CH618970A5 - Process for the preparation of 4-amido-trans-decahydroquinoline derivatives - Google Patents

Abstract

The decahydroquinoline derivatives of general formula: <IMAGE> in which R1 represents a C1 to C4 alkyl or alkoxy chain, an optionally substituted phenyl radical or an unsaturated heterocycle, R2 represents a C1 to C4 alkyl, optionally substituted phenyl, naphthyl, heterocyclic, aralkyl or alicyclic radical and R3 represents a furyl group substituted by lower alkyl, aralkyl or a group of formula: <IMAGE> where An, Y, R4 and R5 have the meaning given in Claim 1, are obtained by acylating the corresponding secondary amine with the chloride or anhydride of the acid R1COOH. The compounds of formula I are essentially useful as analgesics and/or antihypertensive agents.

Description

The present invention relates generally to processes for the preparation of 4-amido-trans-decahydroquinoline derivatives and their pharmaceutically acceptable acid addition salts.

The compounds prepared according to the invention correspond to the following general formula:

40

r1-C-K-R2

O-CH2,

R4 and R5 which are identical or different, each represent a hydrogen atom, a halogen atom or a methyl, methoxy or acetyl group and n is 0 or an integer from 1 to 4, it being understood that when n is 0, Y represents a carbonyl group, as well as its pharmaceutically acceptable acid addition salts, characterized in that a compound of general formula is heated at reflux:

VN:

r?

in which R2 and R3 have the above meaning with a compound of general formula:

55 in which R1 represents a C1 to C6 alkyl or alkoxy chain, an optionally substituted phenyl group or a. unsaturated heterocyclic group such as furyl or pyridyl, R2 represents an alkyl chain, linear or branched and containing from 1 to 4 carbon atoms, an optionally substituted phenyl group 60; a naphthyl group, an unsaturated heterocyclic group such as pyridyl, thienyl, methylthienyl, furyl or pyrimidyl, an aralkyl group such as benzyl, phenetyl, cinnamyl or phenylpropyl, or an alicyclic group such as cyclohexyl, and R3 represents "5 a substituted furyl group by a lower alkyl chain such as 2-methyl furyl, an aralkyl group such as benzyl, phenethyl, cinnamyl or phenylpropyl, or a group represented by the general formula:

3

618,970

II

in which A represents a linear or branched alkylene chain, Y represents an oxygen or sulfur atom, a carbonyl, carbonyl-hydroxyimino, carbonyl-hydra-zono, sulfoxide or group

O-CH2

/ \

Ö-CH2

R4 and R5, which are identical or different, each represents a hydrogen or halogen atom such as, for example, fluorine, chlorine or bromine, or a methyl, methoxy or acetyl radical, n is 0 or a integer between 1 and 4 inclusive, it being understood that when n is 0, Y represents a carbonyl radical.

The compounds of formula I are prepared by refluxing a 4-amino trans-decahydroquinoline substituted in position 1 and corresponding to the general formula:

HN-R2

III

N I

R?

in which R2 and R3 have the same meaning as in formula I, preferably in an inert organic solvent such as, for example, dichloroethane, methylene chloride, benzene or toluene, with a compound of general formula:

O

30

35

40

45

The compounds of formula I can be transformed into their pharmaceutically acceptable acid addition salts by treating them with an appropriate acid, according to well known techniques.

The compounds of formula III can be prepared by reacting a 4-amino-trans-decahydroquinoline of general formula:

HN-R2

\

V

nn '

I

H

VIII

in which R2 has the same meaning as in formula I, with a halogenated compound of general formula:

Hal-R3

IX

in which Hai represents a chlorine, bromine or iodine atom and R3 has the same meaning as in formula I. This reaction is preferably carried out in a liquid medium which can 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, in the presence of 'an acid sensor, preferably an alkali metal carbonate, for example potassium carbonate or baking soda.

The reaction is preferably carried out at the reflux temperature of the liquid medium and can be accelerated by using small amounts of potassium iodide.

The compounds of formula IX are already known while the compounds of formula VIII can be prepared by reacting 4-oxo-trans-decahydroquinoline, known compound, in the presence of a catalyst such as, for example, p-toluene acid -sulfonic, trifluorobore etherate, zinc chloride or titanium tetrachloride, preferably in an inert organic solvent such as, for example, hexane, benzene or toluene and at the reflux temperature of the solvent, with an amine of general formula:

R1 — C — Cl

IV

R2-NH2

50

X

wherein R1 has the above meaning, 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 optionally substituted alkyl, phenyl group or an unsaturated heterocyclic group, can also 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 general formula:

O O

He II

RMH-O-C-R1

V

in which R1 has the above meaning, optionally in the presence of an acid such as, for example, paratoluene sulfonic acid or sulfuric acid.

in which R2 has the same meaning as in formula I, the water formed being removed by azeotropic distillation. The imino derivative obtained is hydrogenated with sodium borohydride in methanol or with lithium hydride in tetrahydrofuran. This hydrogenation can be carried out at various temperatures.

The above method leads to the compounds of formula VIII in the form of a mixture of their axial and equatorial isomers. This mixture can be separated into two fractions by virtue of the difference in solubility of the hydrochlorides of the isomers in an aqueous solution having a pH of 3 or by chromatography.

The compounds of formulas I and III can therefore be obtained in the form of a mixture of axial and equatorial isomers or in the form of one of the isomers.

However, it has not yet been possible to determine whether the water-insoluble fraction at pH 3 is constituted either by the axial isomer or by the equatorial isomer

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4

or by a mixture of the two, the same for the soluble fraction.

For this reason, the term “form a” will be used subsequently to denote the compound of formula VIII whose Rf in the chosen test of thin layer chromatography is lower than the Rf of the corresponding isomer which will be designated subsequently by the term "form b".

The results of the thin layer chromatography test in question are illustrated in the accompanying drawing.

