of the NMDA antagonists, naive gerbils are
injected with either saline or differing doses of the antagonist.
The behavioral changes are assessed using a photobeam locomotor
activity chamber which is a two foot circular diameter arena with
photobeam detection. Animals are individually placed in the 2 foot
diameter chambers. The chambers are housed in a cabinet which is
closed and noise is abated using both a background white noise
generator and a fan. Animals are placed in these chambers in the
case of the initial pharmacological evaluation for a period of 6
hours and the total activity during each successive hour is
accumulated using the computer control systems.
[0405] Saline results in an initial high rate of activity, with the
control animals showing a first hour activity level of about 1600
counts. This level of control activity is typical for the gerbil
under these experimental conditions. As the session progressed,
animals decrease their exploratory activity and at the terminal
period the activity declines to about 250 counts per hour. It is
expected that the NMDA antagonists of the present invention will
have no significant effect on either the initial exploratory rate
or the terminal rate of exploration.
[0406] In a next phase of the evaluation of the NMDA antagonists,
gerbils are pretreated with varying doses of the antagonists and
then exposed to a five minute period of bilateral carotid
occlusion. Following the initiation of reperfusion, animals are
placed into the circular locomotor activity testing apparatus and
the activity at the beginning of the first hour following
reperfusion is monitored for the subsequent four hours.
[0407] Control animals not exposed to ischemia and given injections
of saline prior to being placed in the locomotor activity chamber
show a characteristic pattern of activity which in the first hour
of locomotor activity is substantially higher than during all other
hours and progressively declined over the four hours to a very low
value. In contrast to the progressive decline in activity over the
four hour testing period, control animals that are exposed to five
minutes of cortical ischemia demonstrate a completely different
pattern of locomotor activity. During the first hour there is a
significant decline in activity, which is followed by a progressive
increase in which the activity during the fourth hour is ten-fold
higher than that demonstrated by animals not exposed to carotid
occlusion. These results are typical and are a reliable result of
the alterations caused by five minutes of bilateral carotid
occlusion in the gerbil.
[0408] Separate groups of gerbils are pretreated with the NMDA
antagonists of the invention 30 minutes before the onset of carotid
occlusion and then placed into the locomotor activity following one
hour of reperfusion. It is expected that pretreatment of the
gerbils with the NMDA antagonists of the invention will prevent
both the post-ischemic decrease and increase in activity.
Post-ischemic decreases in activity are expected to be near zero
during the first hour following reperfusion. Pretreatment with the
NMDA antagonists of the invention is expected to reduce or prevent
this early depression of behavior. In addition, the NMDA
antagonists of the invention are expected to prevent the
post-ischemic stimulation of behavior. Subsequent to completion of
the single dose pretreatment evaluations, gerbils are also
evaluated with multiple injections of the NMDA antagonists of the
invention. Doses are administered I.P. at 6 hours, 4 hours, 2 hours
and 30 minutes prior to the onset of 5 minutes of ischemia.
[0409] At 24 hours all animals are evaluated for differences in
patrolling behavior using a 8-arm radial maze. In this procedure,
animals are placed into the center start chamber of the maze, the
barrier removed and the amount of time and the number of times the
animal makes an error recorded prior to completion of exploration
in all 8 arms of the maze. An error is defined as the revisiting of
an arm by entering to the extent of the entire body without
including tail by the animal. If the animal perseveres or fails to
leave the arm for longer than five minutes, the session is
terminated. In the control population of the animals, the number of
errors and exploration of the maze with no prior experience (naive)
is approximately 6 errors. This is an average value for an N of 28
gerbils. Following 5 minutes of bilateral carotid occlusion and
testing at 24 hours, gerbils make an average number of errors of
21. When animals are pretreated with the NMDA antagonists of the
invention, there is expected to be a significant reduction in the
number of errors made.
[0410] There is also expected to be a significant sparing of the
behavioral changes that are induced in the radial arm maze
performance.
[0411] It is also expected that post treatment with the NMDA
antagonists of the invention will reduce the short term memory
impairment 24 hours post ischemic/reperfusion.
[0412] The effects of 5 minutes of bilateral carotid occlusion on
neuronal cell death in the dorsal hippocampus may be evaluated in
animals 7 days after ischemia reperfusion injury. Previous studies
have demonstrated that neuronal degeneration begins to occur around
3 days following cerebral ischemia. By 7 days, those neurons that
have been affected will undergo cytolysis and have either completed
degeneration or are readily apparent as dark nuclei and displaced
nuclei or as cells with eosinophilic cytoplasm and pycnotic nuclei.
The lesion with 5 minutes of ischemia is essentially restricted
within the hippocampus to the CA1 region of the dorsal hippocampus.
The intermedial lateral zone of the horn is unaffected and the
dentate gyrus and/or in CA3 do not show pathology. Gerbils are
anesthetized on day 7 following ischemia with 60 mg/kg of
pentobarbital. Brains are perfused transcardiac with ice-cold
saline followed by buffered paraformaldehyde (10%). Brains are
removed, imbedded and sections made. Sections are stained with
hematoxylin-eosin and neuronal cell counts are determined in terms
of number of neuronal nuclei/100 micrometers. Normal control
animals (not exposed to ischemia reperfusion injury) will not
demonstrate any significant change in normal density nuclei within
this region. Exposure to five minutes of bilateral carotid
occlusion results in a significant reduction in the number of
nuclei present in the CA1 region. In general, this lesion results
in a patchy necrosis instead of a confluent necrosis, which is seen
if 10 minutes of ischemia is employed. Pretreatment with the NMDA
antagonists of the invention are expected to produce a significant
protection of hippocampal neuronal degeneration.
[0413] It is known that NMDA receptors are critically involved in
the development of persistent pain following nerve and tissue
injury. Tissue injury such as that caused by injecting a small
amount of formalin subcutaneously into the hindpaw of a test animal
has been shown to produce an immediate increase of glutamate and
aspartate in the spinal cord (Skilling, S. R., et al., J. Neurosci.
10:1309-1318 (1990)). Administration of NMDA receptor blockers
reduces the response of spinal cord dorsal horn neurons following
formalin injection (Dickenson and Aydar, Neuroscience Lett.
121:263-266 (1991); Haley, J. E., et al., Brain Res. 518:218-226
(1990)). These dorsal horn neurons are critical in carrying the
pain signal from the spinal cord to the brain and a reduced
response of these neurons is indicative of a reduction in pain
perceived by the test animal to which pain has been inflicted by
subcutaneous formalin injection.
[0414] Because of the observation that NMDA receptor antagonists
can block dorsal horn neuron response induced by subcutaneous
formalin injection, NMDA receptor antagonists have potential for
the treatment of chronic pain such as pain that is caused by
surgery or by amputation (phantom pain) or by infliction of other
wounds (wound pain). However, the use of conventional NMDA
antagonists such as MK-801 or CGS 19755, in preventing or treating
chronic pain, is severely limited by the adverse PCP-like
behavioral side effects that are caused by these drugs. It is
expected that the NMDA receptor antagonists that are the subject of
this invention will be highly effective in preventing chronic pain
in mice induced by injecting formalin subcutaneously into the
hindpaw of the animals. Because the NMDA receptor antagonists of
this invention are expected to be free of PCP-like side effects,
these drugs are highly useful in preventing or treating chronic
pain without causing PCP-like adverse behavioral side effects.
[0415] The effects of the NMDA receptor antagonists of the present
invention on chronic pain may be evaluated as follows. Male
Swiss/Webster mice weighing 25-35 grams are housed five to a cage
with free access to food and water and are maintained on a 12 hour
light cycle (light onset at 0800 h). The NMDA receptor antagonist
is dissolved in DMSO at a concentration of 1-40 and 5-40 mg/mL,
respectively. DMSO is used as vehicle control. All drugs are
injected intraperitoneally (1 .mu.L/g). The formalin test is
performed as described (Dubuisson and Dennis, Pain 4:H161-174
(1977)). Mice are observed in a plexiglass cylinder, 25 cm in
diameter and 30 cm in height. The plantar surface of one hindpaw is
injected subcutaneously with 20 .mu.L of 5% formalin. The degree of
pain is determined by measuring the amount of time the animal
spends licking the formalin-injected paw during the following time
intervals: 0-5' (early phase); 5'-10', 10'-15' and 15'-50' (late
phase). To test whether the NMDA receptor antagonists prevent
chronic pain in the test animals, vehicle (DMSO) or drugs dissolved
in vehicle at doses of 1 mg/kg to 40 mg/kg are injected
intraperitoneally 30 minutes prior to the formalin injection. For
each dose of drug or vehicle control at least six animals are
used.
[0416] Compared to vehicle control, it is expected that the
intraperitoneal injection of the NMDA receptor antagonists 30
minutes prior to formalin injection into the hindpaw will
significantly inhibit formalin-induced chronic pain in a
dose-dependent manner as determined by the reduction of the time
spent licking by the mouse of the formalin injected hindpaw caused
by increasing doses of NMDA receptor antagonist.
[0417] Compositions within the scope of this invention include all
compositions wherein the compounds of the present invention are
contained in an amount which is effective to achieve its intended
purpose. While individual needs vary, determination of optimal
ranges of effective amounts of each component is within the skill
of the art. Typically, the compounds may be administered to
mammals, e.g., humans, orally at a dose of 0.0025 to 50 mg/kg, or
an equivalent amount of the pharmaceutically acceptable salt
thereof, per day of the body weight of the mammal being treated for
anxiety disorders, e.g., generalized anxiety disorder, phobic
disorders, obsessional compulsive disorder, panic disorder, and
post traumatic stress disorders or for schizophrenia or other
psychoses. Preferably, about 0.01 to about 10 mg/kg is orally
administered to treat or prevent such disorders. For intramuscular
injection, the dose is generally about one-half of the oral dose.
For example, for treatment or prevention of anxiety, a suitable
intramuscular dose would be about 0.0025 to about 15 mg/kg, and
most preferably, from about 0.01 to about 10 mg/kg.
[0418] In the method of treatment or prevention of neuronal loss in
ischemia, brain and spinal cord trauma, hypoxia, hypoglycemia, and
surgery, to treat or prevent glaucoma or urinary incontinence, as
well as for the treatment of Alzheimer's disease, amyotrophic
lateral sclerosis, Huntington's disease, Parkinson's disease and
Down's Syndrome, or in a method of treating a disease in which the
pathophysiology of the disorder involves hyperactivity of the
excitatory amino acids or NMDA receptor-ion channel related
neurotoxicity, the pharmaceutical compositions of the invention may
comprise the compounds of the present invention at a unit dose
level of about 0.01 to about 50 mg/kg of body weight, or an
equivalent amount of the pharmaceutically acceptable salt thereof,
on a regimen of 1-4 times per day. When used to treat chronic pain,
migrain headache, to induce anesthesia, to treat or prevent opiate
tolerance or to treat opiate withdrawal, the compounds of the
invention may be administered at a unit dosage level of from about
0.01 to about 50 mg/kg of body weight, or an equivalent amount of
the pharmaceutically acceptable salt thereof, on a regimen of 1-4
times per day. Of course, it is understood that the exact treatment
level will depend upon the case history of the animal, e.g., human
being, that is treated. The precise treatment level can be
determined by one of ordinary skill in the art without undue
experimentation.
[0419] The unit oral dose may comprise from about 0.01 to about 50
mg, preferably about 0.1 to about 10 mg of the compound. The unit
dose may be administered one or more times daily as one or more
tablets each containing from about 0.1 to about 10, conveniently
about 0.25 to 50 mg of the compound or its solvates.
[0420] In addition to administering the compound as a raw chemical,
the compounds of the invention may be administered as part of a
pharmaceutical preparation containing suitable pharmaceutically
acceptable carriers comprising excipients and auxiliaries which
facilitate processing of the compounds into preparations that can
be used pharmaceutically. Preferably, the preparations,
particularly those preparations that can be administered orally and
that can be used for the preferred type of administration, such as
tablets, dragees, and capsules, and also preparations that can be
administered rectally, such as suppositories, as well as suitable
solutions for administration by injection or orally, contain from
about 0.01 to 99 percent, preferably from about 0.25 to 75 percent
of active compound(s), together with the excipient.
[0421] Also included within the scope of the present invention are
the non-toxic pharmaceutically acceptable salts of the compounds of
the present invention. Acid addition salts are formed by mixing a
solution of the particular NMDA subunit selective antagonist or
agonist of the present invention with a solution of a
pharmaceutically acceptable non-toxic acid such as hydrochloric
acid, fumaric acid, maleic acid, succinic acid, acetic acid, citric
acid, tartaric acid, carbonic acid, phosphoric acid, oxalic acid,
and the like. Basic salts are formed by mixing a solution of the
particular haloperidol analog of the present invention with a
solution of a pharmaceutically acceptable non-toxic base such as
sodium hydroxide, potassium hydroxide, choline hydroxide, sodium
carbonate and the like.
[0422] The pharmaceutical compositions of the invention may be
administered to any animal which may experience the beneficial
effects of the compounds of the invention. Foremost among such
animals are mammals, e.g., humans, although the invention is not
intended to be so limited.
[0423] The pharmaceutical compositions of the present invention may
be administered by any means that achieve their intended purpose.
For example, administration may be by parenteral, subcutaneous,
intravenous, intramuscular, intraperitoneal, transdermal, or buccal
routes. Alternatively, or concurrently, administration may be by
the oral route. The dosage administered will be dependent upon the
age, health, and weight of the recipient, kind of concurrent
treatment, if any, frequency of treatment, and the nature of the
effect desired.
[0424] The pharmaceutical preparations of the present invention are
manufactured in a manner that is itself known, for example, by
means of conventional mixing, granulating, dragee-making,
dissolving, or lyophilizing processes. Thus, pharmaceutical
preparations for oral use can be obtained by combining the active
compounds with solid excipients, optionally grinding the resulting
mixture and processing the mixture of granules, after adding
suitable auxiliaries, if desired or necessary, to obtain tablets or
dragee cores.
[0425] Suitable excipients are, in particular, fillers such as
saccharides, for example, lactose or sucrose, mannitol or sorbitol,
cellulose preparations and/or calcium phosphates, for example,
tricalcium phosphate or calcium hydrogen phosphate, as well as
binders such as starch paste, using, for example, maize starch,
wheat starch, rice starch, potato starch, gelatin, tragacanth,
methyl cellulose, hydroxy-propylmethylcellulose, sodium
carboxymethylcellulose, and/or polyvinyl pyrrolidone. If desired,
disintegrating agents may be added such as the above-mentioned
starches and also carboxymethyl-starch, cross-linked polyvinyl
pyrrolidone, agar, or alginic acid or a salt thereof, such as
sodium alginate. Auxiliaries are, above all, flow-regulating agents
and lubricants, for example, silica, talc, stearic acid or salts
thereof, such as magnesium stearate or calcium stearate, and/or
polyethylene glycol. Dragee cores are provided with suitable
coatings which, if desired, are resistant to gastric juices. For
this purpose, concentrated saccharide solutions may be used, which
may optionally contain gum arabic, talc, polyvinyl pyrrolidone,
polyethylene glycol and/or titanium dioxide, lacquer solutions and
suitable organic solvents or solvent mixtures. In order to produce
coatings resistant to gastric juices, solutions of suitable
cellulose preparations, such as, acetyl-cellulose phthalate or
hydroxypropymethyl-cellulose phthalate, are used. Dye stuffs or
pigments may be added to the tablets or dragee coatings, for
example, for identification or in order to characterize
combinations of active compound doses.
[0426] Other pharmaceutical preparations that can be used orally
include push-fit capsules made of gelatin, as well as soft, sealed
capsules made of gelatin and a plasticizer such as glycerol or
sorbitol. The push-fit capsules can contain the active compounds in
the form of granules, which may be mixed with fillers such as
lactose, binders such as starches, and/or lubricants such as talc
or magnesium stearate and, optionally, stabilizers. In soft
capsules, the active compounds are preferably dissolved or
suspended in suitable liquids, such as fatty oils, or liquid
paraffin. In addition, stabilizers may be added.
[0427] Possible pharmaceutical preparations that can be used
rectally include, for example, suppositories, which consist of a
combination of one or more of the active compounds with a
suppository base. Suitable suppository bases are, for example,
natural or synthetic triglycerides, or paraffin hydrocarbons. In
addition, it is also possible to use gelatin rectal capsules that
consist of a combination of the active compounds with a base.
Possible base materials include, for example, liquid triglycerides,
polyethylene glycols, or paraffin hydrocarbons.
[0428] Suitable formulations for parenteral administration include
aqueous solutions of the active compounds in water-soluble form,
for example, water-soluble salts and alkaline solutions. In
addition, suspensions of the active compounds as appropriate oily
injection suspensions may be administered. Suitable lipophilic
solvents or vehicles include fatty oils, for example, sesame oil,
or synthetic fatty acid esters, for example, ethyl oleate or
triglycerides or polyethylene glycol-400 (the compounds are soluble
in PEG-400). Aqueous injection suspensions may contain substances
that increase the viscosity of the suspension include, for example,
sodium carboxymethyl cellulose, sorbitol, and/or dextran.
Optionally, the suspension may also contain stabilizers.
[0429] The characterization of NMDA subunit binding sites in vitro
has been difficult because of the lack of selective drug ligands.
Thus, the NMDA ligands of the present invention may be used to
characterize the NMDA subunits and their distribution. Particularly
preferred NMDA subunit selective antagonists and agonists of the
present invention that may be used for this purpose are
isotopically radiolabelled derivatives, e.g., where one or more of
the atoms are replaced with .sup.3H, .sup.11C, .sup.14C, .sup.15N,
or .sup.18F. Alternatively, a fluorescent group Y may be employed.
Examples of such groups include 4-nitrobenzofurazan: 93
[0430] The following examples are illustrative, but not limiting,
of the method and compositions of the present invention. Other
suitable modifications and adaptations of the variety of conditions
and parameters normally encountered in clinical therapy and that
are obvious to those skilled in the art are within the spirit and
scope of the invention.
EXAMPLE 1
Preparation of N-(Methoxycarbonylbutyl)-4-benzylpiperidine
[0431] A mixture of methyl bromovalerate (1.56 g, 8.0 mmol),
4-benzylpiperidine (1.49 g, 8.5 mmol) and potassium carbonate (2.93
g, 21.25 mmol) in 30 mL of acetonitrile was refluxed under N.sub.2
for 12 hr. The inorganic salt was removed through a short column of
silica gel and washed with ethyl acetate (3.times.30 mL). The
filtrate was evaporated in vacuo to give a residue, which was
purified by flash chromatography, giving 1.8 g (78%) of the product
as a pale yellow oil. .sup.1H NMR (CHCl.sub.3), 1.312 (m, 2 H),
1.505-1.593 (m, 7 H), 1.831 (m, 2 H), 2.292 (m, 4 H), 2.505 (d,
J=6.9 Hz, 2 H), 2.860 (d, J=11.4 Hz, 2 H), 3.647 (s, 3 H), 7.136
(m, 5 H).
EXAMPLE 2
Preparation of 4-Benzylpiperidylpentamide
[0432] To a solution of N-(methoxycarbonylbutyl)-4-benzylpiperidine
(289 mg, 1.0 mmol) in 5 mL of methanol was added 5 mL of 30%
ammonium hydroxide solution at room temperature. The resulting
solution was allowed to stir at rt overnight. The solvent was
evaporated in vacuo to give a residue. Water (5 mL) was added into
the residue, which was extracted with ethyl acetate (3.times.10 mL)
and dried over sodium sulfate. The solvent was evaporated in vacuo
to give a residue, which was purified by flash chromatography,
giving 120 mg (44%) of the product as off-white solid. mp
95-96.degree. C. .sup.1H NMR (CHCl.sub.3) 1.285 (m, 2 H),
1.537-1.595 (m, 7 H), 1.835 (m, 2 H), 2.212 (m, 2 H), 2.274 (m, 2
H), 2.495 (d, J=6.9 Hz, 2 H), 2.853 (d, J=9.9 Hz, 2 H), 5.942 (s, 2
H), 7.104-7.228 (m, 5 H).
EXAMPLE 3
Preparation of 4-Benzylpiperidylpentahydrazide
[0433] To a solution of N-(methoxycarbonylbutyl)-4-benzylpiperidine
(289 mg, 1.0 mmol) in 5 mL of methanol was added 3 mL of
NH.sub.2NH.sub.2 at room temperature. The resulting solution was
allowed to stir at rt overnight. The solvent was evaporated in
vacuo to give a residue. Water (5 mL) was added into the residue,
which was extracted with ethyl acetate (3.times.10 mL) and dried
over sodium sulfate. The solvent was evaporated in vacuo to give a
residue, which was purified by flash chromatography, giving 217 mg
(75%) of the product as off-white solid. mp 104-106.degree. C.
.sup.1H NMR (CHCl.sub.3) 1.324 (m, 2 H), 1.506-1.655 (m, 7 H),
1.839 (m, 2 H), 2.189 (m, 2 H), 2.291 (m, 2 H), 2.521 (d, J=6.9 Hz,
2 H), 2.853 (d, J=11.4 Hz, 2 H), 3.857 (s, 2 H), 7.104-7.228 (m, 6
H).
EXAMPLE 4
N-(5-(4-Benzylpiperidin-1-yl)valeroyl)-N'-(4-nitrobenzoyl)hydrazine
[0434] To a solution of 5-(4-benzylpiperidin-1-yl)valerhydrazide
(289 mg, 1.00 mmol) in 10 mL of CH.sub.2Cl.sub.2 and 0.21 mL of
Et.sub.3N was added 4-nitrobenzoyl chloride (278 mg, 1.50 mmol).
The resulting solution was allowed to stir at rt for 12 hr. The
mixture was poured into ice water (10 g). The organic layer was
separated and the water phase was extracted with CH.sub.2Cl.sub.2
(2.times.15 mL). The combined organic extracts were dried over
Na.sub.2SO.sub.4. Evaporation of solvent gave the title product as
a brown oil (405 mg, 92%): .sup.1H NMR (CDCl.sub.3) 1.25 (m, 2 H),
1.60 (m, 6 H), 1.90 (m, 2 H), 2.29 (m, 4 H), 2.48 (d, J=6.6 Hz, 2
H), 2.90 (m, 2 H), 3.42 (s, 1 H), 7.07-7.24 (m 5 H), 7.70 (bs, 2
H), 7.96 (d, J=7.8 Hz, 2 H), 8.08 (d, J=7. 8 Hz, 2 H).
EXAMPLE 5
N-(4-Aminobenzoyl)-N'-(5-(4-benzylpiperidin-1-yl)valeroyl)hydrazine
[0435] To a solution of
N-(5-(4-benzylpiperidin-1-yl)valeroyl)-N'-(4-nitro-
benzoyl)hydrazine (200 mg, 0.456 mmol) in 20 mL of methanol was
added 50 mg of 5% Pd/C. The resulting mixture was hydrogenated at
30 psi of hydrogen for 3 hr. The catalyst was removed through a
short column of Celite and was washed with methanol (15 mL). The
extracts were evaporated in vacuo to give an oil, which was
purified by flash chromatography to give the title product as a
solid (60 mg, 32%):. mp 163-165.degree. C.; .sup.1H NMR
(CDCl.sub.3) 1.26 (m, 2 H), 1.59 (m, 9 H), 1.92 (m, 2 H), 2.28 (m,
4 H), 2.52 (m, 2 H), 2.90 (m, 2 H), 3.29 (s, 2 H), 6.83 (d, J=8.1
Hz, 2 H), 7.10 (m, 3 H), 7.20 (m, 2 H), 7.63 (d, J=7.8 Hz, 2
H).
EXAMPLE 6
Preparation of 4-benzyl-1-(3-Butynyl)piperidine
[0436] A mixutre of 3-butyn-1-methanesulfate (3.032 g, 0.02 mol),
4-phenylpiperidine (4.21 g, 0.024 mol) and potassium carbonate
(8.28 g, 0.06 mol) in 50 mL of acetonitrile was refluxed for 12
hrs. The mixutre was filtered and washed with ethyl acetate
(3.times.30 mL). The filtrate was evaporated in vacuo and was
purified by flash chromatography to give 4.30 g (95%) of the
product as pale yellow oil. .sup.1H NMR (CHCl.sub.3) 1.319 (m, 2
H), 1.51 (m, 1 H), 1.652 (m, 2 H), 1.937 (m, 3 H), 2.364 (m, 2 H),
2.543 (m, 4 H), 2.858 (d, J=11.4 Hz, 2 H), 7.121-7.270 (m, 5
H).
EXAMPLE 7
Preparation of
1-(3-Butynyl)-4-(p-chlorphenyl)-4-hydroxypiperidine
[0437] A mixutre of 3-butyn-1-methanesulfate (1.48 g, 0.01 mol),
4-(p-chlorophenyl)-4-hydroxypiperidine (2.54 g, 0.012 mol) and
potassium carbonate (4.14 g, 0.03 mol) in 25 mL of acetonitrile was
refluxed for 12 hrs. The mixture was filtered and washed with ethyl
acetate (3.times.30 mL). The filtrate was evaporated in vacuo and
was purified by flash chromatography to give 2.30 g (87%) of the
product as a white solid. mp 98-100.degree. C. .sup.1H NMR
(CHCl.sub.3) 1.550 (s, 1 H), 1.749 (m, 2 H), 1.997 (m, 1 H), 2.109
(m, 2 H), 2.423 (m, 4 H), 2.655 (m, 2 H), 2.798 (m, 2 H), 7.329 (d,
J=7.2 Hz, 2 H), 7.429 (d, J=7.2 Hz, 2 H).
EXAMPLE 8
Preparation of m-Fluorobenzyltriphenylphosphonium bromide
[0438] To a solution of triphenylphosphine (45.24 g, 0.12 mol) in
200 mL of ether was added 3-fluorobenzyl bromide (22.7 g, 0.12
mol). The resulting solution was allowed to stir at rt overnight.
The white solid was collected by filtration and dried to give 58.0
g (85%) of the product as a white solid. mp 290-292.degree. C.
