CH484870A - Process for the preparation of new anilide derivatives - Google Patents

Description

  

  



  Process for the preparation of new anilide derivatives
The present invention relates to a process for the preparation of new, very strongly fungistatic anilide derivatives of the formula (D
EMI1.1

Hydrochloric acid can be split off from this new compound, compounds of the formula (s)
EMI1.2
 respectively
EMI1.3
 arise, where in the forms I, II and III Y is instead of a chlorine atom or the nitro group and R, R 'and R "are hydrogen or lower alkyl.



   Examples of such effective compounds that can be prepared according to the invention are: c. "B-dichloropropionyl (4-chloro-2-nitro) anilide, a -dichloro-butyroyl- (4-chloro-2-nitro) anilide, a, p-dichloropropionyl- (2, 4-dichloro) anilide, a, P-dichloro r-butyroyl- (2,4-dichloro) anilide, oc, P-dichloro-m-methylpropionyl - (2,4-dichloro) -anilide, 3-chloro-α-methyl-acroyl- (2,4-dichloro) -anilide.



   The following new compounds can be obtained by splitting off HCl from the compounds which can be prepared according to the invention: x-chloroacryl- (4-chloro-2-nitro) -anilide, α-chloro-crotonyl- (4-chloro-2-nitro) -anilide , cc-chloroacroyl- (2, 4-dichloro) -anilide, and α-chlorocrotonyl- (2, 4-dichloro) -anilide.



   These relatively simple compounds show exceptionally strong growth-inhibiting activity against the most important pathological mycoses and some pathological yeast species.



   The preferred highly effective compound is x-dichloropropionyl (4-chloro-2-nitro) anilide of the formula
EMI1.4

Due to the enormous increase in dermatomycoses in the last 10 years, the fungistatic compounds are becoming increasingly important.



   The fungus genera Micro sporon, Epidermophyton and Trichophyton are particularly widespread.



   . To this day, salicylanilides or general hydroxy-benzanilides have been used to treat dermatomycoses.



   These compounds combine relatively good effectiveness with good tolerance. However, they have the disadvantage that the addition of serum significantly reduces their fungistatic activity, in the case of salicylanilides by up to 50 to 100 times.



   In addition, these substances are not very effective against the very common pathogenic yeast Candida albicans.



   Another major disadvantage of these phenol-containing fungistats is their easy oxidizability, which is always associated with a loss of effectiveness and with undesirable discoloration.



   Even the recently used mycrostatic antibiotics still leave a lot to be desired in terms of effectiveness.



   The following table provides a comparison of the growth-inhibiting activity of two of the compounds which can be prepared according to the invention with some previously known compounds which are used as mycostatic agents and which characterize the prior art in this field. genes are particularly valuable in antimicrobial solutions, ointments and powders.



   The process according to the invention for preparing the new anilide derivatives is characterized in that an aniline derivative of the formula (IV)
EMI2.1
 TABLE
Efficacy expressed in the minimum growing concentration of the compound in r / ml compound
Candida albicans Microsporum canis
EMI2.2
    1) 1) Example 1 1 10 0, 1
EMI2.3
 Example 2 10 100 1 10 Previously known comparative preparations which are used for the same indication:

   3)
EMI2.4
   100500mut00 4) Hydroxyanilide ¯30 ¯60 ¯10 ¯30 5) Nystatin (antibiotic isolated from cultures of 12, 5 25 12, 5 25
Streptomyces noursei) I) Minimal-tInd maximal digits, denote the range of minimal concentration.



   From this it can be seen that compound no. 1: xss- -Dichlorpropionyl- (4-chloro-2-nitro) -aniline, is by far the most active substance and even surpasses the well-known fungistatically highly active antibiotic nystatin. The hydrochloric acid cleavage product, compound no. 2, is somewhat less effective; its activity is of the same order of magnitude as that of the antibiotic tested.



   In relation to protozoa, x is. u-Dichloropropionyl- (4- chloro-2-nitro) -aniline also 10 to 20 times more effective than nystatin.



   The new compounds are also characterized by a good long-term effect and good skin fixation. These are properties which dictate the preferred intended use of this compound with a reactive functional derivative of an acid of the formula
EMI2.5
 converts to the corresponding anilide, the symbols Y, R, R 'and R "having the meanings defined at the outset.



   The preferred process product is x-dichloro-propionyl- (4-chloro-2-nitro) -anilide, which is obtained by reacting 4-chloro-2-nitro-aniline with the acid chloride, acid anhydride or an ester of arp dichloro - Can represent propionic acid.



   As already mentioned above, hydrogen chloride can be split off from the new compounds of the formula I.



  This elimination of hydrochloric acid can take place immediately after the reaction of the compound (IV) with the compound (V).



   Example I.
17.25 g of 4-chloro-2-nitro-aniline and 20 g of antipyrine are dissolved in 200 cc of chloroform. 17.5 g of dichloropropionic acid chloride in 20 cc of chloroform are added to this solution at approx. 0 ° C. with vigorous stirring. The mixture is then stirred for a further 2-4 hours at room temperature. The reaction solution is evaporated in vacuo. The evaporation residue is removed with Diethy! ether and ice water added and stirred. The ethereal phase, which contains the desired product, is dried and concentrated.



   This gives 24.5 g (82%) of crude @ -dichloropropionyl (4-chloro-2-nitro) anilide. After repeated recrystallization from isopropanol, this compound melts at 73-76 ° C. It is insoluble in water, but easily soluble in chloroform, glacial acetic acid and ethyl acetate. Approx. 0.3 to 0.5 g / 100 ccm dissolve in cold isopropanol, 25 g / 100 ccm at the boiling point.



   Example 2
15 g of cs, 5-dichloropropionyl (4-chloro-2-nitro) aniline are mixed with 50 ccm of 2.0 normal sodium hydroxide solution and 30 ccm of water. The reaction mixture is vigorously turbined. After about 30 to 60 minutes it is filtered, the filter residue is washed with water, dried and then recrystallized from isopropanol.



   About 10 g of x-chloroacroyl- (4-chloro-2-nitro) anilide with a melting point of 87 to 88 ° C. are obtained.



   This new compound is insoluble in water, but easily soluble in acetone, ethyl acetate, warm chloroform and at boiling point in lower alcohols.



   In a manner analogous to that described in Examples I and 2, the other compounds mentioned on page I can also be prepared.

 

Claims (1)

PATENT CLAIM I Process for the preparation of new anilide derivatives of the formula (D EMI3.1 in which Y is chlorine or the nitro group and R, R 'and R "are hydrogen or lower alkyl groups, characterized in that an aniline derivative of the formula EMI3.2 with a reactive functional derivative of an acid of the formula EMI3.3 to the corresponding anilide derivative. SUBClaims 1. The method according to claim I, characterized in that the reactive functional derivatives of an acid of the formula V used are acid chlorides, esters or anhydrides. 2. The method according to claim I, characterized in that 4-chloro-2-nitroaniline with the acid chloride, acid anhydride or ester of 5e, -Dichlor- propionic acid to oc, P-dichloropropionyl- (4-chloro-2-nitro) - -anilide converts. PATENT CLAIM II Use of the compounds of the formula I obtained by the process according to claim I for the preparation of compounds of the formula (II) EMI3.4 wherein Y, R, R 'and R "have the meaning given in claim I, characterized in that the corresponding compounds of the formula) I are split off hydrochloric acid. Approval from the Federal Office for Intellectual Property: If parts of the description are not in accordance with the definition of the invention given in the patent claim, it should be remembered that according to Art. 51 of the Patent Act, the patent claim is decisive for the material scope of the patent.