SUBSTITUTED ARYLAMINES AND HETEROARYLAMINES. THEIR
PREPARATION PROCESS AND PHARMACEUTICAt_
COMPOSITION CONTAINING THEM
The present invention relates to novel compounds having a
structure similar to that of 1-(2-benzo(b)thiophenyl)1-
piperidino>-cyclohexane <BTCP> of formula:
y.~
BTCP is a molecule derived from phencyclidine, which has
properties differing from the latter as a result of the presence
of the benzothiophenyl nucleus.
Phencyclidine<PCP), i.e. N-C1-phenylcyclohexyl>-piperidine of
formula:'
,o
has been synthesized and studied for its pharmacological
properties since 1958. As a result of these studies, it has
been introduced as an analgesic and anesthetic under the name
Sernyl and was then abandoned as a result of its psychodysleptic
side effeets.
Phencyclidine and most of its analogs or derivatives have i~
their behavioural pharmacological spectrum a dopaminergic
component, incorrectly called an amphetaminic component by
certain authors. Thus, it has been demonstrated that sa6d
component corresponds to an inhibition of the recapture of
dopamine rather than a stimulation of release as in
8. 10089 t~T
_ 2 _
amphetamines, Thus, phencyclidine has an indirect dopaminergic
action.
BTCP, which differs from PCP as a result of a benzothiophenyl
nucleus in place of the phenyl nucleus has different properties,
as has been described by J. Vignon et al in European Journal of
Pharmacology, 148, 1988, pp.427-436.
Thus, to a much greater extent BTCP has the capacity to inhibit
the in vitro recapture of dopamine, whilst it has a very low
affinity for the PCP receptor. This property makes BTCP of
interest for other applications, e.g. in the field of anti-
depression and vigilance. ,
It has also been demonstrated by M. Slimani et al in Domino,
E.F, and Itamenka, J.M. <eds.), Sigma and Phencyclidine-Like
Corr~ounds as Molecular Probes in Biology, NPP Books, Ann Arbor,
1988, pp.511-520, that BTCP also had an inhibiting action of the
same type on the recapture of noradrenaline.
Research has also been carried out to find molecules of the same
type having the greatest possible dopaminergic action, but also
and in particular a minimum affinity for the receptor of PCP.
2p The present invention specifically relates to novel substituted
amines having these interesting properties.
According to the invention, the novel substituted amines comply
with the formula:
(dt4)n
RS
R3_r~~ R,1
(H)
N'
R2
2 5 in which R9 and R2, which can be the same or different,
represent an alkyl radical or an alkyl radical substituted by at
least one substituent chosen fr~n among the halogen atoms, the
alkoxy radicals and the hydroxyl radical, or R' and R2 form with
B. 10089 MDT
_ 0 _
the nitrogen atarr to which they are bonded, a piperidine cycle
optionally incorporating one or more substituents chosen from
among Oli, the aralkyl radicals, the alkyl radicals, the alkyl
radicals substituted by at least one substituent~chosen from
among the halogen atoms and the hydroxy, alkoxy, arylalkoxy and
oxycarbonylalkyl groups, the divalent radical
and = 0, or in which R~ and R2 form together with the nitrogen'.
atom to which they are bonded a piperazine cycle of formula:
'H~-R~
in which Re represents H, an aralkyl radical, an alkyl radical
or an alkyl radical substituted by at least one substituent
chosen from among the halogen atoms and the hydroxy, alkoxy,
arylalkoxy and oxycarbonylalkyl groups, R3 is a hydrogen atom or
a radical chosen from among the alkyl, alkoxy and hydroxy
radicals, R4 is an alkyl, hydroxy or alkoxy radical, n is equal
to 0 or is an integer from 1 to 8, whereby the R4 can differ
when n ;; 2, Y represents a nitrogen atom or CR6 with R6
representing a hydrogen atom, an alkyl radical, a hydroxy
0 radical or an alkoxy radical, provided that R3 represents a
hydrogen atom or an alkyl radical when Y represents a nitrogen
acorn and R5 represents a radical chosen from among the radicals
complying with the formulas:
c~'~~ cn~~e tAa~a
eae~ ~ ~ sraa> ' a~vm
i
B . 1009 t~T
~~~~~~2
- 4 -
in which Z is a sulphur or oxygen atom, R7 is an alkyl radical,
p is equal to 0, 1 or 2 and the R7 can be different when p - 2,
provided that R3 does not represent a hydrogen atom when Y
represents -CH, RS represents
(R7)p
S
n and p are equal to 0 and R' and R2 form together with the
nitrogen atom to which they are bonded an unsubstituted
piperidine cycle.
The aforementioned amines differ from BTCP either by the
presence of substituents on the cyclohexyl, aromatic and/or
piperidine nucleus, or by the replacement of the piperidine
nucleus by alkyl radicals, or by the replacement of the benzo-
thiophenyl nucleus by a benzofuranyl or naphthyl nucleus.
As a result of these modifications, there is a significant
irr~rovement to the inhibiting power of recapture of dopamine
and/or noradrenaline, whilst still having a low affinity for the
site of the PCP.
When the substituents used in the invention are alkyl radicals,
they can be straight or branched alkyl radicals preferably with
1 to 4 carbon atoms. In the case of R3, preference is given to
radicals having t or 2 carbon atoms. For R~ and Rz goad results
are obtained with 2 to 3 carbon atoms.
When the substituents used in the invention are araikyl
radicals, the alkyl part of these radicals preferably has 1 to 3
carbon atoms. !=xarr~les of these radicals are benzyi and
dipheny9 rrtethyt radica9s.
in certain cases, the alkyl radicals used for R9, R~ or as sub-
stituents of a piperidine or piperazine cycle can be substituted
~ . 10009 t~T
- 5 -
by at least 9 substituent chosen from among the halogen atoms
and the alkoxy, hydroxy, arylkoxy and oxycarbonylalkyl groups.
The oxycarbonylalkyl radicals can comply with the formula
R-C00-, in which R is an alkyl..
The halogens which can be used are fluorine, chlorine, bromine
and iodine.
The alkoxy radicals used can be straight or branched and have i
to 3 carbon atoms. Examples of such radicals are methoxy,
ethoxy and propyloxy radicals.
In the oxycarbonylalkyl radicals, the alkyl radical can also be
straight or branched and preferably has 1 to 3 carbon atoms.
Examples of such radicals are:CH3-C00, C2HSCCeO, C3H7C00.
Examples of substituted alkyl radicals used as substituents of a
piperazine or piperidine cycle are wCH2CH20H, -CH2CH20CH2CH2CHa
,5 and -CH2CH20CH<CeH5>2. In the case of a piperazine cycle with
RB representing a substituted alkyl radical
R~
R2
can comply e.g. with R2 formulas given below:
-H / CH2 - CH2 0 H-CH /CHZ-CHZ
3 d ~H fd-CH~CHZ~DH ;
~ cHZ _ cH~ / ' ~HZ°~H~
r CH2 CH2
20 -H td-CHZ CHI 0 CHZ CHZ CHI ; o~'
\ CH2 - CH20'
-H e,,.CH2 CHI ° H-CHZ CHZ 0 CH tC~HS)~
~ CH2 - CH2 ~~
8. 10089 t~T
- 6 -
When R4 represents OH and Y is a nitrogen atom, R4 is preferably
in the f3 position with respect to the nitrogen atom. In the
same way, when
R~
-N
R2
represents a piperidine cycle having an OH substituent, the
latter is preferably not in the a position with respect to N.
When the substituents R3, R4 and Rb are aikoxy radicals, it is
possible to use those referred to hereinbefore.
According to a first embodiment of the invention, RS represents
the radical of formula:
tR~)p
r
t
S /
in which R~ and p have the meanings given in claim i.
Preferably, in this case, the benzothiophenyi nucleus is not
substituted and p is equal to 0.
~5 In this first embodiment, Y advantageously represents CH and
consequently khe substituted amines are derivatives of 1-
benzothiophenyl-cyclohexyi amine.
In this case, good results are obtained when Ri and R2 represent
a piperidine cycle and the latter is substituted in the 3
position and/or the cyclohexyl nucleus is substituted in the 4
position by an alkyl radical, preferably an ethyl or methyl
radical.
Exar~les of such substituted amines are (benzo(b> thiophenyl-2)-
1c-methyl-4-r-Cpiperidino-t)-i cyclohexane, (benzo(b>thiophenyl-
2)-1 (methyl-3 piperidino)-f)-9 cyclohexane, and
B . 10089 i~'f
_,_
(benzo(b)thiophenyl-2>-1 (dimethyl-3,5 piperidino>-1)-1
cyclohexane.
According to the invention, very good results are also obtained
when Rt and R2 are alkyl radicals, e.g, propyl or ethyl
radicals. !n this case, it is not necessary for the benzo-
thiophenyi or cyclohexyl nucleus to be substituted by alkyl
groups.
Examples of such substituted amines are I-(2-
benzo<b)thiophenyi)-1-dipropylamino)-cyclohexane.
According to a second err~odiment of the invention, R5 is the
radical of formula:
(RT)p
FYI)
0
in which R~ and p have the meanings given hereinbefore.
An example of such a substituted amine is 1-(2-benzo<b)furanyl)-
~5 1-(9-piperidino)-cyclohexane.
The substituted amines according to the invention can be pre-
pared by different processes.
In the case of the substituted amines of formula (1)
6R~Dn
R5
R~p~~~ aR~ ~l)
. la
R2
B . 10089 hiA)T
_g_
in which R~ and R2, which can be the same or different,
represent an alkyl radical or an alkyl radical substituted by at
least one substituent chosen from among the halogen atoms, the
alkoxy radicals and the hydroxyl radical, or R~ and R2 form with
the nitrogen atom to which they are bonded, a piperidine cycle
optionally incorporating one or more substituents chosen from
among OH, the aralkyl radicals, the alkyl radicals, the alkyl
radicals substituted by at least one substituent chosen from
arrrong the halogen atoms and the hydroxy, alkoxy, arylalkoxy qnd.
i0 oxycarbonylalkyl groups, the divalent radical
0
~0
and = C, or in which R~ and R2 form together with the nitrogen
atom to which they are bonded a piperaaine cycle of formula
-PI ~M_R8
.
in which R8 represents H, an aralkyl radical, an alkyl radical
or an alkyl radical substituted by at least one substituent
chosen from among the halogen acorns and the hydroxy, alkoxy,
arylalkoxy and oxycarbonylalkyl groups, Rs is a hydrogen atom or
a radices! chosen from ~anong the alkyl, alkoxy and hydroxy
radicals, R~ is an alkyl, hydroxy or alkoxy radical, n is equal
to 0 or is an integer from 1 to 8, whereby the R~ can differ
when n ; 2, Y represents a nitrogen atcxn or CR6 with R6
representing a hydrogen atom, an alkyl radical, a hydroxy
radical or an alkoxy radical, provided that R3 represents a
hydrogen atom or an alkyl radical when Y represents a nitrogen
atom and RS represents a radical chosen frcxn a<reqng the radicals
complying with the formulas:
'Rr)~ :~r)~ , dW')p
i))) . ~ ~ t191H ~ ll~I)
8. (0089 ~hiDT
in which Z is a sulphur or oxygen atom, R' is an alkyl radical,
p is equal to 0, 1 or 2 and the R~ can be different when p ~ 2,
provided that R~ does not represent a hydrogen atom when Y
represents -Ctl, R5 represents
(R~)
P
I ~ ~ (V9
S
n and p are equal to 0 and R~ and R2 form together with the
nitrogen atom to which they are bonded an unsubstituted
piperidine cycle, It is possible to use a process consisting of:
a) preparing an a-aminonitrile of formula:
fR~)n
CN
R3_)~~~ ' t9i~ 1 )
JJ '' a R
R2
in which R~, R2, R3, R4, n and Y have the meanings given herein-
before and
. b) reacting the thus prepared a-~ninonitriie with a halide
of formula: MgXRS, in which X represents a halogen atom,
excepting fiuor~ine an~i. RS has the meaning given hereinbefore.
When
Rs
-N' represents -N ~ t~l,
R2
prior to the stage a>, the hll-i group of the piperazin~ cycle is
~. 10089 MDT
_ io _
protected from the a-arninonitrile of formula (VII) by an
appropriate radical, such as the acetile radical and the de-
protection of said NH group takes place after stage b>.
According to this process, it is possible to prepare the a-
aminonikrile of formula (VII) from cyclohexanones of formuPa
(VIII):
~Ry)n
R3..~ p t~I I I ) .
in which R3, R4, n and Y have the meanings given hereinbefore
with an amine or piperidine of formula <IX):
R'
PIH~ ~ tIX)
R
in which R~ and R2 have the meanings given hereinbefore.
For this preparation, it is possible to react the acetone
cyanohydrin (cyanide ion donor) with the amine or piperidine of
formula (1X) and the cyclohexanone of formula CVI11) in the
,5 presence of magnesium sulphate, which acts as a dehydrating
agent, in a solvent such as dimethyl acetamide (DPiA>. Following
treatment and purification; the corresponding~o~-aminonitrile is
isolated with a purity of at least 95y and it is possible to use
it as it is for the second stage of the process, in which said
a-aminonitriie of formu6a (V11) is reacted with the halide of
formula XRS using the so-called 8ruylants synthesis.
