IE44355B1 - 4-amino-trans-decahydroquinoline derivatives - Google Patents

Abstract

1515540 4 - Amino - trans - decahydroquinoline derivatives LABAZ 24 Nov 1976 [16 Dec 1975] 51507/75 Heading C2C Novel trans decahydroquinoline derivatives of the Formula I and pharmaceutically acceptable acid addition salts thereof, wherein R1 is alkyl, alkoxy, dialkylamino, a saturated heterocyclic ring attached through a ring nitrogen atom, an unsaturated heterocyclic group or an optionally substituted phenyl, R2 is alkyl, optionally substituted phenyl, naphthyl, unsaturated heterocyclic optionally substituted by alkyl, aralkyl, aralkenyl or alicyclic and R3 is alkyl substituted furyl, aralkyl, aralkenyl or a group where A is C 1-4 -alkylene, Y is oxygen, sulphur, carbonyl > C = NOH, >C = NNH 2 or sulphoxide or a group X R4 and R5 each are hydrogen, halogen, methyl, methoxy or acetyl and n is zero or 1, with the proviso that when n is zero, Y is carbonyl, where alkyl groups unless otherwise specified have 1 to 4 carbon atoms, may be prepared, when R 1 is other than dialkylamino or saturated heterocyclic group attached by a ring nitrogen atom and when R3 is a group II, Y is other than hydroxyiminomethylene or hydrazonomethylene by reacting a compound III with R1COCl or (R1CO) 2 O or when R1 is dialkylamino or a saturated heterocyclic group attached by a ring nitrogen atom, and when R3 is a group II, Y is other than hydroxyiminomethylone or hydrazonomethylene by reacting a compound VI with an amine R1H, optionally followed by acid addition salt formation and/or reacting a carbonyl at Y with hydroxylamine or hydrazine to form a hydroxylimino methylene or a carbonyl hydrazonomethylene. Intermediates of the Formula III are prepared by reacting 4-oxo-trans-decahydroquinoline with an amine R2NH 2 and reducing the imine so formed to produce a compound VIII which is reacted with R3-Hal, where Hal is chlorine, bromine or iodine. When R3 is a group II and Y is carbonyl, the carbonyl group is protected with a group X and thereafter optionally hydrolysed. The isomers of the compound VIII are separated. Pharmaceutical compositions of the compounds I with the usual excipients show analgesic activity when administered orally, parenterally or rectally. The compounds I in which R1 is alkoxy also show antihypertensive action.

Description

This invention relates to b-amino-trans-decahydroquinoline derivatives, with processes for preparing these derivatives and with pharmaceutical compositions containing them.

The b-amino-trans-decahydroquinoline derivatives with 5 which the present invention is concerned are those represented by the general formula: H 2 R —-C—if—fi •25 K3 and the pharmaceutically acceptable acid addition salts thereof, wherein R1 represents a branched- or straight-chain alkyl or alkoxy group containing from I to b carbon atoms; a dialkylamino group in which the alkyl groups each contain.from 1 to b carbon atoms, such as dimethylamino; a saturated heterocyclic group attached by a ring nitrogen atom such as pyrrolidino, piperidino or morpholino; an optionally substituted phenyl group; or an unsaturated 2 heterocyclic group such as furyl or pyridyl; R represents a.. branched- or straight-chain alkyl group containing from 1 to b carbon atoms; an optionally substituted phenyl group; a naphthyl group; an unsaturated heterocyclic group optionally substituted by a alkyl radical such as pyridyl, thienyl, methylthienyl, furyl or pyrimidyl; an aralkyl or aralkenyl group such as benzyl, phenethyl, cinnamyl or phenylpropyl; or an alicyclic group such as 3 cyclohexyl; and R represents a alkyl substituted furyl group such as 2-metbylfuryl; an aralkyl or aralkenyl group such as benzyl, phenethyl, cinnamyl or phenylpropyl; or a group represented by the general formula: wherein A represents a branched- or straight-chain alkylene group containing from 1 to b carbon atoms; Y represents an oxygen or sulphur atom, a carbonyl, hydroxyiminomethylene, hydrazonomethylene or sulphoxide group, or a group: - 2 4 5. .

R and Β , which are identical or different, each represent hydrogen, a halogen atom, for example, fluorine, chlorine or bromine, or a methyl, methoxy or acetyl group; and n is 0 or 1 with the proviso that when n is 0, Y represents a carbonyl group.

The compounds of formula I in which R^ represents an alkyl or alkoxy group as hereinbefore defined,an optionally substituted phenyl group, or an unsaturated heterocyclic group and in which when R represents a group of formula II, Y does not represent a hydroxyiminomethylene or hydrazonomethylene group, may be prepared by refluxing a 1-substituted 4-amico-trans-decahydroquinoline having the general formula: 3 wherein R and E have the same meanings as m formula I with the 3 proviso that when R represents a group of formula II, Y does not represent a hydroxyiminomethylene or hydrazonomethylene group, preferably in an inert organic solvent such as, for example, dichloroethane, methylene chloride, benzene or toluene, with a compound of the general formula: bJL wherein R^ has the meanings specified hereabove, optionally in the presence of a base such as, for example, triethylamine, trimethylamine or pyridine.

The compounds of formula I in which R1 represents an alkyl, optionally substituted phenyl or unsaturated heterocyclic group may alternatively be prepared by refluxing a compound of general formula III, preferably in an inert organic solvent such as, for example, dichloroethane, methylene chloride, benzene or toluene, with a compound of the general formula: wherein R^ has the meanings specified hereabove, optionally in the presence of an acid such as, for example, jr-toluene-sulphonie acid or sulphuric acid.

The compounds of formula I in which R^ represents a - 3 44355 dialkylamino group as hereinbefore defined or a saturated • . 3 heterocyclic group and in which when R represents a group of formula II, Y does not represent a hydroxyiminomethylene or hydrazonomethylene group, may be prepared by reacting a compound of formula III, preferably in an inert organic solvent such as, for example toluene, with phosgene, optionally in the presence of a base such as, for example, triethylamine, trimethylamine or pyridine, to give a compound of the general formula: VI R3 . 2 3 . . . wherein R and R have the same meanings as m formula I with the proviso that when R represents a group of formula II, Y does not represent a hydroxyiminomethylene or hydrazonomethylene group, and thereafter reacting the compound of formula VI, preferably in an inert organic solvent such as, for example,benzene, with an appropriate amine of the general formula R^H (VII) wherein R^ has the meanings specified hereabove.

