Note: Descriptions are shown in the official language in which they were submitted.
W093J21179 2 1 ~ 9 ~ 1 S PCT/SE93/~29~
Novel~ aml oalkyl- and imidoalkvl-PiPerazines
Field of the invention
The present invention relates to novel, 1-ary1-4(~-amido-
~-alkyl and ~-imido-1-alkyl)piperazines, intermediates
and processes for their preparation, pharmaceutical
compositlons containing the piperazines and to the use of
said compounds in therapy.
The object of the present invention is to provide novel
compounds that will be useful in the treatment of
psychiatric disorders such as schizophrenia and other
psychoses, anxiety, depression and manic-depressive
psychosis.
Prior art
2Q Buspirone is a known substance that has been recently
tested in a variety of central nervous system diseases
including depression. It has affinity for both SHTlA
receptors and for D2 receptors.
Glennon and colleagues (Glennon RA, Naiman NA, Lyon RA,
;, Titeler M: Journal of Medicinal Chemustry, 1988, 31,
1968-1971) describe some aryl piperazine derivatives,
including NAN190 [=1-(2-methoxyphenyl)-4-(4-~2-
phthalimido)butyl)piperazine] that bind to SHTlA
receptors as labelled by ~3H)-8-hydroxyDPAT. In another
report, the same group (Raghuparthi RK, Rydelek-
Fitzgerald L, Teitler M, Glennon RA: Journal of Medicical
Chemistry 1991, 34, 2633-2638) describe some analogs of
the SHTlA agonist NAN190 that have affinity at SHTlA
receptors, as well as some binding affinity at al
receptors. Further synthetic work in a related area is
also described (Glennon RA, Naiman NA, Pierson ME, Smith
~:
WOs3/2117s 2 1 ~ 3 8 1 6 PCT/SE93/0029~
JD, Ismaiel AM, Titeler M, Lyon RA: Journal of Medicinal
Chemistry 1989, 32, 1921-1926).
Disclosure of the invention
s
According to the present invention it has been found that
new compounds of the general formula
fCH2~1 C\ ~ ~ R4
W I _~ C H 2]m N N~\ ~> I
[ R ] B ~¦-- R 5
n2
or pharmaceutically acceptable salts thereof, wherein
R is a hydrogen atom or a phenyl group,
m is an integer 3 to 8,
R4 is situated in the meta or para position of the ring
and represents an NO2-group or a group NR7R8 wherein R7
:~ and R8 are the same or different and each represents a
hydrogen atom or an alkyl group having 1-3 carbon atoms,
R5 is situated in the ortho, meta or para position and
Z0 represents a hydrogen atom, a halogen atom, or CF3,
R6 is situated in the ortho, meta or para position and
represents a halogen atom or CF3,
25 W is an optionally substituted aromatic ring(s), a
~:
W~093/21179 21 ~ 9 ~1 ~ PCT/SE93/0029~
heterocyclic ring, a carbocyclic ring(s), or an
optionally substituted methylene group,
A is a hydrogen atom, a hydroxy group, a halogen atom,
CF3, an alkyl group having 1-3 carbon atoms, an alkoxv
group having 1-3 carbon atoms, a phenyl group, or a
pheno~y group,
B is a hydrogen atom, or
A and B together constitute a carbonyl group,
n1 is 0 or 1, and
n2 is 0 or 1,
in racemic or optically active form, or as a mixture of
diastereomers, provided that
1) when W is an optionally substituted aromatic ring(s)
then
R, m, R4, R5, and R6 are as defined above,
n1 is 0 or 1,
n2 is 0 or 1,
A is a hydrogen atom, a halogen atom, CF3, a hydroxy
`' group, an alkyl group having 1-3 carbon atoms, an alkoxy
group having 1-3 carbon atoms, a phenyl group, or a
phenoxy group, and
B is a hydrogen atom or
.~ and B together constitute a carbonyl group,
2) when W is a carbocyclic ring~s) or a heterocyclic ring
~: then
:~ R, m, R4, R5, and R6 are as defined above,
3S n1 is 0 or 1,
n2 is 0 or 1,
A and B are hydrogen atoms or
O93/21179 PCT/SE93/0029~
2 1 0 9 ~ I b~ 4
A and B together constitute a carbonyl group,
3) when w is an optionally substituted methylene group
then
~, m, R4, R5, and R6 are as defined above,
n1 and n2 are 1 or
n1 is 1 and n2 is 0 or
n1 is 0 and n2 is 1,
A and B together constitute a carbonyl group,
exhibit an affinity for D2 and 5HTlA receptors. ThiS
effect makes it possible to use the compounds defined
above in the treatment of mental disturbances e.g.
psychosis, schizophrenia and depression.
An aromatic ring(s) in the definition above is preferably
phenyl or naphthyl and is mono- or disubstituted, wherein
the substituents are preferably chosen from the
following: a hydrogen atom, a halogen atom, a hydroxy
group, CF3, an alkyl group(s) having 1-3 carbon atoms,
or an alkoxy group(s~ having 1-3 carbon atoms.
Heterocyclic ring in the definition above is preferably
furyl, thienyl, pyrrolyl, pyridyl, or indolyl.
A carbocyclic ring(s) in the definition above is
preferably mono, bi, or polycyclic rings having 3-12
carbon atoms.
The substituents on the carbocyclic ring(s) in the
definition abo~e are preferably a hydrogen atom or an
alkyl group having 1-3 carbon atoms.
The substituent on the methylene group in the definition
above is preferably a hydrogen atom or an alkyl group
having 1-4 carbon atoms.
WO 93/21179 2 1 0 ~ PCI`/SE93/002
Halogen in the definition above is preferably a chlorine,
bromine, or fluorine atom.