.sup.1H NMR (CHCl.sub.3) 5.516 (d, J=14.7 Hz, 2 H), 6.725 (d, J=9.6
Hz, 1 H), 6.893 (m, 2 H), 7.084 (m, 2 H), 7.622-7.762 (m, 15
H).
EXAMPLE 9
Preparation of 1-Benzyl-4-(m-fluorobenzylidene)piperidine
[0439] To a suspension of m-fluorobenzyltriphenylphosphonium
bromide (16.98 g, 0.03 mol) in 50 mL of THF was added 14.5 mL of
BuLi (M=2.5 M) at -78.degree. C. under N.sub.2. After stirring at
-78.degree. C. for 45 min., a solution of 4-benzylpiperidone (5.67
g, 0.03 mol) in 10 mL of THF was added dropwise at -78.degree. C.
under N.sub.2. The resulting mixture was allowed to warm to room
temperature and stirred for another 5 hr. Then the mixture was
poured into ice (100 g) and extracted with ether (3.times.40 mL).
The combined extracts were dried over sodium sulfate. The solvent
was evaporated in vacuo to give a residue, which was purified by
flash chromatography, giving 0.6 g (7%) of the product as pale
yellow oil. .sup.1H NMR (CHCl.sub.3) 2.413 (m, 2 H), 2.466 (m, 2
H), 2.558 (m, 4 H), 3.558 (s, 2 H), 6.257 (s, 1 H), 6.905 (m, 3 H),
7.284 (m, 6 H).
EXAMPLE 10
Preparation of 4-[N-IDDC (.+-.)]-4'-fluorobutyrophenone
[0440] A solution of 88 mg (0.398 mmol) of IDDC (.+-.), 142 mg
(0.707 mmol) of 4-chloro-4'-fluorobutyrophenone and 100 mg (0.99
mmol) of Et.sub.3N in 4 mL of DMF was heated at 75.degree. C. for
48 h. It was cooled to room temperature and added into 10 mL of
water and the mixture was extracted by CHCl.sub.3 (2.times.6 mL).
The extract was washed by water (2.times.5 mL), dried and
evaporated to leave liquid, which was treated with 2 mL of water.
The oily precipitate was separated by preparative TLC (ethyl
acetate:hexane=25:30, R.sub.f=0.72-0.58) to give 85 mg (55%) of
almost colorless oil. .sup.1H NMR (CDCl.sub.3), 1.94 (m, 2), 2.6
(m, 1), 2.7 (m, 1), 2.88-3.02 (m, 4), 3.40-3.62 (m, 2), 3.81 (d,
1), 3.975 (t, 1), 6.96-7.20 (m, 10), 7.90 (m, 2).
EXAMPLE 11
Preparation of 4-(N-MK801)-4'-fluorobutyrophenone
[0441] A solution of 102 mg (0.396 mmol) of MK801 HCl, 76 mg (0.38
mmol) of 4-chloro-4'-fluorobutyrophenone, 80 mg (0.79 mmol) of
Et.sub.3N and 10 mg of NaI in 2 mL of DMF was heated at 80.degree.
C. for 3 days. It was cooled to room temperature and added into 10
mL of water and the mixture was extracted by CHCl.sub.3 (3.times.10
mL). The extract was washed by water (5.times.10 mL), dried and
evaporated to leave liquid which was separated by preparative TLC
(ethyl acetate:hexane=1:1, R.sub.f=0.70-0.59) to give 45 mg (30%)
of pale-yellow oil. .sup.1H NMR (CDCl.sub.3), 1.792 (s, 3), 2.075
(m, 2), 2.488 (d, 1), 2.50-2.66 (m, 4), 2.99 (m, 1), 3.097 (m, 1),
3.350 (dd, 1), 4.545 (d, 1), 6.903 (m, 1), 7.00-7.14 (m, 7), 7.217
(m, 1), 7.308 (m, 1), 7.912 (m, 2).
EXAMPLE 12
Preparation of 4-(4-Benzylpiperidinyl)-4'-fluorobenzophenone and
4,4'-Bis(4-benzylpiperidinyl)benzophenone
[0442] A solution of 299 mg (1.37 mmol) of
4,4'-difluorobenzophenone and 486 mg (2.77 mmol) of
4-benzylpiperidine in 2 mL of anhydrous DMF was heated at
150.degree. C. for 24 h. It was cooled to room temperature, diluted
by 10 mL of ethyl acetate and washed by brine (3.times.10 mL) and
water (1.times.10 mL). The solution was dried and evaporated. The
residue was separated by chromatography (silica gel), eluted by
hexane:ethyl acetate=10:1 to give 180 mg of 25 as white solid.
.sup.1H NMR (CDCl.sub.3), 1.20-1.40 (m, 3), 1.77 (d, 2), 2.583 (d,
2), 2.840 (t, 2), 3.909 (d, 2), 6.872 (d, 2), 7.10-7.30 (m, 7),
7.75 (m, 4). Another fraction gave 50 mg of 26 as white solid.
.sup.1H NMR (CDCl.sub.3), 1.39 (m, 6), 1.759 (d, 4), 2.582 (d, 4),
2.803 (t, 4), 3.871 (d, 4), 6.877 (d, 4), 7.154-7.302 (m, 10),
7.728 (d, 4). MS, 528 (M.sup.+, 100), 436 (20). HRMS, Calcd for
C.sub.37H.sub.40N.sub.2O 528.3129, Found 528.3127.
EXAMPLE 13
Preparation of 4-(4-Hydroxypiperidinyl)butyrophenone
[0443] A mixture of 4-hydroxypiperidine (550 mg, 5.4 mmol),
4-chlorobutyrophenone (490 mg, 2.7 mmol), NaI (160 mg),
K.sub.2CO.sub.3 (760 mg) and toluene (25 mL) was refluxed for 24 h,
cooled to rt, filtered and washed with hexane (2.times.10 mL). The
filtrate was evaporated, and the residue was chromatographed over
silica gel (EtOAc-EtOH-NH.sub.4OH, 60:40:2) to give 21 mg (3%) of
the free base as a yellow powder, mp 101-2.degree. C. .sup.1H NMR
(CDCl.sub.3-D.sub.2O): 1.50-1.57 (m, 2H), 1.83-1.98 (m, 3H),
2.08-2.17 (m, 3H), 2.397 (t, 2H, J=7), 2.73-2.78 (m, 2H), 3.00 (t,
2H, J=7), 3.60-3.70 (m, 1H), 7.43-7.56 (m, 3H), 7.96-7.98 (m, 2H).
Analysis, Calcd for C.sub.15H.sub.21NO.sub.2: C, 72.84; H, 8.56; N,
5.66; Found: C, 72.31; H, 8.45; N, 5.32.
EXAMPLE 14
Preparation of 4-Benzyl-4-hydroxy-1-(2-phenylethyl)piperidine and
the hydrochloride
[0444] From 2-phenylethyl bromide (702 mg, 3.8 mmol),
4-benzyl-4-hydroxypiperidine (1.51 g, 7.9 mmol) and NaI (50 mg) in
toluene (20 mL) was obtained 960 mg (83.6%) of the free base as a
yellow viscous oil. .sup.1H NMR (CDCl.sub.3): 1.20-1.27 (m, 1H),
1.54-1.60 (m, 4H), 1.75-1.85 (m, 2H), 2.35-2.42 (m, 2H), 2.60-2.65
(m, 2H), 2.78-2.85 (m, 4H), 7.19-7.34 (m, 10H). The hydrochloride
mp 233-5.degree. C. Analysis, Calcd. for C.sub.20H.sub.26ClNO: C,
72.38; H, 7.90; N, 4.22; Found: C, 72.06; H, 7.90; N, 3.97.
EXAMPLE 15
Preparation of 1-(2-Phenylethyl)-4-benzylidenepiperidine and the
hydrochloride
[0445] A suspension of
4-benzyl-4-hydroxy-1-(2-phenylethyl)piperidine hydrochloride (400
mg, 1.28 mmol) in 20 mL of 40% (w/w) aq H.sub.2SO.sub.4 was
refluxed for 16 h, then cooled in an ice-water bath and basified to
pH 10 with 1N aq NaOH. The resulting mixture was extracted with
CH.sub.2Cl.sub.2(3.times.10 mL). The extracts were combined, washed
with brine (10 mL), dried (MgSO.sub.4) and evaporated. The residue
was chromatographed over silica gel (EtOAc-EtOH, 10:0.5) to give
180 mg (50%) of the free base as a yellow viscous oil. .sup.1H NMR
(CDCl.sub.3): 2.04-2.18 (m, 2H), 2.56-2.68 (m, 4H), 2.82-2.87 (m,
2H), 3.066 (bs, 2H), 3.307 (bs, 2H), 5.400 (bs, 1H), 7.17-7.31 (m,
10H). The hydrochloride, mp 193.degree. C. .sup.1H NMR (D.sub.2O):
2.15-2.32 (m, 2H), 3.042 (t, 2H, J=7.5), 3.10-3.88 (m, 8H), 5.483
(s, 1H), 7.23-7.39 (m, 10H). Analysis, Calcd. for
C.sub.20H.sub.24ClN.0.2H.sub.2O: C, 75.66; H, 7.75; N, 4.41; Found:
C, 75.73; H, 7.60; N, 4.22.
EXAMPLE 16
Preparation of 4-Benzyl-4-hydroxy-1-(3-phenylpropyl)piperidine and
the hydrochloride
[0446] From 1-bromo-3-phenylpropane (598 mg, 3.0 mmol),
4-benzyl-4-hydroxypiperidine (1.15 g, 6.0 mmol) and NaI (150 mg,
1.0 mmol) in toluene (20 mL) was obtained 780 mg (84%) of the free
base as a yellow viscous oil. .sup.1H NMR (CDCl.sub.3): 1.183 (s,
1H, OH), 1.50-1.54 (m, 2H), 1.71-1.89 (m, 4H), 2.24-2.32 (m, 2H),
2.397 (t, 2H, J=8), 2.60-2.70 (m, 4H), 2.755 (s, 2H), 7.12-7.34 (m,
10H). The hydrochloride, mp 156-7.degree. C. Analysis, Calcd. for
C.sub.21H.sub.28ClNO: C, 72.92; H, 7.87; N, 4.05; Found: C, 73.07;
H, 8.10; N, 4.13.
EXAMPLE 17
Preparation of 4-Benzylidene-1-(3-phenylpropyl)piperidine and the
hydrochloride
[0447] A mixture of 4-benzyl-4-hydroxy-1-(3-phenylpropyl)piperidine
hydrochloride (320 mg, 0.92 mmol) in 15 mL of 40% (w/w) aq
H.sub.2SO.sub.4 was refluxed for 3 days, then cooled in an
ice-water bath and basified to pH 10 with 1N aq NaOH. The resulting
mixture was extracted with CH.sub.2Cl.sub.2 (3.times.10 mL), and
the extract was washed with brine (10 mL), dried (MgSO.sub.4) and
evaporated. The residue was chromatographed over silica gel
(EtOAc-EtOH, 10:1) to give 120 mg (44%) of the free base as a
yellow viscous oil. .sup.1H NMR (CDCl.sub.3): 1.80-1.85 (m, 2H),
2.064 (bs 2H), 2.427 (t, 2H, J=7), 2.517 (t, 2H, J=7.5), 2.642 (t,
2H, J=7.5), 2.963 (bs, 2H), 3.288 (bs, 2H), 5.370 (bs, 1H),
7.17-7.31 (m, 10H). The hydrochloride, mp 156-7.degree. C.
Analysis, Calcd. for C.sub.21H.sub.26ClN: C, 76.92; H, 7.99; N,
4.27; Found: C, 76.79; H, 8.02; N, 4.30.
EXAMPLE 18
Preparation of N-(2-Phenoxyethyl)-1,2,3,4-tetrahydroisoquinoline
and the hydrochloride
[0448] From 1,2,3,4-tetrahydroisoquinoline (1.077 g, 8.1 mmol),
3-phenoxypropyl bromide (806 mg, 4.0 mmol) and NaI (40 mg) in
toluene (15 mL) was obtained 990 mg (89%) of the free base as a
yellow viscous oil. .sup.1H NMR (CDCl.sub.3): 2.88-2.96 (m, 2H),
3.012 (t, 2H, J=6), 3.806 (s, 2H), 4.223 (t, 2H, J=6), 4.171 (t,
2H, J=5.7), 6.92-7.32 (m, 9H). The hydrochloride, mp 181-2.degree.
C. Analysis, Calcd. for C.sub.17H.sub.20ClNO: C, 70.46; H, 6.96; N,
4.83; Found: C, 70.29; H, 7.02; N, 4.80.
EXAMPLE 19
Preparation of N-(3-Phenoxypropyl)-1,2,3,4-tetrahydroisoquinoline
and the hydrochloride
[0449] From 1,2,3,4-tetrahydroisoquinoline (1.077 mg, 8.1 mmol),
3-phenoxypropyl bromide (863 mg, 4.0 mmol) and NaI (36 mg) in
toluene (15 mL) was obtained 990 mg (89%) of the free base as a
yellow viscous oil. .sup.1H NMR (CDCl.sub.3): 2.04-2.19 (m, 2H),
2.720 (t, 2H, J=7), 2.760 (t, 2H, J=7), 2.925 (t, 2H, J=7), 3.678
(bs, 2H), 4.072 (t, 2H, J=7), 6.89-7.30 (m, 9H). The hydrochloride,
mp 194-5.degree. C. Analysis, Calcd. for C.sub.18H.sub.22ClNO: C,
71.16; H, 7.30; N, 4.61; Found: C, 71.01; H, 7.41; N, 4.41.
EXAMPLE 20
N-[(3-(4-Fluorobenzoylpropyl)]-1,2,3,4-tetrahydroisoquinoline
[0450] From 1,2,3,4-tetrahydroisoquinoline (530 mg, 4.0 mmol) and
4-chloro-4'-fluorobutyro-phenone (402 mg, 2.0 mmol) there was
obtained 190 mg (30%) of the title compound as a viscous yellow
oil. .sup.1H NMR (CDCl.sub.3): 2.00-2.09 (m, 2H), 2.595 (t, 2H,
J=7), 2.71-2.75 (m, 2H), 2.86-2.90 (m, 2H), 3.055 (t, 2H, J=7),
3.622 (s, 2H), 7.00-7.12 (m, 6H), 7.988 (dd, 2H, J=8.5; 5.5). The
hydrochloride, mp 213-5.degree. C. Anal, Calcd. for
(C.sub.19H.sub.20FNO+HCl): C, 68.36; H, 6.34; N, 4.30; Found: C,
68.09; H, 6.31; N, 4.16.
EXAMPLE 21
6,7-Dimethoxy-2-(3-phenoxypropyl)-1,2,3,4-tetyrahydroisoquinoline
[0451] From 3-phenoxypropyl bromide (212 mg, 0.98 mmol) and
6,7-dimethoxyl-1,2,3,4-tetrahydroisoquinoline (380 mg, 1.96 mmol)
there was obtained 160 mg (45%) of the title compound as a
yellowish viscous oil. .sup.1H NMR (CDCl.sub.3): 2.03-2.12 (m, 2H),
2.67-2.76 (m, 4H), 2.81-2.83 (m, 2H), 3.584 (s, 2H), 3.834 (s, 3H),
3.842 (s, 3H), 4.068 (t, 2H, J=6), 6.524 (s, 1H), 6.596 (s, 1H),
6.90-6.95 (m, 3H), 7.25-7.30 (m, 2H). The hydrochloride, mp
193-5.degree. C. Anal. Calcd. for (C.sub.20H.sub.24NO.sub.3+HCl):
C, 66.20; H, 6.94; N, 3.86; Found: C, 65.88; H, 6.87; N, 3.81.
EXAMPLE 22
2-N-[3-(4-Fluorobenzoyl)propyl]-1,2,3,4-tetrahydropyrido[3,4-b]indole
[0452] From 1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole (276 mg, 1.6
mmol) and 4-chloro-4-fluorobutyrophenone (301 mg, 1.5 mmol) there
was obtained 59 mg (22%) of the title compound as a yellow powder,
mp 188-190.degree. C. .sup.1H NMR (CDCl.sub.3): 2.01-2.11 (m, 2H),
2.693 (t, 2H, J=7), 2.78-2.80 (m, 2H), 2.85-2.89 (m, 2H), 3.063 (t,
2H, J=7), 3.682 (s, 2H), 7.06-7.16 (m, 4H), 7.301 (d, 1H, J=7),
7.465 (d, 1H, J=7), 7.732 (s, 1H, NH), 7.980 (dd, 2H, J=8.5; 5.5).
Anal. Calcd. for (C.sub.21H.sub.21FN.sub- .2O+0.25H.sub.2O) C,
73.99; H, 6.28; N, 8.22; Found: C, 74.06; H, 5.99; N, 8.09.
EXAMPLE 23
6-Methoxy-2-(3-phenoxypropyl)-1,2,3,4-tetyrahydro-9H-pyrido-[3,4-b]indole
[0453] From 3-phenoxypropyl bromide (215 mg, 1.0 mmol) and
6-methoxy-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole (404 mg, 2.0
mmol) there was obtained 56 mg (16.6%) of the title compound as a
white powder, mp 141-2.degree. C. .sup.1H NMR
(CDCl.sub.3):2.05-2.13 (m, 2H), 2.77-2.91 (m, 6H), 3.695 (s, 2H),
3.851 (s, 3H), 4.075 (t, 2H, J=6.5), 6.76-6.80 (m, 1H), 6.90-6.96
(m, 5H), 7.16-7.30 (m, 3H), 7.590 (s, 1H, NH). Anal. Calcd. for
C.sub.21H.sub.24N.sub.2O.sub.2: C, 74.97; H, 7.19; N, 8.32; Found:
C, 74.71; H, 7.16; N, 8.19.
EXAMPLE 24
Preparation of
2-(2-Phenoxyethyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indol- e
[0454] From 1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole (445 mg, 2.6
mmol), .beta.-bromophenetole (260 mg, 1.3 mmol) and NaI (34 mg) in
toluene (20 mL) was obtained 200 mg (53%) of the free base as a
yellow powder, mp 181-2.degree. C. .sup.1H NMR (CDCl.sub.3): 1.653
(bs, 1H) 2.82-2.88 (m, 2H), 3.026 (t, 2H, J=6), 3.089 (t, 2H, J=6),
3.806 (bs, 2H), 4.226 (t, 2H, J=6), 6.93-6.99 (m, 2H), 7.06-7.16
(m, 2H), 7.26-7.32 (m, 3H), 7.478 (d, 1H, J=7.5), 7.747 (bs, 1H).
Analysis, Calcd. for C.sub.19H.sub.20N.sub.2O: C, 78.05; H, 6.90;
N, 9.58; Found: C, 77.88; H, 7.15; N, 9.55.
EXAMPLE 25
Preparation of
2-(3-Phenoxypropyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indo- le
[0455] From 1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole (430 mg, 2.5
mmol), 3-phenoxypropyl bromide (264 mg, 1.23 mmol) and NaI (48 mg)
in toluene (20 mL) was obtained 270 mg (72%) of the free base as a
yellow powder, mp 123-4.degree. C. .sup.1H NMR (CDCl.sub.3):
2.05-2.15 (m, 2H), 2.79-2.93 (m, 7H), 3.734 (bs, 2H), 4.080 (t, 2H,
J=7), 6.90-6.96 (m, 2H), 7.06-7.16 (m, 2H), 7.26-7.32 (m, 3H),
7.476 (d, 1H, J=7), 7.716 (bs, 1H, NH). Analysis, Calcd. for
C.sub.20H.sub.22N.sub.2O: C, 78.40; H, 7.23; N, 9.14; Found: C,
78.03; H, 7.15; N, 9.07.
EXAMPLE 26
Preparation of
2-(3-Phenylpropyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indol- e
[0456] From 1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole (200 mg, 1.16
mmol), 3-phenylpropyl bromide (125 mg, 0.63 mmol) and NaI (48 mg)
in toluene (5 mL) was obtained 120 mg (66%) of the free base as a
yellowish powder, mp 130-1.degree. C. .sup.1H NMR (CDCl.sub.3):
1.90-2.00 (m, 2H), 2.646 (t, 2H, J=7.5), 2.706 (t, 2H, J=7.5),
2.82-2.87 (m, 4H), 3.695 (s, 2H), 7.05-7.32 (m, 8H), 7.470 (d, 1H,
J=7), 7.695 (bs, 1H, NH). Analysis, Calcd. for
C.sub.20H.sub.22N.sub.2: C, 82.72; H, 7.64; N, 9.65; Found: C,
82.39; H, 7.62; N, 9.60.
EXAMPLE 27
Preparation of 4-Benzoyl-1-(2-phenoxyethyl)piperidine and the
hydrochloride
[0457] From .beta.-bromophenetole (302 mg, 1.5 mmol) and
4-benzoylpiperidine (568 mg, 3.0 mmol) in toluene (15 mL) was
obtained 387 mg (83%) of the free base as a yellowish viscous oil.
.sup.1H NMR (CDCl.sub.3): 1.84-1.91 (m, 4H), 2.26-2.34 (m, 2H),
2.853 (t, 2H, J=7), 3.07-3.11 (m, 2H), 3.20-3.30 (m, 1H), 4.129 (t,
2H, J=7), 6.90-6.97 (m, 3H), 7.28-7.31 (m, 1H), 7.44-7.58 (m, 4H).
7.92-7.95 (m, 2H). The hydrochloride mp 161-2.degree. C. Analysis,
Calcd. for C.sub.20H.sub.24ClNO.sub.2: C, 69.45; H, 6.99; N, 4.05;
Found: C, 69.37; H, 7.11; N, 3.99.
EXAMPLE 28
Preparation of 4-Benzyl-1-(3-sulfopropyl)piperidinium inner
salt
[0458] To a solution of 1,3-propanesultone (383 mg, 3.14 mmol, in
2-butanone (8 mL) neat 4-benzylpiperidine (500 mg, 2.85 mmol, was
added in one portion. The vessel was stoppered and the reaction was
allowed to stir at 25.degree. C. for 24 h. A colorless suspension
was present. Ether (40 mL) was added and the suspension was stirred
an additional 20 min. The solvent was decanted, fresh ether added
and the suspension was re-stirred. This was repeated. The solid was
collected from the resulting suspension and washed with ether
(3.times.2 mL). The ether damp solid was crystallized from water
(dissolved in warm solvent (3 mL cloudy solution), hot filtered
through Celite (still cloudy solution), allowed to cool to
4.degree. C.). A solid mass was obtained. This was diluted with ice
water (10 mL), the resulting slurry filtered and the collected
solid washed with ice water (3.times.3 mL). The damp filter cake
was dried in vacuo (0.005 Torr, 25.degree. C., then 100.degree. C.
(some high boiling material came off at the higher temperature) to
give a colorless powder (320 mg, 38%, pure by NMR as a mixture of
isomers); mp 167-172.degree. C.; .sup.1H NMR (D.sub.2O)
.delta.1.13-1.60 (m, 2 H), 1.77-1.95 (m, 2 H), 2.13 (p, J=7.5 Hz, 2
H), 2.52-2.67 (m, 2 H), 2.78-3.00 (m, 4 H), 3.20 (t, J=7.5 Hz, 2
H), 3.45-3.61 (m, 2 H), 7.21-7.39 (m, 5 H).
[0459] An analytical sample was prepared according to the following
procedure. The above powder (180 mg) was dissolved in hot water (2
mL), hot filtered and allowed to cool to 25.degree. C. A solid
formed. The water was decanted and the solid washed with water (0.5
mL). The wet solid was re-dissolved in hot water (0.5 mL) and the
resulting solution allowed to cool to 25.degree. C. The resulting
solid was collected washed with water (3.times.0.5 mL) and dried in
vacuo (100.degree. C., 0.005 Torr) to give a colorless crystalline
solid (29 mg); mp 177-178.degree. C. when added to an oil bath of
this temperature. When added to a cooler oil bath the solid melts
at 224-225.degree. C. (dec). Anal. Calcd for
C.sub.15H.sub.23NO.sub.3S.1.5 H.sub.2O: C, 55.55; H, 8.08; N, 4.32.
Found: C, 55.72; H, 7.95; N, 4.32.
EXAMPLE 29
Preparation of 1-[2-aza-1-oxo-2-phenylethyl]-4-benzylpiperidine
[0460] To a stirred solution of 4-benzylpiperidine (500 mg, 2.85
mmol, in toluene (10 mL) neat phenylisocyanate (341 mL, 374 mg,
3.14 mmol) was added in one portion. The reaction was allowed to
stir at 90.degree. C. under N.sub.2 for 24 hours. The toluene was
removed in vacuo (water aspirator, 45-50.degree. C.) to give a
colorless oil that solidified upon standing. The solid was dried
further (25.degree. C., 0.005 Torr). The solid was crystallized
from 95% EtOH (dissolved in hot solvent (2 mL), hot filtered,
allowed to cool to 25.degree. C., collected solid, washed with ice
cold 95% EtOH (3.times.2 mL) and dried in vacuo (56.degree. C.,
0.005 Torr)) to give a fluffy, colorless solid (530 mg, 63%); mp
130-131.degree. C.; .sup.1H NMR (CDCl.sub.3) .delta.1.16-1.37 (m, 2
H), 1.61-1.82 (m, 3 H), 2.57 (d, J=6.9 Hz, 2 H), 2.75-2.90 (m, 2
H), 4.04 (d, J=14 Hz, 2 H), 6.43 (bs, 1 H), 6.95-7.38 (m, 10 H).
Anal. Calcd for C.sub.19H.sub.22NO: C, 77.52; H, 7.53; N, 9.52.
Found: C, 77.58; H, 7.67; N, 9.54.
EXAMPLE 30
Preparation of
1-[2-aza-1-oxo-2-(4-nitrophenyl)ethyl]-4-benzylpiperidine
[0461] From 4-benzylpiperidine (1.00 g, 5.70 mmol, and
4-nitrophenylisocyanate (1.03 g, 6.27 mmol, there was obtained the
product as a pale yellow solid (1.51 g, 78%, pure by NMR); mp
129.5-130.5.degree. C.; .sup.1H NMR (CDCl.sub.3) .delta.1.16-1.37
(m, 2 H), 1.67-1.87 (m, 3 H), 2.58 (d, J=6.6 Hz, 2 H), 2.80-2.95
(m, 2 H), 4.07 (d, J=14 Hz, 2 H), 6.88 (s, 1 H), 7.12-7.35 (m, 5
H), 7.52 (d, J=9.0 Hz, 2 H), 8.16 (d, J=9.0 Hz, 2 H).