The compounds of formula I can be converted into the corresponding pharmaceutically acceptable acid addition salt by treatment with an appropriate acid, in accordance with techniques well known in the art.

The compounds of formula III may be prepared by reacting a b-amino-trans-decahydroquinoline of the general formula: HN —R2 wherein R has the same meanings as in formula I, with a halogenated *5 compound of the general formula Hal—F. (IX) wherein Hal represents . . . . 3 an atom of chlorine, bromine or iodine and R has the same meanings as in formula I. This reaction is preferably carried out in a liquid medium which may be an inert organic solvent such as, for example, benzene, toluene, xylene, dicbloroethane 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 - b 44355 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, is preferably carried out at the reflux temperature of the liquid medium.

The compounds of formula IX are already known while the compounds of formula VIII may be prepared by reacting the known compound 4-oxo-trans-decahydroquinoline, in the presence of a catalyst such as, for example, g-toluenesulphonic acid, trifluoroboron etherate, zinc chloride or titanium tetrachloride, preferably in an inert organic solvent such as, for example, hexane, benzene, benzene or toluene and at the reflux temperature of the solvent, with an amine of the general formula: R2-NH2 x wherein R has the same meanings as in formula I, the water formed being eliminated by azeotropic distillation. The imino derivative which is obtained is hydrogenated by means of sodium horohydride 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 formula VIII 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 is 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 4.3 SB with the soluble fraction. In view of this, the term form a will hereinafter be used to designate that compound represented by formula VIII of which Rf in the chosen assay of thin-layer chromatography is smaller than that of the corresponding isomeric compound of formula VIII 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: Silica gel 60 F.254 (produced by MERCK) Thickness : 0.25 mm.

Development and saturation solvent (in ammonia atmosphere) Hexane : 80 ml. 2-Propanol : 20 ml.

Technique : ascending 13 cm.

Deposits : 200 pg. (chloroform solution) Revealing : U.V. at 2,540 S in iodine vapour (1) 4-phenylamino-trans-decahydroquinoline (form a) (2) 4-phenylamino-trans-decahydroquinoline (form b) The 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 VIII. Consequently, the above-described process for obtaining the derivatives of formula I using derivatives of formula VIII as starting-products is equally applicable to either form a or form b of the derivatives of formula VIII for the preparation of the corresponding isomers of formula 1.

The compounds of the invention have been found to possess valuable pharmacological properties and, in particular, at least 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. 443 5 5 Thus the invention induces within its scope a method of relieving pain in a non-human subject in need of such trs&imsnt by administering to the subject an effective amount of at least one compound of formula I or of a pharmaceutically aceptable acid addition salt thereof.

Analgesics are agents which relieve pain by acting centrally to elevate the pain threshold without disturbing consciousness or altering other sensory conditions.

Agents which are used principally for the symptomatic relief of pain may, for convenience of classification, be divided into two general groups: 1) Narcotic analgesics, such as the opium derivatives Amongst these, morphine is one of the most important drugs and possesses numerous useful properties, analgesia being one of its main activities.

No other drugs are so generally useful in relieving various categories of severe pain, Unfortunately, morphine causes euphoria and addiction and it depresses respiration.

If morphine, or a related compound, is given over a long period of time, tolerance to the analgesic effect develops so that the dose must be increased periodically to obtain equivalent pain relief. For these reasons, it is generally agreed that morphine and its derivatives should not be used for pain when some other analgesic will suffice.

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 derivatives. 2) Nonynarcotic_anal2esics_such_asi_for_examgleti, „the These are generally less active than the narcotic analgesics but, on the other hand, they do not depress respiration and do not cause any or only very slight addiction.

It will be seen that the analgesic compounds of the 44335 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 pressure.

A further object of the invention is therefore a method of treating pathological disorders of arterial pressure and, in particular, hypertension in a non-human subject in need of such treatment by administering to the said subject at least one compound of formula I or a pharmaceutically acceptable acid addition salt thereof.

There are numerous types of hypertension but no universal remedy is at present know which is capable of combating these different types of disease, individual cases varying widely as regards their response to various drugs.

There are therefore many antihypertensive agents which are used to treat the different types of hypertension.

Amongst them, some 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 therapeutic and toxic doses.

Finally, it is known that certain antihypertensive agents 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 view to demonstrating either the analgesic action or the antihypertensive effects of the compounds of the Invention.

I 1) Analgesic action The following compounds of the invention were found to be particularly useful as analgesics: 4 3 3 5 4-[(N-phenyl-N-acetyl)-amino3-l-C3-(4-fluorobenzoyl)-propyljtrans-decahydroguinoline (Compound A). 4-Γ(N-phenyl-N-propionyl)-aminoJ-l-i'3-(4-fluorobenzoyl)-propyl ’ trans-decahydroquinoline (Compound B). 4-Γ(N-phenyl-N-butyryl)-aminoJ-1-C3-(4-fluorobenzoyl)-propyljtrans-decahydroguinoline (Compound C). 4-L(N-phenyl-N-valeryl)-amino3-l“C3-(4-fluorobenzoyl)-propylljtrans-decahydroquinoline (Compound D). 4-L(N-4-methoxyphenyl-N-propionyl)-amino ZJ-1-C3-(4-fluorobenzoyl propyIj-trans-decahydroguinoline (Compound E).

The first test was carried out according to the technique of KOSTER (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 of characteristic contortions made by the animals was noted. The absence of contortions corresponds to animals under the influence of analgesia.

Note was taken of the AD50, i.e. the dose of the compound under study which provoked analgesia in half of the animals treated.

The results of this test are given in the following Table: TABLE 1 : ’Compound : AD50 mg/kg A : 38 B 25 C : 30 D : 25 E 55 The same test was carried out with five commonly used analgesics and the following results were obtained: TABLE Xl : Compound : AD50 mg/kg : : Acetylsalicylic acid · 150 : : Antipyrine 120 : Phenacetine 160 : Glafenine 110 : Pentazocine 45 The second test was carried out according to the technique of NILSEN (Acta Pharmacol, et toxicol. IB,10, 1961) on batches of 10 mice.

The animals were connected to a source of electric current by means of two electrodes inserted into the tail.

The throshold-voltage vac then determined, i.e, the minimum voltage which, in the cource 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 intragastric route.

At various times after administration, 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 wae taken of tho dose of compound (AD50) which suppressed the squeak in half of the treated animals.

