FR2471378A1 - Alkylated 2:phenyl morpholine derivs. - having antidepressant and cardiovascular activity, prepd. by cyclising hydroxyalkyl phenyl ethanol(s) - Google Patents

Abstract

2-Phenyl morpholine derivs. of formula (I) and their acid addn. salts are new (where R1,R2 and R3 are each H or 1-4C alkyl, at least one of these being other than H). (I) are antidepressants and cardiovascular agents. (I) may be prepd. using a cpd. of formula (II) as starting material.

Description

Derivatives of 2-phenyl-morpholine, process for their preparation and their therapeutic application

 The present invention relates to 2-phenyl morpholine derivatives as new industrial products. It also relates to a process for their preparation and their therapeutic application, especially as active substances on the central nervous system and / or the cardiovascular system.

The products according to the invention are characterized in that they are chosen from the group consisting of: (i) 2-phenyl-morpholine derivatives corresponding to the
general formula

in which R11 R2 and R3, identical or different,
each represent the hydrogen atom or a group
C1-C4 alkyl, at least one of R1, R2 and R being 3
different from H; and (ii) their addition salts.

Of the C 1 -C 4 alkyl groups which
According to the invention, in the definition of the groups R 1, R 2 and R 3, the groups which are preferred from the point of view of the therapeutic properties are CH 3, CH (CH)
32 and C (CH3) 3.

By addition salts, here is meant the
acid addition salts obtained by reacting a free base of formula I with a mineral acid or
organic, and quaternary ammonium salts. Among
acids that can be used to salify the bases of
Formula I may include hydrochloric, hydrobromic, acetic, propionic, oxalic, fumaric, maleic, succinic, benzoic, cinnamic, mandelic, citric, malic, tartaric, p-toluenesulfonic and methanesulphonic acids. Among the compounds which make it possible to obtain ammonium salts, mention may in particular be made of ICH3 and ClCH3. Non-toxic acid addition salts are the preferred salts.

 In no way limiting, it is noted in Table I below a number of representative compounds according to the invention.

(où R1, R2 et- R3 sont définis comme ci-dessus) en milieu acide1 de préférence au moyen d'acide sulfonique, le mécanisme réactionnel étant le suivant::

The compounds of formula I can be prepared according to a method known per se by application of conventional reaction mechanisms. The process according to the invention for the preparation of a compound of formula I consists of cyclizing a 2- (N-hydroxyalkyl) amino-1-phenyl-1-ethanol of formula

(where R 1, R 2 and R 3 are as defined above) in an acidic medium, preferably by means of sulfonic acid, the reaction mechanism being as follows:

Advantageously this cyclization will be carried out at room temperature (15-25 C) for 1 hour using 300 to 800 ml of concentrated H2SO4 (d = 1.84) for 1 mole of IIo
The 2 - (- hydroxyalkyl) -amino-1-phenyl-1-ethanols of formula II which are used as starting materials in this cyclization reaction can be obtained according to the reaction scheme.

According to a variant of the process recommended above, it is also possible to prepare the compounds of formula I in which R 1 = CH 3 from a compound of formula I in which R 1 is, the reaction mechanism being, in this case, illustrated by the following scheme ::

 The compounds of formula I and their non-toxic addition salts are therapeutically useful.

They all act on the central nervous system (CNS) as anti-depressant agents. They also act on the cardiovascular system. They may be administered in humans for one or both of these properties, as the case may be.

 According to the invention, a therapeutic composition is recommended which is particularly useful in the treatment of diseases of the CNS and / or the cardiovascular system, characterized in that it contains, in association with a physiologically acceptable excipient, a pharmaceutically effective amount of at least one compound of formula I or one of its non-toxic addition salts.

 Other advantages and characteristics of the invention will be better understood on reading the following examples of preparation on the one hand, and the results of pharmacological tests, on the other hand. Nonlimiting examples of preparation have been given below.

PREPARATION I
Obtaining 2-phenyl-5,5-dimethyl morpholine fumarate

Example 1, CRL Code No. 40740 1) Preparation of 1-phenyl-2- (2-hydroxy-1,1-dimethylethylamino) -1-ethanol.