A preferred group of compounds are those of the general
formula
R1 0
11
C ~ ~=X R 4
~N [CH2]m N~~N~ Ia
o R6
; or pharmaceutically acceptable salts thereof, wherein
Rl is situated in the 3- or 4-position and represents a
hydrogen atom, a halogen atom, CF3, an alkyl group having
1-3 carbon atoms, an alkoxy group having 1-3 carbon
: atoms, NO2, COCH3, or NR2R3 wherein R2 and R3 are the
~a~e or different and each represents a hydrogen atom or
an alkyl group having 1-6 carbon atoms,
m is an integer 3 to 8,
R4 is situated in the meta or para position of the ring
and rep:resents an N02 group or a group NR7R8 wherein R7
and R8 are the same or different and each represen~s a
hydrogen atom or an alkyl group having 1-3 carbon atoms,
R5 is situated in the ortho, meta, or para position of
the ring and represents a hydrogen atom, a halogen atom,
or CF3,
'
WO93/~1179 PCT/SE93/0029~
21~S ~1; 6
R6 is situated in the ortho, meta, or para position of
the ring and represents a halogen atom or CF3
W is preferably chosen from the following groups:
the substituents preferably being a
" ^~ ~ halogen atom, a hydroxy group, or a
i r~r methoxy group, mcst preferred are
~ bromine, hydroxy, or methoxy in the
ortho and/or meta positions. t
1S b
j;j ~
:~ ,
:
2S ;V
' :
V ~ L
~
vi ~
:~:
:~
WO93/2l179 21 0 9 g 1 ~ PCT/SE93/0029~
CH3
vii Q~
viii
' Q ' -
O <
i
X ~ the substituents being a halogen atom or
~ a methoxy group
3~
Xi \ ¢
When W is chosen from one of the groups i-xi, then
WO93/21179 ~1 O~i~1 S PCT/SE93/0029
m is preferably 4-6,
R4 is preferably NH2,
most preferred R4 is NH2 in the meta or para positions,
R5 is preferably hydrogen or halogen,
particularly preferred are compounds where R5 is
hydrogen, chlorine, or bromine,
most preferred R5 are hydrogen or chlorine in the meta or
para positions,
R6 is preferably CF3 or halogen,
further preferred are compounds where R6 is CF3 or
chlorine,
most preferred R6 are CF3 or chlorine in the meta
position.
When W is i-x, then R is preferably H. -
When W is i, then
n1 is preferably 0 and n2 is preferably 0 or 1,most preferred n2 is 0,
A is preferably hydrogen, methoxy, or hydroxy in the
ortho position.
When W is ii, then
n1 is preferably 0.
When W is iii-vii, then
n1 is preferably 0,
A is preferably a hydrogen atom or an alkyl group with 1-
3 carbon atoms,
and B is preferably a hydrogen atom.
When W is viii, then
n1 and n2 are preferably 0 and
A and B preferably constitute a carbonyl group.
~'
`:
WO93/21179 PCT/SE93/0029~
9 2IO9~1~
When W is ix, then
nl and n2 are pref erably 1 and
A and B preferably constitute a carbonyl group.
When W is x, then
n1 and n2 are preferably 0 and
A and B preferably constitute a carbonyl group.
Most preferred are the following compounds
o
Il
[~C N--ICH234--N ~N~NH2
O CF3
and
O
Cl 11
N--~ C H 2]4--N~N~ N H z
O CF3
and
:.
WO 93f21179 PCI/SEg3/0029
2109~16
O F
~ F
and N~_~ N~--NH2
and
o Sr<~ ? F
~H ~F
N H 2
~ 15
~,
and
~`
N N~ N~Z
F
-;~
WO 93/21179 2 1 0 9 ~1 6 PCI/SE93/0029~
~\ N N~NH2
and
N
~=o ~ NH~
Cl
and
~ ,/ ~NH
N~ F F
~: ~ 25
~:"
~: and
~;; 3 0
WO93/21179 PCT/SE93/0029~
2iO981~ 12
N N~--NH2
r ~,F
F
NH F
0~
and
O
~ ~ O N J ~ Cl
~ N H2
Both organic and inorganic acids can be employed to form
non-toxic pharmaceutically acceptable acid addition salts
of the compounds of this invention. Illustrative acids
' are sulfuric, nitric, phosphoric, oxalic, hydrochloric,
formic, hydrobromic, citric, acetic, lactic, tartaric,
pamoic, ethanedisulfonic, sulfamic, succinic, propionic,
glycollic, malic, mandelic acid, gluconic, pyruvic,
phenylacetic, 4-aminobenzoic, anthranilic, salicylic, 4-
aminosalicylic, 4`-hydroxybenzoic, nicotinic,
methanesulfonic, ethanesulfonic, hydroxyethanesulfonic,
~; benzenesulfonic, p-toluenesulfonic, sulfanilic,
naphthalenesulfonic, ascorbic, cyclohexylsulfamic,
fumaric, maleic and benzoic acids. These are readily
prepared by methods known in the art.
::
W~ O ~3/21179 21 0 9 8 1 (~ PCr/SE93/0029
13
Preparat ion
The compounds of the general formula I
f 2~1 \ ~ ~ R4
C --A l [ C H 2 ] m N N ~R 5
¦F~H]n2 R6
wherein R is a hydrogen atom or a phenyl group,
s
m is an integer 3 to 8,
R4 is situated in the meta or para position of the ring
and represents an NO2-group or a group NR7R8 wherein R7
: 10 and R8 are the same or different and each represents a
hydrogen atom or an alkyl group having 1-3 carbon atoms,
R5 is situated in the ortho, meta or para position and
represents a hydrogen atom, a halogen atom, or CF3,
R6 is situated in the ortho, meta or para position and
represents a halogen atom, or CF3,
W is an optionally substituted aromatic ring(s),~ a
; 20 heterocyclic ring, a carbocyclic ring(s), or an
optionally substituted methylene group,
A is a hydrogen atom, a hydroxy group, a halogen atom,
CF3, an alkyl group having 1-3 carbon atoms, an alkoxy
W~O 93/21179 2 1 ~ 9 8 1 ~ PCI /SE93/0029~;
1~
group ha~lng 1-3 carbon atoms, a phenyl group, or a
phenoxy group,
B is a hydrogen atom, or
A and B together constitute a carbonyl group,
nl is 0 or 1, and
n2 is 0 or 1,
in racemic or optically active form, or as a mixture of
. diastereomers, provided that
lj when W is an optionally substituted aromatic ring(s)
then
: R, m, R4, R5, and R6 are as defined above,
:~ nl is 0 or 1,
-~ n2 is 0 or 1~
A is a hydrogen atom, a halogen atom, CF3, a hydroxy
: group, an alkyl g~oup having 1-3 carbon atoms, an alkoxy
group having 1-3 carbon atoms, a phenyl group, or a
phenoxy group and
B is a hydrogen atom or
A and B together constitute a carbonyl group,
: . ~
2) when W is a carbocyclic ring(s) or a heterocyclic ring
then
R, m, R4, R5, and R6 are as defined above,
nl is 0 or 1,
n2 is O or 1,
A and B are hydrogen atoms or
A and B together constitute a carbonyl group,
,
:: 35 3) when W is an optionally substituted methylene group
~; then
~: R, m, R4, R5, and R6 are as defined above,
WO93/21179 21 0 9 8 1 ~ PCT/SE93/0029
nl and n2 are l or
nl is l and n2 is 0 or
nl is 0 and n2 is l,
A and B together constitute a carbonyl group,
are prepared by any of the following alternative methods.
