CH492741A - Chlorethyl group-containing phosphoramide - derivs - Google Patents

Abstract

Chlorethyl group-containing phosphoramide derivatives. N-left brace 4- N,N-bis(2-chlorethyl) aminophenyl right brace- phosphoramide acid-bis(morpholide) is prepared by reacting N,N-bis-(2-chlorethyl)-p-phenylene diamine, PO2Cl and morpholine in any desired sequence, and opt. converting to non-toxic salts. It is an alkylating substance with cytostatic properties at low toxicity, and is used in malignant tumour therapy, partic. neoplasma of lymphatic diseases and immunological patterns associated with undesired cell increase, and can be given by mouth, injection or as suppositories.

Description

  

  
 



  Process for the preparation of N- (4- [N, N-bis (2-chloroethyl) laminophenyl} -phosphoramic acid bis (morpholide)
The present invention relates to a process for the preparation of N - {4 - [N, N - bis (2-chloroethyl) jaminophenyl) -phosphoramic acid bis (morpholide) (formula I, see formula sheet) and its acid addition salts, characterized in that that N, N-bis- (2-chloroethyl) -p-phenylenediamine, phosphorus oxychloride and morpholine are reacted with one another in any chronological order and the compound of formula I thus obtained is converted into its acid addition salts by reaction with organic or inorganic acids, if appropriate.



   The process is advantageously carried out as follows: The reaction mixture of phosphorus oxychloride and N, N-bis (2-chloroethyl) -p-phenylenediamine in an inert solvent, e.g. Methylene chloride, ethylene chloride, chloroform, tetrahydrofuran, dioxane or acetone, the reaction product obtained by adding a tertiary base is mixed with morpholine. After stirring for several hours at room temperature, the mixture is evaporated and the N- {4- [N, N-bis (2-chloroethyl)] aminophenyl} phosphoramic acid bis (morpholide) obtained is purified by methods known per se and, if necessary, into its therapeutically usable salts with organic or inorganic salts.



   N - {4- [N, N - bis (2-chloroethyl) jaminophenyl} phosphoramic acid bis (morpholide) is an alkylating substance and is characterized by pronounced cytostatic properties with low toxicity. It is suitable for the treatment of malignant tumors and sarcomas.



  In particular, it is used in the therapy of neoplasms of lymphatic diseases, especially of the immunological type, which are associated with undesired cell proliferation.



     N- (4- [N, N-bis- (2-chloroethyl)] aminophenyl} phosphoramic acid bis (morpholide) can be used as a medicament alone or in appropriate dosage forms for enteral or parenteral administration or organic, pharmacologically indifferent auxiliary substances are processed



  for tablets and dragees:
Lactose, starch, talc, etc.



  for syrups:
Cane sugar, invert sugar, glucose solutions and the like a.



  for injection preparations:
Water, alcohols, glycerine, vegetable oils and the like.



  for suppositories: natural or hydrogenated oils, waxes, etc. more.



   In addition, the preparations can contain suitable preservatives, stabilizers, wetting agents, solubilizers, sweeteners, colorants, flavorings, etc.



   The dose to be administered daily should preferably be 10 to 500 mg.



   In the following example, which explains the implementation of the method but is not intended to restrict the scope of the invention in any way, all temperatures are given in degrees Celsius.
EMI1.1
  



   Example I N- {4- [N, N-bis (2-chloroethyl)] aminophenyl} phosphoric acid bis (amorpholide)
34 ml of phosphorus oxychloride are dissolved in 500 ml of methylene chloride, cooled to 00, a solution of 100 g of N, N-bis (2-chloroethyl) -p-phenylenediamine and 103 ml of triethylamine in 1000 ml of methylene chloride is added dropwise with stirring at 00, and stirring is continued 1 hour at 00 and evaporate to dryness. The residue is suspended in 1500 ml of dioxane, stirred for 15 minutes at 250, then cooled to 100 and 130 ml of morpholine are added.

  After stirring for 3 hours at 250, the filtrate is filtered, evaporated, the residue is dissolved in a mixture of ethyl acetate-water, the organic phase is washed with water, dried over sodium sulfate, evaporated and the N - {4 - [N, N - bis (2-chloroethyl)] aminophenyl} phosphoramidic acid bis (morpholide) in acetone. M.p. 1340.

 

   Example 2 N- C4-N, N-bis (2-chloroethyl) laminophenyl) ph ccinidic acid bis (rnorpholide)
34 ml of phosphorus oxychloride are dissolved in 1000 ml of methylene chloride, cooled to 00, a mixture of 65 ml of morpholine and 103 ml of triethylamine is added dropwise with stirring at 00, stirring is continued for one hour at 00 and another solution of 100 g of N, N-bis is added dropwise (2-chloroethyl) -p-phenylenediamine and 103 mol of triethylamine in 1000 mol of methylene chloride. After 3 hours at 250 it is washed with water, dried over sodium sulfate, evaporated to dryness and recrystallized from acetone. M.p. 1350.

 

Claims (1)

PATENT CLAIM Process for the preparation of N- {4- [N, N-bis (2-chloro-äthylfiaminophenyl} -phosphoramic acid bis (morpholide) (formula I, see formula sheet) and its acid addition salts, characterized in that N, N-bis - (2-chloroethyl) -p-phenylenediamine, phosphorus oxychloride and morpholine are reacted with one another in any chronological order and the compound of formula I thus obtained is optionally converted into its acid addition salts by reaction with organic or inorganic acids. SUBCLAIMS 1. The method according to claim, characterized in that the reaction product of N, N-bis - (2-chloroethyl) -p-phenylenediamine is condensed with phosphorus oxychloride with morpholine. 2. The method according to claim, characterized in that the reaction product of one equivalent of phosphorus oxychloride is condensed with two equivalents of morpholine and with N, N-bis (2-chloroethyl) -p-phenylenediamine.