CZ405191A3 - derivatives of 2-|(piperidinyl-4)methyl¨-1,2,3,4-tetrahydroisoquinoline, process of their preparation and pharmaceutical compositions in which said derivatives are comprised - Google Patents

Abstract

Compounds of general formula I: <IMAGE> in which X represents a hydrogen atom or a methyl or methoxy group, Y represents a methyl or methoxy group, and R represents a group of general formula -Z-R' in which Z represents a -CH2- group or a -CO- group and R' represents a phenyl group optionally carrying from 1 to 3 substituents chosen from halogen atoms and trifluoromethyl, linear or branched (C1-C3)alkyl and linear or branched (C1-C3)alkoxy groups. Application in therapeutics.

Description

TTJDr. J. TRAPL AND PARTNERS OF RtBVOCAT AND PATENT OFFICES

178? R ?úja 7 »U průhonu 36

-o i o -T i_ m

2- ((Oiperidinyl-1-4) methyl) -1,2,3,4-tetranes: trans -rinoline derivatives, process for their preparation and pharmaceutical compositions containing these derivatives

Technical field

The present invention relates to 2 - [(piperidinyl-4) methyl] 1,2,3,4-tetrahydroisoquinoline derivatives, processes for their preparation, and pharmaceutical compositions containing them as active ingredient.

BACKGROUND OF THE INVENTION

The present invention relates to French Patent Application No. 8711288 of August 7, 1987. This application describes compounds of the general formula

Wherein R represents either a hydrogen atom or a methyl or benzyl group, optionally substituted by a chlorine atom or a methyl or methoxy group, or still a phenethyl group.

SUMMARY OF THE INVENTION

The present invention provides compounds of formula I

in which

X represents a hydrogen atom or a methyl or methoxy group,

Y represents a halogen atom or a methyl or methoxy group; and

R represents a group of formula -zr \ wherein Z is -CH "- or -CO- group, and R is phenyl * · from ^among alkylcarbonyl, optionally bearing one to three substituents selected from halogen atoms, trifluoromethyl group, a linear or branched alkyl group having 1 to 3 carbon atoms and a linear or branched chain alkoxy group having 1 to 3 carbon atoms.

These compounds can exist either in the free base state or in the acid addition salt state.

Compounds of formula (I) may be prepared by the process of the invention, which is shown schematically in Reaction Scheme 1 below.

First, a compound of formula I wherein Z is -CO- is prepared by reacting 1,2,3,4-tetrahydroisoquinoline of formula II (wherein X and Y are as defined above) with a tosylate of formula III (wherein Tos represents a tosyl group and R 'is as defined above) either in the absence or in the presence of an inert solvent such as dimethylformamide, toluene or xylene at a temperature of 20 to 150 ° C and optionally in the presence of an organic base such as a tertiary amine; a base such as an alkali metal carbonate or bicarbonate.

In this way, a compound of formula (Ia) is obtained which corresponds to a compound of formula (I) when Z is a group of formula Ia.

If it is desired to prepare a compound of formula I in which Z is -CH 2, then the compound of formula Ia is reduced with a boron or aluminum hydride or complex hydride, for example lithium aluminum hydride, aluminum hydride, diborane / tetrahydrofuran or dibcran / dimethyl sulfide, or any other equivalent agent in an ether solvent such as diethyl ether, tetrahydrofuran or dioxane at a temperature of 20 to 100 ° C.

which

In this way, a compound is obtained corresponding to a compound of formula Ib, I when Z is a group

The 1,2,3,4-tetrahydroisoquinolines of formula II can be obtained by the method described by D.J. Sall and G.L. Grunewald, J. Med. Chem., 1987, 30, 2208-2216 or any other analogous method.

TosO

Reaction Scheme 1

co-r '(III)

(la) what-r '

CH ₂ -R '

Tosvlátv formula III may bv manner which is schematically illustrated by following the reaction Scheme 2.? Piperidino-4-methanol A Formula IV is reacted with an acid chloride of formula R COC1 (in which R ^a is as defined above) in an inert solvent such as a chlorinated solvent at a temperature of 20 to 80 ° C. In this way, an ester amide of formula (V) is obtained which is saponified, for example with sodium hydroxide or potassium hydroxide, in a solvent formed from a lower aliphatic alcohol, preferably ethanol, to give an alcohol of formula (VI), from which the tosylate is finally prepared by tosyl chloride such as pyridine.