The results of this test are givon in the following Table : TABLE III : Compound : AD50 mg/kg : : A ; 110 : S • 50 : : c : 70 : The same test waG also carried out with threo well-known analgesics and the following results were obtained : TABLE IV Compound ADJ50 mg/kg : Acetylsalicylic : • • acid Antipyrine 1100 b00 : Phenacetine : b50 ! Further pharmacological tests were carried out with a view to determining the analgesic action of the preferred compound of the invention, namely : b-[(N~phenyl~N-propionyl)-amino3-1-[3-(b-fluorobcnzoyl)-propylDtrans-decohydroquinoline (Compound B).

The first test was carried out according to the technique of KOSTER described above but using a sub-cutaneous injection of tho product to be tested, Compound B was compared to two'major analgesics and the following results were obtained : TABLE V ί Compound s AD50 mg/kg • : B : 2 « : Pethidine : 7 β : Pentazocine : 5 : The second test was carried out according to the technique of NILSEN described above but using a sub-cutaneous injection of the compound to be tested.

Compound B was compared to pethidine and pentazocine, two well-known analgesics, and the following results were obtained : TABLE VI Compound : AD50 mg/kg s B 4 : . Pethidine : 7 β Pentazocine s 12 : The third test was carried out according to the technique of 5IEGMUND and al (Proc. Soc. Exp. Biol. Med. 95, 729, 1957) on batches of 10 male mice.

A typical syndrome was produced in the animals by intraperitoneal injection of 0.25 ml. of a 0.02^ aqueous solution of 2-phenyl-1,4benzoquinone (phenylbenzoquinone).

The syndrome in question is characterized hy intermittent contractions of the abdomen, twisting and turning of the trunk and extension of the hind legs. Note was taken of the number of movements occurring over a period of 30 minutes starting 15 minutes after the injection of phenylbenzoquinone.

The compound to he tested was injected 30 minutes before the phenylbenzoquinone in such a way that each batch received a higher dose 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 : TABLE VII Compound AD50 mg/kg : B 7 : Acetylsalicylie 50 • • acid Antipyrine 100 : Phenacetinc 80 Glafenine 325 : io The fourth tost was carried out according to the technique of CHARLIER and al (Arch. int. Pharmacodyn. 306, 1961) on batches of 10 rats.

The animals were connected to a source of electric current by 15 means of two electrodes of which one was attached to the tail and the other maintained in the rectum.

The pain-threshold voltage was then determined for each rat by passing a current of 2 volts and increasing tho current by one volt at a time until the animal gave a squeal:. This control test was repeated three times at intervals of 15 minutes. The 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 FLATAICER scale (J.Pharmacol. Exp. Therap. 98, 505, 1950) and the AD's 50 obtained are listed in the Table given hereunder : TABLE VIII Compound : AD50 mG/kg : 30 B ! 30 Acetylsalicylie s acid 1500 Antipyrine : 500 : Phenacetinc : 750 ! 43 55 5θ : Pethidine Finally, a tect was carried out according to tho technique of D’AMOUE and SMITH (J. Pliarm. Exp. Ther. 72, ?k, 19^1) on batches of 10 male rats weighing about 200 g.

A JOO-vzatt heating-bulb was focused on the tip of tho rat’s tail at such a distance that a typical twitch of tho tail (flick-tail) was obtained after A to 6 seconds of irradiation.

The animals, with the exception of a control batch, were given 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 of 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 : TABLE IX : Compound t AD50 mg/kg s : B • 2.5 • Pethidine : 5.5 : : Pentazocine : 5 : From the above tests, it may be concluded that the compounds of the invention possess analgesic properties vzhich are far superior to those of vzell-known analgesics. 2) Antihypertensive action The compoundsof formula I wherein e’’ represents a branched- or straight-chain alkoxy group have been found to possess a useful antihypertensive action capable of rendering them of considerable value in the treatment of human hypertension.

As far as the treatment of hypertension is concerned, the preferred compound of the invention is : i(-[(N-phenyl-N-carbethoxy)-amino3-1-C2-(4-fluorobenzoyl)-propyl3trans-decahydroquinoline (Compound F).

A pharmacological test whg undertaken with a view to demonstrating the antihypertensive action of Compound F.

This test was carried out on male rate belonging to a strain which haG been specially bred to’ produce animals having high blood pressure, according to the technique of OKAMOTO and AOKI (Jap. Circul.

J. 2£, 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 scries. In the first series, one single dose of the compound under study was administered by intragastric route to each animal and the arterial pressure of the latter was measured every hour for six hours after administration.

In the second series, the product under study was given by the same route every day for eleven 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 series of tests was concerned.

The following results were obtained : TABLE X Type of treatment Dose mg/kg Max. fall in A.P. (mm.Hg) Moment of max fall in A.F. Single dose 5 27 3 hours 10 44 4 hours Daily dose (eleven days) 10 29 8 days From these results, it may be concluded that Compound F has a powerful antihypertensive action. 3) Acute toxicity Acute toxicity trials were carried out on rats and mice which were kept under observation for 12 days following one single administration.

The following results were obtained : a) Compound B 4435® : Animals : Administration : LD50 (mg/kg) : : Mice : intragastric : 500 ! : Rats : intragastric : 550 ; : Mice : intrap eri toncal : .55 : : Rato : intraperitoneal s 55 : : Mice : sub-cutaneous : 550 : b) Compound F : Animals : Administration ί 1D50 (mg/kg) : ! Mice : intragastric : 750 : : Rats : intragastric : 450 : : Rats : intravenous : 15 ! : Mice : intravenous 52 ! These figures compare very favourably with the active doses of which the effects are described above and show that there is 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 principle at least one compound of formula I or a pharmaceutically acceptable acid addition salt thereof in association with a 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 rectal administration.

Irrespective of the form which the composition takes, the pharmaceutical composition will normally comprise at least one of the compounds of formula I or a pharmaceutically acceptable acid addition salt thereof associated with an appropriate pharmaceutical diluent or excipient comprising, for example, one or more of the following substances : milk, sugar, starches, talc, magnesium stearate, polyvinylpyrrolidone, alginic acid, colloidal silica or flavouring agent.

Tho following Examples illustrate tho invention.

