FR2584402A2 - New 4-(arylpiperazinylethylaminoethoxy)phenol derivatives, method for their preparation and their therapeutic application - Google Patents

Abstract

The derivatives forming the subject of the present invention are represented by the general formula: in which R5 represents either a phenyl ring substituted by one or more substituents, which can be similar or different, chosen from the hydroxyl, methoxy, ethoxy, propoxy, chloro or methyl groups, or a 2-, 3- or 4-pyridyl ring. These products can be in the form of free bases or of salts of pharmaceutically compatible acids, such as their hydrochlorides. They are prepared, for example, from a suitably substituted arylpiperazine and a 4-(2-haloethoxy)-5-isopropyl-2-methylphenol. Application of the products according to the present invention in cardiovascular and antiallergy therapeutics.

Description

 This certificate of addition to French patent No. 84 12 580 filed on 07.08.1984 concerns new phenoxypiperazine derivatives, their method of preparation and their therapeutic application.

dans laquelle n est égal a O ou 1, R1 représente un atome dthydrogène ou un groupement méthyle, et R2, R3, R4, semblables ou différents représentent
H ou un substituant alcoxy ( par exemple méthoxy, éthoxy ), trifluorométhyle, chloro, fluoro ou alkyle ( par exemple méthyle ou éthyle ), ces produits peuvent être sous forme de base libre ou de sels d'acides pharmaceutiquement compatibles tels que leurs chlorhydrates.French Patent No. 84 12 580 relates to products of general formula (I)

in which n is equal to O or 1, R1 represents a hydrogen atom or a methyl group, and R2, R3, R4, similar or different represent
H or an alkoxy (for example methoxy, ethoxy), trifluoromethyl, chloro, fluoro or alkyl (for example methyl or ethyl) substituent, these products can be in the form of a free base or of pharmaceutically compatible acid salts such as their hydrochlorides.

dans laquelle R5 représente soit un cycle phényle substitué par un ou plusieurs substituants semblables ou différents choisis dans le groupe hydroxy, méthoxy, éthoxy, propoxy, chloro ou méthylé, soit un cycle pyridyl-2, -3 ou -4. Ces produits peuvent être sous forme de base libre ou de sels d'acides pharmaceutiquement compatibles tels que leurs chlorhydrates.The products covered by this addition certificate have the general formula

in which R5 represents either a phenyl ring substituted by one or more similar or different substituents chosen from the hydroxy, methoxy, ethoxy, propoxy, chloro or methyl group, or a pyridyl-2, -3 or -4 ring. These products may be in the form of the free base or of salts of pharmaceutically compatible acids such as their hydrochlorides.

 The new products which are the subject of this addition certificate have pharmacological properties allowing them to be used in human and veterinary therapy, in particular in cardiovascular, psychotropic, lipid-lowering and anti-platelet therapy.

The term halo designating, in the following text, a bromine or chlorine atom, the products of formula II are generally prepared by a reaction involving a (2-halo-ethoxy) -4-isopropyl-2-methyl-2 phenol and an arylpiperazine of general formula (III) in which R5 represents either a phenyl ring substituted by one or more similar or different substituents chosen from the group hydroxy, methoxy, ethoxy, propoxy, chloro or methyl, or a pyridyl-2 ring, -3 or -4.

 The following examples will better illustrate the present invention without, however, limiting its scope.

Example 1
5-isopropyl-2-methyl-2 ((4-methoxy phenylpiperazinyl) ethoxy) -4 phenol or COR28 60 dihydrochloride; dihydrochloride of the product of formula (II) in which R5 = 4-methoxyphenyl.