The details of this test are as follows:

Support

Silica gel 60 F 254 (produced by MERCK) thickness: 0.25 mm

Development and saturation solvent (under an ammonia atmosphere)

Hexane: 80 ml Propanol-2: 20 ml

Upward technique on 13 cm

Deposits

200 | xg (in solution in chloroform)

Revelation UV at 2,540 Å or iodine vapor

(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 subsequently to designate the corresponding isomers of the substances of formulas I and III, the starting product of which is either “form a” or “form b” of the compound of formula VIII. Consequently, the processes described above for the preparation of the derivatives of formula I starting from the derivatives of formula VIII are also applicable either to the "form a" or to the "form b" of the derivatives of formula VHI for the preparation of the corresponding isomers of formula I.

It has been found that the compounds prepared according to the invention have remarkable pharmacological properties, in particular some of them have a powerful analgesic power while being devoid of any morphine effect.

These properties make the compounds concerned particularly interesting for the treatment of pain.

Pain relievers are pain relievers by acting on the central nervous system to raise the pain threshold without affecting consciousness or other sensory conditions.

The agents which are generally used for the symptomatic elimination of pain can for reasons of ease of presentation be divided into two main groups:

1) Narcotic pain relievers, such as opium derivatives

Among these, morphine is one of the most important drugs and has many useful properties, analgesia being one of its main activities. No other drug is used as widely for the relief of various categories of severe pain. Unfortunately, morphine causes euphoria and addiction; moreover it depresses breathing. When morphine, or a similar compound, is administered to a patient for a fairly long period of time, tolerance to the analgesic effect is observed such that the dose administered must be increased periodically to obtain constant pain relief. For all these reasons, it is generally accepted that morphine and its derivatives should not be used when another analgesic may suffice.

The analgesic compounds prepared according to the invention are completely devoid of morphine effect and one can therefore recommend their use in a greater number of cases than morphine derivatives.

2) Non-narcotic analgesics, such as salicylated derivatives

These are generally less active than narcotic pain relievers, but on the other hand, they do not depress breathing and cause little or no addiction.

It will be seen that the analgesic compounds prepared according to the invention compare very favorably with the non-narcotic analgesics most used at present.

In addition, it has been found that some compounds of formula I have remarkable pharmacological properties capable of making them extremely advantageous for the treatment of disorders of the cardiovascular system such as hypertension.

There are many types of hypertension but there is no known universal therapy for these conditions, patient responses to different drugs can vary widely depending on the individual case.

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

Among these, compounds are known which exert a ganglioplegic effect characterized by an interruption of sympathicotonic impulses, thereby causing a relaxation of the vascular walls.

Others are characterized by a narrow margin between their therapeutic and toxic doses. Finally, it is known that certain antihypertensive agents exert an antihypertensive effect so sudden and powerful that their action is difficult to control.

The antihypertensive compounds prepared according to the invention do not have these drawbacks.

Pharmacological tests were carried out in order to demonstrate either the analgesic action or the antihypertensive effects of the compounds of the invention.

1) Analgesic action

We have found that the following compounds are particularly useful as pain relievers:

[(N-Phenyl N-acetyl) amino] -4 [(4-fluoro benzoyl) -3 propyl] -l trans-decahydroquinoline (Compound A) [(N-Phenyl N-propionyl) amino] -4 [(fluoro- 4 benzoyl) -3 propyl] -l transdecahydroquinoline (Compound B) [(N-Phenyl N-butyryl) amino] -4 [(4-fluoro benzoyl) -3 propyl] -! trans-decahydroquinoline (Compound C) [(N-Phenyl N-valeryl) amino] -4 [(4-fluoro benzoyl) -

3 propyl] -l trans-decahydroquinoline (Compound D) [(N-Methoxy-4 phenyl N-propionyl) amino] -4 [(fluoro-

4 benzoyl) -3- propyl] -l trans-decahydroquinoline (Compound E)

The first test was carried out according to the KÖSTER technique (Fed. Proc. 18,412,1959) on batches of 20 mice deprived of food for 18 hours.

The animals of each batch, with the exception of the control batch, are administered an intragastric dose of the test compound, so that each batch is administered a dose greater than that of the previous batch. Thirty minutes after administration, all animals including controls are given,

s

10

15

20

25

30

35

40

45

50

55

60

65

5

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0.2 ml per 10 g of a 0.25% acetic acid solution intraperitoneally.

The number of characteristic contortions made by the animals during the 20 minutes following the injection of acetic acid is noted. The absence of contortions corresponds to analgesized animals.

The calculated DA 50 is given in the table below, that is to say the doses of the test compound which cause analgesia in half of the animals treated.

Table I

10

the invention, namely: [(N-Phenyl N-propionyl) amino] -4 [(4-fluoro benzoyl) -3 propyl] -! trans-decahydroquinoline (Compound B).

The first test was carried out according to the KÖSTER technique described above, but using a subcutaneous injection of the product to be tested.

Compound B was compared to two major pain relievers and the results were obtained below:

Table V

Compound

DAso mg / kg

AT

38

B

25

VS

30

D

25

E

55

The same test was performed with five widely used pain relievers and the following results were obtained:

Table II

Compound

SAR 0 mg / kg

Acetylsalicylic acid

150

Antipyrine

120

Phenacetin

160

Glafenin

110

Pentazocine

45

25

Compound

AD50 mg / kg

B

2

Pethidine

7

Pentazocine

5

The second test was carried out using the NILSEN technique

above but using a subcutaneous injection of the test tablet.

Compound B

has been compared to pethidine and pentazo-

cine, two well-known pain relievers, and the following results were obtained:

Table VI

Compound

DAso mg / kg

B

4

Pethidine

7

Pentazocine

12

The second test was carried out according to the technique of NILSEN (Acta Pharmacol. And Toxicol. 18,10,1961) on batches of 10 mice.

The animals are connected to a source of electric current by means of two electrodes applied in the subcutaneous tissue of the tail.

