Note: Descriptions are shown in the official language in which they were submitted.
103~91
The present invention relates to piperidinobutyro-
phenone derivatives, and their production and use. More
particularly, it relates to novel piperidinobutyrophenone
compounds which are useful as psychotropic agents as well as
analgesic agents, and their production and use.
There is a growing demand for new psychotropic
agents, though a large number of agents has been developed
in this field. As the result of the extensive study, it has
now been found that piperidinobutyrophenone compounds of
the formula:
R1 ~ COC~2C~2C~2 W ~ R3 (I)
wherein Rl and R3 are halogen, R2 is amino or Cl 4 acylamino
and R4 is halogen, Cl_4 alkyl or trifluoromethyl, and their
non-toxic pharmaceutically acceptable salts have excellent
pharmacological properties such as as psychotropic (par-
ticularly neuroleptic and sedative) and analgesic activities
and are useful as psychotropic and analgesic agents.
Accordingly, a main object of the present inven-
tion is to provide the piperidinobutyrophenone compounds (I)
20 and their non-toxic pharmaceutically acceptable salts.
Another object of this invention is to provide a pharma-
ceutical composition containing at least one of the piperidino-
butyrophenone compounds (I) and their non-toxic pharma-
ceutically acceptable salts as an active ingredient. A
further object of the invention is to provide a process for
'~
- 2 - ~ I
preparation of the piperidinobutyrophenone compounds (I) and
their non-toxic pharmaceutically acceptable salts. These
and other objects of the invention will be apparent from the
foregoing and subsequent descriptions.
As used herein, the term "Cl 4 alkyl" means
straight or branched alkyl having one to four carbon atoms.
The term "Cl 4 acylamino" means acylamino having one to four
carbon atoms, and it preferably includes formylamino and
alkanoylamino such as acetamino. The term "halogen"
1~ includes fluorine, chlorine, bromine and iodine, and it
preferably includes fluorine when used with respect to R
and chlorine when used with respect to R3 and R4.
Among the piperidinobutyrophenone compounds (I),
preferred are those wherein R3 and R4 are present re
spectively at the 3- and 4-positions of the phenyl group
linked to the piperidino ring or vice versa. In such
compounds, those wherein Rl is fluorine, R2 is amino,
formylamino or acetamino, R3 is chlorine and R4 is chlorine,
methyl or trifluoromethyl are particularly preferable.
2-0 The piperidinobutyrophenone compound (I) of this
invention or its salt can be prepared by oxidative cleavage
of the corresponding indole compound of the formula:
Rl)~. R5 ~R3 ~II)
wherein R5 is hydrogen or Cl 3 alkyl and Rl, R3 and R4 are
- 3 -
-
l03sasl
each as defined above, or its salt to give the corresponding
acylamino compound of the formula:
1 ~ CCN2C~2C~2 N ~ ~ R3 (IA)
r NHCOR5 ~
\ R4
wherein Rl, R3, R4 and R5 are each as defined above and,
if necessary, hydrolytic deacylation of the latter to give
the corresponding amino compound of the formula:
1 ~ COC~2C~2C~2-N ~ R
2 ~ 3 (IB)
R4
wherein Rl, R3 and R4 are each as defined above.
For the oxidative cleavage, it is preferable to
use an oxidizing agent such as ozone, chromic anhydride,
chromic acid, chromates, periodic acid, periodates, per-
acetic acid or permanganates. Among them, the use of ozone,
chromic anhydride, chromic acid or periodates is particularly
preferred. The reaction is usually effected in the pre-
sence of a solvent. The choice of the solvent depends on
the oxidizing agent employed, and it may be selected from
water, acetone, carbon tetrachloride, acetic acid, sulfuric
acid, pyridine and the like. The oxidizing agent is used
in a stoichiometric amount or more. The reaction temper-
ature varies depending on the oxidizing agent employed.
The most preferred oxidizing agent is ozone and
- 103~391
chromic acid. When the oxidation is effected using
ozone, the reaction is preferably carried out at room
temperature or below. The indole compound (II) is dissolved
or suspended in a solvent such as formic acid, acetic acid
or carbon tetrachloride and then ozonized oxygen is intro-
duced therein with stirring.
When the oxidation is performed with chromic acid
in the presence o acetic acid, it is preferable to use the
chromic acid in 2 - 10 times the equimolar amount and to
effect the reaction at a temperature between 15 to 60C.
The indole compound (II) is dissolved or suspended in a
solvent, and the oxidizing agent is added thereto with
stirring. Generally, the reaction terminates within about
24 hours.
; The produced acylamino compound (IA) can be
separated from the reaction mixture in a crude form by
extraction with or without prior neutralization and evapo-
ration to dryness. The product may be further purified, for
instance, by recrystallization from a suitable solvent
~0 system in a conventional manner.
