Derivatives of 5-carbamoyloxymethyl-3-substituted-2-oxazolidinones, process of preparation thereof and therapeutic application

Abstract

A compound of the formula ##STR1## in which R is H, halogen, alkyl having 1 to 4 carbon atoms or trifluoromethyl, and R₁ and R₂ each is H or dialkylaminoalkyl or together with N comprise methylpiperazino. in which (1) ##STR2## is -NH₂ and R is H, m-CH₃, o-CF₃, m-Cl, p-Cl, m-Br, m-F, p-F, o-F, p-CH₃ or m-CH₃, or ##STR3## and R is H, m-CF₃ or m-F, or ##STR4## and R is H, m-CF₃ or m-F.

The compound is prepared by treating the corresponding 5-hydroxymethyl compound with ammonia or an amine in the presence of phosgene.

The compounds possess anti-depressive, myorelaxing, tranquilizing, sedative, analgesic, anti-convulsive, anti-pyretic, anti-inflammatory and uricosuric activities.

Description

This application is related to our application Ser. No. 20,020, filed Mar. 16, 1970 now abandoned.

The present invention concerns novel derivatives of 5-carbamoyloxy-methyl-3-substituted-2-oxazolidinone, their process of preparation and their therapeutic application.

The compounds according to the present invention correspond to the general formula: ##STR5## in which: R is a hydrogen atom, a halogen atom, an alkyl radical having 1 to 4 carbon atoms or a trifluoromethyl radical; and

R₁ and R₂ each represent a hydrogen atom or a dialkylaminoalkyl radical, or together with the nitrogen atom to which they are attached form a methylpiperazino radical.

in which (1) ##STR6## is --NH₂ and R is H, m-CF₃, o-CF₃, m-Cl, p-Cl, m-Br, m-F, p-F, o-F, p-CH₃ or m-CH₃, or ##STR7## and R is H, m-CF₃ or m-F, or ##STR8## and R is H, m-CF₃ or m-F.

The process for the preparation of the compounds according to the present invention comprises treating an oxazolidinone of the general formula: ##STR9## in which R has the same significance as in Formula I, with phosgene in the presence of ammonia or an amine of formula: ##STR10## in which R₁ and R₂ have the same significance as in Formula I.

The oxazolidinone of Formula II is prepared by cyclising, by the action of ethyl carbonate, a 1-phenylamino-2,3-propanediol of the general formula: ##STR11## in which R has the same significance as in Formula I.

The following preparation is given, by way of nonlimitative example, to illustrate the present invention.

EXAMPLE

5-carbamoyloxymethyl-3-m-trifluoromethylphenyl- 2-oxazolidinone (Code No. 68175).

(1) Preparation of 5-hydroxymethyl-3-(m-trifluoromethylphenyl)-2-oxazolidinone (Code No. 68121).

59 g. of 1-(m-trifluoromethylphenylamino)-2,3-propanediol and 118 g. of ethyl carbonate are introduced into a distillation apparatus. The mixture is progressively heated to about 110°C when dissolution is obtained. Then, 12 ml. of 5% solution of sodium methylate in methanol is added thereto. The distillation of the ethanol formed in the course of the reaction is then observed. Upon completion thereof, any excess ethyl carbonate is removed under reduced pressure; the solid residue obtained is crystallised in isopropyl ether.

Melting point=80°C

Yield=80%.

Empirical formula=C₁1 H₁0 F₃ NO₃.

Elementary analysis.--Calculated (percent): C, 50.58; H, 3.86; N, 5.36. Found (percent): C, 50.74; H, 3.76; N, 5.56.

(2) Preparation of 5-carbamoyloxymethyl-3-m-trifluoromethyl phenyl)-2-oxazolidinone.

300 ml. of a 20% solution of phosgene in toluene is rapidly added to a solution of 100 g. of 5-hydroxymethyl-3-(m-trifluoromethylphenyl)-2-oxazolidinone in 250 ml. of benzene. 63 g. of N,N-diethylaniline is then slowly added thereto with agitation. The hydrochloride which precipitates is dried and the clear organic solution also obtained is treated with a rapid current of gaseous ammonia. The solution is then treated with water, decanted and the organic phase is concentrated. The solid residue obtained is crystallised in absolute ethanol.

Melting point=123°C

Yield=50%.

Empirical formula=C₁2 H₁1 F₃ N₂ O₄.

Elementary analysis.--Calculated (percent): C, 47.37; H, 3.64; N, 9.21. Found (percent): C, 47.50; H, 3.86; N, 9.39.

The following Table I lists a certain number of intermediate compounds of Formula II prepared according to the first part of the above example, and Table II enumerates a certain number of compounds of Formula I prepared according to the second part of the above example.