The threshold voltage is determined, that is to say the minimum voltage which causes at least one cry during two consecutive stimulations. The animals are then administered, intragastrically, the compound to be studied. At different times after administration, four consecutive stimulations are provoked at the voltage threshold determined above and it is considered that the animal is analgesized if it does not cry during the four stimulations.

Note the dose of the compound (DAso) which suppresses the cry in half of the animals treated.

The following results were obtained:

Table III

Compound

DAso mg / kg

AT

110

B

30

VS

70

55

The third test was carried out according to the technique of SIEG-MUND and al (Proc. Soc. Exp. Biol. Med. 95, 729.1957) on batches of 10 male mice.

A typical syndrome is caused in animals by an intraperitoneal injection of 0.25 ml of a 0.02% aqueous solution of 2-phenyl-1,4-benzoquinone (phenylbenzoquinone).

The syndrome in question is characterized by intermittent contractions of the abdomen, torsions and rotations 40 of the trunk and extensions of the hind legs.

Fifteen minutes after the injection of phenylbenzoquinone, the number of movements is noted for thirty minutes.

The test compound is injected 30 minutes before phenylbenzoquinone so that each batch receives a dose 45 greater than that of the previous batch, the control batch receiving only phenylbenzoquinone.

Note the DA 50, that is to say the dose of substance which reduces at least half the number of contortions in half of the animals, compared to the number of contortions of the control animals.

The following results were obtained:

Table VII

"Compound

SAR 0 mg / kg

The same test was performed with three well known pain relievers and the results below were obtained:

Table IV

B

Acetylsalicylic acid Antipyrine Phenacetin Glafenine

7

50 100 80 325

Compound

DA5o mg / kg

Acetylsalicylic acid

1100

Antipyrine

400

Phenacetin

450

Additional pharmacological tests were carried out in order to specify the analgesic action of the preferred compound of

The fourth test was carried out according to the technique of CHARLIER et al (Arch. Int. Pharmacodyn. 134, 306,1961) on batches of 10 rats.

The animals were connected to a source of electric current by means of two electrodes, one of which is attached to the tail and the other introduced into the rectum.

We then determined for each animal the voltage threshold of

18,970

6

pain by passing a current of 2 volts and increasing it by one volt at a time until the animal calls.

This control test was repeated three times at fifteen minute intervals. The test compound is then administered intragastrically and, starting from the voltage threshold determined previously, the voltage which causes the animals to cry is recorded every ten minutes, for two hours.

The results are noted according to the scale of WINTER and FLATAKER (J. Pharmacol. Exp. Therap. 98, 305.1950) and the DAso obtained are given in the Table below:

Table VIII

Compound DA50 mg / kg

B 30

Acetylsalicylic acid 1300

Antipyrine 500

Phenacetin 750

Phetidine 50

Finally, a test was carried out according to the technique of D'AMOUR and SMITH (J. Pharm. Exp. Ther. 72, 74, 1941) on batches of 10 male rats weighing approximately 200 g.

A 300 watt heat lamp is directed at the tip of a rat's tail at a distance such that after 4 to 6 seconds of irradiation a typical flick-tail withdrawal is obtained animal.

The compound to be tested is administered to the animals, with the exception of the control animals, subcutaneously and the time which elapses between the start of irradiation and the first reaction of the animal is noted. reaction), relative to the reaction time of the control animals.

The DAso obtained are listed in the Table below:

Tables IX

Compound

DAso mg / kg

B

2.5

Pethidine

5.5

Pentazocine

3.0

From all of these tests, it can be concluded that the compounds prepared according to the invention have analgesic properties far superior to those of the best known analgesics.

2) Antihypertensive action It has been found that the compounds of formula I, in which R 1 represents a linear or branched alkyloxy chain, have remarkable antihypertensive properties capable of making them very useful for the treatment of human hypertension.

Regarding the treatment of hypertension, the preferred compound is:

[(N-Phenyl N-carbethoxy) amino] -4 [(4-fluoro benzoyl) -3 propyl] -l trans-decahydroquinoline (Compound F)

A pharmacological test was carried out in order to demonstrate the antihypertensive properties of Compound F.

This test was carried out on male rats belonging to a breed which was specially bred to give animals having a high blood pressure according to the technique of OKA-MOTO and AOKI (Jap. Circuì. J., 27, 282, 1963) .

The animals used are about ten weeks old and have a blood pressure of about 180 mm Hg.

We divided this test into two series. In the first series, a single dose of the test compound is administered intragastrically to each animal and the blood pressure of the latter is measured every hour for six hours after administration. In the second series the product to be tested is given by the same route daily for eleven consecutive days and the blood pressure is measured every day during this period. The amount of compound administered varies from animal to animal for the first set of tests.

The following results were obtained:

Paintings

Type of treatment

Dose

Max fall from P.A.

Time of

mg / kg

(mmHg)

max fall

Single dose

5

27

3 hours

10

44

4 hours

Daily dose

10

29

8 days dienne (11 days)

From these results, we can conclude that Compound F has a powerful antihypertensive action.

3) Acute toxicity Acute toxicity tests were carried out on rats and mice which were kept under observation for 12 days after a single administration.

The following results were obtained:

a) Compound B Table XI

Animal

Administration

LD 50 (mg / kg)

Intragastric mouse

500

Intragastric rats

350

Intraperitoneal mouse

55

Intraperitoneal rats

55

Subcutaneous mouse

550

b) Compound F

Tables XII

Animal

Administration

LD 50 (mg / kg)

Intragastric mouse

750

Intragastric rats

450

Intravenous rats

15

Intravenous mouse

32

These figures compare very favorably with the active doses whose effects have been described above and show that there is a very large safety margin between the toxic and therapeutic doses of the preferred compounds.

For therapeutic use, the compounds prepared according to 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 one of its pharmaceutically acceptable acid addition salts, in combination with a pharmaceutical carrier or excipient.

For clinical use, the composition will preferably be presented in a form suitable for the chosen mode of administration, for example, a tablet, coated or not, a capsule or a capsule for oral administration, a solution for injection. or a suppository for rectal administration.