Reaction Scheme 2

OH

(IV)

(III)

(VI) 'COR'

For example, the -piperidine-4-methanol of formula IV can be obtained by reduction of ethyl piperidine-4-carboxylate with lithium aluminum hydride or the same reduction of ethyl 1-benzylpiperidine-4-carboxylate followed by catalytic hydrogenolysis under pressure.

Otherwise, both the aforementioned French Patent Application No. 8711288 and the French Patent Application Nos. 8718342 and 8805129 disclose various processes for the preparation of compounds of the formula I in which X a: a named hydrogen atom.

It goes without saying that these methods are also substantially applicable to the preparation of the substituted compounds of the invention.

In the following, the invention will be illustrated by means of specific examples. These examples are illustrative only and are not intended to limit the scope of the invention as defined by the claims. The preparation of several compounds of the invention is detailed in these examples. The chemical structures of the prepared compounds are confirmed by elemental microanalysis and by infrared and nuclear magnetic resonance spectra. The compound numbers indicated in brackets next to the example numbers correspond to the compound numbers listed in the table below.

Examples in the Invention

Example 1 (Compound No. 16)

5,8-Dimethoxy-2- [1 - [(3-methylphenyl) carbonyl] piperidinyl-4] methyl] -1,2,3,4-tetrahydroisoquinoline fumarate

Stage 1.1

Piperidine-4-methanol

In a 4 L three-necked flask equipped with a mechanical stirrer condenser was charged 28.5 g (0.75 mol) of lithium aluminum hydride and 1.2 L of tetrahydrofuran. 117.9 g (0.75 mol) of ethyl piperidine-4-carboxylate in solution in 1.2 L of tetrahydrofuran are added to the suspension obtained and the mixture is stirred for 6 hours at 20 ° C. The reaction mixture was then cooled to 0 ° C and hydrolyzed by the sequential addition of 22 mL of water, mL of 1N aqueous sodium hydroxide solution and 46 mL of water. The mixture was stirred for 30 minutes at 20 ° C and then filtered. The separated precipitate was washed with tetrahydrofuran and then with ether. Evaporation of the solvents under reduced pressure yielded 84.4 g of an oil which was used as such in the next step.

Step 1.2 / 1- (3- (ethylbenzoyl) piperidinyl-4) methyl-3-methylbenzoate

42.25 g (0.367 mole) of piperidine-4-methanol, 430 ml of 1,2-dichloroethane, 82 g (0.81 mole) of triethylamine are added to a 3 L three-necked flask and then 125, 2 g (0.81 mol) of 3-methylbenzoyl chloride. The mixture was heated at reflux for 4 hours 30 minutes, then 8.2 g (0.08 mol) of triethylamine and 12.5 g (0.08 mol) of 3-methylbenzoyl chloride were added, and the mixture was heated for a further 3 hours.

The reaction mixture is then filtered, the salts are washed with 1,2-dichloroethane and the filtrate is evaporated under reduced pressure, the residue is dissolved in ethyl acetate, the solution is washed with an aqueous saturated sodium chloride solution, the solvent is evaporated under reduced pressure and the residue is recrystallized from isopropyl alcohol. 1: 1 by volume. 80 g of a white solid are obtained having a melting point of 80-83 ° C.

Stage 1.3

1- (3-Methylbenzoyl) piperidine-4-methanol

To a solution of 80 g (0.23 mol) of [1- (3-methylbenzoyl) piperidinyl-4] methyl-3-methylbenzoate was added a solution of 12.76 g (0.23 mol) of potassium hydroxide in 75 ml of ethanol and 75 ml of water. The mixture was then stirred for 3 hours at 20 ° C, the solvent was evaporated under reduced pressure, the aqueous phase was extracted with ethyl acetate, the organic phase was washed with water and then with saturated aqueous sodium chloride solution and dried over magnesium sulfate. 53 g of alcohol is obtained, which is used as it is in the following stage.

