FR2564462A1 - 2-phenylmorpholine derivatives which are useful in therapy - Google Patents

Abstract

The present invention relates to novel 2-phenylmorpholine derivatives, characterised in that they are chosen from: - 2-(ortho-methylphenyl)-4-(tert-butyl)morpholine; - 2-(para-methylphenyl)-4-(tert-butyl)morpholine; - 2-(meta-(trifluoromethyl)phenyl)-2-hydroxy-4-ethylmorpholine, and their addition salts; - and the compositions for therapeutic use containing at least one of the said derivatives. n

Description

Derivatives of 2-phenyl-morpholine useful in therapeutics.

 The present invention relates to novel products which are derivatives of 2-phenyl morpholine and which are useful in therapy.

 Various derivatives of the 2-phenyl-morpholines family have already been described and some of these derivatives may have interesting pharmacological properties, especially as exciting agents, stimulants, tranquillizers, sedatives, anti-inflammatories, analgesics and / or hypotensive.

We have just discovered that, among the derivatives of this family, the following products
a) (orthomethylphenyl) -2-tert-butyl-4-morpholine
b) (paramethylphenyl) -2-tert-butyl-4-morpholine
c) (metatrifluoromethyl) 2-phenyl-2-hydroxy-4-ethyl-4-morpholine and their salts had remarkable pharmacological properties which are described below.

 The present invention thus relates to said novel products, their preparation product and the drugs containing said products.

 The term "addition salts" means the addition salts with pharmaceutically acceptable inorganic and organic acids and the ammonium salts. The salts with hydrochloric acid are the preferred products.

Products a) and b) are prepared by a process consisting of cyclizing a 2- (N-alkyl-N-ss-hydroxyethyl) -amino-1-tolylethanol of formula

wherein the tolyl radical is selected from ortho and para tolyl and R is tert-butyl radical, said cyclization being
made with concentrated sulfuric acid at a temperature
of the order of 0 to 250C.

 Product c) is prepared by direct reaction of metatrifluoromethylacetophenol carrying a bromine atom on ethylamino-2-ethanol, said reaction being carried out in a solvent such as ether.

These two syntheses can therefore be represented schematically from the acetophenone derivative by the following equations:
a) and b)
tolyl-COCH3 + Br2 # tolyl-COCH2Br
tolyl-COCH2Br + t Bu-NH-CH2-CH2OH

<tb><SEP> t <SEP> tolyl-CO-CH2-N / <SEP> t <SEP> Bu
<tb><SEP>'<SEP> tolyl-CO-CH2-N
<tb><SEP> \ <SEP> CH2-CH20H
<tb><SEP> 22
<tb><SEP> t <SEP> Bu
<tb> tolyl-CO-CH2 <SEP> + <SEP> + <SEP> NaBH4 <SEP> (hydrogenation)
<tb><SEP> CH2-CH20H
<tb><SEP> t <SEP> Bu
<tb><SEP> tolyl <SEP> CHOH-CH2-N
<tb><SEP> CH2-CH2OH
<tb><SEP> t <SEP> Bu
<tb><SEP>.<SEP> tolyl-CHOH-CH2-N <SEP> cyclization <SEP> product
<tb><SEP> final
<tb><SEP> C112-CH2OH <SEP> (S04H2)
<tb>. Finally, the hydrochloride is produced.

tolyl-COCH2Br . tolyl-COCH2Br + C2H2 -NH-CH2-CH2OH

c) tolyl-COCH3 + Br2

tolyl-COCH2Br. tolyl-COCH2Br + C2H2 -NH-CH2-CH2OH

<tb><SEP> 5 <SEP> N <SEP> 2 <SEP> 3
<tb> tolyl <SEP> 7 (c'N-CH2'CH3
<tb><SEP> OH
<Tb>
According to the invention, there are also provided pharmaceutical compositions which comprise, in combination with known physiologically acceptable excipients, at least one product such as a) b) c) or at least one salt of said products.