A) Reaction of a compound of the general formula II
1 0
~[CH2]n1--C~
W N [ C H 2]m--X
~ I H~A
LR ~
n2
wherein R, m, W, A, B, nl and n2 are as defined above and
X is a suitable leaving group such as halogen,
arylsulfonate or alkylsulfonate, with a compound of the
general formula III
~ ~ 4
H - NN ~ R5 lll
R6
wherein R4, R5 and R6 are as defined above in a suitable
: solvent,~such as an alcohol, DMF, acetonitrile or DMSO in
: the presence of a base such as triethylamine, sodium
: hydroxide, or potassium carbonate and a catalyt.ic amount
of a sodium or potassium halide, such as KI at ambient or
higher temperature for a prolonged time.
W~093/21179 2 1 ~ 9 8 1 6 l6 PCT/SE93/0029~
B`) Conversion of a compound of the general formula IV
[CH2]n1 C~ /--\ /~
~C Hl--A N--[ C H Z]m--N N ~ IV
nz
wherein R, m, R5, R6, W, A, B, n1 and n2 are as defined
above and Y is situated in the meta or para position and
represents a group which can be transformed to a group
R41, where R41 is situated in the meta or para position
of the ring and represents a group NR7R8, wherein R7 and
: 10 R8 are as defined above, by a suitable hydrolytic,
reductive, electrochemical or other known processes.
Compounds of the formula IV can be prepared according to
Method A~ Such a group Y may be chosen from easily
clea~ed amides, carbamates, imines, benzylic amines or
~`` }5 other suitably protected amino groups. Such groups can be
: trifluoroacetamido, formamido, t-butoxycarbonylamino, or
N-benæylamino.
.~.
In addition, Y can be a group such as nitro, azido,
hydroxyamino, hydrazono, amido or imino, which can be
transformed to R41 by known reductive processes.
:
;:~
WO93J21179 2 1 0 3 8 1 ~ PCT/SE93/0029~
17
C) Reaction of a compound of the general formula V
~tCH2]n 1 C~ O
W N rC H2]m- 1 V
iC H~A
LR ~ ~
n2
wherein R, m, W, A, B, nl and n2 are as defined above and
S Z is hydrogen, hydroxy, halogen, or alkoxy, with a
compound of the general formula III
~ ~ R4
H - N N ~ R5 lll
R6
wherein R4, R5 and R6 are as defined above in the
presence of a suitable reducing agent such as sodium
, cyanoborohydride or lithium aluminium hydride in a direct
: or stepwise manner.
D) Reaction of a compound of the general formula VI
O
11
[C H2]n1 C ~ T
W
\ V I
[CI H~A
~ ~: n 2
`
~:
W~93/21179 2 ~ 81 6 PCT/SE93/0029
18
wherein w, nl, n2, and A are as defined above, and T
independently or together with A represents a suitable
derivative of an aliphatic, cycloaliphatic, aromatic or
heterocyclic acid or acid derivative, such as a halide,
an ester, an imide, an anhydride, or other acid
activating group, with a compound of the general formula
VII
~ ~ R 4
H 2 N--[ C H 2 ] m N~~N ~ R 5 V I I
R 6
wherein m, R4, R5 and R6 are as defined above, in a
suitable solvent such as dichloromethane, chloroform,
toluene, acetic acid, or tetrahydrofuran or neat at
ambient or elevated temperature for a prolonged time.
E) Reaction of a compound of the general formula VIII
i
]n,~--C~ /--\ /=XR4
N--tcH2]m--N ~N~R5
[~C ~--A
"2
:~ whexein R, m, R4, W, A, B, nl and n2 are as defined above
and R5 is H,halogen, or CF3 with a suitable halogenating
reagent such as sulfuryl chloride, or bromine in a
suitable solvent such as chloroform or dioxane.
:~
WO93/21179 21 ~ 9 81 ~ PCT/SE93/~29~
19 , . .
F) Reaction of a compound of the general formula IX
~cH2]n1 C~
W N--M IX
CH ~A
I
R '12
i
wherein W, nl and n2 are as defined above, A and B
together represent a carbonyl group, and M represents a
suitable alkali metal such as sodium or potassium, with
a compound of the general formula X
~}~
X [C H2]m N N ~ R5 X
R 6
:
wherein X, R4, R~ and R6 are as defined above in a
suitable solvent such as DMF, acetonitrile, or DMSO in
the presence of a base such as triethylamine, sodium
hydroxide, or potassium carbonate at ambient or higher
temperature for a prolonged time.
,Intermediates
A compound of the general formula II
3S
,~ ` .
WO93/21179 PCT/SE93/0029~
21 99 81 ~ 20
~[CH2]n 1--C
\ I [CH2]m--X I I
CH--A
I
R
n2
wherein R, m, W, A, B, nl, n2 and X are as defined above,
can be prepared by reacting a compound of the general
formula VI
~5
/~CH2]n 1 C~T
V
~CH~A
LR ~
n2
.
:: wherein W, nl, n2, and A are as defined above, and T
~ independently or together with A represents a suitable
:: 25 derivative of an aliphatic, cycloaliphatic, aromatic or
~' heterocyclic acid or acid derivative, such as a halide,
:; an ester, an imide, an anhydride, or other acid
activating group, with a compound of the general formula
, :
XI
H2N tC H2]m - O H Xl
wherein m is as defined above, in a suitable solvent such
as dichloromethane, chloroform, toluene, acetic acid, or
tetrahydrofuran or neat at ambient or elevated
temperature for a prolonged time, and subsequently
H reacting the intermediate of the general formula XII
~: '
W093/21179 2l 2 ~ 0 9 8 I 6 PCT/SE93/0029
o
/[CH2]n --C
W l [CH2]m--OH Xll
~ H~ A E3
lR J
~2
wherein R, m, W, A, B, nl and n2 are as defined above,~
with a suitable halogenating agent such as thionyl
chloride, phosgene, oxalyl chloride, or phosphorous
tribromide, or with a suitable sulfonating agent such as
tosyl chloride or other arylsulfonyl chloride or
alkylsulfonyl chloride.