Regardless of the form the composition takes, it will normally include at least one of the compounds s

10

15

20

25

30

35

40

45

50

55

60

65

7

618,970

of formula I, or a pharmaceutically acceptable acid addition salt thereof, combined with a suitable pharmaceutical solvent or excipient comprising, for example, one or more of the following substances: milk, sugar, starch, talc, magnesium stearate, polyvinylpyrrolidone, alginic acid, colloidal silica or taste correcting agent.

The following examples illustrate the invention:

Example 1 io

[(N-phenyl N-propionyl) amino] hydrochloride -4 [(4-fluoro benzoyl) -3 propyl] -l trans-

decahydroquinoline (form a)

a) Preparation of 4-phenylamino-

decahydroquinoline is

A solution of 76.8 g (0.5 mol) of 4-ox-trans-decahydroquinoline and 1.0 g of p-toluene sulfonic acid in 350 ml of hexane is heated to reflux in a 1 liter flask. 46.3 g (0.5 mole) of aniline are added.

The reflux is continued until all the water formed is removed using a Dean-Stark apparatus and then 140 ml of hexane are removed by distillation. The solution is allowed to cool and 250 ml of benzene are added.

The reaction medium is washed first with water, then with a dilute solution of sodium hydroxide and finally again with water. The resulting solution is dried over anhydrous sodium sulfate, filtered and the solvents are removed to obtain 102.4 g of 4-phenylimino-trans-decahydroquinoline in the crude state (yield: 89%).

102.4 g of phenylimino-4 trans-decahydroquinoline, obtained as above, are dissolved in 190 ml of methanol containing 200 mg of sodium hydroxide in a one-liter flask, the temperature of the solution being maintained at around 20 ° C.

A solution of 20 g of sodium borohydride in 200 ml of methanol, stabilized with 600 mg of sodium hydroxide, is then added and the temperature of the medium is maintained at between 20 and 22 ° C for a few hours.

The solution is finally heated at 40 ° C for 8 hours and then allowed to cool. The solvent is removed and the residue is taken up in 150 ml of benzene and 250 ml of water.

The mixture is decanted and the aqueous phase is extracted with benzene. The organic phase is then extracted with 240 ml of 4N hydrochloric acid. The mixture is decanted and sodium hydroxide is added until a pH of 3 is obtained.

It is filtered and an acidic aqueous filtrate is obtained and a precipitate which is dried to give 43.8 g of 4-phenylamino-trans-decahydroquinoline hydrochloride (form a).

Yield: 33%, melting point: 265-270 ° C.

Isolation of form b

The acidic aqueous filtrate is made alkaline by addition of sodium hydroxide and is extracted with benzene.

The mixture obtained is decanted and the organic phase is washed with water, dried over anhydrous sodium hydroxide and filtered. Benzene is removed and the residue is taken up in 35 ml of diethyl ether. The solution is cooled to a temperature between 0 and 5 ° C, filtered and washed with diethyl ether to obtain 9.2 g of 4-phenylamino-trans-decahydroquinoline (form b).

Yield: 7%, melting point: 118-120 ° C. .

Following the same method, but using the appropriate starting materials, we also prepared:

Compound Melting point ° C

(4-methylphenyl) 4-amino trans-decahydroquinoline 92—94

(4-methoxyphenyl) 4-amino trans-decahydroquinoline 144—145

Non-crystallized 4-trans-decahydroquinoline benzylamino

(Naphthyl-1) 4-amino trans-decahydroquinoline non-crystallized

Cyclohexylamino-4 trans-decahydroquinoline non-crystallized

b) Preparation of [(4-fluoro-benzoyl) -3 propyl] dihydrochloride-4-phenylamino-trans-decahydroquinoline (form a)

A solution of 230 g (1 mole) of 4-phenylamino-trans-decahydroquinoline (form a) in 920 ml of n-butanol is heated to reflux in a four-liter flask in the presence of 100 g of sodium bicarbonate.

While continuing to heat at reflux, a solution of 274 g (1.12 mole) of 3-chloro-ethylenedioxy-1,1 (4-fluoro-phenyl) -1 butane in 200 ml of n-butanol is added. The reflux is continued until all of the water that forms is removed by a Dean-Stark apparatus. The solution is allowed to cool to 50 ° C and the salts which have formed are filtered.

The solvent is removed in vacuo and the residue is taken up in 2500 ml of benzene. The solution is then extracted with 250 ml of concentrated hydrochloric acid in 1250 ml of water. The mixture is decanted, the hydrochloric solution is stirred for 3 hours, it is made alkaline and it is extracted with benzene. The organic phase is washed with water, then dried over anhydrous sodium sulfate.

The solution is filtered and the benzene is removed.

The residue is taken up in ethyl acetate and a solution of hydrochloric gas in 2-propanol is added thereto. The precipitate which forms is filtered, washed with ethyl acetate and dried. The crude product obtained is recrystallized from a mixture of ethyl acetate and methanol and 303 g of [(4-fluoro-benzoyl) -3 propyl] dihydrochloride-4-phenylamino-trans-decahydroquinoline (form a) are obtained.

Yield: 64.8%, melting point: 204-206 ° C.