This synthesis consists of reacting the a-aminonitrile with a
Grignard reagent obtained from the halide XRS in ether or
anhydrous tetrahydrofuran (THF). Following an appropriate
treatment and purification, the sought substituted ~nine.is
isolated. Anhydrous hydrochloric gas is then bubbled into an
13. 10089 i~T
ethereal solution of the pure substituted amine and in this way
the corresponding hydrosoluble hydrochloride is precipitated.
It is possible to prepare other addition salts to the acids by
replacing the hydrochloric gas by the desired acid, e.g.
sulphuric or tartaric acid. This synthesis route is
stereospecific and consequently only gives access to one of the
possible isomers.
The substituted amines obtained by this process, in which R~ and
R2 form with the nitrogen atom to which they are bonded, a
piperidine cycle having one or more constituents constituted by
alkyl radicals substituted by a hydroxyl group, can be used for
the preparation of substituted amines according to the invention
in which R~ and R2 form with the nitrogen atom to which they are
bonded, a piperidine cycle having one or more substituents con-
stituted by alkyl radicals substituted by a halogen atom or by
an oxycarbonylalkyl radical.
1n this case, the hydroxyalkylated substituted amines are re-
acted with a halogenating agent or an appropriate carboxylic
acid for replacing the hydroxyl group by a halogen stare or an
oxycarbonylaikyi radical.
When the halogen atom is bromine, it is possible to use thionyl
bromide as the hatogenating agent. When the halogen atom is
chlorine, thionyl chloride can be used. When the halogen atom
is iodine, trimethyl silane iodide can be used.
2 5 When the substituent to be introduced is an oxycarbonylalkyl
radical of formula OCQR with R representing an alkyl radical,
the corresponding carboxylic acid RCi70H, a halide or an
anhydride of said acid is used.
It is also possible to prepare the substituted amines of formula
(i) of the invention in which R~ and R2 form with the nitrogen
atom to which they are bonded, a piperidine cycle which is
either unsubstituted or is substituted by at least one
substituent chosen from among tt~e alkyl radicals and alkyl
radicals substituted by a halogen atom or the hydroxyl radical
35 using a 4 stage process having the particular advantage of not
B . 10089 t~T
_ 12_
being stereospecific and of permitting access to the two
possible isomers.
Thisi process consists:
a) of preparing an alcohol of formula:
tR'~7~
R3
R3-Y' - X tX7
~' OH
in which R3, R4, RS, n and Y have the meanings indicated herein-
before,
b) of transforming the alcohol prepared in stage a) into a
corresponding azide derivative of formula:
fR~7~
RS
R3°Y~ ~f~l)
' H3
c)' of reducing the azide derivative into a mixture of
primary amines and
d) of reacting thR mixture of primary amines with a 1,5-
dihalogenopentane optionally having one or more substituents
ehosen from among alkyl radicals, alkyl radicals substituted by
a halogen atom or a hydroxyl group.
Thus, this synthesis takes place in 4 stages, which ire:
a) the preparation of the alcohol of formula <X); which can
be carried out by reacting the cyclohexanone of formula <VI11)
8. 10019 h~T
2~ ~.~~~~
- f3-
tR4)~
R3_Y~ p tVIII)
with a Grignard reagent obtained from the halides of formula XR5
in anhydrous ether, which gives the corresponding alcohols which
are subjected to a rapid purification and
b) the preparation of the corresponding azide derivatives
of formula (XI>.
This can be carried out by using a process similar to that used
in the Schmidt and Curtius reactions; by carrying out the sub-
stitution of the alcohol function by the azide function by
adding crude alcohols to a sodium azide suspension in triehloro-
acetic acid, or trifluoroacetic acid and chloroform in cold
form. Following the treatment, isolation takes place of a crude
mixture of epimerlc azides and which is subsequently used as
such.
95 This is followed by
c) reduction of the azides and for this purpose the
preceding mixture can be reacted with Raney nickel in
isopropanol in order to supply, after treatment, a mixture of
epimeric primary amines used as such subsequently.
d) The final stage is the formation of the piperidine cycle
and purification. For this stage hot reaction takes place in
acetonitrile ar ethanol of 1,5-dibromopentane optionally sub-
stituted by one or more substituents chosen frown among the alkyl
radicals and alkyl radicals substituted by a halogen ~tc~rs or the
8. 10089 NiOT
- 14-
hydroxyl group on the preceding mixture of primary amines,
Following treatment, isolation takes place of a residue
essentially containing a crude mixture of two epimers. 1t is
possible to obtain the two pure isomers by chromatography. By
bubbling anhydrous hydrochloric gas into the ethereal solutions
of the thus separated amines, the corresponding hydrosoluble
hydrochlorides are precipitated.
In an identical manner, it is possible to prepare addition salts
to the acids other than the hydrochloride referred to herein- '
before.
As a result of their indirect dopaminergic action, the sub-
stituted amines according to the invention can be used in
pharmaceutical compositions, e.g. for the treatment of
depression and for stimulating vigilance.
Thus, as will be shown hereinafter, the substituted amines
according to the invention have a non-amphetaminic stimulating
effect on the dopaminergic system by also stimulating the
noradrenergie system, which makes it possible to treat nervous
depression under good conditions.
The invention also relates to pharmaceutical compositions in-
corporating at feast one substituted amine of formula (1)
according to the invention, or its addition salt to a pharma-
ceutically acceptable acid. The acids which can be used are
e.g. hydrochloric, sulphuric and tartaric acid.
2 5 For the preparation of pharmaceutical compositions, it is
possible to dissolve an addition salt to the acids of the sub-
stituted amines according to the invention in an aqueous
solution which is injectabte or administrable by the oral route,
e.g. physiological serum.
It is also possible to include these amines in solid
preparations, such as tablets or ora9ly administrable gelatin
capsules by using standard excipients and methods.
These pharmaceutics! compositions can incorporate excipients,
diluents, plasticizers and other pharms,ceuticaliy acceptable
35 additives such as those generally used in pharmaceutical
B . 7 0089 t~T
- Is-
preparations. The doses used can vary from 2.5 to 20 mglkg of
body weight, as a function of the administration route and the
state of the patient.
For intramuscular or subcutaneous ac~ninistration doses of 2.5 to
10 mg/kg can be used. For oral administration doses of 10 to 20
mg/kg can be used.
When the pharmaceutical composition is in the form of a
solution, the amino derivative concentration of the salution is
preferably such that the administered vo9ume varies from 0.5 to~
2 ml .
For these pharmaceutical compositions, it is possible to use the
amines according to the invention in the form of their different
isomers or a mixture of isomers. However, and as will be shown
hereinafter, when the substituted amines according to the
~5 invention incorporate an alkyl substituent R3 on a cyclohexyl
nucleus, it is preferable to use the cis-isomer for the position
of R3 relative to the nitrogen atom of the piperidine cycle.
in the case where the substituted amine comprises an alkyl
substituent R4 in the 2 position of a cyclohexyi nucleus, it is
preferable to use the cis-isomer for the position of R4 relative
to the nitrogen atom.
However, in the case where the substituted amine comprises an
alkyl substituent R~ in the 3 position of the cyclohexy)
nucleus, it is preferable to use the traps-isomer.
Other features and advantages of the invention can be gathered
from the following examples, which are obviously given in an
illuskrative and non-limitative manner.
Exar~ies 1 to it illustrate the preparation of a-~ninonitriles
usable for preparing substituted amines aocording to the
invention of examples l2 to 28 for a two-stage process.
Examples 29 to 32 illustrate the preparation of the two substi-
tuted aunine isomer forms using the ~ stage process. Examples 34
to 36 and 38 illustrate the properties of substituted amines
according to the invention in in vitro tests, whilst examples 37
B . 10089 tJDT
- 16-
and 39 illustrate the activity of substituted mines according
to the invention in an in vivo test.
EXAMPLE 1. Preparation of 1-cyano-1-(1-piperidino)-cyclohexane
<synthon I).
15 g (0.15 mote) of cyclohexanone, 13.4 C0.15 mole) of acetone
cyanohydrin, 55 g (0.45 mole) MgSOa tdried) are mixed into 26 g
<0.3 mole) of piperidine and 8.7 g (0.1 mole) of dimethyl
acetamide <DrIA). The mixture obtained is stirred strongly at
45°C and for 48 h, followed by pouring into a large volume of
water and ice violently stirred for 30 min. Following ether
extraction, drying on Na2C03 and vacuum evaporation of the
p solvent a solid residue is obtained which, after crystallization
in hexane or petroleum ether, gives 20.2 g (70%) of the synthon
I in the form of an analytically pure white solid melting at 68
to 69°C (1R 2200cm-~, GG/MS : 100-250°C (20°C/min) RT =
5.06
min, m/e 206.15)
5 The characteristics are as follows:
1R spectrometry : 2200m--~,~
mass spectrometry coupled with gas chromatography CGCIMS)
injector temperature : 100-250°C C20°C/min);
retention time RT = 5.06 min, m/e 206.15.
EXAMPLE 2: Preparation of 1-cyano-1-(3-methyl-1-piperidino>-
~clohexane Csynthon I1).
20 3 g (0.039 mole) of cyclohexanone, 3.3 g C0.039 mole) of acetone
cyanohydrin, 23.4 g C0.19 mole) of dried MgSO.e are mixed into
5.77 g 10.058 mole) of 3-methyl-piperidine and 5g C0.058 mole)
of DMA. The mixture is stirred strongly at 45'C fnr 48 h and is
then poured into a large volume of water and ice which is
25 violently stirred for 30 min. Following ether extraction,
drying on Na2C03 and vacuum evaporation of the solvent, 7 g
(87.5%) of synthon II are obtained in the form of a yellow oil
with a purity greater than 95% and adequate for the remainder of
the syntheses <IR 2200cm-j, GC/MS : 100-250°C (20°C/min), RT =
0 4.75 min, m/e : 992.15.
8. 10089 h~T
-17_
EXAMPLE 3: Preparation of t-cyano-t-(4-ethyleneketal-
piperidino)-1-cyclohexane (synthon ltl>.
3.2 g (0.034 mole) of cyclohexane, 2.85 g (0.034 mole) of
acetone cyanohydrin and 20.2 g <0.17 mole) of dried MgS04 are
mixed into 7.16 g (0.05 mole) of 1,4-dioxa-8-azaspiro decane
(4.5> and 4.4 g (0.05 mole) of DMA. The mixture is stirred
strongly at 45°C for 48 h and is then poured into a large volume
of water and ice, which is violently stirred for 30 min.
Following ether extraction, drying on Na2C0a and vacuum
evaporation of the solvent, 6 g of synthon III are obtained in
the form of a solid white residue (73.5%) which melts at 108 to
109°C (~IR 2200cm-~, GC/MS : 100-250°C (20°C/min), RT =
8.32min,
m/e 250.15.
EXAMPLE 4; Preparation of 9-cyano-1-(3-hydroxymethyl-
_piperidino)-1-cyclohexane <synthon IV).
8.83 g (0.09 mole) of cyclohexanone, 7.66 g <0.09 mole) of
acetone cyanohydrin, 32.4 g (0.27 mole) of dried MgSOa are mixed
with 20.7 g (0.18 mole) of 3-hydroxymethyl-piperidine and 10 ml
of DMA. The mixture is stirred strongly at 45°.C for 48 h and
Isthen poured into a large volume of water and lee, which is
violently stirred for 30 min. Extraction takes place with
3x250m1 of ether, drying takes place on Na2S04 and vacuum
evaporation is carried out to obtain 99 g of a yellowish solid
20 residue. Successive crystallizations in ethanol precipitate
g (38% of synthon IV in the form of colourless crystals
melting at 94 to 95'C (IR 2200cm-t, GC/MS : 100-250°C
(20°C/min), RT = 8.94min, m/e 222.15).
EXAMPLE 5: Preparation of i-cyano-1-f3,5-dimethyl-piperidino>-
1-cyclohexane (synthon V).
fig 10.06 mole) of cyclohexanone, 5.2 g (0.06 mole) of acetone
cyanohydrin and 22 g (0.18 mole) of dried MgS04 are mixed into
27.6 g C0.122 e~le) of 3,5-dimethyl-piperidine and 11.3 g (0.13
mole) of DMA. The mixture is stirred strongly at 45°C for 48 h
and, is then poured into a large volume of water and ice, which
is violently stirred for 30 man. Following ether extraction,
8. 10089 t~T
_ 18_
drying on NapC03, as well as vacuum evaporation of the solvent,
g <76%) of synthon V is obtained in the form of a whitish
solid residue with a purity better than 95%, which is adequate
for the remainder of the syntheses (IR 2200cm-~, GCfMS 100-250°C
5 (20°C/min), RT = 5.44min, m/e 220.25).
E)CAhWi_E 6: Preparation of 4-cyano-1,2,2,6,6-pentamethyl-4-(I-
piperidino)-piperidine <synthon V).
17.6 g (0.11 mole) of 1,2,2,6,b-pentamethyl-4-piperidinone, 9.5
g C0.11 mole) of acetone cyanohydrin and 50 g C0.42 mole) of
dried MgS04 are mixed into 19.1 g (0.22 mole) of piperidine and
1 g of DMA. The mixture is stirred strongly at 45°C for 48 h
10 and is then poured into a large volume of water and ice, which
is violently stirred for 30 min. The precipitate obtained is
suction filtered, dried and crystallized in petroleum ether to
give 31 g (92%) of synthon VI in the form of white crystals
melting at 98 to 99°C (analytically pure) (IR 2200cm-~).
EXAMPLE 7: Preparation of 1-cyano-1-(1-dipropylamino)-
cyclohexane Csynthon VI1).
