FR2582650A1 - New morphine derivatives, their preparation and their application as medicaments - Google Patents

Abstract

The morphine derivatives according to the invention correspond to the general formula: in which: R represents a 2-hydroxyethyl radical (-CH2CH2OH), a 2-chloroethyl radical (-CH2CH2Cl) or a trans-3-(methoxycarbonyl)acrylyl radical R1 and R2, which are identical or different, represent a hydrogen atom or an acetyl radical .

Description

 The present invention relates to novel morphine derivatives, their method of preparation, and their application as medicaments.

dans laquelle:
R représente un radical 2-hydroxyethyle (-CH2CH2OH), un radical
2-chloroéthyle (-CH2CH2Cl) ou un radical trans-3-(méthoxycarbonyl)acrylyle

The new derivatives, object of the present invention, return to the general formula I

in which:
R represents a 2-hydroxyethyl radical (-CH 2 CH 2 OH), a radical
2-chloroethyl (-CH2CH2Cl) or a trans-3- (methoxycarbonyl) acrylyl radical

R1 and R2, identical or different, represent a hydrogen atom or an acetyl radical

 The present invention also relates to the physiologically acceptable salts of the compounds of general formula I.

 The derivatives of general formula I and their salts have interesting pharmacological, cytostatic and antagonist properties of the opiate receptor.

The present invention also relates to a process for the preparation of the derivatives of general formula. According to the invention, these compounds are prepared according to the following reaction scheme:

 Compound 2, N- (2-hydroxyethyl) -3,6-diacetylnormethylmorphine is obtained by reaction in a sealed tube of 3,6-diacetylnormethylnorphine (Borowitz, IJ, Diakiw, V., J. Heterocyc Chem., 1975, 12, 1123), 1, with oxirane at temperatures ranging from -5 ° C to + 50 ° C, for periods ranging from 24 to 96 hours, in a wide variety of solvents, such as, for example, diethyl ether. , chloroform, methylene chloride.

N- (2-chloroethyl) -3,6-diacetylnormethylmorphine hydrochloride, 3.HCl, is synthesized by reaction at room temperature of compound 2 with nitric chloride in a chlorinated solvent or in the absence of solvent. By treatment of 3.RCl with sodium bicarbonate, N- (2-chloroethyl) -3,6-diacetylnormethylmorphine is obtained.
By saponification of compound 3 with hydroalcoholic potash for a very short time (from 1 to 5 minutes) at temperatures of 60 to 100 ° C., N- (2-chloroethyl) -normethylmorphine, 4, is obtained.
N- (2-chloroethyl) -6-acetylnormethylmorphine, 5,
The compound 6,6,6-diacetyl-N- [trans-3- (methoxycarbonyl) acryloyl] normethylmorphine is obtained by reaction of 3,6-diacetylnormethylmorphine, 1, with the monomethyl ester of fumaroyl chloride in
acetone and using sodium carbonate as a proton sensor. The reaction takes place at room temperature for periods of between 30 minutes and 2 hours.

 The preparation of some derivatives of general formula I will be described below, by way of a non-limiting example only.

Example 1
Preparation of N- (2-chloroethyl) -3,6-diacetylnormethylmorphine (3)
2.6 g (7.3 mmol) of 3,6-diacetylnormethylmorphine (Borowitz, IJ, Diakiw, V., J. Heterocyc Chem., 1975, 12, 1123), 1, are mixed with 30 ml of dichloromethane and 40 ml of oxirane (800 mmol) and stirred in a sealed tube at 35 ° C. for 90 hours. The resulting solution is evaporated to dryness under reduced pressure and the residue is passed through a chromatographic column of silica gel using as eluent a chloroform / methanol (99: 1). The solvent was evaporated, the residue was recrystallized with anhydrous diethyl ether and 2 g (69%) of N- (2-hydroxyethyl) -3,6-diacetylnormethylmorphine, 2, mp 137-9 ° C were obtained.
Spectroscopic data:
Compose 2
IR (RBr) 3450 (e, -CH 2 OH); 1770

