Note: Descriptions are shown in the official language in which they were submitted.
1077~40
This invention relates to heterocyclic compounds and is
concerned with 4-amino-trans-decahydroquinoline derivative, with
processes for preparing these derivatives and with pharmaceutical
compositions containing them.
The compounds with which the present invention is
concerned are those represented by the general formula:
Rl -C -N-R2
~ r~ (I)
\ N
R3
and the pharmaceutically acceptable acid addition salts thereof,
wherein Rl represents a branched- or straight-chain alkyl group
or alkoxy group containing from 1 to 4 carbon atoms, or a phenyl,
furyl or pyridyl group; R2 represents a branched- or straight-
chain alkyl group containing from 1 to 4 carbon atoms, a phenyl
group, a phenyl group substituted by an alkyl or alkoxy group
containing 1 to 4 carbon atoms, a naphthyl group, a benzyl or
cyclohexyl group; and R3 represents a benzyl, phenethyl, cinnamyl
or phenylpropyl group or a group of the formula:
R4 R5
n Y ~ (II)
wherein A represents a branched- or straight-chain alkylene group;
Y represents an atom of oxygen or sulphur or a carbonyl group,
n is zero or an integer of from 1 to 4, with the proviso that
whell n is zero, Y is a carbonyl group, R4 and R5 which are
identical or different each represents an atom of hydrogen or
halogen or a methyl or methoxy group.
.s,~
,
~(~77040
The compounds of formula (I) are prepared according
to the invention by refluxing a l-substituted 4-amino-
trans-decahydroquinoline having the general formula:
HN-R
(III)
N
R3
wherein R2 and R3 have the aforesaid meanings, preferably
in an inert organic solvent such as, for example, dichloro-
ethane, methylenechloride, benzene or toluene, with a
compound of the general formula:
R -C-Cl (IV)
wherein Rl has the aforesaid meanings, optionally in the presence
of a base such as, for example, triethylamine, trimethylamine
or pyridine.
The compounds of formula (I) thus obtained can
be converted into the corresponding pharmaceutically acceptable
acid addition salt by treat.ment with an appropriate organic or
inorganic acid in accordance with technique well known in the
art.
The compoullds of formula (III) may be prepared by
-- 2
. ', `,i
.. ,, .,~
" " 107704()
.
reacting a 4-amino-trans-decahydroquinoline of the general
formula :
E~-R
11 (v)
H
wherein R2 has the same meanings as in formula (I), with a
halogenated compound of the general formula :
Hal-R3 (VI)
wherein Hal represents an atom of chlorine, bromine or iodine
and R3 has the same meanings as in formula (I). lhis reaction
is preferably carried out in a liquid medium which may be an
inert organic solvent such as, for example, benzene, toluene,
xylene, dichloroethane or tetrahydrofuran, or an alcoholic medium,
for example butanol or aqueous ethanol, or a ketone, for example
acetone or methyl ethyl ketone, and in the presence of an acid
acceptor, preferably an alkali metal carbonate, for example
potassium carbonate or sodium bicarbonate.
The reaction, which may be accelerated by the use of
small quantities of potassium iodide, i9 preferably c,rried
out at the reflux temperature of the liquid medium.
~he compounds of formula (VI) are already known while
the compounds of formula (v) may be prepared by reacting the
known compound 4-oxo-trans-decahydroquinoline, in the presence
of a catalyst such as, for example, ~-toluene-sulphonic acid,
trifluoroboron etherate, æinc chloride or titanium tetra-
chloride, preferably in an inert organic solvent such as7 for
example, hexane, benzene or toluene and at the reflux tempera-
ture of the solvent, w th an amine of the general formula :
R -NH2 ( VII)
wherein R2 has the same meanings as in formula (I), the water
..,
` 1077040
formed being eliminated by azeotropic distillation. The imino
derivative which is obtained is hydrogenated by means of sodium
borohydride in methanol or lithium hydride in tetrahydrofuran.
This hydrogenation may be carried out over a wide range of
temperature.
The foregoing method produces the compounds of for~ula
(V) in the form of a mixture of axial and equatorial isomers.
This mixture may be separated into two fractions by virtue of
differing solubilities of the hydrochloride of the isomers in an
aqueous solution having a pH value of 3 or by chromatography.
Hence the compounds of formulae (I) and (III) may be obtained either
in the form of a mixture of their axial and equatorial isomers,
or in the form of the axial or equatorial isomer. However it has
not yet been possible to determine whether the fraction which i8
insoluble in water having a pH value of 3 is constituted by either
the axial or equatorial isomer or possibly by a mixture of the
two, and likewise with the soluble fraction. In view of this,
the term "form a" will hereinafter be used to designate that
compound represented by formula (V) of which the Rf in the chosen
2C assay of thin-layer chromatography is smaller than that of the
corresponding i30meric compound of ~ormula (V) which will be
designated hereinafter by the term "form b". The results of the
thin-layer chromatographic assay in question are illustrated in
the drawing accompanying this specification, details of the assay
being as follows :
Support : Silicagel 60 P.254 (produced by MERCK)
thickne3s : 0.25 mm.
Development and saturation_solven_ (in ammonia atmosphere)
Hexane : 80 ml.
2-Propanol : 20 ml.
Technique : ascending 13 cm.
Deposits : 200 ug. (chloroform solution)
_ 4 _
.~ ",~
1077040
Revealing : U.S. at 2,540 A in iodine vapour
(1) 4-phenylamino-trans-decahydroquinoline (form a)
(2) 4-phenylamino-tran~-decahydroquinoline (form b)
~ he same denominations "form a" and "form b" will be
used hereinafter to designate the corresponding isomers of the
substances of formulae (III) and (I) of which the starting-product
is either "form a" or "form b" of the compound represented by
formula (v). Consequently, the above-described process for
obtaining the derivatives of formula (I) using derivatives of
formula (v) a~ starting-product~ is equally applicable to either
"form a" or "form b" of the derivatives of formula (v) for the
preparation of the corresponding isomers of formula (I).
The compounds of the invention have been found to
possess valuable pharmacological properties and, in particular,
some of them have been found to possess a powerful analgesic
action which is devoid of any morphine-like effects.
Said properties render the compounds concerned of
particular interest in the treatment of pain.
Thus the invention includes within its scope a method
of relieving pain in a subject in need of such treatment by
administering to the subject an effective amount of the appro-
priate compound of formula (I) orof a pharmaceutically acceptable
acid addition salt thereof.
Analgesics are agents which relieve pain by acting
centrally to elevate the pain threshold without disturbing
consciousness or altering other sen~ory conditions.
