FR2534915A1 - New 2-(phenoxymethyl)morpholine derivatives, their therapeutic use and process for preparing them - Google Patents

Abstract

The present invention relates to 2-(phenoxymethyl)morpholine derivatives, as new industrial products, which are chosen from the set consisting of: i. the 2-[(2-chloro-3,5-dimethoxyphenoxy)methyl]-N-alkylmorpholine of general formula: in which: X represents CO or CH2 and R represents CH(CH3)2 or C(CH3)3, and; ii. their addition salts when X is CH2. These new products are useful in therapeutic treatment, especially as sedative agents.

Description

Novel 2- (phenoxymethyl) morpholine derivatives, therapeutic use and method of preparation

 The present invention relates as novel industrial products to 2- (phenoxymethyl) morpholine derivatives. It also relates to the therapeutic use and the method of preparation of these new products.

The novel 2- (phenoxymethyl) morpholine derivatives according to the invention are characterized in that they are selected from the group consisting of
(i) 2 - [(2-chloro-3,5-dimethoxyphenoxy)
methyl] -N-alkylmorpholine corresponding to the
general formula

(où R est défini comme ci-dessus), d'une part, et les 2-[(2-chloro-
3,5-diméthoxyphénoxy)-méthyl]-4-alkylmorpholine de formule

(où R est défini comme ci dessus) et leurs sels d'addition, d'autre part. where x is CO or CH2 and
R represents CH (CH 3) 2 2 or C (CH 3) 3; and
(ii) their addition salts when X is
The invention therefore relates to 2 - [(2-chloro-3,5-dimethoxyphenoxy) -methyl] -4-alkyl-5-morpholinone of formula

(where R is defined as above), on the one hand, and 2 - [(2-chloro
3,5-dimethoxyphenoxy) methyl] -4-alkylmorpholine of formula

(where R is defined as above) and their addition salts, on the other hand.

 The term "addition salts" here means, on the one hand, the acid addition salts obtained by reaction of a free base of formula III with inorganic and organic acids and on the other hand 'ammonium. Among the acids that can be used for salifying the bases of formula III, mention may in particular be made of hydrochloric acid, hydrobromic acid, acetic acid, propionic acid, oxalic acid, fumaric acid, maleic acid, succinic acid, benzoic acid, cinnamic acid, mandelic acid, citric acid, salic acid, tartaric acid, aspartic acid and glutamic acid. , methanesulfonic, p-toluenesulfonic. Among the compounds which make it possible to obtain ammonium salts, mention may be made especially of ICH3 and ClCH3. The acid addition salts, in particular the hydrochlorides, are the preferred salts.

 A number of compounds of formula I according to the invention have been recorded in no way limiting in Table I below.

TABLE I

<tb><SEP> Product <SEP> N <SEP> of <SEP> code <SEP> X <SEP> R <SEP><SEP> Point of <SEP> Merge
<tb> Example <SEP> 1 <SEP> CRL <SEP> 41 <SEP> 046 <SEP> CO <SEP> CH (CH3) 2 <SEP> 131 C
<tb> Example <SEP> 2 <SEP> CRL <SEP> 41 <SEP> 059 <SEP> CO <SEP> C (CH3) 3 <SEP> 142 C
<tb> Example <SEP> 3 <SEP> (a) <SEP> CRL <SEP> 41 <SEQ> 047 <SEP> CH2 <SEP> CH (CH3) 2 <SEP> 208 C
<tb> Example <SEP> 4 <SEP> (a) <SEP> CRL <SEP> 41 <SEP> 060 <SEP> CH2 <SEP> C (CH3) 3 <SEP> 235 C
<tb><SEP> Note
<tb><SEP> (a) <SEP>: <SEP> hydrochloride
<Tb>
The products of formula I are interesting in therapeutics. They act on the central nervous system as sedatives.

 According to the invention, it is advocated a therapeutic composition which is characterized in that it contains, in combination with a physiologically acceptable excipient, at least one derivative of formula I or one of its non-toxic addition salts when X = CH2, as active ingredient.

 In such a composition, the active ingredient is used, of course, at a therapeutically effective dose.