 A mixture of 60 g (0.5 mole) of styrene oxide, 45.5 g (0.5 mole) of 2-amino-2-methyl-1-propanol and 200 ml is refluxed for 4 hours. ethanol. It is evaporated to dryness, the residue is taken up in water and the insoluble material is collected by filtration, washed with water and then with acetone and, by drying, 50 g (yield: 45%) of phenyl-2- (2-hydroxy-1,1-dimethyl-ethylamino) -1-ethanol.

 Mp = 142.50 C.

20) Obtaining 2-phenyl-5,5-dimethyl morpholine.

 72.1 g (0.345 mol) of 1-phenyl-2- (2-hydroxy-1,1-dimethylethylamino) -1-ethanol are thrown in small shreds in 170 ml of concentrated H 2 SO 4 (d = 1.84), and then the reaction medium is stirred for 1 hour at room temperature (15-250 ° C.). The reaction medium is then poured into 500 ml of ice-water mixture. NaOH is added to pH 11. The mixture is extracted with diethyl ether, the ethereal phase is washed with water and dried over MgSO.sub.4. After filtration of MgSO 4, the ether phase is evaporated (to remove the ether) and the evaporation residue is distilled under vacuum. 51.4 g (yield: 77% of the expected free base are obtained.

Eb (8 mm Hg) = 132 - 134 C.

% N mésuré = 7,20% % N théorique = 7,32% 30) Obtention du CRL 40740
On dissout 5,8 g (0,05 mole) d'acide fumarique et 19,1 g (0,1 mole) de la base libre obtenue du point 20) ci-dessus, dans de méthanol au reflux.Analysis

% N measured = 7.20%% N theoretical = 7.32% 30) Obtaining the CRL 40740
5.8 g (0.05 mol) of fumaric acid and 19.1 g (0.1 mol) of the free base obtained from (20) above are dissolved in refluxing methanol.

After cooling, the expected fumarate is filtered,
Recrystallization from ethanol gives 17.8 g (yield = 71%) of CRL 40740. F = 18006 with decomposition.

%N mesuré = 5,60 % %N théorique = 5,62%
PREPARATION II
Obtention du fumarate acide de 2-phényl4-tertiobutyl-morpholine

Analysis

% N measured = 5.60% N% theoretical = 5.62%
PREPARATION II
Obtaining 2-phenyl-4-tert-butyl-morpholine acid fumarate

Example 5, Code No. CRL 40769
102.5 g (0.854 mol) of styrene oxide are poured dropwise into a solution of 100 g (0.854 mol) of 2-tert-butylamino-1-ethanol in 500 ml of methanol. Refluxed 6 hours, cooled, evaporated to dryness, the residue is taken up in water, extracted with methyl acetate and the ethyl acetate solution is washed with water. The ethyl acetate solution is extracted with water. 500 ml of water + 100 ml of concentrated HCl (d = 1.19). The aqueous phase is washed with ethyl acetate. The aqueous phase is neutralized with NaOH to a pH of 11, extracted with ethyl acetate and the organic phase is washed with water. dry on magnesium sulfate.

The ethyl acetate is evaporated to dryness and the evaporation residue which contains 2- (N-ss-hydroxy-ethyl-N-tert-butyl) -amino-1-phenyl-1-ethanol is collected.

 The residue is poured into 100 ml of concentrated H 2 SO 4 (d = 1.84). The sulfuric acid may be cooled, if necessary, by means of an ice bath so that the temperature of the reaction medium is less than or equal to about 250C. The mixture is stirred for 1 hour and then the reaction medium is poured into 500 ml of ice-water mixture. It is basified with NaOH and extracted with ethyl acetate. The organic phase (which contains the free base of CRL 40769) is washed with water and dried over MgSO4. After evaporation to dryness, 12 g (0.105 mol) of fumaric acid are added to the residue.

The resulting mixture is dissolved in hot methanol. Crystallization gives 10 g (yield 6.5%) of CRL 40769. F = 208-210 C with decomposition.

% N mesuré = 4,15% % N théorique = 4,17%
PREPARATION III
Obtention du fumarate acide de 2-phényl 4,5,5-triméthyl-morpholine

Analysis

% N measured = 4.15%% N theoretical = 4.17%
PREPARATION III
Obtaining the acid fumarate of 2-phenyl 4,5,5-trimethyl morpholine

Example 2: CRL Code No. 40742
19.1 g (0.1 mol) of the free base of CRL 40740 are dissolved in 10.4 ml of 99% formic acid. 11.7 ml of formol in 30% aqueous solution are added and the mixture is heated at 45-550 ° C. until the end of the CO 2 evolution. Evaporate to dryness. The residue is taken up in water. The mixture is basified with NaOH until pH = 11. It is extracted with diethyl ether, the ethereal phase is washed with water and dried over magnesium sulphate. It is filtered and evaporated to dryness to give 19.25 g (0.094 mol). ) of the free base of CRL 40742].