Agents which are u3ed principally for the symptomatic
relief of pain may, for convenience of classification, be divided
into two general groups :
0 1) Narcotic analgesics, such as the o~ium derivatives.
3 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
Amongst these, morphine is one of the most important
drugs and possesses numerous useful properties, analgesia being
- 5 -
~i. "
., ~, .,
iO770~0
one of its main activities.
No other drugs i8 no generally useful in relieving
various catagories of severe pain. Unfortunately, morphine
causes euphoria and addiction and it depresses respiration.
If morphine, or a related compound, i9 given over a
long period of time, tolerance to the analgesio effect de~elops
90 that the do~e must be incr~a~ed periodically to obtain
equivalent pain relief. For these reasons, it is generally
agreed that morphine and its derivatives ~hould not be uqed
for pain when some other analgesic will ~uffice.
The analgesic compounds of the invention are completely
devoid of any morphine-like effects and their use may therefore
be recommended in a larger number of cases than the morphine
deri~atives.
2) Non-narcotic analge~ics such as, for example, the
; salicylate derivatives.
_ _ _ _ _ _ _ _ _ _ _ !
These are generally le~s active than the narcotic
analgesics but, on the other hand, they do not depress respira-
tion and do not cause any or only very slight addiction.
It will be seen that the analgesic compounds of the
invention compare very favourably to the most commonly used non-
narcotic analgesics.
In addition to the above, some compounds of formula I
have been found to possess useful pharmacological properties
capable of rendering them of considerable value in the treatment
of disorders of the cardiovascular system characterized by high
blood pre~qure.
A further object of the invention is therefore a method
of treating pathological disorders of arterial pressure and, in
particular, hyper~ention in a subject in need of such treatment
by administering to the said subject at least one appropriate
compound of formula I or a pharmaceutically acceptable acid
B
-` 1077040
addition salt thereof,
There are numerous types of hypertension but no universal
remedy is at preeent know~ which is capable of combating these
different types of diseases, indi~idual cases varying widely as
regards their response to various drugs.
They are therefore many antihyperten3ive agents which
are used to treat the different types of hypertension.
Amongst them, ~ome compounds are known to exert a
ganglioplegic effect in that they interrupt the sympathicotonic
impulses thus causing relaxation of the vascular walls. Others
are characterized by a rather narrow margin between their thera-
peutic and toxic doses.
~ inally, it is known that certain antihypertensive
agent~ exert such a sudden and powerful antihypertensive effect
that their action is difficult to control.
; The antihypertensive compounds of the invention do not
present these disadvantages.
Pharmacological tests have been undertaken with a ~iew
to demonstrating either the analgesic action or the antihyper-
tensive effects of the compounds of the in~ention.1) Analgesic action
The following compounds of the invention were found to
be particularly useful a~ analgesics :
4-~(N-phenyl-N-acetyl)-aminoJ -l-l 3-(4-fluorobenzoyl)-propyl1 -
trans-decahydroquinoline (Compound A).
4-[(N-phenyl-N-propioryl)-amino~ -1- t3-(4-fluorobenzoyl)-propyl~-
trans-decahydroqulnoline (Compound B).
4-~(N-phenyl-N-butyryl)-amino 7~ 3(4-fluorobenzoyl-propyl~ -
trans-decahydroquinoline (Compound C).
4-~(N-phenyl-N-~aleryl)-amino] ~ 3(4-fluorobenzoyl)-propyl~ -
tran~-decahydroquinoline (Compound D).
4-r(N-4-methoxyphenyl-N-propionyl)-amino~ 3-(4-fluorobenzoyl)-
,, ~..,~ 1
~ -~8'-
~, .
1(~7'7040
propyl~ -trans-decahydroquinoline (Compound E).
The first test was carried out according to the technique
of KOS~ER (Fed. Proc. 18, 412, 1959) on batches of 20 mice which
had been deprived of food for 18 hours.
Each batch of animals with the exception of the controls
was given an intragastric dose of the compound to be studied so
that each batch received a higher dose than the preceding batch.
Thirty minutes after administration, the animals of each batch,
as well as the control animals, were given intraperitoneally
0.2 ml. of a 0.25~ acetic acid solution per 10 g. of body-weight.
During the 20 minutes following the injection of acetic
acid, the number o~ characteristic contorsions made by the animals
was noted. The absence of contor~ions corresponds to animals
under the influence of analgesia.
Note wa~ taken of the AD50, i.e. the dose of the
compound under study which provoked analgesia in half of the
animals treated.
me result~ of thi~ test are given in the following
Table :
TABLE I
~ . . . .. .
: Compound : AD50 mg~kg
.
: A : 38
: ~ : 25
: C : 30
: D : 25
: E : 55
The ~ame te~t was carried out with five commonly u~ed
analgesics and the following result~ were obtained :
10770~0
TABLE II
: Compound : AD50 mg/kg
. .
:Acetylsalicylic :
acid 150
: Antipyrine : 120
: Phenacetine : 160
: Glafenine : 110
: Pentazocine : 45
.. .. .
10 - The second test was carried out according to the
technique of NILSEN (Ac~a Pharmacol, et toxicol. 18, 10 1961)
on batches of 10 mice.
The animals were connected to a source of elec$ric
current by means of two electrodes inserted into the tail.
The threshold-voltage was then determined, i.e. the
minimum voltage which, in the course of two successive shocks,
caused the animals to squeak at least one time out of two. After
this, the compound to be studied was administered by intragestric
ro~te. At various times after ad~inistration, four successive
shocks were given at the threshold-voltage determined and it was
considered that the animal was protected if it did not squeak
after any of the shocks.
Note was taken of the dose of compound (AD50) which
suppre~sed the squeak in half of the treated animals.
The results of this test are given in the following
Table :
TABLE III
. ._
.
: Compound : AD50 mgtkg
: A : 110
: B : 30
-~ : C : 70
1077040
The ~ame test was also carried out with three well-
known analgenic~ and the following results were obtained :
TAB~E IV
_ _
: Compound : AD50 mg/kg
:
: Acetylsalicylic:
: acid4 : 1100
:
. Antipyrine 400
: Phenacetine : 450
- Further pharmacological tests were carried out with a
~iew to determining the analgesic action of the preferred compound
of the invention, namely :
4- ~(N-phenyl N-propionyl)-amino ~-1- r(4-fluorobenzoyl)-propyl~-
trans-decahydroquinoline (Compound B).
The first test was carried out according to the
technique of KOSTER described above but using a sub-cutaneous
injection of the product ot be tested.