EXAMPLE 1 4-r(W-phcnyl-N-propionyl)-amino3-1-C3-(4-fluorobcnzoyl)-propyl]trans-dccahydroquinolino hydrochloride (form a) a) Preparation of 4-phonylranino-trnnG-decahydroquinoline A eolution of 76.8 g. ( 0.5 mol) of 4-oxo-trans-decahydroquinoline and 1.0 g. of jx-toluencculphonic acid in 250 ml. of hexane was refluxed in a one-litre flask and 46,2 6. (0.5 mol) of aniline were added, Refluxing was continued until the water which formed was completely eliminated by meane 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 reaction medium was firstly washed with water, then with a diluted solution 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-decahydroquxnoline (yield : 89%).

In a one-litre flask were dissolved the 102,4 g. of 4-phenylimino20 trans-decahydroquinoline so obtained in 190 ml. of methanol containing 200 mg. of sodium hydroxide, the temperature of the solution being maintained at about 20eC, A solution of 20 g. of sodium borohydride in 200 ml. of methanol, stabilized by 600 mg. of sodium hydroxide, was added following which the temperature of the reaction medium was maintained between 20 and 22°C. for a few hours.

The solution was finally heated to 40°C. 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 benzene. The organic phase was then extracted with 240 ml. of 4H hydrochloric acid. The mixture was decanted and sodium hydroxide was added until a pH of 2 was obtained. Filtration was effected to obtain an aqueous acid filtrate and· a precipitate which was dried so as to give 42.8 g, of 4-phenyIamino~tmns-dC!cahydronuinoline hydrochloride (form a).

Yield : 225!, m.p. 265 - 270’C. 43 S S Isolation of form b The aqueous acid filtrate waa made alkaline by adding sodium hydroxide and was extracted 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 so formed was cooled to a temperatute between 0 and 5°C., filtered and washed with diethyl ether to give 9.2 g. of 4-phenylamlno-trgnsdecahydroquinoline (form b), Yield s 7%, m.p. 118 - 120°C.

By following the same method but using the appropriate startingproducts, the compounds listed hereunder were prepared : Compound Molting Point °C, k-(4-methylphenyl)-amino-transdecahydroquinolihe 92 - 94 4-(4-methoxyphenyl)-amino-transd.ecahydroquinoline 144 - 145 4-benz.Ylamino-trans-decahydroquinoline uncrystallized 4-(1-naphthyl)-amino-transdecahydroquinoline uncrystallized 4-Cyclohexylamino-transdecahydroquinoline uncrystallized b) Preparation_of 1-E5-(fluorobenzoyl)-propyl]-4-phenyl-amino-tra«sdecahydroquinoline dihydrochloride (form a) 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 bicarbonate. While refluxing, a solution of 274 g. (1.12 mole) of 4-ehloro-1,1ethylenedioxy-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 system. The solution was allowed to cool to 50°C, and the salts so formed were filtered off.

The solvent was eliminated under vacuum from the solution and th resulting residue was taken up in 2-,500 ml. of benzene. The rcsultin solution was extracted with a solution of 250 ml. of concentrated hydrochloric acid in 1,250 ml, of water. The mixture obtained was . decanted and tho hydrochloric solution was stirred for 5 hours, made alkaline and then extracted with benzene, Tho organic phacc obtained was washed with water, dried over anhydrous sodium sulphate and filtered and the benzene was eliminated. The residue obtained was taken up in 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 obtained was reerystallized from a mixture of ethyl acetate ond methanol and 303 g. of 1-[3-(b-fluorobenzoyl)-propyl3-b-phenylaminotrans-decahydroquinoline dihydrochloride were obtained (form a).

Yield : 6b.8%, m.p. 20b - 206°C.

By following the same method but using the appropriate startingproducts, the compounds listed hereunder were prepared and their melting points obtained after recrystallization from the indicated solvents : bO Compound 1-C3-(b-fluorohcnzoyl)-propyl? ~b(b-methoxyphcnyl)-amino-transdecahydroquinoline dihydrochloridc (form a) 1-C5-(b-fluorobenzoyl)-propyl3-b(b-methylphenyl)-amino-transdecahydroquinoline dihydrochloride (form a) Melting Point °C. 179 - 182 (ethyl acetate/methanol) 188 - 19b (ethyl acetate/methanol) 1-(5-benzoylpropyl)-b-phenylaminotrans-decahydroquinoline hydrochloride 206 - 208 (form a) (ethanol) 1-C3-(b-mothylbenzoyl)-propyl3-b~ phenylamino-trans-decahydroquinoline hydrochloride (fora a) 1-C3-(b-chlorobenzoyl)-propyl3-bphenylamino-trnns-decahydroquinoline hydrochloride (fora a) 1-C3-(b-fluorobenzoyl)-propyl3-bphenylamino-trans-decahydroquinoline dihydrochloride (form b) 1-[3-(b-fluorobenzoyl)-propyl3-b(b-methylphenyl)-amino-transdecahydroquinoline dihydrochloride (form b) 226 - 227 (ethyl acetate/methanol) 2b8 - 2b9 (methanol, ethanol) 227 - 250 (ethyl acetate/methanol) 235 - 258 (ethyl acetate/methanol) 443 5 5 1-r3-(4-bromobcnzoyl)-propyl]-4phcnylnmino-trans-decnhydroquinoline hydrochloride (form a) 1-C3-(4-methoxybenzoyl)-propyl]-4phcnylamino-trnns-decahydroquinoline hydrochloride (form a) 1-(4-fluorobcnzoyl-methyl)-4-phenylaminotrans-dccahydroquinoline hydrochloride (form a) l-Benzcy3jnetiyl-4-phenylamino-transdecahydroquinoline hydrochloride 1-Phonethy1-4-phenylamino-transdecahydroquinoline hydrochloride (form a) 1-Cinnamyl-4-phenylamino-transdecahydroouinoline acid oxalate (form a) 1-(3-phenyl-propyl)~4~phenylamino-transdecahydroquinoline oxalate (form a) 1-(3-(4-chlorobenzoy1)-propyl]-4C(4-methoxyphenyl)-amino]-trancdccahydroquinoline dihydrochloride (form a) 241 - 243 (ethanol/methanol) 230 - 232 (ethanol) 255 - 257 (2-propnnol) c. '230 (decomposition) (ethanol/methanol) 258 - 260 (ethanol) 170 - 172 (2-propanol) 148 - 150 (2-propanol) 224 - 226 (ethyl acetate/methanol) 1-C4-(4-fluorobenzoyl)-butyl]-4phenylamino-trans-decahydroquinoline 182 - 184 hydrochloride (form a) (ethanol) 1-(2-Phenoxy-ethyl)-4-phenylamino- 165 -167 trans-decahydroquinoline (form a) (methanol) 1“C3-(4-Fluoro-phenylthio)-propyl]-4- 83-85 phenylamino-trans-decahydroquinoline (heptane) (form a) 1-C3-(4-fluorobenzoyl)-propyl]-4bon zylamino-trans-de cahydro quinoline hydrochloride (form a) 255 - 256 (ethyl acetate/methanol) 1-C3-(4-fluorobcnzoyl)-propyl]-4cyclohexylaraifto-trans-decahydroquinoline hydrochloride (form a) 211 - 214 (ethyl acetate/methanol) - 20 44355 1-C3-(/i-fluorobonzoyl)-propyl3-/i- uncryctallized (l-nnphthylamino)-tronn-decahydroquinoline c) Preparation of ^-[(H-phenyl-P-propionyl J-nminol-l-r^C^-fluorobcnzoyl)-progyl]-tranr.-decnliydroquinolinc_hydroehlorido While stirring, 39'f β. (1 mol) of 1-C3-(if-fluorobenzoyl)-propyl3fr-phenylamino-tranB-decahydroquitiolinc (form a) were dissolved in 800 ml. of dichloroethane in a two-litre flask. The resultinG solution waG cooled to about 20°C, and a eolution of 105 ml. of propionyl chloride in 105 ml. of dichloroethane was added.