TABLE I
__________________________________________________________________________
##STR12##
Elementary analysis
Code    Empirical
Mol.
M.P.,
Yield,
Calculated
Found
No. R   formula
Wt. °C
percent
C  H  N  C  H  N
__________________________________________________________________________
67360
H   C10 H11 NO3
193.20
129 75  62.16
5.74
7.25
63.20
5.87
7.40
68292
m.F.
C10 H10 FNO3
211.19
96  87  56.87
4.77
6.63
56.88
4.92
6.79
69155
p.F.
C10 H10 FNO3
211.19
116 68  56.87
4.77
6.63
56.97
4.77
6.83
69275
o.F.
C10 H10 FNO3
211.19
94  60  56.87
4.77
6.63
56.75
4.73
6.67
6922
p.Cl.
C10 H10 ClNO3
227.64
104 55  52.75
4.43
6.15
53.01
4.53
6.05
69204
p.CH3
C11 H13 NO3
207.22
145 66  63.75
6.32
6.76
63.93
6.10
6.88
69276
m.CH3
C11 H13 NO3
207.22
76  70  63.75
6.32
6.76
63.70
6.43
6.78
69217
o.CH3
C11 H13 NO3
207.22
64  69  63.75
6.32
6.76
63.71
6.37
6.88
__________________________________________________________________________

table ii
__________________________________________________________________________
##STR13##
elementary analysis
Code        Empirical
Mol.
M.P.,
Yield,
Calculated  Found
No. R   Salt
formula  wt. °C
percent
C  H  N  Cl C  H  N  C1
__________________________________________________________________________
6878
H   --  C11 H12 N2 O4
236.22
130 50  55.93
5.12
11.86
-- 55.73
5.27
11.72
--
6978
o.CF3
--  C12 H11 F3 N2 O4
304.22
135 --  47.37
3.64
9.21
-- 47.40
3.82
9.41
--
68291
m.Cl
--  C11 H11 Cl N2 O4
270.67
102 40  48.81
4.10
10.35
-- 48.80
3.88
10.22
--
6902
p.Cl
--  C11 H11 Cl N2 O4
270.67
120 74  48.81
4.10
10.35
-- 49.01
4.25
10.35
--
6945
m.Br
--  C11 H11 Br N2 O4
315.12
132 50  41.92
3.52
8.89
-- 42.01
3.72
9.06
--
6901
m.F.
--  C11 H11 FN2 O4
254.21
110 70  51.97
4.36
11.02
-- 51.93
4.44
11.13
--
69254
p.F.
--  C11 H11 FN2 O4
254.21
140 60  51.97
4.36
11.02
-- 52.07
4.34
10.82
--
69263
o.F.
--  C11 H11 FN2 O4
251.21
80 40  51.97
4.36
11.02
-- 52.16
4.34
10.94
--
69252
p.CH3
--  C12 H14 N2 O4
250.25
148 60  57.59
5.64
11,20
-- 57.40
5.56
11.40
--
59237
m.CH3
--  C12 H14 N2 O4
250.25
105 70  57.59
5.64
11.20
-- 57.40
5.44
11.13
--
69239
O.CH3
--  C12 H14 N2 O4
250.25
126 35  57.59
5.64
11.20
-- 57.79
5.72
11.26
--
__________________________________________________________________________
##STR14##
__________________________________________________________________________
68327
H   --  C15 H21 N3 O4
307.34
77 50  58.62
6.89
19.67
-- 59.18
7.14
-- --
--  HCl C15 H22 Cl N3 O4
313.80
168 90  52.40
6.45
12.22
-- 52.32
6.68
12.43
--
6985
m.CF1
--  C16 H20 F3 N2 O4
375.34
78 40  51.20
5.37
11.20
-- 51.18
5.52
11.40
--
69253
m.F --  C15 H20 FN3 O4
325.33
78 35  55.37
6.20
12.92
-- 55.27
6.13
12.96
--
--  HCl C15 H21 Cl FN3 O4
361.80
140 --  49.79
5.85
11.62
-- 49.59
5.97
11.50
--
__________________________________________________________________________
##STR15##
__________________________________________________________________________
68306
H   --  C16 H21 N3 O4
319.35
70 50  60.17
6.63
13.16
-- 59.98
6.42
13.36
--
--  HCl C16 H22 ClN3 O4
355.82
220 98  54.01
6.23
11.81
9.96
53.81
6.39
11.78
10.13
6089
m.CF3
--  C17 H20 F3 N3 O4
359.34
66 --  52.71
5.20
10.85
-- 52.71
5.33
10.76
--
--  Maleate
C21 H24 F3 N3 O4
503.43
120 80  50.10
4.81
8.35
-- 49.96
5.12
8.54
--
69235
m.F --  C16 H20 FN3 O4
337.34
75 31  56.96
5.98
12.46
-- 56.77
5.79
12.58
--
--  HCl C16 H21 FN3 O4
373.81
210 40  51.41
5.66
11.24
-- 51.33
5.46
11.26
--
__________________________________________________________________________

the compounds of Formula I experimentally exert anti-depressive, myorelaxing, tranquillising, sedative, analgesic, anti-convulsive, anti-pyretic, anti-inflammatory and uricosuric activities. Moreover, their toxic effects on animals in the laboratory are little marked.