 The following examples illustrate the invention.

Example 1
Process for the preparation of (paramethylphenyl) -2-tert-butyl-4-morpholine

 A solution of 36.64 g (0.172 mol) of paramethyl-α-bromoacetophenone in acetone in a solution of 80.4 g (0.887 mol) of tert-butylamino-2-ethanol is added dropwise. Refluxed for 4 hours. The following successive operations are then carried out: the mixture is evaporated to dryness, taken up in water and extracted with ethyl acetate, the solvent is washed with water and the solvent is extracted with 200 ml of water containing 20 ml of water. concentrated hydrochloric acid, the aqueous phase is washed with ethyl acetate, neutralized with sodium hydroxide, extracted again with ethyl acetate, washed. with water, the solvent is dried over magnesium sulfate and evaporated to dryness.

 The dry product obtained is taken up in 500 ml of absolute methanol and 10 g of sodium borohydride are added thereto. It is left in contact for several hours to carry out the reduction reaction; then 20 ml of acetic acid are added and then evaporated to dryness, extracted with ethyl acetate, the solvent washed with water and dried over magnesium sulfate. Then evaporate to dryness.

 The dry residue is then poured into 50 ml of concentrated sulfuric acid so as to carry out the cyclization.

 The mixture is allowed to stand for one hour and poured into a mixture containing 500 ml of water, 250 ml of 10 N sodium hydroxide solution and ice.

 The mixture obtained is extracted with ether, the ether is washed with water and dried over magnesium sulphate. It is possible on the product obtained to precipitate the hydrochloride by addition of hydrochloric ethanol and the product is purified by crystallization from a mixture of ether and ethanol.

dont on a déterminé par analyse une teneur en Cl de 13,32 % (Cl théorique 13,17 %). Le produit a une température de fusion instantanée de 2280C.About 10 g of a product of formula (CRL 40 903) are thus obtained

analyzed by a Cl content of 13.32% (theoretical Cl 13.17%). The product has an instantaneous melting temperature of 2280C.

(CRL 40 910) dont la température de fusion est de 230 C. By a completely identical process, the product of formula

(CRL 40 910) having a melting point of 230 ° C.

Example 2
Preparation of (metatrifluoromethyl) 2-phenyl-2-hydroxy-ethyl-4-morpholine

 38 g (0.19 moles) of metatrifluoromethylacetophenone are dissolved in 300 ml of ether and 30.64 g (0.19 moles) of bromine are added dropwise. Allowed to react for about 1 hour, evaporated to dryness and left in a desiccator under vacuum, in the presence of KOH, to complete the drying.

 The residue is taken up in 300 ml of ether and this solution is poured into a solution of 34.08 g (0.38 mol) of ethylamino-ethanol in 400 ml of ether. It is allowed to react with stirring for 24 hours.

The following operations are then carried out
filtration of the insoluble material, washing with ether, washing with water, extraction of the ether with 200 ml of water containing 25 ml of concentrated hydrochloric acid, washing the aqueous phase with ether, neutralizing until at pH 11 with sodium hydroxide solution, extracted with ether, washed with water and dried.

 The hydrochloride of the product is filtered and precipitated by the addition of hydrochloric ethanol.

 Recrystallized from an acetone-alcohol mixture.

23 g of a product of formula (CRL 41 092) were thus obtained

 The analysis of the product obtained made it possible to determine a Cl of 11.9% (theory 11.40%); said product has a melting temperature of 1940C.

 The products according to the invention were subjected to the following tests in order to determine their pharmacological properties.

 Toxicity (intraperitoneal injection in mice).

