BE879804A - NOVEL PENTACYCLIC INDOLIC DERIVATIVES, PROCESS FOR OBTAINING SAME AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME - Google Patents

Description

       

  NEW PENTACYCLIOULE INDOLIC DERIVATIVES, THEIR PROCESS

PRODUCT AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM

  
 <EMI ID = 1.1>

  
indolic pentacyclic, process for their preparation

  
and their use as drugs.

  
The new derivatives of the invention correspond to the formulas

  
following general
 <EMI ID = 2.1>
  <EMI ID = 3.1>

  
The invention also relates to the salts of the compounds of general formula I, with mineral or organic acids, preferably a pharmaceutically acceptable acid.

  
The numbering used is the biogenetic numbering proposed by Le Mon and Taylor (Exporientia 21, 508, 1965).

  
 <EMI ID = 4.1>

  
chemically modified to provide new compounds with interesting pharmacological properties. As an example, let us quote the Belgian patents of the

  
 <EMI ID = 5.1>

  
The compounds of the invention are therefore capable of being used in therapy, for example as medicines for regulating blood pressure and heart failure

  
and peripheral circulatory systems.

  
The indole compounds of the invention are obtained by decarboxylation of the corresponding 16-carboxylic heteroyohimbane derivatives. Examples of derivatives having the heteroyohimbane skeleton include raumitorine, cabucine, aric ine, tetraphylline and ajmalicine.

  
The decarboxylation of these 16-heteromohimbane carbomethoxy derivatives is carried out by saponification of the ester group and then treatment in an acid medium.

  
The saponification is preferably carried out by adding alcoholic potash. The mixture is then advantageously heated to between 40 ° C. and the reflux temperature of the reaction medium for 1/2 to 3 hours. After neutralization

  
mixing and removing the inorganic precipitate formed,

  
 <EMI ID = 6.1>

  
aqueous of a strong acid. Preferably sulfuric or hydrochloric acid will be used.

  

 <EMI ID = 7.1>


  
 <EMI ID = 8.1>

  
general two majority products in variable proportions
(la ot Ib, R3 &#65533; H) which can be conventionally separated and purified by chromatography.

  
Compounds la and Ib can be further processed

  
in many derivatives with interesting chemical structures, among others 17-18 seco-yohimbanes.

  
The following diagrams illustrate these transformations.

  
These transformations further confirming the structures proposed for la and Ib.

  
 <EMI ID = 9.1>

  

 <EMI ID = 10.1>
 

  

 <EMI ID = 11.1>
 

  
The compounds of the invention la and Ib can er, besides serving as precursors to the "semi dimeric" alkaloids of

  
type of isocinchophyllamine (Potier, Kan, Le Men, Janot, Budzikiewicz, Djerass, Bull. Soc. Chim. Fr. 2309, 1966)

  
by condensation of Pictet Splenger with the appropriate tryptamine derivative.

  
17-18 secoyohimbanes (corynanes) II to IX are new compounds, themselves capable of being used as medicaments.

  
In view of their therapeutic application, the compounds

  
of the invention are presented in the form of pharmaceutical compositions containing as active substance at least one compound according to the invention, optionally in admixture with other active substances and the adjuvants, diluents, vehicles or excipients customary in pharmacies as well as colors, sweeteners , preservatives, antioxidants, etc ...

  
The following examples illustrate the invention without, however, limiting it.

  
EXAMPLE 1

  
Preparation of oxayohimbanes

  
 <EMI ID = 12.1>

  
4 g of tetraphylline base are dissolved in 1 1 of ethanolic potassium hydroxide (40 g of KOH / 1). The mixture is heated at reflux under nitrogen for 75 minutes. After cooling and neutralization with a hydrochloric acid solution, a KCl precipitate is removed by filtration.

  
The filtrate is concentrated under reduced pressure until the alcohol has completely evaporated.

  
 <EMI ID = 13.1>

  
The preceding residue, dissolved in 800 ml of an aqueous solution of 1N hydrochloric acid, is heated at reflux for 1 hour 30 minutes. After cooling, a precipitate
(very polar in C.C.M.) is removed by filtration.

  
The filtrate brought to pH 9 with an ammonia solution and extracted in a conventional manner, provides a residue weighing 3 g (R - 91%). The C.C.M. (eluent: pure acetone or benzene, ether, methanol mixture; 60:40:10) indicates the presence of two majority products:
- the '(+ 40%; the least polar) <EMI ID = 14.1> accompanied by very polar compounds.

  
The above residue is purified by column filtration

  
 <EMI ID = 15.1> <EMI ID = 16.1>
- S.M.: M + 342 (100%) m / e: 341, 324, 323, 299, 297, 271, 269, 255, 253,

  
251, 239, 227, 214, 200, 199, 186.

  
 <EMI ID = 17.1>

  

 <EMI ID = 18.1>


  
Constants of Ib '
- F: 140 - 142 [deg.] C <EMI ID = 19.1>
- S.M.: M + 342 m / e: 341, 324 (100%), 323, 299, 297, 295, 281, 271,

  
269, 253, 251, 214, 200, 199, 186.

  
- R.M.N. <1> H (pyridine -d5)
 <EMI ID = 20.1>
 EXAMPLE 2

  
 <EMI ID = 21.1>

  
of acetic anhydride, is kept for 17 hours at laboratory temperature. The solution is evaporated under reduced pressure and the residue is taken up in three times 30 ml of benzene with successive distillations under reduced pressure, so as to cause the last traces of reagent.

