Note: Descriptions are shown in the official language in which they were submitted.
vo 91/06297 PC~r/US90/06102
~E
(N-Pht
~ d of the Inve~t;5~n
This invention relates to novel (N-
phthalimidoalkyl) piperidine compounds, pharmaceutical
compositions containing them and methods of using these
compounds and compositions to treat physiological or
drug induced psychoses in mammals and also as
0 antidyskinetic agents.
Pr; or Art
U.S. Patent 4,849,431 (Sigimoto et al.) discloses
compounds of the formula:
Rl-X-A_R2
wherein:
Rl denotes a univalent group derived from one selected
among substituted or unsubstituted benzene,
pyridine, pyrazine, indole, anthraquinone,
quinoline, substituted or unsubstituted phthalimide
including specifically:
' ~0
O O
- , ~ N and
O O
WO91/06297 ~ v PCT/US90/06102
o~,,N~,~o
~ ;
pyridinecarboxylic acid imide, pyridine N-oxide,
pyrazinedicarboxylic acid imide, substituted or
unsubstituted quinazolinedione and pyromerylimide;
X denotes a group of the formula -~CH2)n~, -O(CH2)n~,
-S(CH2)n~, -NH(CH2)n~t ~SO2NH(CH2)n~, -NH-C-(CH2)n-
o
NH(CH2)n~C-~ ~C-o(cH2)n~~ -CH2NH(CH2)n~,
O O
-C-N-~CH2)n
Il I
o R3
OH
or -OCH2-CH-CH2 (in all the above formulas, n is an
integer of 1 through 7 and R3 represents a lower
alkyl group or a benzyl group);
ring A denotes a group of the formula,
--N3 , {~ =C
r\
o
5 R2 denotes hydrogen, lower alkyl, substituted or
unsubstituted benzyl, substituted or unsubstituted
benzoyl, pyridyl, 2-hydroxyethyl, pyridylmethyl or
2 " ~ ~ 3 1 ~
~ ~91/06297 PCT/US90/06102
a group of the formula
Z~3 OH
(wherein Z represents a halogen atom).
These compounds are disclosed as being useful in
the treatment and prevention of demen~ia and sequelae of
cerebrovascular disease.
U.S. 4,495,194 and U.S. 4,600,758 describe 3-
oxoisoindole derivatives having antihypertensive and/or
diuretic properties characterized by a compound of the
formula:
H2N502~XN ~ R2
1 ~
wherein:
X is halogen or trifluoromethyl;
R1 and R2 are independently hydrogen, lower alkyl, lower
alkoxy, lower alkenyloxy, lower alkylthio,
trifluoromethyl, cyano, or nitro;
Y is a single bond or a divalent straight or branched
chain alkylene radical of 1 to 4 carbon atoms
inclusive.
U.S. 4,495tl94 and U.S. 4,600,758 also describe the
following compounds as intermediates:
W O 91/06297 P~r/US90/06102 .^
O O
H2NS02)~ H2NSO
OH
/--\
where R - ~ N-Y ~ /
~\J
GB 1,425,578 discloses compounds of the formula:
~ - N ~
and their pharmaceutically acceptable acid addition
salts, wherein:
R1 is hydrogen, alkyl, aralkyl or alkyl substituted by a
heterocyclyl group;
R2 and R3, which may be the same or different, are
hydrogen, halogen, trifluoromethyl, lower alkyl,
lower alkoxy, nitro, hydroxy, amino, monoalkylamino
or dialkylamino.
Th ~e compounds are disclosed as having anti-
convulsant activity and in some cases, anti-inflammatory
activity or anti-arrhythmic activity.
U.S. 4,289,781 (Bengtson et al.) describes
compounds useful for the treatment of psychoses in man
such compounds having the formula:
'~ 91/06297 ~ :3 .~ PC~r/US90/06102
O ~
wherein:
R0 and Rl are the same or different and are each
selected from hydrogen, halogen, alkyl having 1, 2
or 3 carbon atoms, alkoxy having 1, 2, or 3 carbon
atoms, and trifluoromethyl; and
R2 is selected from hydrogen, halogen, alkyl having 1,
2, or 3 carbon atoms, alkoxy having 1, 2, or 3
carbon atoms, and trifluoromethyl.
The compounds described in the prior art, cited
above, do not show the sigma receptor selectivity
demonstrated by the compounds of the present invention.
It is this sigma receptor selectivity which makes the
1~ compounds of the present invention advantageous over
compounds of the prior art. Traditionally,
antipsychotic agents have been potent dopamine receptor
antagonists. For example, phenothiazines such as
chlorpromazine and most butyrophenones such as
haloperidol are potent dopamine receptor antagonists.
These dopamine receptor antagonists are associated with
a high incidence of side effects, particularly
Parkinson-like motor effects or extra-pyramidal side-
effects (EPS), and dyskinesias including tardive
dyskinesias at high doses. Many of these side effects
are not reversible even after the dopamine receptor
antagonist agent is discontinued.
The present invention is related to antipsychotic
agents which are selective antagonists for the sigma
receptor. Unlike dopamine receptor blockers known in
the art, the compounds of the present invention have low
WO91/06297 ~ ;3~ PCT/US90/06102 ;-
potential for the typical movement disorder side-effects
associated with the dopamine antagonist antipsychotic
agents while they maintain the ability to antagonize
aggressive behavior and antagonize hallucinogenic-
induced behavior.
.SUMM~RY OF T~E I~V~5lQ~
The sigma-selective antipsychotic compounds of the
present invention are (N-phthalimidoalkyl) piperidines
of the formula:
R16
--~ CH2 ) nR2
N J 2 (I)
Rl 1
or a pharmaceutically acceptable salt or an N-oxide
thereof wherein:
a is a single or double bond, provided that when a is a
double bond then R2~CH2)n is attached at C-4 and
R16 does not apply;
n is 0-4, provided that when ~CH2)nR2 is attached to the
2-position of the piperidine ring then n is 2-4;
R1 is ~CH2)mR3 or ~CH2)pAr, where m is 1-4 and p is 1-4;
R2 is
'0 91/06297 ~ 3 C,'~ PCI'/Us90/06102
~N-- ~ ~
R4~N-- ~N~ N--
o R4 O R4 O
C~N-- ~N-- ~N--
N ~ ~X
R4 O R4 R4 R4 R4
WO 91/06297 ~ ;) PCr/US90/06102
R4 R4 R4
O~N~ X~N~ O~N'
~X ~0 ~X
R4
XtN ' OtN ~ x~, N ~ro
R4k~ R4 R4 R4
~$ ~N-- R4--~N--
R4 R4 0 0
-'O91/06297 ~J ~?~ PCT/US90/06102
o X O
X 'R 0 R
R4~ R4~ R4~
R4~ R4 X X
X X X
RJ~0 R4~ ' R4~0
~o ' o
R3 is cycloalkyl of 3 to 8 carbon atoms;
R4 is 1-4 substituents independently selected from the
group consisting of H, halogen, NO2, NH2, haloalkyl
of 1 to 3 carbon atoms and 1 to 7 halogen atoms,
C1-C3 alkyl, NHCoR7, NHCO-phenyl~ OH, oR8 and Ar';
R5 and R6 independently are H, alkyl of 1 to 3 carbon
atoms, Ar'' or taken to~ether are -CH=CH-CH=CH-;
10 R7 and R8 independently are H or alkyl of 1 to 3 carbon
atoms;
X is O; H2; H, OH; R9, OH; Ar''', OH; H, R9; or H, oR9;
Y is CH2, CHR10, C~R10)2, O, CH2CH~, (CH2)3,
WO91/06297 ~ PCT/US90/06102
~ , S, ¢ or ¢
Ar, Ar', Ar'' and Ar''' independently are phenyl,
naphthyl, pyridyl, pyrimidyl, quinolyl or
isoquinolyl, each optionally substituted with 1-5
substituents independently selected from the group
consisting of:
H, halogen, OH, alkoxy of 1 to 3 carbon atoms,
NRllR12, SH, S~o)tR13, where t is 0-2, haloalkyl
of 1 to 3 carbon atoms and 1 to 7 halogen atoms,
alkyl of 1 to 3 carbon atoms, CO2H, carboalkoxy
of 2 to 6 carbon atoms, CN, NO2, SO2NH2, SO3H,
Co2NR19R15 or phenyl;
R9 and R10 independently are alkyl of 1 to 3 carbon
atoms;
R11-R15 independently are H or alkyl of 1 to 3 carbon
atoms; and
R16 is H, OH, O-alkyl of 1-6 carbons, O-acyl of 1-8
carbons, alkyl of 1-12 carbons, 1- or 2-naphthyl,
or phenyl optionally substituted with one or two
substituents independçntly selected from the group
consisting of:
F, Cl, Br, I, alkyl, phenyl, perfluoroalkyl,
alkoxy, aryloxy, alkylthio, arylthio,
perfluoroalkoxy, perfluoroalkylthio,
dialkylamino (where alkyl and alkoxy are from 1-
12 carbons and aryl is from 6-12 carbons)
or 2- and 3-pyrrolyl, 2- and 3- furyl, 2- and 3-
thienyl, 2,3, and 4-pyridyl, 2- and 3-benzolfuryl,
2- and 3- indolyl, 2- and 3- benzothienyl, 2, 3,
and 4- quinolyl, and 1, 3, and 4-isoquinolyl;
with the following provisos:
(1) if n is O and R2 is attached at the C-4
VO91/06297 PCT/US90/06102
position of the piperidine ring,
then R2 cannot be:
N if X is O; H2; or H, OH;
o
where there are two R4 substituents and one is
H2NSO2 and the other is halogen or CF3;
~2) if R1 is (CH2)pAr and p is 1 and -(CH2)nR2
~n=1 to 4) is attached at the C-4
position of the piperidine ring,
then R2 cannot be:
5~N~ ~
, or ~ :
(3) if R1 is ~CH2)pAr (where p is 1);
O
R2 is ~ N
X
R4 is H, alkyl, CF3, halogen or alkoxy;
WO 91/06297 ~ r~ PCT/US90/06102
~CH2)nR2, ~n=O), is attached at the C-4
posi~ion on the piperidine ring;
then X cannot be H2 or O;
~4) if Rl is ~CH2)pAr (p is >O);
R2 is attached at the C-3 or C-4 position of
the piperidine ring; and
where R is H,
~ halogen, CF3, alkyl,
R2 is 1 ll N ; alkoxY, NH2,
`~ ~ alkylamino and
X dialkylamino;
1 0
then X cannot be O; and
~5) when (CH2)nR2 is attached to the 4-position of
the piperidine ring Rl6 is H, OH, alkyl or aryl.
Some compounds of the pre~ent invention can exist
as optical isomers and both the racemic mixtures of
these isomers as well as the individual optical isomers
which confer activity are within the scope of the
present invention. The racemic mixtures can be
separated into their individual isomers by techniques
well known to those skilled in the art.
In addition some compounds of the present invention
can exist as ~i~ or tran~ isomers and although these are
not all specifically set forth, the Sia and trans fused
compounds as known to those skilled in the art, are
within the scope of this invention.
Preferred compounds of the present invention are
compounds of formula (I) wherein:
n is 1-4; and/or
Rl is (CH2)pAr; and/or
p is 1-2; and/or
-'0 91/06297 '~ J u '~ i ?~ PCr/usgo/06102
R2 is ~N-- ~N
O O
Rs~
R6 ~ N - ; and/or
o
(CH2)nR2 is attached at the C-4 position of the .
piperidine ring; and/or
X is O or H2; and/or
R4, R5 and R6 are all H; and/or
Ar is phenyl; and/or
Y is (CH2)3 or O.
More preferred compounds of the present invention
0 are the compounds of formula (I) wherein n is l.
Specifically preferred compounds are compounds of
formula (I) wherein:
(l) (CH2)nR2 is attached at the C-4 position of
the piperidine ring;
n is l;
o
R4~\N--
X is O;
R4 is H;
Rl is (CH2)pAr;
p is 2; and
Ar is phenyl.