Compound 2.HCl (mp 150-2 ° C)
IR (KBr): 3500-2800 (e);

 2 g (5 mmol) of compound 2 in 30 ml of dichloromethane and 4 ml (48 mmol) of thionyl chloride are stirred at room temperature for 20 hours. The solvent and the excess of thionyl chloride are evaporated under reduced pressure, the residue is taken up with 25 ml of saturated sodium bicarbonate solution and extracted with 2 × 25 ml of dichloromethane. The organic extract is dried with sodium sulfate and evaporated to dryness. The residue is recrystallized with anhydrous diethyl ether to give 1.65 g (79%) of compound 3, m.p. 116-7 ° C.

1H-RMN (DMSO-d6) # : 6,74(d, 1 H, C2-H, J = 8,2 Hz) ; 6,57 (d, 1 H, C1-H,
J = 8,2 Hz); 5,49 (m, 2 H, C7, C8-H); 5,06 (m, 2 H, C5, C6-H); 3,68 (t, 2 H, -CH2C1); 2,21 (s, 3 H, 3-OAc); 2,04 (s, 3 H, 6-OAc).Spectroscopic data:
IR (KBr):

1H-NMR (DMSO-d6) δ: 6.74 (d, 1H, C2-H, J = 8.2 Hz); 6.57 (d, 1H, C1-H,
J = 8.2 Hz); 5.49 (m, 2H, C7, C8-H); 5.06 (m, 2H, C5, C6-H); 3.68 (t, 2H, -CH 2 Cl); 2.21 (s, 3H, 3-OAc); 2.04 (s, 3H, 6-OAc).

 Compound 3HCl is obtained by dissolving compound 3 in diethyl ether saturated with hydrochloric acid. It is left for 48 hours at 59 ° C. and the compound of melting point 157-160 ° C. is obtained by filtration: IR (KBr) 1770 and 1750 cm -1.

Example 2
Preparation of N- (2-chloroethyl) -normethylmorphine (4) and N- (2-chloroethyl) -6-acetylnormethylmorphine (5)
18.3 ml of a solution of potassium hydroxide at 18 in an ethanol-water mixture (98: 2) is added to a solution of 0.5 g (1.2 mmol) of compound 3 in 70 ml of 96% ethanol. This solution is rapidly immersed in an oil bath at 100 ° C., the solution is stirred for 2 minutes and immediately cooled to 10 ° C. 20 ml of water are added and the mixture is neutralized with acetic acid. Dry solution, the residue was dissolved in 5 ml of chloroform-methanol (95: 5) and passed through a silica gel chromatography column (309) starting with a chloroform-methanol (98: 2) mixture as eluent. .

Elution with 200 ml of chloroform-methanol (95: 5) gave 0.05 g (11%) of the compound of melting point 200-2 ° C. after recrystallization with diethyl ether. The next 430 ml of the same solvent mixture gives 0.13 g (32.5%) of compound 4 with a melting point of 224-5 C after recrystallization with acetonitrile.

Spectroscopic data:
Compound 4
IR (KBr): 3425 and 3260 cm-1 (-OH).

1H-NMR (DMSO-d6): 6.44 (d, 1H, C2-H, J = 8.2 Hz); 6.31 (d, 1H,
C1-H, J s 8.2 Hz); 5.52 (d, 1H, C7-H, J = 10Hz); 5.20 (d, 1H, C8-H,
J = 10 Hz); 4.66 (d, 2H, C 5 C 6 -H, J = 6Hz); 3.45 (t, 2H, -CH 2 Cl)
4.HCl compound
M.p. 190-200 C (d); IR (KBr): 3600-2500 cm-1 (b).