By following the same method but using the appropriate starting materials, the compounds listed below were obtained after recrystallization from the solvents indicated:

55

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8

Compound

Melting point ° C

[(4-Fluoro-benzoyl) -3 propyl] -l dihydrochloride

(4-methoxyphenyl) 4-amino trans-decahydroquinoline (form a)

[(4-Fluoro-benzoyl) -3 propyl] dihydrochloride-4 (4-methylphenyl) 4-amino-trans-decahydroquinoline (form a)

(3-benzoyl-propyl) -l phenylamino-4 trans-decahydroquinoline hydrochloride (form a)

[(4-methyl benzoyl) -3 propyl] -l 4-phenylamino hydrochloride trans-decahydroquinoline (form a)

[(4-Chloro benzoyl) -3 propyl] -l 4-phenylamino hydrochloride trans-decahydroquinoline (form a)

[(4-Fluoro-benzoyl) -3 propyl] -l 4-phenylamino-hydrochloride hydrochloride (form b)

[(4-Fluoro-benzoyl) -3 propyl] dihydrochloride-4 (4-methylphenyl) 4-amino-trans-decahydroquinoline (form b)

[(4-bromo-benzoyl) -3 propyl] -l phenylamino-4 trans-decahydroquinoline hydrochloride (form a)

[(4-methoxybenzoyl) -3 propyl] -l 4-phenylamino hydrochloride trans-decahydroquinoline (form a)

(4-Fluoro-benzoyl methyl) -l phenylamino-4 trans-decahydroquinoline hydrochloride (form a)

Benzoylmethyl-1 phenylamino-4 trans-decahydroquinoline hydrochloride (form a)

[(2-Thenoyl-3) -3 propyl] -l phenylamino-4 trans-decahydroquinoline hydrochloride (form a)

1-Phenethyl-4-phenylamino hydrochloride trans-decahydroquinoline (form a)

Cinnamyl-1 phenylamino-4 trans-decahydroquinoline oxalate acid (form a)

(Phenyl-3 propyl) -l phenylamino-4 trans-decahydroquinoline oxalate (form a)

[(4-Chloro-benzoyl) -propyl] -l dihydrochloride

[(4-methoxyphenyl) -amino] -4 trans-decahydroquinoline (form a)

[(4-fluoro benzoyl) -4 butyl] -l phenylamino-4 trans-decahydroquinoline hydrochloride (form a)

179-182

(ethyl methanol acetate)

(ethyl methanol acetate)

206-208 (ethanol)

(ethyl methanol acetate)

248-249 (methanol-ethanol)

(ethyl methanol acetate)

235—238 (ethyl methanol acetate)

241—243 (ethanol-methanol)

230-232 (ethanol)

255-257 (propanol-2)

± 230 (decomposition) (ethanol-methanol)

167-169

(ethyl acetate- (methanol)

258-260 (ethanol)

170-172 (propanol-2)

148-150 (propanol-2)

224—226

(ethyl acetate-methanol)

182-184 (ethanol)

(2-Phenoxy-ethyl) -1 phenylamino-4 trans-decahydroquinoline (form a) 165 - 167 (methanol)

[(Fluoro-4 phenylthio) -3 propyl] -l phenylamino-4 trans-decahydroquinoline (form a)

[(4-fluoro benzoyl) -3 propyl] -l benzylamino-4 trans-decahydroquinoline hydrochloride (form a)

[(4-Fluoro-benzoyl) -3 propyl] -l cyclohexylamino-4 trans-decahydroquinoline hydrochloride (form a)

[(4-Fluoro benzoyl) -3 propyl] -1 (naphthyl-1 amino) -4 trans-decahydroquinoline

83-85 (heptane)

255-256

(ethyl acetate-methanol) 211-214

(ethyl acetate-methanol) not crystallized

9

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c) Preparation of hydrochloride of [(N-phenyl N-propionyl) amino] -4 [(4-fluoro benzoyl) -3 propyl] -1 trans-decahydroquinoline It is dissolved with stirring in a 2 liter flask 394 g (1 mole ) of [(fluoro-4 benzoyl) -3 propyl] -1 phenylamino-4 trans-decahydroquinoline (form a) in 800 ml of dichloroethane. The solution is cooled to 20 ° C. and a solution of 105 ml of propionyl chloride in 105 ml of dichloroethane is added thereto. The temperature of the reaction medium is maintained at 20 ° C for one hour and then at 45-50 ° C for 16 hours. The solution is then cooled to 10-15 ° C. and the precipitate of [(4-fluoro-benzoyl) -3 propyl] -1-phenylamino-4 trans-decahydroquinoline dihydrochloride is filtered.

The excess propionyl chloride is hydrolyzed with 120 ml of methanol and the solution is evaporated to dryness.

10

15

The residue is taken up in 150 ml of acetone and the solution heated to reflux. The solvent is removed by distillation and this operation is repeated twice.

Finally, the residue is dissolved in 150 ml of acetone at the reflux temperature of the solvent and 2-propanol containing a small amount of hydrochloric gas is added to the solution. The solution is left to crystallize at room temperature and the precipitate is filtered. After washing and drying, 318 g of crude product are obtained. After recrystallization from a mixture of ethyl acetate and methanol (2/1), 263 g of [(N-phenyl N-propionyl) amino) -4 [(4-fluoro ben-zoyl) hydrochloride are obtained - 3 propyl] -l trans-decahydroquinoline (form a). Yield: 54%, melting point: 158-160 ° C.

By the same method but using the appropriate starting materials, the compounds listed below were prepared:

Compound

Melting point ° C

[(N-phenyl N-acetyl) amino] -4 hydrochloride

[(4-fluoro-benzoyl) -3 propyl] -l trans-decahydroquinoline (form a)

168-170

(ethyl acetate-methanol)

[(N-phenyl N-butyryl) amino] -4 hydrochloride

[(4-fluoro-benzoyl) -3 propyl] -l trans-decahydroquinoline (form a)

174-175

(ethyl acetate-methanol)

[(N-phenyl N-valeryl) amino) hydrochloride -4

[(4-fluoro benzoyl) -3 propyl] -1 trans-decahydroquinoline (form a)

158-160

(ethyl acetate-methanol)

[(N-phenyl N-propionyl) amino] -4 oxalate

[4-fluoro-benzoyl) -3 propyl] -l trans-decahydroquinoline (form b)

161-162

(ethyl acetate-acetone)

[(N-methyl-4-phenyl N-propionyl) hydrochloride 201—203

amino] -4 [(4-fluoro benzoyl) -3 propyl] -l trans-decahydroquinoline (form a) (ethyl acetate-methanol)

[(4-N-methoxyphenyl N-propionyl) hydrochloride 193—195

amino] -4 [(4-fluoro benzoyl) -3 propyl] -1 trans-decahydroquinoline (form a) (ethyl methanol acetate)