6.6 g (0.0b7 mole) of cyciohexanone, 5.7 g (0.067 mole) of
acetone cyanohydrin and 40.4 g C0.34 mole) of dried MgSOa are
mixed into 10.2 g (0.1 mole) of dipropylamine and 5 ml of DMA.
Strong stirring takes place at 45°C for 48 h and then the
mixture is poured into a large volume of water and ice, which is
violently stirred for 30 min. Following extraction with ether,
drying on Na2C03 and evaporation of the solvent in vacuo, l0 g
C71.3%) of synthon V!1 are obtained in the form of a yellowish
oil with a purity higher than 9S% and adequate for the sequence
of the syntheses (1R 2200cm-~, GC/MS 100-250°C (20°Clmin>, RT =
2 5 4.bOmin, m/e 208.15).
EXAMPLE 8: Preparation of 1-cyano-1-(t-diethylamino)-
~ciohexane tsynthon Vldl).
i0.9 g (0.11 mole) of cyclohexanone, 9.44 g (0.11 mole) of
acetone cyanohydrin and 40.4 g (0.34 mole) of dried MgS04 are
mixed into 16.2 g (0.22 mole) of diethyl amine and 9.6 g of DMA.
B . 10089 PST
- 19-
Strong stirring kakes place at 45°C for 48 h and then the
mixture is poured into a large volume of water and ice, which is
violently stirred for 30 min. Following ether extraction,
drying on Na2COs and vacuum evaporation of Ehe solvent, 15 g
(77.8%) of synthon Vlll are obtained in the form of a yelicwish
oil with a purity better than 95% and adequate for the sequence
of the syntheses tIR 2200cm-~, GC/MS 100-250°C (20°C/min>, RT =
4.Obmin, mle 180.20').
EXAMPLE 9: Preparation of 1-cyano-1-(4-methyl-1-piperidino)-1-
cyclohexane (synthon 1X).
7.5 g (0.078 mole) of cyclohexanone, b.bg (0.078 mole) of
acetone cyanohydrin and 46.8 g (0.38 mole) of dried MgSO~ are
mixed into 11.5 g (0.12 mole) of 4-methyl-piperidine and 10 g of
DI'tA. Strong stirring takes place at 45°C for 48 h and the
mixture is then poured into a large volume of water and ice,
which is violently stirred for 30 min. Following ether
extraction, drying on Na2C03 and vacuum evaporation of the
solvent, 13 g (81.2%) of synthon IX are obtained in the form of
a yellowish oil with a purity above 95% and adequate for the
sequence of the syntheses (IR 2200cm-~, 6C/MS).
EXAMPLE 10: Preparation of 1-cyano-1-<3,5-dimethyl-1-
piperidino)-4-methyl cyclohexane <synthon X).
4.8 g (0.04 mole) of 4-methyl-cyclohexanone, 3.6 g (0.04 mole)
of acetone cyanohydrin and 15.4 g t0.13 mole) of dried MgS04 are
i mixed into 4.8 g (0.04 mole) of 3,5-dimethyl-piperidine and 3.6
g of DMA. Strong stirring takes place at 45'C for 48 h and the
mixture is then poured into a large volume of water and ice,
which is violently stirred for 30 min. Following ether
extraction drying on Na2CC~ and vacuum evaporation of the
solvent, 7~g (70%) of synthon X are obtained in the form of a
yellowish oil with a purity of better than 95% and sufficient
for the remainder of the syntheses. 1t contains two epimeric
aminanitriles which, in the following 8ruylants reaction,
3p epimerize to the thermodynamically stable compound which is the
B , i 0089 NZQT
- 20 -
only one to react (IR 2200cm-', GC/MS : 100-250'C (20°C/min> RT
= 5.58 min, RT = 5.62 min, m/e 234.10.
EXAMPLE 11: Preparation of 1-cyano-1-(3,5-dimethyi-1-
piperidino)-3-methyl-cyclohexane Csynthon XI).
4.8 g (0.04 mole) of 3-methyl-cyclohexanone, 3.6 g (0.04 mole)
of acetone cyanohydrin and 15.4 g (0.13 mole) of dried MgS04 are
mixed into 4.8 g (0.04 mole) of 3,5-dimethyl-piperidine and 3.6
g of DMA. Strong stirring takes place at 45°C for 48 h and the
mixture is then poured into a large volume of water and ice, '
which is violently stirred For 30 min. Following ether
extraction, drying on Na2C03 and vacuum evaporation of the
solvent, 6 g (60%> of synthon XI is obtained In the form of a
yellow oil with a purity higher than 95% and adequate For the
remainder of the syntheses. 1t contains 2 epimeric
aminonitriles which, in the following Bruylants reaction,
epimerize towards the thermodynamically stable ccxnpound which is
the only one to react (1R 2200crrr~, GC/MS : 100-250°C
<20°C/min) RT = 5.54 min, RT = 5.68 min, m/e 234,10.
EXAi~LE 12: Preparation of 4-(2-benzotb)thiophenyl)-1,2,2,6,6-
pentamethy!-4-(1-piperidino)-piperidine (compound 1).
To a Grignard reagent prepared from 1.9 g 10.0076 mole) of 2-
iodobenzo(b)thiophene and 0.36 g of magnesium in the form of
turnings in 20 ml of anhydrous ether is added dropwise at
ambient temperature 1 g (0.0038 mole) in 10 ml of anhydrous
ether of synthon VI of example 6. The solution is refluxed for
ib h, then cooled and poured into a saturated solution of NHaCt
and ice. After stirring for 30 min and decanting, the mixture
is extracted with ether (3x15 m~) and then the ethers are washed
with 15% NC3 C3x15 mJ?). The cor~ined aqueous phases are
neutralized by 20% NHaOH and extracted with ether (3x15 mt).
The combined ethers are dried on Na2S0d and evaporated under
reduced pressure to give a whitish, yellow residue.
Chranatography on Merck alumina (activity 2-3) in petroleum
ether supplies 0.9 g of compound 1 in the form of a white solid
C64.3%). By bubbling gaseous F!C! into the ethereal solution of
B . 10089 t~T
-21-
this compound, its white solid dihydrochloride is precipitated
and which, recovered by suckion filkering and vacuum drying,
melts at 168-169°C (analytically pure).
The NMR spectrum of the ~3C of this compound and its percentage
analysis are given in the atkached tables 2 and 3.
EXAMPLE 13: Preparation of 1-C2-benzoCb)thiophenyl>-3-methyl-
1-piperidino)-1-cyclohexane (compound 2>.
In 50 ml of anhydrous ether is prepared the Grignard reagent
resulting from the action of 9.4 g (0.036 mole) of 2-
iodobenzoCb>thiophene on 144 g (0.06 mole) of magnesium
turnings. To it is slowly added 5 g (0.024 mole) of synthon II
lp of ex~nple 2 dissolved in 50 ml of anhydrous ether. Stirring
takes place for 12 h at reflux and the complex is decomposed by
a cold saturated NH4C! solution and then, after decanting, the
waters are extracted with ether (3x50 ml). The combined
ethereal phases are extracted by a 20% aqueous HC! solution
~5 (2x50 ml). The acid waters are neutralized by NHaOH, extracted
with ether (3x50 mi) and the collected ethers, after drying on
Na2S04 are vacuum evaporated to give 6 g of a yellowish brown,
solid residue. The latter undergoes chromatography on Merek
alumina (activity 2-3) in a mixture of petroleum ether and ether
(90/10 v/v to give 4.9 g (65%> of compound 2 in the form of a
white solid melting at 85 to 86°C. By bubbling gaseous HC! intro
the ethereal solution of this compound, its white solid
hydrochloride is precipitated and which, when recovered by
suction filtering and vaeuum drying, melts at 180 to 181°C
2 5 (analytically pure) CGC/MS of base; 100-250°C, i5°C/min RT =
17.70min, m/e 313.2). The NMR spectrum of the ~3C of this
compound and its percentage analysis are given in the attached
tables 2 and 3.
EXAMPLE 14: Preparation of 1-C2-benzoCb)thiophenyi)-i-<1-
dipropylamino)-cyclohexane (compound 3).
In 50 mli! of anhydrous ether is prepared the Grdgnard reagent
30 resulting from the action of 13 g (0.05 mole) of 2-iodobenzo(b>-
thiophene on 2g 10.08 mole) of magnesium turnings. To it fs
B . 10089 t~T
- 22 -
slowly added 7 g (0.034 mole) of synthon VII of example 7
dissolved in 50 and of anhydrous ether. Stirring takes place far
96 h at reflux, the ccxnplex is decorr~osed by a cold saturated
NHaC! solution and then, after decanting, extraction takes place
with ether (3x150 ml). The combined ethereal phases are
extracted by an aqueous 20% HCI solution (2x200 m!>. The acid
waters are neutralized by NH40H, extracted with ether (3x150 m!)
and the collected ethers, after drying on Na2S04. undergo vacuum
evaporation to give 8 g of a yellowish oily residue. The tatter
i0 undergoes chromatography on Merck alumina (activity 2-3) in
petroleum ether to give 7.4 g (69%) of compound 3 in the form of
a colourless oil. By bubbling gaseous HC! into the ethereal
solution of this compound, its white solid hydrochloride is
precipitated and which, when recovered by suction filtering and
'5 vacuum drying, melts at 157 -958°C (analytically pure>. C6C/h~a
of base: 100-250°C (20°C/min> RT = 9.58 min, m/e 315.95.
The NMR spectrum of the ~3C of this compound and its percentage
analysis are given in the attached tables 2 and 3.
EXAMPLE 15: Preparation of i-(2-benzo<b)furanyl)-t-(1-
piperidino)-cyclohexane (compound 4)
The Grignard reagent resulting fr~n the action of 7.3 g (0.03
20 mole) of 2-iodobenzo(b)furan on 1,2 g (0.05 mole) of magnesium
turnings is prepared in.70 m~ of anhydrous ether. To it are
slowly added 4 g (0.02 mole) of synthon I of example 1 dissolved
in 70 m! of anhydrous ether. Stirring takes place for 16 h at
reflux, the complex is decomposed by a cold saturated NH4CR
25 solution and then, after decanting, extraction takes place with
ether (3x900 m~). The combined ethereal phases are extracted by
an aqueous 20% HC~ solution (3x100 mt). The acid waters are
neutralized by NH40H, extracted with methylene chloride (2x70
m!) and then with ether (2x70 m!). The collected ethers, after
30 drying on Na2S0~, undergo vacuum evaporation to give 2.5 g of a
yellowish solid residue. The latter undergoes chromatography on
Merck alumina (activity 2-3) in petroleum ether containing ether
(90/90 v/v) to give 2 g (35%) of compound 4 in the form of a
white solid melting at 74-75°C. By bubbling gaseous HC~ into
B . 10089 1~T
- 23 -
the etherea6 solution of this compound, its solid white hydro-
chloride is precipitated and when recovered by suction filtering
and vacuum drying melts at 194-195°C (analytically pure).
(GC/MS of base : 70-250°C (15°C/min) RT = 14.82min, m/e 283.20.
The f~'1R spectrum of the '3C of this compound and its percentage
analysis are given in the attached tables 2 and 3.
EXAMPLE --16: Preparation of 1-(2-benzo<b)thiophenyl)-4-
(ethyleneketai-i-piperidino)-cyclohexane (compound 5).
The Grignard reagent resulting from the action of 7.3 g C0.03
mole) of 2-iodobenzoCb>thiophene on 1.2 g (0.05 mole) of
magnesium turnings is prepared in 50 m! of anhydrous ether. To
~0 it are slowly added 5 g C0.02 mole) of synthon Ill of example 3
dissolved in 30 m! of anhydrous ether. Stirring takes place for
16 h at reflux, the complex is decomposed by a cold saturated
NH4C~ solution and then, after decanting, the waters are
extracted with ether (3x60 ml). The combined ethereal phases
~5 are washed with distilled water C2x100 m!) and, after drying on
Na2S04 undergo vacuum evaporation to give 5 g of a whitish solid
residue. The latter undergoes chromatography on Merck alumina
(activity 2-3) in petroleum ether to give 4 g of compound 5 in
the form of a white solid (56%> melting at 80-81°C. 8y bubbling
20 gaseous HCI into the ethereal solution of said compound, its
' solid white hydrochloride chloride is precipitated, covered by
suction filtering and dried in vacuo and it then melts at 190-
191°C Canatytically pure). <GC/MS of base : 100-250°C
120°C/min> RT = 19.94, m/e 357.25.
25 The i~lR spectrum of the 4~C of Ehis canpound and its percentage
analysis are given in the attached tables 2 and 3.
EXAMPLE 17: Preparation of 1-C2-benaotb>thiophenyl)-3,5-
_(dimethyl-1-piperidino)-1-cyciohexane Ccornpound b).
The Grignard reagent resulting from the action of 10.4 g C0.04
mole) of 2-iodobenzo(b)thiophene on 1,5 g C0.06 mole) of
magnesium turnings is prepared in 50 mle of anhydrous ether. To
30 it are slowly added 4.5 g t0.02 mole of synthon V of example 5
dissolved in 20 ~n~ of anhydrous ether. Stirring takes place for
B . 10089 i~7T
- 24 -
16 h at reflux, the complex is decomposed by a cold saturated
NHaC! solution and then, after decanting, extraction takes place
with ether (3x50 m!). The combined ethereal phases are
extracted by an aqueous 20% HC! solution (3x50 m!). The acid
waters are neutralized by NH~OH and extracted with ether (2x79
m!). The combined ethers, after drying on Na2S0a, undergo
vacuum evaporation to give 5 g of a yellowish solid residue.
