BE875740A - COMPOSITIONS INCLUDING PLATINUM - Google Patents

Description

       

  patent applications filed,

  
ien England on April 20, 1978 and May 26, 1978 under the numbers; 15660/78 and 22968/78.

  
 <EMI ID = 1.1>

  
of platinum pharmaceutical compositions comprising these compounds

  
 <EMI ID = 2.1>

  
in the treatment of malignant tumors and neoplasms.

  
In accordance with a first object of the present invention, it describes a composition comprising a platinum coordination compound having the formula:

  
 <EMI ID = 3.1>

  
in which the groups R can be equal or different and are chosen from H, straight or branched chain alkyl,

  
 <EMI ID = 4.1>

  
 <EMI ID = 5.1>

  
aryloxy, formyl, nitro, amido, amino, sulphonic acids and

  
 <EMI ID = 6.1>

  
salts thereof, or, two R groups together may represent an oxygen or sulfur atom. and X and Y may be the same or different and are selected from the group consisting of sulphate, pnosphate, nitrate, carboxylate, substituted carboxylate and water, and, if R is neither hydrogen nor straight chain alkyl, halogen or pseudohalogen, and

  
Z represents halogen, pseudohalogen or hydroxy.

  
If there is no Z, the composition concerned is a platinum (II) coordination complex and has the following structure:

  

 <EMI ID = 7.1>
 

  
 <EMI ID = 8.1>

  

 <EMI ID = 9.1>


  
If X and / or Y represent a carboxylate or a carboxyla-

  
 <EMI ID = 10.1>

  
preferably, be an integer between 1 and 9, the R groups can be equal or different and are chosen from hydrogen, substituted or unsubstituted straight or branched chain alkyl, aryl, alkaryl, aralkyl, alkenyl, cycoalkyl and cycloalkenyl, halogen , pseudohalogen (defined below), hydroxy, formyl, nitro, amido, amino and salts of sulphonic acid. Two R groups together can also represent an oxygen or sulfur atom linked by a double bond.

  
 <EMI ID = 11.1>

  
also together constitute a carboxylate such as for example an oxalate or compounds or groups having the general formula:

  

 <EMI ID = 12.1>


  
 <EMI ID = 13.1>

  
may be the same or different and are selected from the group consisting of hydrogen, short chain alkyl, aryl, alkaryl, aralkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, OH,

  
 <EMI ID = 14.1>

  
with carbon atoms and then form a cycloalkyl group

  
 <EMI ID = 15.1>

  
of these, and y and z are either 0 or 1 provided that

  
(y + z) is equal to 1 or 2.

  
Suitable dicarboxylates for the present invention are succinate, glutarate (pentanedioate), adipate (hexanedioate), pimelate (heptanedioate), malate (cis-butenedioate) and
 <EMI ID = 16.1>
  <EMI ID = 17.1>

  
or unsubstituted.

  
 <EMI ID = 18.1>

  
invention, the meaning given on page 560 of the book "Advanced Inorganic Chemistry" by Cotton and Wilkinson, Interscience Publishers, 1966. According to this literature "pseudohalogen" denotes a molecule consisting of more than two electronegative atoms which, in the free state, have a resemblance to halogens, these

  
 <EMI ID = 19.1>

  
their behavior, resemble halide ions. Examples of suitable pseudohalogens are cyanide, cyanate, thiocyanate and azide.

  
It has been found that the compounds of the present invention can be used for the treatment of cancers, malignant tumors or malignant neoplasms. Normally the compounds

  
are used in combination with pharmaceutically suitable carriers or diluents. Thus, a second object

  
of the present invention is the description of a pharmaceutical composition comprising a compound as defined above

  
in admixture with a pharmaceutically acceptable carrier or diluent. Such compositions can take various forms so that they can be administered parenterally or orally to animals affected by malignant tumors or neoplasms.

  
Other objects and advantages of the invention are better understood on reading the following description of several exemplary embodiments.

  
Preparation of aquosulphato (platinum (II) N, N'-diethylethylenediamine.

  
50 g of K2PtCl4 in 500 ml of water were filtered and

  
 <EMI ID = 20.1>

  
 <EMI ID = 21.1>

  
 <EMI ID = 22.1>

  
The reaction was collected by filtration and dried in vacuo. The yield was 55 g (81%).