[(N-phenyl N-acetyl) amino] -4 (3-benzoylpropyl) hydrochloride! trans-decahydroquinoline (form a)

227-228

(ethyl acetate-methanol)

[N-phenyl N-propionyl) amino] hydrochloride 4 (3-benzol propyl) -1 trans-decahydroquinoline (form a)

128-130

(ethyl acetate-methanol)

[(N-phenyl N-acetyl) amino] -4 hydrochloride

[(4-methylbenzoyl) -3 propyl] -1 trans-decahydroquinoline (form a)

185-186

(ethyl acetate-methanol)

[(N-phenyl N-propionyl) amino] -4 hydrochloride

[(4-methylbenzoyl) -3 propyl] -1 trans-decahydroquinoline (form a)

[(N-phenyl N-acetyl) amino] -4 hydrochloride

[(4-chloro benzoyI) -3 propyl] -1 trans-decahydroquinoline (form a)

214-215

(ethyl acetate-methanol) 193-194

(ethyl acetate-methanol)

[(N-phenyl N-propionyl) amino] -4 hydrochloride

[(4-chloro benzoyl) -3 propyl] -1 trans-decahydroquinoline (form a)

[(N-phenyl N-acetyl) amino] -4 hydrochloride

[(4-fluoro benzoyI) -3 propyl-1 trans-decahydroquinoline (form b)

[(N-Benzoyl N-phenyl) amino] -4 hydrochloride

[(4-fluoro-benzoyl) -3 propyl] -l trans-decahydroquinoline (form a)

[(N-nicotinoyl N-phenyl) amino) hydrochloride

4 [(4-fluoro-benzoyl) -3 propyl] -1 trans-decahydroquinoline (form a)

[(N-isonicotinoyl N-phenyl) hydrochloride

130-131

(ethyl acetate-methanol) 188-190

(ethyl acetate-methanol) 139-141

(ethyl acetate-hexane) 211-213

(methyl ethyl ketone-hexane) 213-215

amino] -4 [(4-fluoro benzoyl) -3 propyl] -l trans-decahydroquinoinine (form a) (methyl ethyl ketone-hexane)

[(N-furoyl-2 N-phenyl) amino] -4 hydrochloride

[(4-fluoro benzoyl) -3 propyl] -1 trans-decahydroquinoline (form a)

230-231

(ethyl acetate-methanol)

618,970

10

Compound

Melting point ° C

[(N-phenyl N-acetyl) amino] -4 hydrochloride

[(4-bromo benzoyl) -3 propyl] -l trans-decahydroquinoline (form a)

[(N-phenyl N-propionyl) amino] -4 hydrochloride

[(4-bromo benzoyl) -3 propyl] -1 trans-decahydroquinoline (form a)

[(N-phenyl N-acetyl) amino] -4 hydrochloride

[(4-methoxy benzoyl) -3 propyl] -1 trans-decahydroquinoline (form a)

[(N-phenyl N-propionyl) amino] -4 hydrochloride

[(4-methoxy benzoyl) -3 propyl] -1 trans-decahydroquinoline (form a)

[(N-phenyl N-acetyl) amino] -4 hydrochloride

(4-fluoro benzoylmethyl) -l trans-decahydroquinoline (form a)

[(N-phenyl N-propionyl) amino] -4 (4-fluoro-benzoylmethyl) -l trans-decahydroquinoline hydrochloride (form a)

[(N-phenyl N-acetyl) amino] -4 hydrochloride-1-benzoylmethyl-trans-decahydroquinoline (form a)

[(N-phenyl N-propionyl) amino] -4 hydrochloride-1-benzoylmethyl-trans-decahydroquinoline (form a)

[(N-phenyl N-acetyl) amino] hydrochloride -4 [(2-thenoyl) -3 propyl] -l trans-decahydroquinoline (form a)

[(N-phenyl N-propionyl) amino] hydrochloride -4 [(2-thenoyl) -3 propyl] -1 trans-decahydroquinoline (form a)

[(4-N-methoxyphenyl N-acetyl) hydrochloride -

amino] -4 [(4-chloro benzoyl) -3 propyl] -l trans-decahydroquinoline

(form a)

[(N-methoxy-4 phenyl N-propionyl) hydrochloride

amino] -4 [(4-chloro benzoyl) -3 propyl] -1 trans-decahydroquinoline

(form a)

[(N-phenyl N-acetyl) amino] -4 hydrochloride

[(4-fluoro benzoyl) -4 butyl] -l trans-decahydroquinoline (form a)

[(N-phenyl N-propionyl) amino] -4 hydrochloride

[(4-fluoro benzoyl) -4 butyl] -l trans-decahydroquinoline (form a)

[(N-phenyl N-acetyl) amino] -4 hydrochloride 1-benzyl-trans-decahydroquinoline (form a)

[(N-phenyl N-propionyl) amino] -4 hydrochloride-1 benzyl trans-decahydroquinoline (form a)

[(N-phenyl N-acetyl) amino] -4 phenethyl-1 trans-decahydroquinoline hydrochloride (form a)

[(N-methyl N-propionyl) amino] -4 phenethyl-1 trans-decahydroquinoline hydrochloride (form a)

[(N-phenyl N-acetyl) amino] -4 (3-phenylpropyl) -l trans-decahydroquinoline hydrochloride (form a)

[(N-phenyl N-propionyl) amino] -4 (3-phenyl propyl) hydrochloride -1 trans-decahydroquinoline (form a)

[(N-phenyl N-acetyl) amino] -4 cinnamyl-1 trans-decahydroquinoline (form a)

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) 233-235

(ethyl acetate-methanol) 229

(ethyl acetate-methanol) 205-207

(ethyl acetate-methanol)

111-113 (acetone)

193-195

(ethyl acetate-methanol)

213-215 (acetone)

212-214 (acetone)

162-164 (ethyl acetate)

180-182 (ethyl acetate)

