BE843075A - NEW CARBOXYLIC ACIDS AND THEIR PRODUCTION FROM MORPHOLINONES - Google Patents

Description

       

  New carboxylic acids and their production from

  
morpholinones: -

  
The present invention relates to novel acids and carboxylic acid derivatives of formula
 <EMI ID = 1.1>
  <EMI ID = 2.1>

  
drogen or a lower alkyl radical or a lower alkyl radical bearing a hydroxyl or lower alkoxy radical) or

  
 <EMI ID = 3.1>

  
notably a hydrogen atom or a lower alkyl, aryl, aralkyl or lower hydroxyalkyl radical, or else form together '

  
 <EMI ID = 4.1>

  
Z represents the oxygen or sulfur atom; X represents a hydrogen or halogen atom or a lower alkyl, carbo-

  
 <EMI ID = 5.1>

  
as long as, when Z represents the oxygen atom ,! represents an ato. me of hydrogen or halogen or a lower alkyl radical, alkoxy

  
 <EMI ID = 6.1>

  
 <EMI ID = 7.1>

  
acyl (such as lower alkanoyl, aroyl, hemisuccinoyl and nicotinoyl) had a lower alkyl radical, optionally in the form of an alkali metal, d-3 alkaline earth metal or aluminum salt.

  
Among the new compounds of the invention, those of

  
 <EMI ID = 8.1>

  
compounds of formula:

  

 <EMI ID = 9.1>


  
 <EMI ID = 10.1>

  
are obtained by hydrolysis, alcoholysis, ammonolysis or aminolysis of the corresponding morpholinone derivatives of formula:

  

 <EMI ID = 11.1>


  
One such method of preparation is. described in detail below.

  
Stuffed! the new compounds of the invention, those of for-

  
 <EMI ID = 12.1>

  
compounds of formula:

  

 <EMI ID = 13.1>


  
 <EMI ID = 14.1>

  
are obtained by acylation or alkylation of the corresponding compound of formula II. Such a preparation process is described in detail below. The following description illustrates a process

  
 <EMI ID = 15.1>

  
as their salts and mentions the pharmacological properties of these compounds. A process for preparing compounds of

  
 <EMI ID = 16.1>

  
 <EMI ID = 17.1> subject of new acids and carboxylic acid derivatives of for-

  
 <EMI ID = 18.1>

  
formol:

  

 <EMI ID = 19.1>


  
 <EMI ID = 20.1>

  
a heterocyclic radical, such as morpholino or piperidino);

  
Z represents the oxygen or sulfur atom; X represents an atom

  
 <EMI ID = 21.1>

  

 <EMI ID = 22.1>


  
 <EMI ID = 23.1>

  
up to press and have excellent serum lipid lowering activity, so they are useful for the claim or treatment of arteriosclerosis.

  
According to the invention, the derivatives of for-

  
 <EMI ID = 24.1>

  
feels the hydrogen atom, by hydrolysis of a compound of formula:

  

 <EMI ID = 25.1>


  
 <EMI ID = 26.1>

  
medium of an alkali metal hydroxy <3rd, such as sodium or potassium hydroxide. The compounds of formula II are obtained

  
 <EMI ID = 27.1>

  
lower alkyl radical unsubstituted or bearing a radical

  
 <EMI ID = 28.1>

  
phalinone of general formula III with the corresponding alcohol of

  
 <EMI ID = 29.1> using an acid catalyst, such as hydrogen chloride, sulfuric acid, acetic acid or p-toluenesulfonic acid, or a basic catalyst, such as sodium or potassium. metallic. The compounds of general formula are obtained

  
 <EMI ID = 30.1>

  
have the meanings indicated above, by reaction of

  
 <EMI ID = 31.1>

  
 <EMI ID = 32.1>

  
the meanings indicated above. The reaction is executed

  
 <EMI ID = 33.1>

  
 <EMI ID = 34.1>

  
compounds obtained in this way comprise a free hydroxyl radical or, in the case of hydrolysis by means of a hydro-

  
 <EMI ID = 35.1>

  
corresponding alkaline. If necessary, it is possible to convert this alkali metal salt into a corresponding alkali earth metal or aluminum salt by reaction with an alkali earth metal salt or an aluminum compound, for example calcium chloride or aluminum chloride. The resulting novel acids and carboxylic acid derivatives have excellent serum lipid lowering power, as shown in the following description.