EXAMPLE 31
Preparation of
1-[2-aza-1-oxo-2-(4-aminophenyl)ethyl]-4-benzylpiperidine
[0462] A mixture of
4-benzyl-1-((N-(4-nitrophenyl)aza)carbonyl)piperidine (1.50 g, 4.42
mmol) and Pd/C (10%, 150 mg, Aldrich) in MeOH (200 mL) was shaken
under H.sub.2 (20-30 psi, Parr) for 45 min at 25.degree. C. The
catalyst was removed by filtration (Celite). The resulting solution
was acidified with a dilute solution of HBr in MeOH (pH paper to
red). The MeOH was removed in vacuo (rotoevap, 35-40.degree. C.) to
give a colorless solid. The solid was crystallized from
MeOH/H.sub.2O. mp 325.degree. C. dec.; .sup.1H NMR (DMSO-d.sub.6)
.delta.0.90-1.10 (m, 2 H), 1.40-1.70 (m, 3 H), 2.42 (d, J=6.6 Hz, 2
H), 2.55-2.70 (m, 2 H), 4.06 (d, J=13 Hz, 2 H), 7.00-7.25 (m, 7 H),
7.54 (d, J=8.7 Hz, 2 H), 8.65 (s, 1 H), 9.90 (bs, 3 H). Anal. Calcd
for C.sub.19H.sub.24BrN.sub.3O: C, 58.47; H, 6.20; N, 10.76. Found:
C, 58.69; H, 6.26; N, 10.72.
EXAMPLE 32
Preparation of 4-(4-Chlorobenzyl)piperidine hydrochloride
[0463] The procedure of Faraj et al., was adapted (Faraj, B. A.;
Israili, Z. H.; Kight, N. E.; Smissman, E. E.; Pazdernik, T. J. J.
Med Chem. 19:20 (1976)). A near colorless powder was obtained; mp
179-184.degree. C., .sup.1H NMR (D.sub.2O) .delta.1.31-1.50 (m, 2
H), 1.75-1.95 (m, 3 H), 2.58 (d, J=6.9 Hz, 2 H), 2.82-2.99 (m, 2
H), 3.58 (d, J=12.6 Hz, 2 H), 7.20 (d, J=8.1 Hz, 2 H), 7.34 (d,
J=8.4 Hz).
EXAMPLE 33
1-Allyl-4-(4-chlorobenzyl)piperidine hydrobromide and
1,1-Bisallyl-4-(4-chloro-benzyl)piperidinium iodide
[0464] A mixture of 4-(4-chlorobenzyl)piperidine hydrochloride
(1.00 g, 4.06 mmol), K.sub.2CO.sub.3 (1.15 g, 8.32 mmol,) and allyl
iodide (1.02 g, 6.09 mmol) in CH.sub.3CN (25 mL) was stirred at
reflux under N.sub.2 for 4 h. The reaction was added to 5% aqueous
HCl (200 mL). The resulting cloudy solution was extracted with
CHCl.sub.3 (3.times.50 mL). The extract was washed with 10% aqueous
NH.sub.4OH (2.times.50 mL) and water (2.times.50 mL), filtered
through cotton and the solvent was removed in vacuo to give an
orange gum mixed with an amber oil. The mixture was washed with
hexanes (3.times.10 mL) which dissolved the oil, leaving the gum
behind. The solvent was removed from the hexanes portion to give an
amber oil. Purification of this oil was effected by silica gel
chromatography (2.5.times.20 cm column) with CHCl.sub.3 elution to
remove the more mobile impurities and with 1% EtOH/99% CHCl.sub.3
to remove the product. Solvent removal from the pure fractions
yielded an amber oil. This was dissolved in MeOH (10 mL, cloudy
solution) filtered through Celite and the MeOH was removed in vacuo
to yield a clear amber oil. This was dissolved in hexanes (10 mL),
the insoluble portion removed by filtration through Celite and the
solvent was removed in-vacuo to give the monoallyl piperidine as a
clear amber oil (340 mg, 34%;): .sup.1H NMR (CDCl.sub.3) d
1.22-1.68 (m, 5 H), 1.89 (t, J=8.4 Hz, 2 H,), 2.50 (d, J=6.6 Hz, 2
H), 2.83-3.05 (m,4 H), 5.05-5.22 (m, 2 H), 5.79-5.98 (m, 1 H), 7.05
(d, J=8.1 Hz, 2 H), 7.23 (d, J=8.1 Hz, 2 H). The hydrobromide salt
was obtained as a pale yellow powder (413 mg, 92%): mp
114-116.5.degree. C.; HRMS calcd for C.sub.15H.sub.20ClNO 249.1284,
found 249.1279.
[0465] The above described gum was mixed with ether (45 mL) and was
stirred at 25.degree. C. for 24 h to give an orange suspension. The
solid was collected, washed with ether (3.times.4 mL) and was
allowed to air dry to give a pale orange powder (.about.600 mg).
This was suspended in toluene (22 mL). Acetone was added to the
stirred suspension at 25.degree. C. until a homogeneous solution
was obtained (22 mL). The flask was covered with a tissue and was
stored at 25.degree. C. so as to allow the acetone to evaporate. A
crystalline solid formed over the course of six days (a temperature
>25.degree. C. results in the formation of an oil). The solid
was collected, washed with toluene (3.times.2 mL) and was dried in
vacuo (0.005 Torr, 56.degree. C.) to give the bisallyl piperidine
as colorless, fluffy needles (448 mg, 26%): mp 110.5-111.5.degree.
C.; .sup.1H NMR (CDCl.sub.3) d 1.60-1.91 (m, 4 H), 2.16-2.35 (m, 1
H), 2.69 (d, J=7.2 Hz, 2 H), 3.54 (d, J=13 Hz, 2 H), 3.72-3.98 (m,
2 H), 4.10 (d, J=6.9 Hz, 2 H), 4.30 (d, J=6.9 Hz, 2 H), 5.70-6.08
(m, 6 H), 7.12 (d, J=8.1 Hz, 2 H), 7.24 (d, J=8.1 Hz, 2 H). Anal.
Calcd for C.sub.18H.sub.25ClIN: C, 51.75; H, 6.03; N, 3.35. Found:
C, 51.88; H, 5.90; N, 3.27.
EXAMPLE 34
Preparation of 5-(3-Benzylpiperidinyl)valeric acid methyl ester
[0466] 3-Benzylpiperidine hydrochloride. To a solution of
3-benzylpyridine (10 g, 59.8 mmol) in methanol (150 mL) were added
PtO.sub.2(350 mg) and HCl conc. (5 mL). This heterogeneous solution
was hydrogenated in a Parr hydrogenator at 20-25psi at 25.degree.
C. and for 24 hrs then filtered through a celite pad and
concentrated in vacuum. The crude compound was purified by
crystallization from acetone/diethyl ether to give a white solid
(8.5 g, 68%). .sup.1H-NMR (DMSO): 1.05-1.2 (m, 1H); 1.5-1.75 (m,
3H); 1.87-2.05 (m, lH); 2.4-2.55 (m, 3H); 2.57-2.75 (m, 1H); 2.982
(d, J=11.7, 1H); 3.97 (d, J=12.0, 1H); 7.136 (d, J=7.0, 2H); 7.184
(d, J=7.0, 1H), 7.296 (t, J=7.2, 2H); 8.89 (bs, 1H); 9.15 (bs,
1H).
[0467] 5-[(3-Benzyl)-1-piperidinyl]valeric acid methyl ester. To a
solution of 3-benzylpiperidine hydrochloride (2 g, 9.4 mmol) in DMF
(40 mL) were added methyl 5-bromovalerate (1.6 mL, 11.3 mmol) and
potassium carbonate (3.2 g, 23.6 mmol). This heterogeneous mixture
was heated at 110.degree. C. for lhr then cooled at 25.degree. C.,
diluted with water (200 mL) and diethyl ether (200 mL). The aqueous
solution was extracted with diethyl ether (100 mL) and the
collected organic phase was washed with brine (200 mL), dried and
concentrated in vacuum. The crude compound was purified by silica
gel column chromatography using CH.sub.2Cl.sub.2/MeOH as eluant to
afford the title compound as an oil (1.76 g, 65%). .sup.1H-NMR
(CDCl.sub.3): 0.8-1.0 (m, 1H); 1.4-1.7 (m, 8H); 1.8-1.95 (m, 2H);
2.25-2.35 (m, 4H); 2.4-2.6 (m, 2H); 2.75-2.9 (m, 2H); 3.65 (s, 3H);
7.132 (d, J=7.0, 2H); 7.186 (d, J=7.2, 1H); 7.264 (t, J=7.2,
2H).
EXAMPLE 35
Preparation of 4-(3-Benzylpiperidinyl)butyric acid ethyl ester
[0468] From 3-benzylpiperidine hydrochloride (0.7 g, 4.0 mmol),
ethyl 4-bromobutyrate (0.685 mL, 4.8 mmol) and potassium carbonate
(1.1 g, 8.0 mmol) there was obtained the title compound as an oil
(0.75 g, 65%). .sup.1H-NMR (CDCl.sub.3): 0.8-1.0 (m, 1H); 1.241 (t,
J=7.2, 3H); 1.4-2.0 (m, 6H); 1.791 (t, J=7.5, 2H); 2.296 (t, J=7.5,
4H); 2.4-2.6 (m, 2H); 2.7-2.9 (m, 2H); 4.112 (q, J=7.2, 2H);
7.1-7.3 (m, 5H).
EXAMPLE 36
Preparation of 3-Benzyl-1-(5-hydroxypentyl)piperidine
[0469] To a solution of 4-[(3-benzyl)-1-piperidinyl]valeric acid
ethyl ester (0.96 g, 3.31 mmol) in THF dry (20 mL) were added
portionwise LiAlH.sub.4 (0.38 g, 9.95 mmol). The resulting mixture
was stirred at 25.degree. C. for 2 hrs then diluted with NH.sub.4Cl
(sat. solution, 50 mL) and extracted with ethyl acetate (3.times.30
mL). The collected organic phases were washed with brine (50 mL),
dried and concentrated in vacuum. The crude compound was purified
by filtration on silica gel (260-400 mesh) using
CH.sub.2Cl.sub.2/MeOH 8/2 as solvent to give the title compound as
an oil (0.70 g, 81%). .sup.1H-NMR (CDCl.sub.3): 0.8-1.0 (m, 1H);
1.3-1.45 (m, 2H); 1.45-1.75 (m, 9H); 1.8-2.0 (m, 2H); 2.25-2.4 (m,
2H); 2.4-2.6 (m, 2H); 2.78-2.93 (m, 2H); 3.607 (t, J=6.3, 2H);
7.136 (d, J=7.2, 2H); 7.186 (d, J=6.9, 1H); 7.264 (t, J=7.2,
2H).
EXAMPLE 37
Preparation of 3-Benzyl-1-(4-hydroxybutyl)piperidine
[0470] From 4-[(3-benzyl)-1-piperidinyl]-butyric acid ethyl ester
(0.45 g, 1.55 mmol) and LiAlH.sub.4 (0.18 g, 4.6 mmol) there was
obtained the title compound as an oil (0.360 g, 94%). .sup.1H-NMR
(CDCl.sub.3): 0.85-1.05 (m, 1H); 1.5-1.8 (m, 9H); 1.85-2.0 (m, 2H);
2.3-2.4 (m, 2H); 2.4-2.6 (m, 2H); 2.85-3.0 (m, 2H); 3.45-3.6 (m,
2H); 7.133 (d, J=7.2, 2H); 7.186 (d, J=7.2, 1H); 7.261 (t, J=7.2,
2H).
EXAMPLE 38
Preparation of 1-Allyl-2-benzylpiperidine, hydrobromide (A) and
2-benzyl-1,1-diallylpiperidinium iodide (B)
[0471] A mixture of 2-benzylpiperidine hydrochloride (500 mg, 2.36
mmol), K.sub.2CO.sub.3 (652 mg, 4.72 mmol) and allyl iodide (595
mg, 3.54 mmol) in CH.sub.3CN (25 mL) was stirred at reflux under
N.sub.2 for 24 h. The reaction was allowed to cool to room
temperature and was added to 5% aqueous HCl (100 mL). The resulting
cloudy solution was extracted with CHCl.sub.3 (3.times.50 mL). The
extract was washed with 10% aqueous NH.sub.4OH (2.times.50 mL) and
water (2.times.50 mL), filtered through cotton and the solvent
removed in vacuo to give an oil which partially solidified upon
standing. The mixture was washed with hexanes (3.times.2 mL) to
give a solid (vide infra) and a hexanes soluble portion. The
hexanes were removed in vacuo to give an oil. Purification was
effected by silica gel chromatography (CHCl.sub.3 elution) to give
a cloudy amber oil. This was dissolved in MeOH (5 mL, cloudy
solution), filtered through celite (clear solution) and the MeOH
removed in vacuo to yield a clear amber oil (129 mg, 25%); .sup.1H
NMR (CDCl.sub.3) .delta.1.13-1.70 (m, 6 H), 2.25-2.65 (m, 3 H),
2.78-2.89 (m, 1 H), 3.08-3.28 (m, 2 H), 3.45 (dd, J.sub.1=8.4 Hz,
J.sub.2=14 Hz, 1 H), 5.15-5.29 (m, 2 H), 5.90-6.06 (m, 1 H),
7.08-7.32 (m, 5 H)
[0472] The hydrobromide salt; mp 112-114.degree. C.; .sup.1H NMR
(CDCl.sub.3) .delta.1.12-4.00 (m, 13 H), 5.51-5.19 (m, 2 H),
6.03-6.50 (m, 1 H), 7.11-7.38 (m, 5 H), 11.42 (bs, 1 H).
[0473] Analytical sample; mp 116-117.5.degree. C. Anal. Calcd. for
C,.sub.5H.sub.22BrN: C, 60.81; H, 7.48; N, 4.73. Found: C, 60.82;
H, 7.65; N, 4.73.
[0474] The solid obtained from the hexanes wash (vide supra) was
crystallized from acetone to yield colorless cubes (210 mg, 23%);
mp 179-180.degree. C.; .sup.1H NMR (CDCl.sub.3) .delta.1.30-1.50
(m, 1 H), 1.75-2.11 (m, 5 H), 2.86 (t, J=12 Hz, 1 H), 3.33-3.75 (m,
4 H), 4.08-4.19 (m, 1 H), 4.32-4.51 (m, 2 H), 4.88-4.99 (m, 1 H),
5.72-5.86 (m, 2 H), 5.93-6.28 (m, 4 H), 7.13-7.35 (m, 5 H).
[0475] An analytical sample was dried in vacuo (0.005 Torr,
100.degree. C.); mp 180-181.5.degree. C. Anal. Calcd for
C.sub.18H.sub.26IN: C, 56.40; H, 6.84; N, 3.65. Found: C, 56.33; H,
6.84; N, 3.62.
EXAMPLE 39
Preparation of 2-Benzyl-1-cyclopropylmethyl piperidine,
hydrobromide
[0476] From 2-benzylpiperidine hydrochloride (500 mg, 2.36 mmol),
K.sub.2CO.sub.3 (652 mg, 4.72 mmol) and bromomethylcyclopropane
(478 mg, 3.54 mmol) in CH.sub.3CN (25 mL) there was obtained the
free base as a light amber, clear oil (320 mg, 59%, pure by TLC,
and .sup.1H NMR); .sup.1H NMR (CDCl.sub.3) .delta.0.15 (q, J=4.8
Hz, 2 H), 0.45-0.59 (m, 2 H), 0.85-1.03 (m, 1 H), 1.12-1.32 (m, 2
H), 1.38-1.75 (m, 4 H), 2.39-2.55 (m, 3 H), 2.58-2.73 (m, 2 H),
2.96-3.08 (m, 1 H), 3.12 (dd, J.sub.1=13 Hz, J.sub.2=3.6 Hz, 1 H),
7.13-7.31 (m, 5 H).
[0477] The hydrobromide salt; mp 140-143.degree. C.; .sup.1H NMR
(CDCl.sub.3) .delta.0.32-3.78 (m, 18 H), 7.14-7.36 (m, 5 H), 11.24
(bs, 1 H).
[0478] Analytical sample; mp 143-145.degree. C. Anal. Calcd. for
C.sub.16H.sub.24BrN: C, 61.94; H, 7.80; N, 4.51. Found: C, 62.22;
H, 7.80; N, 4.46.
EXAMPLE 40
Preparation of 5-(4-Benzylpiperidinyl)valeric acid (59)
[0479] To a solution of 5-[(4-benzylpiperidine)-1-yl]valeric acid
methyl ester (0.5 g, 1.73 mmol) in MeOH (8 mL) was added 2N NaOH
(1.73 mL, 3.45 mmol). The resulting solution was heated at reflux
for 2 h then neutralized with 5% HCl and concentrated in vacuum.
The crude mixture was triturated with CH.sub.2Cl.sub.2/MeOH 1/1 (12
mL) for 1 h. The resulting solid was further triturated with
diethyl ether (10 mL) for 20 h to give the title compound as a
white solid (0.37 g, 78%), mp 148-151.degree. C. .sup.1H-NMR
(DMSO): 1.3-1.5 (m, 4H), 1.5-1.5 (m, 5H), 2.19 (t, J=7.0, 2H),
2.4-2.5 (m, 2H), 2.56 (t, J=11.4, 2H), 2.79 (t, J=7.6, 2H), 3.19
(d, J=11.7, 2H), 7.1-7.2 (m, 3H), 7.25 (t, J=7.2, 2H).
EXAMPLE 41
Preparation of 4-(4-Benzylpiperidinyl)butyric acid ethyl ester
hydrobromide salt
[0480] From 4-benzylpiperidine (1.0 mL, 5.7 mmol), ethyl
4-bromobutyrate (0.898 mL, 6.27 mmol) and potassium carbonate (1.6
g, 11.4 mmol) there was obtained free base as an oil (1.25 g, 76%).
.sup.1H-NMR (CDCl.sub.3): 1.24 (t, J=7.2, 3H), 1.26-1.4 (m, 2H),
1.45-1.60 (m, 1H), 1.63 (bd, J=12.9, 2H), 1.75-1.95 (m, 4H),
2.25-2.40 (m, 4H), 2.53 (d, J=6.9, 2H), 2.90 (bd, J=11.4, 2H), 4.11
(q, J=7.2, 2H), 7.13 (bd, J=7.2, 2H), 7.19 (d, J=6.9, 1H), 7.27 (t,
J=7.2, 2H).
[0481] The HBr salt; mp 159-160.degree. C. .sup.1H-NMR (DMSO):
1.3-1.45 (m, 2H), 1.6-1.85 (m, 5H), 2.461 (t, J=7.2, 2H), 2.4-2.6
(m, 3H), 2.7-2.9 (m, 2H), 2.9-3.1 (m, 2H), 3.2-3.5 (m, 6H), 7.1-7.3
(m, 5H), 9.0 (bs, 1H).
EXAMPLE 42
Preparation of 4-(4-Benzylpiperidinyl)butyric acid
[0482] From 4-[(4-benzyl)-piperidine)-1-yl]butyric acid ethyl ester
(0.3 g, 1.036 mmol) there was obtained the title compound as a
white solid (0.24 g, 89%); mp=154.degree. C. .sup.1H-NMR (DMSO):
1.07-1.25 (m, 2H), 1.4-1.65 (m, 5H), 1.954 (t, J=11.4, 2H), 2.04
(s, 1H), 2.195 (t, J=6.6, 2H), 2.35 (t, J=6.6, 2H), 2.4-2.5 (m,
2H), 2.88 (bd, J=11.4, 2H), 7.06-7.18 (m, 3H), 7.23 (t, J=7.5,
2H).
EXAMPLE 43
Preparation of 5-(4-Benzylpiperidinyl)valeronitrile
[0483] From 4-benzylpiperidine (2.0 mL, 11 mmol),
5-bromovaleronitrile (2 g, 12 mmol) and potassium carbonate (3.1 g,
22 mmol) there was obtained the title compound as an oil (2.47 g,
85%). .sup.1H-NMR (CDCl.sub.3): 1.2-1.4 (m, 2H), 1.45-1.6 (m, 1H),
1.55-1.75 (m, 6H), 1.866 (t, J=11.4, 2H), 2.25-2.45 (m, 4H), 2.53
(d, J=6.9, 2H), 2.88 (bd, J=11.4, 2H), 7.134 (d, J=7.2, 2H), 7.193
(d, J=7.2, 1H), 7.274 (t, J=7.2, 2H).
EXAMPLE 44
Preparation of 4-Benzyl-1-(5-aminopentyl)piperidine
hydrochloride
[0484] To a solution of 5-[(4-benzylpiperidine)-1-yl]valeronitrile
(0.8 g, 3.12 mmol) in ethanol (50 mL) and conc. HCl (1.5 mL) was
added platinum dioxide (0.15 g). The resulting mixture was
hydrogenated in a Parr hydrogenator at 30 psi for 2 h, then
filtered through a pad of celite and concentrated in vacuum to
afford the title compound as a hygroscopic salt (0.7 g, 67%), mp
200.degree. C. dec. .sup.1H-NMR (D.sub.2O): 1.3-1.55 (m, 4H),
1.6-1.8 (m, 4H), 1.87 (bd, J=13.2 Hz, 2H), 2.60 (d, J=6.6 Hz, 2H),
2.85 (t, J=12.6 Hz, 2H), 2.91-3.10 (m, 4H), 3.51 (d, J=12.3 Hz,
2H), 7.2-7.3 (m, 3H), 7.344 (t, J=7.2 Hz, 2H).
EXAMPLE 45
Preparation of
4-Benzyl-1-(3-p-toluenesulfonyloxypropyl)-piperidine
[0485] To a solution of 4-benzyl-1-(3-hydroxypropyl)piperidine (1.0
g, 4.29 mmol) in CH.sub.2Cl.sub.2 (20 mL) were added TEA (1.2 mL,
8.57 mmol) and dropwise a solution of p-toluenesulfonyl chloride
(1.22 g, 6.4 mmol) in CH.sub.2Cl.sub.2 (10 mL). The resulting
solution was stirred at 25.degree. C. for 2 h then diluted with
CH.sub.2Cl.sub.2 (60 mL) and washed with NH.sub.4Cl (2.times.100
mL), dried and concentrated in vacuum to afford the crude
intermediate, which was purified by trituration with EtOAc (10 mL)
to give the title compound as a white solid (0.63 g, 38%), mp
143-145.degree. C. .sup.1H-NMR (CDCl.sub.3): 1.2-1.45 (m, 2H),
1.65-1.85 (m, 3H), 2.319 (s, 3H), 2.502 (d, J=7.2 Hz, 2H), 2.6-2.8
(m, 2H), 3.338 (t, J=12.6 Hz, 2H), 3.875 (d, J=12.6, 2H), 4.277 (t,
J=8.1 Hz, 2H), 4.421 (t, J=8.4 Hz, 2H), 7.064 (d, J=7.2 Hz, 2H),
7.122 (d, J=7.8 Hz, 2H), 7.15-7.30 (m, 3H), 7.76 (d, J=7.8 Hz,
2H).
EXAMPLE 46
Preparation of 4-Benzyl-1-(3-azidopropyl)piperidine
[0486] Sodium azide was added to a solution of
4-benzyl-1-(3-p-toluenesulf- onyloxypropyl)piperidine (0.216 g,
0.56 mmol) in DMF (5 mL). The resulting solution was stirred at
80.degree. C. for 3 h then cooled at 25.degree. C., diluted with
water (50 mL) and extracted with diethyl ether (2.times.50 mL). The
collected organic phase was washed with water (2.times.50 mL),
dried and concentrated in vacuum to afford crude title compound as
an oil (0.15 g). .sup.1H-NMR (CDCl.sub.3): 1.2-1.4 (m, 2H), 1.4-1.6
(m, 1H), 1.628 (dd, J=13.2 Hz, 2H), 1.761 (t, J=7.2 Hz, 2H), 1.857
(t, J=11.4 Hz, 2H), 2.367 (t, J=7.2 Hz, 2H), 2.53 (d, J=7.2 Hz,
2H), 2.86 (bd, J=11.4, 2H), 3.314 (t, J=6.9 Hz, 2H), 7.14 (d, J=7.5
Hz, 2H), 7.19 (d, J=6.9, 1H), 7.275 (t, J=7.2 Hz, 2H).
EXAMPLE 47
Preparation of 4-Benzyl-1-(3-aminopropyl)piperidine (68).
[0487] To a solution of 4-benzyl-1-(3-azidopropyl)piperidine (0.14
g, 0.54 mmol) in methanol (5 mL) was added Pd/C 5% (6 mg) and the
resulting heterogeneous mixture was hydrogenated at 1 atm for 4 h.
then filtered through a celite pad and concentrated in vacuum. The
crude compound was purified by trituration with diethyl ether (5
mL) to give the title compound as a white solid (0.075 g, 60%), mp
140-141.degree. C. .sup.1H-NMR (DMSO): 1.05-1.21 (m, 2H), 1.35-1.55
(m, 3H), 1.55-1.70 (m, 2H), 1.746 (t, J=11.1 Hz, 2H), 2.281 (t,
J=6.6 Hz, 2H), 2.4-2.5 (m, 2H), 2.5-2.85 (m, 4H), 7.06-7.18 (m,
3H), 7.23 (t, J=7.2 Hz, 2H), 7.8 (bs, 2H).