Stuoene 1,4 / 1- (3-Methylbenzoyl) piperidinyl-4 / methyl-4-methylbenzenesulfonate

To a solution of 52 g (0.22 mol) of 1- (3-methylbenzoyl) piperidine-4-methanol in 100 ml of pyridine was added 53.3 g (0.28 mol) of 4-methylbenzenesulfonyl chloride in 60 ml of pyridine. The mixture was stirred at 20 ° C for 4 hours, then poured onto ice. The phases are extracted with dichloromethane, the organic phase is washed

N aqueous hydrochloric acid solution and dried over magnesium sulfate. Evaporation of the solvents under reduced pressure gave 70 g of a white solid, m.p. 68-70 ° C.

*

Stage 1.5

5,8-Dimethoxy-2 - [[1 - [(3-methylphenyl) carbonyl] piperidinyl] -4,3,2,3,4-tetrahydroisoquinoline fumarate

A mixture of 3.86 a (0.02 mol) of 5,8-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 8.5 g of 1- (3-methylbenzoyl) pipridinyl-4 / methyl-4-methylbenzenesulfonate is heated under argon atmosphere for 20 hours. Dichloromethane and then concentrated ammonia are added to the mixture, the organic phase is separated, washed twice with water, dried over magnesium sulphate and filtered, and then the solvent is evaporated off under reduced pressure.

2j.sk and s>.

at-'. which is called

The ether was evaporated

Purify from 0 sloupci by chromatography on a silica gel column, eluting with a dichloromethane / methanol (93/2 by volume) mixture. 3.2 was isolated from the corresponding eluate fraction

pure base. 1.6 g of this base are added dissolve i knows ethanol, to the solution is added 0,45 g ky- abandoned in 60 ml ethanol, eth sncl ss ocpa crystallizes from isopropyl alcohol Finally

1.3 g of fumarate having a melting point of 156-153 are isolated

Example 2

5,8-Dimethoxy-2- [1 - [(3-methylphenyl) methyl] piperidinyl-4] methyl] -1,2,3,4-tetrahydroisoquinolinedifumarate

X of a solution of 1.6 g (0.0038 mol) of 5,8-dimethoxy-2- [1 - [(3-methylphenyl) carbonyl] piperidinyl-4] methyl] -1,2,3,4-tenrahydroisoquinoline in 30 ml of ether 0.29 g (0.0073 mol) of lithium aluminum hydride is added, the mixture is stirred for 3 hours at ambient temperature, then cooled in an ice bath and hydrolysed with 2.4 ml of 1 M aqueous sodium hydroxide solution. The mixture was then filtered and the filtrate was evaporated to give 1.4 g of base. This base is dissolved in a minimum of ethanol, 0.32 c of fumaric acid dissolved in 100 ml of ethanol is added, the ethanol is evaporated and the residue is recrystallized from isopropyl alcohol. Finally, 1.5 g of difumarate having a melting point of 198 to 201 C is isolated.

The chemical structures and physical properties of some of the compounds of the invention are shown in the following table.

In the sixth column of this table, the salts are abbreviated as follows: hydrochloride is designated as HCl, dihydrochloride is designated as diHCl, fumarate is designated as fum., Difumarate is designated as difum. and the hemifumarate is indicated as 1/2 µm. In the last column of the table, (d) indicates the decomposition of the compound that occurs at the melting point.