WO91~06297 PCT/US90/06102
.J ~ t ~
14
(2) (CH2)nR2 is attached at the C-4 position of
the piperidine ring;
n is 1;
X
R is ~ N
X is O;
Y is (cH2)3;
R5 and R6 are H;
Rl is (CH2)pAr;
p is 2; and
Ar is phenyl.
(3) ~CH2)nR2 is attached at the C-4 position of
the piperidine ring;
n is l;
R6 ~ O N - ;
X is O;
Y is O;
R5 and R6 are H;
Rl is (CH2)pAr;
p is 2; and
Ar is phenyl.
"O 91/06297 ~ 3 ` ~ ~ PC~r/U590/06102
(4) (CH2)nR2 is attached at the C-4 position of
the piperidine ring;
n is l;
X
R is ~ N - ;
O
X is H2;
R4 is H;
Rl is (CH2)pAr;
p is 2; and
Ar is phenyl.
Also provided are pharmaceutical compositions and
methods of using them for the treatment of physiological
or drug induced psychosis or dyskir,esia in a mammal,
said compositions comprising a pharmaceutically
acceptable carrier and an antipsychotic or an
antidyskinetic effective amount of a compound having the
formula
R16
a~ 3 (CH2)nR2
J 2 ~I)
Nl 1 1
or a pharmaceutically acceptable salt or an N-oxide
thereof wherein:
WO91/06297 ~ PCT/US90/06102
16
a is a single or double bond, provided that when a is a
double bond, then R2(CH2)n is attached at C-4 and
R16 does not apply;
n is 0-4, provided that when (CH2)nR2 is attached to the
2-position of the piperidine ring then n is 2-4;
R1 is (C~2)mR3 or (C~2)pAr, where m is 1-4 and p is 1-4;
R2 iS
j~N-- 0~ ~
R4~N-- ~N-- 5~N--
O R4 R4 0
~XXN-- C~N-- ~N--
o X 2~
R4k~ R4
'''~91/06297 ~, 3'3'~ ~ g PCI/US90/06102
R4 R4 R4
~X ~0 ~X
R4
X N~ O~N~ X~,N~O
R4 R4
R4 R4 0
WO91/06297 ~ PCT/US90/06102
o X O
C~X ' R4 R Q~X
O O X
O 0 ~0
R4 ~ R4 ~ o ' R4 ~ 0 '
Rs ~ N - ~ N - ~ N -
R3 is cycloalkyl of 3 to 8 carbon atoms;
R4 is 1-4 substituents independently selected from the
group consisting of H, halogen, NO2, NH2, haloalkyl
of 1 to 3 carbon atoms and 1 to 7 halogen atoms,
C1-C3 alkyl, NHCoR7, NHCO-phenyl, OH, oR8 and Ar';
R5 and R~ independently are H, alkyl of 1 to 3 carbon
atoms, Ar'' or taken together are -CH=CH-CH-CH-;
R7 and R8 independently are H or alkyl of 1 to 3 carbon
atoms;
X is O; H2; H, OH; R9, OH; Ar''', OH; H, R9; or H, OR9;
Y is CH2, CHRl0, C(R10)2, O, CH2CH2, (CH2)3,
~'091/06297 rS~ PCT/US90/06102
19
~ , S, ¢ or ¢
Ar, Ar', Ar'' and Ar''' independently are phenyl,
naphthyl, pyridyl, pyrimidyl, quinolyl or
isoquinolyl, each optionally substituted with 1-5
substituents independently selected from the group
consisting of:
H, halogen, 0~, alkoxy of 1 to 3 carbon atoms,
NR11R12, SH, S(o~tR13, where t is 0-2, haloalkyl
of 1 to 3 carbon atoms and 1 ~o 7 halogen atoms,
alkyl of 1 to 3 carbon atoms, C02H, carboalkoxy
of 2 to 6 carbon atoms, CN, N02, S02NH2, S03H,
Co2NR14R15 or phenyl;
R9 and R10 independently are alkyl of 1 to 3 carbon
atoms;
Rl1-R15 independently are H or alkyl of 1 to 3 carbon
atoms; and
R16 is H, OH, O-alkyl of 1-6 carbons, O-acyl of 1-8
carbons, alkyl of 1-12 carbons, phenyl or l-or 2-
naphthyl optionally substituted with one or two
substituents independently selected from the group
consisting of:
F, Cl, Br, I, alkyl, phenyl, perfluoroalkyl,
2~ alkoxy, aryloxy, alkylthio, arylthio,
perfluoroalkoxy, perfluoroalkylthio, and
dialkylamino (where alkyl and alkoxy are from 1-
12 carbons and aryl is from 6-12 carbons)
or 2- and 3- pyrrolyl, 2- and 3- furyl,
2- and 3- thienyl, 2,3, and 4-pyridyl, 2- and 3-
benzolfuryl, 2- and 3- indolyl, 2- and 3-
benzothienyl, 2, 3, and 4- quinolyl and 1, 3, and
4-isoquinolyl;
with the following provisos:
WO91/06297 '~ PCT/US90/06102
(1) when R1 is ~CH2)pAr (p is 1);
o
R2 iS ~N ; and
(CH2)nR2, (n=O), is attached at the C-4 position on
the piperidine ring;
then X cannot be H2; and
(2) When ~CH2)nR2 is attached to the 4-position of the
piperidine ring, then the R16 is H, OH, alkyl or
aryl.
Detailed Descri~Ilon of thç InventiQn
Compounds of formula ~I) may be made by various
methods set forth herein.
~ethod A
The reaction of amines of type 1 with the
anhydrides corresponding to R2 ~in which N- is replaced
by O) in solvents such as tetrahydrofuran, toluene, or
dimethylformamide at temperatures of about 0-100C gives
2~ amide acid intermediates of type ~. These can be
converted into the compounds of formula ~I), of this
invention, by a number of methods including: heating to
about 100-250C in a high-boiling solvent such as
dimethylformamide, xylene, or 2-methoxyethyl ether;
treatment with an acid chloride such as acetyl chloride
at temperatures of about 25-100C; or treatment with
anhydrides such as acetic anhydride, optionally in the
presence of a base such as so~lum acetate, at
temperatures of about 50-200~. This method, which can
be used to prepare the compounds of this invention where
X=O, is illustrated by the following Scheme:
`~091/06297 ~ PCT/US90/06102
Sohem~ ~
(CH2) nNH2 + E~
Rl 1 0
[~J ~C0211 ~lCII2) nN~3
Rl Rl
Alternatively, the two reactions of Scheme A may be
carried out in a single step by heating amines l with
anhydrides corresponding to R2 ~where N- is replaced by
O) in high-boiling solvents, such as dimethylformamide
or ethylene glycol dimethyl ether, or without solvents
to temperatures of about 140 to 200.
The amines l and the anhydrides corresponding to R2
where N- is replaced by 0 are known in the literature or
can be prepared by standard methods: Harper, N.J.,
Chignell, C.F.; ~L ~ed. Chem~ tq~4, l, 729; Abou-
Gharbia, M., et al., i~ 2~ l, 1382.
~ethod ~
In a variation of Method A, amines l are replaced
by the corresponding pyridine derivatives ~.
Preparation of the imides of type g is carried out in
the same way as described in Method A. The
intermediates of type ~ are then reacted with an
alkylating agent of type RlZ, where Z is Cl, Br, I or an
activated ester group such as OSO2-alkyl or OSO2-aryl,
at temperatures of about 0 to 200~C in solvents such as
ether, tetrahydrofuran, acetonitrile, alcohols such as
W O 91/06297 PC~r/us9O/06102 _.
`'`'' " 1"~
ethanol or n-butanol, or dimethylformamide. The
quaternary pyridinium salt~ of type ~ so obtained are
then reduced to the compounds of the invention by
treatment with hydrogen in the presence of a catalyst
such as platinum at temperatures of about 0 to 200C and
hydrogen pressures of 1-100 atm. in solvents such as
acetic acid or ethanol optionally in the presence of an
acid such as hydrochloric acid. This method, which can
be used to prepare compounds of this invention where X=0
that do not contain functionalities that are reduced
under the conditions of the catalytic hydrogenation, is
illustrated by the following Scheme:
Cch~me B
o
N
~J ~ 2)n ~ CO2~ ~ ~
O
O O
RIS ¢~ ~CH2) nN~ --~ ~J ICH2) n N~
Rl Z O Rl
Amines ~ are known in the literature or can be
prepared by standard methods: Satoh, T. and Suzuki, S.,
19~3~ 464~ 4555-
~ ~ t~ r~
~vo 91/06297 PC~r/~S90/06102
~et~o~ C
Imides, R2H, are treated with a base, such as
sodium hydride or potassium hydride in aprotic solvents
such as tetrahydrofuran, dimethylformamide or
dimethylsulfoxide at temperatures of about 0 to 100C to
give salts of type h. The salts are then reacted with
pyridine derivatives of type l where Z is Cl, Br, I or
an activated ester such as OSO2-alkyl or OSO2-aryl in
the same solvents at temperatures of about 0 to 150C to
give intermediates of type 8. These are then treated
with an alkylating agent R1Z and the quaternary
pyridinium salts so obtained are reduced to the
compounds of this invention as described in Method B.
This method, which can be used to prepare compounds of
this invention where nzl-4, X=0; H2; H,R9; H,OR9 and
that do not contain groups that are reduced under the
conditions of the catalytic hydrogenation, is
illustrated by the following scheme:
WO 91/06297 .~ t! ~ Pcr/uss
24
~sh~me c
~--NH ~~ NNa ¢~ (CH2) nZ
O ~ O
CN2)_N~
CH2) nN~
In a variation of this ~ethod C, salts of type ~
are reacted with alkylating agents of type ~ where Z is
as defined above under the same conditions as described
above to give the compounds of th~s invention where
n=0-4 and X=0; H2; H,R9 or H,OR9, as illustrated by the
following scheme:
O 91/06297 ~ ;` PC~r/US90/06102
c~e~e ~-1
O O
O~N21a~J--(C~2) nZ ~J(C~2) nl~3
Rl Rl
The imides R2H are known in the literature or can
be prepared from the corresponding anhydrides by methods
well known in the literature: Kitahonoki, K;
~akehi, M., U.S. Patent 3,126,395 (1964).
Method D
Amines of type 1 (as specified in Method A) are
allowed to react with maleic anhydride or maleic
anhydrides substituted with one or two R4 groups to give
maleamic acids of type 10. The latter are converted
into the maleimides of type 11 by well-known methods
such as those given in Method A. The maleimides of type
11 are then subjected to the Diels-Alder reaction with
dienes listed below which are optionally substituted
with R5 and R6 in solvents such as tetrahydrofuran,
acetonitrile, or aromatic hydrocarbons such as toluene
or xylene, or chlorinated aromatic hydrocarbons such as
chlorobenzene or dichlorobenzene; at temperatures of 0-
250C and pressures of 1-15,000 atm. to give certain
compounds of this invention. The Diels-Alder reaction
is optionally carried out in the presence of a radical
inhibitor such as hydroquinone or phenothiazine to
prevent polymerization of the dienes.