(où R est défini comme ci-dessus) avec un halogénure d'halogénoacétyle de formuls
Hal-CO-CH2-Hal (V) (où Hal est notamment Br ou Cl, le groupe Hal préféré sur le plan de la synthèse étant Cl) en présence d'un alcali (notamment choisi parmi KOH et NaCH), sous agitation et à une température comprise entre 0 et 5 C pendant au moins 1 h, pour obtenir un dérivé 1-(2- chloro-3,5-diméthoxyphénoxy)-3-(N-balogénoacétyl-Nalkylamino)-2-propanol de formule

The compounds of formula I may be prepared according to a method known per se by application of conventional reaction mechanisms. The process according to the invention consists in preparing a morpholinone of formula II
1) reacting a 3-alkylamino-1- (2-chloro-3,5-dimethoxy)
phenoxy) -2-propanol of the general formula

(where R is defined as above) with a haloacetyl halide of formers
Hal-CO-CH 2 -Hal (V) (where Hal is in particular Br or Cl, the group Hal which is preferred in terms of synthesis being Cl) in the presence of an alkali (in particular chosen from KOH and NaCH), with stirring and at a temperature between 0 and 5 ° C. for at least 1 h, to obtain a 1- (2-chloro-3,5-dimethoxyphenoxy) -3- (N-balogenoacetyl-N-alkylamino) -2-propanol derivative of formula

(where Hal and R are defined as indicated above) then
20) cyclizing the VI derivative; and - to prepare a morpholine of formula III, to reduixe the morpho
linone II using AlLiH4 in excess of the conditions
stoichiometric.

 The compounds of formula 17 may be prepared according to the procedures described by the applicant in its French patent application No. 82-17934 filed on the same day as the present invention.

Other advantages and characteristics of the invention will be better understood on reading the following non-limiting examples of preparation, but given in
as an illustration.

PREPARATION I
Obtaining 2 - [(2-chloro-3,5-dimethoxyphenoxy) methyl] -4-isopropyl-5-morpholinone
(Example 1, code nr: CRL 41,046) 1) 1- (2-Chloro-3,5-dimethoxyphenoxy) -3- (N-chloroacetyl-N-isopropyl)
amino) -2-propanol
In a suspension stirred vigorously and maintained between 0 and 5 ° C. of 30.8 g (0.0905 mole) of 1- (2-chloro-3,5-dimethoxyphenoxy) -3-isopropylamino-2-propanol hydrochloride (n of
Code: CRL 41 045), 7.65 g (0.1910 moles) of sodium hydroxide pellets in 90 ml of water and 180 ml of methylene chloride, poured in -30 min. 10.22 g (0.0905 g). mole) chloroacetyl chloride. Stirring is continued for 1.5 h, the organic phase is decanted and washed with water and dilute hydrochloric acid; after drying and evaporation of the solvent, 35 g (yield: about 100%) of the expected product which is in the form of a brown-orange oil are obtained.

(b) CRL 41,046
In a solution maintained at +5 ° C. of 0.0905 mol of the product of step a) in 160 ml of anhydrous ethanol, a solution of 6.8 g (0.1040 mol) is cast in 0.5 h. of potash in 85% pellets in 80 ml of anhydrous ethanol. Stir 1.5 h at room temperature (15-20 C) and bring to dryness the reaction medium. The residue thus obtained is taken up in warm ethyl acetate and the organic phase is then washed with water. The organic phase is dried over dry sodium sulphate and the solvent is evaporated to give 30.2 g of a beige powder.

After purification of this crude product by crystallization from isopropanol, 26.1 g (yield, 84%) of CRL 41,046 is obtained which is in the form of a beige powder, insoluble in water. F. inst. (Köfler) = 131 C.