- CRL 40 903
64 and 128 mg / kg: sedation, depressed respiration,
exophthalmos, no mortality
256 mg / kg: convulsions and death
- CRL 40 910
64 mg / kg: dyspnea, sedation
128 mg / kg: dyspnea, sedation, hyporeactivity
to the touch, no mortality
. 512 and 256 mg / kg: respiratory depression,
mydriasis, convulsions and death
1024 mg / kg: convulsions and death
- CRL 41 092
64 mg / kg: no reaction
128 mg / kg: sedation, staggering gait, no
mortality
256 mg / kg: same symptoms as for 128 mg / kg,
no mortality
. 512 mg / kg: convulsions and death
1024 mg / kg: convulsions and death
Global behavior and reactivities
The three products, in solution in distilled water (pH 5), were administered intraperitoneally in mice (male, NIMRI, Evic Ceba) and in rats (male, CD> SPRAGUE DAWLEY
Charles River).

 The following results were noted: 15 min, 30 min, 1 h, 2 h, 3 h and 24 h after administration.

- CRL 40 903
In mice at doses used 1 mg / kg, 4 mg / kg,
16 mg / kg and 64 mg / kg, no changes were observed.
behavior and reactivity.

In rats at 32 mg / kg sedation was observed
(for 1 hour), depressed breathing (during
15 min) and mydriasis (for 3 hours).

- CRL 40 910
In mice at 64 mg / kg, sedation was observed (for 30min to 3h), depressed respiration
(for 30 minutes to 3 hours) and hypothermia
moderate (for 30 min).

- CRL 41 092
In mice a dose of 32 mg / kg causes a
moderate hypothermia (for 30 min) and one dose of
128 mg / kg causes sedation (for 30 min) with
decreased reaction of fear, responsiveness
touch and muscle tone.

In the rat, a dose of 64 mg / kg causes
fugitive sedation with decreased responsiveness
touch and muscle tone.

Action on the cardiovascular system
Four dogs, anesthetized with nembutal, received intraduodenally the products of the invention at successive doses of 0.5 - 1 - 2.5 - 5 - 10 - 20 mg / kg; then, in some cases, an additional dose of 10 mg / kg was injected intravenously.

 Blood pressure, heart rate, femoral artery flow, vertebral arterial flow, rectal temperature are measured. The coloration of the skin and the coloration of the bile collected by catheterization of the bile duct are observed after ligation of the cystic.

 The following findings were made.

-CRL 40 903
CRL 40 903 is tachycardic starting at a dose of 1 mg / kg. The femoral flow rate increases to 2.5 mg / kg. There is no increase in vertebral flow. No effect appeared on the blood pressure.

 The rectal and cutaneous temperatures rise as well as the venous pressure.

 The effects of isoprenaline tested after the cumulative dose of 39.1 mg / kg ID are very significantly decreased on diastolic blood pressure and moderately decreased on heart rate: at lc mcg / kg of isoprenaline, diastolic blood pressure passes from 120 mmHg to 60 mmHg after product, instead of 106 mmHg to 28 mmHg in control, and the heart rate goes from 195 beats / min to 275 beats / min, instead of 150 beats / min to 285 beats / min as a witness .

 Norepinephrine hypertension was not changed at 2 mcg / kg norepinephrine, systolic blood pressure increased from 176 mmHg to 252 mmHg, compared with 140 mmHg at 264 mmHg as control.

The propanolol 1 mg / kg injected at the end of the test brings the heart rate to 160 beats per minute and does not reduce the femoral flow rate to its control value since it is still at 125 ml / min.

 In conclusion, studied intraduodenally, then intravenously, in two anesthetized dogs, CRL 40 903 has no effect on blood pressure; it is tachycardic starting from 1 mg / kg. The femoral flow rate increases from 2> 5 mg / kg (maximum + 150% to 20 mg / kg). Vasodilation is not completely suppressed by propanolol.

 Rectal and cutaneous temperatures rise.

Hypertension with norepinephrine is not modified;
The hypotension to isoprenaline is decreased.

- CRL 40 910
CRL 40 910 is tachycardic starting at 1 mg / kg.

The femoral flow increases at the dose of 0.5 mg / kg very importantly, as well as the vertebral flow.