The reaction medium was then maintained at 20°C. for one hour after which it was heated to ^5-5O°C. for 16 hours. The solution was thereafter cooled to 10-15°C. and the resulting precipitate of 1-E3-(^-fluorobenzoyl)-propyl3-4-phenylaroino-trans-decahydroquinoline dihydrochloride wae filtered off.

The excess of propionyl chloride was hydrolysed vzith 120 ml. of methanol and the solution was evaporated to dryness.

The residue obtained was taken up in 1$0 ml. of acetone, refluxed and the solvent distilled off. This 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 quantity of gaseous hydrochloric acid was added. The resulting solution 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-C(N-phenyl-l’-propiQnyl)-amino3-1“C3-(A-fluorobenzoyl)-propyl3-transdecahydroquinolinc hydrochloride (form a) were obtained.

Yield : 5^, 'm.p, 158 - l60eC.

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 A-[(N-phenyl-H-acetyl)-amino3-1C3-(l*-fluorobenzoyl)-propyl3-tranndecohydroquinoline hydrochloride (form a) Melting Point °C. 168 - 170 (ethyl acetate/methanol) 1?4 - 175 (ethyl acetate/methanol) 4-[(N-phenyl-H-butyryl)-amino]-1[3-(4-fluofobcnsoyl)-propyl]-tronsdccahydroquinolinc hydrochloride (form a) 4-[(H-phcnyl-N-valeryl)-nmino]-1[3-(4-fluorobonzoyl)-propyl]-tranBdecahydroquinoline hydrochloride (form a) 158- 160 (etliyl acetate/methanol) 4-[(H-phenyl-N-propionyl)-amino]1 -[3- (zl -fluorob ensoyl) -propyl]-transdecahydroquinoline oxalate (form b) 4-[(H-4-methylphcnyl-H-propionyl)amino]-1-[3-(4-fluorobenzoyl)propyl]-trans-decahydroguinoline hydrochloride (form a) 161 - 162 (ethyl acetate/acetone) 201 - 203 (ethyl acetate/methanol) 4-[(N-4-methoxyphenyl-N-propionyl)amino]-1-[3-(4-fluorobenzoyl)-propyl]trans-decahydroquinoline hydrochloride (form a) 193 - 195 (ethyl acetate/methanol) 4-[(H-phenyl-H-ac etyl)-amino]-1(3-benzoylpropyl)trano-decahydroquinoline 227 - 228 hydrochloride (form a) (ethyl acetate/methanol) 4-[(H-phenyl-H-propionyl)-amino]-1(3-benzoyl-propyl)-trans-decahydroguinoline 128 - 130 hydrochloride (form a) (ethyl acetate/methanol) 4-[(N-phenyl-H-acetyl)-amino]-1[3-(4-methylbenzoyl)-propyl]-transdecahydroquinoline hydrochloride (form a) 185 - 186 (ethyl acetate/methanol) 4-[(H-phenyl-N-propionyl)-amino]-1[3-(4-methylbenzoyl)-propyl]-transdecahydroquinoline hydrochloride (form a) 4-[(N-phenyl-N-acetyl)-amino)-1[3-(4-chlorobenzoyl)-propyl]-transdecahydroquinoline hydrochloride (form a) 4-[(N-phenyl-N-propionyl)-anino]-1[3- ( 4-chlorobenzoyl) -propyl]-trail sdecahydroquinolino hydrochloride (form a) 4-[(N-acetyl-N-phenyl)-omino]-1[3-(4-fluorobenzoyl)-propyl]-tran cdecahydroquinoline hydrochloride (form b) 214 - 215 (ethyl acetate/methanol) 193 - 194 (ethyl acetate/methanol) 188 - 190 (ethyl acetate/methanol) 130 - 131 (ethyl acetate/methanol) 159 - 141 (ethyl acetate/hexane) to 4-E(N-benzoyl-N-phcnyl)-amino]-1E3-(4-fluorobenzoyl)-propyl)-tr2nsdecahydroquinoline hydrochloride ' (form a) 4-E(N-Nicotinoyl-N-phcnyl)-araino]1-E3“(4-fluorobenzoyl)-propyl]-transdecahydroquinoline dihydrochloride (form a) 4-[(N~l6onicotinoyl~N-phenyl)-araino]1-r5-(4-fluorobcnzoyl)-propyl3-transdocahydroquinoline dihydroehloride (form a) 4-E(H-2-Furoyl-K-phcnyl)-amino]-1E3-(4-fluorobenzoyl)-propyl]-transdecahydroquinoline hydrochloride (form a) 4-E(N-Acetyl-W-phenyl)-amino]-1E5-(4-bromobcnzoyl)-propyl]^tranEdecahydroquinoline hydrochloride (form a) 4-E(N-Phenyl-K-propionyl)-araino]-1Γ3- (4-bromobengoyl)-propyl]-trcnsdecahydroquinoline hydrochloride (form a) 4-E(N-Acetyl-H-phenyl)-amino]-1E3- (4-methoxybenzoyl)-propyl]-trancdecahydroquinoline hydrochloride (form a) 4-[(N-Phenyl-H-propionyl)-amino]-1C5-(4-methoxybenzoyl)-propyl]-jtrwi>sdecahydroquinoline hydrochloride (form a) 4-E(H-Acetyl-N-phenyl)-amino]-1(4-fluorobcnzoyl-methyl)-trnnGdecahydroquinoline hydrochloride (form a) 4-E(H-Phenyl-U-propionyl)-amino]-1(4-fluorobenzoyl-methyl)-tranedecahydroquinoline hydrochloride (form a) 4-E(N-Acctyl-N-phcnyl)-araino]-1bcnzoylmethyl-trans-decahydroquinoline hydrochloride (form a) 4-E(N-Phenyl-N~propionyl)-amino]~1benzoyImethyl-trana-dccahydroquinoline