CA1077040A - Pharmaceutically active decahydroquinoline derivatives - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE:

The invention relates to decahydroquinoline derivatives represented by the general formula:

(I) and the pharmaceutically acceptable acid addition salts thereof, wherein R1 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:

(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 when 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. Certain compounds of formula (I) have been found to possess useful analgesic properties while others have been found to be potentially useful in the treatment of high blood pressure.

Description

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

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:

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

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 . ', `,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 _ .~ ",~

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 ~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 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
~ ? ~_ 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 "
_...

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 ,~

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~).

~: .

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 :

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 ~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 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/
- _ ,~ _ 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) . _ ,~ _ -~ . .

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 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.

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.

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.

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 _ ,~_ _~ .

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) 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.

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.

_ ~ _ ' ~ . . '.

1 ) 4-phenylamino-trans-decahydroquinoline (form a) 2) 4-phenylamino-trans-dccahydroquinoline (form b) . . .
~''~ . .

Claims (10)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A process for the preparation of decahydro-quinoline derivatives having the general formula:

(I) and the pharmaceutically acceptable acid addition salts thereof, wherein R1 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:

(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 all integer of from 1 to 4, with the proviso that when n is zero, Y is a carbonyl group, and R4 and R5 which are identical or different each represents an atom of hydrogen or halogen or a methyl or methoxy group, which comprises:

a) refluxing a compound of the general formula:

(III) wherein R2 and R3 have the aforesaid meanings, with a compound of the general formula:

(IV) wherein R1 has the aforesaid meanings, to obtain a compound of the above formula (I), and b) where a pharmaceutically acceptable acid addition salt thereof is desired, reacting the compound of formula (I) thus obtained with a pharmaceutically acceptable organic or inorganic acid to provide the desired salt.

2. Process according to claim 1, wherein the compound of formula (III) is refluxed in an inert organic solvent.

3. Process according to claim 2, wherein the solvent is selected from the group consisting of dichloroethane, methylene-chloride, benzene and toluene.

4. Process according to claim 1, wherein the compound of formula (III) is refluxed in the presence of a base.

5. Process according to claim 4, wherein the base is selected from the group consisting of triethylamine, trimethylamine and pyridine.

6. Process according to claim 1, which comprises refluxing l-[3-(4-fluorobenzoyl)-propyl]-4-phenylamino-trans-decahydroquinoline with acetyl chloride to obtain 4-[(N-phenyl-N-acetyl)-amino]-1-[3-(4-fluorobenzoyl)-propyl]-trans-decahydroquino-line and, where a pharmaceutically acceptable acid addition salt thereof is desired, reacting the compound thus obtained with a pharmaceutically acceptable organic or inorganic acid to provide the desired salt.

7. Process according to claim 1, which comprises refluxing l-[3-(4-fluorobenzoyl)-propyl]-4-phenylamino-trans-decahydroquinoline with ethyl chloroformiate to obtain 4-[(N-phenyl-N-carbethoxy)-amino]-1-[3-(4-fluorobenzoyl)-propyl]-trans-decahydroquinoline and, where a pharmaceutically acceptable acid addition salt thereof is desired, reacting the compound thus obtained with a pharmaceutically acceptable organic or inorganic acid to provide the desired salt.

8. The decahydroquinoline derivatives having the general formula:

(I) and the pharmaceutically acceptable acid addition salts thereof, wherein R1 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; R 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:

(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 when n is zero, Y is a carbonyl group, and R4 and R5 which are identical or different each represents an atom of hydrogen or halogen or a methyl or methoxy group, whenever obtained by a process according to claims 1, 2 or 4, or their obvious chemical equivalents.

9. 4-[(N-Phenyl-N-acetyl)-amino]-1-[3-(4-fluorobenzoyl)-propyl]-trans-decahydroquinoline and the pharmaceutically acceptable acid addition salts thereof, whenever obtained by a process according to claim 6 or its obvious chemical equivalents.

10. 4-[(N-Phenyl-N-carbethoxy)-amino]-1-[3-(4-fluoro-benzoyl)-propyl]-trans-decahydroquinoline and the pharmaceutically acceptable acid addition salts thereof, whenever obtained by a process according to claim 7 or its obvious chemical equivalents.