Compound B was compared to two major analgesics and
the following results were obtained :
TAB~E V
. _
: Compound : AD50 mg/kg
B : 2
. Pethidine : 7
: Pentazocine : 5
The second test wa~ carried out according to the
technique of NI~SEN described above but using a sub-cutaneous
injection of the compound to be tested.
~ ompound B was compared to pethidine and pentazocine,
two well-known analgesics, and the following results were obtained.
~ ~ /0
~ -- a~r-
~ ,~, ....................................................... .
~077040
TABLE VI
-
: Compound : AD50 mg/kg
B : 4
Pethidine : 7
: Pentazocine : 12
The third te~t wa~ carried out according to the tech-
nique of SIEGMUND and al (Proc. Soc. Exp Biol. Med. 95, 729,
1957) on batches of 10 male mice
A typical syndrome was produced in the animal~ by intra-
peritoneal injection of 0.25 ml. of a 0.02% aquecus ~olution of
2-phenyl-1,~-benzoquinone (phenylbenzoquinone).
The syndrome in que~tion is characteriaed by intermittent
contractions of the abdomen, twi~ting and turning of the trunk
and exten~ion of the hind legs. Note was taken of the number of
movements occurring over a period of 30 minute~ starting 15
minutes after the injection of phenylbenzoquinone.
The compound to be tested was injected 30 minutes
before the phenylbenzoquinone in such a way that each batch
received a higher do~e than the preceding batch, a control batch
receiving only the phenylbenzoquinone.
Note was taken of the AD50, i.e. the dose of substance
which reduced at least by half the number of contorsions in half
of the animals, as compared to the number of contorsions observed
in the control group.
The following results were obtained :
.... .. .. . . ..
.. ... . _ .. _ .. ... ... . .. . . ......... . .. .... .. ... . . .. .. _ _ _ _
'i~', i /J
~ ? ~_
1077040
TABLE VII
: Compound : AD50 mg/kg)
!
B : 7
: Acetylsalicylic:
acid 50
Antipyrine : 100
Phenacetine : 80
: Glafenine : 325
The fourth test was carried out according to the tech-
nique of CHAR~IER and al (Arch. int. Pharmacodyn. 1~4, 306, 1961)
on batches of 10 rats.
The animals were connected to a source of electric
current by means of two electrodes of which one was attached to
the tail and the other maintained in the rectum.
lhe pain-threshold voltage was then determined for each
rat by passing a current of 2 volts and i~creasing the current by
one volt at a time until the animal gave a squeak. ~his control
test was repeated three times at intervals of 15 minutes. lhe
compound under study was then administered by intragastric route
and, starting from the threshold-voltage already determined
note was taken, every 10 minutes for 2 hours, of the voltage which
caused the animals to squeak.
The results were noted according to the WINTER and
FIATAKER scale (J.Pharmacol. Exp. Therap. 98, 305, 1950) and the
AD's 50 obtained are li~ted in the Table given hereunder :
TABLE VIII
: Compound : AD50 mg/kg
-
B : ~0
:Acetylsalicylic 1300
: acid
/~
.,~, . ~
1(~770~()
Antipyrins :500
. Phenacetine : 750
: Pethidine :50
.
Finally, a test wa~ carried out according to the tech-
nique of D'AMOUR and SMI~H (J Pharm. Exp. ~her. 72, 74, 1941)
on batche6 of 10 male rat~ weighing about 200 g.
A 300-watt heating-bulb was focu~ed on the tip of the
rat' 9 tail at such a distance that a typical twitch of the tail
(flick-tail) wa~ obtained after 4 to 6 second3 of irradiation.
~ he animals, with the exception of a control batch,
were giYen the compound to be tested by sub-cutaneous route and
note was taken of the time which elapsed between the beginning
of irradiation and the first reaction pf the animal (reaction
time), as compared to the reaction time of the control animals.
; The AD's 50 obtained are given in the following Table :
~ABLE IX
-
: Compound : AD50 mg/kg
B : 2.5
Pethidine: 5.5
: Penta~ocine: 3
From the above test~, it may be concluded that the
compounds of the invention posse~s analgesic properties which are
far superior to those of well-known analgesic~.
2) Antihyperten~ive action
lhe compound of formula I wherein Rl represents a
branched- or straight-chain alkoxy group have been found to possesq
a useful antihyperten~ive aotion capable of rendering the~ of
considerable value in the treatment of human hypertension.
As far a~ the treatment of hypertension is concerned,
l3
"
_...
1077040
the preferred compound of the invention i9:
4- ~(N-phenyl-N-carbethoxy)-amino ~ 3-(4-fluorobenzoyl)-
propylJ -trans-decahydroquinoline (Compound F).
A pharmacological test was undertaken with a view to
demonstrating the antihypertensive action of Compound F.
This test was carried out on male rats belonging to a
race which has been specially bred to produce animals having
high blood pressure, according to the technique of OKAMO~O and
AOKI (Jap. Circul. J. 27, 282, 1963).
The animals employed were about ten weeks old and had
a blood pressure reading in the region of 180 mm.Hg.
This test was divided into two series. In the first
series, one single dose of the compound under study was admini ter-
ed by intragastric route to each animal and the arterial pressure
of the latter was measured every hour for six hours after adminis-
tration. In the second series, the product under study was given
by the same route every day for ele~en consecutive days and
arterial pressure was measured daily throughout this period.
The amount of compound administered varied from one
animal to another, as far as the first ~eries of tests was
concerned.
The following results were obtained :
TABLE X
-
Max. fallMoment of
~ype of treatment Dose mg/ke in A.P. max. fall
(mm.Hg) in A.P.
Single dose 5 27 3 hours
44 4 hours
_ _ _ _ _ .. ,
Daily dose
(eleven day~) 10 29 8 day~
__ _
From these results, it may be concluded that Compound ~
~1 ,~
1077040
has a powerful antihypertensive action.
3) Acute toxicity
Acute toxicity trials were carried out on rats and mice
which were kept under ob~ervation for 12 days following one
single administration.
The following results were obtained :
a) Compound B
l . ,
Animals Administration ~D50 (mg/kg)
_ _ ,
Mice intragastric 500
Rats intragastrlc 350
Mice intraperitoneal 55
Rat~ intraperitoneal 55
Mice sub-cutaneous 550
b) Compound F
Animals Administration ~D50 (mg/kg)
_
Mice intragastric 750
Rats intragastric 450
Rats intravenous 15
Mice intravenous 32
These figures compare very favourably with the active
doses of which the effect~ are described above and show that
there i8 a very wide safety margin between the toxic doses and
the therapeutic doses of the preferred compounds of the invention.