(I)--Anti-depressive properties

The compounds of Formula I are capable of opposing hypothermia and the ptosis provoked by reserpine in the rat and the mouse, as well as the ulcers provoked by reserpine in the rat. Moreover, they oppose the catalepsy provoked by prochlorperazine in the art.

By way of example, several results obtained are listed in the following table:

TABLE III
__________________________________________________________________________
Ptosis
Hypothermia  Rat     Mouse   Ulcers  Catalepsy
Code     Effect, Effect, Effect  Effect, Effect,
Number
Dose1
°C
Dose1
percent
Dose1
percent
Dose1
percent
Dose1
percent
__________________________________________________________________________
6878 200 -3.4
200 53  200 55  200 60  --  --
68175
100 -4  --  --  100 85  --  --  --  --
6901 100 -2.4
100 50  100 60  100 55  200 2.9
68921
100 -3  100 60  100 50  --  --  --  --
6902 100 -2.7
100 45  100 50  --  --  --  --
6945 100 -2.5
100 55  100 45  --  --  --  --
69237
--  --  100 45  100 45  --  --  --  --
69252
--  --  100 50  100 50  --  --  --  --
6985 100 -2  --  --  --  --  --  --  --  --
69254
--  --  --  --  100 54  --  --  --  --
69263
--  --  --  --  100 50  --  --  --  --
__________________________________________________________________________
1 Expressed in mg./kg./P.O.

(II)--Myorelaxing properties

The compounds of Formula I provoke in the mouse the loss of the righting reflex and inhibit the traction reflexes and the maintenance on a rotating rod.

By way of example, for the compound No. 68175, the Ed₅0 in the traction test and also on the rotating rod is 130 mg./kg./P.O.

(III)--Tranquilising and sedative action

These effects are shown by a diminution of the exploration curosity in the enclosure of an actimetric cage and of escape in an open field. The compounds of Formula I reduce the aggresiveness provoked by the passage of an electric current and lower the body temperature of animals. The narcotic effects of penthiobarbital are equally reinforced.

The results obtained with two compounds of Formula I are listed in the following table:

TABLE IV
______________________________________
Potentialisation
of penthio-
Actimetric     Evasion test
barbital
Code           Effect,       Effect,      Effect,
Number Dose1
percent Dose1
percent
Dose1
percent
______________________________________
6878   --      --      --    --    180    50
68175  95      50      200   50    100    60
______________________________________
1 Expressed in mg./kg./P.O.

(IV)--Analgesic activity

This activity is particularly pronounced against the painful stretching provoked in the mouse by the intraperitoneal administration of phenyl benzoquinone or acetic acid.

The results obtained with two compounds of Formula I are shown in the following table:

TABLE V
______________________________________
Protection against
phenyl benzoquinone
Dose in        Effect,
Code Number   mg./kg./P.O.   percent
______________________________________
68175         62             60
6902          100            40
______________________________________

(V)--Anti-convulsive properties

The compounds of Formula I exert in the mouse an antagonism against the lethal effects of cardiazol, strychnine and nicotine. They equally show activity against the tonic hyperextension of an excessive electric shock.

By way of example, the results obtained with several compounds of Formula I are listed in the following table:

TABLE VI
__________________________________________________________________________
Antagonism against-
Cardiazol
Strychnine
Nicotine
Electric shock
Effect, Effect, Effect, Effect,
Code Number
Dose1
percent
Dose1
percent
Dose1
percent
Dose1
percent
__________________________________________________________________________
6878    --  --   43  60 --  --  --  --
68175    90 50   20  50 100 90  100 80
6901    --  --   50  90 --  --  --  --
68291   --  --  100 100 100 90  --  --
6902    100 60  100 100 100 80  --  --
6945    --  --  100 100 100 75  --  --
69239
--  --  --  --  100 40  --  --
69237   --  --  100  80 --  --  --  --
69252   --  --  100  80 --  --  --  --
6985    --  --  --  --  100 70  --  --
69254   --  --  100 100 100 55  --  --
69263   --  --  100  90 --  --  --  --
__________________________________________________________________________
1 Expressed in mg./kg./P.O.