% N mesuré 4.33% % N théorique 4.36%
PREPARATION IV
Obtention du chlorhydrate de 2-phényl-4isopropyl-morpholine

100 ml of ethanol and 5.45 g (0.047 mole) of fumaric acid are added to the evaporation residue and dissolved in the hot state. It is cooled, evaporated to dryness and the residue is taken up in diethyl ether. The crystals are filtered and recrystallized in acetone. 12 g (yield: 37%) of CRL 40742 are obtained. F = 1400 Co
Analysis

% N measured 4.33%% N theoretical 4.36%
PREPARATION IV
Obtaining 2-phenyl-4isopropyl-morpholine hydrochloride

Example 4; CRL Code Number 40768
In a refluxing solution of 92.9 g (0.9 mol) of 2-isopropylaminoethanol in 500 ml of
CH 3 OH, 108 g (0.9 mol) of styrene oxide are added dropwise. The reflux is then maintained for 6 hours, cooled, evaporated to dryness, the evaporation residue is taken up in water and extracted with ethyl acetate. The ethyl acetate phase is washed with water and extracted. said phase with a mixture of 500 ml of water and 100 ml of concentrated hydrochloric acid (d = 1.19).

The aqueous phase is collected and washed with ethyl acetate and then basified with NaOH to pH 11. It is then extracted with ethyl acetate, washed with water, dried over MgSO 4, filtered and evaporate to dryness.

 The evaporation residue which contains 2- (N-ss-hydroxyethyl-N-isopropyl) -amino-1-phenyl-1-ethanol is poured into 50 ml of cooled concentrated sulfuric acid (d = 1.84). by means of an ice bath.

The mixture is stirred for 1 hour, the reaction mixture is poured into 500 ml of the water-ice mixture. The mixture is basified with sodium hydroxide to pH 11 and extracted with ethyl acetate.
The expected hydrochloride is precipitated with hydrochloric methanol. Recrystallization from acetone-ethanol (1: 1) v / v gives 20 g (30% yield) of CRL 40768 ° F = 198-2020 ° C. with decomposition.

,0 N mesuré = 5,72% % N théorique = 5,79%
Les résultats des essais pharmacologiques ont été résumés ci-après.Analysis

, 0 N measured = 5.72% N% theoretical = 5.79%
The results of the pharmacological tests have been summarized below.

A) CRL 40740 assays (example 1) 10) CNS effects
In treated animals, the main characteristic effects of amphetamine substances are observed:
-excitation in mice and rats, with increased reactivity and aggression,
- presence of stereotypical movements,
- existence of a particular toxicity in the grouped mice
- increase in motor activity which explains the improvement of motor recovery in the anoxic mouse, and the recovery of activity in the mouse accustomed to its enclosure,
-antagonism of hypothermia caused by apomorphine, reserpine or oxotremorine,
- a component α - stimulating (objectified by the reterpinic ptosis agonism) much less pronounced than that produced by amphetamine or ephedrine, but of the same order as that exerted by methylphenidate.

 Some anticholinergic activity may exist (mydriasis, antagonism of tremor and peripheral signs due to oxotremorine).

2) Effects on the cardiovascular system
CRL 40740 administered intravenously, is bradycardic starting at the dose of 5 mg / kg, femoral vasodilator from the dose of 10 mg / kg, and hypotensive from the dose of 20 mg / kg.

 CRL 40740 administered intraduodenally is not a femoral vasodilator.

 In short, on the cardiovascular system, CRL 40740 differs from amphetamine, which causes hypertension, tachycardia and a decrease in femoral flow.

 In conclusion the CRL 40740 seems to have properties of type B1.

B) CRL 40742 assays (example 2) 10) CNS effects
The neuropsychopharmacological study of CRL 40742 shows:
an excitation accompanied by hyperreactivity in the mouse and in the rat,
- stereotyped movements;
- hypermotility,
antagonism of hypothermia caused by reserpine, oxotremorine and apomorphine in mice;
a particular toxicity in the grouped mice;
These observations indicate that CRL 40742 is close to amphetamine substances.