EXAMPLE 48
Preparation of 1-(4-phenoxybutyl)-2-hydroxymethylpiperidine,
hydrobromide (78)
[0488] From 2-hydroxymethylpiperidine (1.00 g, 8.68 mmol,
K.sub.2CO.sub.3 (1.32 g, 9.55 mmol) and 4-phenoxybutyl bromide
(9.94 g, 43.4 mmol, in CH.sub.3CN (50 mL) there was obtained the
free base as a clear amber oil (1.52 g, 67%); .sup.1H NMR
(CDCl.sub.3) .delta.1.20-1.90 (m, 10 H), 2.19-3.06 (m, 6 H),
3.40-3.50 (m, 1 H), 3.75 (dd, J.sub.1=10.5 Hz, J.sub.2=4.2 Hz, 1H),
3.97 (t, J=6.3 Hz, 2 H), 6.85-6.94 (m, 3 H), 7.23-7.32 (m, 2
H).
[0489] The hydrobromide salt; mp 113-115.degree. C.; .sup.1H NMR
(CDCl.sub.3) .delta.1.42-2.32 (m, 10 H), 2.80-4.49 (m, 10 H),
6.83-7.32 (m, 5 H), 9.95 (bs, 1 H).
[0490] Analytical sample; mp 114.5-116.5.degree. C. Anal. Calcd for
C.sub.16H.sub.26BrNO.sub.2: C, 55.82; H, 7.61; N, 4.07. Found: C,
55.72; H, 7.70; N, 3.95.
EXAMPLE 49
1-(2-(4-Fluorophenoxy)ethyl)-2-(hydroxymethyl)piperidine
hydrobromide
[0491] From 2-hydroxymethylpiperidine (500 mg, 4.34 mmol) and
2-(4-fluorophenoxy)ethyl bromide (999 mg, 4.56 mmol) there was
obtained a colorless oil (970 mg, 88%): .sup.1H NMR (CDCl.sub.3) d
1.60-2.11 (m, 6 H), 2.67-3.59 (m, 6 H), 3.80 (dd, J.sub.1=11 Hz,
J.sub.2=3.9 Hz, 1 H), 4.15 (dd, J.sub.1=11 Hz, J.sub.2=3.9 Hz, 1 H)
4.37-4.42 (m, 2 H), 7.13-7.35 (m, 4 H). The hydrobromide was
obtained as a colorless powder (1.08 g, 96%): mp
103.5-105.5.degree. C.; Anal. Calcd for
C.sub.14H.sub.21BrFNO.sub.2: C, 50.31; H, 6.33; N, 4.19. Found: C,
50.39; H, 6.15; N, 3.99.
EXAMPLE 50
DL-3-Phenoxypropyl-1-(3-phenoxypropyl)pipecolinate,
hydrobromide
[0492] From DL-pipecolinic acid (1.00 g, 7.74 mmol),
K.sub.2CO.sub.3 (2.20 g, 15.9 mmol) and 3-phenoxypropyl bromide
(1.75 g, 8.13 mmol) in DMF (25 mL) there was obtained an oil (800
mg, 25%): .sup.1H NMR (CDCl.sub.3) d 1.61-2.61 (m, 11 H), 2.75-2.88
(m, 1 H), 2.99-3.11 (m, 1 H), 3.38-3.51 (m, 2 H), 4.22-4.40 (m, 4
H), 4.65 (t, J=6.0 Hz, 2 H), 7.17-7.32 (m, 6 H), 7.60 (t, J=7.5 Hz,
4 H); The hydrobromide was obtained as a colorless powder (825 mg,
97%): mp 94-96.degree. C.; HRMS calcd for C.sub.24H.sub.31NO.sub.4
397.2253, found 397.2265.
EXAMPLE 51
(s)-2-(Hydroxymethyl)-1-(3-phenoxypropyl)pyrrolidine
hydrobromide
[0493] From (s)-(+)-2-pyrrolidinemethanol (1.00 g, 9.89 mmol) and
3-phenoxypropyl bromide (2.23 g, 10.4 mmol) there was obtained a
pale yellow oil (1.01 g, 43%): 1H NMR (CDCl.sub.3) d 1.60-2.10 (m,
6 H), 2.20-2.75 (m, 4 H), 2.80-3.05 (m, 1 H), 3.15-3.25 (m, 1 H),
3.37 (d, J=9.0 Hz, 1 H), 3.64 (dd, J.sub.1=10 Hz, J.sub.2=3.3 Hz, 1
H), 4.04 (t, J=6.3 Hz, 2 H), 6.87-6.98 (m, 3 H), 7.23-7.32 (m, 2
H). The hydrobromide was obtained as a colorless solid (820 mg,
61%): mp 100-101.5.degree. C.; Anal. Calcd for
C.sub.14H.sub.22BrNO.sub.2: C, 53.17; H, 7.01; N, 4.42. Found: C,
53.27; H, 6.72; N,, 4.28.
EXAMPLE 52
Preparation of 3-benzyl-1-(3-phenoxypropyl)piperidine
hydrobromide
[0494] From 3-benzyl piperidine (0.2 g, 1.14 mmol),
2-phenoxypropylbromine (0.27 ml, 1.7 mmol) and potassium carbonate
(0.315 g, 2.28 mmol) there was obtained the free amine as an oil
(0.306 g, 87%). .sup.1H NMR (CDCl.sub.3): 0.9-1.1 (m, 1H), 1.5-1.8
(m, 4H), 2.4-2.65 (m, 4H), 2.867 (t, J=10.5 Hz, 2H), 4.01 (m, 2H),
6.85-7.0 (m, 3H), 7.15-7.35 (m, 7H).
[0495] The HBr salt was obtained as a white solid; m.p.
148-149.degree. C. .sup.1H NMR (CDCl.sub.3): 1.05-1.15 (m, 1H),
1.8-2.0 (m, 2H), 2.3-2.7 (m, 7H), 2.7-2.9 (m, 1H), 3.1-3.3 (m, 2H),
3.4-3.55 (m, 1H), 3.623 (d, J=10.8 Hz, 1H), 4.0-4.15 (m, 2H), 6.83
(d, J=8.1 Hz, 2H), 6.967 (t, J=7.5 Hz, 1H), 7.146 (d, J=6.9 Hz,
2H), 7.2-7.35 (m, 5H), 11.32 (bs, 1H). MS (m/z): 309, 307, 188, 91.
Anal. Calcd. for C.sub.21H.sub.28BrNO; C, 64.6; H, 7.0; N, 3.6;
Found: C, 64.28; H, 7.26; N, 3.50.
EXAMPLE 53
Preparation of 3-benzyl-1-(2-phenoxyethyl)piperidine
hydrobromide
[0496] From 3-benzyl piperidine (0.2 g, 1.14 mmol),
1-p-toluenesulfonate-2-phenoxyethane (0.4 g, 1.3 mmol) and
potassium carbonate (0.315 g, 2.28 mmol) there was obtained the
free amine as an oil (0.22 g, 64%). .sup.1H NMR (CDCl.sub.3):
0.9-1.05 (m, 1H), 1.5-1.8 (m, 3H), 1.8-2.0 (m, 2H), 2.088 (t,
J=11.1 Hz, 1H), 2.52 (dd, J=6.9 & 6.3 Hz, 2H), 2.7-2.9 (m, 2H),
2.9-3.0 (m, 2H), 4.084 (t, J=6.0 Hz, 2H), 6.88 (d, J=8.1 Hz, 2H),
6.94 (t, J=7.2 Hz, 1H), 7.143 (d, J=7.2 Hz, 2H), 7.19 (d, J=6.9 Hz,
1H), 7.2-7.35 (m, 4H).
[0497] The HBr salt was obtained as a white solid (0.148 g, 60%).
m.p. 93-94.degree. C. .sup.1H NMR (CDCl.sub.3): 1.0-1.23(m, 1H),
1.8-2.0(m, 2H), 2.2-2.8(m, 5H), 2.59(d, J=6.9 Hz, 1H), 3.3-3.5(m,
2H), 3.56(d, J=11.4 Hz, 1H), 3.68(d, J=10.5 Hz, 1H), 4.5-4.63(m,
2H), 6.84(d, J=7.8 Hz, 2H), 7.014(t, J=7.5 Hz, 1H), 7.13(d, J=6.9
Hz, 2H), 7.15-7.35(m, 5H), 11.55(bs, 1H). MS (m/z): 295, 188, 91.
Calcd. for C.sub.20H.sub.26BrNO; C, 43.8; H, 6.7; N, 3.72; Found:
C, 63.63; H, 6.76; N, 3.73.
EXAMPLE 54
Preparation of 3-benzyl-1-(4-phenylbutyl)piperidine
hydrobromide
[0498] From 3-benzyl piperidine (0.3 g, 1.7 mmol),
1-p-toluenesulfonate-4-- phenylbutane (0.781 g, 2.56 mmol) and
potassium carbonate (0.473 g, 3.42 mmol) there was obtained the
free amine as an oil (0.313 g, 60%). .sup.1H NMR (CDCl.sub.3):
0.7-1.0 (m, 1H), 1.4-1.7 (m, 8H), 1.7-2.0 (m, 2H), 2.317 (bs, 2H),
2.4-2.7 (m, 4H), 2.7-2.9 (m, 2H), 7.1-7.35 (m, 10H).
[0499] The HBr salt was obtained as a solid; m.p. 105-107.degree.
C. .sup.1H NMR (CDCl.sub.3): 1.0-1.2 (m, 1H), 1.55-1.6 (m, 4H),
1.80-2.0 (m, 4H), 2.15-3.0 (m, 11H), 3.389 (d, J=11.1 Hz, 1H), 3.51
(bd, J=9.6 Hz, 1H), 7.0-7.5 (m, 10H), 11.2 (bs, 1H). MS (m/z): 307,
188, 91. Anal, Calcd. for C.sub.21H.sub.30BrN; C, 68.00; H, 7.5; N,
3.6; Found: C, 67.68; H, 7.69; N, 3.44.
EXAMPLE 55
Preparation of 3-benzyl-1-(2-phenylethyl)piperidine
hydrobromide
[0500] From 3-benzylpiperidine (0.2 g, 1.14 mmol),
2-bromoethylbenzene (0.23 mL, 1.7 mmol) and potassium carbonate
(0.315 g, 2.28 mmol) there was obtained the free amine as an oil
(0.313 g, 98%). .sup.1H NMR (CDCl.sub.3): 0.95-1.1 (m, 1H), 1.4-1.8
(m, 4H), 1.9-2.1 (m, 2H), 2.4-2.5 (m, 4H), 2.5-3.1 (m, 4H),
7.1-7.32 (m, 10H).
[0501] HBr salt was obtained as a solid; m.p. 137-142.degree. C.
.sup.1H NMR (CDCl.sub.3): 1.0-1.3 (m, 3H), 1.7-2.0 (m, 2H), 2.2-2.5
(m, 2H), 2.5-2.65 (m, 2H), 2.7-2.9 (m, 1H), 3.1-3.4 (m, 4H), 3.622
(d, J=11.1 Hz, 1H), 7.0-7.5 (m, 10H), 11.47 (bs, 1H). MS (m/z):
278, 188, 124, 91. Analysis, Calcd. for C.sub.20H.sub.26BrN; C,
66.6; H, 7.0; N, 3.9; Found: C, 66.66; H, 7.13; N, 3.73.
EXAMPLE 56
Preparation of
1-p-toluenesulfonate-2-(3-trifluoromethylphenyl)ethane
[0502] To a solution of 3-trifluoromethylphenethyl alcohol (1.0 g,
5.2 mmol) in CH.sub.2Cl.sub.2 (30 mL) were added Et.sub.3N (1.5 mL,
10.5 mmol) and dropwise a solution of p-toluenesulfonyl chloride
(1.5 g, 7.9 mmol) in CH.sub.2Cl.sub.2 (20 mL). The resulting
solution was stirred at 25.degree. C. for 3 h then diluted with
CH.sub.2Cl.sub.2 (50 mL) and washed with HCl 5% (2.times.100 mL),
brine (100 mL), dried and concentrated in vacuum. The crude
compound was purified by flash-chromatography on silica gel using
EtOAc/n-hexane as eluant to afford the title compound as an oil
(1.68 g, 94%). .sup.1H NMR(CDCl.sub.3): 2.42 (s, 3H), 3.01 (t,
J=6.6 Hz, 2H), 4.24 (t, J=6.9 Hz, 2H), 7.26 (d, J=8.1 Hz, 2H), 7.32
(d, J=6.3 Hz, 2H), 7.378 (t, J=7.8 Hz, 1H), 7.504 (d, J=7.5 Hz,
1H), 7.65 (d, J=8.1 Hz, 2H).
EXAMPLE 57
Preparation of
3-benzyl-1-[2-(3-trifluoromethylphenyl)ethyl]piperidine
hydrobromide
[0503] From 3-benzylpiperidine hydrochloride (0.2 g, 0.94 mmol),
1-p-toluenesulfonate-2-(3-trifluoromethylphenyl)ethane (0.45 g,
1.32 mmol) and potassium carbonate (0.25 g, 1.9 mmol) there was
obtained the free amine as an oil (0.23 g, 70%). NMR(CDCl.sub.3):
0.9-1.1 (m, 1H), 1.5-1.8 (m, 4H), 1.83-2.1 (m, 2H), 2.4-2.6 (m,
4H), 2.7-3.0 (m, 4H), 7.163 (d, J=7.5 Hz, 2H), 7.20 (d, J=6.9 Hz,
1H), 7.24-7.48 (m, 6H).
[0504] The HBr salt was obtained as a solid; m.p. 152-154.degree.
C. .sup.1H NMR (DMSO): 1.0-1.2 (m, 1H), 1.55-1.75 (m, 2H),
1.75-1.90 (m, 1H), 1.95-2.1 (m, 1H), 2.53 (d, J=6.6 Hz, 2H), 2.68
(q, J=11.7 Hz, 1H), 2.75-2.4 (m, 1H), 2.95-3.15 (m, 2H), 3.2-3.4
(m, 3H), 3.39 (d, J=10.8 Hz, 1H), 3.53 (d, J=11.1 Hz, 1H), 7.16 (d,
J=7.5 Hz, 2H), 7.207 (d, J=6.9 Hz, 1H), 7.289 (t, J=7.2 Hz, 2H),
7.5-7.65 (m, 2H), 7.649 (s, 1H), 9.4 (bs, 1H). MS (m/z): 347, 254,
188, 91. Anal., Calcd. for C.sub.21H.sub.25BrF.sub.3N: C, 58.88; H,
5.88; N, 3.27; Found: C, 58.49; H, 5.90; N, 3.46.
EXAMPLE 58
Preparation of 4-tert-butoxycarbonylaminophenethyl alcohol
[0505] To a solution of 4-aminophenethyl alcohol (1.0 g, 7.3 mmol)
in THF (30 mL) was added di-tert-butyl dicarbonate (2.0 g, 9.5
mmol) and the resulting solution was stirred at 25.degree. C. for
24 h; then the solution was concentrated under vacuum and purified
by filtration on silica gel using ethyl acetate/n-hexane as eluant
to afford the title compound as a white solid (1.63 g, 94%). m.p.
108.degree. C. .sup.1H NMR (CDCl.sub.3): 1.513 (s, 9H), 2.813 (t,
J=6.6 Hz, 2H), 3.817 (d, J=5.1 Hz, 2H), 6.47 (bs, 1H), 7.145 (d,
J=8.4 Hz, 2H), 7.30 (d, J=8.1 Hz, 2H).
EXAMPLE 59
Preparation of
1-p-toluenesulfonate-2-(4-tertbutoxycarbonylaminophenyl)eth-
ane
[0506] To a solution of 4-tert-butoxycarbonylaminophenethyl alcohol
(1.56 g, 6.57 mmol) in CH.sub.2Cl.sub.2 (50 mL) were added
Et.sub.3N (1.8 mL, 13.0 mmol) and dropwise a solution of
p-toluenesulfonyl chloride (1.63 g, 8.54 mmol) in CH.sub.2Cl.sub.2
(30 mL). The resulting solution was stirred at 25.degree. C. for 3
h then diluted with CH.sub.2Cl.sub.2 (50 mL) and washed with HCl 5%
(2.times.100 mL), brine (100 mL), dried and concentrated in vacuum.
The crude compound was purified by flash-chromatography on silica
gel using EtOAc/n-hexane as eluant to afford the title compound as
a white solid (1.95 g, 76%). m.p. 102-104.degree. C. .sup.1H NMR
(CDCl.sub.3): 1.514 (s, 9H), 2.429 (s, 3H), 2.889 (t, J=7.2 Hz,
2H), 4.162 (t, J=7.2 Hz, 2H), 6.438 (bs, 1H), 7.012 (d, J=8.4 Hz,
2H), 7.232 (d, J=8.4 Hz, 2H), 7.28 (d, J=8.7 Hz, 2H), 7.68 (d,
J=8.1 Hz, 2H).
EXAMPLE 60
Preparation of
3-benzyl-1-[2-(4-tertbutoxycarbonylaminophenyl)ethyl]piperi-
dine
[0507] From 3-benzylpiperidine hydrochloride (0.44 g, 2.08 mmol),
1-p-toluenesulfonate-2-(4-tertbutoxycarbonylaminophenyl)ethane
(1.06 g, 2.7 mmol) and potassium carbonate (0.56 g, 4.16 mmol)
there was obtained the title compound as a foam (0.67 g, 82%);
.sup.1H NMR (CDCl.sub.3): 0.85-1.02 (m, 1H), 1.50 (s, 9H), 1.4-1.6
(m, 1H), 1.62-1.80 (m, 3H), 1.82-2.02 (m, 2H), 2.45-2.60 (m, 4H),
2.65-2.80 (m, 2H), 2.80-3.0 (m, 2H), 6.405 (bs, 1H), 7.05-7.35 (m,
9H).
EXAMPLE 61
Preparation of 3-benzyl-1-[2-(4-aminophenyl)ethyl]piperidine
hydrobromide
[0508]
3-benzyl-1-[2-(4-tert-butoxycarbonylaminophenyl)ethyl]piperidine
(0.67 g, 1.69 mmol) was dissolved in HBr (saturated solution in
methanol, 10 mL) and the resulting solution stirred at 25.degree.
C. for 20 h. Then, after concentration in vacuum, the resultant
mixture was treated with NaHCO.sub.3(water saturated solution, 50
mL) and extracted twice with EtOAc (2.times.50 mL). The collected
organic phase was washed with brine (50 mL), dried and concentrated
in vacuum. The crude compound was purified by filtration on silica
gel using CH.sub.2Cl.sub.2/MeOH as eluant to afford the free amine
as a pale yellow oil (0.272 g, 55%). .sup.1H NMR (CDCl.sub.3):
0.85-1.05 (m, 1H), 1.5-1.9 (m, 4H), 1.9-2.1 (m, 2H), 2.4-2.6 (m,
4H), 2.65-2.8 (m, 2H), 2.85-3.05 (m, 2H), 3.53 (bs, 2H), 6.61 (d,
J=8.1 Hz, 2H), 6.97 (d, J=8.1 Hz, 2H), 7.145 (d, J=7.8 Hz, 2H),
7.18 (d, J=7.2, .sup.1H), 7.275 (t, J=7.2 Hz, 2H).
[0509] The HBr salt was obtained as a solid (0.3 g, 75%). m.p. dec.
148.degree. C. .sup.1H-NMR (DMSO): 1.0-1.2 (m, 1H), 1.55-1.7 (m,
2H), 1.7-1.9 (m, 1H), 1.95-2.2 (m, 1H), 2.4-2.6 (m, 2H), 2.55-2.75
(m, 1H), 2.75-2.9 (m, 1H), 2.9-3.1 (m, 2H), 3.15-3.3 (m, 2H),
3.3-3.8 (m, 3H), 7.1-7.4 (m, 9H), 9.45 (bs, 1H). Anal. Calcd. for
C.sub.20H.sub.28Br.sub.2- N.sub.2: C, 52.65; H, 6.19; N, 6.14;
Found: C, 50.62; H, 6.07; N, 5.89.
EXAMPLE 62
Preparation of 1-p-toluenesulfonate-2-(4-chlorophenyl)ethane
[0510] From 4-chlorophenethyl alcohol (2.0 mL, 14.8 mmol),
Et.sub.3N (4.1 mL, 30.0 mmol) and p-toluenesulfonyl chloride (4.2
g, 22.2 mmol) there was obtained the title compound as a white
solid (2.8 g, 61%). 77-79.degree. C. .sup.1H NMR (CDCl.sub.3):
2.439 (s, 3H), 2.909 (t, J=6.6 Hz, 2H), 4.191 (t, J=6.6 Hz, 2H),
7.016 (d, J=8.1 Hz, 2H), 7.19 (d, J=8.4 Hz, 2H), 7.27 (d, J=7.2 Hz,
2H), 7.645 (d, J=8.1 Hz, 2H).
EXAMPLE 63
Preparation of 3-benzyl-1-[2-(4-chlorophenyl)ethyl]piperidine
hydrobromide
[0511] From 3-benzylpiperidine hydrochloride (0.40 g, 1.89 mmol),
1-p-toluenesulfonate-2(4-chlorophenyl)ethane (0.76 g, 2.46 mmol)
and potassium carbonate (0.52 g, 4.72 mmol) there was obtained the
free base as an oil (0.314 g, 54%). .sup.1H NMR (CDCl.sub.3):
0.85-1.05 (m, 1H), 1.45-1.65 (m, 1H), 1.6-1.8 (m, 3H), 1.8-2.0 (m,
2H), 2.4-2.6 (m, 4H), 2.7-3.0 (m, 4H), 7.06-7.32 (m, 9H).
[0512] The HBr salt was obtained as as a white solid; m.p.
143-145.degree. C. .sup.1H NMR (DMSO): 1.0-1.2 (m, 1H), 1.5-1.7 (m,
2H), 1.75-1.9 (m, 1H), 1.9-2.1 (m, 1H), 2.45-2.55 (m, 1H), 2.6-3.0
(m, 4H), 3.1-3.3 (m, 3H), 3.3-3.43 (m, 1H), 3.505 (d, J=11.7 Hz,
1H), 7.146 (d, J=7.5 Hz, 2H), 7.18-7.33 (m, 5H), 7.36 (d, J=8.4 Hz,
2H), 9.3 (bs, 1H). MS (m/z): 313, 188, 91. Anal. Calcd. for
C.sub.20H.sub.25BrClN: C, 60.8; H, 6.1; N, 3.5; Found: C, 60.15; H,
6.61; N, 3.35.
EXAMPLE 64
Preparation of 1-p-toluenesulfonate-2-(4-fluorophenyl)ethane
[0513] From 4-fluorophenethyl alcohol (1.85 mL, 14.8 mmol),
Et.sub.3N (4.1 mL, 30 mmol) and p-toluenesulfonyl chloride (4.2 g,
22.16 mmol) there was obtained the title compound as an oil (3.1 g,
71%). .sup.1H NMR (CDCl.sub.3): 2.434 (s, 3H), 2.919 (t, J=6.9 Hz,
2H), 4.186 (t, J=6.9 Hz, 2H), 6.921 (t, J=8.5 Hz, 2H), 7.06 (dd,
J=8.4 and 5.4, 2H), 7.28 (d, J=8.4 Hz, 2H), 7.67 (d, J=8.1 Hz,
2H).
EXAMPLE 65
Preparation of 3-benzyl-1-[2-(4-fluorophenyl)ethyl]piperidine
hydrobromide
[0514] From 3-benzylpiperidine hydrochloride (0.4 g, 1.89 mmol),
1-p-toluenesulfonate-2-(4-fluorophenyl)ethane (0.723 g, 2.46 mmol)
and potassium carbonate (0.52 g, 4.73 mmol) there was obtained the
free amine as an oil (0.385 g, 67%). .sup.1H NMR (CDCl.sub.3):
0.85-1.1 (m, 1H), 1.45-1.65 (m, 1H), 1.6-1.8 (m, 3H), 1.8-2.0 (m,
2H), 2.4-2.6 (m, 1H), 2.65-2.8 (m, 2H), 2.8-3.0 (m, 2H), 6.944 (t,
J=8.7 Hz, 2H), 7.05-7.23 (m, 5H), 7.273 (t, J=7.2 Hz, 2H).
[0515] The HBr salt was obtained as a solid (0.45 g, 93%). m.p.
137-140.degree. C. .sup.1H NMR (DMSO): 1.0-1.2 (m, 1H), 1.5-1.7 (m,
2H), 1.75-1.9 (m, 1H), 1.9-2.1 (m, 1H), 2.45-2.6 (m, 2H), 2.6-2.72
(m, 1H), 2.73-2.9 (m, 1H), 2.9-3.05 (m, 2H), 3.15-3.3 (m, 2H),
3.45-3.6 (m, 1H), 7.08-7.32 (m, 9H), 9.4 (bs, 1H). Anal., Calcd.
for C.sub.20H.sub.25BrFN: C, 63.49; H, 6.66; N, 3.70; Found: C,
63.11; H, 6.79; N, 3.81.
EXAMPLE 66
Preparation of 1-p-toluenesulfonate-2-(4-methoxyphenyl)ethane
[0516] From 4-methoxyphenethyl alcohol (2.0 g, 13.1 mmol),
Et.sub.3N (3.67 mL, 26.3 mmol) and p-toluenesulfonyl chloride (3.75
g, 19.7 mmol) there was obtained the title compound as a white
solid (1.6 g, 40%). .sup.1H NMR (CDCl.sub.3): 2.432 (s, 3H), 2.890
(t, J=6.9 Hz, 2H), 3.78 (s, 3H), 4.163 (t, J=6.9 Hz, 2H), 6.78 (d,
J=8.4 Hz, 2H), 7.022 (d, J=8.4 Hz, 2H), 7.281 (d, J=8.1 Hz, 2H),
7.691 (d, J=8.1 Hz, 2H).
EXAMPLE 67
Preparation of 3-benzyl-1-[2-(4-methoxyphenyl)ethyl]piperidine
hydrobromide
[0517] From 3-benzylpiperidine hydrochloride (0.4 g, 1.89 mmol),
1-p-toluenesulfonate-2-(4-methoxyphenyl)ethane (0.75 g, 2.46 mmol)
there was obtained the free amine as an oil (0.4 g, 68%) . .sup.1H
NMR (CDCl.sub.3): 0.85-1.1 (m, 1H), 1.5-1.65 (m, 1H), 1.6-1.8 (m,
3H), 1.85-2.0 (m, 2H), 2.4-2.6 (m, 4H), 2.65-2.8 (m, 2H), 2.8-3.0
(m, 2H), 3.781 (s, 3H), 6.816 (d, J=8.4 Hz, 2H), 7.095 (d, J=8.0
Hz, 2H), 7.146 (d, J=7.2 Hz, 2H), 7.195 (d, J=7.2 Hz, 1H), 7.274
(t, J=7.2 Hz, 2H).