A compound of the general formula III
R41
H--N N~2 R 5
R
~ wherein R41, R5 and R6 are as defined abo~e can be
:~ prepared from a compound of the general formula XIII
~ Y
H--N N ~ ~
--/ ~R5 Xlll
R
: 6
O
WO93/21179 ~ I ~ 9 ~ 1 G 22 PCT/SEs3/00295
wherein Y, R5 and R6 are as defined above in analogy with
method B.
A compound of the general formula XIII
~ Y
H--N N ~_~ X l l I
R6
wherein R5 and R6 are as defined above and Y is N02 can
be prepared by reacting a compound of the general formula
XIV
t,Y
~R5 XIV
R6
wherein R5 and R6 are as defined above, Y is N02 and U is
a halogen, with piperazine or a suitably monosubstituted
piperazine, where the substituent is easily removeable,
~:; such as a benzyl or an ethoxycarbonyl group,
or by reacting a compound of the general formula XV
H z N~ XV
~: 30
~`
WO93/21179 2 1 0 3 8 1 ~ PCT/SE93/0029~
23
wherein R5 and R6 are as defined above and Y is NO2, with
a compound of the general formula XVI
~CH2cH2x
V--N XV I
CH2CH2X
wherein X is as defined above and V is hydroyen or an
easily removable group such as benzyl or ethoxycarbonyl.
A compound of the general formula x
~ ~ R4
X - ~C H2~m N ~ ~ 5 X
wherein X, m, R4, R5 and R6 are as defined above, can be
~: 20 prepared b~ reacting a compound of the general formula
XVII
X [C H2~m - X XVII
.
'~ wherein X and m are as defined above,
with a compound of the general formula III
3 0 /~ R 4
H--N N~R5 111
R
: ~ 35
. ~
W~93~21179 21 ~ 9 S 1 ~ PCT/SE93/0029~
24
wherein R4, R5 and R6 are as defined above, under
- suitable reaction conditions analogous to method A.
Pharmaceutical formulations
According to the present invention the compounds of the
formula I will normally be administered orally, rectally
or by injection, in the form of pharmaceutical
preparations comprising the active ingredient either as
a free base or a pharmaceutically acceptable non-toxic,
acid addition salt, e.g. the hydrochloride, hydrobromide~
lactate, acetate, phosphate, sulfate, sulfamate, citrate,
tartrate, oxalate and the like in association with a
pharmaceutically acceptable dosage form. The dosage form
may be a solid, semisolid or liquid preparation. Usually
the active substance will constitute between O.l and 99
~ by weight of the preparation, more specifically
between 0.5 and 20 ~ by weight for prepar~ations intended
for injectioil and between 0.2 and 50 % by weight for
preparations suitable for oral administration.
To produce pharmaceutical formulations containing a
compound of the formula I in the form of dosage units for
oral application the selected compound may be mixed with
a solid excipient, e.g. lactose, saccharose, sorbitol,
mannitol, starches such as potato starch, corn starch or
amylopectin, cellulose derivatives, a binder such as
gel~tine or polyvinylpyrrolidone, and a lubricant such as
magnesium stearate, calcium stearate, polyethylene
glycol, waxes, paraffin and the like, and then compressed
into tablets. If coated tablets are required, the cores,
prepared as described above, may be coated with a
concentrated sugar solution which may contain, e.g. gum
arabic, gelatine, talcum, titanium dioxide, and the like.
Alternatively, the tablet can be coated with a polymer
well known in the art, dissolved in a readily volatile
organic solvent or mixture of organic solvents or in
W~93/21179 2 I 0 9 ,~1 S PCT/SE93/0029~
water. Dyestuffs may be added to these coatings in orde~
to readily disti~guiish between tablets containins
different active substances or different amounts of the
active compounds.
For the preparation of soft gelatine capsules, the active
substance may be admixed with e.g. a vegetable oil or
polyethylene glycol. Hard gelatine capsules may contain
granules of the active substance using either the above
mentioned excipients for tablets e.g. saccharose,
sorbitol, mannitol, starches (e.g. potato starch, corn,
starch or amylopectin), cellulose derivatives o-
gelatine. Also liquids or semisolids of the drug can bc
filled into hard gelatine capsules.
Dosage units for rectal application can be solutions or
suspensions or can be prepared in the form of
suppositories comprising the active substance in
admixture with a neutral fatty base, or gelatine rectal
capsules comprising the active substance in admixture
with vegetable oil or paraffin oil.
Liquid preparations for oral application may be in the
form of syrups or suspensions, for example, solutions
containing from about 0.2 % to about 20 ~ by weight of
the active substance herein described, the balance being
sugar and mixture of ethanol, water, glycerol, and
propyl~ne glycol. Optionally such li~uid preparations may
contain colouring agents, flavouring agents, saccharin
and carboxymethylcellulose as a thickening agent or other
excipients well known in the art.
. .
Solutions for parenteral applications can be prepared in
an aqueous solution of a water-soluble pharmaceutically
acceptable salt of the acti~e substance preferably in a
concentration of from about 0.5 ~ to about 10 ~ by
weight. These solutions may also contain stabilizing
WO93/21179 PCT/SE93/0029~
21 0 3 81 ~ 26
agents and/or buffering agents and may conveniently ~e ~:
provided in various dosage unit ampoules.
Suitable daily doses of the compounds of the invention in
the therapeutic trëatment of humans are 50 - 500 mg by
oral administration and up to lO0 mg via parenteral -~
administration.