PREPARATION II
Obtaining 2 - [(2-chloro-3,5-dimethoxyphenoxy) methyl] -4-isopropyl-morpholine hydrochloride
(Example 3, n code: CRL 42 047)
In a suspension maintained at -5 ° C. of 8 g (0.2111 mol) of LiAlH 4 in 300 ml of tetrahydrofuran, a solution of 20.8 g (0%) is introduced under a nitrogen atmosphere over a period of 1 hour. 0605 moles) of CRL 41,046 in 100 ml of tetrahydrofuran. It is stirred for 3 hours at room temperature (15-20 ° C.) and then for 1 h at 60 ° C., and the excess LiAlH 4 is neutralized by addition of 42 ml (0.4222 moles) of ethyl acetate. successively 8 ml of water, 8 ml of 4M sodium hydroxide and 24 ml of water, the mixture is stirred and the insoluble material is filtered off, the filtrate is brought to dryness; the residue thus obtained is taken up in diethyl ether which is treated with hydrochloric ethanol. After purifying the precipitate which formed by crystallization with carbon black treatment in the nil mixture ethemol methamol (2: 1) v / v, 16 g (yield: 72.25%) of CRL was obtained. 41 047 in the form of a slightly pink powder, soluble in water at 25 g / l. Finst. (Köfler): 208 C.

 The results of the tests which have been undertaken pharmacologically with the compounds according to the invention were resumed below. In these tests, the products to be studied in solution in distilled water (in the case of the derivatives of formula III, such as the products of Examples 3 and 4) or in suspension in an aqueous solution of gum arabic (in the case of the products Formula II, such as the products of Examples 1 and 2) were administered intraperitoneally in a volume of 20 ml / kg in male mice and in a volume of 5 ml / kg in male rats.

I - TESTS RELATING TO CIL 41 046
(product of example 1)
A - TOXICITY
CRL 41 046 shows in the mouse a DL-O (maximal non-lethal dose) higher than 2024 mg / kg ip.

B-GLOBAL BEHAVIOR and REACTIVITIES
Batches of six animals were observed before, then 15 min, 30 min, 1 h, 2 h, 3 h and 24 h after CRL 41 046 administration. We note the following
1) in the mouse
- the doses of 8 mg / kg, 32 mg / kg and 128 mg / kg
do not lead to clear symptoms,
doses of 256 mg / kg, 512 mg / kg and 1024 mg / kg
cause the onset of sedation; in part
the dose of 512 mg / kg causes (i) sedation
tlon for 3 hours with reduced reactivity
touch, strength and muslim tone,
(ii) piloerection (in four out of six animals)
for 3 hours, and (iii) depressed breathing
for 3 hours;
2) in rats
- doses of 4 mg / kg, 16-mg / kg and 64 mg / kg pro
do not mention any particular symptoms,
- the dose of 256 mg / kg leads to (i) a piloerection
(four animals out of six) for 3 hours and (ii) a
depressed breath for 3 h.

C - INTERACTION WITH APOMORPHINE
1) In the mouse
Lots of 6 mice receive CIL 41 046 half an hour before the subcutaneous injection of 1 or 16 mg / kg of apomorphine.

It is observed that, at a high dose (512 mg / kg), CRL 41 046 causes a drop in temperature and aggravates the hypothermic effect of apomorphine, without modifying the behavior of verticalization and stereotypies.

20) In the rat
CRL 41 046 is administered to batches of 6 rats half an hour before the subcutaneous injection of 0.5 mg / kg of apomorphine.

 Apormorphine-induced stereotypies are not modified by CRL 41 046.

D - INTERACTION WITH AMPHETANIN
Amphetamine (2 mg / kg) is injected intraperitoneally to groups of 6 rats half an hour after administration of CRL 41 046.

 It is observed that CRL 41 046 does not modify amphetamine stereotypes.

E - INTERACTION WITH THE RESERPINE
Four hours after the intraperitoneal injection of 2.5 mg / kg reserpine, lots of 6 mice receive CRL 41 046.

 It can be seen that CRL 41 046 does not appreciably modify resverpine hypothermia and ptosis.

F - INTERACTION WITH OXOTREMORINE
CRL 41,046 is administered in batches of 6 mice half an hour before the intraperitoneal injection of 0.5 mg / kg of oxotremorine.

1) Action on the temperature
At doses of 128 and 512 mg / kg, CRL 41 046 exerts a hypothermic effect and worsens the temperature decrease induced by oxotremorine. It should be noted that the CRL 41 046 at the dose of 512 mg / kg gives a toxic association with oxotremorine: on a batch of 6 animals, one sees at the instant T = 0 (administration of oxotremorine) the death animal, at the moment
T = + 1 h the death of 2 animals, and at the moment T = + 1.5 h the death of 1 animal.