[0518] The HBr salt was obtained as a solid (0.22 g, 46%). m.p.
74-78.degree. C. .sup.1H NMR (DMSO): 0.95-1.2 (m, 1H), 1.55-1.73
(m, 2H), 1.75-1.87 (m, 1H), 1.95-2.1 (m, 1H), 2.4-2.6 (m, 3H),
2.6-2.75 (m, 1H), 2.75-3.0 (m, 3H), 3.1-3.25 (m, 1H), 3.45-3.55 (m,
1H), 3.687 (s, 3H), 6.853 (d, J=8.4 Hz, 2H), 7.1-7.24 (m, 5H),
7.283 (t, J=6.9 Hz, 2H), 9.3 (bs, 1H). MS (m/z): 310, 309, 188,
91.
EXAMPLE 68
3-Benzyl-1-(3-phenylpropyl)piperidine hydrobromide
[0519] From 3-benzylpiperidine (500 mg, 2.36 mmol) and
3-phenylpropyl bromide (705 mg, 3.54 mmol) there was obtained a
clear amber oil (315 mg, 46%) (Carter. P. A.; Singh, S. Eur. Pat.
Appl. 435387, Jul. 3, 1991): .sup.1H NMR (CDCl.sub.3) d 0.86-1.00
(m, 1 H), 1.44-1.95 (m, 8 H), 2.25-2.64 (m, 6 H), 2.75-2.89 (m, 2
H), 7.10-7.31 (m, 10 H); The hydrobromide was obtained as a beige
solid (297 mg, 94%): mp 134-136.degree. C.; Recrystallization
(2-butanone/ether) gives a colorless solid, mp 140-141.5.degree. C.
Anal. Calcd for C.sub.21H.sub.28BrN: C, 67.38; H, 7.54; N,3.74.
Found: C, 67.26; H, 7.69; N, 3.72.
EXAMPLE 69
Preparation of 1-benzyl-3-phenyl-3-hydroxypiperidine
[0520] To a solution of 1-benzyl-3-piperidinone (0.193 g, 1.02
mmol) in toluene dry (10 mL) cooled at 0.degree. C. was added a
solution of phenyl magnesium bromide 3.0M in THF (0.48 mL, 1.4
mmol). The resulting solution was maintained at 0.degree. C. for 2
h, then was allowed to warm at 25.degree. C. for 1 h. Water (50 mL)
was added and the mixture was extracted with EtOAc (2.times.50 mL).
The collected organic phase was dried and concentrated under
reduced pressure. The crude compound was purified by flash
chromatography on silica gel using EtOAc/cyclohexane as eluant to
afford the title compound as a white solid (0.235 g, 80%). .sup.1H
NMR (CDCl.sub.3): 1.65-1.85 (m, 3H), 1.9-2.15 (m, 1H), 2.067 (bd,
J=8.1 Hz, 1H), 2.34 (d, J=11.1 Hz, 1H), 2.77 (d, J=11.1 Hz, 1H),
2.95 (bd, J=8.1 Hz, 1H), 3.60 (s, 2H), 4.005 (bs, 1H), 7.2-7.4 (m,
8H), 7.50 (s, 1H), 7.525 (s, 1H).
EXAMPLE 70
Preparation of 3-phenyl-3-hydroxypiperidine hydrobromide
[0521] To a solution of 1-benzyl-3-phenyl-3-hydroxypiperidine (0.95
g, 3.5 mmol) in ethanol (15 mL) was added Pd/C 10% (0.3 g). This
heterogeneous solution was hydrogenated at 1 atm at 25.degree. C.
and for 40 h then filtered through a celite pad and concentrated
under reduced pressure. The crude compound was dissolved in MeOH
(10 mL) and treated with a diluted solution of HBr in MeOH (1.2M, 5
mL). This solution was stirred at 25.degree. C. for 5 min. then the
solvent was removed under vacuum to give an oil. Acetone was added
(15 mL) and the mixture was vigorously stirred for 2 h to give a
white suspension. The solid was collected, washed with acetone
(2.times.4 mL) and dried under vacuum to afford the title compound
as a white solid (0.43 g, 47%). m.p. 168-170.degree. C. .sup.1H NMR
(DMSO): 1.699 (t, J=9.2 Hz, 2H), 1.95-2.05 (m, 2H), 2.9-3.0 (d,
J=12.3 Hz, 2H), 3.07-3.29 (m, 3H), 7.26 (t, J=7.2 Hz, 1H), 7.353
(m, 2H), 7.50 (d, J=7.5 Hz, 2H), 8.55(bs, 2H).
EXAMPLE 71
Preparation of 3-phenyl-3-hydroxy-1-(2-phenylethyl)piperidine
hydrobromide
[0522] From 3-phenyl-3-hydroxypiperidine hydrobromide (0.2 g, 0.77
mmol), 2-bromoethylbenzene (0.138 mL, 1.0 mmol) and potassium
carbonate (0.267 g, 1.9 mmol) there was obtained the free amine as
an oil (0.15 g, 70%). .sup.1H NMR (CDCl.sub.3): 1.6-1.85 (m, 3H),
1.9-2.05 (m, 1H), 2.156 (bt, J=11.7 Hz, 1H), 2.39 (d, J=11.1 Hz,
1H), 2.6-2.9 (m, 5H), 3.02 (bd, J=10.5 Hz, 1H), 3.92 (bs, 1H),
7.15-7.40 (m, 8H), 7.53 (d, J=7.5 Hz, 2H).
[0523] The HBr salt was obtained as a brown solid; m.p.
159-161.degree. C. .sup.1H-NMR (DMSO): 1.788 (t, J=12.9 Hz, 2H),
1.94-2.06 (m, 1H), 2.06-2.2 (m, 1H), 2.85-3.0 (m, 1H), 3.0-3.15 (m,
2H), 3.15-3.27 (m, 2H), 3.27-3.5 (m, 3H), 7.2-7.34 (m, 6H), 7.38
(t, J=7.5 Hz, 2H), 7.525 (d, J=7.5 Hz, 2H). Anal. Calcd. for
C.sub.19H.sub.24BrNO: C, 63.0; H, 6.67; N, 3.87. Found: C, 62.89;
H, 6.81; N, 3.83.
EXAMPLE 72
Preparation of 3-phenyl-3-hydroxy-1-(3-phenylpropyl)piperidine
hydrobromide
[0524] From 3-phenyl-3-hydroxypiperidine hydrobromide (0.2 g, 0.77
mmol), 1-bromo-3-phenylpropane (0.153 mL, 1.0 mmol) and potassium
carbonate (0.267 g, 1.9 mmol) there was obtained the free amine as
an oil (0.127 g, 56%). .sup.1H NMR (CDCl.sub.3): 1.65-1.90 (m, 5H),
1.9-2.1 (m, 2H), 2.286 (d, J=11.1 Hz, 1H), 2.35-2.55 (m, 2H), 2.652
(t, J=7.8 Hz, 2H), 2.754 (bd, J=10.8 Hz, 1H), 2.95 (bd, J=7.5 Hz,
1H), 7.14-7.32 (m, 6H), 7.356 (t, J=7.2 Hz, 2H), 7.52 (d, J=7.5 Hz,
2H).
[0525] The HBr salt was obtained as a brown solid m.p.
166-170.degree. C. .sup.1H NMR (DMSO): 1.74 (t, J=11.5 Hz, 2H),
1.83-2.2 (m, 4H), 2.555 (t, J=7.5 Hz, 2H), 2.9-3.1 (m, 3H),
3.15-3.3 (m, 2H), 5.85 (s, 1H), 7.1-7.3 (m, 6H), 7.36 (t, J=7.5 Hz,
2H), 7.49 (d, J=7.5 Hz, 2H), 9.01 (bs, 1H). Anal. Calcd. for
C.sub.20H.sub.26BrNO: C, 63.8; H, 6.67; N, 3.7. Found: C, 62.89; H,
6.89; N, 3.65.
EXAMPLE 73
Preparation of N-acetylisonipecotic acid
[0526] Isonipecotic acid (25.0 g, 0.19 mol) was dissolved in acetic
anhydride (100 mL) and the solution stirred at reflux for 8 h, then
the solvent was removed under reduced pressure and the crude
compound crystallized from MeOH/ether to afford the title compound
as a white solid (24.4 g, 74%). m.p. 171.degree. C. .sup.1H NMR
(DMSO): 1.2-1.5 (m, 2H), 1.65-1.85 (m, 2H), 1.942 (s, 3H), 2.35-2.5
(m, 1H), 2.641 (t, J=11.7 Hz, 1H), 3.038 (t, J=11.7 Hz, 1H), 3.69
(d, J=13.5 Hz, 1H), 4.15 (d, J=13.2 Hz, 1H), 12.22 (bs, 1H). IR
(KBr): 1721, 1613, 1316, 1202 (cm.sup.-1). MS (m/z): 171, 128,
82.
EXAMPLE 74
Preparation of N-acetylisonipecotic acid chloride
[0527] N-acetylisonipecotic acid (0.67 g, 3.9 mmol) was added to
SOCl.sub.2 (4.1 mL). The acid chloride precipitated from solution
and petrol (60 mL) was added. The mixture was filtered and the
residue was washed several times with petrol to afford the title
compound as a white solid (0.716 g, 97%). m.p. 133-138.degree. C.
.sup.1H NMR (DMSO): 1.2-1.5 (m, 2H), 1.65-2.0 (m, 2H), 1.94 (s,
3H), 2.3-2.5 (m, 1H), 2.639 (t, J=11.4 Hz, 1H), 3.036 (t, J=11.4
Hz, 1H), 3.692 (d, J=13.2 Hz, 1H), 4.144 (d, J=13.2 Hz, 1H). IR
(KBr): 1789, 1745, 1660 (cm.sup.-1). MS (m/z): 189, 126, 146,
84.
EXAMPLE 75
Preparation of 4-(p-fluorobenzoyl)-1-acetylpiperidine
[0528] N-acetyl-isonipecotic acid chloride (2.0 g, 10.5 mmol) was
slowly added to a stirring mixture of aluminum trichloride (2.8 g,
21.1 mmol) in fluorobenzene (10 mL). After the addition was
completed, the mixture was refluxed for 1 h. The mixture was poured
into ice and the resulting layers were separated. The aqueous layer
was extracted twice with CH.sub.2Cl.sub.2 (2.times.30 mL) and the
combined organic phase was dried and concentrated under reduced
pressure to afford the title compound as an oil (1.3 g, 50%).
.sup.1H NMR (CDCl.sub.3): 1.5-1.7 (m, 1H), 1.7-2.0 (m, 3H), 2.104
(s, 3H), 2.813 (t, J=12.0 Hz, 1H), 3.15-3.3 (m, 1H), 3.4-3.55 (m,
1H), 3.902 (d, J=13.2 Hz, 1H), 4.574 (d, J=13.2 Hz, 1H), 7.145 (t,
J=8.4 Hz, 2H), 7.967 (dd, J=5.7 & 8.4 Hz, 2H).
EXAMPLE 76
Preparation of 4-(p-fluorobenzoyl)piperidine hydrobromide
[0529] A solution of 4-(p-fluorobenzoyl)-1-acetylpiperidine (1.2 g,
4.8 mmol) in HCl 6N (15 mL) was refluxed for 2 h. The cooled
solution was made basic (NaOH) and then extracted with benzene
(2.times.40 mL). The collected organic phase was washed with brine
(50 mL), dried and concentrated under reduced pressure. The free
amine was dissolved in HBr (saturated solution in methanol, 10 mL)
and the hydrobromic salt precipitated was collected, washed with
ether (2.times.4 mL) and dried under vacuum to afford the title
compound as a white solid (1.54 g, 98%). m.p. 198.degree. C.
.sup.1H NMR (CD.sub.3OD): 1.8-2.0 (m, 2H), 2.05-2.18 (m, 2H),
3.12-3.28 (m, 2H), 3.4-3.5 (m, 2H), 3.7-3.85 (m, 1H), 4.856 (s,
2H), 7.243 (t, J=8.3 Hz, 2H), 8.099 (dd, J=5.7 & 8.7 Hz,
2H).
EXAMPLE 77
Preparation of
4-(p-fluorobenzoyl)-1-(3-hydroxypropyl)piperidine
[0530] To a solution of 4-(p-fluorobenzoyl)piperidine hydrobromide
(0.3 g, 1.04 mmol) in DMF (10 mL) were added 3-bromo-1-propanol
(0.11 mL, 1.25 mmol) and potassium carbonate (0.29 g, 2.08 mmol).
This heterogeneous solution was heated at 110.degree. C. for 3 h
then cooled at 25.degree. C., diluted with water (100 mL) and
extracted with EtOAc (3.times.30 mL). The collected organic phase
was washed with water (2.times.50 mL), dried and concentrated in
vacuum. The crude compound was purified by filtration on silica gel
using CH.sub.2Cl.sub.2/MeOH as eluant to afford the title compound
as a pale yellow solid (0.13 g, 47%). m.p. =106-108.degree. C.
.sup.1H NMR (CDCl.sub.3): 1.55-1.68 (m, 2H), 1.68-1.95 (m, 5H),
2.05-2.2 (m, 2H), 2.642 (t, J=5.4 Hz, 2H), 3.13 (bd, J=11.7 Hz,
2H), 3.15-3.3 (m, 1H), 3.808 (t, J=4.8 Hz, 2H), 7.137 (t, J=8.4 Hz,
2H), 7.95 (dd, J=5.4 & 8.4, 2H). Anal. Calcd. for
C.sub.15H.sub.20FNO.sub.2: C, 67.90; H, 7.60; N, 5.28; Found: C,
66.71; H, 7.38; N, 5.44.
EXAMPLE 78
1-(3-Hydroxypropyl)-4-(4-methoxybenzoyl)piperidine
[0531] A) 1-Acetyl-4-(4-methoxybenzoyl)piperidine. To a suspension
of aluminum trichloride (3.40 g, 25.7 mmol) in CS.sub.2 (15 mL)
were added anisole (1.90 mL, 17.6 mmol) and, portionwise,
N-acetylisonipecotoyl chloride (2.40 g, 11.7 mmol). After the
addition was complete, the mixture was refluxed for 1 h. The
solvent was decanted and the red residue was dissolved in 5% HCl
(50 mL) and was extracted with EtOAc (4.times.30 mL). The combined
organic phase was dried and was concentrated under reduced pressure
to afford the title compound as a colorless solid (1.8 g, 60%): mp
102-105.degree. C.; .sup.1H NMR (CDCl.sub.3) d 1.50-1.75 (m, 1H),
1.70-2.00 (m, 3H), 2.10 (s, 3H), 2.70-2.90 (m, 1H), 3.15-3.30 (m,
1H), 3.40-3.53 (m, 1H), 3.86 (s, 3H), 3.85-4.00 (m, 1H), 4.56 (d,
J=13.2 Hz, 1H), 6.94 (d, J=8.7 Hz, 2H), 7.92 (d, J=9.0 Hz, 2H).
[0532] B) 4-(4-Methoxybenzoyl)piperidine. This compound was
prepared in a manner similar to example 76. From
1-acetyl-4-(4-methoxybenzoyl)piperidin- e (1.80 g, 6.90 mmol) and 6
N HCl (10 mL) there was obtained the hydrobromide salt as a
colorless solid (1.65 g, 80%): mp 230-233.degree. C.; .sup.1H NMR
(DMSO-d.sub.6) d 1.60-1.80 (m, 2H), 1.87 (bd, J=13.2 Hz, 2H), 3.03
(t, J=10.5 Hz, 2H), 3.29 (d, J=12.6 Hz, 2H), 3.65-3.80 (m, 1H),
3.84 (s, 3H), 7.02 (d, J=8.4 Hz, 2H), 7.97 (d, J=8.4 Hz, 2H), 8.54
(bs, 2H)
[0533] C) 1-(3-Hydroxypropyl)-4-(4-methoxybenzoyl)piperidine. This
compound was prepared in a manner similar to example 77. From
4-(4-methoxybenzoyl)piperidine hydrobromide (0.60 g, 2.0 mmol) and
3-bromo-1-propanol (0.28 mL, 3.0 mmol) there was obtained the
hydrobromide salt as a colorless solid (0.38 g, 53%): mp
148-151.degree. C.; .sup.1H NMR (DMSO-d6) d 1.70-1.88 (m, 4H),
1.90-2.03 (m, 2H), 2.98-3.20 (m, 4H), 3.45 (t, J=5.4 Hz, 2H), 3.54
(bd, J=12.0 Hz, 2H), 3.60-3.75 (m, 1H), 3.81 (s, 3H), 4.75 (bs,
1H), 7.04 (d, J=8.4 Hz, 2H), 7.96 (d, J=8.4 Hz, 2H), 9.1 (bs, 1H);
MS (m/z): 277, 232, 114.
EXAMPLE 79
4-(2-Hydroxybenzoyl)-1-(3-hydroxypropyl)piperidine
[0534] A) Phenyl N-acetylisonipecotate. To a suspension of
N-acetylisonipecotoyl chloride (3.70 g, 19.50 mmol) in THF (60 mL)
were added phenol (2.70 g, 27 mmol) and Et.sub.3N (5.0 mL, 36
mmol). The resulting heterogeneous mixture was stirred at
25.degree. C. for 20 h, diluted with EtOAc (50 mL) and was washed
with a saturated solution of NH.sub.4Cl (50 mL). The crude compound
was purified by filtration on silica gel using EtOAc/n-hexane as
eluant to afford the title compound as a colorless solid (3.45 g,
80%): mp 96-98 C.; .sup.1H NMR (CDCl.sub.3) d 1.60-1.95 (m, 2H),
2.00-2.2 (m, 5H), 2.70-3.00 (m, 2H), 3.10-3.30 (m, 1H), 3.75-3.90
(m, 1H), 4.40-4.60 (m, 1H), 7.06 (d, J=7.5 Hz, 2H), 7.22 (d, J=7.5
Hz, 1H), 7.38 (t, J=7.5 Hz, 2H).
[0535] B) 4-(2- and 4-Hydroxybenzoyl)-1-acetyl piperidine. To a
solution of phenyl N-acetylisonipecotate (3.40 g, 13.7 mmol) in
4-nitrobenzene (16 mL) was added portionwise AlCl.sub.3 (3.70 g,
27.5 mmol). The resulting solution was heated at 60.degree. C. for
4 h, diluted with 6 M HCl (40 mL) and was washed with ether
(3.times.50 mL). The aqueous solution was neutralized with NaOH and
was extracted with EtOAc (4.times.50 mL). The collected organic
phase was washed with a saturated solution of NH.sub.4Cl (50 mL),
dried and was concentrated under reduced pressure to afford a
mixture of isomers as a solid (2.32 g, 70%, The 4-isomer was the
major product as shown by .sup.1H NMR): .sup.1H NMR (4-isomer,
DMSO-d.sub.6) d 1.20-1.38 (m, .sup.1H), 1.38-1.60 (m, .sup.1H),
1.65-1.80 (m, 2H), 1.96 (s, 3H), 2.66 (t, J=12.0 Hz, .sup.1H), 3.14
(t, J=12.6 Hz, 1H), 3.50-3.65 (m, 1H), 3.80 (bd, J=13.2 Hz, 1H),
4.35 (bd, J=12.6 Hz, 1H), 6.82 (d, J=8.7 Hz, 2H), 7.85 (d, J=8.4
Hz, 2H).
[0536] C) 4-(2-Hydroxybenzoyl)piperidine hydrobromide. An solution
of 4-(2- and 4-hydroxybenzoyl)-1-acetyl piperidine (2.30 g, 9.30
mmol) in 6 N HCl (20 mL) was refluxed for 2 h. The cooled solution
was extracted with ether (2.times.30 mL), made basic (NaOH) and was
extracted with EtOAc (2.times.30 mL). An insoluble solid formed
which was removed. The EtOAc portion was dried and was concentrated
under reduced pressure. The free amine was dissolved in HBr
(saturated solution in methanol, 5 mL) and the precipitated
hydrobromide salt was collected, washed with ether (2.times.4 mL)
and was dried in vacuo to afford the title compound as a colorless
solid (0.26 g): mp 253.degree. C. (dec); .sup.1H NMR (DMSO-d.sub.6)
d 1.60-1.83 (m, 2H), 1.94 (bd, J=12.9 Hz, 2H), 2.90-3.10 (m, 2H),
3.30 (bd, J=12.3 Hz, 2H), 3.65-3.90 (m, 1H), 6.94 (t, J=8.7 Hz,
2H), 7.50 (t, J=7.5 Hz, 1H), 7.88 (d, J=7.5 Hz, 1H), 8.33 (bs, 1H),
8.58 (bs, 1H), 11.63 (s, 1H).
[0537] D) 4-(2-Hydroxybenzoyl)-1-(3-hydroxypropyl)piperidine. This
compound was prepared in a manner similar to example 77. From
4-(2-hydroxybenzoyl)piperidine hydrobromide (0.26 g, 0.87 mmol) and
3-bromo-1-propanol (0.08 mL, 0.9 mmol) there was obtained the title
compound as a brown solid (0.10 g, 43%): mp 77-80.degree. C.;
.sup.1H NMR(DMSO-d.sub.6) d 1.65-1.78 (m, 2H), 1.80-1.90 (m, 4H),
2.00-2.20 (m, 2H), 2.62 (t, J=5.4 Hz, 2H), 3.14 (d, J=11.4 Hz, 2H),
3.20-3.40 (m, 1H), 3.78 (t, J=5.1 Hz, 2H), 4.80 (bs, 1H), 6.88 (t,
J=7.5 Hz, 1H), 6.97 (d, J=8.4 Hz, 1H), 7.45 (t, J=8.1 Hz, 1H), 7.73
(d, J=7.8 Hz, 1H), 12.42 (bs, 1H). MS (m/z) 263, 218, 114, 70.
EXAMPLE 80
4-(4-Fluorobenzoyl)-1-(2-(4-fluorophenoxy)ethyl)piperidine
hydrochloride
[0538] The compound was prepared in a manner similar to example 77.
From 4-(4-fluorobenzoyl)piperidine hydrobromide (1.5 g, 6.1 mmol)
and 2-(4-fluorophenoxy)ethyl bromide (2.0 g, 9.2 mmol) there was
obtained the free amine as a brown solid (1.0 g, 50%): mp 88-91 C.;
.sup.1H NMR (CDCl.sub.3) d 1.80-1.95 (m, 4H), 2.20-2.35 (m, 2H),
2.82 (t, J=6.0 Hz, 2H), 3.07 (bd, J=11.4 Hz, 2H), 3.15-3.30 (m,
1H), 4.07 (t, J=5.7 Hz, 2H), 6.80-6.90 (m, 2H), 6.96 (t, J=8.7 Hz,
2H), 7.13 (t, J=8.4 Hz, 2H), 7.96 (dd, J=5.7 and 8.4 Hz, 2H). The
HCl salt was obtained as a brown solid (0.17 g, 54%): mp
138-141.degree. C.; HRMS calcd for C.sub.20H.sub.21F.sub.2NO.sub.2
345.1540, found 345.1547.
EXAMPLE 81
4-((4-Fluorophenyl)hydroxymethyl)-1-(2-(4-fluorophenoxy)ethyl)piperidine
hydrochloride
[0539] A solution of
4-(4-fluorobenzoyl)-1-(2-(4-fluorophenoxy)ethyl) piperidine (0.77
g, 2.22 mmol) in THF (10 mL) was added dropwise manner to a
suspension of LiAlH.sub.4 (0.42 g, 11 mmol) in THF (10 mL). The
mixture was heated at reflux for 5 h. Excess hydride was decomposed
with a saturated solution of Na.sub.2SO.sub.4. The inorganic
precipitate was removed by filtration, the filtrate was dried over
Na.sub.2SO.sub.4 and was concentrated under reduced pressure. The
crude compound was dissolved in a saturated solution of HCl in MeOH
(5 mL) and the resulting solution was stirred at 25.degree. C. for
5 min. After concentration in vacuo, the resulting mixture was
triturated with ether for 10 h to afford the title compound as a
colorless solid (0.40 g, 52%): mp 71-75.degree. C.; .sup.1H NMR
(DMSO-d.sub.6) d 1.20-1.50 (m, 3H), 1.50-1.70 (m, 1H), 1.80 (d,
J=12.3 Hz, 1H), 2.45-2.65 (m, 2H), 3.00-3.15 (m, 2H), 3.20-3.35 (m,
2H), 4.10-4.20 (m, 2H), 4.28 (d, J=6.3 Hz, 1H), 6.93 (dd, J=4.2 and
8.7 Hz, 2H), 7.05-7.15 (m, 4H), 7.25-7.35 (m, 2H).
EXAMPLE 82
4-Benzyl-1-(2-hydroxyethyl)piperidine
[0540] 94
[0541] To a solution of 4-benzylpiperidine (0.50 mL, 2.8 mmol) in
DMF (15 mL) were added 2-chloroethanol (0.25 mL, 3.70 mmol) and
K.sub.2CO.sub.3 (0.79 g, 5.70 mmol). The heterogeneous mixture was
heated at 110.degree. C. for 2 h. It was then cooled to 25.degree.
C. and was diluted with water (100 mL) and extracted with ether
(2.times.70 mL). The collected organic phase was washed with water
(2.times.100 mL), dried and concentrated in vacuo. The crude
compound was purified by filtration on silica gel using
CH.sub.2Cl.sub.2/MeOH as eluant to afford the title compound as a
colorless solid (0.25 g, 40%): mp 62-64.degree. C.; .sup.1H NMR
(CDCl.sub.3) .delta.1.15-1.35 (m, 2H), 1.45-1.60 (m, 1H), 1.63 (bd,
J=13.8 Hz, 2H), 1.99 (t, J=11.7 Hz, 2H), 2.48 (t, J=5.7 Hz, 2H),
2.53 (d, J=6.9 Hz, 2H), 2.87 (bd, J=11.7 Hz, 2H), 2.9 (bs, 1H),
3.574 (t, J=5.4 Hz, 2H), 7.14 (d, J=7.2 Hz, 2H), 7.20 (d, J=6.9 Hz,
1H), 7.28 (t, J=6.2 Hz, 2H); MS (m/z) 219, 188, 91. Anal. Calcd for
C.sub.14H.sub.21NO: C, 76.71; H, 9.65; N, 6.40. Found: C, 74.49; H,
9.29; N, 6.08.