It is especially preferred to admirister a compound of ~.
the formula ~
Il
N - [C Hz] - N N ~ N H2
O CF3
or
~ ;
~ F F
: 20
O 93~21179 21 a 9 81 ~ PCr/SE93/0029
27
EXAMPLES
Examx)le_ ~Method A)
1 (4-Amino-3-trifluoromethvl~henvl)-4-(4-Phthalimido-1-
butvl)~iPerazine dihvdrochloride
A mixture of 3.18 g (O.Oi mol~ of 4-amino-3-
trifluoromethylphenylpiperazine, a catalytic amount of
KI, 4.1 g ~O.03 mol) of potassium carbonate and 3.0 g
(0.01 mol) of N-(4-bromo~utyl)phthalimide in 25 ml of DM~
was stirred at lOO'C overnight. After addition of 500 ml
of water, the mixture was extracted with ether. The
extract was washed with water and extracted with dilute
hydrochloric acid. The water layer was separated, made
alkaline with sodium hydroxide and again extracted with
ether. The extract was dried (Na2SO4) and acidified with
hydrogen chloride in ether. The yielded precipitate was
filtered off and recrystallized from ethanol-ether.
Yield 3.0 g (58%).
M.p. 226-227 C.
In an analogous way the following compounds (2-12) were
prepared:
ExamDle 2
1-L4-Amino-3-trifluoromethYlDhenYl)-4-(3-~hthalimido~
~ro~yl)~i~erazine dihydrochloride.
M.p. 167-169'C.
WO93/21179 21 OYXl fi 28 PCr/SE93/0029~ ~;
~xaml?le 3
~ '
~ ~9= ~ fl_oromethvl~henvl)-4-~5-(3-
methoxvphthalimido)~ ntYll~i~erazine oxalate
~-
M.p. 114-118 C.
Exam~?le 4
1- (4-Amino-3-trifl oromethYlPhenyl) -4- F4- (4-
~hlorophthalimido)-l-bu-~llpi~erazine dihYdrochloride.
M.p . 203-204 C .
Exam~le 5
1-~4-Amino-3-~rifluoro~thylphenyl)-4-(5-phthalimido-1-
Pentyl)piPerazine trihvdrochloride.
M.p. 109-113-C.
.: .
~xamDle 6 ~
~ .
1-~4-Amino-3~5-dichlc-oPhenyl)-4 - ( 4 -Dhthalimido-l - ~
butYl)piP erazine ~.
M.p. 116-ll9 C. -
2xamD1e 7
1-(4-Amino-3-trifluoromethYl~henyl)-4 - ~ 3-(1,8- -~
na~hthalimido)-l-~ropYl lpiperazine ~-
M.p. 156-158-C. ~
~:
W093/21179 21 0 9 .~1 ~ P~/SE93/~29~
29
Example 8
1-(4-Amino-3 -tri f luoromethvlPhenyl ) -4 - ~ 4 - ( 3, 3 -
dimethvlqlutarimido)-l-butvllpiperazine dihYdrochloride
M.p. 235-236 C.
Examplè 9
1-(4-Amino-3-trifluoromethvl~henYl)-4-f4-(3,3-
tetrameth~leneqlutarimido~ -l-butYllpiperazine
dihvdrochloride
M.p. 243-245 C.
Exam~le 10
1- ( 4 -Amino-3 -tri f luoromethYlPhenYl ) -4 - ~ 5 - ( 3 - ~ :
~henvlalutarimido) -1-PentYl l Pierazine hYdrochloride
M . p . 13 6 -140 C .
~:xamDle 11
1- (3-Amino-4-chloroDhènvl) -4- ~5- (2-furanecarboxamido) -1-
~entYl 1 Pi~)erazine oxalate
M.p. 165-170-C.
~':-.'
~xam~le 12 ~:.
. ".
1-(4-Amino-3-trifluoromethYlPhen~1)-4-(4- :~
cyclohexanecarboxamido-l-butYl)PiPerazine .. ~:
:,~
M.p. 127-128-C. -.
WO93/21179 PCT/SE93/00295
71 0~ 81 ~ 30 :~
~xam~le 13 (Method s) ~ -
1-(4-Amino-3-trifluoromethylphen~l~=4-~4-phthalimido-1-
butvl?Pi~erazine acetate. ~ :
The product from example 38, (9.53 g, 20 mmol), dissolved ~
in 100 ml ethanol and 50 ml acetic acid was hydrogenated :
with Pd/C (1.0 g) as catalyst for 5 h. The mixture was
filtered, the solvent evaporated and the residue :
crystallized from diisopropylether and ethanol to yield
10.0 g of the title product. , -
M.p. 101-103-C.
-'
In an analogous way the following compounds (examples 14-
24) were prepared:
Exam~le 14
: .
1-(4-Amino-3-trifluoromethYl~henYl)-4-(6-~hthalimido-1- ~:
hexvl~piperazine acetate
M.p. 125-127-C.
~xiIm~le 15
~~
1-(4-Amino-3-trifluoromethvlPhenvl)-4-(8-~hthalimido~
:
octYl)~i~erazine aceta~te -
M.p. 94-96 C.
ExamDle_16
1-(3-Amino-4-c Yll= ~ hthalimido-l-bUtYlL~
~i~erazine acetate. :
M.p. 159-162-C.
W~93/21179 2 1 0 9 ~ 1 6 PCT/SE93/0029~
31
Exam~le 17
1-(3-Amino-4-chloro~henyl)-4-(5-~hthalimido-1-Dentvl)-
i_L"~
:-
M.p. 149-150-C.
~xam~le 18
1-(4-Amino-3-methvl~heny1)-4-(4-~hthalimido-1-butyl)- :
~iPerazine acetate.
M.p. 123-126-C. ~:~
Exam~le 19
1-(3-Amino-4-chloro~henvl)-4-~4-(3,3-tetramethYlene-
alutarimido~-l-butYllpiPerazine -~
M.p. 133-136-C. ;
:`.''~
~xamPle 20 ~-~
~,
1-(4-Amino-3-trifluoromethvlPhenvl!-4-[6-(3-Phenox~-
benzamido~ hexvl~ erazine acetate
M.p. 128-131-C.
ExamDle 21
~0
1-(4-Amino-3-trifluoromethvlPhenvl)~4-~6-cYclohexane
carb,oxamido-l-hexYl)piperazine dihydrochlor de
M.p. 112-115-C.
WO 93/21179 PCl/SE93/0029~
210981(~ 32
~xam~le 22
1-(4-Amino-3-trifluoromethvlPhenvl)-4-(4-adamantane-
carboxamido-l-butyl)pi~erazine dihvdrochloride
M.p. 123-125-C.