It will be appreciated that, for therapeutic use, the
compounds of the invention will normally be administered in the
form of a pharmaceutical composition containing as active prin- ..
ciple at least one compou~d of formula I or a pharmaceutically
acceptable acid addition salt thereof in association with a
.. . - .
4(~
pharmaceutical carrier and/or excipient therefor.
Advantageously, for clinical use the composition will
be made up in a dosage unit form appropriate to the desired mode
of administration, for example a coated or uncoated tablet or
a hard- or soft gelatin capsule for oral administration, a
solution for injection or a suppository for r~ctal administration.
Irrespective of the form which the composition takes,
the pharmaceutical composition will normally comprise at lea~t
one of the compounds of formula I or a pharmaceutically acceptable
acid addition ~alt thereof associated with an appropriate
pharmaceutical diluent of e~cipient comprising, for example, o~e
or more of the following substances : milk, sugar, starches,
talc, magnesium stearate, polyvinylpyrrolidone, alginic acid,
colloidal silica or fla~ouring agent.
The following Examples illustrate the invention.
EXAMP~E 1
4~ -Phenyl-~-propionyl)-amino ~ 3-(4-fluorobenzoyl)-
propyl J-trans-decahydroquinoline h2~rochloride (form a)
a) Preparation of 4-phenylamino-trans-decah~dro~uinol_ne
A solution of 76.8 g. (0.5 mol) of 4-oxo-trans-
decahydroquinoline and 1.0 g. of _-toluenesulphonic acid in 350 ml.
of hexane was refluxed in a one-litre flask and 46.3 g. (0.5 mol)
of aniline were added.
Refluxing was continued until the water which formed
- was completely eliminated by means of a Dean-Stark system and
140 ml. of hexane was distilled off. The solution was allowed
to cool and 250 ml. of benzene were added. The reactlon medium
was firstly washed with water, then with a diluted ~olution of
sodium hydroxide and finally again with water. The resulting
solution was dried over anhydrous sodium sulphate, filtered and
the solvents were eliminated to give 102.4 g. of crude (4-
phenylimino-trans-decahydroquinoline (yield : 89~).
~: .
1077040
In a one-litre flask were dissolved the 102.4 g. of
4-phenylimino-trans-decahydroquinoline ~o obtained in 190 ml.
of methanol containing 200 mg. of ~odium hydroxide, the temperature
of the ~olution being maintained at about 20C.
A solution of 20 g. of ~odium borohydride in 200 ml.
of methanol, ~tabilized by 600 mg. of sodium hydroxide, was added
following which the temperature of the reaction medium was
maintained between 20 and 22C, for a few hours.
The solution was finally heated to 40C. for 8 hours and
was then allowed to cool. The solvent was eliminated and the
residue taken up in 150 ml. of benzene and 250 ml. of water.
The mixture was decanted and the aqueous phase was
extracted with benzenes. The organic phase wa3 then extracted
with 240 ml. of 4N hydrochloric acid. The mixture wa~ decanted
and sodium hydroxide was added until a pH of 3 was obtained.
; Filtration was effected to obtain an aqueous acid filtrate and
a precipitate which was dried so as to give 43.8 g. of 4-phenyl-
amino-trans-decahydroquinoline hydrochloride (form a).
Yield : 33~, m.p. 265 - 270C.
Isolation of form b
The aqueous acid filtrate was made alkaline by adding
~odium hydroxide and was extractsd with benzene. The resulting
mixture was decanted and the organic phase was washed with water,
dried over anhydrous sodium sulphate and filtered. The benzene
- was eliminated and the residue taken up in 35 ml. of diethyl
ether. The solution RO formed was cooled to a temperature
between 0 and 5~C., filtered and washed with diethyl ether to
give 9~2 g. of 4-phenylamino-trans-decahydroquinoline (form b).
Yield : 7%, m,p. 118 - 120C.
By following the same method but using the appropriate
~tarting-products, the compounds listed hereunder were prepared :
7040
Compound Melting Point C.
4-(4-methylphenyl)-amlno-trans-
decahydroquinoline 92 - 94
~-(4-methoxyphenyl)-amino-trans-
decahydroquinoline 144 - 145
4-benzylamino-trans-
decahydroquinoline uncristallized
4-(1-naphthyl)-amino~trans-
decahydroquinoline uncristallized
4-Cyclohexylamino-trans-
decahydroquinoline uncristallized
b) Preparation of l-~-(fluorobenzoyl)-pro~yl~ -4-~hen~l-amino-
trans-decahydroq_inoline dih~drochloride (form_ )
In a four-litre flask was refluxed a solution of 230 g.
(1 mol) of 4-phenylamino-trans-decahydroquinoline (form a) in
920 ml. of n-butanol, in the presence of 100 g. of sodium bicar-
bonate. While refluxing, a solution of 274 g. (1.12 mols) of
3-chloro-1,1-ethylenedioxy-1-(4-fluoro-phenyl)-butane in 200 ml.
of n-butanol was added and the reflux was maintained until the
water which formed was completely eliminated by means of a
Dean-Stark ~ystem. lhe ~olution was allowed to cool to 50C. and
the salts so formed were filtered off.
The solvent was eliminated under vacuum from the
solution and the resulting residue was taken up in 2,500 ml. of r
benzene. The re~ulting solution was extracted with a solution
of 250 ml. of concentrated hydrochloric acid in 1,250 ml. o~
water. The mixture obtained WaB decanted and the hydrochloric
solution was stirred for 3 hours, made alkaline and then extract-
ed with benzene. The organic phase obtained was washed with
water, dried over anhydrous ~odium sulphate and filtered and the
benzene wa~ eliminated. The residue obtained was taken up in
~0 ethyl acetate and a solution of gaseous hydrochloric acid in
2-propanol was added. The precipitate which formed was filtered
off, washed with ethyl acetate and dried. The crude product
/8
~3~J
10770~
obtained was recrystallized from a mixture of ethyl acetate and
methanol and 303 g. of 1- ~3-(4-fluorenzoyl)-propyl~ -4-phenyl-
amino-trans-decahydroquinoline dihydrochloride were obtained
(form a).
Yield : 64.8%, m.p. 204 - 206C.
By following the same method but using the appropriate
starting-products, the compounds listed hereunder were prepared
and their melting points obtained after recrystallization from
the indicated solvents :
Compound Meltin~ Point C.