1H-RMN (DMSO-d6) 6 : 6,45 (d, I H, C2-H); 6,38 (d, 1H, C1-H); 5,50(m, 2 H,
Oléfine); 5,20 (m, 2 H, C5, C6-H); 3,50 (t, 2 H, -CH2Cl); 2,01 (s, 3 H, 6-OAc),
Exemple 3
Préparation du 3,6-diacétyl-N-[trans-3-(méthoxycarbonyl)acryloyl]
norméthylmorphine (6)
On ajoute 2,3 g (1,54 mmoles) de monométhyl) ester du chlorure de
fumaroyle (Acheson, R.M., Feinberg, R.S., Hands, A.R., J. Chem, Soc.,
1964, 526) dans 5 ml d'acétone à un mélange de 0,5 g (1,4 mmoles) de
3,6-diacéthylnorméthylmorphine, 1, 20 Il d'acétone, 0,3 ml d'eau et 0,22
g (2,1 mmoles) de carbonate de sodium.Compound S
IR (Kar):

1H-NMR (DMSO-d6) δ: 6.45 (d, 1H, C2-H); 6.38 (d, 1H, Cl-H); 5.50 (m, 2H,
Olefin); 5.20 (m, 2H, C5, C6-H); 3.50 (t, 2H, -CH 2 Cl); 2.01 (s, 3H, 6-OAc),
Example 3
Preparation of 3,6-diacetyl-N- [trans-3- (methoxycarbonyl) acryloyl]
normethylmorphine (6)
2.3 g (1.54 mmol) of monomethyl chloride ester are added.
fumaroyl (Acheson, RM, Feinberg, RS, Hands, AR, J. Chem, Soc.
1964, 526) in 5 ml of acetone to a mixture of 0.5 g (1.4 mmol) of
3,6-diacetylnormethylmorphine, 1, 20 μl of acetone, 0.3 ml of water and 0.22
g (2.1 mmol) of sodium carbonate.

Stirred for 30 minutes and filtered. We evaporate the solution to
and the residue is passed through a chromatographic column of silica gel using chloroform as eluent. We evaporate the soil
the residue is recrystallized with anhydrous diethyl ether and
0.17 g (26.1%) of compound 6 with a melting point of 170-3 C. is obtained.

1H-RMN (DMSO-d6) # : 6,83 (d, 1 H, C2-H, J = 8,2 Hz); 6,61 (d, 1 H, C1-H,
J = 8,2 Hz); 6,77 (d, 1 H, #, J = 15,3 Hz); 6,72 (d, 1H, =CH-C02-,
J = 15,3 Hz); 5,59 (m, 2 H, Oléfine); 5,14 (m, 2 H, C5, C6-H), 3,80 (s, 3 H, -CO2CH3) ; 2,28 (s, 3 H, 3-OAc) ; 2,13 (s, 3 H, 6-OAc).Spectroscopic data:

1H-NMR (DMSO-d6) δ: 6.83 (d, 1H, C2-H, J = 8.2 Hz); 6.61 (d, 1H, C1-H,
J = 8.2 Hz); 6.77 (d, 1H, #, J = 15.3 Hz); 6.72 (d, 1H, = CH-C02-,
J = 15.3 Hz); 5.59 (m, 2H, Olefin); 5.14 (m, 2H, C5, C6-H), 3.80 (s, 3H, -CO2CH3); 2.28 (s, 3H, 3-OAc); 2.13 (s, 3H, 6-OAc).

Antagonist activity of morphine
In this test the inhibition of the analgesic activity of morphine, observed in the heating plate test (G. Noolfe and AD McDonald, J. Pharm Exp Ther, 1944, 80, 300-307) is determined. , subsequently amended by Eddy, NB and Leimbach, DJ Pharm. Exp. Ther., 1953, 107, 385.