20) Effects on the cardiovascular system
CRL 40 742 is administered to dogs anesthetized with nembutal. Depending on the route of administration, the effects of the product are diCerento
- intravenously, we find:
hypotension,
. a variable action on the frequency
cardiac (2/3 bradycardia, 1/3 tachy
cardie) and
a sharp increase in femo flow
ral, from 1 mg / kg;
- intraduodenally:
. hypertension,
. tachycardia, and
. a slight decrease in femoral flow
C) Tests for CRL 40750 (Example 3)
CRL 40 750 has a complex activity profile, although it can extract a number of effects which (i) bring it closer to that of apomorphine and (ii) differentiate it from it.

(i) Similar effects to those of apomorphino: oz hyperreactivity
presence of stereotypies (but less intense than with apomorphine), probably responsible for the potentiation of amphetamine,
. hypothermia
. biphasic action on spontaneous motility
Q increase in residual motility
. antagonism of neuroleptic catalepsy
antagonism of reserpine hypothermia.

(ii) Effects different from those of apomorphine.

Unlike apomorphine, the CRL 40 750:
- does not cause palpebral ptosis in the rat,
- does not oppose the reserpinic ptosis,
- does not involve aggressiveness, on the contrary, it reduces the aggressive behavior of the mouse
In addition, it causes the appearance of a mydriasis in the rat, and it opposes hypothermia and tremor caused by oxotremorine.

These two effects could be due to an anticholinergic component, although CRL 40 750 does not reduce the incidence of the peripheral effects of oxotremorine and does not oppose the toxic effects of eserin0.
Finally, the CRL 40 750 delays the onset of convulsions and death following asphyxial anemia caused by a curarisant. This effect, which disappears at doses that lead to hypermotility, may only reflect the action of CRL 40 750 on motility and / or temperature.

D) Tests relating to CRL 40,768 (Example 4)
The most remarkable fact observed in the study of CRL 40 768 is its biphasic dose-related effect on a number of tests:
- action on the temperature,
- action on motility,
- action on the four-plate test (presumably correlated with the effect on motility),
- action on resistance to asphyxial anoxia (in relation to effect on ethos temperature on motility);
- action on amphetamine stereotypies.

 Most of these actions may be suggestive of pre- and post-synaptic dopaminergic receptor activity but the absence of stereotypies in rats and mice, emetic effect in dogs, and Sulpiride antagonism. The hypomotility and hypothermia induced by CRL 40768 makes this hypothesis obsolete.

A pre- and then post-synaptic b-adrenergic mechanism seems more likely, supported by:
- the presence of salivation and mydriasis in high dose,
antagonism of the reserpinic ptosis,
- the biphasic effect on amphetamine stereotypies;
worsening of the lethal effects of hypobaric hypoxia already observed with ClonidineO
Moreover, CRL 40 768, despite its intrinsic hypothermic effect, is resistant to reserpine-induced hypothermies, lgoxotremorine and apomorphine, and therefore has potential antidepressive activity that is tricyclic or stimulant-like. 3-adrenergic receptors.

 Briefly, CRL 40768 has classical tricyclic or anti-stimulatory antidepressant activity, and it may have low antimanic activity and, to a lesser degree, antipsychotic activity.

 In addition CRL 40 768 was administered intraduodenally to dogs anesthetized with nembutal at doses of 2.5 mg / kg, 5 mg / kg, 10 mg / kg and 20 mg / kg. The results are as follows.

 At low doses: 2.5 and 5 mg / kg, stimulating actions are observed: increase in systolic, diastolic, differential and mean arterial pressures, increase in heart rate, respiratory stimulation.

 From 10 mg / kg, the increase in systolic blood pressure is less important; diastolic blood pressure decreases, resulting in a decrease in mean arterial pressure; and the heart rate remains very much increased.

AA small dose, CRL 40768 has one profile at a time (increase in heart rate up to 225 beats / min) and <+ mentation of systolic, diastolic, mean arterial pressures). It is an action of the norepinephrine type but which, by its duration, would rather suggest an action of the liberating type of norepinephrine.
At higher doses, this action decreases and even is reversed on the diastolic blood pressure; it may be a tachyphyllaxia phenomenon or the appearance of an ss2 + effect
E) Tests relating to CRL 40,769 (Example 5?
CRL 40 769 has some characteristics of antidepressants (antagonism of reserpine-induced hypothermies, oxotremorino or apomorphine), but the intensity of these effects remains modest. In addition, the presence of stereotyped movements, although fugitive and not very intense, could bring CRL 40 769 closer to amphetamine substances, despite the absence of hypermotility and clear sympathomimetic effects (mydriasis or antagonism of ptosis reserpine).