Synthesis 5.5 g of (2-bromo-ethoxy) -4 isopropyl-5-methyl-2-phenol and 9.6 g of (4-methoxy-phenyl) piperazine are dissolved in 100 cm3 of ethanol. This solution is heated for 12 hours at reflux with stirring. The solvent is evaporated in vacuo. The residue is made alkaline with a dilute ammonia solution, then extracted with chloroform. The chloroform solution is dried, the solvent is evaporated and the residue is taken up in a dilute solution of hydrochloric acid and then extracted with chloroform. The chloroform phase is washed using a dilute hydrochloric acid solution, then dried and evaporated. The crude product thus obtained is purified by recrystallization from a mixture of 40 ml of methanol and 120 ml of ethyl ether. Yield 42Z.

Physicochemical properties
Melting point of the dihydrochloride measured using a Mettler FP5 device: 181.9 - 182.8 C
NMR spectrum of the dihydrochloride in DMSOD6: 1.1 ppm, 6 protons, doublet, C (CH3) 2; 2.1 ppm, 3 protons, singlet, CH3 on the phenolic cycle; 2.9-4.1 ppm, 14 protons, complex massif, 5 CH2-N + -CH- +
OCH3 at 3.7 ppm; 4.4 ppm, 2 protons, poorly resolved triplet, oCH2; 6.7 and 6.8 ppm, 2 protons, singlets, aromatic protons of the phenol ring; 7.1 ppm, 4 protons, seventh AA '' BB ', aromatic protons of the phenylpiperazine ring; 9.5-12.7 ppm, 3 protons, very spread peaks, labile protons; exchangeable with D20.

Example 2
5-isopropyl-methyl-2 hydrochloride ((2,3-dimethylphenylpiperazinyl) ethoxy) -4 phenol or COR28 61; hydrochloride of the product of formula (II) with
R5 = 2,3-dimethylphenyl.

Synthesis
The mixture consisting of 8.19 g of brom> 4-ethoxy-5-isopropyl-2-methyl-phenol, 3.8 g of (2,3-dimethylphenyl) piperazine, 100 ml of ethanol and 40 ml of triethylamine is heated for 12 h at reflux. The reaction mixture is then evaporated in vacuo and the residue is taken up in a dilute ammonia solution and then extracted with chloroform. The chloroform solution is dried and evaporated. The residue obtained is taken up in a dilute solution of hydrochloric acid and then extracted with chloroform; the chloroform phase is washed with a dilute solution of hydrochloric acid and dried; the chloroform is evaporated. The liquid residue obtained is triturated in ethyl ether. The crude solid obtained is purified by recrystallization from 35 ml of methanol. Yield 49z.

Physicochemical properties
Melting point of the hydrochloride measured using a Mettler FP5 234 OC device.

NMR spectrum of the hydrochloride in DMSOD6: 1.1 ppm, 6 protons, doublet,
C (CH3) 2; 2.1 - 2.2 - 2.23 ppm, 9 protons, singlets, 3 CH3 on the phenyl rings; 2.9-4.0 ppm, 11 protons, complex, 5 CE2-N + -CH4.4 ppm, 2 protons, poorly resolved triplet, OCH2; 6.7 and 6.8 ppm, 2 protons, singlets, aromatic protons of the phenolic cycle; 6.8-7.2 ppm, 3 protons, complex massif, aromatic protons of the phenylpiperazine ring; 8.9 ppm, 1 proton, dome, OH, exchangeable with D20; 11.9 ppm, 1 proton, dome, NH +, exchangeable with D2O.

Example 3
5-isopropyl-methyl-2 hydrochloride ((2-chloro-phenyl) piperazinylethoxy) -4 phenol or COR 28 64; hydrochloride of the product of formula (II) in which
R5 = 2-chloro-phenyl.

Synthesis
The mixture consisting of 8.19 g of 4-bromoethoxy-5-isopropyl-2-methyl-phenol, 3.93 g of (2-chloro-phenyl) piperazine, 100 ml of ethanol and 40 ml of triethylamine is heated for 12 h at reflux. . The reaction mixture is then evaporated in vacuo and the residue is taken up in a dilute ammonia solution and then extracted with chloroform. The chloroform solution is dried and evaporated. The residue obtained is taken up in a dilute solution of hydrochloric acid and then extracted with chloroform; the chloroform phase is washed with water and dried over anhydrous sodium sulfate; the chloroform is evaporated. The solid obtained is triturated in ethyl ether to remove the excess of brominated derivative, then purified by recrystallization from a methanol-ethyl ether mixture. Yield 26 Z.

