CH374645A - Process for the preparation of new thiocolchicine derivatives - Google Patents

Description

  

  



  Process for the preparation of new thiocolchicine derivatives
The present invention relates to a process for the preparation of new thiocolchicine derivatives of the general formula I,
EMI1.1
 in which Ri is a lower alkyl mercapto group and R2 is an alkyl, alkenyl, alkynyl or cycloalkyl group or an aromatic or heterocyclic radical which is optionally substituted by a hydroxyl, alkoxyl, alkyl, nitro or amino group or by a halogen atom, and X is O or S.



   According to the process of the present invention, the new derivatives of the formula I are prepared by adding a deacetylcolchicine derivative of the general formula II,
EMI1.2
 with an organic isocyanate or isothiocyanate of the general formula III, R2-N = C = X III and the reaction product is purified by crystallization or, if it does not crystallize, by precipitation.



   The method according to the invention is preferably carried out as follows:
An amine of the formula II is in a little abs.



  Dissolved benzene and with a solution of 1. 1 equivalent of isocyanate or isothiocyanate in abs. Benzene added. After 4-24 hours at 20, crystallization generally takes place, possibly only after the addition of ether. Otherwise the products are obtained by precipitation with petroleum ether and purified by reprecipitation. Yellow crystals or amorphous powders are obtained in this way, the melting points of which are not very characteristic, since they are usually accompanied by decomposition. They dissolve easily in most organic solvents, e.g. B. in chloroform, methylene chloride and lower Alkanoleny are sparingly soluble in ether and petroleum ether and insoluble in water.

   The substances are characterized by measuring the molecular rotation and the infrared spectrum. The purity can be checked using paper chromatography.



   The new thiocolchicine derivatives are characterized by a strong and selective inhibitory effect on the division processes in the cell nucleus or by specific mitosis-inhibiting properties. When tested in vitro on the fibroblast culture, they inhibit cell division in the early metaphase to the same extent, sometimes even more so than known colchicine derivatives. The in vivo test was carried out on the experimental Ehrlich ascites tumor of the mouse: When the substances are administered intraperitoneally, cell division is maintained in the early metaphase. Completely inhibited for 10 to 40 hours. With this long duration of action, however, the new compounds prove to be non-cytotoxic and hardly generally toxic.

   As a result of this low toxicity and the lack of the known side effects of colchicine, such as nausea, vomiting and diarrhea, they can advantageously be used in the various classic areas of application of colchicine. They are to be introduced into therapy, but also represent intermediate products for the manufacture of drugs.



   In the following examples, all temperatures are given in degrees Celsius. The melting points are determined and uncorrected in the evacuated tube.



   Example 1 N- (N'-phenyl-thiocarbamido) -desacetyl-thiocolchicine
5 g of crystalline deacetyl-thiocolchicine are dissolved in chloroform and the solution is brought to dryness in vacuo. The amorphous residue is in 50 cm3 abs. Dissolved benzene and mixed with 1.80 g of phenyl isothiocyanate in 5 cm3 of benzene. After standing for 18 hours at a temperature of 200, the yellow crystals are suction filtered and washed with benzene ether 1: 1. M.p. 235-236 (dec.), [Al2t = -77 (c = 0.935 in chloroform).



   Example 2 N- (I'-methyl-thiocarbamido) -desacetyl-thiocolchicine
As in Example 1, the derivative mentioned in the title is prepared using methyl isothiocyanate.



  Decomp. P. 190-201; [C] 21 = chloroform).



   Example 3 N- (N'-Ethyl-thiocarbamido) -desacetyl-thiocolchicine
As in Example 1, the derivative mentioned in the title is prepared using ethyl isothiocyanate.



     Decomp. P. 170-1870; ta] E) l = -109 (c = 0.830 in chloroform).



   Example 4 N- (N'-Allyl-thiocarbamido) -desacetyl-thiocolchicine
As in Example 1, the derivative mentioned in the title is prepared using allyl isothiocyanate.



  Decomp. P. 2392460. [a] 21 = -115 (c = 0.780 in chloroform).



   Example p
N- (N'-a-naphthyl-carbamido) -desacetyl-thiocolchicine
Analogously to Example 1, the derivative mentioned in the title is represented with a-naphthyl isocyanate.



  M.p. 200-202 (dec.); [a] 2D2 = +200 (c = 0.935 in chloroform).



   Example 6 N- (N'-phenyl-carbamido) -desacetyl-thiocolchicine
As in Example 1, the derivative mentioned in the title is prepared using phenyl isocyanate.



  Since the product cannot be made to crystallize, it is precipitated by dripping the benzene solution into petroleum ether. Reprecipitation from methylene chloride petroleum ether gives a pure product with a melting point of 175-185 (decomp.); [iDt = -119 (c = 0.43 in chloroform).



   Example 7 N-w-n-Nonyl-carbamido) -desacetyl-thiocolchicine
As in Example 1, the derivative mentioned in the title is prepared using n-nonyl isocyanate.



  The pure preparation takes place again as in Example 6 by precipitation with petroleum ether. 120-140 D-670 (c = 0.705 in chloroform).

 

Claims (1)

PATENT CLAIM Process for the preparation of new thio colchicine derivatives of the general formula I, EMI2.1 in which Rt is a lower alkyl mercapto group and R2 is an alkyl, alkenyl, alkynyl or cycloalkyl group or an aromatic or heterocyclic radical which is optionally substituted by a halogen atom or a hydroxyl, alkoxyl, alkyl, nitro or amino group, and X is O or S, characterized in that one desacetylcolchicine derivative of the general formula II, EMI2.2 with an organic isocyanate or Isothiocyanate of the general formula III, R2-N = C = X III and the reaction product is purified by crystallization or, if it does not crystallize, by precipitation.