WO91/06297 ,~ PCT/US90/06102 --
26
Y~ ~ Y=~CH2, CHR9, C~R9)2, CH2CH2, ~CH2)3, O, S)
~ O O
1~ ~ ~
Dienes of type ~ ~W and ~ .
are obtained in Si$~ by methods well known in the
literature, for instance by heating compounds of
type ~ ~ and
respectively to temperatures of about 60-200C. Dienes
of type ~ ~ ~ and ~ are known to
undergo the Diels-Alder reaction in the form of their
valence isomers ~ , ~ and
respectively to give compounds of this invention where
Y is ~ , ~ and ~
-vo 91/06297 ~ ;J PCT/US90/06102
This method, which can be used to prepare compounds
of this invention where X50 and R2 is specified by the
dienes listed above, is illustrated with the following
scheme:
9~h~m~
~- (CH2)nNH2 + ~ ~ CH2)~NHCO
Rl ~ RlH02C
--(CII~)nN~ C~z)nN~
1 0
The products of the Diels-Alder reaction are
optionally subjected to catalytic hydrogenation in
solvents such as tetrahydrofuran, ethyl acetate, or
ethanol, with catalysts such as palladium or platinium,
at temperatures of about 0 to 200~C and hydrogen
pressures of 1-100 atm. to give certain compounds of
this invention as illustrated by the following example:
O O
(CH2) nN~ (CH2) n N~
Rl O Rl
WO91/06297 ~ J ~ ? I ~ () PCT/US90/06102 - `
28
A variation of this me.hod uses amines ~, as
specified in Method B, as the starting materials. The
pyridine imides of type 1~ obtained in this way are
converted into certain compounds of this invention by
quaternization followed by reduction as described in
Method B. The double bond introduced in the Diels-
Alder reaction is also reduced in the last step, as
illustrated in the following scheme:
1 0 Sc~eTne T~-l
o
E~, (CH2 ) nNH2 ~ N~ 3
O H02C
N~ ~3 N~ ~3
N~ I z ~ ~J (CH ~) n N~3
~ethod E
Compounds of this invention where the (CH2)nR2
group is attached to the 2- or 4-positions of the
piperidine ri~g, where n~2 and where X=0; H2; HR9; or
H,OR9 can be prepared as followc: compounds R2H react
with 2-vinylpyridine or 4-vinylpyridine in the presence
of a base such as Triton B or sodium hydride in high-
boiling solvents such as N-methylpyrrolidone or,
'O 9lt06297 ~ ;3 '~ 3 PCT/Us90/06102
preferably, using the vinylpyridines as solvents, at
temperatureq of about 100-250C to give imides of type
1~. These are then converted into certain compounds of
this invention, as specified above, by quaternization
followed by reduction as described in Method B. The
following scheme is an illustration of this method.
che~e E
+ ~ NH
~ N ~ ~ N
R
Vari~ion of ~h~ x Suhst~i~uen~
Compounds of this invention where XsH, OH are made
from compounds where X=0 by reaction with hydride
reducing agents such as sodium borohydride in methanol,
or sodium borohydride in ethanol in the presence of a
mineral acid such as hydrochloric acid, or lithium
borohydride in an aprotic solvent such as
tetrahydrofuran, at temperatures of about -20 to 60C
as shown in the following example:
WO 91/06297 PCI'/US90/06102 -.
OH
--~ (CH2) n N~ ~ ~ CH2) n N~
Rl O ~
Phthalimides may also be reduced to compounds of
type 1~ by the action of zinc and acetic acid.
Compounds of this invention where X=H, OR9 are
prepared from compounds where X=~, OH (such as 1~ above)
by reaction with an alcohol R90H in the pre~ence of an
acid such as hydrochloric acid or methanesulfonic acid
at temperatures of about 0-100C. Alternatively,
compounds where X=H, OH ~such as 14 above) can be
treated with a base such as sodium hydride in
appropriate solvents such as tetrahydrofuran, or metal
alkoxides such as sodium methoxide in alcohol solvents
such as methanol, followed by addition of an alkylating
agent R9Z where Z is Cl, Br, I; OSO2-alkyl or OSO2-aryl,
at temperatures of about 0-100C, for instance:
OH R9 OH. H OR9
ICH2)n N~3 ~N~
Rl O 2. R9X Rl O
Compounds of this invention where X-R9, OH are made
by allowing compounds where X~0 to react with
organometallics such as R9Li or R9MgM where M=Cl, Br, I,
in aprotic solvents such as tetrahydrofuran or diethyl
ether at temperatures of about -7Q to +70C followed by
hydrolysis as shown in the following example:
-"O9l/06297 2 i} ~ 3.~ ~ PCT/US90/06102
--(C112)nN~ ~ (CV
Compounds of this invent~on where XsR9,H are
prepared from compounds where X=R9,OH (such as 1~ above)
by the action of hydride reducing agents such as sodium
cyanoborohydride in the presence of a carboxylic acid
such as acetic acid in solvents such as methanol at
temperatures of about 0-100C as illustrated in the
following example:
1 0
[~J (C1~2)n;~ ~--(C~2)~
Compounds of this invention where X=H2 are prepared
from compounds where X=0 or X=H,OH by reaction with
metals such as zinc in acetic acid or tin in acetic acid
in the presence of hydrochloric acid at temperatures of
about 50-200C, for instance:
~7(CN2).~N~3 ~J (Cs2)l~N~3
WO 91/06297 r~ PCT/US90/06102 --
32
An alternate method for the preparation of
compounds of this i.vention where X=H2 uses anhydrides
corresponding to R2 (N- replaced by O) as starting
materials. Reaction with amines 1 give the amide acids
2 as shown in Scheme A and described in Method A.
Selective reduction of compounds of type ~ with diborane
or with hydride reducing agents such as lithium
aluminium hydride in aprotic solvents such as
tetrahydrofuran at temperatures of about ~30 to +30C
give the alcohols of type 1~. These are converted into
activated esters 11 by the action of al~yl or
arylsulfonyl halides such as methanesulfonyl chloride in
solvents such as tetrahydrofuran or methylene chloride
in the presence of a base such as pyridine or
triethylamine at temperatures of about 0 to 50C.
Treatment of compounds 17 with a base such as sodium
hydride in aprotic solvents such as tetrahydrofuran or
dimethylformamide gives compounds of the invention where
X=H2 as illustrated in the following example:
-VO9l/06297 h ~ PCT/US90/06102
(CH2) n~C02H ~_ ~J (Cff2) nNHC~H2oH
(CH2 ) nNHC,~,<~CH20SO2Me
~ ~J (cH2~ nN~
Rl
Alternatively, the anhydrides corresponding to R2 (N-
replaced by 0) are allowed to react with alcohols such
as methanol, ethanol, or t-butanol at temperatures of
about 0-100C to give half esters of type 1~- These are
reduced selectively with diborane in solvents such as
tetrahydrofuran at temperatures of about -20 to 50C to
give the alcohols of type 12- These are converted into
compounds ~Q where Z=Cl, Br, I, SO2-alkyl or SO2-aryl by
well known methods, such as treatment with thionyl
chloride, phosphorus tribromide or alkyl- or
arylsulfonyl halides in the presence of a base such as
pyridine or triethylamine. Compounds 2Q are then
allowed to react with amines 1 to give compounds of this
invention where X~H2. This method is illustrated by the
following example:
WO 91/06297 PCI/IIS90/06102 --
,J i ,;~
34
o
CO2t-Bu ~ CO2t-Bu
~( C02EI CH20H
18 ~
~ ~C~i2) nNH2 0
CO2t-Bu
C~2Z R ~ ~ J (CH2)
2Q Rl
Variation of the Rl_a~hg~l~n~
The substituent Rl can be introduced as described
in methods A-E above. Alternatively, a protecting group
P may be used in place of Rl. The group P is removed at
the end of the synthesis and replaced by Rl. For
instance, a benzyl group may be used as shown in the
following example. The benzyl group may be then
replaced by hydrogen using well-known methods such as
hydrogenolysis in the presence of a catalyst such as
palladium and the Rl group may be introduced by treating
the secondary amine with alkylating agents RlZ where Z
is Cl, Br, I, OSO2-alkyl or OSO2-aryl in the presence of
a base such as alkali carbonates at temperatures of.
about 0 to 150C in solvents such as acetonitrile or
dimethylformamide.
'~'091/06297 PCT/US90/06102
~J (CH2)oRZ ~ I I H2
~ CH2Ph
CJ (CHZ~nRZ r ~J (CH2~,~R2
CH2Ph H
Rl Z ~ ~J ( CH2 ) nR2
Rl
Alternatively, a methyl group may serve as a
protecting group P. It may be removed by well-known
methods such as reaction with cyanogen bromide followed
by hydrolysis, or reaction with alkyl chloroformates
followed by hydrolysis.
Pre~arati2~ of ~.4-Unsatu~ted ~erivatives
0 Compounds where R2~CH2) n is attached to C4 and a is
a double bond are prepared by reduction of quaternary
salts such as 5 with metal borohydrides such as sodium
or potassium borohydride in alcoholic solvents or
lithium borohydride in tetrahydrofuran at low
temperature (-50 to 0).
WO91/06297 ~ jJ PCT/U590/06102 --
MBH~ ~
R1 R1
An alternate route, which avoids possible
complications due to reduction of the imide, involves
quaternization of the known 4-pyridinealkanols followed
by reduction with metal borohydrides in alcohol solvents
at low temperatures (-50 to 25) to give the
unsaturated alcohols 21. These are then coupled to
imides R2H by reaction with triphenylphosphine and
diethyl azodicarboxylate in anhydrous solvents such as
tetrahydrofuran at temperatures of -20 to 60
(Mitsuhobu et al., IJ. ~m_ C~em_ So~., q4, 679 (1983)).
(CH2)nOH
(CH2)nOH ~b~
RlX~ ~ N J MBH
N 1, x-
(CH2)nOH (CH2)nR2
Ph3P,R2H
N Eto2CN--Nco2Et N
R1 R1
The invention can be further understood by the
following examples in which temperatures are in degrees
Centigrade and parts and percentages are by weight
unless otherwise indicated.
~ ?
'~tO91/06297 ~ ~ 2~'~ PCT/US90/06102
~Z~m~
2- ~1- (2-ph~D~ 4-Di~2eridirlvlmeth~ll-c; ~-3a~ ~ . 7,
t~ rdro-~ -1.. 3 ~2~)-dione
~Rl=CH2CH2Ph; n=l; R2=
--N~
chain attached to C-4 of piperidine)
To 0.45 g ~2.0 mmoles) of 1-~2-phenylethyl)-4-
piperidinemethylamine was added 5 mL of
dimethylformamide and 0.32 g ~2.0 mmoles) of ~i~-
1,2,3,6-tetrahydrophthalic anhydride. After heating
1 5 under reflux for 17 hours, the mixture was cooled,
diluted with water, and made strongly basic with aqueous
potassium hydroxide. The mixture was extracted with
ethyl acetate and the extracts were washed with
saturated solutions of sodium bicarbonate and sodium
chloride, dried and evaporated to give 0.34 g of the
title compound as a brown oil.
The fumaric acid salt had m.p. 179-181 after
crystallization from 2-propanol. NMR ~CDCl3:DMSO-d6):
7.04-7.34 (m, 5H); 6.63 (s, 2H); 5.78-5.90 (s, 2H);
3.19-3.45 ~d, 2H); 2.97-3.17 (m, 4H); 2.72-2.85 (m, 2H);
2.S8-2.72 (m, 2H); 2.40-2.57 (m, 2H); 2.06-2.30 (m, 4H);
1.49-1.80 (m, 3H); 1.13-1.43 (m, 2H).
The starting material, 1-(2-phenylethyl)-4-
piperidinemethylamine was prepared as follows:
A mixture of 1.31 g (3.8 mmoles) of 2-[1-(2-
phenylethyl)-4-piperidylmethyl]-lH-isoindole-1,3(2H)-
WO~1/06297 ~ PCT/US90/06102
4 J iJ '. V..] '3
38
dione ~Example 2) and 0.25 mL (7.8 mmoles) of hydrazine
in 20 mL of ethanol was heated under reflux for 4 hours.
The solvent was removed and the residue was made basic
with aqueous potassium hydroxide and extracted with
chloroform to give 0.90 g of 1-(2-phenylethyl)-4-
piperidinemethylamine as an oil. NMR (CDC13): ~ 7.14-
7.35 ~m, SH); 2.93-3.10 (d, 2H); 2.72- 2.85 (m, 2H);
2.52-2.65 ~m, 4H); 1.92-2.05 (t, 2H); 1.61-1.87 (m, 2H);
1.08-1.48 (m, 5H).