Physicochemical properties
Melting point of the hydrochloride measured using a Mettler FP5 205.2 OC device.

NMR spectrum of the hydrochloride in DMSOD6: 1.1 ppm, 6 protons, doublet,
C (CH3) 2; 2.1 ppm, 3 protons, singlet, CH3 on the phenolic cycle; 2.9-4.0 ppm, 11 protons, complex massif, 5 CH2 N + -CH-; 4.4 ppm, 2 protons, poorly resolved triplet, OCH2; 6.7 and 6.8 ppm, 2 protons, singlets, aromatic protons of the phenolic cycle; 6.9 - 7.7 ppm, 4 protons, complex massif, aromatic phenylpiperazine protons; 8.8 ppm, 1 proton, dome,
OH, exchangeable with D20; 11.5 ppm, 1 proton, dome, -NH, exchangeable with DO
Example 4
5-isopropyl-methyl-2 ((2-ethoxyphenyl) piperazinylethoxy) -4 phenol hydrochloride or COR 28 65; hydrochloride of the product of formula (II) in which
R5 = 2-ethoxyphenyl.

Synthesis
The mixture is heated under reflux of ethanol for 6 hours, with stirring, the mixture consisting of 8 g of (2-bromo-ethoxy) -4-isopropyl-5-methyl-2-phenol, 6 g of (2-ethoxy-phenyl) -4 piperazine, 100 ml of ethanol and 5 ml of triethylamine.

The reaction is followed by thin layer chromatography, eluting with a 10/90 V / V methanol / chloroform mixture. The solvents are evaporated. 150 ml of 1N hydrochloric acid are added to the evaporation residue; the mixture is subjected to strong stirring. The aqueous phase containing (2-ethoxyphenyl) -4 piperazine is eliminated. The pasty product is dissolved in methanol a few drops of concentrated hydrochloric acid are added to the methanolic solution which is concentrated in Rotavapor. Ethyl ether is added to precipitate the product which is filtered and redissolved in methanol. Neutralized using ammonia and the solvent is removed by evaporation. The evaporation residue is dissolved in chloroform; the solution is washed twice with water, dried over sodium sulfate. The chloroform is eliminated by evaporation. The product obtained is purified on a silica column, eluting first with chloroform and then with methanol / chloroform at 3 then 5%. The product obtained is dissolved in ethyl ether. It is transformed into the hydrochloride by addition of ethyl ether saturated with gaseous hydrochloric acid. The precipitate is filtered and then dried.

Yield 52 Z.

Physicochemical properties
Melting point measured using a Mettler FP5 device: 233.1 - 233.60C
NMR spectrum of the hydrochloride in DMSOD6: 1.1 ppm, 6 protons, doublet,
C (CH3) 2; 1.4 ppm, 3 protons1 triplet, CH3 of the ethoxy group; 2.1 ppm, 3 protons, singlet, CH3 on the phenolic cycle; 2.9-4.7 ppm, 15 protons, complex massif, 7 CH2 + -CH-; 6.6 - 7.1 ppm, 6 protons, complex massif, aromatic protons; 8.8 ppm, 1 proton, dome, OH, exchangeable with
D20; 11.7 ppm, 1 proton, dome, NH, exchangeable with D20.

Example 5
5-isopropyl-methyl-2 ((pyridyl-2) piperazinylethoxy) -4 phenol or COR 28 73 dihydrochloride; dihydrochloride of the product of formula (II) in which
R5 X pyridyl-2.