198-200

(ethyl acetate-methanol) 232-234

(ethyl acetate-methanol) 231-233

(ethyl acetate-methanol) 196-198

(ethyl acetate-methanol) 210-212

(ethyl acetate-methanol)

136-138 (heptane)

11

618970

Compound

Melting point ° C

[(N-Benzyl N-propionyl) amino] hydrochloride -4 147—149

[(4-fluoro-benzoyl) -3 propyl] -1 trans-decahydroquinoline (form a) (ethyl acetate-

[(N-naphthyl-1 N-propionyl) amino] hydrochloride -4 122-124

[(4-fluoro-benzoyl) -3 propyl] -l trans-decahydroquinoline (form b) (ethyl acetate-

[(N-cyclohexyl N-propionyl) amino] hydrochloride -4 154—156

[(4-fluoro benzoyl) -3 propyl] -l trans-decahydroquinoline (form a) (ethyl acetate-

[(N-cyclohexyl N-propionyl) amino] acid oxalate -4 178—180

[(4-fluoro-benzoyl) -3 propyl] -l trans-decahydroquinoline (form b) (ethyl acetate-

[(N-phenylN-acetyl) amino) hydrochloride -4 158-160

[(4-fluoro benzoyl) -3 propyl] -l trans-decahydroquinoline (form a) (ethyl acetate-

[(N-phenyl N-propionyl) amino] hydrochloride -4 159—161

(2-phenoxyethyl) -1 trans-decahydroquinoline (form a) (ethyl acetate-

[(N-phenyl N-propionyl) amino] hydrochloride -4 120-122

[(4-fluoro-phenylthio) -3 propyl] -1 trans-decahydroquinoline (form a) (ethyl acetate-

[(N-phenyl N-acetyl) amino) hydrochloride -4 150-152

[(4-fluoro pheny! thio) -3 propyl] -1 trans-decahydroquinoline (form a) (ethyl acetate-

diethyl ether)

methanol)

methanol)

methanol)

methanol)

methanol)

methanol)

methanol)

Example 2

[(N-phenyl N-propionyl) amino] hydrochloride -4 [(4-fluoro benzoyl) -3 propyl] -l trans-decahydroquinoline (form a)

3.94 g (0.085 mol) of [(4-fluoro-benzoyl) -3 propyl] -l phenylamino-4 trans-decahydroquinoline hydrochloride (form a), prepared as in Example 1, is dissolved in 20 ml of ' dimethylformamide and 3.5 ml of propionyl chloride are added to the solution. The mixture is heated to 60-80 ° C for 40 hours and to it is added 5 ml of methanol.

The reaction medium is distilled at 80 ° C under vacuum until 12 ml of the solution has distilled and the residue is poured into dilute sodium hydroxide.

The reaction medium is extracted with diethyl ether 40 and the organic solution is washed with water, then it is treated with active carbon. The solvent is removed and the residue is dissolved in 150 ml of acetone at the reflux temperature of the solvent.

A solution of propanol-2 containing a small amount of hydrochloric gas is added to the solution and the solution is allowed to crystallize at room temperature.

The precipitate which forms is filtered, washed with acetone and dried and 318 g of crude product are obtained. After recrystallization from a mixture of ethyl acetate and methanol (2/1), 263 g of [(N-phenyl N-propionyl) 50 amino] -4 [4-fluoro-benzoyl) -3 hydrochloride are collected. propyl] -l trans-decahydroqui-noline (form a).

Yield: 65.1%, melting point: 158-160 ° C.

Example 3 55

[(N-phenyl N-propionyl) amino] hydrochloride -4 [(4-fluoro benzoyl) -3 propyl] -l trans-decahydroquinoline (form a)

A solution containing 6 g (0.015 mol) of [(4-fluoro-benzoyl) -3 propyl] -l 60-phenylamino-4 trans-decahydroquinoline (form a), prepared as in Example 5, is heated at 100 ° C. for 20 hours. 1.45 ml of propionic anhydride and traces of paratoluenesulfonic acid. After cooling, methanol is added and the reaction is continued as described in Example 1 (c). 4.5 g of [(N-65 phenyl N-propionyl) amino] -4 [(4-fluoro benzoyl) -3 propyl] -1 trans-decahydroquinoline hydrochloride (form a) are obtained.

Yield: 61.6%, melting point: 158-160 ° C.

Example 4

[(N-phenyl N-propionyl) amino] -4 [(4-fluoro benzoyl) -3 propyl] -l trans-decahydroquinoline methanesulfonate (form a)

A benzene solution containing 98 g (0.22 mole) of [(N-phenyl N-propionyl) amino] -4 [(4-fluoro-benzoyl) -3 propyl] -1 trans-decahydroquinoline (form a) is acidified, prepared as in Example 1, using 30 g of an aqueous solution at 69.5% methanesulfonic acid containing propanol-2 until a pH of 3.5 to 4 is obtained.

The acid solution is evaporated to dryness and the residue is taken up in 600 ml of toluene. 100 ml of toluene are removed by azeotropic distillation and after crystallization and filtration, 104 g of [(N-phenyl N-propio-nyl) amino] -4 [(4-fluoro-benzoyl) -3 propyl] -l methanesulfonate are collected. trans-decahy-droquinoline (form a).

Yield: 88%, melting point: 132-134 ° C.

Example 5

[(N-phenyl N-propionyl) amino] -4 [(4-fluoro phenyl) -4 hydrazono-4 butyl] -l trans (decahydro-quinoline (form a)

A solution containing 2.5 ml of hydrazine hydrate in 15 ml of ethanol is mixed with 3.6 g (0.008 mole) of [(N-phenyl N-propionyl) amino] -4 [(fluoro- 4 benzoyl) -3 propyl] -1 trans-decahydroquinoline (form a) and the mixture is heated to reflux for 3 hours.

The solution is concentrated and poured into 100 ml of water. The precipitate which forms is filtered, washed with water and dried.