The latter is crystallized twice in methanol to give 4 g of
compound 6 in the form of white crystals <61%) melting at 98-
99°C. By bubbling the gaseous HC! into the ethereal solution of
this compound, its white solid hydrochloride is precipitated and
following recavery by suction filtering and vacuum drying melts
at 192-193°C (analytically pure). (GC/MS of base : 70-250°C
(15°C/min) RT - 17.62min, m/e 327.25).
The NMR spectrum of the ~~C of this compound and its percentage
analysis are given in the attached tables 2 and 3.
EXAMPLE 18 Preoaratlon of 1-C2-benzo(b)thiophenyl)-4-(meth
piperidino)-1-cyclohexane (corr~ound 7).
The Grignard reagent resulting from the action_of 10.4 g (0.04
mole) of 2-iodobenzo(b>thiophene on 1.5 g C0.06 mole) of
magnesium turnings is prepared in 70 m! of anhydrous ether. To
it are slowly added 4.3 g (0.02 mole) of synthon 1X of example 9
dissolved in 50 m! of anhydrous ether. Stirring takes place for
16 h at reflux and the complex is decc~riposed by a cold saturated
NH4C! solution and then, after decanting, extraction takes place
with ether (3x100 m!). The combined ethereal phases are
extracted by an aqueous 20% HC! solution (3x100 m!). The acid
waters are neutralized by NHAOH, extracted with ether (2x100 m!)
and with methyiene chloride C2xt00 m!). The combined organic
phases, after drying on Na2S0~, undergo vacuum evaporation to
give 4 g of a yellowish solid residue. The latter undergoes
chromatography on Merck alumina (activity 2-3) in a mixture of
ether and hexane (10190 v/v) to give 3.7 g of core~ound 7 in the
form of a white solid (59%) melting at 84-85°C. By bubbling
gaseous IiC! into the ethereal solution of this ca~apound, its
wf~ite solid hydrochloride is precipitated and, when recovered by
B . 10089 i~T
-25-
suction filtering and vacuum drying, melts at 190-191'(
(analytically pure). (GC/MS of base : 70-250°C (15°C/rnin, RT =
18.52min, m/e 313.25).
The 1~1R spectrum of the ~3C of this compound and its percentage
analysis are given in the attached tables 2 and 3.
EXAMPLE 19: Preparation of 1-<2-benzo(b)thiophenyl)-1-C1-
diethylamino)-1-cyclohexane (compound 8>.
In 150 mt of anhydrous ether is prepared the Grignard reagent
resulting from the action of 17.3 g (0.066 mole) of 2-
iodobenzo(b)thiophene on 1.7 g (0.07 mole) of magnesium
turnings. To it are slowly added b g (0.033 mole) of synthon
V111 of example 8 dissolved in 50 rn! of anhydrous ether.
Stirring takes place for l6 h at reflux, the complex is
decomposed by a cold saturated NH4C! solution and then, after
decanting, extraction takes place with ether (3x100 m!). The
combined ethereal phases are extracted by an aqueous 20% HCF
solution (3x100 m:!). The acid waters are neutralized by NH40H,
. extracted with ether (3x100 m,!) and the co fined ethers, after
drying on 1~2S04, undergo vacuum evaporation to give 6 g of a
yellowish solid residue. The latter undergoes chromatography on
Merck alumina (activity 2-3) in petroleum ether to give 5.4 g of
2 0 compound 8 in the form of a colourless oil (58%). By bubbling
gaseous HC! into the ethereal solution of said compound, its
white solid hydrochloride is precipitated and after recovery by
suction fi4tering and vacuum drying melts at 160-161°C
(analytically pure). (GC/MS of base ; 100-250°C (20°C/min, RT =
2 5 9.58min, m/e 287.15).
The t~lR spectrum of the ~3C of this compound and its percentage
analysis are given in the attached tables 2 and 3.
EXAf'iPt_E 20: Preparation of 1-C2-benzo<b>thiopheny_I>-3-
(hvdroxvmethvl-1-piperidino>-1-cyclohexane (compound 9).
The Grignard reagent resu9ting from the action of 12.5 g (0.048
mole) of 2-iodobenzo(b)thiophene on 1,7 g (0.07 mole) of
30 magnesium turnings is prepared in 100 ml of anhydrous ether. To
it are slowly added 5.4 g (0.024 mole) of synthon IV of example
8. 10089 t~T
_ 26 -
4 dissolved in 50 ml of anhydrous ether, Stirring takes place
for 16 h at reflux and the complex is decomposed by a cold
saturated NHaCiI solution and then, after decanting, the waters
are extracted with ether (3x100 mP), The combined ethereal
phases are extracted by an aqueous 20% HC! solution (2x100 ml>.
The acid waters are neutralized by 20% NNQOH and extracted with
ether (3x70 m!>. After drying on Na2S04, the combined ethers
undergo vacuum evaporation to give 6 g of a yellowish oily
residue. The latter undergoes chranatography on Merck alumina,
(activity 2-3> in a mixture of ether and petrole~n ether (90/10
v/v) to give 5 g (b3%) of compound 9 in the form of a clear
yellow oil. The latter slowly transforms into colourless
crystals melting at 102-103°C. By bubbling gaseous HC! into the
ethereal solution of this compound, its solid white
hydrochloride is precipitated and, after recovery by suction
filtering and vacuum drying, melts at 188-189°C (analytically
pure). (GC/h1S of base : 50-250°C (20~C/min, RT = 17.28min, m/e
39.15).
the NMR spectrum of the 13C of this compound and its percentage
analysis are given in the attached tables 2 and 3.
EXAMPLE 21: Preparation of 1-(2-benzo(b)thiophenyl)-1-(3-
bromomethyl-1-piperidino>-cyclohexane Cc
ornpound 10) .
To 5.7 g (0.017 nnole) of compound 9 of example 20 and 5 m9 of
methylene chloride are very slowly added (with evacuation or
trapping for acid gases) and accompanied by stirring, 3.6 g
(0.017 rnole) of thionyl bromide dissolved in 2 m! of methylene
chloride. Stirring takes place for one night at mnbient
temperature and the solvent is then evaporated in vacuo. The
residue obtained is taken up in ether and washed with 10% HCB
t2x200 mk). The aqueous phase is neutralised by 20% NH40H,
extracted with ether (2x70 m!) and then with methyiene chloride
(70 mR). After combining and drying on Na2S04, the organic
phases are evaporated in vacuo to give 3 g of a brownish oily
residue. The latter is purified by flash chromatography on
silica in petroleum ether to give 2.7 g t41%) of compound 10 in
the form of a colourless oil. By bubbling gaseous HCl: into the
8 . 10089 I~T
- 27 -
ethereal solution of the base, its white solid hydrochloride is
precipitated and after recovery by suction filtering and vacuum
drying melts at 178-t79°C (analytically pure). (GC/MS of base
100-250°C (20°C/min, RT = 15.42min, m/e 391.5 and 393.05).
The NMR spectrum of the ~3C of this compound and its percentage
analysis are given in the attached tables 2 and 3.
EXAMPLE 22: Preparation of t-(2-benzo(b)thiophenyl)-1-<3-
iodomethyl-1-piperidino)-cyclohexane (compound 11).
To 2 g (0.006 mole) of compound 9 of example 20 and 10 mB of
methylene chloride are slowly added accompanied by stirring and
in a nitrogen atmosphere, 4.86 g (0.024 mole) of trimethyl
silane iodide. Accompanied by stirring, the mixture is heated
to 40°C for 24 h, cooled and poured into a cold sodium
disulphite solution and then extracted with methytene chloride
(3x30 ml). The organic phase is dried on Na2S04 and evaporated
in vacuo to give 1.2 g of brownish oily residue. The latter is
purified by chromatography on Merck alumina (activity 2-3> in a
mixture of petroleum ether and ether (90/10 v/v) to give 0.7 g
(18%) of compound 11 in the forr» of a clear oil. By bubbling
gaseous HC1 into the ethereal solution of this compound, its
white solid hydrochloride is precipitated and, after suction
filtering and vacuum drying, melts at 155-156°C (analytically
pure). tOC/MS of base : 100-250°C (20°C/min, RT = 19.07min,
m/e 439).
The IJtIR spectrum of the ~3C of this compound and its percentage
analysis are given in the attached tables 2 and 3.
EXAMPLE 23: Preparation of 1-(2-benzo<b>thiophenvl>-1-t3-
chlor~nethyl-1-piperidino)-cyclohexane (compound 12).
To 3 g (0.009 mole) of compound 9 of example 20 and 5 and of
methylene chloride are very slowly added (accompanied by
evacuation or trapping for the acid gases) and aecorr~aanied by
stirring, 1.9 g (0.009 mole) of thionyl chloride dissolved in 2
ml of methylene chloride. Stirring takes place for 6 h at 60°C
and then, after cooling, the medium is poured into a Na2C03
solution. After stirring for 15 min extraction takes place with
8. 10089 t~T
_28_
methylene chloride (3x20 m1>, followed by drying on Na2S0a and
vacuum evaporation of the solvent to give 2 g of a brownish oily
residue. The latter is purified by flash chromatography on
silica in petroleum ether and ether (90/10 v/v) to give 1 g
(32%) of compound 12 in the form of colourless oil. By bubbling
gaseous HC~ into the ethereal solution of this compound, its
white solid hydrochloride is precipitated and which, recovered
by suction filtering and vacuum drying, melts at 182-183°C
(analytically pure). (GC/MS of base : 100-250°C <20°C/min, RT =
29min, m/e 347.25>.
The t~'1R spectrum of the ~3C of this co~ound and its percentage
analysis are given in the attached tables 2 and 3.
EXAMPLE 24: Preparation of 1-<2-benzo(b>thiophenyl)-r-i-(3,5-
dimethyl-1-piperidino)-4-c-methyl-cyclohexane (compound 13>.
The Grignard reagent resulting from the action of 15 g (0.06
mole) of 2-iodobenzo(b)thiophene on 1.7 g f0.07 mole) of
i5 magnesium turnings is prepared in 150 m! of anhydrous ether. To
it are slowly added 6.75 g C0.03 mole) of synthon X of example
10 dissolved in 50 m! of anhydrous ether. Stirring takes place
for 1b h at reflux, the complex is decomposed by a cold
saturated NH4C! solution and then, after decanting, extraction
takes place with ether (3x100 m6). The combined ethereal phases
are extracted by an aqueous 20% HC! solution (3x100 mI). The
acid waters are neutralized by NH40H, extracted with ether
(2x70) m~) and then with methylene chloride <2x?0 m!>. The
cor~ined organic phases, after drying on Na2S04, are evaporated
in vacuo to give 6 g of an oily residue. Following flash
chromatography on silica in petroleum ether, the latter gives
5.4 g (53%) of compound 13 in the form of a white solid melting
at 115-116°C. By bubbling gaseous HC! into the ethereal
solution of this compound, its white solid hydrochloride is
precipitated and, after recovery by suction filtering and vacuum
drying, it melts at 198-199°C (analytically pure). fGC/MS of
base : 100-250°C (20°C/min, RT = 90.90min, m/e 341.15).
The PitlR spectrum of the ~3C of this car~ound and its percentage
analysis are given in the attached tables 2 and 3.
B. 10089 h~T
~~~.r~
- 29 -
EXAMPLE 25; Preparation of 1-<2-benzo(b)furanyi)-1-r-(3,5-
dimethyl-tt-piperidino>-3-methyl-cyclohexane (compound 14).
In 100 m! of anhydrous ether is prepared the Grignard reagent
resulting from the action of 10.4 g (0.04 mole) of 2-
iodobenzo(b)furan on 1.2 g (0.05 mole) of magnesium turnings.
To it are slowly added 5 g (0.02 mole) of synthon X1 of example
11 dissolved in SO m! of anhydrous ether. Stirring takes place
for 16 h at reflux. The complex is decomposed by a cold
saturated NH~C! solution and then, after decanting, is extracted
with ether (3x100 m!). The combined ethereal phases are
extracted by a 20% aqueous HC! solution (3x100 m!). The acrd
waters are neutralized by NH40H, extracted with ether (2x100 m!>
and then with methylene chloride (2x100 m!). The combined
organic phases, after drying on Na2S04, undergo vacuum
evaporation to give 3.1 g of an oily residue. Following flash
chromatography on silica in petroleum ether, the latter gives
~5 2.7 g (41.5%) of compound 14 melting at 92-93°C. By bubbling
gaseous NC! into the ethereal solution of this compound, its
white solid hydrochloride is precipitated and, after recovery by
suction filtering and vacuum drying, it melts at 185-186°C
(analytically pure). CGC/MS of base : 100-250°C (20°C/min, i~T
2 p = 8.9min, m/e 325.15).
The i~IR spectrum of the ~3C of this compound and its percentage
analysis are given in the attached Fables 2 and 3.
EXAT1P!_E 26: Preparation of 1-<2-benzo(b)thiophenyl)-1-(3-
hydroxymethyl-1-piperidino)-cyclohexane acetate (oom~ound 15).