 In this test, male Swiss mice weighing 20 to 25 grams are used. At the beginning of the test all the mice are treated with 5 mg / kg morphine i.v. after 5 minutes, the iv-treated products are administered to batches of 6 mice, and at different times after the treatment (5, 15, 30 and 60 minutes) the time for licking the paws is measured previous when placed on a plate at 55 + 0.5 C (HOT-PLATE SOCSEL model DJ-37).

The antagonistic activity of morphine is demonstrated by the decrease of the analgesic activity as a function of time, due to the products studied in comparison with the reference treatment (physiological serum + morphine).

 As a non-limiting example of the morphine antagonist activity of the products of the present invention, the activity of product 3 of Example 1 (dose of 5 and 10 mg / kg, iv route) in comparison with naloxone is considered. (mg / kg, iv).

 The results obtained are summarized in Table 1, which presents the areas of the response curves as a function of the time elapsed after the treatment, up to 24 hours.

Table 1
Antagonist activity of morphine in mice. Analgesic activity by heating plate test. Lots of 6 mice per dose.

<Tb>

<SEP> Area <SEP> under <SEP><SEP> curve <SEP> (0-24 <SEP>% <SEP> Inhibition
<tb><SEP> Product <SEP> Dose <SEP> Path <SEP> hours) <SEP> by <SEP> report <SEP> at
<tb><SEP> (mg / kg) <SEP> Time <SEP> of <SEP> response <SEP> = <SEP> f <SEP> (time <SEP> treatment <SEP> SP
<Tb>

<SEP> after <SEP> the <SEP> treatment) <SEP> + <SEP> morphine
<tb><SEP> 3 <SEP> 10
<tb><SEP> + <SEP> + <SEP> iv <SE> 1326.0 <SEP> 59.9%
<tb> Morphine <SEP> 5
<tb><SEP> 3 <SEP> 5
<tb><SEP> + <SEP> + <SEP> iv <SEP> 1274.0 <SEP> 61.4%
<tb> Morphine <SEP> 5
<tb><SEP> Naloxone <SEP> 1
<tb><SEP> + <SEP> + <SEP> iv <SEP> 800.5 <SEP> 75.8%
<tb> Morphine <SEP> 5
<tb><SEP> SP
<Tb>

<SEP> + <SEP> iv <SEP> 3304.0 <SEP>
<tb> Morphine <SEP> 5
<Tb>
Cytostatic activity, cell culture method, HeLa
The stored cells are fed 24 hours before the start of the test. The products are added on day 0 or day 1. The results are expressed by the dose which inhibits 50% of the growth relative to the growth of the control after 3 days of the addition of the product.

 Three to five doses per product and two tubes per dose are used. The number of the control group varies according to the number of problem groups (n) according to formula 2. The protein of the control tubes is determined according to the method of Oyama and Eagle (Oyama, VI, Eagle, H., Proc. Biol Exp.

Med., 91, 305-307, 1956).

Experimental method:
Day 0: The stored cells are diluted to 10-20 μg / ml (20,000-30,000 cells / ml) in complete medium. The cells are added to the tubes and the products are added simultaneously or on day 1. The total volume is approximately 3-4 ml. A positive control is performed for each odd control lot.

Day 1: If we use a 24-hour crop we must feed & new and add the product to try. The protein values of the control tubes are determined.

Day 3: Protein analysis of the probes, controls, positive control and at least 3 standard proteins is performed.

Day 4: If 24-hour cultures are used, protein analysis is performed as for day 3.

dosage:
The products of synthesis are dosed by weight at 100, 10 and 1 μg / ml.

If a product does not reach an end point at these dose levels, it is tested again at lower concentrations.

 The control tubes should grow at least six times that of the control tubes.

6-Mercaptopurine (NSC-755) is used as a positive control, the limits of its effective dose fifty (ED50) should be between 0.05 and 0.5 rg / ml,
The results obtained are summarized in Table 2.

Table 2
Cytostatic activity, HeLa cell method.