hydrochloride (form a) 211 - 215 (methyl ethyl tetone/hexane) 213 - 215 (methyl ethyl ketone/hexane) 250 - 231 (ethyl acetate/methanol) 219 - 221 (ethyl acetate/methanol) 143 - 145 (ethyl acetate/methanol) 184 - 186 (ethyl acetate/methanol) 214 - 216 (ethyl acetate/methanol) 236 (acetone) 225 - 227 (ethyl acetate/methanol) 229 (ethyl acetate/methanol) 233 - 235 (ethyl acetate/methanol) <*4353 4-((N-Acetyl H-4-methoxyphenyl)-amino]1-E3-(4-ehlorobenzoyl)-propyl]-transdecahydroquinoline hydrochloride (form a) 193 - 195 (ethyl acetate/methanol) 4-C(M-4-Methoxyphenyl-N-propxonyl)amino]-1-C3-(4-chlorobenzoyl)-propyl]trans-decahydroquinoline hydrochloride 213 - 215 (form a) (acetone) 4-C(N-Acetyl-N-phenyl)-amino]-1-C4(4-fluorobenzoyl)-butyl]-transdecahydroquinoline hydrochloride 212 - 214 (form a) (acetone) 4-C(N-Phenyl-N-propionyl)-amino]-1C4-(4-fluorobenzoyl)-butyl]-transdecahydroquinoline hydrochloride (form a) 4-[(N-Acetyl-N-phenyl)-amino]-1benzy l-trans-decahydroquinolir.e hydrochloride (form a) 4-[(N-Phenyl-N-propionyl)-amino]-1benzyl-trans-decahydro quinoline hydrochloride (form a) 4-C(N-Acetyl-N-phenyl)-amino]-1phenethyl-trans-decahydroquinoline hydrochloride (form a) 4-[(N-Phenyl-N-propionyl)-amino]-1r phenethyl-trans-decahydroquinolxne hydrochloride (form a) 4-C(N-Acetyl-N-phenyl)-amino]-1(3-phenylpropyl)-trans-decahydroqui] hydrochloride (form a) 162 - 164 (ethyl acetate) 180 - 182 (ethyl acetate) 198 - 200 (ethyl acetate/methanol) 232 - 234 (ethyl acetate/methanol) 221 - 233 (ethyl acetate/methanol) 196 - 198 (ethyl acetate/methanol) 4-C(N-Phenyl-N-propionyl)-amino]-1(3-phenylpropyl)-trans-decahydroquinoline 210 - 212 hydrochloride (form a) (ethyl acetate/methanol) 4-E(N-Acetyl-N-phenyl-amxno]-1-cinnamyl- 136 - .138 trans-decahydroquinoline (form a) (heptane) 4-[(N~Bcnzyl-N-propionyl)-amino]-1[3-(4-fluorobensoyl)-propyl]-trnnGdccahydroquinoline hydrochloride (form a) 4-r(N-1-Naphthyl-K- propionyl)-amino]1-C3-(4-fluorobcnzoyl)-propyl]^trnnsdeeahydroquinoline hydrochloride (form b) 4-C(N-Cyclohexyl-N-propionyl)-amino]~1r3-(4-fluorobenzoyl)-propyl]-transdccahydroquxnolinc hydrochloride (form a) 4-C(N-Cyclohexyl-K-propionyl)-amino3-1[3-(4-fluorobenzoyl)-propyl]-transdecahydroquinoline acid oxalate (form b) 4-C(N-Phenyl-lJ~acetyl)-amino3-1C3-(4-fluorobenzoyl)-propyl]-transdecahydroquinoline hydrochloride (form a) 147 - 149 (ethyl acetate/diethyl ether) 122 - 124 (ethyl acetate/methanol) 154 - 156 (ethyl acetate/methanol) 1?8 - 180 (ethyl acetate/methanol) 158 - 16O (ethyl acetate/methanol) 4-C(N-Phenyl-N-propionyl)-amino]-1(2-phcnoxy-ethyl)-ti‘,-;ns-decaliydroquinoline 159 - 161 hydrochloride (form a) (ethyl acetate/methanol) 4-C(N-Phenyl-N-propxonyl)-amino]-1 [3-(4-fluoro-phenylthio)-propyl]-transdecahydroquinoline hydrochloride (form a) 4-C (N-Ac et yl-N-plienyl) -amino] -1 C3-(4-fluoro-phenyIthio)-propyl3-transdecaliydroquinoline hydrochloride (form a) 120 - 122 (ethyl acetate/methanol) 150 - 152 (ethyl acetate/methanol) EXAMPLE 2 4-C(N-Phenyl-N-propionyl)-ai.'iino]-1-r5-(4“fluorobcnzoyl)-propyl]-tiv;nsdecahydroguinoline hydrochloride (form a) 3.94 c· (0,085 mol) of I-E3-(4-fluorobcnzoyl)~propyl]-4-phenylamino· trans-dccahydroquinoline hydrochloride (form a), prepared as in Example 1 were dissolved in 20 ml. of dimethylformamide and 3.5 ml. of propionylchloride were added to the solution.

The mixture was heated to 60 - 8o°C. for 40 hours and 5 ml. of methanol were added.

Tlie reaction medium was distilled at 80eC. under vacuum until 12 ml. of tho solution had distilled and the residue was poured into diluted sodium hydroxide. The reaction medium was extracted with 443 5 5 diethyl other and tho organic eolution 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 quantity of gaseous hydrochloric acid was added and the resulting solution was allowed to crystallizo 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 (K-phenyl-N10 propionyl)-amino3-1-C3-(^-fluorobcnzoyl)-propyl3-trans-dccahydroquinoline hydrochloride (form a) were obtained.

Yield : 65.1%, m.p. 158 - 16O°C.