EXAMPLE 83
4-Benzyl-1-(3-hydroxypropyl)piperidine hydrobromide
[0542] 95
[0543] This compound was prepared in a manner similar to example
82. From 4-benzyl piperidine (5.00 mL, 28.4 mmol) and
3-bromo-1-propanol (2.70 mL, 29.9 mmol) there was obtained the free
amine as a colorless oil (6.25 g, 94%). .sup.1H NMR (CDCl.sub.3)
.delta.1.20-1.40 (m, 2H), 1.45-1.65 (m, 1H), 1.60-1.75 (m, 3H),
1.89 (t, J=11.1 Hz, 2H), 2.51 (d, J=6.9 Hz, 2H), 2.58 (t, J=5.7 Hz,
2H), 3.04 (bd, J=11.4 Hz, 2H), 3.80 (t, J=5.1 Hz, 2H), 7.12 (d,
J=7.2 Hz, 2H), 7.19 (d, J=7.2 Hz, 1H), 7.27 (t, J=7.2 Hz, 2H).
[0544] The free amine (1.50 g) was dissolved in a solution of HBr
in MeOH (1.0 M, 10 mL). The resulting solution was stirred at
25.degree. C. for 10 min. and was concentrated in vacuo. The
resulting crude product was triturated with acetone (10 mL) for 2 h
to give the title compound as a colorless solid (1.2 g, 60%): mp
122-124.degree. C.; .sup.1H NMR (DMSO-.sub.6) .delta.1.30-1.50 (m,
2H), 1.60-1.82 (m, 4H), 2.50 (d, J=6.6 Hz, 2H), 2.70-2.90 (m, 2H),
2.95-3.08 (m, 2H), 3.10-3.23 (m, 1H), 3.35-3.50 (m, 4H), 4.71 (bs,
1H), 7.10-7.20 (m, 3H), 7.27 (t, J=7.2 Hz, 2H), 9.00 (bs, 1H);
Anal. Calcd for C.sub.15H.sub.24BrNO: C, 57.32; H, 7.69; N, 4.46.
Found: C, 57.46; H, 7.74; N, 4.46.
EXAMPLE 84
4-Benzyl-1-(3-hydroxy-1-methylpropyl)piperidine
[0545] 96
[0546] A) Ethyl 3-(4-benzylpiperidin-1-yl)butyrate. A solution of
4-benzyl piperidine (0.50 mL, 2.8 mmol) and ethyl crotonate (0.46
mL, 3.4 mmol) in isopropanol (10 mL) was refluxed for 24 h and was
concentrated in vacuo. The crude compound was purified by
filtration on silica gel using CH.sub.2Cl.sub.2/MeOH as solvent to
afford the title compound as a pale yellow oil (0.64 g, 74%):
.sup.1H NMR (CDCl.sub.3) .delta.1.09 (d, J=6.6 Hz, 3H), 1.30 (t,
J=6.9 Hz, 3H), 1.20-1.40 (m, 2H), 1.45-1.61 (m, 1H), 1.68 (bd,
J=12.3 Hz, 2H), 2.10-2.35 (m, 3H), 2.57 (d, J=6.9 Hz, 2H),
2.50-2.70 (m, 1H), 2.82 (bd, J=10.8 Hz, 2H), 3.15-3.30 (m, 1H),
4.18 (q, J=6.9 Hz, 2H), 7.18 (d, J=7.2 Hz, 2H), 7.24 (m, 1H), 7.32
(t, J=6.9 Hz, 2H).
[0547] B) 4-Benzyl-1-(3-hydroxy-1-methylpropyl)piperidine. To a
solution of ethyl 3-(4-benzylpiperidin-1-yl)butyrate (0.60 g, 2.0
mmol) in dry THF (10 mL) was added portionwise LiAlH.sub.4 (0.15 g,
3.9 mmol). The resulting heterogeneous mixture was stirred at
25.degree. C. for 2 h then quenched with MeOH. The resulting
mixture was diluted with EtOAc (100 mL), washed with NH.sub.4Cl
(100 mL) and brine (100 mL), dried and was concentrated under
reduced pressure. The crude compound was purified by filtration on
silica gel using CH.sub.2Cl.sub.2/MeOH as solvent to afford the
title compound as a colorless solid (0.38 g, 80%): mp 74-76.degree.
C.; .sup.1H NMR (CDCl.sub.3) .delta.1.00 (d, J=6.6 Hz, 3H),
1.15-1.45 (m, 3H), 1.50-1.65 (m, 1H), 1.65-1.80 (m, 2H), 1.85-2.15
(m, 3H), 2.40-2.60 (m, 3H), 2.82 (bd, J=11.1 Hz, 1H), 2.90-3.10 (m,
2H), 3.80-4.00 (m, 2H), 6.55 (bs, 1H), 7.19 (t, J=7.2 Hz, 2H), 7.24
(d, J=6.9 Hz, 1H), 7.32 (t, J=7.2 Hz, 2H); MS (m/z) 247, 248, 232,
202, 91. Anal. Calcd for C.sub.16H.sub.25NO: C, 77.68; H, 10.18; N,
5.66. Found C, 77.56; H, 10.22; N, 5.63.
EXAMPLE 85
4-Benzyl-1-(2,3-dihydroxypropyl)piperidine
[0548] 97
[0549] A) 2,2-Dimethyl-4-tosylmethyl-1,3-dioxolane. To a solution
of solketal (2.00 mL, 16.0 mmol) in CH.sub.2Cl.sub.2 (50 mL) was
added Et.sub.3N (4.50 mL, 32 mmol). A solution of p-toluensulfonyl
chloride (4.30 g, 22 mmol) in CH.sub.2Cl.sub.2 (30 mL) was then
added dropwise at 0.degree. C. The resulting solution was stirred
at 25.degree. C. for 6 h, then was diluted with CH.sub.2Cl.sub.2
(50 mL). This solution was washed with HCl (5%, 100 mL) and brine
(100 mL), dried and concentrated in vacuo to afford the crude
product. This was purified by flash-chromatography on silica gel
using EtOAc/n-hexane as eluant to give the title compound as a
colorless oil (2.03 g, 45%): .sup.1H NMR (CDCl.sub.3) .delta.1.31
(s, 3H), 1.34 (s, 3H), 2.45 (s, 3H), 3.77 (q, J=5.1 and 8.7 Hz,
1H), 3.90-4.10 (m, 3H), 4.28 (p, J=5.7 Hz, 1H), 7.35 (d, J=8.1 Hz,
2H), 7.80 (d, J=8.1 Hz, 2H);
[0550] B) 4-(4-Benzylpiperidin-1-yl)-2,2-dimethyl-1,3-dioxolane.
This compound was prepared in a manner similar to example 1. From
4-benzylpiperidine (1.00 mL, 5.70 mmol) and
2,2-dimethyl-4-tosylmethyl-1,- 3-dioxolane (2.00 g, 7.00 mmol)
there was obtained the title compound as a yellow oil (0.95 g,
58%): .sup.1H NMR (CDCl.sub.3) .delta.1.33 (s, 3H), 1.39 (s, 3H),
1.10-1.40 (m, 2H), 1.40-1.57 (m, 1H), 1.59 (d, J=13.2 Hz, 2H),
1.85-2.05 (m, 2H), 2.39 (dd, J=5.1 and 12.9 Hz, 1H), 2.45-2.60 (m,
3H), 2.85 (d, J=11.1 Hz, 1H), 2.95 (bd, J=11.1 Hz, 1H), 3.56 (t,
J=7.8 Hz, 1H), 4.04 (t, J=7.8 Hz, 1H), 4.20-4.30 (m, 1H), 7.12 (d,
J=7.2 Hz, 2H), 7.18 (d, J=6.9 Hz, 1H), 7.26 (t, J=7.2 Hz, 2H).
[0551] C) 4-Benzyl-1-(2,3-dihydroxypropyl)piperidine. A solution of
4-(4-Benzyl-piperidin-1-yl)-2,2-dimethyl-1,3-dioxolane (0.65 g) in
methanolic HBr (1.0 M, 20 mL) was prepared. The solution was
stirred at 25.degree. C. for 2 h then was concentrated in vacuo.
The resulting crude product was dissolved in water (50 mL), washed
with ether (20 mL), made basic with saturated NaHCO.sub.3 (20 mL)
and extracted with CH.sub.2Cl.sub.2 (3.times.30 mL). The crude
compound was purified by trituration with EtOAc (5 mL) for 2 h to
give the title compound as a colorless solid (0.45 g, 80%): mp
92-94.degree. C.; .sup.1H NMR (CDCl.sub.3) .delta.1.15-1.40 (m,
2H), 1.45-1.65 (m, 1H), 1.64 (bd, J=13.5 Hz, 2H), 1.92 (t, J=11.4
Hz, 1H), 2.20 (t, J=11.4 Hz, 1H), 2.30 (dd, J=3.9 and 12.3 Hz, 1H),
2.45-2.60 (m, 3H), 2.81 (bd, J=11.4 Hz, 1H), 2.98 (bd, J=11.1 Hz,
1H), 3.65-3.85 (m, 2H), 7.14 (d, J=7.2 Hz, 2H), 7.20 (d, J=6.9 Hz,
1H), 7.28 (t, J=7.2 Hz, 2H; MS (m/z) 249, 232, 218, 188, 91. Anal.
Calcd for C.sub.15H.sub.23NO.sub.2: C, 72.25; H, 9.30; N, 5.62.
Found C, 72.19; H, 9.43; N, 5.75.
EXAMPLE 86
4-Benzyl-1-(4-hydroxybutyl)piperidine hydrobromide
[0552] 98
[0553] A) Ethyl 4-(4-benzylpiperidin-1-yl)butyrate hydrobromide.
This compound was prepared in a manner similar to example 82. From
4-benzylpiperidine (1.00 mL, 5.70 mmol) and ethyl 4-bromobutyrate
(0.90 mL, 6.3 mmol) there was obtained the free amine as a pale
yellow oil (1.25 g, 76%). .sup.1H NMR (CDCl.sub.3) .delta.1.24 (t,
J=7.2 Hz, 3H), 1.26-1.40 (m, 2H), 1.45-1.60 (m, 1H), 1.63 (bd,
J=12.9 Hz, 2H), 1.75-1.95 (m, 4H), 2.25-2.40 (m, 4H), 2.53 (d,
J=6.9 Hz, 2H), 2.90 (bd, J=11.4 Hz, 2H), 4.11 (q, J=7.2 Hz, 2H),
7.13 (bd, J=7.2 Hz, 2H), 7.19 (d, J=6.9 Hz, 1H), 7.27 (t, J=7.2 Hz,
2H).
[0554] The free amine (0.10 g) was dissolved in HBr (1.0 M in MeOH,
5 mL). The resulting solution was stirred at 25.degree. C. for 10
min. and was concentrated in vacuo. The crude product was
triturated with acetone (10 mL) for 2 h to give the title compound
as a colorless solid (0.12 g, 94%): mp 159-160.degree. C.; .sup.1H
NMR (DMSO-d.sub.6) .delta.1.30-1.45 (m, 2H), 1.60-1.85 (m, 5H),
2.46 (t, J=7.2, 2H), 2.40-2.60 (m, 3H), 2.70-2.90 (m, 2H),
2.90-3.10 (m, 2H), 3.20-3.50 (m, 6H), 7.10-7.30 (m, 5H), 9.00 (bs,
1H).
[0555] B) 4-Benzyl-1-(4-hydroxybutyl)piperidine hydrobromide. To a
solution of ethyl 4-(4-benzylpiperidin-1-yl)butyrate hydrobromide
(0.50 g, 1.7 mmol) in dry THF (30 mL) was added portionwise
LiAlH.sub.4 (0.13 g, 3.4 mmol). The resulting mixture was stirred
at 25.degree. C. for 2 h. The reaction was diluted with saturated
NH.sub.4Cl (100 mL) and extracted with EtOAc (2.times.100 mL). The
collected organic phases were washed with brine (100 mL), dried and
concentrated in vacuo. The crude compound was purified by
filtration on silica gel using CH.sub.2Cl.sub.2/MeOH 8/2 as solvent
to give the free amine as a colorless oil (0.34 g, 80%): .sup.1H
NMR (CDCl.sub.3) .delta.1.30-1.47 (m, 4H), 1.47-1.60 (m, 1H),
1.60-1.75 (m, 6H), 1.95 (t, J=11.4 Hz, 2H), 2.37 (bs, 2H), 2.53 (d,
J=6.9 Hz, 2H), 3.00 (bd, J=11.4 Hz, 2H), 3.53-3.63 (m, 2H), 7.12
(d, J=6.9 Hz, 2H), 7.19 (d, J=6.9 Hz, 1H), 7.27 (t, J=6.9 Hz,
2H).
[0556] The free amine (0.30 g) was dissolved in HBr (1.0 M in MeOH,
10 mL). The resulting solution was stirred at 25.degree. C. for 10
min. and was concentrated in vacuo. The crude product was
triturated with acetone (10 mL) for 2 h to give the title compound
as a colorless solid (0.35 g, 88%): mp 129-130.degree. C.; .sup.1H
NMR (DMSO-d.sub.6) .delta.1.35-1.52 (m, 5H), 1.57-1.80 (m, 5H),
2.48 (d, J=6.6 Hz, 2H), 2.70-2.90 (m, 2H), 2.90-3.04 (m, 2H),
3.06-3.23 (m, 1H), 3.30-3.45 (m, 3H), 4.00 (bs, 1H), 7.10-7.20 (m,
3H), 7.25 (t, J=7.2 Hz, 2H), 9.22 (bd, 1H); MS (m/z) 247, 188, 91.
Anal. Calcd for C.sub.16H.sub.26BrNO: C, 58.53; H, 8.02; N, 4.33.
Found: C, 57.93; H, 8.12; N, 4.17.
EXAMPLE 87
4-Benzyl-4-hydroxy-1-(3-hydroxypropyl)piperidine
[0557] 99
[0558] This compound was prepared in a manner similar to example
82. From 3-bromopropanol (0.453 g, 3.26 mmol) and
4-benzyl-4-hydroxypiperidine (0.52 g, 2.7 mmol) there was obtained
the title compound as a pale yellow oil (0.3 g, 44%): .sup.1H NMR
(CDCl.sub.3) .delta.1.45 (m, 2 H), 1.60 (m, 3 H), 2.26 (m, 4 H),
2.52 (m, 2 H), 2.64 (m, 4 H), 3.64 (t, J=5.1 Hz, 2 H), 4.80 (bs, 1
H), 7.09-7.20 (m, 5 H); MS (m/z) 249 (M.sup.+, 10), 204 (100), 158
(10), 91 (18). HRMS Calcd for C.sub.15H.sub.23NO.sub.2: 249.1737.
Found: 249.1733.
EXAMPLE 88
7-Benzyl-1,2,3,5,6,7,8,9-octahydro-2-(hydroxymethyl)indolizine
[0559] 100
[0560] A) 4-Benzylpyridine-N-oxide. A mixture of 4-benzylpyridine
(5 mL, 30 mmol), acetic acid (30 mL) and 30% hydrogen peroxide (10
mL) was heated at 80-90.degree. C. for 5 h. Concentration under
reduced pressure gave an oil that was diluted with NaHCO.sub.3 (100
mL) and extracted with CH.sub.2Cl.sub.2 (2.times.100 mL). The
collected organic phase was washed with brine (100 mL) and
evaporated in vacuo to give the title compound as a colorless oil
(5.68 g, 98%): .sup.1H NMR (DMSO-.sub.6) .delta.3.90 (s, 2H),
7.15-7.35 (m, 7H), 8.08 (d, J=6.3 Hz, 2H).
[0561] B) 4-Benzyl-2-cyanopyridine. To a solution of
4-benzylpyridine-N-oxide (8.8 g, 48 mmol) in acetonitrile (50 mL)
was added Et.sub.3N (9.9 mL, 71.2 mmol). Neat trimethylsilyl
cyanide (15.8 mL, 118 mmol) was added dropwise. The resulting
solution was heated at reflux for 10 h under nitrogen then after
cooling, diluted with CH.sub.2Cl.sub.2 (150 mL). The resulting
solution was washed with NaHCO.sub.3 (2.times.150 mL), dried over
Na.sub.2SO.sub.4 and concentrated in vacuo. The crude compound was
purified by filtration on silica gel using EtOAc/n-hexane as eluant
to afford the title compound as a pale yellow oil (7.2 g, 78%):
.sup.1H NMR (CDCl.sub.3) .delta.4.03 (s, 2H), 7.16 (d, J=7.2 Hz,
2H), 7.20-7.40 (m, 4H), 7.49 (s, 1H), 8.59 (d, J=5.1 Hz, 1H); IR
(film) 2240, 1600, 1500 cm.sup.-1.
[0562] C) Methyl 4-benzylpicolinate. A solution of
4-benzyl-2-cyanopyridin- e (7.1 g, 37 mmol) in MeOH (70 mL) was
saturated with HCl and heated at reflux for 4 h.
[0563] The reaction mixture was concentrated under reduced pressure
and was diluted with NaHCO.sub.3 (100 mL) and EtOAc (100 mL). The
organic phase was washed with brine (100 mL), dried over
Na.sub.2SO.sub.4 and concentrated under reduced pressure. The crude
compound was purified by filtration on silica gel using
EtOAc/n-hexane as eluant to afford the title compound as a pale
yellow oil (6.3 g, 76%): .sup.1H NMR (CDCl.sub.3) .delta.3.98 (s,
3H), 4.03 (s, 2H), 7.17 (d, J=6.9 Hz, 2H), 7.20-7.37 (m, 4H), 7.99
(s, 1H), 8.61 (d, J=4.8 Hz, 1H); IR (film) 1747, 1726, 1603, 1310
cm.sup.-1.
[0564] D) 4-Benzyl-2-(hydroxymethyl)pyridine. To a solution of
methyl 4-benzyl-picolinate (5.80 g, 26.0 mmol) in EtOH (100 mL)/THF
(66 mL) was added a mixture of NaBH.sub.4 (1.90 g, 51.0 mmol) and
LiCl (2.16 g, 51.0 mmol). The resulting mixture was stirred at
25.degree. C. for 4 h then concentrated under reduced pressure,
diluted with brine (200 mL) and extracted with EtOAc (2.times.200
mL). The collected organic phase was washed with brine, dried over
Na.sub.2SO.sub.4 and concentrated under reduced pressure. The crude
compound was purified by flash chromatography on silica gel using
EtOAc/n-hexane as eluant to afford the title compound as a pale
yellow oil (4.4 g, 80%). .sup.1H NMR (CDCl.sub.3) .delta.3.8 (bs,
1H), 3.97 (s, 2H), 4.70 (s, 2H), 7.03 (d, J=4.5 Hz, 1H), 7.06 (s,
1H), 7.17 (d, J=6.9 Hz, 2H), 7.20-7.40 (m, 3H), 8.43 (d, J=4.8 Hz,
1H).
[0565] E) 4-Benzyl-2-(chloromethyl)pyridine. A solution of
4-benzyl-2-(hydroxymethyl) pyridine (2.85 g, 14.6 mmol) in
SOCl.sub.2 (7.50 mL, 102 nmol) was stirred at 25.degree. C. for 30
min. and was concentrated under reduced pressure. The crude
compound was diluted with EtOAc (100 mL), washed with NaHCO.sub.3
(2.times.100 mL), dried over Na.sub.2SO.sub.4 and was concentrated
under reduced pressure to afford the title compound as a dark oil
(3.2 g, 98%): .sup.1H NMR (CDCl.sub.3) .delta.4.00 (s, 2H), 4.66
(s, 2H), 7.08 (d, J=5.1 Hz, 1H), 7.18 (d, J=7.2 Hz, 2H), 7.20-7.40
(m, 4H), 8.46 (d, J=5.1 Hz, 1H).
[0566] F) Diethyl 2-((4-benzylpyridin-2-yl)methyl)malonate. Diethyl
malonate (1.15 mL, 7.60 mmol) was added to a solution of sodium
ethoxide (0.106 g of sodium in 5.0 mL of EtOH). To the clear
solution was then added gradually a solution of 4-benzyl-2-(
chloromethyl)pyridine (0.59 g, 2.7 mmol) in EtOH (5 mL). After the
mixture had been heated at reflux for 4.5 h, the EtOH was removed
under reduced pressure. The residue was dissolved in EtOAc (50 mL),
washed with NH.sub.4Cl (2.times.50 mL), dried over Na.sub.2SO.sub.4
and was concentrated under reduced pressure. The crude compound was
purified by filtration on silica gel using EtOAc/n-hexane as eluant
to afford the title compound as a colorless oil (0.9 g, 98%):
.sup.1H NMR (CDCl.sub.3) .delta.1.12 (t, J=7.2 Hz, 4H), 1.28 (t,
J=7.2 Hz, 2H), 3.25-3.40 (m, 2H), 3.92 (s, 2H), 4.00-4.30 (m, 5H),
6.93 (d, J=4.8 Hz, 1H), 7.00 (s, 1H), 7.15 (d, J=7.2 Hz, 2H),
7.20-7.40 (m, 3H), 8.38 (d, J=5.1 Hz, 1H); IR (film) 2984, 1752,
1736, 1606 cm.sup.-1.
[0567] G) Diethyl 2-((4-benzylpiperidin-2-yl)methyl)malonate. To a
solution of diethyl 2-((4-benzylpyridin-2-yl)methyl)malonate (2.6
g, 7.6 mmol) in EtOH (30 mL) were added PtO.sub.2 (70 mg) and conc.
HCl (0.7 mL). The heterogeneous mixture was hydrogenated in a Parr
hydrogenator at 30-35 psi at 25.degree. C. for 16 h. The reaction
was filtered through a Celite pad and was concentrated under
reduced pressure to give the crude title compound as a yellow oil
(3.0 g, 100%): .sup.1H NMR (CDCl.sub.3) .delta.1.10-1.30 (m, 6H),
1.50-2.00 (m, 6H), 2.20-2.35 (m, 1H), 2.50-2.65 (m, 2H), 2.65-2.85
(m, 1H), 3.00-3.15 (m, 1H), 3.55-3.70 (m, 1H), 3.90-4.05 (m, 1H),
4.05-4.30 (m, 4H), 7.08-7.32 (m, 5H), 9.70 (bs, 2H); IR (film)
2927, 1735 cm.sup.-1.
[0568] Diethyl 2-((4-benzylpiperidin-2-yl)methyl)malonate
hydrochloride (2.7 g, 7.0 mmol) was dissolved in EtOAc (100 mL) and
washed with NaHCO.sub.3 (2.times.60 mL), dried over
Na.sub.2SO.sub.4 and concentrated under reduced pressure to afford
the free base as a yellow oil (2.28 g): .sup.1H NMR (CDCl.sub.3)
.delta.1.10-1.40 (m, 6H), 1.50-1.95 (m, 6H), 2.20-2.35 (m, 1H),
2.50-2.65 (m, 2H), 2.65-2.80 (m, 1H), 3.00-3.15 (m, 1H), 3.61 (d,
J=11.7 Hz, 1H), 3.95 (t, J=6.3 Hz, 1H), 4.05-4.30 (m, 4H); MS (m/z)
347, 301, 180, 174. HRMS Calcd for C.sub.20H.sub.29NO.sub.4:
347.2096: Found: 347.2099.
[0569] H) Ethyl
7-benzyl-2-carboxy-1,2,3,5,6,7,8,9-octahydroindolizine-3-o- ne. The
neat free base obtained above was kept at 25.degree. C. for 16 h.
The crude cyclized product was crystallized from EtOAc/n-hexane to
afford the title compound as a colorless solid (0.65 g, 50%): mp
108.degree. C.; .sup.1H NMR (CDCl.sub.3) .delta.1.00-1.30 (m, 2H),
1.31 (t, J=7.2 Hz, 3H), 1.60-1.81 (m, 2H), 1.81-2.10 (m, 2H),
2.30-2.50 (m, 1H), 2.50-2.70 (m, 3H), 3.30-3.50 (m, 2H), 4.12 (dd,
J=3.0 and 12.9 Hz, 1H), 4.24 (q, J=7.2 Hz, 2H), 7.14 (d, J=7.2 Hz,
2H), 7.20-7.35 (m, 3H); IR (KBr) 2936, 1733, 1693 cm.sup.-1; MS
(m/z) 301, 272, 228, 137. HRMS Calcd for C.sub.18H.sub.23NO.sub.3:
301.1678: Found: 301.1684.
[0570] I)
7-Benzyl-1,2,3,5,6,7,8,9-octahydro-2-(hydroxymethyl)indolizine. To
a solution of ethyl
7-benzyl-2-carboxy-1,2,3,5,6,7,8,9-octahydroindoli- zine-3-one
(0.30 g, 1.0 mmol) in THF (19 mL) was added LiAlH.sub.4 (0.080 g,
2.0 mmol). The resulting mixture was heated at reflux for 2 h then,
after cooling to 0.degree. C., the excess reducing agent was
decomposed by the dropwise addition of a saturated Na.sub.2SO.sub.4
solution. The heterogeneous mixture was filtered. The filtrate was
dried over Na.sub.2SO.sub.4 and was concentrated under reduced
pressure. The crude compound was purified by crystallization from
EtOAc/n-pentane to afford the title compound as a colorless solid
(0.23 g, 93%): mp 85-87.degree. C.; .sup.1H NMR (CDCl.sub.3)
.delta.1.00-1.20 (m, 1H), 1.20-1.50 (m, 2H), 1.50-1.70 (m, 3H),
1.79 (d, J=12.6 Hz, 1H), 1.85-2.10 (m, 3H), 2.15-2.40 (m, 1H),
2.40-2.70 (m, 2H), 2.90-3.00 (m, 1H), 3.00-3.35 (m, 2H), 3.40-3.70
(m, 2H), 7.14 (d, J=7.2 Hz, 2H), 7.20-7.35 (m, 3H).