2) Action on tremors
At the highest dose used (512 mg / kg), the
CRL 41 046 results in a moderate decrease in tremor intensity due to oxotremorine, possibly related to the occurrence of the toxic effects of CRL 41 046-oxotrèmorine.

3) Action on peripheral cholinergic symptoms
CRL 4f 046 does not substantially modify the signs of peripheral cholinergic stimulation due to liosotremorine.

G - ACTION ON THE TEST OF THE FOUR PLATES, TRACTION AND ELECTROCHOC
The test is convenient on batches of 10 mice half an hour after the administration of CRL 41 046.

 At the highest dose used (512 mg / kg), CRL 41 046 causes a decrease in the number of passages punished it does not cause major motor incoordination, it does not modify the convulsive and lethal effects of electroshock.

H-ACTION FOR SPONTANEOUS MOTILITY
Half an hour after receiving the CIL 41 046, the mice (6 per dose, 12 controls) are placed in an actimeter where their motility is recorded for 30 minutes.

At doses of 128 and 512 mg / kg, it is found that
CRL 41 046 markedly decreases spontaneous motor activity in mice.

I - INTERACTION WITH THE BARBITAL
Half an hour after the administration of CRL 41 046, batches of 10 mice receive an intraperitoneal injection of barbital (220 mg / kg).

 It is observed that CIL 41 046 hardly modifies the duration of barbiturate sleep.

J - ACTION ON "BEHAVIORAL DISASTER"
Half an hour after receiving CRL 41 046, batches of 12 mice are placed in a beaker filled with water to a height of 6 cm. The total duration of immobility between the 2nd and 6th minute after immersion is recorded.

 It can be seen that CRL 41 046 hardly modifies the duration of immobility "in despair". The few increases that are observed are only a reflection of the abnormally low score of the witnesses.

K - CONCLUSION
As a result of all these tests, CRL 41 046 is a sedative agent.

II - TESTING RELATED TO CRL 41 059
(product of example 2)
A - TOXICITY
CRL 41 059 present in male mice by ip route

LD-O greater than 1024 mg / kg.

B - GLOBAL BEHAVIOR AND REACTIVITIES
Following the procedures described above for CIL 41 046, we obtain the following results with the
CRL 41 059.

1) In the mouse
- at 8 mg / kg: no clear changes in behavior
and reactivity,
at 32 mg / kg: hypothermia (-2.7 C at 2 h, duration 24 h),
at 128 mg / kg: sedation for 2 h, decreased reactivity
1 hour hang and hypothermia (-3 C to 1 h,
durén 24 h),
- at 512 mg / kg: sedation for 2 7, decreased activity
for 1 h and hypothermia (-5.8 C to
30 min, for 24 hours).

2) In the rat
- 4 mg / kg, 16 mg / kg and 64 mg / kg: no modifications
net of behavior and reactivity,
at 256 mg / kg: hypothermia (-1 C to 1 h, duration 2 h) at
muscle tone decreased at 2 h, during 1 b.

C - CNS ACTION
The tests carried out with CIL 41 059 show that this product is a sedative agent; it induces hypomotility, causes hypothermia and worsens the hypotermia induced by reserpine.

III - TESTS RELATING TO CRL 41 047
(product of example 3)
A-TOXICITY
By ip in mice, CIL 41,047 has an LD-O greater than 128 mg / kg.

B - CLOBAL COMPONENT AND REACTIVITIES
Following the operating procedures given above for CRL 41 046, the following results are obtained with
CRL 41 047.

1) In the mouse
- at 1 mg / kg, 4 mg / kg and 16 mg / kg z no clear symptoms
at 64 mg / kg: sedation (0.5 h after administration),
dyspnea and piloerection.

at 128 mg / kg: convulsive movements appearing
4 min then dyspnea and sedation.

20) In the rat
- at 0.5 mg / kg, 2 mg / kg and 8 mg / kg no net symptoms,
at 32 mg / kg: sedation 30 min after administration,
mydriasis for 30 minutes and breathing
depressed for 30 min.

C - CNS ACTION
CNS trials show that; from a neuropsychopharmacological point of view, CIL 41 047 is a sedative agent; it aggravates the hypothermia induced by reserpine and oxotrémo.

rine.