  
1.- Effect of lowering blood lipid content on

  
 <EMI ID = 36.1>

  
Table 1 below indicates the variations in coccentration in serum of cholesterol and. triglycerides after treatment with the compounds administered in various doses,

  
 <EMI ID = 37.1>

  
 <EMI ID = 38.1>

  
to rats in groups of ten. Usually the blood was taken

  
 <EMI ID = 39.1>

  
serum cholesterol content according to the Levine technique and <EMI ID = 40.1>

  
Zak and the triglyceride content following the technique of

  
Kassler and Laderer using an automatic analysis device.

  
In all the examples shown in Table I, the reduction in for ceni in the treated group is given on the basis of the reference group

  
 <EMI ID = 41.1>

  
Decrease in serum lipid content after oral administration to 8 week old rats with normal lipid content <EMI ID = 42.1>

  

 <EMI ID = 43.1>


  
Note: In the table above, the compounds are identified

  
 <EMI ID = 44.1>

  
2. - Lowering of the triglyceride content of the blood in

  
 <EMI ID = 45.1>

  
 <EMI ID = 46.1>

  
The compounds are administered orally for 3 days! <EMI ID = 47.1>

  
res before the sacrifice, we continue to give them as

  
 <EMI ID = 48.1>

  
fast after the last administration, blood is drawn.

  
 <EMI ID = 49.1>

  
the treated group is given as a percentage, based on the control group receiving fructose. The change in triglyceride content before and after administration of fructose to the control group corresponds to 100%. These compounds have more potent inhibitory activity than that of clofibrate.

TABLE II

  
 <EMI ID = 50.1>

  

 <EMI ID = 51.1>


  
Note: The compounds are identified in the table above by

  
the number assigned to table 17.

  
 <EMI ID = 52.1>

  
The compounds are administered orally for 4 days.

  
 <EMI ID = 53.1>

  
 <EMI ID = 54.1>

  
After 18 hours of fasting after the last administration, blood is drawn. In all the examples given in Table III, the inhibition for the treated group is given as a percentage, on

  
 <EMI ID = 55.1> <EMI ID = 56.1>

  
 <EMI ID = 57.1>

TABLE III

  
 <EMI ID = 58.1>

  

 <EMI ID = 59.1>


  
Note: In the table above, the compounds are identified

  
by the number assigned to them in Table 17.

  
The invention is illustrated without being limited by the examples below.

  
EXAMPLE 1.-

  
This example describes the preparation of 1- (p-chlorophenoxy) -

  
 <EMI ID = 60.1>

  
mixing under reflux for 20 hours, a small amount of active carbon is then added and filtered. The filtrate is concentrated and the resulting residue is solidified in ether. By filtration and drying, 29.2 g of product are obtained. By recris-

  
 <EMI ID = 61.1>
 <EMI ID = 62.1>
 EXAMPLE 2.-

  
 <EMI ID = 63.1>

  
posed 36).

  
 <EMI ID = 64.1>

  
propylamine, then the solution is left to stand until the next

  
 <EMI ID = 65.1>

  
vacuum pad. The residue is solidified by adding a little ether. The solid is separated by filtration, washed with ether and dried to obtain 8.7 g of product. By recrystallization from ethanol, 5.5 g are obtained (yield of

  
 <EMI ID = 66.1>

  