  
25 g of PtI2 (Et2En) were added to a solution of
13.75 g of silver sulphate in 200 ml of water and stirred for three hours at 50 [deg.] C. The supernatant was analyzed to confirm that there was no excess silver. The silver iodide was removed by filtration and the pale yellow liquid dried <EMI ID = 23.1>

  
 <EMI ID = 24.1>

  

 <EMI ID = 25.1>


  
 <EMI ID = 26.1>

  
 <EMI ID = 27.1>

  
diamine). ',

  
 <EMI ID = 28.1>

  
of an excess of amine of 10%. The product was washed with water

  
(3 x 100 mL) and ethanol and dried in vacuo at 50 [deg.] C. The yield was 157.1 g (94.6%)

  
50 g (0.093 moles) of PtI2 (N-Et en) was added

  
 <EMI ID = 29.1>

  
of 31.3 g (0.184 moles) of silver nitrate in water.

  
 <EMI ID = 30.1>

  
treated with activated carbon and filtered through a sintered filter

  
 <EMI ID = 31.1>

  
 <EMI ID = 32.1>

  
silver.

  
19.4 g (0.205 moles) of chloroacetic acid was added

  
to a stirred solution of N-ethylethylenediamine diaquo complex

  
(0.92 moles). The pH of the solution was adjusted to a value of 5 to

  
6 using potassium hydroxide and the mixture was heated

  
so as to have a pale yellow precipitate. The mixture was stirred

  
overnight and the solid product collected by filtration.

  
The product was then washed with water (20 mDethanol

  
 <EMI ID = 33.1>

  
The yield was 35.0 g (80%).

  
The product thus obtained was recrystallized from 600 ml of boiling water.

  
The yield of recrystallization was 20.4 g.

  

 <EMI ID = 34.1>


  
Other compounds according to the present invention are

  
those in which all the R groups are hydrogen, for example:

  
 <EMI ID = 35.1>

  
An example of a compound where X and Y are halogen

  
 <EMI ID = 36.1>

  
Of course, various modifications can be made by those skilled in the art to the devices and methods which have just been described only by way of non-limiting examples. depart from the scope of the invention.

  
claims:

  
1. Composition comprising a platinum coordination compound, characterized in that the coordination compound of

  
 <EMI ID = 37.1>

  
 <EMI ID = 38.1>

  
 <EMI ID = 39.1>

  
 <EMI ID = 40.1>

  
wherein the R groups may be equal or different and are selected from the group consisting of hydrogen, straight or branched chain alkyl, aryl, alkaryl, aralkyl, alkenyl, cycloalkyl, cycloalkenyl, halogen, pseudohalogen, hydroxy, alkoxy, aryloxy, formyl, nitro, amido &#65533; amino sulphonic acid

  
acids

  
 <EMI ID = 41.1>

  
salts thereof, optionally two groups R may represent, together, an oxygen atom or sulfur, X and Y are equal or different and selected from the group comprising sulphate, phosphate, nitrate, carboxylate, substituted carboxylate and water and ,

  
if R is neither H or straight chain alkyl, halogen or pseudohalogen, and

  
Z is halogen, pseudohalogen or hydroxy.


    

Claims (1)

2. Composition according to claim 1, characterized in that it comprises a platinum coordination complex (II) of the structure: <EMI ID = 42.1> 3. Composition according to claim 1, characterized in that it comprises a platinum (IV) coordination complex having the structure: (vs) <EMI ID = 43.1> 4. Composition according to any one of claims 2 or 3, characterized in that X and / or Y represent a carboxylate or a substituted carboxylate having the formula: <EMI ID = 44.1> 1 and 9 and the groups R are equal or different and chosen from hydrogen, substituted or unsubstituted straight or branched chain alkyl, aryl, alkaryl, aralkyl, alkenyl, cycloalkyl, cycloalkenyl, halogen, pseudohalogen, hydroxy, formyl, nitro, amido , amino and sulphonic acid salts. 5. Composition according to claim 4, characterized in <EMI ID = 45.1> oxygen or sulfur linked by double bond. 6. Composition according to any one of claims 1 to 4, characterized in that X and Y together represent a dicarboxylate. 7. Compositions according to any one of claims 1 to 4, characterized in that X and Y together represent an oxalate having the general formula: <EMI ID = 46.1> <EMI ID = 47.1> equal or different and selected from the group consisting of hydrogen, short chain alkyl, aryl, alkaryl, aralkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, hydroxy, halogen, pseudohalogen, or are combined with the carbon atoms and form then a cycloalkyl, cycloalkenyl or aryl group, and the substituted derivatives thereof, y and z are 0 to 1 provided that (y + z) is equal to 1 or 2. <EMI ID = 48.1> that the dicarboxylate is substituted or unsubstituted and selected from the group consisting of succinate, glutarate, (pentanedioate) ,, <EMI ID = 49.1> 9. Use of the compositions according to any one of claims 1 to 8, in pharmaceutical compositions together with diluents and carriers suitable for the treatment of cancers, tumors and malignant neoplasms.