IV - TESTS RELATING TO CRL 41 060
(product of example 4)
A - TOXICITY
In the male mouse, ip, the LD-O is greater than 128 mg / kg.

B - GLOBAL BEHAVIOR AND REACTIVITIES
By following them. operating procedures given above for the. CIL 41,046, the following results are obtained with the
CIL 41 060.

1) In the mouse
- from 1 to 16 mg / kg no clear symptoms,
at 64 mg / kg: sedation with decreased reactivity at
touching for 2 hours and depressed breathing
for 2 hours.

2) In the rat
- from 0.5 to 8 mg / kg: no clear symptoms,
- at 32 mg / kg: sedation for 1 hour and depressed respiration
for 2 hours.

C - TESTING ONMC
The neuropsychopharmacological study of CRL 41 060 shows that this product is a sedative agent; it causes hypomotility, leads to hypothermia and aggravates reserpine-induced hypothermia.

 Moreover, in clinical trials, CIL 41046 (product of Example 1) and CRL 41059 (product of Example 2) have been found to have good results in humans as sedating agents, 2 to 3 capsules per day, each capsule containing 100 mg of active ingredient.

Claims (10)

1. New derivative of 2- (phenoxymethyl) morpholine, characterized in that it is selected from the group consisting of  (i) 2 - ((2-chloro-3,5-dimethoxyphenoxy) methyl] -N-  alkylmorpholine answering the general formula

 (ii) their addition salts when X is CH2.  CH (CH 3) 2 or C (CH 3) 3; and  wherein X is CO or CH 2 and R is 2. New derivative of 2- (Phenoxymbthyl) -morpholine according to claim 1, characterized in that it is chosen from the group consisting of 2 - [(2-chloro-3,5-dimethoxyphenoxy) methyl) ] - 4-alkyl-5-morpholinone of formula

 where R is CH (CH3) 2 or C (CH3) 3 3. New 2- (phenoxymethyl) morpholine derivative according to claim 1, characterized in that it is chosen from the group consisting of  (1) 2 - [(2-chloro-3,5-dimethoxyphenoxy) methyl]  4-alkylmorpholine of formula

 where R is CH (CH3) 2 or C (CH3) 3; and (ii) their addition salts. 4. 2 - [(2-Chloro-3,5-dimethoxyphenoxy) methyl] -4-isopropyl-5-morpholinone. 5. 2 - [(2-Chloro-3,5-dimethoxyphenoxy) methyl] -4-tributyl-5-morpholinone. 6. 2 - [(2-Chloro-3,5-dimethoxyphenoxy) methyl] -4-isopropylmorpholine and its addition salts. 7. 2 - [(2-Chloro-3,5-dimethoxyphenyl) methyl] -4 tert-butylmorpholine and its addition salts. 8. Therapeutic composition characterized in that it contains, in combination with a physiologically acceptable excipient, at least one 2- (phenoxymethyl) morpholine derivative of formula I according to claim 1, or one of its non-addition salts. toxic. 9. A process for preparing a compound of formula I wherein X is CO according to claim 1, said process being characterized in that:  15) a 3-alkylamino-1- (2-chloro-3,5-dimethoxy) is reacted  phenoxy) -2-propanol of formula

 (where R is defined as above) with a halogenoacetyl halide of formula  Hal-CO-CH2-Hal (v) (where Hal is in particular Br or C1, the preferred Hal group being Cl), in the presence of an alkali (in particular chosen from ÙaOH and KOH), with stirring and at a temperature between 0 and 5 C for at least 1 hour, to obtain a 1- (2-chloro-3,5-dimethoxyphenoxy) -3- (N-haloacetyl-N-alkylamino) -2-propanol derivative of formula

 20) to cyclize the VI derivative thus obtained.  then,  (where Hal and R are defined as indicated above), 10. Process for preparing a compound of formula I or X is CH 2 according to claim 1, said process being characterized in that a 2- [2 (2-chloro-1,5-dimethoxyphenoxyp) methyl] -4-alkyl-5-morpholinone of the formula is reduced

 where R is CH (CH3) 2 or C (CH3) 3 'or LiAlH4 means.