Stirring takes place for 24 h at 50°C of 3 g t0.009 mole) of
compound 9 with 1.8 g (0.018 mole) of acetic anhydride and 1.4 g
2 5 (0.018 mole) of pyridine. The mixture is then poured into iced
water and extracted with ether (3x50 m!). The dried ethers
<Na2S0a) are evaporated under reduced pressure to give 2 g of
oily residue. By silica column chromatography in petraleum
ether 1.7 g of compound 15 is collected in the form of a
30 colourless oil C51%). By bubbling gaseous HCt into the ethereal
solution of the compound, its solid white hydrochloride is
precipitated and, after recovery by suction filtering and vacuum
8. 10089 i~T
- 30 -
drying, melts at 145-147°C (analytically pure). (GC/MS of base
. 70-250°C (15°C/min RT = 21.09min, m/e 371.20).
The PA~1R spectrum of the ~3C of this compound and its percentage
analysis are given in the attached tables 2 and 3.
EXAMPLE 27: Preparation of 1-(2-naphthyl)-1-(1-piperidino)-
cyclohexane (compound 16).
The Grignard reagent resulting from the action of 5 g (0.024
mole) of 2-bromonaphthalene on 0.6 g of magnesium turnings is
prepared in 30 m9 of anhydrous ether. To it are slowly added 3.
g (0.016 mole) of synthon 1 of example 1 dissolved in 30 m1 of
anhydrous ether. Stirring takes place for 16 h at reflux and
the complex is decorr~osed by a cold saturated NH~CI solution and
' then, after decanting, extraction takes place with ether (3x30
ml). The combined ethereal phases are extracted by an aqueous
159 HC! solution (3x30 mi). The acid waters are neutralized by
NH40H and extracted with ether (3x30 m!>. The combined ethers,
after drying on Na2S0a, are vacuum evaporated to give a
yellowish solid residue of 2 g. Chromatography on Merck alumlna
(activity 2-3) in petroleum ether supplies 1.3 g (28%) of
compound 16 in the form of white crystals melting at 80-82°C.
By bubbling gaseous HCl into the ethereal solution of the base,
2p its white solid hydrochloride is precipitated and, after
recovery by suction filtering and vacuum drying, melts at 155-
156°( <anaiytieally pure). CGC/MS of base : 100-250°C
C20~C/min RT = 10.38min, m/e 293.20>.
The 1~1R spectrum of the ~3C of this compound and its percentage
analysis are given in the attached tables 2 and 3.
EXAMPLE 28: Preparation of 1-(1-naphthyl)1-(1-piperid _in_o>-_
cyclohexane (compound 17).
The Grignard reagent resulting from the action of 91.3 g (0,036
mole) of 1-bromonaphthalene on 1.3 g of magnesium turnings, is
prepared in 50 m9 of anhydrous ether. To it are slowly added
3.5 g (0.018 mole) of synthon I of example 1 dissolved in 20 ml
of anhydrous ether. Stirring takes Qlace for 16 h at reflux,
B. 10089 i~T
the complex is decomposed by a cold saturated NH~aC! solution and
then, after decanting, extraction takes place with ether (3x20
m!!). The combined ethereal phases are exkracted by an aqueous
15% EIC! solution (3x20 m!>. The acid waters are neutralized by
NH40H, extracted with ether (3x20 ml) and the combined ethers,
after drying on Na2S0a, are evaporated in vacuo to give 4 g of a
yellowish oily residue. Chromatography on Merck alumina
(activity 2-3) in petroleum ether and ether (90/10 v/v) gives
3.3 g of compound 17 in the form of a colourless oil C62%). By
bubbling gaseous HCl into the ethereal solution of the base, its
white solid hydrochloride is precipitated and, after recovery by
suction filtering and vacuum drying, melts at 190-191°C
(analytically pure). (GC/MS of base : 1000-250°C (20°C/mln RT
= 9.86min, m/e 293.20>.
i5 The t~1R spectrum of the ~3C of this compound and its percentage
analysis are given in the attached tables 2 and 3.
EXAMPLE 29: Preparation of 1-<2-benzoCb)thioohenvl)-t-ter-
butyl-4-r-C1-piperidino)-1 cyciohexane (compound 18) and 1-(2-
benzo(b>thiophenyl)-c-ter-butyl-4-r-(1-piperidino)-1 cyclohexane
Ccompaund 99).
A) The Grignard reagent resulting from the action of 27 g
C0.09b mole) of 2-iodobenzo(b>thiophene on 3.1 g (0.13 mole) of
magnesium turnings is prepared in 150 m! of anhydrous ether. To
2 0 it are added 10.7 g (0.069 mote) of ter butyl 4 cyclohexanone
dissolved in 150 m! of anhydrous ether. Stirring takes place
for 16 h at reflux, the complex is decomposed by a cold
saturated NH~Ct solution and then, after decanting, the waters
are extracted with ether C2x100 m~) and methylene chloride
25 C2x100 m1). The organic phases, after drying on Na2S0a, are
evaporated in vacuo to give 18 g of crude alcohols. By
crystallization in hexane, 16.5 g (82.5%> of white powder are
isolated. (1R, GC/MS : 100-250°C 120°C/min> RT = 10.96min, RT =
11.72min, m/e 288:25). The foliowlng reaction takes place by
30 carbocation, so that the alcohols are not otherwise purified.
B) At -15°C a highly stirred suspension containing 6,77 g
C0.104 mole) of sodium azide, 86.5 g 00.52 mole) of trichloro-
B . 10089 I~T
acetic acid and 100 m! of ehloroform is prepared. To it is
rapidly added, dissolved in 100 m! of chloroform and at the same
temperature, 15 g C0.052 mole) of the previously obtained
alcohols. The stirring and temperature are maintained for 3 h
Cor until the alcohols disappear) at -10°C, followed by the cold
neutralization by 20% NN40H, decanting, and extraction of the
aqueous phase with methylene chloride (3x60 m!). The collected
organic phases are washed to a neutral pH. After drying on
Na2S04 and vacuum evaporation an oily residue is recovered
i0 weighing 15 9. which essentially contains an unsaturated
derivative (highly minority) and two epimeric azides (IR
2150cm-~, GC/MS : 100-250°C (20°C/min) RT = 10.72min, RT =
11.28min, m/e 316.25), which, taking account of their relative
instability, are not otherwise purified.
C) The 15 g of mixture of the two previously obtained
azides is dissolved in 100 m! of isopropanol and heated at b5°C
for 30 min. To it is added portionwise Raney nickel (whilst
maintaining the temperature) until the evolution of gas stops.
It is then heated to 70°C for 15 min, cooled to ambient
temperature, diluted with water and filtered on celite. The
aqueous phase collected is extracted with methylene chloride
C3x100 m!), dried on MgS04 and evaporated in vacuo to give 9.5 g
of a brown oily residue essentially containing 2 epimeric
primary amines (1R disappearance N9, GC/MS : 100-250°C
(10°C/min>, RT = 9.02min, RT = 9.98min, m/e 287.15).
D> 7 g of the aforementioned amines are dissolved in 100 m!
of ethanol containing 5.61 g C0.024 mole) of 1,5-dibromopentane
and 6.7 g C0.049 mole) of K2C03. The highly stirred mixture is
refluxed for 48 h and then cooled to and ent temperakure. After
filtering and evaporating the solvent, 150 m! of 10% HC! are
added to the residue and extraction takes place with ether (3x50
m!). The acid waters neutralized by 20% NN40N are in turn
extracted with ether <3xi00 m!). After drying on Na2C03, the
ethers are evaporated in vacuo to give a white solid of 5 g.
The mixture obtained undergoes chromatography on a Merck alumina
column (activity 2-3). The petroleum ether makes it possible to
collect 2.4 g of the solid white compound 19 melting at 139-
B . 10089 t~T
- 33 -
140°C and a mixture of petroleum ether and ether (70/30 v/v)
makes it possible to collect 1,6 g of solid white compound 18
melting at 148-149°C (24% overall yield based on the ketone>.
By bubbling gaseous HC! into the ethereal solution of the
compounds, their solid white hydrochlorides are precipitated
and, after recovery by suction filtering and vacuum drying melt
respectively at 146-147°C (no. 19> and 208-209°C (no. 18)
(analytically pure). (GCIN~ of bases : . 100-250°C (15°C/min>
no. 18 RT = 13.40min, m/e = 313.25.; no. 19 RT = 14.88min, m/e
313.25>.
The (~1R spectrum of the ~3C of this compound and its percentage
analysis are given in the attached tables 2 and 3.
EXAMPLE 30: Preparation of t-(2-benzo(b)thiophenyl)-t-methy_I-_4-
r-(1-piperidino)-cyclohexane (compound 20) and _1-_<2-
benzo(b)thiophenyl)-c-methyl-4-r-(1-piperidino)-cyclohexa_n_e
(compound 21).
A) The Grignard reagent resulting from the action of 29 g
(0.192 mole) of 2-iodobenzo(b)thiophene on 3.1 g (0.13 mole) of
magnesium turnings is prepared in 150 and of anhydrous ether. To
it are added 9.1 g (0.018 mole) of 4-methyl-cyclohexanone
dissolved in 150 m1 of anhydrous ether. Stirring takes place
for 12 h at reflux, the complex is decomposed by a cold
saturated NI-IaCt solution and then, after decanting,~the waters
are extracted with ether (2xf50 m!) and then with methylene
chloride (2x150 ml). The organic phases, dried on Na2S04, are
evaporated in vacuo to give 17 g of a pale yellow oil
essentially containing two epimeric alcohois. C1R, GC/MS
100-250°C (20°C/min, RT = 14.28min, m/e 246.10 ; RT = 14.50min,
m/e 244.10>. The following reaction (B) takes peace by
carbocation, so that the alcohols are not otherwise purified.
B> At -20°C a suspension containing 7.9 g (0.12 mole) of
sodium azide, 49.5 g (0.6 mole) of trichloroacetic acid and 250
ml of chloroform is prepared and strongly stirred. To it are
rapidly added, dissolved in 150 m!? of chloroform and at the same
temperature, 15 g of previously obtained crude alcohols. The
stirring and terr~erature are maintained for 3 h or until the
B. 10089 f~T
- 34 -
alcohols disappear. The pasty medium obtained is poured into a
cold Na2C03 solution. After decanting, extraction takes place
with chloroform (2x100 m!> and the collected organic phases are
washed to a neutral pH. After drying on Na250a and evaporation
in vacuo an oily residue weighing 16 g is recovered and which
essentially contains an unsaturated derivative (highly minority)
and two epimeric azides (IR) which, taking account of their
relative instability, are not otherwise purified.
C> 15 g of the mixture of the two previously obtained
azides are dissolved in 150 m! of isopropanol and heated at 65°C
for 30 min. Raney nickel is added portionwise, whilst
maintaining the temperature, until the gaseous evolution stops.
Heating then takes place to 70°C for 15 min, cooling to ambient
temperature and filtering on celite. The filtrate, diluted with
methylene chloride, is washed with water, dried on IJa2C03 and
evaporated in vacuo to finally give an oily residue. The latter
is dissolved in 10% HC! and washed with ether (2x200 m!), the
aqueous phase being neutralized by 20% NH40H and extracted with
ether (2x200 m!). After drying on Na2C03 and evaporation in
vacuo, an oily residue weighing 9 g is obtained, which
essentially contains two epimeric primary amines (iR).
D) 7 g of the mixture of amines referred to hereinbefore
are dissolved in 100 m! of acetonitriie containing 6.6 g of 1,5-
dibromopentane (0.028 mote) and 7.9 g (0.057 mole) of KzC03.
2 5 The highly stirred mixture is refluxed for 48 h and then cooled
to ambient temperature. After filtering addition takes place of
100 m! of 20% HC! and extraction with ether (2x50 m!). The two
acids, neutralized by NH40H, are In turn extracted with ether
(3x50 m!). After drying on Na2C03. said ethers are evaporated
3p in vacuo to give 7.1 g of red oily residue. The tatter
undergoes chromatography on t°lerck alumina (activity 2-3). The
petroleum ether elutes a first 4 g fraction of white crystals of
compound 2 matting at 113-1140( and a mixture of petroleum ether
and ether (50/50 v/v) elutes a second 2.3 g white crystal
35 fraction of compound 20 melting at 120-121'( (38.8%) overall
yield based on the ketone. By bubbling gaseous HC! into the
ethereal solution of the compounds, their solid white
B . 10089 i~'~T
- 35 -
hydrochlorides are precipitated and, after recovery by suction
filtering and drying in vacuo, they respectively melt at 195-
196°( <no. 21) and 209-210°C (no, 20) (analytically pure).
(GC/MS of bases : 100-250°C <20°C/min, no. 20 : RT = 10.56min,
m/e 313.15) ; no. 21 : RT = 10.8bmin, m/e 313.15).
The NMR spectrum of the ~3C of this compound and its percentage
analysis are given in the attached tables 2 and 3.
EXAMPLE',: 31: Preparation of 1-(2-benzoCb)thiopheny i)-c-methyl-
3-r-<1-piperidino)-cyclohexane (compound 22) and 1-C2-
benzoCb)thiophenyl)-t-methyl-3-r-C1-pi~eridino)-cyclohexane
(compound 23),
A) The Grignard reagent resulting from the action of 15.6 g
(0.06 mole) of 2-iodobenzo(b>thiophene on i.9 g <0.08 mole) of
magnesium turnings is prepared in 50 m~ of anhydrous ether. To
it are added 5.6 g (0.05 mole) of 3-methyl-cyclohexanone
dissolved in 50 mt of anhydrous ether. Stirring takes place for
12 h at reflux, the complex is decomposed by a cold saturated
NHaC! solution and then, after decanting, the waters are
35 extracted with ether C2x100m1> and then with methyiene chloride
(2x100 ml). The organic phases dried on Na2S04 are evaporated
in vacuo to give a yellow oil which, after filtering on a Merck
alumina column (activity 2-3) in petroleum ether - ether (50/50
v/v) supplies 9 g of viscous clear oil essentially containing
two epimeric alcohols. (IR, CGC/MS : 100-250°C t20°C/min, RT =
12.20min; m/e 24b.20); RT = 12.42min, m/e 246.20), The
following reaction takes place by carbocation, so that the
alcohols are not otherwise purified.