Synthesis
The mixture consisting of 8.1 g of 4-bromoethoxy-5-isopropyl-2-methylphenol, 15 g of 2-pyridyl piperazine and 100 ml of ethanol is heated with stirring for 8 h at reflux. The precipitate is removed by filtration. The filtrate is evaporated in vacuo. The evaporation residue is taken up in ethyl ether and extracted with a hydrochloric solution. The acidic aqueous phase is made alkaline, then extracted with chloroform. The chloroform phase is washed with water, dried over sodium sulfate and evaporated. The evaporation residue is dissolved in the minimum amount of methanol. Ethyl ether is added and the solution is saturated with gaseous hydrochloric acid. The precipitate formed is filtered and washed with ethyl ether. Yield 38%.

Physicochemical properties
Melting point of the dihydrochloride measured using a Mettler instrument
FP5: 213.7-215.20C.

NMR spectrum of the dihydrochloride in DMSOD6: 1.1 ppm, 6 protons, doublet, C (CH3) 2; 2.1 ppm, 3 protons, singlet, CH3 on the phenyl ring; 2.9-5.2 ppm, 13 protons, complex massif, 6 CH2 + -CH-; 6.6-8.3 ppm, 6 protons, complex massif, aromatic protons; 10.1 - 13.2 ppm, 3 protons, spreading peaks, OH + 2 NH, exchangeable with D20.

Example 6
5-isopropyl-methyl-2 (2-propoxy-phenyl) piperazinylethoxy-4-phenol hydrochloride or COR 2876; hydrochloride of the product of formula (II) in which
R5 - 2-propoxyphenyl.

Synthesis
The mixture consisting of 15 g of 4-bromoethoxy-5-isopropyl-2-methylphenol, 200 ml of ethanol, 8 g of (2-propoxyphenyl) piperazine and 20 ml of triethylamine is heated overnight at reflux. The solvent is removed by evaporation. The residue is dissolved in chloroform. The solution is extracted twice with 1N hydrochloric acid to remove the unreacted (2-propoxyphenyl) piperazine. The chloroform solution is dried and then evaporated. The residue obtained is taken up in ether, then filtered. The solid phase is dissolved in methanol. The solution is neutralized with ammonia to basic pH and then acidified with concentrated hydrochloric acid. The solvent is removed by evaporation. The residue is dissolved in chloroform; the chloroform phase is washed with water, dried, then evaporated. The residue is washed with a little ethyl ether and then is filtered.

Yield 73Z.

Physicochemical properties
Melting point of the hydrochloride measured using a Mettler FP5 223.2 - 223.6 C instrument.

NMR spectrum of the hydrochloride in DMSOD6: 0.8 - 1.4 ppm, 9 protons, complex solid, C (CH3) 2 + CH3 of the propoxy group; 1.8 ppm, 2 protons, multiplet, CCH2C of the propoxy group; 2.1 ppm, 3 protons, singlet, CH3 on the phenolic cycle; 2.9-4.7 ppm, 15 protons, complex massif, 7 CH2 (piperazine + 2 OCH2C + NCH2C) + -CH-; 6.6-7.2 ppm, 6 protons, complex massif, aromatic protons; 6 - 9 ppm, 1 proton, very spread peak, OH, exchangeable with D20; 12 ppm, 1 proton, dome, NH +, exchangeable with D2O.

Example 7
5-isopropyl-methyl-2 (2-hydroxyphenyl) piperazinylethoxy-4-phenol hydrochloride or COR 28 77; hydrochloride of the product of formula (II) in which
R5 w 2-hydroxyphenyl.

Synthesis
The mixture consisting of 20 g of 4-bromoethoxy-5-isopropyl-2-methylphenol, 150 ml of ethanol, 10 g of (2-hydroxyphenyl) piperazine and 20 ml of triethylamine is heated for 12 h at reflux. The solvent is removed by evaporation. Strip and then concentrated ammonia are added to the residue; two chloroform extractions are performed. The chloroform solution is dried and then evaporated. The residue obtained is taken up in 50 ml of methanol. A stream of gaseous hydrochloric acid is passed through the solution so as to synthesize the hydrochloride. After cooling, the precipitate is filtered, washed with methanol and then with ethyl ether. Yield 68%.