In addition, CRL 40 769 decreases intergroup aggression in mice and seems to result in a moderate potentiation of the lethal effects of electroshock.
CRL 40 769 administered intraduodenally to dogs anesthetized with nembutal, has a significant femoral and vertebral vasodilator activity from the dose of 1 mg / kg. These effects appear quickly and last more than 30 minutes. The maximum femoral vasodilator effect (+ 108%) is obtained at 2.5 mg / kg. At the same time, we observe a tachycardia0
Clinically, good results have been obtained in both the CNS and the cardiovascular system.

 CRL 40740 and 40742 have been successfully used as CNS stimulants in humans.

 CRLs 40750 and 40768 are psychotropic agents that have been used in humans as sedatives and antidepressants.

 CRL 40769 because of its good vasodilator properties has been used successfully in the treatment of pressure ulcers.

TABLE I

Example <SEP> No <SEP> of <SEP> code <SEP> R1 <SEP> R2 <SEP> R3 <SEP><SEP> Point of <SEP> Merge
<tb><SEP> 1 <SEP> (a) <SEP> CRL <SEP> 40740 <SEP> H <SEP> CH3 <SEP> CH3 <SEP> F <SEP> = <SEP> 180 C <SEP> ( d)
<tb><SEP> 2 <SEP> (b) <SEP> CRL <SEP> 40742 <SEP> CH3 <SEP> CH3 <SEP> CH3 <SEP> F <SEP> = <SEP> 140 C
<tb><SEP> 3 <SEP> (c) <SEP> CRL <SEP> 40750 <SEP> H <SEP> CH3 <SEP> H <SEP> F <SEP> = <SEP> 190 C <SEP> ( d)
<tb><SEP> 4 <SEP> (c) <SEP> CRL <SEP> 40768 <SEP> CH (CH3) 2 <SEP> H <SEP> H <SEP> F <SEP> = <SEP> 198- 202 C <SEP> (d)
<tb><SEP> 5 <SEP> (b) <SEP> CRL <SEP> 40769 <SEP> C (CH3) 3 <SEP> H <SEP> H <SEP> F <SEP> = <SEP> 208- 210 C <SEP> (d)
<tb> Notes
(a): fumarate; (b) = acid fumarate
(c): hydrochloride
(d): with decomposition

Claims (8)

Claims. 1. New derivative of Z-phenyl-morpholine characterized in that it is chosen from the group consisting of (i) the compounds corresponding to the general formula

 in which R1, R2 and R3, which may be identical or different, each represents a hydrogen atom or a C1 - C4 alkyl group, at least one of R1, R2 and R3 being different from H; and (ii) their addition salts. 2. New 2-phenyl-morpholine derivative according to claim 1, characterized in that R1, R2 and R3, which are identical or different, each represent H, CH3, CH (CH3) 2 or C (CH3) 3, with the additional proviso that at least one of R1, R2 and R3 is other than H. 3. 2-phenyl-5,5-dimethylmorpholine and its addition salts. 4. 2-phenyl-4,5,5-trimethylmorpholine and its addition salts. 5. 2-Phenyl-5-methylmorpholine and its addition salts. 6. 2-phenyl-4-isopropylmorpholine and its addition salts. 7. 2-phenyl-4-tert-butylmorpholine and its addition salts. 8. Process for the preparation of a 2-phenyl-morpholine derivative of the formula I according to claim 1, said process being characterized in that an 2- (N-hydroxyalkyl) -amino-1-phenyl- l-ethanol of formula

 where R1, R2 and R3 are defined as indicated above. 90. The method of claim 8 characterized in that the cyclization is carried out at 15-25 C in the presence of 300 to 800 ml of sulfuric acid density 1.84, for 1 mole of II. 10o therapeutic composition characterized in that it contains, in combination with a physiologically acceptable excipient, at least one 2-phenyl-morpholine derivative according to any one of claims 1 to 7, or one of its addition salts non-toxic