1- ~3-(4-fluorobenzoyl)-propyl~ -4-
~4-methoxyphenyl)-amino-trans- 179 - 182
decahydroquinoline dihydrochloride (ethyl acetate/methanol)
(form a)
1- [3-(4-fluorobenzoyl)-propyl]-4-
(4-methylphenyl)-amino-trans- 188 - 194
decahydroquinoline dihydrochloride (ethyl acetate/methanol)
(form a)
: 1-(3-benzoylpropyl)-4-phenylamino-
trans-decahydroquinoline hydrochloride 206 - 208
a) (ethanol)
1- r3-(4-methylbenzoyl)-propyl 7-4-
phenylamino-trans-decahydroquinoline 226 - 227
hydrochloride ~form a) 1 (ethyl acetate/methanol)
l-r 3-(4-chlorobenzoyl)-propyl7 -4-
phenylamino-trans-decahydroquinoline 248 - 249
hydrochloride (form a) (metha~ol, etha~ol)
1- ~3-(4-fluorobenzoyl)-propyl~ -4-
phenylamino-trans-decahydroquinoline 227 - 30
dihydrochlori~ rform b) (ethyl acetate/methanol)
1- ~3-(4-~luorobenzoyl)-pro pylJ -4-
(4-methylphenyl)-amino-trans- 235 - 238
decahydroquinollne dihydrochloride (ethyl acetate/methanol)
(form b)
1- ~3-(4-bromobenzoyl)-propylJ -4-
phenylamino-trans-decahydroquinoline 241 - 243
hydrochloride ~form a) (ethanol/methanol)
1- r3-(4-methoxybenzoyl)-propylJ -4-
phenylamino-trans-decahydroquinoline 230 - 232
hydrochloride ~ orm a) (ethanol)
3 1-(4-fluorobenzoyl-methyl)-4-phe~yl-
amino-tran~-decahydroquinoline 255 - 257
hydrochloride (form a) (2-propa~ol)
/q
_ ~_
.... ~ ~,
~, . .
10'77~0
l-Benzomethyl-4-phenylamino-trans-
decahydroquinoline hydrochloride + 230 (decomposition)
(form a) (ethanol/methanol)
1- ~3-(2-Thenoyl)-propyl~ -4-phenyl-
amino-trans-decahydroquinoline 167 - 169
dihydr~hl~ride (form a) (ethyl acetatelmethanol)
l-Phenethyl-4-phenylamino-trans-
decahydroquinoline hydrochloride 258 - 260
(form a) (ethanol)
l-Cinnamyl-4-phenylamino-trans-
decahydroquinoline acid oxalate 170 - 172
(form a) (2-propanol)
1-~3-phenyl-propyl)-4-phenylamino-
trans-decahydroquinoline oxalate 148 - 150
(form a) (2-propanol)
1- f3-(4-chrobenzoyl)-propylJ -4-
b(4-meth~xyphe~yl)-amino 7 -trans- 224 - 226
decahydroquinoline dihydrochloride (ethyl acetate/methanol) (form a)
1- ~4-(4-fluorobenzoyl)-butyl-4-
phenylamino-trans-decahydroquinoline 182 - 184
hydrochloride ~form a) (ethanol)
1-(2-Phenoxy-ethyl)-4-phenylamino- 165 - 167
; tran~-decahydroquinoline (form a) (methanol)
1- ~3-(4-Fluoro-phenylthio)-propyl~ -4-
phenylamino-trans-decahydroquinoline 83 - 85 r
(form a)
1- ~3-(4-fluorobenzoyl)-propyl~ -4-
benzylamino-tran~-decahydroquinoline 255 - 256
hydrochloride (form a) (ethyl acetate/methanol)
3-(4-fluorobenzoyl)-propyl ~-4-
cyclohexylamino-trans-decahydro- 211 - 214
quinoline hydrochloride (form a) (ethyl acetate/methanol)
1 ~3-(4-fluorobenzoyl)-propyl~ -4-
(l-naphthylamino)-trans-decahydro- uncrystallized
quinoline
- c) Preparation of 4- r(N-~henyl-N-pro~ion~l)-amino~ 3-(4-
fluorobenzoyl)-pro~yl~ -tranq-decahydroq_inoline h~drochloride
While stirring, 394 g. (1 mol) of 1- ~(4-fluorobenzoyl)
-propylJ -4-phenylamino-trans-decahydroquinoline (form a) were
dissolved in 800 ml. of dichloroethane in a two-litre flask. ~he
resulting solution was cooled to about 20C. and a solution of
105 ml. of propionyl chloride in 105 ml. of dichloroethane wa~
added.
~j ~0
1077040
The reaction medium wa~ then maintained at 20C. for
one hour after which it wa~ heated to 45-50C. for 16 hours.
The solution wa~ thereafter cooled to 10-15C. and the resulting
precipitate of 1- ~3-(4-fluorobenzoyl)-propyl ~-4-phenylamino-
trans-decahydroquinoline dihydrochloride was filtered off.
The excess of propionyl chloride was hydrolyxed with
120 ml. of methanol and the solution wa~ evaporated to dryness.
The residue obtained was taken up in 150 ml. of acetone,
refluxed and the solvent di~tilled off. Thi~ operation was
repeated twice more.
At the reflux temperature of the solvent, the residue
was dissolved in 150 ml. of acetone and a solution of 2-propanol
containing a small quan~ity of gaseou~ hydrochloric acid was
added. The resulting ~olution was allowed to crystallize at
room-temperature and the precipitate obtained was filtered off,
washed with acetone and dried to give 318 g. of crude product.
After recrystallization from a mixture of ethyl acetate/methanol
(2:1 by volume), 263 g. of 4~ -phenyl-N-propionyl)-amino~
r3-(4-fluorobenzoyl)-propylJ -tran~-decahydroquinoline hydro~
chloride (form a) were obtained.
Yield : 54%, m.p. 158 - 160C.