 <EMI ID = 67.1>

EXAMPLE% ,. -

  
 <EMI ID = 68.1>

  
sodium suspended in 200 ml of water and the mixture is heated

  
at 90 - 100 [deg.] C for 1 hour. In this way, the mixture is hydrolyzed which gives a solution. A small amount of insolubles was filtered off. On the other hand, 3.50 g (0.0315 mol) of calcium chloride are dissolved in 50 ml of water. By rapidly adding this solution to the filtrate obtained above, a solid is precipitated. After 1 hour of stirring, it is collected. precipitated by filtration and washed with water, then dried to obtain 23.2 g. By recrystallization in

  
 <EMI ID = 69.1>

  
 <EMI ID = 70.1>

  

 <EMI ID = 71.1>


  
Various compounds of formula II are prepared by applying the same procedure. These compounds are listed in Table IV.

  
 <EMI ID = 72.1>

  

 <EMI ID = 73.1>
 

  

 <EMI ID = 74.1>


  

 <EMI ID = 75.1>
 

  

 <EMI ID = 76.1>


  

 <EMI ID = 77.1>
 

  

 <EMI ID = 78.1>


  

 <EMI ID = 79.1>
 

  

 <EMI ID = 80.1>


  

 <EMI ID = 81.1>
 

  

 <EMI ID = 82.1>


  

 <EMI ID = 83.1>
 

  
The following description relates to the compounds of

  
 <EMI ID = 84.1>

  
 <EMI ID = 85.1>

  
 <EMI ID = 86.1>

  
 <EMI ID = 87.1>

  

 <EMI ID = 88.1>


  
 <EMI ID = 89.1>

  
drogen or a lower alkyl radical or an alkyl radical

  
 <EMI ID = 90.1>

  
X represents a hydrogen or halogen atom or a lower alkyl, carboxyl, lower alkoxy, (lower alkoxy) radical -

  
 <EMI ID = 91.1>

  
Y represents a hydrogen or halogen atom or a lower alkyl radical, while when Z represents the oxy atom

  
 <EMI ID = 92.1>

  
(lower alkoxy) carbonyl or cyano.

  
The starting compounds as well as the products obtained are new and have excellent serum lipid lowering activity, which makes them useful for the prevention or treatment of arteriosclerosis. According to the above process; the reaction is carried out using an acylating agent, such as acetic anhydride, succinic anhydride, benzoyl chloride or nlcotinoyl chloride, or a

  
 <EMI ID = 93.1>

  
For acylation, it is preferable to take an organic base, such as pyridine or triethylamine, which captures

  
 <EMI ID = 94.1>

  
temperature below 10 [deg.] C in an inert solvent, such as ether or benzene. The starting compounds of general formula II are easily obtained by hydrolysis of morpholinones of general formula:

  

 <EMI ID = 95.1>


  
 <EMI ID = 96.1>

  
the manner already described above.

  
The resulting new acids and carboxylic acid derivatives have a remarkable effect of lowering the lipid content of serum, as will be apparent from the description below. Table V mentions Blood lipid lowering inactivity in 8 week old male rats with normal serum lipid content.

TABLE V

  
Decrease in serum lipid content in percent after

  
oral administration to male rats with normal

  
 <EMI ID = 97.1>

  

 <EMI ID = 98.1>


  
Note: The compounds are identified in Table V by

  
the number assigned to them in Table VI.

  
The results shown in Table V are the variations in the concentration of cholesterol and triglycerides in the serum after treatment with the various daily doses indicated for 3.5 days. The compounds are administered by

  
 <EMI ID = 99.1>

  
 <EMI ID = 100.1>

  
after the last administration. The cholesterol content of the serum is determined according to the Levine and Zak technique and the triglyceride content of the serum according to the Kessler and Lederer technique by means of an automatic analysis apparatus. In all the examples shown in Table V, the reduction in percent

  
 <EMI ID = 101.1>

  
treaties to which the value of 100% is assigned. These compounds

  
 <EMI ID = 102.1>

  
greater than that of clofibrate at a dose of 20 mg per kg per day. The examples below illustrate these embodiments of the invention, the compounds being identified by the

  
 <EMI ID = 103.1>

  
 <EMI ID = 104.1>

  
 <EMI ID = 105.1> <EMI ID = 106.1>

  
(compound 1).