EXAMPLE 89
4-(4-Chlorobenzyl)-1-(3-hydroxypropyl)piperidine hydrobromide
[0571] 101
[0572] This compound was prepared in a manner similar to example
82. From 4-(4-chlorobenzyl)piperidine hydrochloride (1.00 g, 4.06
mmol) and 3-bromopropanol (592 mg, 4.26 mmol, Aldrich) there was
obtained the title compound as a colorless solid (820 mg, 60%), mp
139.5-140.degree. C.; .sup.1H NMR (CDCl.sub.3) .delta.1.65-2.19 (m,
7 H), 2.52-2.69 (m, 4 H), 3.10-3.22 (m, 2 H), 3.55-3.90 (m, 5 H),
7.06 (d, J=8.4 Hz, 2 H), 7.25 (d, J=7.8 Hz, 2 H), 10.30 (bs, 1 H);
Anal. Calcd for C.sub.15H.sub.23BrClNO: C, 51.67; H, 6.65; N, 4.02.
Found: C, 51.77; H, 6.60; N, 3.88.
EXAMPLE 90
4-(4-Fluorobenzyl)-1-(3-hydroxypropyl)piperidine hydrobromide
[0573] 102
[0574] This compound was prepared in a manner similar to example
82. From 4-(4-fluorobenzyl)piperidine hydrobromide (0.26 g, 0.96
mmol) and 3-bromo-1-propanol (0.13 mL, 1.4 mmol) there was obtained
the free amine as an oil (0.20 g, 41%): .sup.1H NMR (CDCl.sub.3)
.delta.1.15-1.35 (m, 2H), 1.40-1.57 (m, 1H), 1.55-1.75 (m, 4H),
1.85 (t, J=11.1 Hz, 2H), 2.46 (d, J=6.9 Hz, 2H), 2.55 (t, J=5.7 Hz,
2H), 3.01 (d, J=11.4 Hz, 2H), 3.76 (t, J=5.1 Hz, 2H), 5.25 (bs,
1H), 6.93 (t, J=8.7 Hz, 2H), 7.00-7.10 (m, 2H).
[0575] The HBr salt was obtained as a colorless solid (0.05 g,
54%): mp 108-110.degree. C.; .sup.1H NMR (DMSO-d.sub.6)
.delta.1.35-1.55 (m, 2H), 1.60-1.85 (m, 5H), 2.70-2.85 (m, 2H),
2.90-3.05 (m, 2H), 3.05-3.20 (m, 1H), 3.30-3.50 (m, 4H), 4.73 (bs,
1H), 7.08 (t, J=8.7 Hz, 2H), 7.14-7.23 (m, 2H), 9.80 (bs, 1H); MS
(m/z) 251. HRMS Calcd for C.sub.15H.sub.22FNO: 251.1685. Found:
251.169.
EXAMPLE 91
4-(4-Fluorobenzyl)-1-(3-hydroxybutyl)piperidine hydrochloride
[0576] 103
[0577] A) 4-(4-(4-Fluorobenzyl)piperidin-1-yl)-2-butanone. To a
solution of 4-(4-fluorobenzyl)piperidine (0.50 g, 2.2 mmol) in
isopropanol (5 mL) was added methylvinyl ketone (0.25 mL, 3.0
mmol). The resulting solution was stirred at reflux for 1 h then
concentrated under reduced pressure to afford the title compound as
a pale yellow oil (0.58 g, 99%): .sup.1H NMR (CDCl.sub.3)
.delta.1.15-1.35 (m, 2H), 1.38-1.56 (m, 1H), 1.603 (bd, J=12.6 Hz,
2H), 1.894 (t, J=11.7 Hz, 2H), 2.155 (s, 2H), 2.486 (d, J=6.9 Hz,
2H), 2.615 (s, 3H), 2.8-2.9 (m, 2H), 6.9-7.0 (m, 2H), 7.0-7.1 (m,
2H); IR (film) 2928, 1720, 1514, 1219 cm.sup.-1.
[0578] B) 4-(4-Fluorobenzyl)-1-(3-hydroxybutyl)piperidine
hydrochloride. To a solution of
4-(4-(4-fluorobenzyl)piperidin-1-yl)-2-butanone (0.15 g, 0.57 mmol)
in EtOH (5 mL) was added NaBH.sub.4. The resulting mixture was
stirred at 25.degree. C. for 1 h. After quench of the excess
reducing agent with water, the solution was concentrated under
reduced pressure. The crude compound was dissolved in EtOAc (50 mL)
and washed with NaHCO.sub.3 (50 mL), dried and was concentrated
under reduced pressure to give the free base as a colorless oil
(0.15 g): .sup.1H NMR (CDCl.sub.3) .delta.1.13 (d, J=6.0 Hz, 3H),
1.10-1.30 (m, 3H), 1.40-1.70 (m, 6H), 1.95-2.10 (m, 1H), 2.45 (d,
6.9 Hz, 2H), 2.40-2.60 (m, 2H), 2.75-2.90 (m, 1H), 3.00-3.20 (m,
1H), 3.80-4.00 (m, 1H), 6.91 (t, J=8.7 Hz, 2H), 7.00-7.10 (m,
2H).
[0579] The HCl salt was obtained as a colorless solid (0.12 g,
70%): mp 99-103.degree. C.; .sup.1H NMR (DMSO-d.sub.6) .delta.1.20
(d, J=6.3 Hz, 3H), 1.35-1.55 (m, 2H), 1.60-1.95 (m, 6H), 2.59 (d,
J=6.3 Hz, 2H), 2.75-3.00 (m, 2H), 3.05-3.30 (m, 2H), 3.55 (t,
J=11.5 Hz, 2H), 3.75-3.90 (m, 1H), 7.00 (t, J=8.7 Hz, 2H), 7.18
(dd, J=5.7 and 7.8 Hz, 2H); MS (m/z) 265, 206, 109.
EXAMPLE 92
(R)-4-(4-Fluorobenzyl)-1-(3-hydroxy-2-methylpropyl)piperidine
hydrochloride
[0580] 104
[0581] This compound was prepared in a manner similar to example
82. From 4-(4-fluorobenzyl)piperidine hydrochloride (0.25 g, 1.1
mmol) and (R)-3-bromo-2-methyl-1-propanol (0.14 mL, 1.3 mmol) there
was obtained the free amine as an oil (0.20 g, 70%): MS (m/z) 265,
206; HRMS Calcd for C.sub.16H.sub.24FNO: 265.1842. Found:
265.1842.
[0582] The HCl salt was obtained as a colorless solid; mp
128-130.degree. C.; .sup.1H NMR (DMSO-d.sub.6) .delta.0.87 (d,
J=6.6 Hz, 3H), 1.40-1.60 (m, 3H), 1.60-1.80 (m, 3H), 1.90-2.10 (m,
1H), 2.65-2.85 (m, 2H), 2.90-3.05 (m, 1H), 3.40-3.50 (m, 3H), 4.90
(bs, 1H), 7.09 (t, J=8.7 Hz, 2H), 7.15-7.24 (m, 2H), 9.10 (bs, 1H);
MS (m/z) 265, 206.
EXAMPLE 93
1-(3-Hydroxypropyl)-4-(4-methoxybenzyl)piperidine hydrobromide
[0583] 105
[0584] This compound was prepared in a manner similar to example
82. From 4-(4-methoxybenzyl)piperidine hydrobromide (0.54 g, 1.9
mmol) and 3-bromo-1-propanol (0.25 mL, 2.8 mmol) there was obtained
the free amine as a pale yellow oil (0.20 g, 41%): .sup.1H NMR
(CDCl.sub.3) .delta.1.05-1.35 (m, 2H), 1.40-1.60 (m, 1H), 1.55-1.75
(m, 4H), 1.87 (t, J=11.4 Hz, 2H), 2.45 (d, J=7.2 Hz, 2H), 2.57 (t,
J=5.7 Hz, 2H), 3.03 (d, J=11.1 Hz, 2H), 3.78 (s, 3H), 3.70-3.80 (m,
2H), 6.82 (d, J=8.1 Hz, 2H), 7.04 (d, J=8.1 Hz, 2H).
[0585] The HCl salt was obtained as a colorless solid (0.13 g,
64%): mp 129-131.degree. C.; .sup.1H NMR (DMSO-d.sub.6)
.delta.1.30-1.55 (m, 2H), 1.55-1.70 (m, 3H), 1.70-1.85 (m, 2H),
2.42 (d, J=6.3 Hz, 2H), 2.70-2.85 (m, 2H), 2.90-3.05 (m, 2H),
3.05-3.20 (m, 1H), 3.20-3.5 (m, 3H), 3.68 (s, 3H), 6.82 (d, J=8.4
Hz, 2H), 7.05 (d, J=8.4 Hz, 2H), 9.90 (bs, 1H); MS (m/z): 263, 218,
121.
EXAMPLE 94
4-Benzyl-1-(5-hydroxypentyl)piperidine
[0586] 106
[0587] This compound was prepared in a manner similar to example
82.
EXAMPLE 95
1-(4-Benzoyloxybut-2-ynyl)-4-benzylpiperidine
[0588] 107
[0589] A) 1-Benzoyloxybut-4-ol-2-yn. To a solution of
but-2-yne-1,4-diol (19 g, 0.22 mol) in a mixture of dry benzene (50
mL) and dry pyridine (22 mL) was added dropwise a solution of
benzoyl chloride (22 mL) in dry chloroform (40 mL) at 0-5.degree.
C. The resulting solution was allowed to stir at room temperature
for another 4 hr and was washed with 1 N H.sub.2SO.sub.4
(4.times.20 mL), water (3.times.20 mL) and was dried over
Na.sub.2SO.sub.4. Evaporation of solvent gave a residue, which was
purified by flash chromatography to give the title compound as a
colorless oil (3.5 g, 10%): .sup.1H NMR (CDCl.sub.3) d 1.74 (bs, 1
H), 4.34 (s, 2 H), 4.97 (s, 2 H), 7.45 (m, 2 H), 7.56 (m, 2 H),
8.06 (d, J=7.5 Hz, 2 H).
[0590] B) 1-Benzoyloxy-4-bromobut-2-yne. To a stirred solution of
1-benzoyloxybut-4-ol-2-yn (3.5 g, 18 mmol) in benzene (50 mL) was
added dropwise phosphorus tribromide (1.25 mL). The resulting
solution was allowed to stir at room temperature for 24 hr. The
mixture was poured into ice water (50 g). The organic layer was
separated and the aqueous phase was extracted with ether
(3.times.30 mL). The combined organic layer was washed with
saturated NaHCO.sub.3 (2.times.20 mL), water (2.times.20 mL) and
was dried over Na.sub.2SO.sub.4. Evaporation of solvent gave the
product as pale yellow oil (3.72 g, 82%): .sup.1H NMR (CDCl.sub.3)
d 3.96 (s, 2 H), 4.99 (s, 2 H), 7.46-7.59 (m, 3 H), 8.06 (d, J=7.8
Hz, 2 H).
[0591] C) 1-(4-Benzoyloxybut-2-ynyl)-4-benzylpiperidine. A mixture
of 1-benzoyloxy-4-bromobut-2-yne (1.26 g, 5.00 mmol),
4-benzylpiperidine (0.964 g, 5.50 mmol) and K.sub.2CO.sub.3 (1.52
g, 11.0 mmol) in 50 mL of CH.sub.3CN was refluxed under N.sub.2 for
24 hr. The inorganic salt was removed through a short column of
silica gel and was washed with EtOAc (3.times.30 mL). The filtrate
was evaporated in vacuo to give a residue, which was purified by
flash chromatography to give the product as a brown oil (0.55 g,
32%): .sup.1H NMR (CDCl.sub.3) d 1.34 (m, 2 H), 1.50 (m, 1 H), 1.63
(m, 2 H), 2.11 (m, 2 H), 2.51 (d, J=6.9 Hz, 2 H), 2.78 (m, 2 H),
2.86 (d, J=11.1 Hz, 2 H), 3.31 (s, 2 H), 4.94 (s, 2 H), 7.12-7.52
(m, 8 H); MS (m/z) 348 (M.sup.++1, 20), 347 (M.sup.+, 100), 346
(M.sup.+-1, 60), 226 (30), 105 (100).
EXAMPLE 96
4-Benzyl-1-(4-hydroxybut-2-yn-1-yl)piperidine
[0592] 108
[0593] A steam of ammonia gas was bubbled through dry-ice/acetone
cooled methanol until the concentration of ammonia was about 20%.
To this solution was added a solution of
1-(4-benzoyloxybut-2-yn-1-yl)-4-benzylpi- peridine (300 mg, 0.860
mmol) in 2 mL of methanol. The resulting solution was allowed to
stir at room temperature for 24 hr. Methanol was evaporated in
vacuo to give a residue, which was purified by flash chromatography
to give the title compound as a brown oil (140 mg, 67%): .sup.1H
NMR (CDCl.sub.3) d 1.35 (m, 2 H), 1.50 (m, 1 H), 1.62 (m, 2 H),
2.08 (m, 2 H), 2.51 (d, J=6.9 Hz, 2 H), 2.89 (d, J=11.1 Hz, 2 H),
3.25 (s, 2 H), 4.24 (s, 2 H), 4.50 (bs, 1 H), 7.10-7.26 (m, 5 H).
HRMS calcd for C.sub.16H.sub.21NO 243.1613, found 243.1618.
EXAMPLE 97
4-Benzyl-1-(but-2-ynyl)piperidine
[0594] 109
[0595] A) 1-Bromobut-2-yne. To a solution of 2-butyn-1-ol (2.5 g,
40 mmol) in 30 mL of ether and 0.22 mL of pyridine was added
dropwise a solution of phosphorus tribromide (2.6 mL) in 5 mL of
ether at -20 to -30.degree. C. The resulting solution was allowed
to warm to room temperature and was refluxed for an additional 2
hr. After cooling to room temperature, the mixture was poured into
ice-water (20 g). The mixture was extracted with ether (3.times.50
mL). The combined extract was washed with brine (20 mL) and was
dried over Na.sub.2SO.sub.4. Evaporation of solvent gave the
product (2 g, 38%): .sup.1H NMR (CDCl.sub.3) d 1.59 (s, 3 H), 3.56
(s, 2 H).
[0596] B) 4-Benzyl-1-(but-2-ynyl)piperdine. A mixture of
1-bromobut-2-yne (1.19 g, 9.00 mmol), 4-benzylpiperidine (1.58 g,
9.00 mmol) and K.sub.2CO.sub.3 (2.5 g, 18 mmol) in 25 mL of
CH.sub.3CN was refluxed for 12 hr. The mixture was filtered and was
washed with EtOAc (3.times.30 mL). The filtrate was evaporated in
vacuo and was purified by flash chromatography to give the product
as a colorless oil (0.9 g, 50%): .sup.1H NMR (CDCl.sub.3) d 1.31
(m, 2 H), 1.60 (m, 1 H), 1.63 (m, 2 H), 1.81 (s, 3 H), 2.04 (m, 2
H), 2.52 (d, J=9.9 Hz, 2 H), 2.88 (m, 2 H), 3.16 (s, 2 H),
7.15-7.27 (m, 5 H); HRMS calcd for C.sub.16H.sub.21N 227.1670,
found 227.1670.
EXAMPLE 98
4-(4-Chlorobenzyl)-1-(tetralin-2-yl)piperidine hydrochloride
[0597] 110
[0598] To a stirred solution of 4-(4-chlorobenzyl)piperidine (2.00
g, 9.54 mmol) in MeOH (20 mL), 2-tetralone (1.39 g, 9.54 mmol) was
added at 25.degree. C. Upon addition, the solution turned deep
blue. Solid NaCNBH.sub.3 (1.19 g, 19.1 mmol) was added and the
resulting deep blue solution was allowed to stir at 25.degree. C.
under N.sub.2. After 7 days, the reaction mixture was added to a
solution of 10% HCl (100 mL) to give a yellow gum. The gum was
dissolved in EtOAc (50 mL). The aqueous portion was extracted with
EtOAc (2.times.50 mL). The combined EtOAc portion was washed with a
saturated solution of NaHCO.sub.3 (2.times.50 mL) and water (50
mL). The EtOAc portion was filtered through cotton and the solvent
was removed to give a brown oil (2.9 g). Initial purification was
effected by chromatography on silica gel with CHCl.sub.3 elution.
More mobile impurities eluted initially and subsequently the
product eluted as a mixture. The purest fractions (TLC) were
combined and the solvent was removed to give a brown oil. The oil
was dissolved in MeOH (10 mL), filtered through Celite and the
solvent was removed to give a brown oil. The oil was dissolved in
hexanes (10 mL, a dark gum didn't dissolve), filtered through
Celite and the solvent was removed to give an amber oil. The oil
was dissolved in MeOH (10 mL) and a solution of HCl in MeOH
(.apprxeq.1 M) was added until the amine solution was permanently
acidic (pH paper red). The solvent was removed to give a beige
solid. The solid was triturated with ether (30 mL) and was
collected. The collected solid was crystallized from
2-butanone/MeOH. The collected solid was mostly dissolved in a
boiling solution of 2-butanone (100 mL)/MeOH (6 mL). The resulting
suspension was hot filtered and the filtrate was concentrated to
approximately 70 mL at which point it turned cloudy. This was
allowed to cool to 25.degree. C. and was stored overnight at
4.degree. C. The solid was collected from the resulting suspension,
washed with 2-butanone (3.times.2 mL) and was dried in vacuo
(100.degree. C., 0.005 Torr) to yield the title compound as a
colorless, fluffy solid (705 mg, 20%): mp 243-245.degree. C. (dec);
.sup.1H NMR (CDCl.sub.3 d 1.50-2.00 (m, 4 H), 2.15-2.35 (m, 2 H),
2.50-3.58 (m, 12 H) 6.96-7.20 (m, 6 H), 2.24 (d, J=7.5 Hz, 2 H),
12.40 (bs, 1 H); MS m/z 339 (M.sup.+ (.sup.35Cl), 100). Anal.
Calcd. for C.sub.22H.sub.27Cl.sub.2N: C, 70.21; H, 7.23; N,
3.72.
EXAMPLE 99
4-(4-chlorobenzyl)-1-(3-hydroxybutyl)piperidine hydrochloride
[0599] 111
[0600] a) 2[1-(4-(4-chlorobenzyl)piperidin)]ethyl methyl ketone. To
a solution of 4-(4-chlorobenzyl)piperidine (1.0 g, 4.78 mmol) in
methyl vinyl ketone (1.0 ml) was added H.sub.2O (1 drop) and the
resulting solution stirred at 110.degree. C. for 2 h. The crude
mixture was purified by filtration on silica gel using
CH.sub.2Cl.sub.2/MeOH as eluant to afford the title compound (1.20
g, 90%) as a pale yellow oil: .sup.1H NMR (CDCl.sub.3) 1.35-1.55
(m, 5H), 1.63 (d, J=12.3, 2H), 2.055 (t, J=9.6, 2H), 2.154 (s, 2H),
2.40 (d, J=6.3, 2H), 2.748 (s, 2H), 2.972 (d, J=11.4, 2H), 7.034
(d, J=8.1, 2H), 7.218 (d, J=8.1, 2H).
[0601] b) 4-(4-chlorobenzyl)-1-(3-hydroxybutyl)piperidine
hydrochloride. To a solution of
2[1-(4-(4-chlorobenzyl)piperidin)]ethyl methyl ketone (1.10 g, 3.93
mmol) in ethanol (5 mL) was added NaBH.sub.4. (0.22 g, 5.90 mmol).
The resulting mixture was stirred at 25.degree. C. for 2 h then,
after quench of the excess reducing agent with water, the solution
was concentrated under reduced pressure. The crude compound was
dissolved in EtOAc (50 ml) and washed with NaHCO.sub.3 (50 ml),
dried and concentrated under reduced pressure. The crude compound
was purified by filtration on silica gel using
CH.sub.2Cl.sub.2/MeOH as eluant to give the free base (0.75 g, 70%)
as a pale yellow oil: .sup.1H NMR (CDCl.sub.3) 1.170 (d, J=6.0),
1.10-1.40 (m, 2H), 1.4-1.55 (m, 2H), 1.55-1.70 (m, 3H), 1.765 (t,
J=11.4, 1H), 2.047 (t, J=11.4, 1H), 2.473 (d, J=6.9, 2H), 2.45-2.70
(m, 2H), 2.937 (d, J=10.2, 1H), 3.159 (d, J=10.8, 1H), 3.86-4.0 (m,
1H), 6.4 (bs, 1H), 7.034 (d, J=8.1, 2H), 7.223 (d, J=8.1, 2H). The
HCl salt as a white solid: mp 96-101.degree. C. Anal. Calcd for
C.sub.16H.sub.25Cl.sub.- 2NO: C, 60.38; H, 7.92; N, 4.40; found C,
60.06; H, 7.88; N, 4.41.
EXAMPLE 100
4-benzyl-1-(3-hydroxy-butyl)piperidine hydrochloride
[0602] 112
[0603] The title compound was prepared from 4-benzylpiperidine
(2.00 g, 11.41 mmol) and methyl vinyl ketone (3.80 ml) in two steps
(0.80 g) as a white solid: mp 133-135.degree. C.; .sup.1H NMR
(CD.sub.3OD) 1.20 (d, J=6.0, 3H), 1.40-1.60 (m, 2H), 1.70-1.95 (m,
6H), 2.59 (d, J=6.3, 2H), 2.80-2.95 (m, 2H), 3.05-3.25 (m, 2H),
3.25-3.35 (m, 2H), 3.50-3.62 (m, 2H), 3.75-3.90 (m, 1H), 7.12-7.22
(m, 3H), 7.22-7.30 (m, 2H); Anal calcd for C.sub.16H.sub.26ClNO: C,
67.70; H, 9.23; N, 4.94; found C, 67.57; H, 9.10; 4.93.
EXAMPLE 101
4-(4-nitrobenzyl)-1-(3-hydroxybutyl)piperidine hydrochloride
[0604] 113
[0605] The title compound was prepared from
4-(4-nitrobenzyl)-piperidine (3.50 g, 15.81 mmol) and methyl vinyl
ketone (5.00 ml) in two steps as a white solid: mp 105-107.degree.
C.; .sup.1H NMR (CD.sub.3OD) 1.20 (d, J=6.0, 3H), 1.40-1.63 (m,
2H), 1.63-2.05 (m, 6H), 2.74 (d, J=6.9, 2H), 2.80-3.00 (m, 2H),
3.05-3.25 (m, 2H), 3.50-3.65 (m, 2H), 3.75-3.90 (m, 1H), 7.44 (d,
J=8.4, 2H), 8.16 (d, J=8.4, 2H); Anal calcd for
C.sub.16H.sub.25ClN.sub.2O.sub.3 1/2 H.sub.2O: C, 57.0; H, 7.78; N,
8.32; found C, 56.24; H, 7.69; N, 8.07.
EXAMPLE 102
4-benzyl-1-(3-hydroxy-3-methylbutyl)piperidine hydrochloride
[0606] 114
[0607] To a solution of 2[1-(4-benzylpiperidin)]ethyl methyl ketone
(0.50 g, 2.04 mmol) in dry THF (10 mL) was added dropwise at
-60.degree. C. a solution 1.4 M of methyl magnesium bromide in
toluene/THF. The resulting solution was stirred at -60.degree. C.
for 2 h then warmed up to 25.degree. C. for 1 h. After this period
the reaction solution was diluted with NaHCO.sub.3 (50 mL) and
extracted with EtOAc (2.times.30 mL). The collected organic phase
is washed with brine (50 mL), dried and concentrated under reduced
pressure. The crude mixture is purified by flash-chromatography
using CH.sub.2Cl.sub.2/MeOH as eluant to give the free base (0.31
g) as a colorless oil, which was converted to the Hcl salt to
afford the title compound (0.14 g) as a white solid: mp
136-138.degree. C.; .sup.1H NMR (CD.sub.3OD) 1.25 (s, 6H),
1.40-1.58 (m, 2H), 1.80-1.98 (m, 5H), 2.62 (d, J=6.6, 2H), 2.91 (t,
J=11.7, 2H), 3.16-3.24 (m, 2H), 3.52-3.63 (m, 2H), 4.89 (bs, 2H),
7.15-7.38 (m, 5H); HRMS Calcd. for C.sub.17H.sub.27NO: 261.2093;
Found: 261.2099.
EXAMPLE 103
2-[2-(4-Hydroyphenyl)ethylamino]-5-benzyl-1,3-diazacyclohexene
[0608] 115
[0609] a) Benzyl malonamide. To a solution of diethyl
benzylmalonate (50 g, 0.2 mol) in 150 mL of methanol was added 72
mL of 30% ammonium hydroxide. The resulting solution was allowed to
stir for 2 days. A white solid was filtered off and dried in vacuo
to give 23 g (60%) of the title product. mp 221-223.degree. C.
.sup.1H NMR (CDCl.sub.3) 2.934 (d, J=7.5, 2 H), 3.232 (t, J=7.5, 1
H), 7.186 (m, 5 H).
[0610] b) 2-Benzyl-1,3-diaminopropane. To a suspension of benzyl
malonamide (18.2 g, 95 mmol) in 200 mL of tetrahydrofuran was added
dropwise 1 M solution of B.sub.2H.sub.6.THF (416 mL) at 0.degree.
C. After addition, the solution was brought to reflux for 3 hrs.
The reaction mixture was allowed to cool to rt, and the excess of
diborane was destroyed by very cautious dropwise addition of
distilled water (100 mL). The solution was evaporated to dryness on
a rotary evaporator to yield a dry, white solid mess, which was
slowly treated with 6 N HCl aqueous solution (350 mL). The
resulting mixture was heated at reflux for 1 hr and then again
taken to dryness on a rotary evaporator. The residue was dissolved
into 150 mL of water and then 6 N NaOH aqueous solution was added.