Physicochemical properties
Melting point of the hydrochloride measured using a Mettiez FP5 device: 279.1 - 279.3 OC.

NMR spectrum of the hydrochloride in DMSOD6: 1.1 ppm, 6 protons, doublet,
C (CH3) 2; 2.1 ppm, 3 protons, singlet, CH3 on the phenoxy cycle 2.8-4.0 ppm, 11 protons1 massive complex, 5 CH2 + -CH-; 4.4 ppm, 2 protons, poorly resolved triplet, 0CH2; 6.6-7.1 ppm, 6 protons, complex massif, aromatic protons; 8.9 and 9.4 ppm, 2 protons, wide peaks, 2 OH exchangeable with
D2O; 11.5 ppm, 1 proton, very spread peak, NH, exchangeable with D2O.

 The toxicopharmacological properties of the products which are the subject of the present invention will be described below.

P harmacotoxicology
Toxicity: Administered to the mouse orally at a dose of 300 mg / kg, COR 2860, COR 2861, COR 2864 cause no mortality; in this animal and by this route of administration, the LD50 of COR 2865 is 1444 (1212-1719) mg / kg.

Administered to mice intraperitoneally, COR 2860, COR 2861,
COR 2864, COR 2865 used at a dose of 200 mg / kg do not cause any mortality.

 Administered to mice intravenously, COR 2865 resulted in 0% mortality at 6.2 mg / kg, 10% at 12.5 mg / kg, 20Z at 25 mg / kg, 5% at 50 mg / kg and 90 % at 100 mg / kg.

 Alpha-1 blocking activity: it is determined in mice in the test of inhibition of mydriasis induced by norepinephrine. The animals receive the product to be tested intraperitoneally; 30 minutes later, they receive 0.75 mg / kg of norepinephrine intravenously. Under these conditions, COR28 65, a non-cholinergic product, administered at doses of 2.5 and 1 mg / kg, causes respectively 80 and 54 Z of inhibition of mydriasis, while labetalol causes 58 Z of inhibition at 25 mg / kg.

In vivo, the alpha blocking activity is also appreciated by the determination of the antagonism of the hypertension induced by phenylephrine.

The test products are administered intravenously to amyelated and bivagotomized rats according to the technique of J.S. Gillespie and T.S. Muir (Br.J. Pharmac. Chemother., 1967, 30, 78-87). The dose administered, the maximum activity recorded and the time after which the residual activity is equal to 50% of the maximum activity are indicated below: COR2860 (3.106 M / kg - 39.7% - 4 minutes ); COR2861 (3.10-6 M / kg - 66.4X - 9 min); COR2864 (3.10 M / kg - 98.6% - 37 min; COR2865 (10 M / kg - 121.8: 109 min; 3.10 7 M / kg - 116.1% - 32 min). The ED50 determined under these conditions for COR2865 is 1.17.10 8 mole / kg after 2 min, 3.18.10-7 7 mole / kg after 30 min and 5.0.10 7 mole / kg after 60 inn.

 Antihypertensive activity: the products to be tested are administered orally to alert rats who are spontaneously hypertensive. Blood pressure is measured indirectly on the tail 2, 4, 6 hours after administration of the product. For COR 28 65 administered at a dose of 100 mg / kg, the pressure reduction is 19, 21, 23 Z respectively at these times.

 The neuroleptic activity of COR28 65 was determined in the "climbing" test; preselected mice placed in cages specially fitted for the test receive the product to be tested intraperitoneally and their climbing behavior is rated from 0 to 2 within 30 min following the injection. As the animals do not have a significant agonist effect, they are administered 1.5 mg / kg of apomorphine so as to induce maximum hill climbing. Under these conditions, COR 28 65 results, at doses of 25 and 10 mg / kg respectively 100 and 83 Z of inhibition of climbing induced by apomorphine.