EXAMPLE 3 ^-C(H-;Phenyl-K-propionyl)-amino3-1-(3-( A-f luorobenzoyl) ~propyl3-trgr.s15 decahydropuinoline hydrochloride (form a) A solution containing 6 g. (0.015 mol) of 1-C3-(^-fluorobenzoyl)propyl3-*t-phenylamino-trans-decahydroquinolinc (form a), prepared as in Example 1, Αβ ml. of propionic anhydride and a trace of jv-toluenesulphonic acid vas heated to 100°C, for 20 hours. Aftei’ cooling methanol was added and the same method as described in Example 1 (c) was followed to give A,5 g. of 4-[(N-phenyl)-N-propionyl3-amino1- E3-(^-fluorobenzoyl)-propyl3-trsns-decahydroquinoline hydrochloride (form a).

Yield : 61.6%, m.p. 158 - 16O°C.

EXAMPLE A ^-C(N-Phcnyl-H-prgpi onyI)-a,mino3-1-C3-(;i-fluorobenzoyl)-propyl3-tra.nsdecahydroquinoline methanesulfonatc (form a) A solution of benzene containing 98 g. (0.22 mol) ofA-C(H-phenylM-propipnyl)-amino3-1-C3-(^-fluorobenzoyl)-propyl3-trans-deeahydro30 quinoline (form a), prepared as 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-^ was obtained.

The acid solution 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 filtration, 10(f g, of W (H-nhenyl-K-propionvl)-amino3 -1-Γ 5- ( ^-f luorobenzoyl) -propyl3- tre.u s26 44355 docohydroquinoline methanenulfonate (form a) were obtained.

Yield : 88%, m.p. : 132 - 13b °C.

EXAMPLE 5 b-C(N-l,licnyl-H-propionyl)-nmino3->1-rb-(b-fluorophcnyl)-b-hydrazono5 butyll-trnns-decnhydroquinolino (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 b-[(N-phenyl-K-propionyl)amino]-1-C3-(b-fluorobengoyl)-propy;i]-trann-decah:ydroquinoline (form a) and the mixture was refluxed for 3 hours. The solution was concentrate and the residue was poured into 100 ml. of water. The precipitate which formed was filtered off, washed with water and dried.

The substance was reerystallized from 2-propanol to give b-C(N-phenyl-N-propionyl)-amino3-1-[b-(b-fluorophenyl)-b-hydrazono“ butylD-trans-decahydroquinoline (form a).

Yield : 8b%, m.p. ; 155 - 156°C.

EXAMPLE 6 I b-Γ (N-Phenyl-N-propionyl )-n.mino]-1-rb-(b-f luorophenyl )-b-]:ydroxyj minobutyll-trans-decahydroqninoline (form a) g. (0.011 mol) of b-[(If-phenyl-K~propionyl)-amino3-1-L3“(b20 fluorobenzoyl)-propyl3-trans-decahydroquinoline, prepared as in Example 1, v/ere dissolved in 100 ml. of ethanol and a solution of 3.5 E. of hydroxylamine hydrochloride in 25 ml. of water and 7 g, of sodium hydrogen carbonate were added. The reaction medium was refluxed for 12 hours and was concentrated under vacuum. The residue was poured into water and the precipitate which formed was filtered off, washed with water and dried, Recrystallization from 2-propanol gave 2.5 E· °f ^-C(N-phcnyl-N-propionyl)-araino3-1-[b-(b-fluorophexiyl-bhydroxyimino-butyl3-trans-decflhydroquinoline (form a).

Yield : b8%, m.p. : about 80°C.

EXAMPLE 7 g. (0.1b mol) of 1-C3-(b-fluorohenzoyl)-propyl3-b-phenylaminotrans-docahydroquinolino, prepared as in Example 1, were dissolved in 200 ml. of dichloroethane. While stirring, 16 g. of ethyl chloroformate wore added drop-by-drop ond the medium was heated to 50 - 60C. for 16 hours. The reaction medium was cooled to 20°C. ond a colution of gaseous hydrochloric acid in 2-propanol was added. Stirring was 4 3 5 5 continued for between 2 and 3 minutes, the mixture wao evaporated to dryness and tho residue wao taken up in acetone.

The reaction medium wao cooled to 0°C, for 16 hours and the excess of 1-E3-(4-fluorobcnzoyl)-propyl]-4-pheiiylaniino-trans-decahydronuinoline was removed by filtration. The filtrate was evaporated to dryness and the residue was taken up in ethyl acetate.

The organic solution was cooled to 0°C. for 16 hours and 4-E(N-carbethoxy-N-phenyl)-amino]-1-E3-(4-fluorobenzoyl)-propyl3trans-d.ecahydroquinoline hydrochloride (form a) crystallizod and was filtered off and recrystallized from ethyl acetate/methanol.

Yield ϊ 3<, m.p. : 134 - 136°C.

By following the same method but using the appropriate startingproducts, the compounds listed hereunder were prepared ϊ Compound Melting Point °C. 4-f (N-carboraethoxy-JI-phenyl)-amino]-1E3-(4-fluorobenzoyl)-propyli-trans- 194 - 196 decahydroquinoline hydrochloride (form a) (ethyl acetate) 4-E(N-Carbo-sec-butoxy-H-phenyl)-amino]1-E3-(4-fluorobenzoyl)-propyl]-trans- 1?8 - 18O decahydroquinoline hydrochloride (form a) (ethyl acetate) 4-E(N-Carbo-n-butoxy-N-phenyl)-amino]-1E3-(4-fluorobenzoyl)-propyl]-1-trans- 181 - 183 dccahydroquinoline hydrochloride (form a) (ethyl acetate) 4-E(H-carbethoxy-H-phonyl)-amino]-125 phcncthyl-trans-decahydroquinoline 191 - 195 hydrochloride (form a) (ethyl acetate/methanol) EXAMPLE 8 Soft-gelatin capsules containing the following ingredients were prepared in accordance with well-known pharmaceutical techniques : Ingredients 4-E(N-phenyl-H-acetyl)-amino]-1E3-(4-fluorobenzoyl)-propyl]-transdecahydroquinoline hydrochloride .

Weight (1) (2) mg. mg.

Corn-ctarch ColloEdal-cilica 194.3 me. 0,7 mg. 220 mg.

BXAHPI.E 9 An injectable solution containine the following ingredientc vac prepared in accordance with well-known pharmaceutical techniques : Ingredients Weight ίο 4-[ (N-ph cn 'j 1-K-ac e t y 1) - amino 3 -1 - Γ3-(4-fluorobenzoyl)-propyl]-tranc- 60 decahydroquinolinc hydrochloride Eg. sorbitol 187 mg. water q.s. 5 ml.