1 0
Exam~le 2
?-r1-(2-Ph~ylethyl~-4-p'Der;dinyLm~thyll-L~-
isolnd~le-~ 2H)-d;Qn~
~ethod s~
(Rl=CH2CH2Ph; n=l, R2=
-N ~
chain attached to C-4 of piperidine)
A mixture of 10.11 g of 1-(2-phenylethyl)-4-[(2,3-
dihydro-1,3-dioxo-lH-isoindol-2-yl)methyl]pyridinium
bromide, 150 mL of acetic acid and 0.51 g of prereduced
platinum (IY) oxide was shaken under 52 psi initial
hydrogen pressure at room temperature for 6 hours. Most
of the solvent was removed under reduced pressure and
the residue was made strongly alkaline with 15% aqueous
sodium hydroxide. Methylene chloride was added and the
mixture was filtered. Separation of the layers in the
filtrate, extraction of the aqueous layer with methylene
chloride and removal of the solvent from the dried
organic layers gave 8.04 g of the crude title compound.
Ç ~ S~
~vo 91/06297 PC~r/US90/06102
The hydrochloride had m.p. 277-278 after
crystallization from 90% ethanol.
Anal. Calcd. for C22H25ClN2O2: C, 68.65; H, 6.55;
N, 7.28. Found: C, 68.52; H, 6.63; N, 7.33.
NMR spectrum (DMSO-d6): ~ 7.9 (m, 4H); 7.2-7.4 (m,
5H); 1.5-3.6 (m, l5H).
The starting material, 1-(2-phenylethyl)-4-[(2,3-
dihydro-1,3-dioxo-lH-isoindol-2-yl)methyl]pyridinium
bromide, was prepared as follows:
A mixture of 74 g (0.5 mole) of phthalic anhydride,
60 g (0.56 mole) of 4-pyridinemethylamine and 200 mL of
dimethylformamide was heated under reflux for 2 hours.
The cooled mixture was filtered and the solids were
washed with ether and dried to give 85.1 g of 2-(4-
15 pyridinylmethyl)-lH-isoindole-1,3(2H)-dione, m.p. 164-
165. Another 24.0 g was obtained by crystallization o~
the concentrated mother liquors from dimethylformamide.
Combined yield: 99.1 g (83~).
The above compound (25.1 g), 2-bromoethylbenzene
(50 mL) and 100 mL of dimethylformamide were stirred at
85 bath temperature for 3 hours. The solvent was
removed under vacuum, and the residue was stirred with
ether. The solids were collected by filtration, washed
with ether, dried, and crystallized from 95% aqueous 2-
propanol to give 34.68 g of 1-(2-phenylethyl)-4-[(2,3-
dihydro-1,3-dioxo-lH-isoindol-2-yl)methyl]pyridinium
bromide, m.p. 206-208.
NMR (DMSO-d6): 9.0 (d, 2H); 8.2 (d, 2H); 7.8-8.0
(m, 4H); 7.2-7.4 (m, 5H); 5.0 (s, 2H); 4.8 (t, 2H) and
3.2 (t, 2H).
WO91/06297 PCT/US90/06102
I~J ~ C~ ~ l 'J
Example_~
2-rl-~2-Phenyl~t~v~ erld;nyl~ethyll-~i~-
3a 4.5.6.7.7~a-Oegah~ o~ndol~-l.3(2~)-d;one
~Method B ?
(Rl=CH2CH2Ph; n=1; R2=
0~
-N
O H
chain attached to C-4 of piperidine)
To 10.0 g ~23 mmoles~ of 4-[(sL~-octahydro-1,3-
dioxo-lH-isoindol-2-yl)methyl]-1-(2-phenylethyl)
pyridinium bromide was added 200 mL of glacial acetic
acid and 1.0 g of platinum (IV) oxide. The mixture was
hydrogenated at 50 p.s.i. and room temperature for 2.5
hours. The reaction mixture was filtered, concentrated,
and the residue was dissolved in water. The aqueous
solution was made strongly basic with aqueous sodium
hydroxide, and extracted with ethyl acetate. The
organic extracts were washed with saturated sodium
bicarbonate solution and saturated sodium chloride
solution, dried and evaporated to afford 7.61 g (92%
yield) of the title compound. The fumaric acid salt was
crystallized from 2-propanol and had m.p. 199-200; NMR
(DMSO-d6): ~ 7.17-7.48 ~m, 5H); 6.6 (s, 2H); 3.23-3.34
25 (d, 2H); 3.07-3.22 (d, 2H); 2.90-3.00 (m, 2H); 2.69-2.86
(m, 4H); 2.21-2.40 (t, 2H); 1.48-1.89 (m, 7H); 1.14-1.48
(m, 6H).
Anal. Calcd. for C26H34N2O6: C, 66.36; H, 7.28; N,
5.95. Found: C, 66.35; H, 7.41; N, 5.94.
The starting material, 4-[(si~-octahYdro-1,3-
dioxo-lH-isoindol-2-yl)methyl]-1-(2-phenylethyl)
O91/06297 ~ ~ ~ jJ PCT/US90/06102
pyridinium bromide was prepared as follows.
To 17.0 g (157 mmoles) of 4-aminomethylpyridine was
added 40 mL of dimethylformamide and 24.2 g (157 mmoles)
of cis-1,2-cyclohexanedicarboxylic anhydride. The
mixture was heated under reflux for 2 hours. The cooled
solution was diluted with water, made basic with aqueous
potassium hydroxide, and extracted with ethyl acetate.
The organic extracts were washed with saturated sodium
bicarbonate solution and saturated sodium chloride
solution, dried and evaporated to afford 16.8 g of 2-~4-
pyridinylmethyl)-c;~-3a,4,5,6,7, 7a-hexahydro-lH-
isoindole-1,3(2H)-dione, m.p. 91-92; NMR (CDCl3):
8.53-8.63 (d, 2H); 7.19-7.29 (d, 2H); 4.63 (s, 2H);
2.80-3.00 (m, 2H); 1.78-2.00 (m, 2H); 1.63-1.78 (m, 2H);
1.33-1.58 (m, 4H).
To 16.8 g (68 mmoles) of the above compound was
added 70 mL of 2-propanol and 12.6 g (68 mmoles) of 2-
bromoethylbenzene. The mixture was heated u~der reflux
- for 24 hours, and then cooled in an ice bath. The
precipitated solid was collected by suction filtration
and washed with cold ethyl ether to afford 19.85 g (67%
yield) of 4-[(si~-octahydro-l~3-dioxo-lH-isoindol-2
yl)methyl]-1(2-phenylethyl)pyridinium bromide, m.p.
208; NMR (DMSO-d6): ~ 9.03-9.10 (d, 2H); 7.96-8.07 (d,
2H); 7.20-7.37 (m, 5H); 4.82-4.97 (m, 4H); ~.22-3.36 (t,
2H); 3.08-3.20 (m, 2H); 1.72-1.90 Sm, 2H); 1.54-1.72 (m,
2H); 1.26-1.54 (m, 4H).
~m~g
2-r3-r1-(pheoylmethvl~-3-~i~er~dinyll~ropy
;soindole-1.3(2~-dio~e
(R1=CH2Ph; n=3; R2-
WO91/06297 PCTtUS90/06102
o 42
chain attached to C-3 of piperidine)
A mixture of 1.10 g (2.5 mmol) of 3-[3-(2,3-
6 dihydro-1,3-dioxo-lH-isoindol-2-yl)propyl~
(phenylmethyl)pyridinium bromide, 50 mL of glacial
acetic acid and 0.11 g of platinum oxide was
- hydrogenated at room temperature and atmospheric
pressure for 6 hours with rapid stirring. The reaction
mixture was filtered and concentrated, and the residue
was dissolved in water. The aqueous solution was made
strongly basic with aqueous potassium hydroxide and
extracted several times with ethyl acetate. The
combined organic extracts were washed with a saturated
sodium bicarbonate solution and a saturated sodium
chloride solution, dried and evaporated to give 0.77 g
of 2-[3-[1-tpheDylmethyl)-3-piperidinyl]propyl]-lH-
isoindole-1,3(2H)-dione as a yellow oil.
The fumaric acid salt had m.p. 151-152 after
crystallization from 2-propanol.
Anal. Calcd. for C23H30N2O6: C, 67.77; H, 6.32; N,
5.85. Found: C, 67.50; H, 6.29 N, 6.01.
The starting material, 3-[3-(2,3-dihydro-1,3-dioxo-
1-H-isoindol-2-yl)propyl]-1-(phenylmethyl)pyridinlum
bromlde, was prepared as follows:
To 17.0 g (124 mmoles) of 3-(3-pyrldyl)-1-propanol
was added 240 mL of 48% hydrobromic acid. The mlxture
was heated under reflux for 4 hours, and then evaporated
to dryness to afford the hydrobromide salt of 3-(3-
pyridyl)-1-bromopropane as an oil ln quantitative yield.
`'O 91/0629~ b~ ,3 " PC~r/US90/06102
?
43
NMR (CDCl3): ~ 16.40-16.94 (bs, lH); 8.76-9.00 (m,
2H); 8.29-8.46 (d, lH); 7.96-8.18 (m, lH); 3.32-3.53 (t,
2H); 3.00-3.19 (t, 2H); 2.16-2.41 (m, 2H).
To 7.9 g (28 mmoles) of 3-(3-pyridyl)-1-
bromopropane HBr was added lS0 mL of dimethylformamide
and 27.0 g ~145 mmoles) of potassium phthalimide. The
reaction mixture was heated under reflux for 3 hours.
The mixture was cooled, diluted with water, and made
basic with aqueous potassium hydroxide. The product was
then extracted with ethyl acetate, and the ex~racts were
washed with saturated solutions of sodium bicarbonate
and sodium chloride, dried and evaporated to give 11.0 g
of 2-[3-~3-pyridinyl)propyl]-lH- isoindole-1,3~2H)-
dione, m.p. 88-90; NMR (CDCl3) ~ 8.36-8.50 (m, 2H);
7.75-7.90 (m, 2H); 7.57-7.75 (m, 2H); 7.47-7.56 (d, lH);
7.13-7.32 (m, lH); 3.63-3.29 (t, 2H); 2.53-2.71 (t, 2H);
1.94-2.10 (m, 2H).
A mixture of 2.00 g (7.5 mmoles) of 2-[3-(3-
pyridinyl)propyl]-lH-isoindole-1,3(2H)-dione, 8 mL of 2-
propanol, and 1.71 g (10 mmoles) of benzyl bromide washeated under reflux for 1 hour. The solution was cooled
to 0, and the precipitated product was collected by
suction filtration, washed with cold ethyl ether, and
dried to afford 3.08 g of 3-[3-(2,3-dihydro-1,3-dioxo-
lH-isoindol-2-yl)propyl]-1-(phenylmethyl) pyridinium
bromide.
NMR (CDCl3/DMSO-d6) ~ 59.45-9.56 (d, lH); 9.39-9.44
(s, lH); 8.18-8.29 (d, lH); 7.90-8.00 (t, lH); 7.12-
7.91 (m, 6H); 7.29-7.46 ~m, 3H); 6.28 ~s, 2H); 3.58-
3.77 ~t, 2H); 2.78-2.97 (t, 2H); 2.04-2.23 ~m, 2H).
WO 91/06297 PC~/US90/06102
4~
E ~,caTn~ le S
c;~-Octahvdro-3-~ydroxy-2- ~ rl~ t2-~h~nyl e~hyl) -4-
piDeridi~yll ~ethy~ -; sQ; n~Q~ nP
(Rl=CH2CH2Ph; nsl; R2=
OH H
-N
o H
chain attached to C-4 of piperidine)
To 2.25 g (6.3 mmoles) of 2-[1-(2-phenylethyl)-4-
piperidinylmethyl]-~ia-3a, 4, 5,6,7,7a-hexahydro-lH-
isoindole-1,3~2H)-dione (Example 3) dissolved in 10 mL
of methanol was added 0.42 g (11 mmoles) of sodium
borohydride in portions with stirring at 0. The
mixture wz stirred at 0 for-2.5 hours. To t~e
1 5 reaction mixture was added 15 mL of precooled water and
the product was extracted with chloroform. The dried
organic phase was evaporated to afford 1.90 g of the
title compound.