The solution was extracted with chloroform (4.times.200 mL). The
combined extracts were dried over sodium sulfate and evaporated to
give 12.6 g (81%) of the product as a clear oil. .sup.1H NMR
(CDCl.sub.3) 1.75 (m, 1H), 2.625 (d, J=7.2 Hz, 2 H), 2.728 (m, 4 H)
, 7.191-7.260 (m, 5 H).
[0611] c) 5-Benzylhexahydropyrimidine-2-thione. To a solution of
2-benzyl-1,3-diaminopropane (1.64 g, 10 mmol) in 10 mL of 95%
ethanol was added dropwise a solution of 4 mL of carbon disufide in
10 mL of 95% ethanol at 0.degree. C. A gummy solid formed. The
resulting mixture was heated under reflux for 2 hrs and cooled to
rt. To this mixture was added 0.5 mL of concnetrated HCl aqueous
solution and heated to reflux again for 24 h. A white solid was
collected by filtration to give 1.2 g (58%) of the product: mp
162-163.degree. C. .sup.1H NMR (DMSO-d.sub.6) 2.0 (m, 1H), 2.536
(d, J=7.2, 2 H), 2.787 (m, 2 H), 2.988 (m, 2 H), 7.155-7.269 (m, 5
H), 7.845 (s, 2 H).
[0612] d) 5-Benzyl-2-methylmercaptotetrahydropyrimidinium Iodide.
To a solution of 5-benzylhexahydropyrimidine-2-thione (0.657 g,
3.19 mmol) in 5 mL of ethanol was added a solution of methyl iodide
(0.453 g, 3.19 mmol) in 2 mL of ethanol at 50.degree. C. The
resulting solution was allowed to stir at rt for 24 hrs. Ethanol
was evaporated in vacuo to give an oil, to which was added 10 mL of
ether. A white solid was collected by filtration and dried to give
0.65 g (63%) of the product. mp 138-140.degree. C. .sup.1H NMR
(CDCl.sub.3) 2.25 (m, 1H), 2.669(s, 3 H), 2.780 (d, J=5.0, 2 H),
3.170 (m, 2 H), 3.612 (m, 2 H), 7.131-7.306 (m, 5 H), 8.810 (s, 2
H).
[0613] e)
2-[2-(4-Hydroyphenyl)ethylamino]-5-benzyl-1,3-diazacyclohexene. A
solution of 5-benzyl-2-methylmercapto-2-tetrahydropyrimidinium
iodide (0.348 g, 1.0 mmol), tyramine (0.206 g, 1.5 mmol) in 10 mL
of ethanol was allowed to stir at reflux for 24 hrs. After cooling
down, ethanol was evaporated to give a residue, which was purified
by flash chromatography (10% methanol in chloroform), giving 150 mg
(49%) of the title compound as white-off solid. mp 153-155.degree.
C. .sup.1H NMR (CDCl.sub.3) 1.980 (s, 2 H), 2.245 (m, 1H), 2.659(m,
2 H), 3.046 (m, 2 H), 3.276 (m, 2 H), 5.010 (s, 2 H), 7.131-7.306
(m, 9 H) . HRMS Calcd for C.sub.19H.sub.23N.sub.3O: 309.1831;
Found: 309.1836.
EXAMPLE 104
4-(4-methylbenzyl)-1-(3-hydroxy-butyl)piperidine hydrochloride
[0614] 116
[0615] The title compound was prepared from
4-(4-methylbenzyl)piperidine (0.61 g) and methyl vinyl ketone (2.00
ml) in two steps (0.62 g) as a white solid: mp 134-136.degree. C.;
.sup.1H NMR (DMSO) 1.07 (d, J=6.3, 3H), 1.36-1.56 (m, 2H),
1.58-1.80 (m, 5H), 2.42-2.52 (m, 6H), 2.68-2.88 (m, 2H), 2.89-3.10
(m, 2H), 3.34-3.46 (m, 1H), 3.56-3.71 (m, 1H), 4.77 (bs, 1H), 7.04
(d, J=7.5, 2H), 7.09 (d, J=7.8, 2H), 9.75 (bs, 1H); Anal calcd for
C.sub.17H.sub.28ClNO: C, 68.55; H, 9.48; N, 4.70; found C, 68.36;
H, 9.55; N, 4.65.
EXAMPLE 105
4-(4-aminobenzyl)-1-(3-hydroxy-butyl)piperidine hydrochloride
[0616] 117
[0617] A mixture of 4-(4-nitrobenzyl)-1-(3-hydroxy-butyl)piperidine
hydrochloride (0.17 g, 0.53 mmol) in methanol (10 mL) with Pd/C 10%
(0.06 g) was hydrogenated at 1 atm and 25.degree. C. for 18 h then,
after filtration through a celite pad and concentration under
reduced pressure, the crude compound was triturated with EtOAc (10
mL) for 15 h to afford the title compound (0.13 g, 80%) as a pale
pink solid: mp 155-160.degree. C.; .sup.1H NMR (D.sub.2O) 1.038 (d,
J=6.0, 3H), 1.28-1.36 (m, 2H), 1.58-1.82 (m, 5H), 2.342 (d, J=6.3,
2H), 2.65-2.80 (m, 2H), 2.90-3.10 (m, 2H), 3.32-3.43 (m, 2H),
3.65-3.80 (m, 1H), 6.64 (d, J=8.7, 2H), 6.909 (d, J=8.4, 2H); Anal
calcd for C.sub.16H.sub.27ClN.sub.2O H.sub.2O: C, 60.65; H, 9.22;
N, 8.84; found C, 61.45; H, 8.76; N, 8.81.
EXAMPLE 106
4-(4-Chlorobenzyl)-1-(N-(2-(4-fluorophenoxy)ethyl)amino)piperidine
hydrobromide
[0618] 118
[0619] a) 4-(4-Chlorobenzyl)-1-nitrosopiperidine A stirred solution
of 4-(4-chlorobenzyl)piperidine (1.60 gm, 7.63 mmol) in H.sub.2O (3
mL) containing concd HCl (0.8 mL) was warmed to 65-70.degree. C. A
solution of NaNO.sub.2(658 mg, 9.54 mmol) in H.sub.2O (1 mL) was
added dropwise so as to maintain the above temperature. After
addition, the reaction was allowed to stir at the above temperature
for 10 min. The reaction was allowed to cool to 25.degree. C. and
was extracted with toluene (5 mL and 2 mL). The yellow extract was
dried over Na.sub.2SO.sub.4, filtered, and the solvent removed to
give a yellow liquid. The liquid was dried further (25.degree. C.,
0.005 Torr) to give a yellow liquid (1.69 g, 93%): .sup.1H NMR
(CDCl.sub.3) 1.00-1.15 (m, 1H), 1.30-1.47 (m, 1H), 1.68-1.98 (m,
3H), 2.42-2.60 (m, 3H), 3.60 (dt, J=12 and 3.0 Hz, 1H), 4.75 (dp,
J=14, 2.1 Hz, 1H), 5.04 (dp, J=14 and 2.1 Hz, 1H), 7.08 (d, J=8.4
Hz, 2H), 7.28 (d, J=8.4 Hz, 2H)
[0620] b) 1-Amino-4-(4-chlorobenzyl)piperidine A suspension of
LiAlH.sub.4 (535 mg, 14.1 mmol) in dry THF (10 mL) was heated to
refux with stirring. The mixture was removed from the heat source
and a solution of 4-(4-chlorobenzyl)-1-nitrosopiperidine (1.68 g,
7.04 mmol) in dry THF (10 mL) was added with stirring so as to
maintain a gentle reflux. After addition, the reaction was allowed
to stir at reflux for 10 min. The reaction was allowed to cool to
25.degree. C. and ether (60 mL) was added. Water (10 mL) was slowly
added with stirring so as to destroy the excess hydride. The ether
layer was separated and the aqueous portion was washed with ether.
The combined ether portion was dried over Na.sub.2SO.sub.4 and the
solvent was removed to give a near colorless liquid. This was
filtered through a column of silica gel (2.5.times.10 cm) with 2%
EtOH/98% CHCl.sub.3 elution to remove a low TLC R.sub.f impurity.
Solvent removal and drying in vacuo (0.005 Torr, 25.degree. C.)
gave a colorless liquid that solidified with scratching (1.20 g,
76%): mp 49-51.degree. C.; .sup.1H NMR (CDCl.sub.3) 1.24-1.52 (m,
3H), 1.56-1.68 (m, 2H), 2.00 (t, J=10, 2H), 2.48 (d, J=6.6, 2H),
2.86 (bs, 2H), 3.08 (d, J=11, 2H), 7.05 (d, J=8.4, 2H), 7.23 (d,
J=8.4, 2H).
[0621] c)
4-(4-Chlorobenzyl)-1-(N-(2-(4-fluorophenoxy)ethyl)amino)piperidi-
ne hydrobromide. From a mixture of
1-amino-4-(4-chlorobenzyl)piperidine (500 mg, 2.22 mmol),
2-(4-fluorophenoxy)ethyl bromide (511 mg, 2.33 mmol) and
K.sub.2CO.sub.3 (322 mg, 2.33 mmol) in CH.sub.3CN (10 mL) was
obtained the title compound as colorless flakes (165 mg, 17%): mp
214-215.degree. C. (dec). .sup.1H NMR (CD.sub.3OD) 1.75-2.05 (m,
5H), 2.70 (d, J=6.9, 2H), 3.40-3.52 (m, 2H), 3.83 (d, J=13, 2H),
4.00 (t, J=4.5, 2H), 4.52 (t, J=4.5, 2H), 6.96-7.10 (m, 4H), 7.22
(d, J=8.7, 2H), 7.30 (d, J=8.7, 2H); Anal Calcd for
C.sub.20H.sub.25BrClFN.sub.2O: C, 54.13; H, 5.68; N, 6.31. Found:
C, 54.23; H, 5.59; N, 6.23.
EXAMPLE 107
4-(1-Adamantylmethyl)-1-(2-(4-hydroxyphenoxy)ethyl)piperidine
[0622] 119
[0623] a) 4-(1-Adamantylmethyl)piperidine hydrochloride A mixture
of 4-(1-adamantylmethyl)pyridine (500 mg, 2.20 mmol) and PtO.sub.2
(15 mg) in MeOH (20 mL) containing concd HCl (1 mL) was allowed to
shake under H.sub.2 (25-30 psi) for 24 h. NMR analysis showed only
about 45% reaction. An additional portion of catalyst was added and
the reaction was allowed to proceed as above for an additional 24
h. The analysis now showed about 70% reaction. The reaction was
allowed to proceed at 50 psi for a final 24 h (72 h total). A
crystalline solid was observed in the reaction mixture. The
addition of CH.sub.2Cl.sub.2 and warming dissolved this material.
The analysis now showed .about.95% reaction. The catalyst was
removed by filtration (Celite) and the solvent was removed to give
a yellow solid. The solid was dissolved in boiling MeOH (12 mL) and
the solution was hot filtered. The filtrate was concd to 8 mL and
was cooled in an ice bath to give a suspension. The solid was
collected, was washed with ice cold MeOH (3.times.1 mL) and was
dried in vacuo (100.degree. C., 0.005 Torr) to give the title
compound as a pale yellow crystalline solid (365 mg, 62%): mp
>300.degree. C.; .sup.1H NMR (DMSO-d.sub.6) 0.95 (d, J=4.5, 2H),
1.22-1.78 (m, 17H), 1.90 (s, 3H), 2.81 (dd, J=22 and 11, 2H), 3.13
(d, J=12, 2H), 8.68 (bs, 1H), 8.89 (bs, 1H).
[0624] b) The title compound was prepared from
4-(1-adamantylmethyl)piperi- dine hydrochloride (350 mg, 1.30 mmol)
and 2-(4-hydroxyphenoxy)ethyl bromide (295 mg, 1.36 mmol) as a
beige crystalline solid (387 mg, 81%): mp 178-179.degree. C.;
.sup.1H NMR (DMSO-d.sub.6) 0.93 (d, J=5.1, 2H), 1.05-1.70 (m, 17H),
1.85-2.07 (m, 5H), 2.56 (t, J=6.0, 2H), 2.72-2.88 (m, 2H), 3.90 (t,
J=6.0, 2H), 6.63 (d, J=9.0, 2H), 6.71 (d, J=9.0, 2H), 8.88 (bs,
1H); Anal. calcd for C.sub.24H.sub.35NO.sub.2: C, 78.00; H, 9.55;
N, 3.79. Found: C, 78.03; H, 9.44; N, 3.77.
EXAMPLE 108
N-(3-(2-oxobenzimidazol-5-oxy)propyl)-1,2,3,4-tetrahydroisoquinoline
[0625] 120
[0626] a) From a mixture of 1,2,3,4-tetrahydroisoquinoline (285 mg,
2.14 mmol), 3-(4-amino-3-nitrophenoxy)propyl chloride(231 mg, 1.0
mmol) and NaI (103 mg) in toluene (15 mL) was obtained 250 mg (76%)
of
N-[3-(4-amino-3-nitrophenoxy)propyl]-1,2,3,4-tetrahydroisoquinoline
as a yellow powder. .sup.1H NMR (CDCl.sub.3): 2.05-2.18 (m, 2H),
2.779 (t, 2H, J=7), 2.83-2.88 (m, 2H), 2.93-2.97 (m, 2H), 3.753 (s,
2H), 4.049 (t, 2H, J=6), 6.752 (d,1H, J=9), 7.03-7.15 (m, 5H),
7.556 (d, 1H, J=3).
[0627] b) From a mixture of
N-[3-(4-amino-3-nitrophenoxy)propyl]isoquinoli- ne (250 mg, 0.76
mmol) and stannous dihydrate (860 mg, 3.8 mmol) in EtOH (50 mL) was
obtained 220 mg (97%) of N-[(3,4-diaminophenoxy)propyl]-1,2,3-
,4-tetrahydroisoquinoline as a yellow viscous oil. .sup.1H NMR
(CDCl.sub.3): 2.00-2.08 (m, 2H), 2.686 (t, 2H, J=7), 2.761 (t, 2H,
J=5.5), 2.916 (t, 2H, J=5.5), 3.063 (s, 2H), 3.496 (s, 2H), 3.650
(s, 2H), 3.995 (t, 2H, J=7), 6.267 (dd, 1H, J=8.5; 2.5), 6.340 (d,
1H, J=2.5), 6.670 (d, 1H, J=8.5), 7.01-7.12 (m, 4H).
[0628] c) A mixture of
N-[(3,4-diaminophenoxy)propyl]-1,2,3,4-tetrahydrois- oquinoline
(200 mg, 0.67 mmol) and CDI (162 mg, 1.0 mmol) in toluene (15 mL)
was refluxed for 16 h, then evaporated. The residual solid was
washed with EtOAc (2.times.5 mL) and CHCl.sub.3 (5 mL), then dried
to give 107 mg (48%) of the title compound as a yellow powder.
.sup.1H NMR (DMSO-d.sub.6): 1.90-1.96 (m, 2H), 2.591 (d, 2H, J=7),
2.662 (t, 2H, J=5), 2.803 (t, 2H, J=5), 3.560 (s, 2H), 3.967 (t,
2H, J=6), 6.50-6.52 (m, 2H), 6.76-6.80 (m, 1H), 7.05-7.10 (m, 4H),
10.359 (s, 1H), 10.483 (s, 1H). The hydrochloride, mp.
210-5.degree. C. (dec). Analysis, Calcd. for
(C.sub.19H.sub.22ClN.sub.3O.sub.2+0.3 HCl): C, 61.55; H, 6.06; N,
11.33; Found: C, 61.57; H, 6.14; N, 11.05.
EXAMPLE 109
N-(2-(2-oxobenzimidazol-5-oxy)ethyl)-1,2,3,4-tetrahydroisoquinoline
[0629] 121
[0630] a) From a mixture of 1,2,3,4-tetrahydroisoquinoline (400 mg,
3.0 mmol), (4-amino-3-nitrophenoxy)ethyl bromide (390 mg, 1.5 mmol)
and NaI (56 mg) in toluene (15 mL) was obtained 282 mg (60%) of
N-[(4-amino-3-nitrophenoxy)ethyl]-1,2,3,4-tetrahydroisoquinoline as
a yellow powder. .sup.1H NMR (CDCl.sub.3): 2.87-3.00 (m, 6H), 3.781
(s, 2H), 4.173 (t, 2H, J=6), 5.889 (bs, 2H), 6.762 (d, 1H, J=9),
7.02-7.04 (m, 1H), 7.11-7.14 (m, 4H), 7.602 (d, 1H, J=3).
[0631] b) A mixture of
N-[(4-amino-3-nitrophenoxy)ethyl]-1,2,3,4-tetrahydr- oisoquinoline
(250 mg, 0.8 mmol) and Raney Ni (about 200 mg) in MeOH (15 mL) was
shaken under H.sub.2 (25 parr) for 4 h, then filtered. The filtrate
was evapoated, and the residue was purified by chromatography over
silica gel (CHCl.sub.3-EtOH-NH.sub.4OH, 60:40:0.5) to give 218 mg
(96%) of
N-[(3,4-diaminophenoxy)ethyl]-1,2,3,4-tetrahydroisoquinoline as a
brown viscous oil. .sup.1H NMR (CDCl.sub.3): 2.87-2.96 (m, 10H),
3.764 (s, 2H), 4.122 (t, 2H, J=5), 6.545 (dd, 1H, J=8; 2), 6.362
(d, 1H, J=2), 6.633 (d, 1H, J=8), 7.01-7.20 (m, 5H).
[0632] c) From a mixture of
N-[(3,4-diaminophenoxy)ethyl]-1,2,3,4-tetrahyd- roisoquinoline (218
mg, 0.77 mmol) and CDI (190 mg, 1.17 mmol) in toluene (15 mL) was
obtained 218 mg (70%) of the title compound as a white powder, mp
210-212.degree. C. .sup.1H NMR (DMSO-d.sub.6): 2.76-2.85 (m, 6H),
3.654 (s, 2H), 4.087 (t, 2H, J=5.5), 6.51-6.54 (m, 2H), 6.780 (d,
1H, J=9), 7.02-7.09 (m, 4H), 10.360 (s, 1H), 10.496 (s, 1H). The
hydrochloride, mp 234-6.degree. C.
[0633] The Xenopus oocyte expression system. Mature female Xenopus
laevis were anaesthetized (20-40 min) using 0.15% 3-aminobenzoic
acid ethyl ester (MS-222) and 2-4 ovarian lobes were surgically
removed. Oocytes at developmental stages IV-VI (Dumont, J. N., J.
Morphol. 136:153-180 (1972)), were dissected from the ovary still
surrounded by enveloping ovarian tissues. Follicle-enclosed oocytes
were micro-injected with 1:1 mixtures of cRNA:NR1A+NR2A, 2B, 2C or
2D; injecting .about.2, 5, or 20 ng of RNA encoding each receptor
subunit. NR1A encoding cRNA was injected alone at .about.20 ng.
Oocytes were stored in Barth's medium containing (in mM): NaCl, 88;
KCl, 1; CaCl.sub.2, 0.41; Ca(NO.sub.3).sub.2, 0.33; MgSO.sub.4,
0.82; NaHCO.sub.3, 2.4; HEPES 5; pH 7.4, with 0.1 mg/mL gentamycin
sulphate. While oocytes were still surrounded by enveloping ovarian
tissues the Barth's medium was supplemented with 0.1 bovine serum.
Oocytes were defolliculated 1-2 days following injections by
treatment with collagenase (0.5 mg/mL Sigma Type I for 0.5-1 hr)
(Miledi and Woodward, J. Physiol. (Lond.) 416:601-621 (1989)) and
subsequently stored in serum-free medium.
[0634] Electrical recordings were made using a conventional
two-electrode voltage clamp (Dagan TEV-200) over periods ranging
between 3-21 days following injection. Oocytes were placed in a 0.1
mL recording chamber continuously perfused (5-15 mL min.sup.-1)
with frog Ringer's solution containing (in mM): NaCl, 115; KCl, 2;
CaCl.sub.2, 1.8; HEPES, 5; pH 7.4. Drugs were applied by bath
perfusion. When using the more rapid flow rates, half-times for
mid-chamber solution changes were between 2-3 sec, however,
exchange rates for drug solutions at the oocyte surface (i.e.
beneath the vitelline envelope and among the tangles of microvilli)
were probably considerably longer (Woodward et al., Mol. Pharmacol.
41:89-103 (1992)). Zero-Ca.sup.2+/Ba.sup.2+ Ringer had the
composition (in mM): NaCl, 115; KCl, 2; BaCl.sub.2, 1.8; HEPES, 5;
pH 7.4. Intraoocyte injections were made by pneumatic
pressure-pulse ejection from micropipettes (Miledi and Parker, J.
Physiol. (Lond.) 357:173-183 (1984)). Injection solutions of EGTA
(40-400 mM) and BAPTA (50-500 mM) were made up in H.sub.2O, pH
adjusted to 7.4 with KOH or HCl, and filtered to minimize plugging
(Acrodisc-13, 0.2 .mu.M). Pressure was set between 200-400 kPa. The
volume of injections was regulated by adjusting the time of pulses
(0.1-1 sec) and was estimated by measuring the diameters of ejected
droplets.
[0635] Data Analysis. The logistic equation (equation 1) was fit to
the data for individual concentration-response relations by
adjusting the slope factor, n, and the parameter pEC.sub.50;
pEC.sub.50=-log EC.sub.50 where EC.sub.50 is the agonist
concentration that produces half the maximum response (De Lean et
al., Am. J. Physiol. 235:E97-E102 (1978)) (Origin: Microcal
Software).
I/I.sub.max=1/(1+(10.sup.-pEC50/[agonist]).sup.n) Eq. 1
[0636] Concentration-inhibition curves were fit with equation
2.
I/I.sub.control=1/(1+([antagonist]/10.sup.-pIC.sup..sub.50).sup.n)
Eq. 2
[0637] in which I.sub.control is the current evoked by agonists
alone, pIC.sub.50=-log IC.sub.50, IC.sub.50 is the concentration of
antagonist that produces half maximal inhibition, and n is the
slope factor. For incomplete curves analysis by fitting was
unreliable and IC.sub.50 values were calculated by simple
regression over linear portions of the curves (Origin: Microcal
Software).
[0638] Drugs. The drugs were synthesized as described in the
Examples above.
[0639] Drugs were initially dissolved at concentrations of 10-100
mM in DMSO. Dilutions were then made to generate a series of DMSO
stock solutions over the range 10 .mu.M to 100 mM. Working
solutions were made by 1000-3000 fold dilution of stocks into
Ringer. At these dilutions DMSO alone had no measurable effects on
membrane current responses. DMSO stock solutions were stored for up
to two weeks in the dark at 4.degree. C. without apparent
reductions in potency. Ringer solutions of drugs were made up fresh
each day of use.
[0640] Maximal Electroshock-induced Seizures. Seizures were induced
by application of current (50 mA, 60 pulses/sec, 0.8 sec pulse
width, 1 sec duration, d.c.) through saline-coated corneal
electrodes using a Ugo Basile ECT device (Model 7801). Mice were
restrained by gripping the loose skin on their dorsal surface,
electrodes were held lightly against the two cornea, then current
was applied and mice were observed for a period of up to 30 sec for
the occurrence of a tonic hindlimb extensor response. A tonic
seizure was defined as a hindlimb extension in excess of 90 degrees
from the plane of the body. Results were treated in a quantal
manner.
[0641] Results
[0642] The results from the in vitro and in vivo assays are shown
in Table 1.
1TABLE 1 Example # 1A/2A 1A/2B 1A/2C Mes. ED.sub.50 (Compound)
IC.sub.50.mu.M IC.sub.50, .mu.M IC.sub.50, .mu.M mg/kg Ex. 2
>300 1.6 >300 Ex. 3 >300 4.0 >300 Ex. 6 >300 2.3
>300 Ex. 7 >300 65 >300 Ex. 8 >300 65 >300 Ex. 9 240
14 >300 Ex. 13 80.0 53.0 140 Ex. 15 60 5.5 230 Ex. 16 20.0 17.0
80.0 Ex. 18 140 35.0 >100 Ex. 19 75 10 275 Ex. 25 60.0 9.0 175
Ex. 26 30 15 105 Ex. 27 >300 50 >300 Ex. 30 95 8.0 >100
Ex. 34 >300 240 >300 Ex. 35 >300 150 >300 Ex. 38(A) 25
72 65 Ex. 38(B) 28 50 50 Ex. 41 >300 >300 >300 Ex. 47 270
40 >300 Ex. 82 290 3.3 >300 Ex. 83 224 1.8 >300 3.5 Ex. 84
270 6 >300 Ex. 85 >300 6 >300 Ex. 86 >300 12 >300
Ex. 87 >300 7 >300 Ex. 88 >300 5 >300 Ex. 89 150 0.3
>100 5.0 Ex. 90 >300 1.3 >300 Ex. 91 230 2.5 >300 6.0
Ex. 92 >300 8 >300 Ex. 93 >300 9 >300 8.0 Ex. 99
>300 1.6 >300 6.0 Ex. 100 >300 3.0 >300 3.5 Ex. 101 260
280 300 Ex. 102 >300 3.5 >300 Ex. 103 3.5 0.2 58 Ex. 104 110
0.8 >300 2.0 Ex. 105 120 17 >300 Ex. 106 8.5 5.0 23 Ex. 107
250 160 75 Ex. 108 24 7.5 >300 Ex. 109 190 140 >300 (A)
>300 5.0 >300 (B) >300 25.0 >300 (C) >300 10.0
>300 Notes: Cmp. A is 4-benzyl-1-hexylpiperidine Cmp. B is
4-benzyl-1-butylpiperidine Cmp. C is
4-(3'-fluorobenzoyl)-1-(4"-phenylbutyl)piperidine
[0643] Having now fully described this invention, it will be
understood by those of ordinary skill in the art that the same can
be performed within a wide and equivalent range of conditions,
formulations and other parameters without affecting the scope of
the invention or any embodiment thereof. All patents and
publications cited herein are fully incorporated by reference
herein in their entirety.
* * * * *