8) At -15°C preparation takes place of a suspension con-
twining 4,23 g (0.065 mole) of sodium azide, 7.42 g (O.Ob5 mole)
of trifluoroacetic acid and 80 m! of chloroform, accompanied by
strong stirring. To it are rapidly added, dissolved in 80 mR of
chloroform and at the same temperature, 8 g of previously
obtained crude aicohols. The stirring and temperature nre
maintained for 3 h or until the alcohols disappear.
Neutralization takes place cold with 20% NH40H, followed by
decanting. extraction with methyfene chloride (3x75 m!) and the
8. 10089 hDT
-36-
washing of the collected organic phases to a neutral pH. After
drying on Na2S04 and vacuum evaporation, an oily residue
weighing 7.8 g is collected, which essentially contains an un-
saturated derivative (highly minority) and two epimeric azides
(1R, GC/MS : 70-250°C (15°Clmin) RT = 12.78min, RT = 12.90min,
m/e 271.20) which, bearing in mind their relative instability,
are not otherwise purified.
C> 7 g of the mixture of the two previously obtained azides
are dissolved in 80 m! of isopropanol and heated at 65°C for 30
min. Raney nickel is added thereto in portions twhilst
maintaining the temperature) until gaseous evolution stops.
Heating then takes place to 70°C for 15 min, cooling to ambient
temperature and filtering on cefite. The filtrate, diluted with
methylene chloride, is washed with water, dried on Na2C0~ and
~5 evaporated in vacuo and finally gives an oily residue. The
latter, dissolved in 10% HCl, is washed with ether (2x100 m!>,
the aqueous phase is neutralized by 20% NHaOH and extracted with
ether (2x100 ml>. After drying on Na2COs and vacuum
evaporation, an oily residue weighing 3.b g is collected, which
essentially contains two epimerlc primary amines (1R, GC/h~
100-250'C (20°C/min) RT = 9.20min, RT = 9.60min, m/e 245.20>.
D) 3 g of the aforementioned mixture of amines are
dissolved in 50 m! of acetonitrile containing 2.B g of 1,5-
dibromopentane (0.012 mole) and 3.3 g (0.024 mole) of KpC03.
The highly stirred mixture is refluxed for 48 h and then cooled
to ambient temperature. After filtering, 100 m! of 10% HCt are
added, followed by extraction with ether C2x30 mt>. The acid
waters, neutralized by NHoOH, are in turn extracted with ether
C3x70 m~). After drying on Na2C03, these ethers are evaporated
in vacuo to give 2.5 g of a reddish oily residue. The tatter is
chromatographed on a silica column. The petroleum ether elutes
s first 1.2 g white crystal fraction of compound 23 melting at
80-81°C and an ether - petroleum ether mixture (50/50 v/v>
elutes a second i.1 g white crystal fraction of c~pound 22
melting at 83-84°C (22% overall yield based on the ketone>. By
bubbling gaseous HC~ into the ethereal solution of the bases,
their solid white hydrochlorides are precipitated and, when
B. 10089 hDT
~~~~.~~?
- 37 -
recovered by suction filtering and vacuum drying, respectively
melt at 162-163°C (no. 22) and lb5-166°C (no. 23) (analytically
pure) (GC/MS of bases : 100-250°C (20'C/min no. 22 RT =
12.26min, m/e 313.25) ; no. 23 12T = 12.62min, m/e 313.25).
The NMR spectrum of the ~3C of this compound and its percentage
analysis are given in the attached tables 2 and 3.
EXAMPLE 32: Preparation of 1-(2-benzo<b)thiophenvl)-c-methyl-2-
r-<1-piperidino>-cyclohexane (compound 24) and t-<2-
benzo(b>thiophenyl)-t-methyl-t-r-(1-piperidino>-cyclohexane
(compound 25).
A) The Grignard reagent resulting from the action of 33 g
(0.13 mole) of 2-iodobenzo(b)thiophene on 3.b g (0.15 mole) of
magnesium turnings is prepared in 100 m! of anhydrous ether. To
it are added 9.52 g (0.085 mole) of 2-methyl-cyclohexanone
dissolved in 100 m! of anhydrous ether. Stirring takes place
for 12 h aE reflux, the complex is decomposed by a cold
saturated NH4C! solution and then, after decanting,, the waters
are extracted with ether (2xi00 m!) and then with methylene
chloride (2x100 m!).~The organic phases dried on Na2S04 are
evaporated in vacuo to give 15 g of a yellowish oil essentially
containing two epimeric alcohols <IR, GC/MS : 100-250°C
(20°C/min) RT = 7.bOmin, m/e 246.20 ; RT = 7.78min, mle
246.20). The following reaction takes place by carbocation, so
2p that the alcohols are not otherwise purified.
B) At -15°C preparation takes place of a suspension con-
taining 10.5 g (0.16 mole) of sodium azide, 18.5 g (0.16 mole)
of trifluoroacetic acid and 50 m! of chloroform and strong
stirring takes place. To it are rapidly added, dissolved in 50
5 m! of chloroform and at the same temperature, 10 g of the
previously obtained crude alcohols. The stirring and
temperature are maintained for 3 h or until the alcohols
disappear. Neutralization takes place cold with 20% NH40H,
followed by decanting, extraction with methylene chloride (3x75
30 m!) and washing of the collected organic phases to a neutral pH.
After drying on Na2S0a ahd vacuum evaporation, 9.1 g of an oily
residue are recovered essentially containing two unsaturated
B. 10089 h~T
derivatives (highly minority) and two epimeric azides (1R,
GC/MS : 100-250°C (20'C/min) RT = 8.1 min, RT = 8.22 min, m/e
271.15) which, bearing in mind their relative instability, are
not otherwise purified.
C) 8 g of the mixture of the two previously obEained azides
ace dissolved in 80 m~ of isopropanol and heated at b5°C for 30
min. Raney nickel is added portionwise, whilst maintaining the
temperaEure until the gaseous evolution stops. Heating then
takes place to 75°C for 15 min, followed by cooling to ambient
i0 temperature and filtering on celite. The filtrate, diluted with
methylene chloride, is washed with water, dried on Na2C03 and
evaporated in vacuo, finally giving an oily residue. The latter
is dissolved in 10% HCl and washed with ether (2x100 mt>. The
aqueous phase is neutralized by 20% NH40H and extracted with
75 ether 12x100 mt). After drying on Na2C03 and vacuum
evaporation, an oily residue weighing 5 g is collected and which
essentially contains two epimeric primary amines CIR, GC/MS
100-250°C C20°C/min) RT = 7.44 min, RT = 7.84min, m/e 245.20).
0) 3 g of the previously obtained mixture of amines are
20 dissolved in 30 and of acetonitriie containing 2.8 g of 1,5-
dibromopentane (0.012 mole) and 3.3 g (0.024 mole) of K2C03.
The highly stirred mixture is refluxed for 48 h and then cooled
to ambient temperature. After filtering, 100 ml! of 10% HC~ are
added and extraction takes place with ether (2x30 ml!). The acid
2 5 waters, neutralized by NH~OH, are in turn extracted with ether
(3x70 m~). After drying on Na2C03, said ethers are evaporated
in vacuo to give 1.8 g of a reddish oily residue, which is
chromatographed on a Merck alumina column (activity 2-3). The
petroleum ether elutes a first fraction of 0.7 g of white
30 crystals of compound 25 melting at 103-104°C and a mixture of
petroleum ether and ether (90/10 v!v) elutes a second fraction
of 0.7 g of white crystals of compound 24 melting at 105-106°C
<10% overall yield based on the ketone). By bubbilng gaseous
fIC~ into the ethereal solution of the bases, their solid white
35 hydrochlorides are precipitated and, when recovered by suction
filtering and vacuum drying, respectively melt at 177-178°C Cno.
24) and 124-125°C <no.25) (analytically pure) tGC/MS of bases
8. 10089 f~T
- 39 -
100-250°C (20°C/min) no.24 RT = 11.02min, m/e 313.25 ; no. 25 RT
- 10.94min, m/e 313.25).
The NMR spectrum of the ~~C of this compound and its percentage
analysis are given in the attaehed tables 2 and 3.
EXAMPLE 33: Preparation of 1-(2-benzo(b>thiophenyl)-1-(0l-4-
piperidino)-cyclohexane (compound 26>.
To i g C2, 89 rrxno I e) of corr~ound 5 d i sso I ved i n 20 m~ of acetone
are added 10 m! of a 20% HC1 solution. The mixture is refluxed
until the starting product completely disappears (4h - TLC),
The acetone is evaporated under reduced pressure, the aqueous
residue neutralized (20% NN40H) and extracted by CH2C12 (2x10
70 ml). After washing with water, drying on MgSOa and evaporation
under reduced pressure of the organic phase, 0.8 g C88%) of the
ketonic derivative is obtained (IR, GC/MS). Said 0.8 g <2.56
rrmole) is dissolved in 20 m! of anhydrous THF to which are added
2.6 m! of a 1N 8Hs solution in THF. The mixture is stirred at
ambient temperature until the ketonic derivative disappears <1h,
TLC. IR). The solution is hydrolyzed by a little water, the THF
evaporated under reduced pressure and the residue taken up in 15
mL of CHIC&2. The organic solution is washed with water, dried
on MgS04, evaporated under reduced pressure and gives 0.6 g
(84%> of alcohol melting at 111-112oC (analytically pure>. The
f~iR spectrum of the ~3C of said co~ound and its percentage
analysis are given in the attached tables 2 and 3.
EXAMPLE 34: Inhibition Test of the Capture of 3H Dopamine by
Striated Synaptosomes of the Rat.
This test is carried out according to the method used by Vignon
and Lazdunski operating in the following way. Wistar rats
weighing 200-250 g are killed by cervical dislocation. Their
brains are rapidly removed and the striate are dissected on ice.
the striate are then homogenized (10 backward and forward
movements) with a Potter homorgenizing agent in 50 volumes of
Tris HC~ 10 mM buffer at pH 7.4 and containing 0.32 M of
B. 10089 MDT
- 40 -
sucrose. The homogenate is then centrifuged at 1000 g for 10
min at 4°C and then the supernatant obtained is recentrifuged at
10000 g for 20 min at 4°C. The resulting P2 deposits containing
crude synaptosomes are then used without supplementary
purification.
The deposits are taken up in a Ringer medium (mhl : 140 NaCI, 5
ICCl, 2.6 CaCl2, 1.3 HgSOa 10 Tris-HCl, pH = 7.4) t 200 NM of
pargyline and equilibrated for 30~min at 30°C. The compound to
be tested is preincubated at the desired concentration for 30
min at 30°C in the presence of the P2 deposit to a final protein
concentration of 0.15 to 0.20 mg/m! in the Ringer medium.
Tritiated dopamine « 3H)DA, Amersham) is then added to a con-
centration of 5 nM for 5 min at 30°C and its capture is
interrupted by filtering 150 p! of incubation medium on glass
fibre filters GF/B <Whatman). The radioactivity retained by the
filters is measured in a liquid scintillation counter with 3 m!
of ACS CAmersham> as the scintillating agent. The non-specific
capture is measured at 4°C in parallel incubations and is then
subtracted frorn the total capture measured at 30°C. The lCso is
the concentration of compound inhibiting 50% of the specific
capture obtained in the absence of an inhibitor.
The compounds to be tested are initially solubiiized in water to
a concentration of 1 mM and the other concentrations are
obtained by successive dilutions of said mother solution in
water.
The results obtained are given in the attached table 4. The
table shows that the tested cor~ounds are able, at a very low
concentration, to inhibit the synaptosomal capture of dopamine.
EXAMPLE 35: Affinity of the Corr~ounds for the Bonding Sites of
the(~H>BTCP on Striatal irtembranes of Rat Brains. t
The striate of rat brains rapidly dissected in ice are
homogenized with an Ultraturax for 30 s (position 6) in 50
volumes of a 0.32 M sucrose solution buffered by Tris-HC! 10 mM
B . 10089 PST
- 41 -
at pH 7.4. The homogenate is centrifuged at 4°C and 1000 g for
min, whilst the supernatant obtained is centrifuged at 40000
g at 4°C for 30 min, the deposits obtained being taken up in 1
m! of buffer/striatum.
5 The affinity of the compounds for the dopamine recapture complex
is determined by competition experiments on striatum membranes
prepared as described hereinbefore. The radioactive ligand used
is C3H)BTCP (Service des Molecules Marquees du CF~4, Saclay
France) at 55Ci/mmol.
10 The membranes (final protein concentration 0.1 to 0.2 mg/m! are
incubated in 1 m! of 50 mM sodium phosphate buffer, pH 7.4, in
the presence of a fixed tritiated tigand concentration (0.2 nM)
and increasing concentrations of the compound to be tested.