 Neuroleptic activity was also demonstrated in the test for the inhibition of apomorphine-induced stereotypies in rats; the animals receive the product to be tested intraperitoneally and then, 30 min later, 2.5 mg / kg of apomorphine subcutaneously; their behavior is noted for the next 30 minutes. Under these conditions, COR 28 65, administered at a dose of 100 mg / kg, inhibits by 67 X the stereotypes associated with apomorphine.

 Lipid-lowering activity: in mice made hypercholesterolemic by a diet rich in cholesterol and cholic acid for 7 days, the administration of 100 mg / kg of COR 28 65 orally, on the 60 and 70 day, leads to a decrease in serum cholesterol by 31% and a decrease in HP-betalipoproteins by 38% accompanied by a decrease in the VLDL + LDL / cholesterol ratio.

 Anti-platelet activity: platelet aggregation induced by 50 microg / ml of sodium arachidonate in the presence or not of 1 microg / ml of aspirin, in a rabbit plasma rich in platelets is inhibited by the products of the present invention; thus in the presence of aspirin, this inhibition is 100 X at concentrations of 2.5 microg / ml for COR28 60 and 5 microg / ml for COR28 64. In the absence of aspirin, this inhibition is 100 Z at concentrations of 5 microg / ml for COR28 60 and 10 microg / ml for C0R28 64.

 Given their low toxicity and their pharmacological properties and in particular their alpha-1 blocking and antihypertensive properties, the products which are the subject of the present invention can be used for example in the treatment of hypertension (alone or in combination with a diuretic or other antihypertensive drugs), in the treatment of peripheral vascular disorders such as acrocyanosis and Raynaud's syndrome, in the treatment of glaucoma.

 Given their anti-aggregation activity, the products which are the subject of the present invention are useful in the long-term treatment after myocardial infarction.

 Given their lipid-lowering activity, the products which are the subject of the present invention are useful in the treatment of hyperlipemia.

Given their neuroleptic activity, the products which are the subject of the present invention are useful in the treatment of psychoses, anxiety states and states of aggression.

 The doses and treatment regimens will depend on the subject and the condition to be treated. The products may be administered orally (for example in the form of capsules, tablets, oral drops), by injection (solution for injection for the intramuscular or intravenous route; solution for intravenous infusion), by rectal route (suppositories), locally (eye drops for the treatment of glaucoma, creams, ointments, gels). According to the indications, the daily dose will vary from 1 to 100 mg in 1 to 3 taken for the oral route, from 1 to 100 mg in 1 or 2 taken for the rectal route; the dose administered intravenously may vary between 0.1 and 10 mg. The eye drops will contain 0.05 to 0.5% of active ingredient and the ointments, creams or gels will contain 0.5 to 5% of active ingredient.

Claims (7)

1. New products of general formula

 in which R5 represents either a phenyl ring substituted by one or more similar or different substituents chosen from the group hydroxy, methoxy, ethoxy, propoxy, chloro or methyl, or a pyridyl-2, -3 or -4 ring, in base form free or pharmaceutically compatible addition salts.  2. Method for preparing the products according to claim 1, characterized in that a (2-halo-ethoxy) -4-5-isopropyl-2-methylphenol and an arylpiperazine of general formula are reacted

 in which R5 represents either a phenyl ring substituted by one or more similar or different substituents chosen from the hydroxy, methoxy, ethoxy, propoxy, chloro or methyl group, or a pyridyl-2, -3 or -4 ring  3. New drugs useful in human or veterinary therapy containing a therapeutically effective amount of at least one compound according to claim 1.  4. New drugs useful in cardiovascular therapy containing a therapeutically effective amount of at least one compound according to claim 1.  5. New drugs useful in psychotropic therapy containing a therapeutically effective amount of at least one compound according to claim 1.  6. New drugs useful in lipid-lowering therapy containing a therapeutically effective amount of at least one compound according to claim 1.  7. Pharmaceutical or veterinary composition characterized in that it contains, as active principle, at least one product according to claim 1 in combination with a pharmaceutical vehicle or an appropriate excipient.