The fumaric acid salt had m.p. 211-213C after
crystallization from 2-propanol.
Anal. Calcd. for C26H36N2O6: C, 66.08; H, 7.68; N,
5.93. Found: C, 66.13; H, 7.72; N, 5.81
NMR ~DMSO-d6) ~ 7.13-7.22 (m, 5H): 6.63 (s, 2H);
5.04-5.10 (d, lH); 2.98-3.33 (m, 4H); 2.83-2.93 (m, 4H);
26 2.37-2.58 (m, 2H); 2.29-2.37 (m, 2H); 1.12-1.93 (m,
13H).
'091/06297 PCT/US90/06102
E~am~l~ 6
~ ,3,q.5 6.7-h~xahvdro-2- rll=iz:~s~ L~
i~er;dinyllm~hyll-1~-isoi~dQl-l-Qne
~Rl=CH2CH2Ph; n=1; R2 =
,~
o
chain attached to C-4 of piperidine)
Concentrated hydrochloric acid was added dropwise
to 0.85 g (2.4 mmoles) of ~i~-octahydro-3-hydroxy-2-[~1-
(2-phenylethyl)-4-piperidinyl]methyl]-lH-isoindol-l-one
(Example 5) dissolved in 20 mL of ethanol until the
solution maintained a pH of 3-4. The mixture was
stirred at 0 for 40 minutes, and was then evaporated to
1~ dryness. The resldual oil was dissolved in water, and
the mixture was made strongly basic with aqueous sodium
hydroxide. The aqueous phase was extracted with
chloroform and the extracts were dried and evaporated to
give 0.75 g of the title compound as a clear oil.
NMR (CDC13): 7.13-7.36 (m, 5H); 3.75-3.80 (s, 2H);
3.26-3.35 (d, 2H); 2.91-3.06 (m, 2H); 2.75-2.86 ~m, 2H);
2.51-2.60 (m, 2H); 2.15-2.30 (m, 4H); 1.92-2.07 (t, 2H);
1.50-1.81 (m, 7H); 1. 9-1.47 (m, 2H).
The salt with fumaric acid had m.p. 211-212 after
crystallization from 2-propanol. Anal. Calcd. for
C26N25H34 -5H2: C, 67.36; H, 7.61; N, 6.04. Found:
C, 67.74; H, 7.47; N, 6.05.
13C NMR (DMS0-d6): ~ 19.9; 21.4; 21.6; 23.4; 27.7;
30.9; 33.7; 46.3; 53.3; 57.7; 51.4; 126.1; 128.2; 128.5;
130.1; 134.5; 138.7; 150.4; 167.1; 170.9.
WO91/06297 s.~ 46 PCT/US90/06102 --
Exam~ 7
~_t~
(R1-CH2CH2Ph; n-1; R2~
OH
chain attached to C-4 of piperidine)
To a mixture of 2.0 g (5.7 mmoles, of 2-[1-(2-
phenylethyl)-4-piperidinylmethyl]-1H-iqoindole-1,3(2H)-
dione (Example 2) and 2.09 g (31 mmoles) of zinc dust in
30 mL of glacial acetic acid was stirred at room
temperature for 45 minutes. The excess solvent was
removed from the filtered mixture by evaporation, and
aqueous sodium bicarbonate was added to the residue.
The aqueous mixture was extracted with ethyl acetate and
the extracts were washed with saturated sodium chloride,
dried and evaporated to afford 0.85 g of the title
compound as a foam.
NMR (CDC13): S 7.41-7.75 (m, 4H); 7.14-7.35 (m,
5H); 5.83 Is, lH); 3.40-3.52 (m, lH); 3.15-3.27 (m, ~H);
2.68-2.90 (m, 4H); 2.43-2.58 (m, 2H); 1.72-2.01 (m, 3H);
1.52-1.72 Im, 2H); 1.01-1.30 (m, 2H).
The fumaric acid salt had m.p. 219-221 after
crystallization from 2-propanol.
091/06297 "~ ~ ! ,!, ' ) PCT/US90/06102
47
F.Y?~TnP1 e R
C; S_OCtahYdrO_3_~YdrOYY-3-n~thV1 -2- r ~ 1- (2-~h ~vle~h ~ 4-
~i~er; ~lir~lm~thyl 1 -1T7-i~o; nd~-1 -QIle
CH
Ho~ ~
= CH2CH2Ph; n = l; R = -N ¦ ;
R2 attached to C-4 of
piperdine) O
To 0.90 g (2.5 mmol) of 2-[1-(2-phenylethyl)-4-
piperidinylmethyl]-cis-3a, 4, 5, 6, 7, 7a-hexahydro-lH-
isoindole-1,3(2H)-dione under nitrogen was added 10 ml
dry THF. The mixture was cooled to 0 and 2.0 ml (2.8
mmol) of 1.4 M methyllithium in ether was slowly added
to the stirring solution. Stirred at 0 continued for
35 minutes. The reaction mixture was quenched by the
slow addition of saturated ammonium chloride solution,
and the product extracted with methylene chloride. The
organic extracts were dried over MgSO4 and e~aporated to
afford 0.72 g of the title compound as a clear oil which
solidified upon standing. The fumaric acid salt had
m.p. 140-142 after crystallization from 2-propanol.
Anal. Calcd. for C27H3gN2O6: C,66.64; H, 7.87; N,
5.76. Found: C, 66.47; H, 7.92, N, 5.54. NMR (DMSO-
d6) 7.15-7.32 ~m, 5H); 6.56 (s, 2H); 3.01-3.18 ~m, 3H);
2.69-2.91 (m, 5H); 2.38-2.47 (m, lH); 2.16-2.33 (m, 2H);
1.97-2.11 (m, lH); 1.72-1.92 (m, 2H); 1.53-1.71 (m, 4H);
1.00-1.50 (m, lOH).
In the following tables, N denotes the carbon atom
of the piperidine ring to which the (CH2)nR2 group is
attached.
WO91/06297 ~?~ PCT/VS90/06102
48
Table 1
~CH2) nR2
N
5 E~_ ~ ~ Bl B2 m~ c)
o~
N~
1 4 1 (CH2)2Ph o ~ 179-181(a)
~3
2 4 1 (CH2)2Ph o 277-278(b)
o~
N~1~
3 4 1 (CH2)2Ph c 199-200(a)
N~3
4 3 3 CH2Ph o 151-152(a)
OH H
4 1 (cH2)2ph N~ 211-213(a)
-'O91/06297 PCT/US90/06102
49
Table 1 (continued)
Ex. ~ ~ Bl B~ m.~.~C)
N/--~0
6 4 1(CH232Ph o 211-212(a)
o}~
7 4 1(CH2)2Ph o 219-221(a)
Ho CH3
N ~
8 4 1(CH2)2Ph O 140-142(a)
Q~> ~
1 0 9 4 2-~CH2)2Ph O ~ 147(dec)
N ~
4 1 -~CH2)2- o 212(dec)(a)
3-indolyl
. 0~
11 4 1 (CH2)2Ph N ~ 228(dec)(b)
Footnotes for Table 1
(a) Fumarate salt.
(b) Hydrochloride salt.
WO 9l/06297 ; ,;,,~ PCT/US90/06102
Table 2
~, (CH2) nN~ HO2C
O H
Rl
Ring
Junction
Stereo-
E~_ ~ n Bl B~ Sh~Li5:~Y m.~.(~)
12 4 0 CH2Ph H ~1~ 198-199
13 4 0 (CH2)2Ph H si~ 217
14 4 1 CH2Ph H ~1~ 181-183
15 4 1 CH2C6H11 H ~i~ 217-219
16 4 1 (CH2)3Ph H ~i~ 196-197
17 4 1 (cH2)2c6Hll H ~i~ 217-218
18 4 1 CH2C6H4CF3-3 H ~i~ 179-180
19 4 1 (CH2)2C6H9OH-4 H ~i~ 215-217
20 4 1 CH2C6H4F-4 H c;s 179-180
21 4 l CH2-cyclopropyl H ;s 159-161
22 4 1 CH2CH2Ph H trans 192-193
23 4 1 CH2CH2Ph Me sia 170-171
24 4 2 CH2CH2Ph H ~i~ 207-208
25 4 1 -(CH2)2C6HgOH-4 H ~i~ 215-217
26 4 1 -(CH2)2C6H4Cl-4 H ~i~ 185-188
27 4 1 -(cH2)2c6H4No2-4 H ~i~ 169-171
28 4 1 -~cH2)2c6H4N(cH3)2-4 H cis 203 (dec.)
29 4 1 -(CH2)2C6H4F-4 H Si~ 174 (dec.)
30 4 1 (CH2)2C6HgBr-4 H Si~ 196
31 4 1 (cH2)2c6H4cF3-4 H Si~ 186-188
32 4 1 (CH2)2-3-indolyl H cts 188 (dec.)
33 4 3 (CH2)2Ph H c' 5 167-168
O 91/06297 ~ PCT/US90/06102
Table 3
~(C~z)nN~ HO cf
5 ~x. ~ 1 m~ C
34 4 1 CH2C6H5 >220
4 1 CH2C6H4F-3 >220
36 4 1 CH2C6H4F - 4 >220
37 4 1 CH2-cyclopropyl 194-196
38 4 2 CH2C6Hs 163 - 165
39 4 2 (CH2~ 2C6H5 183 - 185
4 2 CH2C6H4F - 3 179 - 181
41 4 2 CH2C6H4F-4 177-178
42 4 2 CH2-cyclopropyl 119-121
43 4 3 CH2C6H5 180-182
44 4 3 (CH2) 2C6Hs 161-162
3 0 CH2C6H5 188-191
46 3 0 (CH2)2C6H5 171 (dec.)
47 3 1 CH2C6H5 214-216
48 3 1 (CH2)2C6~5 195 (dec.)
49 3 3 (CH2) 2C6Hs 127-130
2 2 CH2C6H5 103 (dec)
51 2 2 ~CH2) 2C6H5 65 (dec)
PC~r/US90/06102
W O 91/06297 ~ ci ~
52
Table 4
CH2R2
N~ ~07C
E~ample # B~ . m.D.(C
o
Jl ,~
-N.b~
220-223
52a
204-206
53 o
-N~
54 o 227-228
-NJ~
o 199-200
~'
-N~l
207-210
10 56
~91/06297 ~ PCT/US90/06102
53
Table 4 (continued~
Exampl~ # o B2 m.p.(C)
-N~
57b 198-200
~dec.)
-N ~
58c o >220
--N~
59c - >230
O 197
~dec.)
61C ~ >230
62 N ~ 187
~dec.)
~ OH
-N l l
63b O ~ OH 218
~dec.)
WO 91/06297 PCI/US90/06102 . -
~P ,. .~ .-. ~. .9 .-,
:~ ~ S ~
Table 4 ~ccntinued)
~xam~l~ # B2 m.~. (C)
o CH3
N~
64 o H 181-184
o CH3
J'_ ~
N~ ~
~ H3 179-182
N~
66 o CH3 190-192
O CH3
J~ ~
N~, ~
67 O ~ 172 ~dec. )
N~
68 O 201 ~dec. )
N~
69 O 187-188
N~
Ho CH3 224-226
71 ~) 191 ~dec . )
PCT/US90/06102
-091/06297
Table 4 (continued)
~xam~le ~ B2 m.p.t~
72 O ~ 203
N ~
73 HO H 138 ~dec.)
a hydrochloride
b ratio of base: fumaric acid = 2:1
c hydrobromide
WO 91/06297 ~J U 3 J ~ ~ ~ 56 PCI/US90/06102
Table 4a
HO ( CH2 ) nR2
~S CO2H
~ CO2H
E~ . # B~ ~m ~ C~
N~
74 H 218 ~dec.)
O 215-217
N~
76 O >230
N~p
77 O >230
Ogl/06297 ~ ~, & - - PCr/~J590/06102
Table 5
~ ( CH2 ) nR2
N
Ex .