By following the same method but using the appropriate
staring-product6, the compound~ listed hereunder were prepared
and their melting points obtained after recrystallization from
- the indicated solvents :
4- ~(N-phenyl-N-acetyl)-amino~ Melting Point C
l3-(4-fluorobenzoylJ-propyl~ -trans-
decahydroquinol~ne hydrochloride 168 - 170
(form a) ~ethyl acetate/methanol)
4- ~(N-phenyl-N-butyl)-amino ~-1-
~3-(4-fluorobenzoyl)-propyl ~-trans- 174 - 175
decahydroquinoline hydrochloride (ethyl acetate/methanol)
30 (form a)
4- ~(N-phenyl-N-valeryl)-amino ~-1-
~3-(4-fluorobenzoyl)-propyl~ -tran~- 158 - 160
decahydroquinoline hydrochloride (ethyl acet~ e/methanol)
(form a)
o2/
- _ ,~ _
77040
4- ~(N-phenyl-N-propionyl)-aminoJ -
1- r3-(4-fluorobenzoyl)-propyl7 -trans- 161 - 162
decahydroquinoline oxalate ` (ethyl acetate/acétone)
(form b)
4- r(N-4-methylphenyl-N-propionyl)-
amino ~ L~3-C4-fluorobenzoyl)- 201 - 203
propyl l-trans-decahydroquinoline (ethyl acetate/mathanol)
hydrochloride (form a)
4 ~(N-4-methoxyphenyl-N-propionyl)-
amino7-1- ~3-(4-fluorobenzoyl)-propyll- 193 - 195
trans-decahydroquinoline hydrochloride (ethyl acetate/methanol)
r~ a)
4- r(N-phenyl-N-acetyl)-amino~ -1-
(3-benzoylpropyl)-trans-decahydro- 227 - 228
quinollne hydrochloride (form a) (ethyl acetate/methanol)
4- r(N-phenyl-N-propionyl)_amino~ -1-
(3-benzoyl-propyl)-trans- decahydro- 128 - 130
quinoline hydrochloride (form a) (ethyl acetate/methanol)
4- r(N-phenyl-N-acetyl)-aminoJ -1-
l3-(4-methylbenzoyl)-propyl ~-trans- 185 - 186
decahydroquinoline hydrochloride (ethyl acetat2/methanol)(form a)
4- ~(N-phenyl-N-propionyl)-amino¦ -1-
l3-(4-methylbenzoyl)-propyl~ -trans- 214 - 215
: decahydroquinoline hydrochloride (ethyl acetate/methanol)
(form a)
4- r(N-phenyl-N-acetyl)-amino 1-1-
~3-(4-chlorobenzoyl)-propyl ~-trans- 193 - 194
decahydroquinoline hydrochloride (ethyl acetate/methanol)(form a)
4- [(N-phenyl-N-pro ionyl)-amino~ -1-
l3-(4-chlorobenzoyl~-propyl ~-tF.ans- 130 - 131
decahydroquinoline hydrochloride (ethyl acetate/methanol)(form a)
4- ~(N-acetyl-~-phenyl)-amino ~
l3-(4-fluorobenzoyl)-propyl 7-trans- 188 - 190
decahydroquinoline hydrochloride 4 (ethyl acetate/methanol)(form b)
- 4- [(N-benzoyl-~-phenyl)-amino 7-1-
3-(4-fluorobenzoyl)-propyl 7-trans- 139 - 141
decahydroquinoline hydrochloride (ethyl acetate/hexane)
(form a)
4- ~(N-Nicotinoyl-N-phenyl)-a~ino] -
1- [3-(4-fluorobenzoyl)-propyl~- 211 - 213
trans-decahydroquinoline dihydro- (methyl ethyl cetone/
chloride (form a) hexane~
4- r(N-Isonicotinoyl-N-phengl)_
amino~ 3-(4-fluorobenzoyl)- 213 - 215
propyl7 -tran~-decahydroquinoline (methyl ethyl cetone/
dihydrochloride (form a) hexane)
. o2
l077a40
4- L (N-2-Furoyl-~-phenyl)_amino 7 -1-
l3-(4-fluorobenzoyl)-propyl~ -trans- 230 - 231
decahydroquinoline hydrochloride (ethyl acetate/methanol)
(form a)
4- ~(N-Acetyl-N-phenyl)-amino~
l3-(4-bromobenzoyl)-propylJ -tran~- 219 - 221
decahydroquinoline hydrochlorl~~~ (ethyl acetate/methanol)
(form a)
4- ~(N-Phenyl-N-propionyl)-amino~ -1-
~3-(4-bromobenzoyl)-propyl~ -trans- 143 - 145
decahydroquinoline hydrochloride (ethyl acetate/methanol)
(form a)
4- r (N-Acetyl-N-phen l)-amino ~-1-
~3-(4-methoxybenzoyl~-propyl~ -trans- 184 - 186
decahydroquinoline hydrochloride (ethyl acetate/methanol)
(form a)
4- r ( N-Phenyl-N-propionyl)-amino] -1-
~3-(4-methoxygenzoyl)-propylJ -t~ans- 214 - 216
decahydroquinoline hydrochloride (ethyl acetate/methanol)
(form a)
4- r(N Acetyl-N-phenyl)_amino~ -1-
(4-fluorobenzoyl-methyl)-tran~- 236
decahydroquinoline hydrochloride (acetone)
(form a)
; 4- r(N-Phenyl-N-propionyl)-amino J-l
-(4-fluorobenzoyl-methyl)-tran~- 225 - 227
decahydroquinoline hydrochroride (ethyl acetate/methanol)
(form a)
4- r(~-Acetyl-N-phenyl)-amino~
benzoylmethyl-trans-decahydro- 233 - 235
quinoline hydrochloride (form a) (ethyl acetate/methanol)
4- r(N-phenyl-N-propionyl)-amino~ -1-
benzoylmethyl-trans-decahydro- 229
quinoline hydrochloride (ethyl acetate/methanol)
(form a)
4- ~(N-Acetyl-N-phenyl)-aminol -1-
~ -(4-thenoyl)-propyl J-trans- 205 - 207
decahydroquinoline hydrochloride (ethyl acetate/methanol)
(form a)
4- r(N-Phenyl-N-propionyl)-aminoJ -1-
-(2-thenoyl)-propyl~ -trans- 111 - 113
decahydroquinoline hydrochloride (acetone)
(form a)
4- ~(N-Acet l-N-4-methoxyphenyl)-
amino7~ 3-(4-chlorobenzoyl)- 193 - 195
propyl ~-trans-decahydroquinoline (ethyl ~cetate/methanol)
hydrochloride (form a)
30 4- l(N-4-Methoxyphenyl-N-propionyl)-
amino~ 3(4-chlorobenzoyl)- 213 - 215
propyl~ -trans-decahydroquinoline (acetone)
hydrochloride (form a)
. _ ,~ _
-
~ . .