~xamDle 23 ;
1-(4-Amino-3-trifluoromethYlPhenYl!-4-l4-adamantane-
acetamido-l-butvl)~i~erazine
~.
M.p. 115-116-C.
Example 24
1-(4-Amino-3-trifluoromethvl~henYl)-4-(6-adamantane-
carboxamido~l-hexvl)~iperazine
lH NMR (CDC13) d 7.00 (s, 1 H), 6.96 (dd, 1 H), 6.70 (d,
1 H), 5.57 (bs, 1 H), 3.26 (bs, 2 H), 3.24 (m, 2 H), 3.08
(m, 4 H), 2.61 (m, 4 H), 2.39 (m, 2 H), 2.04 (bs, 3 H),
1.84 (bs, 6 H), 1.71 (bs, 6H), 1.52 (m, 4 H), 1.34 (m,
4 H).
~xamole 25_l b5b~Li~L~
-- .
1-(4-Amino-2-trifluoromethvlPhenvl)-4-~4-~hthalimido-1-
butyl)~i~erazine dihYdrochloride.
To a mixture of 1-(4-nitro-2-trifluoromethylphenyl)-4-(4-
phthalimido-l-butyl)-piperazine (7.8 g, 0.01 mol) in 200
ml ethanol and 60 ml water, 11.2 g of sodium dithionite
was added in portions while stirring and heating at
lOO C. The mixture was heated under reflux for 1 h and
the ethanol was evaporated. The residual water solution
WO93/21179 2 1 0 9 S 1 ~ PCT~SE93/0029~
33
was made basic with NaOH and extracted with ether. The
extract was washed with water, dried and the ether was
evaporated. The yielded oil was dissolved in 100 ml dry
ether and the dihydrochloride was precipitated by the
addition of hydrogen chloride in ether. The salt was
recrystallized from ethanol-ether to give 2.3 g (44 ~) of ~-
the target compound.
M.p. 243 -244 C. --~
~xa~Dle 26 (~ethod s)
1-(4-DiethYlamino-3-trifluoromethYlPhenvl)-4-(4
~hthalimido-1-butvl)-~i~erazine
The product from Example 13 (1.0 g, 2 mmol), dissolved in ~-
5 ml acetic acid, was added to a mixture of sodium .-
borohydride (304 mg, 8 mmol) and 20 ml toluene. The --
mixture was heated for 6 h at 80 C, cooled and added to ~ -
50 ml water and 50 ml ether and made alkaline with 2 M
sodium hydroxide. The organic phase was dried and
evaporated. The residue was recrystallized from hexane to
yield 440 mg of the target product.
M.p. 70 - 71-C.
Examole 27 (Method B)
-1-(4-Amino-3-trifluoromethvl~henvl)-4-(4-Phthalimido-1
butYl)-~i~erazine. -~
4-~4-Acetamino-3-trifluoromethylphenyl)-1-(4-phthalimido-
1- butyl)-piperazine (4.9 mg, 0.01 mmol), dissolved in 2
ml ethanol and 0.2 ml 2 M hydrochloric acid, was heated
for 5 h at 80 C. The solvent was removed and the residue
was shown by gas chromatography to be identical with the
product in example 1.
:
. :"
)93/21179 21 (~ I 6 34 PCr/SE93/0029~
Exam~le 28 (Method C) :
4-(4-Amino-3~trifluoromethylPhenvl)-1-(4-Phthalimido-l-
butYl)-piperazine -~
S
To a refluxing solution of 4-phthalimido-1-butanal (0.713 -
g 3.25 mmol) and N-(4-amino-3-trifluoromethylphenyl)-
piperazine (0.804 g, 3.25 mmol) in CHCl3 (10 ml) was
added dropwise 98% formic acid in ^HCl3 (10 ml) n 20
lQ min. The solution was heated under reflux for 2 h. The
solvent was removed and the residue purified b~
chromatography and shown ~ thin laver chromatography and
gas chromatography to be identical to the product in
example 1.
Example 29 (Method D)
1_14-Amino-3-trifluoromethvlPhenYl)-4-~4-~hthalimido-1-
but~l)pi~erazine
4-(4-Amino-3-trifluoromethylphenyl)-1-(4-aminobutyl)-
pipera zine(32 mg, 0.1 mmol) and phthalic anhydride (30
mg, 0.2 mmol) dissolved in 1 ml acetic acid were stirred
at 75 C for 3 hours. The solvent was removed and the
residue was shown by gas chromatography and thin layer
chromatography to be identical with the product in
example 1.
~xamDle 30 (Method D)
1-(4-Amino-3-trifluoromethYlPhenvl)-4-~4-(5-bromo-2,3-
dimethoxYbenzamido)-1-butvll~i~erazine dioxalate
, .
The product from example 1 (3.3 ~, 6.4 mmol) was
dissolved in 60 ml ethanol, made alkaline with 2 M NaOH, `
and the base was heated with hydrazine hydrate (2.0 ml)
at 75C for 3.5 h. After cooling, the solution was
WO93/21179 2 1 0 9 8 1 6 PCT/SE93/0029~ ~
acidified with 27 ml ~ M HCl and evaporated. The residue
was dissolved in 75 ml H2O and 75 ml ether. The aqueous ;~
phase was made alkaline and extracted with chloroform. ~
The solvent was evaporated to yield crude 1-(4- ~-
aminobutyl)-4-(4-amino-3-trifluoromethylphenyl)-piper
azine. A solution o~ 5-bromo-2,3-dimethoxybenzoic acid
(O.52 g, 2.0 mmol) in 10 ml ~oluene, thionylchloride (2
ml, 23 mmol), and a few drops of DMF was heated at 60C --
for 3 h. The solvent was evaporated and the residue was
dissolved in 15 ml of dichloromethane and evaporated
again. The residual acyl chloride was dissolved in 15 ml,
dichloromethane and a solution of the crude amin from
above (O.51 g, 1.6 mmol) and triethylamine (O.45 g, 3.2
mmol) in 10 ml dichloromethane was added with cooling.
After stirring overnight the solvent was evaporated and -
the residue was partitioned between dil. HCl and ether.
The organic phase was extracted with water and the
combined water phases were made alkaline and extracted
repeatedly with chloroform. Drying (Na2SO4) and
evaporation gave 0.57 g of the product as an oil. The ~-
base was dissolved in aceton and treated with oxalic acid -
affording O.9S g of the title product.