Claims (3)

1. 11 2 R —C—Κ—B and the pharmaceutically acceptable acid additon salts thereof, wherein R 1 represents a branched- or straight-chain alkyl group or alkoxy group containing from 1 to 4 caibon atoms; a dialkylamino group in which the alkyl groups each contain from 1 to 4 carbon atoms; a saturated heterocyclic group attached by a ring nitrogen atom; an optionally substituted phenyl group; or an unsaturated heterocyclic 1.. 4-Amino-trans-decahydroquinoline derivatives represented by the general formula: 2. 3 wherein. R and. R are as defined in Claim 1 with the proviso that 3 when R represents a group of formula II, Y does not represent a hydroxyiminomethylene or hydrazonomethylene group, with a compound of the general formula: Cl IV wherein R'' has the meanings specified herein. 8. Process according to Claim 7, wherein the compound of formula III is refluxed in an inert organic solvent. 9. Process according to Claim 7, wherein the compound of formula III is refluxed in the presence of a base. 10. Process for preparing a compound of formula I in which R 1 represents a dialkylamino group in which the alkyl groups each contain from 1 to 4 carbon atoms or a saturated heterocyclic group 3 and in which when R represents a group of formula II, Y does- not represent a hydroxyiminomethylene or hydrazonomethylene group, which comprises reacting a compound of formula III as defined in Claim 7 with phosgene to give a compound of formula: VI 2 3 wherein R and R are as defined in Claim 1 with the proviso that when R represents a group of formula II, Y does not represent a hydroxyiminomethylene or hydrazonomethylene group, vhich is then reacted with an amine of the general formula R^R (VII) wherein R^ has the meanings specified herein. 11. Process according to Claim 10, wherein the compound of formula III is reacted with phosgene in an inert organic solvent. 12. Process according to Claim 10, wherein the compound of formula III is reacted with phosgene in the presence of a base. 13. Process according to Claim 10, wherein the compound of formula VI is reacted with the amine in an inert organic solvent. 14. A pharmaceutical composition containing as an active principle at least one compound or a pharmaceutically acceptable acid addition salt thereof as claimed in Claim 1 in association with a pharmaceutical carrier or excipient therefor. 15. A pharmaceutical composition containing as an active principle 4-C(H-phenyl-N-acetyl)-aminoj-l-C3-(4-fluorobenzoyl)propylH-trans-decahydroquinoline or a pharmaceutically acceptable acid addition salt thereof in association with a pharmaceutical carrier or excipient therefor. 16. A pharmaceutical composition containing as an active principle h-EiN-phenyl-N-carbethoxyl-aminol-l-Cs-Cit-fluorobenzoyl)propyll-trans-decahydroquinoline or a pharmaceutically acceptable acid addition salt thereof in association with a pharmaceutical carrier or excipient therefor. 17. A composition as claimed in Claim 15 or 16 in a dosage unit form suitable for oral administration. l6. A composition as claimed in Claim 15 or 16 in a dosage unit form suitable for administration by injection. 19. A method of treating pain in a non-human subject in need of such treatment, said method consisting in administering to the said subject at least one compound of formula I or a pharmaceutically acceptable acid addition salt thereof. 33 44355 20. A' method of treating hypertension in a non-human subject in need of such treatment, said method consisting in administering to the said subject at least one compound of formula I wherein represents a branched or straight-chain alkoxy group or a 5 pharmaceutically acceptable acid addition salt thereof. 21. A compound in accordance with Claim 1, as described in Example 1 or 2 of the foregoing Examples. 22. A compound in accordance with Claim 1 as described in any one of the foregoing Examples 3 to 7. 10 23. A pharmaceutical composition substantially as described in the foregoing Example 8 or 924, Process for preparing a compound as claimed in Claim 1, substantially as described in the foregoing Example 1 or 2. 25. Process for-preparing a compound as claimed in Claim 1, 15 substantially as described in any one of the foregoing Examples 2. Decahydroquinoline derivatives as claimed in Claim 1, wherein R 1 · represents a dimethylamino group, a pyrroiidino, piperidino or morpholino group, or a furyl or pyridyl group. 3. Decahydroquinoline derivatives as claimed in Claim 1 or 2, wherein R represents a pyridyl, thienyl, methylthienyl, furyl or pyrimidyl group, or a benzyl, phenethyl, cinnamyl or phenylpropyl group, or a cyclohexyl group. 4. Deeahydroquinoline derivatives as claimed in Claim 1, 2 or 3, wherein R represents a 2-methylfuryl group or a benzyl, phenethyl, cinnamyl or phenyl propyl group. 5. 4-C(N-Phenyl-N-acetyl)-amino3-l-C3-(4-fluorobenzoyl)-propyll· trans-decahydroquinoline and its pharmaceutically acceptable acid addition salts. 6. 4-[(N-Phenyl-H-carbethoxy J-amitioJ-l-C 3-( 4~fluor obenzoyl )propylZJ-trans-decahydroquinoline and its pharmaceutically acceptable acid addition salts. 7. Process for preparing a compound of formula I in which R represents a branched or straight-chain alkyl or alkoxy group containing from 1 to 4 carbon atoms, an optionally substituted phenyl . - . 3 group, or an unsaturated heterocyclic group and in which when R represents a group of formula II, Y does not represent a hydroxyiminooethylene or hydrazonomethylene group, which comprises refluxing a compound of the general formula: - 31 44355 ΗΗ-R III

2 . . group; R represents a branched- or straight-chain alkyl group containing from 1 to 4 carbon atoms; an optionally substituted phenyl group; a naphthyl group; an unsaturated heterocyclic group optionally substituted by a alkyl radical; an aralkyl or aralkenyl group; . · 3 or an alicyclic group; and R represents a alkyl substituted furyl group; an aralkyl or aralkenyl group; or a group represented by the general formula: wherein- A represents a branched- or straight-chain alkylene group 20 containing from 1 to 4 carbon atoms; Y represents an oxygen or sulphur atom, a carbonyl, hydroxyiminomethylene, hydrazonomethylene 30 4 4 3 5 5 or sulphoxide group, or a group: 0 -CH, C '^o _ch 2 h 5 R and R , which are identical or different, each represent hydrogen, a halogen atom, or a methyl, methoxy or acetyl group and n is 0 or 1 with the proviso that when n is 0, Y represents a carbonyl group.

3. To 7.