~ Bl O n
78 CH2 --<I ~ CH3~H o 2
79 (CH2) 2--O 02N)X~xN-- 4-CH C684,0H 1 3
CH3 o
~N--
80 (CH2~ 4 ~}C2H5 o 2 4
CH3~N--
81 CH2--O c6~5co2~ ox B, OCH3 2 4
aXN
1 0 82 CH2C6H4Cl--m X }~,OH 3 4
83 (Cil2)2C6llcF3-~ ~X o 2 4
PCI /IJS90/06102
WO 91/06297 2 ~
5B
Table 5 ~continued)
Ex .
al B2 ~ n ~l
X N
84 (CH2) 3C6H4NO2-Q ~ R2 4 4
~X
85 (CR2) 4C6R4SOCR3-m NC X ~ 2 4
86 (CH2) 2C6Hs C~ H,~-C8R7 2 4
O~N~
~X
87 (CH2 ) 2C6HsO~ 1 4
~X
88 (cR2)2c6R5 W R,OH 2 4
Oq~N~f~X
1 0 89 (cH2)2c6H5 H~C CH~ H2 1 4
PCI /US90/06102
'O 91/06297
59
Table 5 tcontinued)
Ex .
t B1 B2 ~ n
X ~N~O
W' O 1 4
11(CH2~ 2C6H5 x
~N--
go (cH2)2c6H5 O H~oC2H5 2 4
~N--
9l (cH2) 2C6H5 XX 9~ OH 3 3
,~
~N--
92 (CH2) 3C6a4NH2-m 4 4
H3C~
N--
93 (CH2) 2c6H4NHcoc2H5--m H2 2 4
C6H5 ~1~
~N--
94 ~CH2) 3C6H5 X o 1 4
~N--
0 95 ~cH2)2c6H5 H2 2 3
WO 91/06297 ~ PCI'/US90/06102
Table 5 ~continued)
Ex .
n
Cl~
N--
96 ~CH2) 2c6H4Br-m X o C6H5, OH 1 4
~;N--
5 97 tCH2)2C6H4C6H5-m CH~ O H,OH 1 4
~N--
98 (CH2) 2--O o H, OC2H5 1 4
X
HO~N--
99 (CH2) 2Ph x H2 2 4
~
~N
00 ~CH2) 2C6H4OMe-m . H, CH3 1 4
~N
101 ~CH2) 2C6H5 1 4
~N
1 0 102 ~cH2)2c6H5 H~OH 1 4
~VO 91/06297 PC~r/US90/06102
61
Table 5 (continued)
Ex.
l B~ ~ n
~ N
103 (cH2)2c6H5 X H2 1 4
~ N -
5 104 ~CH2)2C6H4OH-m H,OH 1 4
C~3 ~ N -
105 ~CH2)2C6H5 H,OCH3 1 4
,~
106 ~cH2j2c6H5 H2 2 4
~ N -
107 CH2C6H5 1 4
~ N -
10B ~cH2)2c6H5 X 1 4
~ N -
1 0 109 ~cH2)2c6H5 H,OH 1 4
WO91/06297 PCT/US90/06102
. 2
62
Table S ~c~ntinued)
Ex .
Bl B~
~ N -
110 (cH2)2c6Hs 1 4
~ N -
111 (CH2)2C6H5 X H2 2 4
~ N -
112 (CH2)3C6HS 1 4
~ N -
113 (cH2)2c6H5 1 4
~m~
1 0 =~_
dirlvl~me~~ -isoindQ~-l . 3 (2~-d~2n
o
= CH2CH2Ph; n =1 ; R2 = -N ~ ;
a = double bond; R ~CH2~ n
attached to C-4 of piper$dine)
To a mixture of 2.2 g of 1-~2-phenylethyl)-1,2,3,6-
tetrahydro-4-pyridinemethanol, 1.5 g of phthalimide, 2.6
g of triphenylphosphine and 15 m$ of dry tetrahydrofuran
was added, over a period of 17 m$nutes, a solution of
1.8 g diethyl azodicarboxylate ~n 5 mL of dry
tetrahydrofuran, keeping the temperature at 0. The
~' 3~
'~0 91/06297 PCT/US90/06102
mixture was stirred at room temperature for 6 hours and
the solvent was removed under vacuum. The residue was
stirred with 25 mL of toluene and 25 mL of ether first
at room temperature, then in an ice bath ~or 15 min.
The solids were removed by filtration and the filtrate
was concentrated. Further purification of the residue
was best achieved by chromotography on silica and
elution with ethyl acetate/triethylamine (98:2). The
free base of the title compound had the following NMR
spectrum (in CDCl3): ~ 7.8 ~m, 2H); 7.7 (m, 2H) 7.2-7.3
(m, 5H); 5.6 (t, lH); 4.2 (s, 2H), 3.0 (narrow m, 2H),
2.8 (m, 2H); 2.6 ~m, 4H); 2.2 (m, 2H). The 2:1 fumorate
had mp 170-174 (dec).
Anal. Calcd. for C24H24N2O4: C, 71.27; H, 5.98; N,
6.93. Found: C, 71.03; H, 6.07; N, 7.17.
The starting material, 1-(2-phenylethyl)-1,2,3,6-
tetrahydro-4-pyridinemethanol, was prepared as follows:
A mixture of 10.9g of 4-pyridinemethanol, 25g of 2-
bromoethylbenzene an 30 mL of dimethylformamide was
stirred in a 90 oil bath for 3 hours. Removal of the
solvent and crystallization of the residue from 30 mL of
ethanol gave 23.4g ~80%) of 1-(2-phenylethyl)-4-hydroxy-
methylpyridinium bromide, mp 132-134. NMR (DMSO)~ 8.9
(d, 2H): 8.0 (d, 2H); 7.2-7.4 (m, 5H); 6.0 (t, lH), 4.8-
4.9 (d+t, 4H); 3.3 (t, 2H).
To a mixture of 16.0 g of the above product and 160
mL of ethanol was added, at 0, 6.0 g of sodium
borohydride over a period of 20 minutes, keeping the
temperature below 5. The mixture was stirred in an ice
bath for 30 minutes and 80 mL of 10% hydrochloride acid
was added below 0. The mixture was made basic with 15%
sodium hydroxide after stirring at room temperature for
1 hour, and the product was extracted into methylene
chloride. Removal of the solvent from the extracts and
short-path distillation of the residue (to 170 bath
W O 91/06297 ~ P~r/US90/06102
64
temperature, 1 micron) gave 7.89 g ~67%) of 1-(2-
phenylethyl)-1,2,3,6-tetrahydro-4-pyridinemethanol. NMR
(CDCl3)~ 7.2-7.3 (m, 5H); 5.6 (t, lH); 4.0 (n, 2H); 3.0
(m, 2H); 2.8 (m, 2H); 2.7 (m, 4H); 2.0-2.2 (m, 2H).
~vo 91/06297 ~ ?~ PCr/US90/06102
Table 6
( CH2 ) nR2
CEl2CH2c6Hs
E~ ~ R~_ n _ m. p .
~N-
114 1 170-174 (dec) b
~N-
115 O 2 216-217 a
116 H o 137-l38o b
~N-
117 HH o 1 238-240 a
~N-
118 H 3 184--185 a
. O
~N-
119 H o 1 172-173 b
WO91/06297 ,'~ 3 PCT/US90/06102
66
Table 6
Ex # R~ _ n m p
l ~
~ N-
120 2 195-A~6 b
O
~` J(
~ ~ N-
121 3 202-203 a
a HCl salt
b Fumarate
1 0
E~m~le ~2
2-r1-~2-Phe~yleth~-4=~henyl-4-~iperi~ln~ hyll-ci~
~a,4.5.6.7.7a-hexahy~ro-lH-isoin~Qle-1,3~2~-dione
H
(Rl = CH2CH2Ph; n = l; R2 = -N
O H
R16 = Ph; R2lCH2) n attached to C-4 of the piperidine~.
A mixture of 0.67g (2.3 mmoles) of 1-~2-
phenylethyl)-4-phenyl-4-piperidinemethylamine, 0.70g
2~ (4.5 mmole) of cis-1,2-cyclohexanedicarboxylic anhydride
and 2 mL of dimethylformamlde was heated under reflux
for 8 hours. The solvent was removed and the residue
was d'issolved in toluene. The solution was stirred with
10% aqueous sodium carbonate solution, the layers were
separated and the aqueous layer was extracted with
toluene. ~oncentration of the dried toluene la,-rs gave
0.85 g (87%) of the title compound. NMR (CDCl3)~ 7.0-
`~O91/06297 ~ PCT/US90/06102
677.4 (m, lOH); 3.6 (s, 2H) and 1.2-2.8 (m, 22H). The
fumaric acid salt had mp 220-221 (dec.) after
crystallization from 90% aqueous 1-propanol.
Anal. Calcd. for C32H3gN2O6: C, 70.31; H, 7.01; N,
5.12. Found: C, 70.05; H, 6.99; N, 5.04.
The starting material, 1-(2-phenylethyl)-4-phenyl-
4-piperidinemethylamine, was prepared as follows:
To a solution of 20.0g (95 mmoles) of N-(2-
phenylethyl)diethanolamine in 40 mL of chloroform was
added, over a period of l hour, 20 mL of thionyl
chloride in 20 mL of chloroform. The mixture was heated
under reflux for 2 hours and concentrated to give N-(2-
phenylethyl)-N,N-bis~2-chloroethyl)amine hydrochloride
as an oil. NMR ~CDCl3) ~ 7.2-7.4 (m, 5H); 4.1 (t, 4H);
3.6 (t, 4H); 3.5 (m, 2H) and 3.2 (m, 2H).
A mixture of 4.25g (15 mmoles) of the above
hydrochloride, 25 mL of 50% aqueous sodium hydroxide
solution, 2.0g (17 mmoles) of benzyl cyanide and O.5g of
hexadecyltributylphosphonium bromide was stirred for 30
minutes and then heated in a 100 oil bath, with
stirring, for 1 hour. The cooled mixture was washed
with 2S mL of water and extracted with toluene. The
extracts were stirred with 20mL of 10% hydrochloric acid
and the precipitate was collected by filtration, washed
with toluene and water, and made basic with sodium
hydroxide. Extraction with methylene chloride, removal
of the solvent from the dried extracts, and short-path
distillation of the residue ~175-210 bath temperature,
1 micron) gave 2.19g (50~) of 1-(2-phenylethyl)-4-
phenyl-4-piperidinecarbonitrile, NMR (CDCl3) ~ 7.2-7.6
(m, lOH); 3.2 (d, 2H); 2.9 (m, 2H); 2.8 (m, 2H); 2.6 (m,
2H) and 2.2 (m, 4H).
To a solution of 2.18g (7.5 mmoles) of the above
compound in 5 mL of toluene was added with cooling 5 mL
(17 mmoles) of sodium bis(2-methoxyethoxy)aluminum
W O 91/06297 ~ ......... 8 PC~r/US90/06102
hydride in toluene. The mixture was stirred for 1 hour
and then heated, with stirring, in a 60 oil ba~h for
one hour. Aqueous sodium hydroxide (15 mL) was added
with cooling, and the mixture was extracted with
toluene. Removal of the solvent from the dried extracts
and short-path distillation of the residue (165-190
bath temperature, 2 micron) gave 2.00g (91%) of 1-(2-
phenylethyl)-4-phenyl-4-piperidinemethylamine. NMR
~CDCl3) ~ 7.1-7.4 ~m, lOH), 2.7-2.8 ~m, 6H); 2.5 ~m,
2H); 2.3 ~m, 4H); 1.8 (t, split further, 2H) and 1.3
(br, 2H).