M.p. 174-175-C. ~`
In an analogous way the following compounds (examples 31-
34) were prepared~
~xamole 31
1-(4~Amino-3-trifluoromethvlPhenvl)-4-(4-benzamido-1- -
butvl)~iperazine
M.p. 117-120-C. ;~
.. . :
WO93/21179 21 09 81 ~ 36 PCT/SEg3/0029
xam~le 32
1-(4-Amino-3-trifluoromethvl~henYl)-4-~5-(5-bromo-2,3=
dimethoxvbenzamido)-1-~entvll~iperazine dioxalate
S ~,
M.p. 151-154-C.
~xample 33
10 1-(4-Amino-3-trifluoromethYlPhenY1)-4-~4-(2-
norbornanecarboxamido)-1-butYll~i~erazine hYdrochloride
M.p. 77-80 C.
15 Example 34
(R,endo)-1-(4-Amino-3-trifluoromethYlPhenvl)-4-~4-(2-
norbor anecarboxamido)-l-but~llPiPerazine hYdrochloride
M.p. 142-146-C.
~xamDle 35 (Method E)
1-(4-Amino-S-bromo-3-trifluoromethYlPhenvl)-4-(4-
2S ~hthalimido-1-butvl)~i~erazine oxalate
The product in Example 13 (1.0 g, 2 mmol) was dissolved
in 20 ml dioxane and 5 ml methanol. Bromine (350 mg, 2.2
~mol) dissolved in 3 ml dioxane was added and the mixture
stirred at ambient temperature for 5 hours, the solvent
evaporated, the residue made alkaline with 2 M aqueous
NaOH and extracted with methylene chloride. The solvent
was removed and the residue dissolved in diisopropyl
ether and a precipitate of the title compound was
obtained with oxalic acid dissolved in ethanol.
M.p. 172-175-C.
WO93/21179 21 0 9 81 6 PCT/SE93/0029~
37
Exam~le 36 (intermediatei com~ound ~I~
N-(5-Bromo~entyl)-3-methoxvphthalimide
3-Methoxyphthalic anhydride (3.0 g, 16.8 mmol) and 5-
amino-l-pentanol(1.7 g, 16.8 mmol) were mixed and heated
to 120C for 2 h. After cooling phosphorus tribromide
(3.5 g, 13 mmol) was added and the mixture heated to
110C for 2 h and poured into ice, extracted with ethyl
acetate and the organic phase was separated, dried and
the solvent evaporated. The residue was crystallized fro~
ethyl acetate/hexane.
M.p. 65-67 C.
Example 37 (intermediate comDound ~I )
N-(5-Tosvloxv~entvl~-5-bromo-2,3-dimethoxYbenzamide
A solution of 5-bromo-2,3-dimethoxybenzoic acid (l.56 g, -
6.0 mmol) in 25 ml toluene, thionyl chloride (6 ml, 70
mmol), and a few drops of DMF was heated at 60C for 3 h.
The solvent was evaporated, and the residue dissolved in
20 ml dichloromethane and evaporated again. The residual
acid chloride was dissolved in 20 ml dichloromethane and -
added to a solution of ~-aminopentanol (l.8 g, 18 mmol)
and triethylamine (4 ml, 28 mmol) in 30 ml
dichloromethane at -35 C and the temperature allowed to
rise to O C in 4 h. The solution was washed with dilute
HCl, the organic phase separated, and the solvent removed
to yield 2.2 g of a crude oil. This oil was dissolved in
20 ml dichloromethane, triethylamine (4 ml, 28 mmol) and
tosylchloride (l.33 g, 7 mmol) were added, and the
mixture was stirred at ambient temperature overnight.
Ethyl ether (lO0 ml) was added and the organic phase
washed with sodium carbonate solution and water. After
drying, the organic solvent was evaporated to yield 2.7
g (5.5 mmol) of the title product as an oil.
.
WO93/21179 2 1 ~ 9 ~1 ~ 38 Pcr/sF93/oo29~
1H NMR(CDCL3) d 7.9 (bs, 1 H), 7.81 (d, 1 H), 7.77 (d, 2
H), 7.34 (d, 2 H), 7.13 (d, 1 H), 4.03 (t, 2 H), 3.89 (s,
3 H), 3.87 (s, 3 H), 3.42 (q, 2 H), 2.44 (s, 3 H), 1.73-
1.40 (m, 6 H).
Example 38 (intermediate com~ound IV)
1-(4-Nitro-3-trifluoromethYlphen~1)-4-(~hthalimido-1-
butvl~piperazlne
''
~he compound from example 39 (8.5 g, 30 mmol), 4-1 -
~romobutylphthalimide (1'.1 g, 40 mmol), potassium
carbonate (S.0 g, 36 mmol) and a catalytic amount of
potassium iodide were warmed to 90 C in 80 ml DMF for 6
h. The mixture was poured into 500 ml water and extracted ~-
with methylene chloride. The organic phase was dried, the ~-
solvent evaporated and the resid~e triturated with
ethanol/diisopropyl ether to yield a yellow, crystalline
product.
M.p. 152-154-C.
ExamDle 39 (intermed~ate compound XIII)
. -..
1-(4-Nitro-3-trifluoromethvl~henvl)PiPerazine
A mixture of 22,4 g (0.1 mol) of 4-nitro-3-trifluoro-
methyl-1-chlorobenzene, 50,0 g (0.58 mol) of anhydrous
piperazine and a catalytical amount of KI in 80 ml of 1-
propanol was stirred and heated at lOO C overnight. After
cooling, 1 1 of ice-water was added with stirring. The
yielded precipitate was filtered off, washed with water
and dried.
Yield 26.6 g (94%). M.p. 81-83-C.
W~093/21179 2 1 ~ 9 8 1 ~ PCT/SE93/00295
39
Example 4 0 ( interme~liate comDound XI~I )
4 -Amino - 2, 6 -di chloroPhenvlPiPeraz ine
2,6-Dichloro-4-nitroaniline (10.4 g, 50 mmol~, dissolved
in 100 ml methanol and 10 ml 2 M HCl, was hydrogenated
with platinum on carbon as catalyst at NTP in 8 h. The
catalyst was filtered off and the solvent removed. The
residue was dissolved in ether and made alkaline to yield
5.1 g (29 mmol) of a grey crystalline powder. This
product was reacted with bis-(2-chloroethyl)amine
hydrochloride (5.4 g, 30 mmol) with heating to lOO C in -
n-butanol with 3xl g sodium carbonate (30 mmol) for 26 h.