(VI)--Anti-pyretic action

This action is manifested by a diminution of the experimental fever provoked by the administration of barm in the cat.

(VII)--Anti-inflammatory effect

The under-planatar oedema provoked in the rat by the administration of carraghenine is diminished by the compounds of the present invention.

The results obtained with two of the compounds of Formula I are shown in the following table:

TABLE VII
______________________________________
Reduction of
Dose in       the oedema,
Code Number  mg./kg./P.O.  percent
______________________________________
68175        200           65
68291        100           40
______________________________________

(VIII)--Uricosuric action

After repeated oral administration in the rat, the compounds of Formula I provoke an augmentation of the urinary elimination of uric acid.

In consequence of the results shown above, and the values appearing in the following table, the difference between the pharmacologically-active dose and the lethal dose is sufficiently great to enable the compounds of Formula I to be utilised in therapeutics.

TABLE VIII
______________________________________
L.D.60 P.O. (mouse)
Code No.:     Mg./kg.
______________________________________
6878          2,700
68175         2,100
6901          2,800
68291         >3,200
6902          1,500
6945          >3,200
69239      >4,000
69237         4,000
69252         >4,000
6985          1,350
69254         2,500
69263         3,400
______________________________________

The compounds of Formula I are indicated in the case of depression and neurosis by depressive and anxious components. They equally possess a favourable effect against contractural and inflammatory pains, with or without hyperthermia.

They may be administered in the form of tablets and gelules containing 50 to 250 mg. of active ingredient.

Hence, according to the present invention there is also provided a therapeutic composition comprising a compound of Formula I together with a therapeutically-acceptable carrier.

Several clinical tests to show the activity of the compounds of the present invention are given below:

EXAMPLE 1.--Compound No. 6901

1st observation: Mr. M. aged 46.

An intellectual, working in a scientific field of high precision, this man was affected by a spasmodic stiff neck due to anxious and hypochondriac grounds. He complained of cervical pains which prevented him from keeping his head upright and concentrating on his work. As a result, he became apathetic, depressed and profoundly restless about his future.

Compound No. 6901, in tablet form containing 100 mg. of active ingredient, was administered three times daily for 15 days. The cervical pains disappeared and he was able to hold his head in an upright position. Besides this myorelaxant action, there is equally ascertained a complete sedation of his depressive anxieties.

2nd observation: Mr. Z. aged 55.

Professional and financial worries were provoked by a reactive neurosis, manifesting itself by an important irritability making family life very difficult. He complained as well as obstinate insomnia and particularly of diverse symptoms characterised by extra-systoles and occasionally of paroxysmic tachycardia, of globus epigastrus and of transient intestinal troubles. His hands trembled uncontrollably. He sometimes had autolysis notions.

Compound No. 6901 in tablet form containing 100 mg. of active ingredient, was administered daily for three weeks, brought the subject back to a normal state, his hands no longer trembled, his sleep returned to normal and he no longer suffered from cardiac or digestive troubles. His troubles disappeared and he was able to attack his commercial problems with courage.

EXAMPLE 2.--Compound No. 68175

Observation: Mrs. A. aged 48.

This woman was in a pre-menopause phase. For two years, she complained apart from menstrual troubles, exacerbated nervousness, interior tension sensations and trouble with precordial striction. She also complained of insomnia and a certain pain in the legs in the sleeping position.

Compound No. 68175, in tablet form containing 100 mg. of active ingredient, was administered 3 times a day for 12 days.

The sedative and tranquillising action is rapidly manifested, causing the irritability to disappear as well as the pain and insomnia. Simultaneously, the myorelaxant action was equally evidenced, as shown by the complete disappearance of the interior tension and the pain in the legs. Moreover, her sleep returned to normal.

Claims

1. A compound of the formula ##STR16## in which R is hydrogen, halogen, alkyl having 1 to 4 carbon atoms and trifluoromethyl, and

R₃ is --H₂, ##STR17##

and the pharmaceutically acceptable acid addition salts thereof.

2. A compound as claimed in claim 1, in which R is a chlorine, bromine or

fluorine atom. 3. A compound of the formula ##STR18## in which (1) ##STR19## is --NH₂ and R is H, m-CF₃, o-CF₃, m-Cl, p-Cl, m-Br, m-F, p-F, o-F, p-CH₃ or m-CH₃, or ##STR20## and R is H, m-CF₃ or m-F, or ##STR21## and R is H, m-CF₃ or m-F, and the pharmaceutically acceptable acid addition salts thereof.