'and bul ixa

ΓΤ

Zj

C. Λ OF P Salt Melting point (° C) 1 H CH _? -5 WHAT ^C S ^h 5 * RC1 211-212 2 H CH ₃ -5 CH ₂ C.H.- o □ d i f um. 194-196 3 H CH _n -5 what Cl-3-C <H.- 6 4 214-216 4 H CH ₃ -5 ch ₂ ^Cl - ³ - ^C 6 ^K 4 - difum. 206-208 5 H CH ₃ -5 what ^C 2 ^H 5 ° ^3_C 6 ^H 4 ' HCl 179-182 6 H CH ₃ O-5 what C, H, - o 5 HCl 230 d 7 H CK ₃ O-5 CH ₂ C, K.6 o dif um 188-190 -in 8 H CK ₃ O-5 WHAT Cl-3-C, H.6 4 f um. 168-170 9 H CH ₃ 0-o what C _c H 6 - 6 □ HCl 183-185 10 H CH ₃ O-8 what ^C 6 ^H 5- HCl 205-215 1 1 H CH ₃ O-8 ^CH 2 ^C 6 ^H 5- difum. 198-201

1

Table ./continued)

C. ί and 'I L Salt Heat ca melting (° C) 12 Cn .C ~ 5 fy c: - ₃ o-8 WHAT C „H-- Ό 0 CC ’. 2 40-246 13 . fy 0 CK, G-3 5 CH. 4 '' β '! di fum. 193-197 1 4 Ch-O-5 fy η -, ϋ - o J WHAT p 1 - Ί -p T - - S '4 £ tini « 151-152 1 5 CH ₃ O-5 C n ₃ 0-3 ^ 2 C1-3-C.K, - 6 4 d i f um. 200-202 16 CH 2 O-S CH ₃ O-3 WHAT Cn.- 3 - C .- * · and ~~ 3 δ 4 f um. 156-158 1 7 CH ₃ O-5 CH ₃ C-8 ch ₂ CH.-3-C.Hj 6 4 di f um. 198-201 12 CK.O-5 O CH., 0-8 what C-H-O-3-C.K 2 3 0 1/2 f um. 134-135 19 Dec ^ ._ ₃ u □ CH.0-3 O CH " of C-H.0-3-C ^ H 2 □ 6 4 difum. 1 78-180 20 May CH <0-5 O CH 2 O-8 CH 2 of Cr.-3 'C <H, fy 0 4 difum. 193-203 d 21 CK, O-6 j CK ₃ O-7 what C. H 0 0 f um. 1 38-139 22nd y Ci-6 CG C.H.0 0 KC1 ZZ2 ~ ZZO 23 H Cl-6 ch ₂ C / H.- O 0 difum. . 136-139 24 n Cl-8 what C.n \ 6 nCl 198-200

The compounds of the invention have been subjected to a number of pharmacological tests which have demonstrated the utility of these compounds as therapeutically effective substances.

In these assays the affinity of the compounds of the invention for serotoninergic 5-HT receptors was studied. .

»A

These compounds displace the hippocampus (hippocampus, a strip of tissue in the cortex) of rats was specifically labeled with Ligands ^ / ^3H / -8hycroxy-2-dipropylaminotetralin (indicated as / H ^3/8-OK1 2

OPAT), which has been described 305, 140-142.

izim et al. in Nature (1933 ', po usnvini animalv iso;

The male opragueDawley weighs 160-200 g. After cutting off the head, the brain is removed and the hippocampus is excised. The hippocampus tissue is separated in an Ultra-Turrax Polytron for 30 seconds at half maximum speed in 10 volumes of 50 mil Tris buffer with p ”. set at 7.4 (i.e., 100 mg fresh tissue per ml). The homogenized tissue is then washed three times at 4 [deg.] C., centrifuged at 48,000 * g each time, and the sediment obtained is then suspended in fresh chilled buffer for 10 minutes. Finally, the last sediment is suspended in buffer to a concentration of 100 mg of starting tissue per milliliter of 50 ml: buffer. Incubation is then carried out at 37 ° C for 10 minutes.

Binding with [1 H] -8-OH-DPAT is determined by incubating 10 microliters of membrane suspension in a final volume of 1 ml of buffer containing 10 micromoles of pargylline.

After incubation, the membranes were re-isolated by filtration through a Whatman GF / S filter, which was washed three times with aliquots of 5 ml ice buffer. The filter is extracted in a scintillation liquid and its radioactivity is measured by liquid scintigraphy. The specific binding of [1 H] -8-On-DP / AT is defined as the amount of radioactivity retained on the filter and can be inhibited by coincubation in 10 µl of 5-hydroxytrvptamine. At a final concentration of 1 nM / H / -8-OH-DPAT, the specific binding represents 70-80% of the total radioactivity recovered on the filter.