The substance is recrystallized from 2-propanol and the [(N-phenyl N-propionyl) amino] -4 [(4-fluoro-phenyl) -4 hydrazono-4 butyl] -l trans-decahydroquinoline (form a) is obtained. Yield: 84%, melting point 155-156 ° C.

Example 6

[(N-phenyl N-propionyl) amino] -4 [(4-fluoro phenyl) -4 hydroxyimino-4 butyl] -l trans-decahydroquinoline (form a)

5 g (0.011 mol) of [(N-phenyl N-propionyl) -amino] -4 [(4-fluoro-benzoyl) -3 propyl] -1 trans-decahydroquinoline, prepared as in 1, are dissolved in 100 ml of ethanol 'Example 1,

30

35

618,970

12

then a solution of 3.5 g of hydroxylamine hydrochloride in 25 ml of water is added to the solution, as well as 7 g of sodium hydrogencarbonate. The reaction medium is heated to reflux for 12 hours and then the solution is concentrated in vacuo. The residue is poured into water and the precipitate which forms is filtered, washed with water and dried. After recrystallization from propanol-2, 2.5 g of [(N-phenyl N-propio-nyl) amino] -4 [4 (fluoro-4 phenyl) -4 hydroxyimino-4 butyl] -l trans-decahydroquinoline are collected. at).

Yield: 48%, melting point: about 80 ° C.

Example 7

[(N-carbethoxy N-phenyl) amino] hydrochloride -4 [(4-fluoro benzoyl) -3 propyl] -1 trans-decahydroquinoline

55 g (0.14 mol) of [(4-fluoro benzoyl) -3 propyl] -1 phenylamino-4 trans-1 decahydroquinoline, prepared as in Example 1, are dissolved in 200 ml of dichloroethane.

While stirring, 16 g of ethyl chloroformate is added dropwise and the reaction medium is heated at 50-60 ° C for 16 hours. The medium is cooled to 20 ° C. and a solution of hydrochloric gas in propanol-2 is added thereto. Stirring is continued for 2 to 3 minutes and the mixture is evaporated to dryness, then the residue is taken up in acetone.

The reaction medium is cooled to 0 ° C for 16 hours and the excess of [(4-fluoro-benzoyl) -3 propyl] -1 phenylamino-4 trans-decahydroquinoline is removed by filtration. The filtrate is evaporated to dryness and the residue taken up in ethyl acetate. The organic solution is cooled to 0 ° C for 16 hours and the hydrochloride of [(N-carbethoxy N-phenyl) amino] -4 [(4-fluoro-benzoyl) -3 propyl] -1 trans-decahydroquinoline (form a) crystallizes , is filtered and recrystallized from a mixture of ethyl acetate-methanol.

Yield: 31%, melting point: 134-136 ° C.

Following the same method but using the appropriate starting materials, the compounds listed below were prepared:

15

Compound Melting point ° C

[(N-carbophenoxy N-phenyl) amino] hydrochloride -4

185-187

[(4-fluoro benzoyl) -3 propyl] -1 trans-decahydroquinoline (form a)

(ethyl acetate)

[(N-carbomethoxy N-phenyl) amino) hydrochloride -4

194-196

[(4-fluoro-benzoyl) -3 propyl] -l trans-decahydroquinoline (form a)

(ethyl acetate)

[(N-sec-carbobutoxy N-phenyl) amino] -4 hydrochloride

178-180

[(4-fluoro-benzoyl) -3 propyl] -l trans-decahydroquinoline (form a)

(ethyl acetate)

[(N-n-carbobutoxy N-phenyl) amino] -4 hydrochloride

181-183

[(4-fluoro benzoyl) -3- propylj-1 trans-decahydroquinoline (form a)

(ethyl acetate)

[(N-methoxy-2 carbethoxy N-phenyl) amino] -4 hydrochloride

159-161

[(4-fluoro benzoyl) -3 propyl] -1 trans-decahydroquinoline (form a)

(ethyl acetate)

Hydrochloride àe ((N-carbethoxy N-phenyl) amino) -4

191-193

1-phenetyl trans-decahydroquinoline (form a)

(ethyl acetate-methanol)

B

1 sheet of drawings

Claims (4)

618,970 2 CLAIMS 1. Process for the preparation of a compound of general formula: O R1 — C — Cl (IV) 0 rLC-N-R2 (I) / r3 in which R1 represents a C1 to C4 alkyl or alkoxy chain, an optionally substituted phenyl group, or an unsaturated heterocyclic group, R2 represents a linear or branched alkyl chain containing 1 to 4 carbon atoms, an optionally substituted phenyl group, a naphthyl group, an unsaturated heterocyclic group, an aralkyl group or an alicyclic group and R3 represents a furyl group substituted by a carbonyl, carbonyl-hydroxyimine, carbonyl-hydrazono or sulphoxide group, or an s group in which R1 has the meaning ci above, or with an anhydride of formula O O He II io Rï-C-O-C — R1, R1 then being different from alkoxy. 2. Method according to claim 1, characterized in that the compound of formula IH is heated to reflux in an inert organic solvent such as dichloroethane, methylene chloride, benzene or toluene. 3. Method according to claim 1, characterized in that the compound of formula III is heated to reflux in the presence of a base such as triethylamine, trimethylamine or pyridine. 4. The process according to claim 1 for preparing [(N-phenyl N-acetyl) amino] -4 [(4-fluoro benzoyl) -3 propyl] -1 trans-decahydroquinoline and its acid addition salts phar -maceutically acceptable. 5. Method according to claim 1 for preparing the [(N- Phenyl N-carbethoxy) amino] -4 [(4-fluoro benzoyl) -3 propyl] -1 trans-decahydroquinoline and its pharmaceutically acceptable acid addition salts. -Aa - * - (II) in which A represents a linear or branched alkylene chain, Y represents an oxygen or sulfur atom, a carbonyl, carbonyl-hydroxyimine, carbonyl-hy-drazono or sulfoxide group, or a group O-CH2 EIÏ-E2 (III) 30