  
 <EMI ID = 107.1>

  
 <EMI ID = 108.1>

  
let the solution stand at room temperature for

  
20 hours, then the reaction mixture is concentrated. The residue is poured into ice water to precipitate a product. The precipitate is collected by filtration, washed with water and

  
 <EMI ID = 109.1>

  

 <EMI ID = 110.1>


  
 <EMI ID = 111.1>

  
 <EMI ID = 112.1>

  
 <EMI ID = 113.1>

  
amino) -2-propanol and 1 g of acetic anhydride, then the mixture is left to stand at room temperature for 20 hours,

  
 <EMI ID = 114.1>

  
ether under reduced pressure, 190 mg is obtained (yield of

  
 <EMI ID = 115.1>

  
 <EMI ID = 116.1>

  

 <EMI ID = 117.1>


  
Various compounds of formula IV are prepared by applying the same procedure. These compounds are listed in Table VI.

  

 <EMI ID = 118.1>


  

 <EMI ID = 119.1>
 

  

 <EMI ID = 120.1>


  

 <EMI ID = 121.1>


  

 <EMI ID = 122.1>


  

 <EMI ID = 123.1>



    

Claims (1)

1. - Acids or derivatives of carboxylic acids of formula: <EMI ID = 124.1> <EMI ID = 125.1> <EMI ID = 126.1> <EMI ID = 127.1> <EMI ID = 128.1> <EMI ID = 129.1> <EMI ID = 130.1> <EMI ID = 131.1> of hydrogen or halogen or a lower alkyl radical, carbo- <EMI ID = 132.1> <EMI ID = 133.1> hydrogen or halogen or a lower alkyl radical, however <EMI ID = 134.1> <EMI ID = 135.1> <EMI ID = 136.1> <EMI ID = 137.1> in the form of an alkali metal, alkaline earth metal or aluminum salt. 2.- Process for the preparation of derivatives of formula: <EMI ID = 138.1> <EMI ID = 139.1> drogen or a lower alkyl radical or a lower alkyl radical bearing a hydroxyl or lower alkoxy radical) or <EMI ID = 140.1> Z represents the oxygen or sulfur atom; X represents a hydrogen or halogen atom or a lower alkyl, carbo- <EMI ID = 141.1> hydrogen or halogen atom or a lower alkyl radical, a: <EMI ID = 142.1> carbonyl or cyano, characterized in that an alcoholysis is subjected to hydrolysis ,. an ammonolysis or an aminolysis a derivative of mor- <EMI ID = 143.1> <EMI ID = 144.1> where X, Y and 2 have the meanings given above, then if the thing is necessary, we form the alkali metal salt, of <EMI ID = 145.1> 3.- Process for preparing a derivative of formula: <EMI ID = 146.1> <EMI ID = 147.1> drogen or a lower alkyl radical or a lower alkyl radical bearing a hydroxyl or lower alkoxy radical) or <EMI ID = 148.1> notably a hydrogen atom or a lower alkyl, aryl, aralkyl or lower hydroxyalkyl radical or else together form a heterocyclic radical, such as morpholino or piperidino); Z represents the oxygen or sulfur atom; X represents a hydrogen or halogen atom or a lower alkyl, carbo- <EMI ID = 149.1> when Z represents the sulfur atom, Y represents a hydrogen or halogen atom or a lower alkyl radical, while, when Z represents the oxygen atom, Y represents a hydrogen or halogen atom or a lower alkyl, lower alkoxy, hydroxyl, aralko &#65533;, carboxyl, (lower alkoxy carbonyl or cyano radical; and R <3> represents an acyl radical (such as lower alkanoyl, aroyl, hemisuccinoyl or nicotinoyl) or a lower alkyl radical , characterized in that a compound of general formula is subjected to acylation or alkylation: <EMI ID = 150.1> <EMI ID = 151.1>