1077040
4- ~(N-Acetyl-N-phenyl)-amino~ -1-
~4-(4-fluorobenzoyl)-butyl-trans- 212 - 214
decahydroquinoline hydrochloride (acetone)
(form a)
4- ~(N-Phenyl-N-pro ionyl)-amino~
~4-(4-fluorobenzoyl~-butyl 7 -trans- 162 - 164
decahydroquinoline hydrochloride (ethyl acetate)
(form a)
4- r(N-Acetyl-N-phenyl)-amino~-l-
benzyl-tranq-decahydroquinoline 180 - 182
hydroch~ e (form a) (ethyl acetate)
4- ~(N-Phenyl-N-propionyl)-amino~ -1-
benzyl-trans-decahydroquinoline 198 - 200
hydrochloride (form a) (ethyl acetate/methanol)
4- ~(N-Acetyl-N-phenyl)-amino ~-1-
phenethyl-trans-decahydroquinoline 232 - 234
hydrochloride (form a~ (ethyl acetate/methanol)
4- ~(N-Phenyl-N-propionyl)-amino~-l-
phenethyl-trans-decahydroquinoline 231 - 233
hydrochloride (form a) (ethyl acetate/methanol)
4- r(N-Acetyl-N-phenyl)-amino~ -1-
(3-phenylpropyl)-trans-decahydro- 196 - 198
quinoline hydrochloride (form a) (ethyl acetate/methanol)
4- t(N-Phenyl-N-propionyl)-amino J -1-
(3-phenylpropyl)-trans-decahydro- 210 - 212
quinoline hydrochloride (form a) (ethyl acetate/methanol)
4- ~(N-Acetyl-N-~henyl-amino] -1-
cinnamyl-trans-decahydroquinoline 136 - 138
(form a) (heptane)
4- ~(N-Benzyl-N-propionyl)-amino ~-1-
~3-(4-fluorobenzoyl)-propyl~ -trans- 147 - 149
decahydroquinoline hydrochloride (ethyl acetate/diethyl
(form a) ether)
4- ~(N-l-Naphthyl-N-propionyl)-
amino7 -1- ~3-(4~1uorobenzoyl)- 122 - 124
propyl~ -trans-decahydroquinoline ~ethyl acetate/methanol)
hydrochloride (form b)
- 4- ~(N-Cyclohexyl-N-propionyl)-
amino.~ 3-(4-fluorobenzoyl)- 154 - 156
propylJ -trans-decahydroquinoline (ethy~ a,ceta~e/methanol)
hydrochloride (form a)
4- ~(N-Cyclohexyl-N-propionyl)-
amino,~ 3-(4-fluorobenzoyl)- 178 - 180
propyl~ -trans-decahydroquinoline (ethyl acetate/methanol)
ae.id oxalate ~form b)
4- ~(N-Phenyl-N-acetyl)-amino~ -1-
~3-(4-fluorobenzoyl)-propylJ -trans 158 - 160
decahydroquinoline hydrochloride (ethyl acetate/methanol)
(form a)
~ 2
1077040
4- ~(N-Phenyl-N-pro i onyl ) -amin o 7
-1-(2-phenoxy-ethyl~-trans-decahydro- 159 - 161
quinoline hydrochloride ~form a) (ethyl acetate/methanol
4- ~(N-Phenyl-N-propionyl)-amino~ -1-
~3 -(4-fluoro-phenylthio)-propyl~ 120 - 122
-trans-decahydroquinoline hydro- (ethyl acetate/methanol)
chloride (form a)
4- C(N-Acetyl-N-phenyl)-amino~ -1-
~3-(4-fluoro-phenylthio)-propyl-7 150 - 152
trans-decahydroquinoline hydro- ~ ( ethyl acetate/methanol)
chloride ( fonn a )
EXAMP~E 2
4-~(~-Phenyl-N-propionyl)-amino~ -1- ~3-(4-fluorobenzoyl)-propyl
-trans-decahydroquinoline hydrochloride (form a)
3~94 g. (0,085 mol) of 1- ~(4-fluorobenzoyl)-propyl~
-4-phenylamino-trans-decahydroquinoline hydrochloride (form a),
prepared as in Example 1 were dissolved in 20 ml. of dimethyl-
formamide and 3.5 ml. of propionylchloride were added to the
solution.
The mixture was heated to 60 - 80C. for 40 hours and
5 ml. of methanol were added.
The reaction medium was distilled at 80C. under vacuum
until 12 ml. of the solution had distilled and the residue was
poured into diluted sodium hydroxide. The reaction medium wa~
extracted with diethyl ether and the organic solution was washed
with water and treated with active charcoal. The solvent was
eliminated end the residue was dissolved in 150 ml. of acetone
at the reflux temperature of the solvent. A solution of 2-propanol
containing a small qua~tity of gaseous hydrochloric acid was added
and the resulting solution was allowed to crystallize at room-
temperature. The precipitate obtained was filtered off, washed
with acetone and dried to give 318 g. of crude product. After
recrystallization from a mixture of ethyl acetate/methanol
(2:1 by volume), 263 g. of 4- ~(~-phenyl-N-propionyl)-amino~
r3-(4-fluorobenzoyl)-propyl~ -tran~-decahydroquinoline hydro-
chloride (form a) were obtained.
_ ,~_
~07704V
Yield : 65.1%, m.p. 158 - 160C.
EXAMPLE 3
4- ~t~-PhenYl-~-propionyl)-amino7 -1- f3-(4-fluorobenzo~l)
propyl~ -trans-decahydroquinoline hydrochloride (form a)
A solution containing 6 g. (0.015 mol) of 1- ~3-(4-
fluorobenzoyl)-propyl~ -4-phenylamino-trans-decahydroquinoline
(form a), prepared as in Exa~ple 1, 45 ml. of propionic anhydride
and trace of ~-toluene-sulphonic acid was heated to 100C. for
20 hours. After cooling methanol was added and the 3ame method
as described in Example 1 (c) was followed to give 4.5 g. of
4- r(~-phenyl)-N-propionyl~ -amino~ 3-(4-fluorobenzoyl)-
propyl~ -trans-decahydroquinoline hydrochloride (~orm a).
Yield : 61.6 %, m.p. 158 - 160C.
EXAMP~E 4
4- ~(N-Phenyl-~-propionyl)-amino~ 3-(4-fluorobenzoyl)-
prop~l~-trans-decahydroquinoline methanesulfonate (form a)
A eolution of benzene containing 98 g. (0.22 mol) of
4- ~(N-phenyl-N-propionyl)-amino~ -1-[3-(4_fluorobenzoyl)-propyl]
-trans-decahydroquinoline (form a), prepared a~ in Example 1, was
acidified by 30 g. of a 69.5% aqueous solution of methanesulfonic
acid containing 2-propanol, until a pH of 3.5-4 was obtained.