<Tb>

<SEP> Product <SEP> DE50 <SEP> (g / ml)
<tb><SEP> 3 <SEP> 10
<tb><SEP> 4 <SEP>> 100
<tb><SEP> 5 <SEP>> 100
<tb><SEP> 6 <SEP> 10
<tb> 6-mercaptopurine <SEP> 0.1
<Tb>
In view of their good pharmacodynamic properties, the morphine derivatives according to the invention can be used satisfactorily in human and animal therapeutics, in particular in the treatment of conditions which require the use of cytostatic and / or antagonist agents. morphine.

 In human therapeutics, the dose of administration of the derivatives of the present invention will generally be from about 0.1 to about 0.4 mg / kg / day. The derivatives of the invention will for example be administered in the form of tablets. As examples, two particular galenic formulas of the derivatives which are the subject of the present invention will be indicated below.

Example of formula per tablet N- (2-chloroethyl) -3,6-diacetylnormethylmorphine ................................ .. 2.0 mg 5.0 mg
Lactose ................................................. ... 52.0 mg 49.0 mg
Corn starch . . 20.0 mg 20.0 mg
Microcrystalline cellulose ......................... 20.0 mg 20.0 mg
Polyvinylpyrrolidone ...................................... 5.0 mg 5.0 mg
Magnesium stearate. 0.5 mg 0.5 mg
Colloidal Silicon Dioxide ..................... 0.5 mg 0.5 mg
100.0 mg 100.0 mg

Claims (12)

 1. New morphine derivatives having the general formula I:  R represents a 2-hydroxyethyl radical (-CH 2 CH 2 OH) a radical  in which:  2-chloroethyl (-CH 2 CH 2 Cl) or a trans-3- (methoxycarbonyl) radical  H nyl) acrylyl (-C ,, - C, = C-COOCH3),  OH  R1 and R2, identical or different, represent a hydro atom  gene or an acetyl radical (CH3-C-) O  as well as their physiologically acceptable salts.  general formula I according to claim 1. 2. The N- (2-hydroxyethyl) -3,6-diacetylnormethylmorphine responding to the  general formula I according to claim 1. 3. N- (2-chloroethyl) -3,6-diacetylnormethylmorphine responding to the  I according to claim 1. 4. N- (2-chloroethyl) -normethylmorphine corresponding to the general formula  General mule I according to claim 1.  5. N- (2-chloroethyl) -6-acetylnormethylmorphine responding to the  morphine of the general formula I according to claim 1.  6. 3,6-Diacetyl-N- [trans-3- (methoxycarbonyl) acrylamido] -normethyl  methane.  solvent such as diethyl ether, chloroform, dichloro  for a period of between 96 and 24 hours, in a  with oxirane & temperatures between -5 and + 50 C  in that 3,6-diacetylnormethylmorphine is reacted  7. Process for the preparation of the compound of claim 2, characterized  a chlorinated solvent or in the absence of solvent.  diacetylnormethylmorphine with thionyl chloride in  rised by reacting N- (2-hydroxyethyl) -3,6-  8. Process for the preparation of the compound of claim 3, characterized  from 60 to 100oC.  for a very short time (1 to 5 minutes) at temperatures  3,6-diacetylnormethylmorphine with hydroalcoholic potash  characterized in that N- (2-chloroethyl) is reacted  9. Process for the preparation of the compounds of claims 4 and 5,  of protons.  acetone and using sodium carbonate as a sensor  phine with monomethyl ester of fumaroyl chloride in  rised by the fact that 3,6-diacetylnormethylmethyl is reacted 10. Process for the preparation of the compound of claim 6, characterized  according to one of claims 1 to 6.  and / or antagonists of morphine, the derivatives of general formula I 11. As new drugs, especially as cytostatics  1 6.  at least one derivative of the general formula I according to one of the claims  contain, in addition to a pharmaceutically acceptable carrier, 12. Pharmaceutical compositions, characterized by the fact that they