After 90 min at 40°C, 3 aliquot portions of 250N~ are filtered
in vacuo on glass fibre filters GF/8 <Whatman). The non-
specific bond is obtained in parallel experiments carried out in
the presence of 10 Nm unlabelled BTCP. It is subtracted from
the total bond to obtain the specific bond. The compound con-
centration preventing 50% of the specific bond of the radio-
active ligand (lCso) reflects the affinity of the latter for the
dopamine recapture complex in the nerve endings.
The results obtained are given in the attached table 4. These
results show that the compounds according to the invention are
very active as inhibitors of the recapture of dopamine by the
nerve endings, because they inhibit in the same way at low
concentrations <ICso approximately 1 nanorrbia~) both the
recapture of dopamine and the fixing of <~H)BTCP'. There is an
excellent correlation between the affinity of the cor~ounds for
the (3H)BTCP site and their inhibiting capacity of the recapture
of (3H)DACR=0.99 ; n = i3 ; p < 0.001). For corr~arison
purpases, the table inctudes the results obtained with
Nomifensine tknown inhibitor of the recapture of DA), which is
much less powerful in its effect than most of the tested
cort~ounds.
B. 10089 NAT
- 42 -
EXAMPLE 36: Affinity of the Cort~ounds for the Bonding Sites of
C3H>TCP on Rat Brain Homogenates,
This test is used for measuring the affinities of the compounds
for the PCP receptor by competition experiments on rat brain
homogenates. The radioactive ligand used is C3H)TCP at a
specific activity of 62 Ci/rm~ole (Service des Molecules
Marquees, CEA Saclay France).
The rat brains (without the cerebellum and the cerebral trunk)
are homogenized with the Ultraturax in 20 volumes of Nepes-Tris
50 mM buffer at pH 7.7. After centrifuging for 30 min at 15000
g, the deposits are taken up in the same volume of buffer and
recentrifuged under the same conditions. The final deposits are
taken up in Hepes-Tris 50 mM buffer at pH 7.7, so as to obtain a
protein concentration of 6 to 8 mg/m!.
The competition experiments are carried out by incubating the
mer~ranes for 30 min (final protein concentration 0.6 to 0.8
mg/m!) in 5 mM Hepes-Tris buffer medium at pH 7.7 and 25°C, in'
the presence of a fixed concentration of tritiated ligand (1 nM)
and increasing concentrations of the eor~ounds to be tested,
Three 600 pL samples are then filtered on glass fibre filters
GF/8 pretreated by PEI <polyethyleneimine) at 0.1%. The filters
are r i nsed wi th 3x5m! of Tr i s HC! i 0 rrd"1, NaC! 100 ~rM buffer and
the radioactivity retained is measured in a liquid scintillation
counter. The non-specific bond is obtained in the presence of
100 NM TCP. The ICSO is the concentration of the compound
inhibiting 50% of the specific bond of the radioactive ligand.
The results obtained are given in the attached table 4. It can
be seen that all the tested compaunds have a very low affinity
for the PCP receptor Co~ even no affinity) and must consequently
have little psychotomimetic activity linked with the interaction
of the molecules with said receptor. However, there is a very
significant selectivity factor for the dopamine recapture
complex compared with the PCP receptor. Thus, compounds 21 and
3 give very good results.
8. 10089 NAT
- 43 -
EXAMPLE 37: Measure of the Noradrenaline Capture.
The capture of tritiated noradrenaline (40 Ci/rm~ole) is
evaluated on the basis of crude synaptosomal preparations of rat
hypothalamus (Sprague-Dawley male, 200-300g, Charles River, St
Aubin I~s Elbeuf, France).
The animals are sacrificed by decapitation and the brains
rapidly removed. The hypothalami, dissected at 0-4°C, are homo-
genized in 10 volumes (weight/volume> of previously cooled 0.32
M saccharose by means of a Potter Elvejhem homogenizes
(clearance 80-130 tam, 800 rpm>. The cell debris and nuclear
tp material are eliminated by centrifuging (1000 g, 10 min, 4°C>.
The supernatant constitutes the crude synaptosomal fraction.
Aliquot portions (50 N~) of synaptosomal preparation are pre-
incubated far 5 minutes at 37°C in the presence of 20 NM
pargyline and increasing concentrations of the compounds to be
tested in 960 pt of a glucose-enriched Krebs-Ringer medium,
(composition in mM : NaCt 103, CaC.~2 1, MgC1lp 1, KH2POs 1,
NaHC03 27, ascorbic acid 0.1 and glucose 5.4). Following said
preincubation, the tritlated noradrenaline (final concentration
50 nM) is added in a volume of 40 Iri! and incubation is continued
at 37°C for 10 min. The reaction is stopped by diluting with 2
ml of iced medium and centrifuging (7000 g, 10 min, 4°C).
After washing the centrifuging deposits in 1 ml of iced medium,
the sample is again centrifuged under the same conditions. The
deposits obtained are resuspended in 250 N3 of distilled water
by sonication (Sonotrode TC 4C). 100 p)1 of this suspension are
used for measuring the radioactivity by liquid scintillation (SL
2000, Kontron Intertechniques, Trapper, France) and 50 N! for
the determination of the protein levels (according to the method
of Lowry et al).
The non-specific capture is studied simultaneously at 0°C in the
presence of different concentrations of the compound. The
specific capture (total capture at 0°C) is expressed in
fentomoles/mg of proteins.
8. 10089 t~T
- 44 -
For each studied concentration the measurement was duplicated, 3
to S experiments being carried out on different days Cdifferent
synaptosomal preparations). For each compound at least 4 con-
centrations were studied, normally between 10-p and 10-6M.
The results are given in the attached table 5.
EXAMPLE 38: Measuring the Locomotor Activity.
The locomotor activity of Swiss mice (males CD1, 25-30 g,
Charles River, St. Aubin I~s Elbeuf, France) is measured in the
Boissier-Simon actinometer CApelex, Bagneux, France).
30 minutes after administering the compounds to be tested, (10
mg/kg, i.p.), the mice are introduced into individual Plexiglass
cages <L = 26 cm, t = 20 cm, h = 10 cm), which are equipped with
two photoelectric cells 1 cm above the floor. Each cell is
connected to an electromechanical counter. The locomotor
activity corresponds to the number of rays traversed from the
20th to the 35th minute following introduction into the
actinometry cages.
The results are given in table 5. These results show that
compounds 2, A and 21 have a better effect than BTCP.
Tables 4 and 5 give in a comparative manner the results obtained
with BTCP, (~lomifensine and Haioperidol in the tests of examples
33 to 36.
The BTCP (2-benzo(b)thiophenyl)-(t-piperidino cyclohexane) was
prepared in the following way. To the Grignard reagent prepared
from 31.2 g (0.12 mole) of 2-iodobenzo<b)thiophene and 2.8 g of
2 5 magnesium turnings in 100 mk of anhydrous ether was added
dropwise at ambient temperature 12 g C0.063 mole) in 200 ml of
anhydrous ether of synthon 1 of example 1. The solution was
refiuxed for 16 h and than cooled, after which it was poured
B. 10089 h~T
~~.~P~n:~
- 45 -
into a saturated solution of NH4C! and ice, After stirring for
30 minutes and decanting, extraction took place with ether
(3x200 m!) followed by washing the ethers with 10% HC! (3x200
m!). The acid waters were neutralized by 20% NHQOH, extracted
with ether (3x200 ml) and the organic phase was washed with
water to a neutral pH. After drying on Na2S04 and evaporating
under reduced pressure, 15.6 g of a white solid residue were
obtained, which were crysta6lized twice in ethanol to give 14 g
of colourless crystals C75%) melting at 80-81°C. By bubbling
gaseous HC~t into khe ethereal solution of the base, its solid
white hydrochloride is precipitated and, after recovery by
suction filtering and vacuum drying, it melts at 194-195°C
(analytically pure) (GC/MS of base: 100-250°C <20°C/min> RT =
10.36 min, m/e 299.20).
Nomifensine, i.e. 8-amino-2-methyl-4-phenyl-1,2,3,4-
tetrahydroisoquinoline is a product known to act on the dopamine
recapture system.
Haloperidol is a dopaminergic antagonist not acting on the
recapture.
The results of tables 3 and 4 show that the amines according to
the invention have a greater effect than Nomifensine and that
their effect is not of the same type as that of Haloperidol.
They also have a selectivity for the dopamine recapture complex
which is better than that of BTCP.
The attached table 6 illustrates the results of the toxicity
tests carried out on mice using the substituted amines of the
invention at a dose of 100 mg/kg intraperitoneally.
EXAMPLE 39: Study of the Inhibition of Dopamine and
Noradrenaline Recapture on Culture Neurons.
a) Primary neuron cultures.
The black substance, a structure rich in dopaminergic cells,
3 0 or the locus coeruleus, containing noradrenergic cellular bodies
B. 10089 t~T
mg/kg, i.p.), the mice are introduce
- 46 -
are dissected from 14 day rat embryos, which is the age at which
the cells have finished their mitosis. The cells are
mechanically dissociated in a medium without calcium or
magnesium.
Seeding takes p ace in wells pretreated with D-polylysin at a
density of 150000 cells/well in 400 ~C! of culture medium con-
sisting of 70% M.E.M, 25% Hanks and 5% decomplemented Nu-serum,
plus 3% D-glucose (1/20>.
One-third of the culture medium is renewed every 3 days up to 9
days of in vitro development, when the cells appear to be
mature. At this age, the culture still does not have glial
cells.
b> Inhibition test of the recapture of dopamine and
noradrenaline.
~5 The cells obtained in a) are preincubated for 15 min at ambient
temperature with 400 N! of a buffer constituted by 5 rrJ~l Ringer
disodium phosphate, pH 7.6, whose final concentration compo-
sition is: NaC! 120c~1; CaCl2 2.6~; MgCl2 l.3rrM; KC! SmM;
D-glucose 3rt~M; Na2HP04 5mM.
This is followed by the incubation far 10 min at 37°C using the
same buffer in the presence of (3H>Da or (3H)NA at a final con-
centration of 90-8M and a 1/5 isotopic dilution and increasing
concentrations of the compound to be tested in a final volume of
400pl.
25 This is followed by rinsing three times rapidly with 750N! of
the same buffer at 4°C, which corresponds to a total time of 10
seconds. The cells are then recovered in twice 500p! of 0.5N
NaOH and their radioactivity is determined by counting with 4m!
of scintillating agent and 50N1 of glacial acetic acid. Prior
30 to the rinsing operations, an aliquot portion of 900 Ie! of
incubation medium was sampled and Ehe free radioactivity thereon
was determined by counting with 5m! of scintillating agent.
B . 10089 I~T
'~ ~ ~' ''
_ 47 _
An evaluation also took place of the passive diffusion of (~H>DA
or (3H)NA in the cells in the presence of 10-4M/1 of Nomifensine
or Desipramine, which are respectively dopamine and
noradrenaline recapture inhibitors whilst following the same
operating procedure~without the compound to be tested.
The specific recapture of C3H)DA or <3H>NA is deduced from the
difference between the total recapture and the passive diffusion
for each of the tested compounds. The results obtained are
given in the attached table 7. On the basis of these results it
1p can be seen that compound 6 is a very powerful inhibitor of the
recapture of dopamine, but also noradrenaline.
EXAMPLE 40: Study of the inhibition of the In Vivo Fixing of
(3H>BTCP in Mice.
This study made use of male Swiss mice weighing 20-25 g. The
mice were placed in two groups and fed with standard laboratory
food and water as required. There were 12 consecutive hours of
artificial light cycles starting from 7 a.m. The experiments
were carried out between 10 a.m. and 6 p.m. The in vivo fixing
measurements of (3H)BTCP were carried out in the manner
described by Maurice et al, 1989, as follows.
The compound to be tested was subcutaneously injected into the
mice in 100 N! of physiological solution for cotrrpounds 4 and 16
and in 100 p! of a 1:1 volume mixture of physiological solution
and DMSO for compound 25. 60 min following this injection,
(3H)8TCP was injected into a vein of the-tail at a dose of 5NCi
in 100N1 of a mixture of physiological solution and 5f ethanol.
The mice were sacrificed 30 min after this injection. The
striate of the brains were rapidly dissected and homogenised
with an Ultraturax <1i44 Verk), with the maximum setting for ZOs
in 80 volumes of a Na2HP04 50mh1hIC! buffer, at pH 7.4 and 4°C.
Two aliquot portions of t000p! were filtered under reduced
8. 10089 t~T
- 48 -
pressure on GF/B filters (Whatman), pretreated with 0.5% poly-
ethyleneimine (Aldrich). The filters were then rinsed twice
with 5 mR of 50 mM NaCt, IOmM Tris-HCII buffer at pH 7.4 and 4°C.
The fixed radioactivity remaining on the filters and the total
radioactivity obtained from the two 200uI aliquot homogenate
portions are measured in 6 m~ bottles containing 3.5m! of ACS
(Amersham) using an Excel 14t0 liquid scintillation
spectrophotometer <LKB>. The non-specific Fixing is defined as
the radioactivity present in each region after the pretreatment
of the animals with BTCP (40 mg/kg in t00 N! of saline
solution), injected subcutaneously 60 min following the
injection of <3H>BTCP. The results are expressed as fixed
radioactivity/free radioactivity <B/F) ratios in which the free
C3H)BTCP level is estimated by subtracting the fixed
radioactivity from the total radioactivity. At feast 7 doses
are used for determining the dose necessary for inhibiting 50%
of the fixing of <3H)BTCP (iDSO) with 5 mice per tested dose.