Hydrolytic deacylation of the thus obtained amino
compound (IA) may be accomplished by a conventional hydro-
lysis procedure, e.g. under an acidic or alkaline condition.
The recovery of the produced amino compound (IB) from the
reaction mixture, if necessary, followed by purification may
be performed in any manner conventionally adopted for
separation.
The thus obtained piperidinobutyrophenone com-
pound (I) can be converted into its non-toxic pharmaceu-
S0 tically acceptable salts by treatment with inorganic or
-- 5 --
., 10~8391 1
organic acids or esters in a conventional manner. When
treatment is made with inorganic or organic acids such as
sulfuric, phosphoric, hydrochloric, hydrobromic, hydroiodic,
sulfamic, citric, lactic, maleic, malic, succinic, tartaric,
cinnamic/ acetic, benzoic, gluconic and ascorbic acids,
there are formed acid addition salts. When treatment is
made with inorganic or organic acid esters such as alkyl
sulfates, alkyl halides and alkyl alkylbenzenesulfonates,
there are formed quaternary ammonium salts.
The indole compound (II) used as the starting
material in the above process may be prepared, for instance,
according to the following scheme:
.
10383gl
W
U~
, I
N H ~N ~ ~N H
U --' .~ U
~ U ~ U ~
V
S~
C) U~
103839~. ;
wherein X is a reactive ester residue such as halogen or
arylsulfonyloxy and Rl, R3, R4 and R5 are each as defined
above.
Specific examples of the piperidinobutyrophenone
compound (I~ obtained by the present invention are as
follows:
~ -[4-(4'-Chloro-3'-trifluoromethylphenyl)-4-
hydroxypiperidino]-2-formylamino-4-fluorobutyrophenone;
y-~4-(4'-Chloro-3'-trifluoromethylphenyl)-4-
hydroxypiperidinol-2-propylamino-4-fluorobutyrophenone;
y-[4-(3',4'-Dichlorophenyl)-4-hydroxypiperidino]-
2-formylamino-4-fluorobutyrophenone;
y-[4-(4'-Chloro-3'-trifluoromethylphenyl)-~-
hydroxypiperidino]-2-isopropionylamino-4-fluorobutyro-
phenone;
y-[4-(3'-Chloro-4'-methylphenyl)-4-hydroxypiperi-
dino]-~-formylamino-4-fluorobutyrophenone, etc.
The piperidinobutyrophenone compounds (I) and
their non-toxic pharmaceutically acceptable salts have
~ central nervous system depressant activity. When, for
instance, orally applied to mice and rats at about 0.1 -
50 mg/kg, they produce characteristic CNS-depressing effects,
and their effe~ts are superior to that of the standard
neuroleptics, e.g. chlorpromazine. Thus, they are useful as
psychotropic agents, particularly as neuroleptic and
sedative agents. They are also useful as analgesic agents.
Besides, the piperidinobutyrophenone compounds (I) wherein
Rl is amino are useful as synthetic intermediates for known
psychotropic and neuroleptic agents.
The piperidinobutyrophenone compounds (I) and
1038391
their non-toxic pharmaceutically acceptable salts may be
administered to mammals orally or parenterally. For this
purpose, these compounds may be utilized as sterile solu-
tions or suspensions in water, polyethylene glycol, vege-
table oils or other pharmaceutically acceptable vehicles.
The compounds may also be administered in tablets, capsules
and suppositories and for this purpose may be combined with
conventional, pharmaceutically acceptable binders and ex-
cipients such as gelatin, sugars (e.g. lactose, glucose,
sucrose), starches, stearic acid or salts thereof (e.g.
magnesium stearate, calcium stearate), talc, vegetable fats
or oils, etc. The usual oral dosage is 0.3 - 100 mg per os
daily.
The following examples illustrate the present
invention in more details but do not limit its scope. In
these examples, % is by weight.
Example 1
Oxygen containing 1 - 2 ~ of ozone was introduced
into a solution of 10.8 g of 1-~y-(6-fluoro-2-methyl-3-
20 indolyl)propyl]-4~(4'-chloro-3'-trifluoromethylphenyl)-4-
hydroxypiperidine in 120 ml of acetic acid at a temperature
of 15 - 20C until the starting compound was not detected in
thin layer chromatogram (silica gel; n-hexane - ethyl
acetate - methanol - ammonia). After acetic acid was
distilled off under reduced pressure, the residual oil was
diluted with water, made alkaline and extracted with ethyl
acetate. The extract was washed with water, dried over
anhydrous sodium sulfate and evaporated to dryness. The
residual free base was converted to the hydrochloride with
~0 hydrogen chloride in ethanol and recrystallized from ethanol
~038~91
to yield y-[4-(4'-chloro-3'-trifluoromethylphenyl)-4-
hydroxypiperidino]-2-acetamino-4-fluorobutyrophenone
hydrochloride. M.P. 232 - 233C.