Q '~ PCI /US90/06102
~vo gl/06297 h J~: ` 3
69
Table 7
J~
N HO2C
Ph
Ex ~ B2 B~ m.p. (C?
o H
--N~
122 o H Ph 220-221 (dec . )
123 --N~J 3-ClC6H4 221-2220 (dec. )
124 --N~J 4-ClC6H4 217-2180 (dec . )
--N~
125 o H 3-MeOC6H4 217-218 ~dec. )
WO 91/06297 ~ J .1 r~ PCT/US90/06102
Table 7 (continued)
~x # B~ B1~ m~ C
--Nb~J
126 o H 3-CF3C6H4 214-215 (dec.)
-N ~
127 H 1-naphthyl 220-222 (dec.)
- N ~
128 o H 3-thienyl 208-212 (dec.)
129 ~ ~ 222-223 (dec.)
--N~
130 3-ClC6H4a 277
-N ~
131 O 3-ClC6H4 253 (dec.)
a HCl salt
C? r~
`VO9l/06297 PCT/US90/06102
EyaTrlpl e 132
2-rl-~2-~henylethyll-4-~4-methvl)~ nylm~thyll-c;~
3a, 4 . 5. 6. 7 . 7a-hexahvdro-~ oindole-1 3~2~ inn~
Method B
R1 = CH2CH2Ph; R16 = CH3; n z 1; R2 =
~~
--N.o~
To 0.44 g (1.9 mmol) of 1-(2-phenylethyl)-4-methyl-
4-aminomethylpiperidine was added 5 mL of DMF and 0.29 g
(1.9 mmol) of cis-1,2-cyclohexanedicarboxylic anhydride.
The mixture was refluxed for 4 hours, diluted with water
and extracted with ethyl acetate. The combined organic
extracts were washed with saturated sodium bicarbonate
solution and saturated sodium chloride solution, dried
and evaporated to give 0.51 g (?3% yield) of the title
compound as a yellow oil.
The fumaric acid salt had m.p. 185 after
crystallization from 2-propanol; NMR (DMSO-d6): ~ 7.17 -
7.45 (m, 5H); 6.58 (s, 2H); 3.27 (s, 2H); 2. 71 - 2.90
(m, 8H); 2.58 (t, 2H); 1.45 - 1.95 (m, 6H); 1.14 - 1.42
(m, 6H); 0.94 (s, 3H). Calculated m/e for C16H25N22
(parent ion minus benzyl) 277.1916; found 277.1915.
The starting material, 1-(2-phenylethyl)-4-methyl-
4-aminomethylpiperidine, was prepared as follows:
A mixture of 5.00 g (33 mmol) of ethyl
isonicotinate, 6.12 g (33 mmol) of 2-bromoethylbenzene
and 25 mL of 2-propanol were heated at reflux for 17
hours. The mixture was evaporated to dryness and
triturated 3 x 75 mL with ether. The excess ether was
removed by evaporation and there was obtained 8.91 g of
WO91/06297 .'~J .. ' .~ 72 PCT/US90/06102
1-(2-phenylethyl)-4-carboethoxypyridinium bromide as a
yellow solia. NMR tCDC13) ~ 8.97 ~d, 2H); 8.34 (d, 2H);
7.13 - 7.26 ~m, 5H); 5.35 - 5.42 (m, 2H); 4.41 - 4.50
(q, 2H); 3.39 - 3.47 (t, 2H); 2.58 - 2.65 ~m, 2~);
-1.37 - 1.46 (t, 3H).
A mixture of 5.90 g (17.5 mmol) of 1-(2-
phenylethyl)-4-carboethoxypyridinium bromide, 0.60 g of
platinum (IV) oxide and lO0 mL of methanol was
hydrogenated at 50 p.s.i. and room temperature for 1.5
0 hours. ~he reaction mlxture was filtered, concentrated
and the residue dissolved in water. The aqueous
solution was made alkaline to pH 9 - lO with aqueous
potassium carbonate and extracted with ethyl acetate.
The organic extracts were washed with saturated sodium
bicarbonate solution, saturated sodium chloride
solution, dried and evaporated to afford 4.11 g of l-(2-
phenylethyl)-4-carboethoxypiperidine as a yellow oil.
NMR (CDCl3) ~ 7.16 - 7.32 ~m, 5H); 9.08 - 4.19 (q, 2H);
2.91 - 3.02 (m, 2H); 2.77 - 2.88 (m, 2H); 2.53 - 2.65
(m, 2H); 2.23 - 2.35 (m, lH); 2.03 - 2.15 ~m, 2H); 1.87
- 1.98 (m, 2H); 1.72 - 1.88 ~m, 4H); 1.20 - 1.30 (t,
3H)-
To 2.64 mL (18.9 mmol) of diisopropylamine in 30 mL
of dry THF at -78 was added 6.9 mL (17.3 mmol) of 2.5 M
n-butyllithium in hexanes. The mixture was allowed to
warm to room temperature and then was cooled once again
to -78. To the stirred solution was added 4.11 g (15.7
mmol) of 1-(2-phenylethyl)-4-carboethoxypiperidine in 25
mL of dry THF. The mixture was allowed to warm to -40
and 0.98 mL (15.7 mmol) of iodomethane was added to the
reaction mixture. The mixture was stirred at -40 for
lS minutes and then allowed to stir at room temperature
for 3 hours. The mixture was evaporated to dryness and
the residue was dissolved in water. The aqueous
solution was extracted with methylene chloride and the
`"O 91/06297 !~ PCT/US90/06102
extracts were dried and evaporated to give 3.70 g of 1-
(2-phenylethyl)-4-methyl-4-carboethoxypiperidine as a
yellow oil. NNR (CDCl3) ~ 7.15 - 7.21 (m, 5H); 4.11 -
4.20 (q, 4H); 2.71 - 2.94 (m, 4H): 2.52 - 2.61 (m, 2H):
2.11 - 2.24 (m, 4H); 1.47 - 1.59 (m, 2H); 1.21 - 1.30
(t, 3H); 1.20 (s, 3H).
To a suspension of 0.51 g (13.4 mmol) of lithium
aluminum hydride in 20 mL of THF under nitrogen was
added dropwise a solution of 3.70 g (13.4 mmol) of 1-(2-
phenylethyl)-4-methyl-4-carboethoxypiperidine in 15 mL
of THF. The solution was heated at reflux for 3 hours.
To the cooled reaction mixture (ice bath) was slowly
added 0.5 mL of water, followed by 0.5 mL of 15% sodium
hydroxide followed by 1.5 mL of water. The precipitated
lithium salts were removed by filtration. The filtrate
was evaporated to dryness. The residue was
reconstituted in methylene chloride, washed with a small
amount of water, dried and evaporated to afford 2.97 g
of l-(2-phenylethyl)-9-methyl-4-hydroxymethyl-piperidine
as a yellow oil. NMR (CDCl3) ~ 7.16 - 7.23 (m, 5H);
3.40 (s, 2H); 2.79 - 2.87 (m, 2B); 2.57 - 2.71 (m, 4H);
2.31 - 2.42 (m, 2H); 1.57 - 1.63 (m, 5H); 0.97 (s, 3H).
A solution of 10 mL of methylene chloride and 0.4
mL (4.4 mmol) of oxalyl chloride was cooled under
nitrogen to -60. A solution of 0.68 mL of
dimethylsulfoxide in 2 mL of methylene chloride was
added dropwise to the solution. After stirring for 2
minutes 0.95 g (4 mmol) of 1-(2-phenylethyl~-4-methyl-4-
hydroxymethyl-piperidine was added in 2-3 mL of
methylene chloride. Stirring was continued for an
additional lS minutes. Triethylamine (2.8 mL, 20 mmol)
was added to the reaction mixture and stirring was
continued for 5 min, then the mixture was allowed to
warm to room temperature. Water (20 mL) was added and
the aqueous mixture was extracted with methylene
W O 91/06297 . , , ~`~ , PC~r/US90/06102 _
74
chloride. The organic extracts were washed with brine,
dried and evaporated to give 1-(2-phenylethyl)-4-methyl-
4-formyl-piperidine as a clear oil in quantitative
yield. NMR (CDCl3) ~ 9.46 (s, lH); 7.16 - 7.27 (m, 5H);
2.89 - 3.00 (br, lH); 2.75 - 2.82 ~m, 2H); 2.65 - 2.75
~m, 2H); 2.55 - 2.63 (m, 2H); 2.27 (t, 2H); 1.98 - 2.09
(m, 2H); 1.51 - 1.63 (m, 2H); l.OS (s, 3H).
To 0.40 g (6.1 mmol) of potassium hydroxide in 3 mL
of water was added 0.42 g ~6.1 mmol) of hydrox~.amine
hydrochloride. After stirring for 5 minutes at room
temperature, a solution of 0.94 (4.1 mmol) of 1-(2-
phenylethyl)-4-methyl-4-formylpiperidine in 20 mL of 2-
propanol was added. The reaction was refluxed for 4
hours. The mixture was evaporated to dryness and the
residue dissolved in 10 mL of water. The aqueous
mixture was extrac~ed with methylene chloride. The
organic extracts were dried and evaporated to give 0.85
g of the oxime as a clear oil. The oxime was
chromatographed on silica gel using chloroform:methanol
(95:5) to elute. There was recovered 0.58 g of 1-(2-
phenylethyl)-4-methyl-4-oximinomethyl-piperidine as a
white solid. NMR (CDCl3) ~ 7.28 (s, lH); 7.17 - 7.24
~m, 5H); 2.80 - 2.84 ~t, 2H); 2.48 - 2.70 ~m, 6H); 1.88
- 2.00 ~m, 2H); 1.58 - 1.65 (m, 2H); 1.11 (s, 3H).
A mixture containing 0.58 g ~2.4 mmol) of 1- 2-
phenylethyl)-4-methyl-4-oximinomethylpiperidine, 100 mL
of methanol, 80 mg of platinum ~IV) oxide and 0.75 mL of
concentrated hydrochloric acld was hydrogenated at 40
p.s.i. for 2 hours. The mixture was filtered and
evaporated. The residue was dissolved in water and made
alkaline with aqueous potassium carbonate. The aqueous
mixture was extracted with methylene chloride. The
organic extracts were dried and evaporated to give 0.44
g of 1-(2-phenylethyl)-4-methyl-4-aminomethyl-
piperidine. NMR (C~Cl3) ~ 7.18 - 7.28 ~m, SH); S.22 -
`~O91/06297 ~`3'" PCT/U590/06102
5.45 (br, 2H); 2.89 (s, 2H); 2.78 - 2.88 (m, 2H); 2.55 -
2.67 (m, 2H); 2.19 (t, 2H); 1.51 - 1.78 (m, 4H); 1.27 -
1.49 (m, 2H); 0.98 (s, 3H).
Table 8
Ex. $ Eormula m.~. I c~
CH,~N~
132 ~ 185 a
C~3 ~ ~
-133* ~ 220 (dec.) a
*fumarate
UTILITY
The compounds of this invention and their
pharmaceutically acceptable salts or N-oxides thereof
possess psychotropic properties, particularly
antipsychotic activity of good duration with selective
sigma receptor antagonist activities while lacking the
typical movement disorder side-effects of standard
dopamine receptor antagonist antipsychotic agents.
These compounds may also be useful as antidotes for
WO91/06297 ~ PCT/US90/06102
I J , . ; ~ J ~
76
certain psychotomimetic agents, such as phencyclidine
(PCP) and as antidyskinetic agents.
;L~ Vit ro
Si~ma Recep~Qr ~indin~ ~ssay
Male Hartley guinea pigs ~250-300 g, Charles River)
were sacrificed by decapitation. Brain membranes were
prepared by the method of Tam (Proc. Natl. Acad. Sci.