The results obtained are given in table 8.
B . t 0089 hIDT
<IMG>
50 -
tR~°)
n
3
TABLE 9.. -( CONTINUED ) R~ _ Y ~ ~ 1 RSR1
~ R2
1 ~ __
.COM-: ~ ~ 4 S
ptDU~iD N~R~ Y R R n R
CH3
N° 6 N CH H ° , 0
CH3 . °'
N° T N~CH~ CH H - o id
CH2 CH3
N° B N CH H - 0 ~d
CH~CH3
CH20H
N° q Nv / CH H - 0 id
HOB f
N° 10 N CH H - 0 id
_CH23
N° 11 ~JCH H - 0 id
0 10089 ~IDT
r :~~
_ 51
tR4)
n
3/
~~ RSR1
TABLE 1 ( CONTINUE1T) R3 - y 4
°~ R2
COM-: N~~ Y R~ R~ n R5 .
POOtaD
CH2Gl
0
N~ 12 N- , CN H .
CH3
N~ 1'~ N CH ~°C H3 - 0 id
CH3
CH3
N~ 14 N ~ CH H ~ _ CH3 1 0
in 3
CH3
H~OOCCH~
N~ 15 N~ CH H - 0 id
N° 16 N~ CH H
0
..
Na 17 N CH H
o
1089 PIDj
- 52 -
(R~)
n
3
TABLE 1 (CONTINUEd) R3 - ~ 4 ~ 1 RSR1
R2
1
COM- N~ Y R3 R4 n ~ R~
POUNti
t
N° 1$ N- , CH -tehC4H9 ~ , 0
N° 19 N CH c-teP-C4H - 0 id
Ne ZQ N CH t-CH3 - ~ id
N° 21 N Ctl c °CH~ ° 0 i d
1d° 22 N~ CH H C-CH3 1 id
in. 3
N° 23 N CH H ~ -CHI '!° id,
3n ~ .
N 100$9 ~IDT
- 53
(R4>
n
3 R
TABLE 1 . (CONTINUEp)R3 - y 4 ~ 1 - SR1
P
~ R2
1
POUND N~2 Y R~ R4 n RS
N° 24 N CH H ~-CH3 1
in Z
N° 25 N CH N t-CH3 1
in 2
N° 26 ~
N , j°OH . CN H ° 0
,,/ ~ ~I
~ 10D~9 P9DT
- 5u °
TABLE 2
NMR spectra of )3C: recorded in COCl3at 20.1b7 MBz, in ppm based
on TMS, in the base (~), or in the form of hydrochloride. The.under-
lined values can be inverted.
iR43
n
5 6
Ar
R'
~
R Y ~ n~
6'
S Om
~~i . Z
R
Zs 30
Compoundn1*~n~Z n3 n'4 nS n'6 nT n~8 n~9
59 69,7 ?0.8 67.9 69.8 6.5 i0.8 74.2
7 69.2
1 ,
2 33.533.1 32,9 29.7 33,0 32~r 33.,237,6
32,7
3 54,423.1 22,6 22.4 23,1 23.1 22.8 28,:
22.7
23,9 23,3 23.4 23,8 23ae 23os 3-OJ2
23,4
S 54,423,1 22,6 22,4 23,1.23'1 228 28.1
22,7
33,533,1 32.9, 29.7 33.0 32,9 33.2 37.6
32.7
d
2~~ 47,353,0 Sl.Sb 47,3 52,5 47.1 44.2 54.6
44,'7
'~ 25,228,7 19.3h 22.7 28.2 30.9 11.5d41.6
31,7
... 24,731.0 21,8 ' 63.8 39.9 2~.6 - 2Q.i.
~~ 26p222.6 19.3b 22,7 28,2 30,9 1165a27,1
31,7
w 47,346,8 51,5b 47,3 52,5 47,1 e4.2d52.2
44,7
83 0~. z1 _ _ -
s7
R 19.3 - 19,1 10.1 20.Y 68.4
C~93 2~'.,9c~ 1'plh ~ 6~o.3a
8 i Ctl2-CH2,b propyl chain,c M'C83~
s .
ethyl ain. .e a DF9S0
ch D~
g ~1~08Q~1DT
_ 55 _
TABLE 2 (continued)
NMR spectra of ~3C: recorded in CDC13 at 20.147 MHz, in ppm based
on TMS, in the base ("), or in the form of hydrochloride. The
underlined values can be inverted.
IR4~~
6 Ar
R
R3 Y ~ g- g- o r H ~
~Ra
.
Z. 3. R
n'10 n'11 n'12 n°13 n'14 n°15 n'16 n°17
70.1 7~v.3 70.2 6~.g 66,~ 70.1 ~ al.t 75,0
2 32.3 33.9 33.0 GS~° 39,7 32,9 , 30,5 35.2
3 23.0 23.1 23.0 "_~ 27.3 23,0 e2,~ 22,6
4 23,7 23.8 23.7 25.~ 30,7 23.7 .,2~.2 24,1
5 23.0 23.1 23,0 27,8 18.3 23.0 22,~ 22.g
6 32 .9 33.0 33 .0 2~ .5 30, 0 32.9 30~ ''
2~~ 50.3 52.2 do;3 52.2 5y ~9.0 d7.0 X9.0
30~ 3~.1 33,g 3a.7 28.1 28:.1 33,1 22.A 22,6
40~ 27.7 29.3 26.1 3°,0~ 3o~g 25~4 c21.9 21.~ ~ ,..
21.7 21.7 21:8 s8,1 27,~ 21.8 22~x.,22,6
6.. ~F~7 afr,e ~:,2 .52.2 52.3 X6.8 ~a~0 ~
R3 o4r ~ ~ lio3 18.T '° "° "
R .
R 36.9 10.1 47:3 l9.dl 18.q 65.6' "
' _ _ 170.5
CO
C~13 - - - ~ °' 2D.5 °- -
8 10U89 ~1D7
- 55
TABLE 2 (continued)
PtMR spectra of 13C: recorded in CDG13 at 20.147 MHz, in ppm base
on ThIS in the form of hydrochloride. The underlined values can b
inverted.
Compound n18 n19 ao20n21 n22aroZ3 :e24az5 na6~
1 69.A 68.9 69.469.9 69,868,7 73.275.3 80,.4
2 33.2 31.6 32,829.6 ~~.5a9,2 35.637,1 ~7
3 2~.1 21.7 313 27.6 27,527,3 30.3318 22.3
45. Q1.8 30,325.5 33:,130,5 18x8224 25.9
4
2d 7 3 "s7.622,818,6 i?,~2= 22.3
1 21 31
, , , , a
6 332 31 32.829.6 31.733,0 26,930.5 3S .7
.6
4'I ~8 47 s7.3 47.547, d9e '3.5 X03
0 5 3 3 .1
. . ,
22.9 22.3 22,922.g 22.822.6 22.7.i2.7 35.$
22,3 a"1.922.22i.d 22.322.1 22.322.a 6$,~O
g 22p9 22,3 22,922.9 22.922.6 22.:22.7 35.8
47 0 4 ~7, ~7. 47, 47. X9.0 to 3
5 48 ), 3 5 4 3 .1
5
, .
R3 t b P44 31. 32 21.117.4 20 18. 18. . -
9 . .5 6 0 18
6 .1
Cli3 27.1b -- - - " -
2?alb
pMS0,D6, b : 2rovp tart-butyl". ~ p base form
E 10089 ltDT
TABLg 3: Percentage Analyses
theoretical experimental
_ .. .. r~~ c H N C1
n~ d ..
crude
formula '
1 CC3y36~~2gC1 62,30 8,13 6.32 16.03 ~ 61,80 8.30 5,95 16.11
2 C H NSC1 68,67 8,01 4,00 10,16 67,62 8,07 3,75 10.12
ZO 28
3 C H NSC1 68.28.8.533,98 10,1068,21 3,7610,48
20 30 8.33
4 C19H26NOC1 71.36 4.38 11.1171,13'8.204.4911.35
8,14
S C ti NOSC1 64.04 3,56 9.02 63.567,093.488.92
21 28 7.11
g C H NSCi 69,71 3.87 9,82 69,608,043,589.65
21 30 7.75
T C20H28NSC1 68,67 4.00 10.1668,997,914.1010.00
8.01
6 C H NSCl 66,77 4.33 10.9766,557.994.2111,06
18 26 8.04
C20H22N0SC165"66 3,83 9.71 65.567.793.589,75
7,66
C20H26N58r 56,01 3,27 55,906.383.14
6.30
11 C N NSI 547 5'682,94 50,315.822.78
26
12 C2pH27~ISC162,50 3,65 18,5062.077.133,4218.72
7,03
13 ~22H32NSC1 69,93 . 9,40 69.8~8,323.47~
8,48 ,3.71 ~
9.63
1~ C22H32NOC1 73.~3 3,87 9,82 72,868.783.5910.10
8.85
15 C22H30N02SC164.80 3.44 8.71 6,63 744 3.219.07
?.36.
16 C21H28NC1 76.46 4.25 10,77'S.~2E.963.9310.47
8.50
1~ C21H28NC1 76.46 8,50 4,25 10.77 76.23 8,51 ~.10 10.63
g 9008$ PiD1'
_ 5$ _
TABLE 3 (continued): Percentage Analyses
theoretical experimental
crude C H N Ct C H N Cl
formula
18 C H N5 77.75 9.30 3.94 77.60 9.54 3..93
23 33
19 C" :~I NS 77. 75 9. 30 3.94 '7, g4 9, 58 3.84
c3 33
ZO C" H NSC168.678.01~.00 10,1688,78 8.263,8710,17-
c0 28
,
21 C H NSC1 68,678,014,00 10,1668, 8.003,T710,39
20 28 , g2
22 C20H28NSC168, 8,014.00 10,.1668,:5 8,013.94'10,
67 . 20
2 C H NSCl 6867 8,014,00 10,1668,29 8,203.9310,06
3 20 28
C20H28NSC168.67801 4.00 10.1668.27.8.013,9410.21
25 C2pH28NSC168.678.014,00 10,1668.20 8,183,7710.02
.
26 C19H25NOS71..038,,19 2 71.10 3 5
4,0 8.2 3.9
8 10089 FiDT
_ - 59 -
TABLE
(3tT1 ~1CP (31~j DA [3sT]tCP Selectivity
COMPOUND IC50(nM) ~ IC50(nM) ~~50(~M) IC (jll]tCP
IC~h( HJOTCP
13 20 2380 .
9
BtCP 8''4 ;. 52 3910
13.3 ~p3
N 2 424 58889
9
i2
N 3 T.2 , 2094
1 w 33,8 40
19
N 4 . . 281b
7 100
b5
N. g 35.5 . .
. 7874
' 7 14.9 100
12
6 , ..
N
. T 30.8 11r5
N ..
N. g 16.7 .. 20.1
N. ~ 18,.1 20,, 9 , .
2898
34 .5 57,1 100
N10 54.3 100 3846
N11 26 . ,.
N'12
302 107
Ni3
635 425
'..
N'14 , 2740
2210
0 44,5
24
N15 x
N1b
14,8 3b.3
N1T 25b0 3250
4
4 112 10
21 5
N~20 2~~7 . 14493
9 9.4 100
6 '
N21 . .
N.22 369 691
N23
590 606
14 e? 30 .6 .
N'24
N.25 l ea80 1280 . 2 00 b
31 a9
N.26 15.9
7 ~5 391
No~uifen~in 1 1~~~ ~ 520
Haloperidol~)
1D DA meCapture inhibitor
2) Dopaminergio system inhibitor°
0 10089 MDT
64 ° ~.~'~ ~~~
TABLE 5
EXAMPLE 37 EXAMPLE
38
Com- Com- Locomotoractivity,
pound 3H-NA capture pound' variation(~) based
on.
o (nM) oontrols ( 10096) ~'or
IC do~a
S 10 mg/kA i.p
T eTe~ ~lZa~lZ
3~O ~
16
~teP . I 9160$25
.
S
~a fO
t . 3 53323
P~ 1 ' '
22
N . 4 +169319
3 g ~
' 2ft
22
4 , g ~siil2
H .
5~8
tt
H . 6 X52321
g f31
N'10 195 9 filg~3g
3
94
3~T
20 . 10 . , 3019
N .
' 1
5+1
15
a1 . 1g tZ693ST
N .
ZO b032a
21 ~ITS~t2t
as olal~a3
ag .asa3as
TABLE 6
U. 1UU89 tlOT
TABLE-T
(3H)DA Recapture . (3H)NA Recapture
Compound 1C 50 1) nH 2) IC 50 1) nH Z)
n° 2 70 nM 0.95
n° 3 - - 6,.2 ~r~ 0.85 . ..
n° 6 ' 1 ,G7 n)1 0. 95 10.5 nM 1 . 2
n° 21 8 nM 1.07 - -
n° 26 17 nM 1.09 - , - ,
1) IC is the concentration of the eompound inhibitin8 50~
of the specific bond of. the radioactive ligand._
2) nH : Hill number. ..
TABLE 8
Inhibiting the fixing of'(3H)BTCP in vivo (ID50) in the'
mouse stratum.
Compound ~ (mg/5kg)limitdw Hill number'
(etCP) 4.98 13,41-5.35D1.12
4 7,,T8 (x.34-19.1.)1.13
~ 16 2..6$ (1.81-4,.10)0.84
~ 2 6 ~0.5t~t0,.44-0.T4DO.T4
~a 10089 ~1DT