In the same manner as above, the following com-
pounds were obtained:
y-[4-(3',4'-Dichlorophenyl)-4-hydroxypiperidino]-
2-acetamino-4-fluorobutyrophenone, M.P. 104 - 109C (hydrate);
y-[4-(3'-Chloro-4'-methylphenyl)-4-hydroxypiperi-
dino]-2-acetamino-4-fluorobutyrophenone, M.P. 91 - 101C
(hydrate).
Example 2
A mixture of 2.0 g of y-[4-(4'-chloro-3'-tri-
fluoromethylphenyl)-4-hydroxypiperidino]-2-acetamino-4-
fluorobutyrophenone hydrochloride, 3 ml of concentrated
hydrochloric acid and 25 ml of ethanol was refluxed for 2
hours. After diluting with water, the resulting mixture
was made alkaline with 10 % sodium hydroxide and extracted
with ethyl acetate. The extract was concentrated to
dryness, and the residue was crystallized from aqueous
methanol-isopropyl ether to yield y-[4-(4'-chloro-3'-tri-
fluoromethylphenyl)-4-hydroxypiperidino]-2-amino-4-fluoro
butyrophenone. M.P. 166 - 167C.
In the same manner as above, the following com-
pounds were obtained:
y-[4-(3',4'-Dichlorophenyl)-4-hydroxypiperidino]-
2-amino-4-fluorobutyrophenone hydrochloride, M.P. 214 -
214.5C;
y-[4-(3'-Chloro-4'-methylphenyl)-4-hydroxypiperi-
dino]-2-amino-4-fluorobutyrophenone hydrochloride, M.P.
207 - 210C.
-- 10 --
1038391
Example 3
Preparation of the starting indole compounds:-
(1) To a stirred solution of 11.1 g of ~-(6-
fluoro-2-methyl-3-indolyl)propionic acid and 5.1 g of
triethylamine in 70 ml of tetrahydrofuran was added dropwise
5.5 g of ethyl chloroformate at a temperature below 0C.
Stirring was continued for additional 20 minutes and thereto
was added dropwise a solution of 14.0 g of 4-(4'-chloro-3'-
trifluoromethylphenyl)-4-hydroxypiperidine in 200 ml of
tetrahydrofuran. After addition was completed, the reaction
mixture was stirred for 3 hours at room temperature. The
resulting mixture was concentrated under reduced pressure,
and the residue was dissolved in ethyl acetate. The ethyl
acetate solution was washed successively with water, diluted
hydrochloric acid, diluted sodium hydroxide, water and
finally saturated sodium chloride, dried over anhydrous
sodium sulfate and evaporated under reduced pressure. The
residue was crystallized from ethanol to yield 1-[~-(6-
fluoro-2-methyl-3-indolyl)propionyl]-4-(4'-chloro-3'-
trifluoromethylphenyl)-4-hydroxypiperidine as crystalline
powder. M.P. 172.5 - 174.0C.
(2) To a stirred mixture of 1.0 g of lithium
aluminium hydride in 15 ml of anhydrous ether was added
dropwise a solution of 4.55 g of crude 1-[~-(6-fluoro-2-
methyl-3-indolyl)propionyl]-4-(4'-chloro-3'-trifluoro
methylphenyl)-4-hydroxypiperidine in 50 ml of anhydrous
tetrahydrofuran at room temperature. After the addition was
completed, the reaction mixture was heated under refluxing
for 2.5 hours and hydrolyzed by addition of water-tetra-
S hydrofuran mixture under cooling. The resulting suspension
-- 11 --
10383~ j
was filtered, and the filtrate was concentrated and ex-
tracted with ethyl acetate. The extract was washed with
water, dried over anhydrous sodium sulfate and evaporated to
yield l-[y-(6-fluoro-2-methyl-3-indolyl)propyl~-4-(4'-
chloro-3'-trifluoromethylphenyl)-4-hydroxypiperidine as
amorphous powder, which was converted to the hydrochloride
by a conventional procedure to give crystals. M.P. 225 -
228C (decomp.).
In the same manner as above, the following com-
pounds were obtained:
l-[y-(6-Fluoro-2-methyl-3-indolyl)propyl]-4-
(3',4'-dichlorophenyl)-4-hydroxypiperidine;
l-[y-(6-Fluoro-2-methyl-3-indolyl)propyl]-4-(3'-
chloro-4'-methylphenyl)-4-hydroxypiperidine.
. ,,: .,
- 12 -