For each concentration of test compound, the percentage inhibition of [@ ³ H] -8-OH-DPAT binding and then the concentration of C1g, i.e. the concentration that inhibits 50% of said binding, is determined. For the compounds of the invention, concentrations of Ο1-θ are between 0.001 and 0.3 micromoles.

Central nervous system activity of the compounds of the invention was evaluated by their effect on reserpine-induced PGO (ponto-geniculo-occipital) peaks (PGO-R test)

3 occavau cats by the method of H. Deooorlers, et al., Sleep 1 976, 3rd Europ. Congr. Sleep Res., Montpellier 1976, 333-361

oas ne '. At the time of 39 minutes after the intraperitoneal injection, a dose of 0.75 mg / kg was searched; Eating curative cats under artificial respiration cumulative doses of study compounds (0.003 to 3 mg / kg, intravenous). Electroencephalographic and phase (PCO-R peaks) activity is recorded using a cortical and deep electrode. For each dose of the test compound, the percentage reduction in the number of PGO peaks and then the dose of ^Α ^θ, which is the dose that reduces the number of these meshes by 50%, is determined. For compounds of the invention, the DA-range is from 0.003 to 3 mg / kg when administered intravenously.

The results of these tests show that the compounds of the formula I have a high affinity and selectivity towards serotonergic 5-HT 1A receptors in vitro. In vivo, these compounds exhibit agonist, partial agonist or antagonist activity at the level of these receptors.

The compounds of the invention can therefore be used for the treatment of diseases and conditions in which serotonin ergic receptors of the 5-KT _1A type play an effective role, either directly or indirectly, in particular. for the treatment of depressive states, anxiety states, sleep disorders, for regulating food intake, and for the treatment of vascular, cardiovascular or cerebrovascular disorders such as hypertension or migraine.

For this purpose, they may take any suitable form for their oral or parenteral administration, may be combined with any suitable pharmaceutical excipients and are dosed at a daily dose of 1 to 1000 mg.

/ Λ

JUDr. Jarmila Traplovdi

4os ~ / - ‘jy

Claims (3)

PATENT CLAIM Compounds of formula (I) R ΑΛ3Γ3Ο * I ΑΣ.3 í ' ^r . · 25 · ~ η í ® i t 6 !! / ε C! ; r · '(I) in which X represents a hydrogen atom or a methyl or methoxy group, Y represents a halogen atom or a methyl or methoxy group; and R is -Z-R ', wherein Z is -CH ₂ - or -CO-, and R' is phenyl optionally bearing one to three substituents selected from the group consisting of halogen atoms, trifluoromethyl, linear or branched alkyl groups having 1 to 3 carbon atoms and linear or branched alkoxy groups having 1 to 3 carbon atoms, as well as their acid addition salts. 2. A process for the preparation of compounds according to claim 1, characterized in that the 1,2,3,4-tetrahydro-isoquinoline of the formula II in which X and Y are as defined in claim 1 is reacted with a tosylate of of formula III TosO (III) CO-R wherein Tos is a tosyl group and R is as defined in claim 1, either in the absence or in the presence of an inert solvent such as dimethylformamide, toluene or xylene, at a temperature of 20 to 150 ° C and optionally in the presence of an organic base such as a tertiary amine or an inorganic base such as a carbonate or bicarbonate of an alkali metal, to give a compound of formula Ia is then when it is desired to prepare a compound of formula I in which Z is _-CH2-, a compound of formula Ia reducing with a hydride or a complex boron or aluminum hydride such as. lithium aluminum hydride, aluminum hydride, diborane / tetrahydrofuran complex or diborane / dimethylsulfide complex, in an ether solvent such as diethyl ether, tetrahydrofuran or dioxane at a temperature of 20 to 100 ° C. 3. A pharmaceutical composition comprising a compound according to claim 1 in combination with a pharmaceutical excipient. JUDr. Jarmila Traplová