The solvent was evaporated, the residue taken up in ether
and made alkaline to yield 3.4 g (48 %) of product as an ~-~
oil. -
lH NMR(CDCL3) d 6.82 (s, 2 H), 4.10 (s, 2 H), 3.02 (m, 8
H~, 1.82 (s, 1 H).
Pharmaceutical ~re~arations
The following examples illustrate suitable pharmaceutical
compositions to be used in the method of the invention.
For the preparation of tablets the following compositions
can be made. -
Com~osition 1
Compound according to Example 1 50 g --
30Lactose 85 g
Potato starch 40 g ~ ~
Polyvinylpyrrolidone 5 g ~-
Microcrystalline cellulose 18 g
Magnesium stearate 2 g ~-
--
WO 93/21179 PCI/SE93/0029
21(~9~1~ 40
Com~osition 2
Co~pound according to Example 1 100 g
Lactose 90 g
Potato starch 50 g
Polyvinylpyrrolidone 5 g
Microcrystalline cellulose 23 g r~
Magnesium stearate 2 g -
. .
From the above compositions 1 000 tablets can be made,
containing S0 mg and 100 mg of active substance,
respectively. If desired, the obtained tablets can be
film coated with e.g. hydroxypropyl methyl cellulose in
an organic solvent or using water.
Pharmacoloqv
It is generally accepted that drugs that bind to dopamine
D2 receptors and are antagonists at these receptors will
be clinically effective as antipsychotic agents (for
example in schizophrenia). It is also believed that a
serotoninergic (5HTlA) receptor affinity as an agonist
can be a useful property by reducing the incidence of
extrapyramidal side effects and by increasing the
efficacy of the substance in psychoses. These substances
by having a certain ratio of D2 and 5HTlA binding will
retain an antipsychotic effect at the same time as having
a reduced incidence of side effects and improved
efficacy.
Table 1 illustrates the binding affinities (Ki values,
nM) of several iof the compounds at dopamine (D2 ) and
serotonin ( 5HTlA) receptors and the ratios D2/5HTlA.
The pharmacological methods are described below.
WO 93/21179 2 1 D 9 81 S PCl/SE93/0029~i
41
D2 Receptor Bindin~ Assav
.. .
Tissue preparation: The rats are decapitated and the
striata dissected out on ice. The tissue is homogenized
at O C in 20 ml 0.05 M Tris-HCl buffer pH 7.7, using a
sranson s30 sonifier. The homogenate is centrifuged at
4 C for 10 minutes at 48000 g, in a Sorvall RC-5B ;
Refrigerated Superspeed Centrifuge. The pellet is
resuspended and recentrifuged. The final pellet is
resuspended in incubation buffer (0.05 M Tris-HCl pH 7.6
containing 0.1% ascorbic acid, 120 mM NaCl, 5 mM KCl, 2
mM CaC12, 1 mM MgCl2 and 10 ~M pargylin), to a final :-
concentration of 2.5 mg wet weight/0.5 ml. The homogenate
is preincubated for 10 min at 37 C.
Receptor binding assay: Various concentrations of the
test compound, the radioligand (lnM 3H-Raclopride) and
the homogenate are incubated for 60 min at room
temperature. Non-specific binding is determined by the
addition of 1 ~M (+)-Butaclamol~ The incubation is
terminated by rapid filtration through glass fiber paper
(Whatman GF/B) and subsequent washing with cold -~
incubation buffer, using a cell harvester equipment. The
radioactivity of the filters is measured in a Packard
2200CA liquid scintillation counter. Data is analyzed by
non-linear regression using the LIGAND program, and -~
presented as Ki values.
.:
5-HTl~ Rece~tor bindina Assa~ -~
Tissue preparation. Cerebral cortex + hippocampus from
each rat was dissected and homogenized in 15 ml ice-cold
50mM Tris-HCl buffer 4.0 mM CaC12 and 5.7 mM ascorbic
acid, pH 7.5 with an Ultra-Turrax (Janke & Kunkel,
Staufen, FRG) for ten s. After centrifugation for 12.5 -
min at 17,000 rpm (39,800 x g in a Beckman centrifuge
with a chilled JA-17 rotor (Beckman, Palo Alto, CA, USA),
WO93/2117~ ~1 0 9 81 6 42 PCT/SE93/00295
the pellets were resuspended in the same buffer and
homogenization and centrifugation repeated. To each
pellet 5 ml ice-cold 0.32 M sucrose were added and
homogenized for 5 sec. These samples were kept frozen at
-70 C. When used they were diluted with the buffer to 8
mg tissue/ml and homogenized for 10 sec. The tissue
homogenates were incubated for ten min at 37 C and then
supplied with 10 ~M pargyline followed by reincubation
for 10 min. The binding assay follow~d that described by
Peroutka, J. Neurochem. 47, 529-540, (1986). The
incubation mixture (2 mi) contained 3H-8-oH-DPAT (0.25
tQ 8 nM), 5 mg ml tissue homogenate in 50 mM Tris-HCl
buffer containing 4.0 mM CaC12 and 5.7 mM ascorbic acid,
pH 7.5. Six different concentrations of 3H-8-oH-DPAT were
analyzed. Binding experiments were started by the
addition of tissue homogeT :e and .ollowed by incubation
at 37 C for ten min. ~ ~ incubation mixtures were
filtered through Whatman GF/B glass filters with a
Brandel Cell Harvester (Gaithersburgh, MD, USA). The
filters were washed twice with 5 ml ice-cold 50 mM Tris-
HCl buffer, pH 7.S, and counted with S ml Ultima GoldTM
(Packard) in a Beckman LS 3801 scintillation counter. `
Non-specific binding was measured by the addition of 10
~M S-~T to the reaction mixture. The binding data were
processed by non-linear least squares computer analysis
~Munson and Rodbard, Anal. Biochem. 107, 220-239, (1980).
Data were presented as Ki values (nM).
WO 93/2117g ~ 1 0 9 ~ 1 ~ PCr/SE93/00295
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