USA 80: 6703-6707, l9B3). Whole brains were homogenized
10 (20 sec.) in lO vol (wt/vol) of ice-cold 0.34 M sucrose
with a Brinkmann Polytron ~setting 8). The homogenate
was centrifuged at 920 x g for lO min. The supernatant
was centrifuged at 47,000 x g for 20 min. The resulting
membrane pellet was resuspended in lO vol ~original
15 wt/vol) of 50 mM Tris HCl (pH 7.4) and incubated at 37C
for 4S min to degrade and dissociate bound endogenous
ligands. The membranes were then centrifuged at 47,000
x g for 20 min and resuspended in 50 mM Tris HCl ~50 mL
per brain).
0.5 mL aliquots of the membrane preparation were
incubated with unlabeled drugs, l nM (+)-[3~]SKF lO,047
in 50 mM Tris HCl, pH 7.4, in a final volume of 1 mL.
Nonspecific binding was measured in the presence of lO
~M (+)-SKF lO,047. The apparent dissociation constant
25 (Rd) for (+)-[3H]SKF lO,047 is 50 nM. After 45 min of
incubation at room temperature, samples were filtered
rapidly through Whatman GF/C glass filters under
negative pressure, and washed 3 times with ice-cold Tris
buffer (S mL).
ICsos were calculated from log-logit plots.
Apparent Kis were calculated from the equation, Ki =
IC50/[l + (L/Kd)] (4), where L is the concentration of
radioligand and Kd is its dissociation constant. Data
are shown in Table I.
3~
~'0 91/06297 - ~ PCT/U590/06102
~f~3~
Membranes were prepared from guinea pig striatum by
the method described for sigma receptor binding. The
membranes were then resuspended in 50 mM Tris HC1 (9 m~
per brain).
O.5 mL ali~uots of the membrane preparation were
incubated with unlabeled drugs, and 0.15 nM
[3H]spiperone in a final volume of 1 mL containing 50 mM
Tris HCl, 120 mM NaCl and 1 mM MgC12 (pH 7.7).
Nonspecific binding was measured in the presence of 100
nM ~+)-butaclamol. After 15 min of incubation at 37C,
samples ~ere filtered rapidly through Whatman GF/C glass
filters under negative pressure, and washed three times
with ice-cold binding buffer (5 mL). Data are shown in
Table I.
The data in Table I indicate that haloperidol, a
typical antipsychotic drug, has potent binding affinity
for both the sigma and dopamine receptors. This binding
profile of haloperidol reflects the therapeutic activity
as well as the motor side effects caused by antagonism
of the dopamine receptors. In contrast, the examples of
this invention shown in Table I indicate potent and
selec~ive binding affinity for sigma receptors without
binding to the dopamine receptors. Therefore these
compounds are not expected to produce the extrapyramidal
symptoms that are typical of that produced by
haloperidol and other typical antipsychotics that are
dopamine receptor antagonists.
Tn V;VO
Tsol ation-ln~Led A~ression in M~ ce
This is a modification of the method of Yen et al.
(Arch. Int. Pharmacodyn. 123: 179-185, 1959) and Jannsen
et al. (J. Pharmacol. Exp. Ther. 129: 471-475, 1960).
Male Balb/c mice ~Charles River) were used. After 2
WO91/06297 2 ~ i v~ v~ ~ PCT~US90/06102
78
weeks of isolation in plastic cages lll-5 x 5.75 x 6 in)
the mice were selected for aggression by placing a
normal group-housed mouse in the cage with the isolate
for a maximum of 3 min. Isolated mice failing to
consistently attack an intruder were eliminated from the
colony.
Drug testing was carried out by treating the
isolated mice with test drugs or standards. Fifteen min
after dosing with drugs by the oral route (po), one
isolated mouse was removed from its home cage and placed
in the home cage of another isolate. Scoring was a yes
or no response for each pair. A maximum of 3 min was
allowed for an attack and the pair was separated
immediately upon an attack. Selection of home cage and
intruder mice was randomized for each test. Mice were
treated and tested twice a week with at least a 2 day
washout period between treatments.
As shown in Table II, haloperidol and Examples 3,
6, 23, 34 and 3g all have potent activities in
inhibiting the isolation-induced aggressive behavior
indicating psychotropic activities.
P--Tn~uce~l Turni~ Rehav~ o-- ~ n Rats
Male Sprague-Dawley rats (CD/CR, Charles River),
weighing 190-290 g, were used for surgery. In order to
spare nonadrenergic neurons, rats were injected with 25
mg/kg imipramine intraperitoneal ~i.p.) 30 min before
surgery. The rats were anesthetized with a l:l.2 ratio
mixture of Xylazlne:Ketamine given 0.l mL/l00 g body
weight intramuscular (i.m.). A Ringers-Wydaze
(l00:0.0l) solution was given to prevent dehydration.
Dopamine was depleted in the right striatum by injecting
the neurotoxin 6-hydroxydopamine (6-OHDA) into the
substantia nigra of the right cerebral hemisphere. Five
mg of 6-OHDA was dissolved in 5 mL of a 0.04% ascorbic
"IO9l/06297 ~ t ~ PCT/US90/n6102
acid solution which had been deoxygenated with nitrogen.
Five ~L of the 6-OHDA solution was injected into the
substantia nigra through a 26 gauge needle over a five
min period. Stereotaxic injection coordinates were -2.5
mm posterior to bregma, -2.1 mm right of the midsagittal
suture, and -8.6 mm below the skull surface with the
incisor bar set at +5.0 mm. Following surgery they were
given 10 days to recover while housed four per cage
(45.0 L x 20.0 H x 26.0 W) wlth ALPHA-dri bedding and ad
lib access to Pro-Lab rodent chow and deionized water.
Following recovery, the wood clips were removedr the
rats were individually housed in suspended cages, and
they were placed on a restricted diet so that their
weight did not exceed 375 g. At all times they were
housed in the animal care facility under a 12-12 hour
light/dark cycle (light on at 6:00 h, light off at 18:00
h).
Rotation rate and direction were determined with
Coulbourn Instruments Rotometry Monitors. Clockwise and
counter clockwise rotations were recorded at 30 and 60
min intervals. The rats were examined for correct
lesion location by testing for rotational activity
induced by subcutaneous ~s.c.) injections of 3.0 mg/kg
D-amphetamine SO4, and 2.0 mg/kg PCP HCl, respectively.
These drugs were administered in the following sequence:
Amphetamine was given 30 sec before testing. Seven days
later, the rats were injected with PCP 30 sec before
testing. Only those rats with an ipsilateral rotation
rate of 2.5 turns per min or higher were used in
subsequent tests.
Methocel~ or test drugs were administered p.o. 20
min before testing. Phencyclidine (1.5 mg/kg) was given
s.c. immediately before testing.
The data was analyzed with an analysis of variance
statistical test~ and individual comparisons of each
W091tO6297 .~ 3 PCT/US90/06102
dose of test drug to control were made with Dunnett's
multiple range test. The EDso was calculated with a
Litchfield and Wilcoxon test using percent of control
values. Data are shown in Table III.
T n d~t i~l f ~3~
This is a modification of the method of Costall and
Naylor (Psychopharmacologia ~Berl.), 43, 69-74, 1975).
Male CD rats (Charles River) weighing 250-300 g were
treated with test drugs and standards and tested for the
presence of catalepsy 30 min, 60 min, and 90 min after
treatment. To test for catalepsy, each rat is placed
with its front paws over a lO cm high horizontal bar.
The intensity of catalepsy is measured by the length of
time it takes the animal to move both forelegs to the
table. A time of 20 sec is considered maximal
catalepsy. Data are shown in Table III.
As shown in Table III, both haloperidol and Example
3 have potent activity ln inhibiting the potent
hallucinogen PCP-induced turning behavior in rats,
supporting their use for treatment of psychosis. In the
catalepsy test which i5 a model for extrapyramidal
symptoms, haloperidol i5 very potent in producing
catalepsy and this agrees well with the side-effect
profile of haloperidol in the clinic. In contrast,
Example 3 does not produce catalepsy and suggests very
low potential for extrapyramidal symptoms and tardive
dyskinesia.
'Vo91/06297 ~ ~tP ~ PCT/US90/06102
81
Tahle I
In vit ro
Receptor Binding Affinity
Dopamine
E~am~l~; gma (n-~
++
2 ++
3 +++
4 +++
+
6 ++
7 +
12 +++
13 ++
14 +++
+++
16 ++
17 +++
18 ++
19 +
+++
~1 +
22 ++
23 +++
2 5 24 +++
34 +++
++
36 +++
37 +
38 +++
39 +++
+++
41 +++
42 +++
3 5 43 +++
WO 91/06297 .~ PCr/US90/06102
82
Tahle T ~
Dopamine
D- 2 )
4 4 +++
~i 4 7 +++
4 8 +++
4 9 +++
++
52 +++
0 53 +++ . +
54 ++
++
5 6 +++
58 +++
5 9 +++
++
6 1 +++
62 +++
63 _ _
2 0 9 +++ +
+++ ++
8 +
+ +
2 6 +++
2 5 27 +++
2 8 +++
29 ~l
+. +
- 31 +
32 +
33 +++
64 ++
++ +
66 ++
67 +
~vo 91/06297 2 i~ t~ PCT/US90/06102
83
Dopamine
E~am~l~ Si~ma
68 +
69 +++
+
71 +++
72 +++
73 ++
86 +
113 ++
115 +++
116 ++
117 +++
118 +++
1 1 9 +++
120 +++
121 +++
74 +
+++
- 76
77 ++
122 +++
123 +++
124 +++
125 ++
126 +++
127 ++
128 +++
129 +++
130 +++
131 ++
132 +++
133 +++
W O 91/06297 ~ 3~ PC~r/~590/06102
84
~able T~
Trl V; VO
Inhibition of
Isolation-induced
e s s i ~
Haloperidol +++
3 ++
0 6 +
23 +
3q ++
39 +
la~ie_III
Tr~ V; VO
Inhibition of
PCP-induced
~mDl~ u~nin~r Catal eDcv
Haloperidol +++ +++
3 +
`VO91/06297 PCT/US90/06102
posa~e Form~
Daily dosage ranges from l mg to 2000 mg. Dosage
forms (compositions) suitable for administration
ordinarily will contain 0.5-95% by weight of the active
5 ingredient based on the total welght of the composition.
The active ingredient can be administered orally in
solid dosage forms, such as capsules, tablets, and
powders, or in liquid dosage forms, such as elixirs,
syrups, and suspensions; it can also be administered
parenterally in sterile liquid dosage forms.
Gelatin capsules contain the active ingredient and
powdered carriers, such as lactose, sucrose, mannitol,
starch, cellulose derivatives, magnesium stearate,
stearic acid, and the like. Similar diluents can be
used to make compressed tablets. Both tablets and
capsules can be manufactured as sustained release
products to provide for continuous release of medication
over a period of hours. Compressed tablets can be sugar
coated or film coated to mask any unpleasant taste and
protect the tablet from the atmosphere, or enteric-
- coated for selective disintegration in the
gastrointestinal tract.
Liquid dosage forms for oral administration can
contain coloring and flavoring to increase patient
acceptance.
In general, water, a suitable oil, saline, aqueous
dextrose (glucose), and related sugar solutions and
glycols such as propylene glycol or polyethylene glycols
are suitable carriers for parenteral solutions.
Solutions for parenteral administration preferably
contain a water soluble salt of the active ingre~ient,
suitable stabilizing agents, and if necessary, buffer
substances. Antioxidizing agents such as sodium
bisulfite, sodium sulfite, or ascorbic acid, either
alone or combined, are suitable stabilizing agents.
WO 91/06297 Pft~/US90/06102 r-
- ` ~ 8 6
Also used are citric acid and its salts and sodium EDTA.
In addition, parenteral solutions can contain
preservatives, such as benzalkonium chloride, methyl- or
propyl-paraben, and chlorobutanol.
Suitable pharmaceutical carriers are described in
Rem;~f~tor's ~harmaceut-cal ~len_es, Mack Publishing
Co., a standard reference text in this field.