~he acid ~olution was evaporated to dryness and taken
up in 600 ml. of toluene. By azeotropic distillation 100 ml.
of toluene was eliminated and, after crystallization and filtra-
- tion, 104 g. of 4- ~(N-phenyl-N-propionyl)-amino ~-1- ~3-(4-
fluorobenzoyl)-propyl~ -tran3-decahydroquinoline methanesulfonate
(form a) were obtained. Yield : 88~, m.p. ; 132 - 134C.
EXAMP~E 5
4- ~(N-Phenyl-~-propionyl)-aminoJ -1- ~4-(4-fluorophe~yl)-4-
hydrazonobutyl~ -tran~-decahydroquinoline (form a)
A solution containing 2.5 ml. of hydrazine hydrate in
15 ml. of ethanol was mixed with 3.6 g. (0.008 mol) of 4-
B~ ~
107~7040
~(N-phenyl-~-propionyl)-amino ~-1- r3-(4-fluorobenzoyl)-propyl~
-trans-decahydroquinoline (form a) and the mixture was refluxed
for 3 hours. The solution was concentrated and the residue was
poured into 100 ml. of water. The precipitate which formed was
filtered off, washed with water and dried.
~ he substance was recry~tallized from 2-propanol to
give 4- [(N-phenyl-N-propionyl)-amino~ -1- r4-(4-fluorophenyl)-
4-hydrazonobutyl7 -trans-decahydroquinoline (form a).
Yield : 84%, m.p. : 155 - 156C.
EXEMPLE 6
4- L (~-Phenyl-N-Prop on~l)-amino 7-1- r4 ( 4-fluorophen~1)-4-
h~droxyiminobutyl~ -trans-decahydroquinoline (form a)
5 g. (0.011 mol) of 4- ~(N-phenyl-~-propionyl)-amin~
-1- ~3-(4-fluorobenzoyl)-propyl~ -tran~-decahydroquinoline,
prepared as in Example 1, were dissol~ed in 100 ml. of ethanol
and a solution of 3.5 g. of hydroxylamine hydrochloride in 25 ml.
of water and 7 g. of sodium hydrogenocarbonate were added. ~he
reaction medium was refluxed for 12 hours and was concentrated
under vacuum. The residue was poured into wator and the precipi-
tate which formed was filtered off, ~ashed with water and dried.
Recry~tallization from 2-propanol gave 2.5 g. of 4- ~N-phenyl-
N-propionyl)-amino~ -1- r4-(4-fluorophenyl-4-hydroxyimino-butylJ
-trans-decahydroquinoline (form a).
Yield : 48~, m.p. : about 80C.
- EXAMPLE 7
55 g. (0.14 mol) of 1- ~3-(4-fluorobenzoyl)-propylJ
-4-phenylamino-trans-decahydroquinoline, prepared as in Example 1,
were dissolved in 200 ml. of dichloroethane, While stirring,
16 g. of ethyl chloroformiate were added drop-by-drop and the
medium was heated to 50 - 60~C. for 16 hours. The reaction medium
was cooled to 20C. and a soiution of gaseous hydrochloric acid
in 2-propanol was added. S~irring was continued for between 2 and
~1
~ ;, '1 _ ,~_
_~ .
1077040
and 3 minutes, the mixture was evaporated to drynes~ and the
re~idue wa~ taken up in acetone.
me reaction medium wa~ cooled to 0C. for 16 hour~ and the
excess of 1- L3-(4-fluorobenzoyl)-propyl J-4-phenylamino-trans-
decahydroquinoline wa~ removed by filtration. The filtrate was
evaporated to dryness and the re3idue was taken up in ethyl
acetate.
The organic ~olution wa~ cooled to 0C. for 16 hour~ and
4- ¦(N-carbethoxy-~-phenyl)-amino~ 3-(4-fluorobenzoyl)-
propylJ -tran~-decahydroquinoline hydrochloride (for~ 2) crystal-
-
lized and wa~ filtered off and recry~tallized from ethyl acetate/
m2thanol.
Yield : 31%, m.p. : 134 - 136C.
By following the ~ame method but using the appropriate
starting-products, the compoundQ li3ted hereunder were prepared:
Compound Melting Point C.
4- ~(N-carbophenoxy-N-phenyl)-aminoJ-
1- r ( 3-(4-fluorobenzoyl)-propyl J - 185 - 187
trans-decahydroquinoline hydro- (ethyl acetate)
chloride (form a)
4- ~;N-carbomethoxy-N-phenyl)-amino~-
1- ~3-(4-fluorobenzoyl)-propyl~ - 194 - 196
trans-decahydroquinoline hydro- (ethyl acetate)
chloride ( f orm a)
4-r(N-Carbo-sec-butoxy-N-phenyl)-
aminoJ-l- r 3-(4-f luorobenzoyl)- 178 - 180
propyl~ -trans- decahydroquinoline (ethyl acetate)
hydrochloride (form a)
4- ~(N-Carbo-n-butoxy-N-phenyl)-
- amino ~ -1- t 3-(4-fluorobenzoyl)- 181 - 183
propyl~ trans-decahydroquinoline (ethyl acetate)
hydrochloride (form a)
4- ~(N-2-methoxy-carbethoxy-N-phenyl)
-amino] -1- ~ 3-( 4-fluorobenzoyl)- 159 - 161
propyl~ -trans-decahydroquinoline (ethyl acetate)
hydrochloride (form a)
4- ~(N-carbethoxy-N-phenyl)-amino~
-l-phenethyl-trans-decahydro- 191 - 193
quinoline hydrochloride (form a) (ethyl acetate~methanol)
EXAMPLE 8
Soft-gelatin capsules containing the following
1~ ~ ~2
~40
ingredients were prepared in accordance with well-known pharma-
ceutical techniques :
Inaredients Weiqht
4- ~(N-phenyl-N-acetyl)-amino~ -1- (1) (2)
~3-(4-fluorobenzoyl)-propyl~ -trans-
decahydroquinoline hydrochloride 25 mg. 50 mg.
Corn-starch 194.3 mg. 259.5 mg.
Colloidal-silica 0.7 mg. 0.5 mg.
225. mg. 260 mg.
EXAMPLE 9
An injectable solution containing the following
ingredients was prepared in accordance with well-known pharma-
ceutical techniques :
Inqredients Weight
4- r (N-phenyl-N-acetyl)-amino~ -1-
~3-(4-fluorobenzoyl)-propyl~ -trans
decahydroquinoline hydrochloride 60 mg.
sorbitol 187 mg.
water q.s. 5 ml.
_ ~ _
'
1077040
~ . . '.
1 ) 4-phenylamino-trans-decahydroquinoline (form a)
2) 4-phenylamino-trans-dccahydroquinoline (form b)
. . .
~''~ . .