 At 10 mg / kg, a decrease in diastolic blood pressure is observed. The rectal and cutaneous temperatures rise gradually. Breathing is stimulated on the four dogs. Venous pressure recorded on three dogs is slightly increased.

 The effects of isoprenaline tested after the cumulative dose of 19 19.1 mg / kg CRL 40 910 are not changed: at 3 mcg / kg of isoprenaline, the diastolic blood pressure increases from 101 mmHg to 44 mmHg, at instead of 128 mmHg to 36 mmHg in control, and the heart rate goes from 187 beats / min to 269 beats / min after CRL 40 910, instead of 152 beats / min to 269 beats / min in control value.

 Norepinephrine hypertension is slightly decreased: at 2 mcg / kg norepinephrine, the systolic blood pressure increases from 165 mmHg to 256 mmHg, compared to 158 mmHg to 278 mmHg as a control.

 The injection of propranolol at 1 mg / kg IV into the four dogs blocked the effects of CRL 40 910 on heart rate and vertebral flow, without reducing the femoral flow rate to its control level (80 ml / min). .

 In conclusion, CRL 40 910, intraduodenally in anesthetized dogs, increases femoral and vertebral flow rates significantly, at very low doses (0.5 mg / kg). Tachycardia appears at 1 mg / kg, but remains low.

 Breathing is stimulated on the four dogs. The rectal and cutaneous temperatures rise gradually, as well as the venous pressure.

 The effects of isoprenaline are not changed noradrenaline hypertension is decreased.

The effects of CRL 40 910 on heart rate and vertebral flow are antagonized by propranolol at 1 mg / kg
IV; on the other hand, the increase in femoral flow is not totally inhibited.

 CRL 40 910 has been shown to be active as a peripheral vasodilator at a dose of 2 capsules per day dosed at 5 or 10 mg per os in the human clinic.

- CRL 41 092
CRL 41 092 strongly increases femoral flow rates at a dose of 1 mg / kg, while a modest and dose-independent decrease in vertebral flow is observed.

 A magnification of the skin begins to appear at 10 mg / kg. The heart rate is not changed. Rectal and cutaneous temperatures decrease slightly.

 The effects of isoprenaline tested after the cumulative 39 mg / kg intraduodenal dose of CRL 41 092 are slightly decreased. At 3 mcg / kg of isoprenaline diastolic blood pressure increased from 144 mmHg to 48 mmHg instead of 142 miRg to 33 mmHg in control and the heart rate rose from 171 beats / min to 234 beats / min after CRL 41 092 instead from 180 beats / min to 265 beats / min.

 Hypertension with norepinephrine is moderately increased. At 2 mcg / kg norepinephrine, the systolic blood pressure went from 202 mmHg to 343 mmHg instead of 188 mmHg in control value.

 In conclusion, in the anesthetized dog administered intraduodenally, CRL 41 092 strongly increases the femoral flow rate from 1 mg / kg. There is a decrease in vertebral flow as well as rectal and cutaneous temperatures.

 The heart rate is not changed and the blood pressure tends to increase.

 I1 is very slightly R I and ss 2; it increases the hyper- tension to norepinephrine. Propanolol, injected at the end of the test to a dog, decreases the heart rate; the femoral flow rate drops very slightly but remains above its control value.

 CRL 41 092 has been shown to be a sedative in human therapy at a dose of 2 capsules per day of 15 mg orally.

Claims (2)

 1. New derivatives of 2-phenyl morpholine characterized in that they are selected from  - (orthomethylphenyl) -2-tert-butyl-4-morpholine  - (paramethylphenyl) -2-tert-butyl-4-morpholine  - (metatrifluoromethyl) 2-phenyl-2-hydroxy-ethyl-4  morpholine and their addition salts.  2. Therapeutic composition characterized in that it contains, in combination with a physiologically acceptable excipient, at least one new derivative according to claim I.