  
 <EMI ID = 22.1>
3480 (thin band: NH)

  
2840, 2820, 2775 (Bohlmann tapes), 1745, 1250 -
1200 (acetate), 1630.

  
- S.M.: the molecular peak (384) does not appear on the spectrum; m / e; 324 (100%), 323, 309, 295, 281, 269,
255, 239, 214, 199, 200, 186. <EMI ID = 23.1>
 <EMI ID = 24.1>
 EXAMPLE 3

  
 <EMI ID = 25.1>

  
amine and 303 mg of sodium acetate is heated at reflux for 2 hours. Subjected to the usual treatment, it provides a residue (1? .9 mg, R - 80%) homogeneous in C.C.M. consisting of pure oxime II ', which crystallizes in methanol.

  
 <EMI ID = 26.1>
1630
- S.M.: M + 357 m / e: 356, 339, 338 (100%), 323, 299, 297, 294, 271,

  
253, 214, 200, 186.

  
- R.M.N. 1H (pyridine -d5):

  
2 s widened 13 to 12.4 ppm exchangeable with D20

  
OH (mixture of syn and anti oximes)
 <EMI ID = 27.1>
 EXAMPLE 4

  
 <EMI ID = 28.1>

  
A solution of 410 mg of oximc II 3 H in 0.5 ml of chloroform and 0.5 ml of trifluoroacetic anhydride is

  
 <EMI ID = 29.1>

  
clearly in the majority.

  
Pac c.c.e. (solvent: benzene-ether-methanol;

  
 <EMI ID = 30.1>
- S.M.: M + 339 m / e: 338 (100%), 324, 299, 294, 271, 253, 214, 200, 186 <EMI ID = 31.1>

  

 <EMI ID = 32.1>
 

  
EXAMPLE 5

  
Reduction of Ib 'by potassium borohydride; diol IV '

  
 <EMI ID = 33.1>

  
solution of 55 mg of Ib 'in 2 ml of methanol placed under magnetic stirring at ordinary temperature. The reaction is complete in 45 minutes. After usual treatment,

  
 <EMI ID = 34.1>
 <EMI ID = 35.1>
 EXAMPLE 6

  
 <EMI ID = 36.1>

  
The acetylation technique used previously (see preparation on 123 page 153) is applied to 50 mg of IV diol.

  
The residue obtained (54 mg, R = 87%) is homogeneous in C.C.M.

  
 <EMI ID = 37.1> at 1200 (acetate), 1630.
- S.M.: M + 428 (100%) m / e: 427 (100%), 385, 383, 367, 341, 339, 313, 279, 255,

  
 <EMI ID = 38.1>

  

 <EMI ID = 39.1>
 

  
EXAMPLE 7

  
 <EMI ID = 40.1>

  
of MeOH, 0.8 ml of water and 360 mg of sodium acetate is brought to reflux for two hours.

  
After drowning in water and alkalinization of the reaction medium, the oxime VII 'precipitates. (It is insoluble in chloroform). The filtered, dried and weighed precipitate (150 mg, R = 84.5%) crystallizes from acetone.

  
 <EMI ID = 41.1> m / e: 356, 340, 323, 298, 297, 271 (100%), 253, 214, 200,

  
186.

  
 <EMI ID = 42.1>
 <EMI ID = 43.1>
 EXAMPLE 8

  
Acetylated derivative VI '

  
 <EMI ID = 44.1>

  
130 mg of the treated according to the technique indicated on page 153 lead to a residue (138 mg, R - 95%) homogeneous in C, C.M. which crystallizes in acetone.

  
 <EMI ID = 45.1>
1700 (C = canonical O), 1630.
- S.M.: M + 384 (100%) <EMI ID = 46.1>
 <EMI ID = 47.1>
 EXAMPLE 9

  
Reduction of the acetylated derivative VI 'by the borohydride of

  
 <EMI ID = 48.1>

  
A solution of 163 mg of acetylated derivative VI in 2 ml of

  
 <EMI ID = 49.1>

  
carried out in the following manner, makes it possible to separate the components of the mixture:

  
the methanol solution drowned in ice water makes a flaky precipitate appear. After evaporation of the methanol under reduced pressure and cooling, the heterogeneous mixture is filtered. The precipitate is dissolved in chloroform and the solution obtained dried over

  
 <EMI ID = 50.1>

  
consisting of 0 (17) -acetylated alcohols IX.

  
The filtrate extracted with chloroform, provides after evaporation of the solvent, another residue (82 mg, R = 50%) consisting of the diols VIII 'forming a single spot more

  
 <EMI ID = 51.1>
2840.2820.2775 (Bohlmann tapes)
1735 and 1250-1200 (acetate), 1630
- S.M.: M + 386 (100%) m / e: 385, 341, 325, 297, 271, 253, 226, 214, 200, 186

CLAIMS

  
1. As new compounds, the oxayohimbanes of

  
general formula

  

 <EMI ID = 52.1>


  
 <EMI ID = 53.1>

  
acetyl radical.


    

Claims (1)

2. Oxayohimbane according to claim 1 characterized in what in the general formula Ia or Ib, R. represents <EMI ID = 54.1> in that the hydrogen atom in position 3 occupies the configuration a. 3. Process for the preparation of the derivatives according to the claims 1 and 2 characterized in that the 16-carbomethoxy oxayohimbanes of general formula <EMI ID = 55.1> are saponified and then decarboxylated in an acid medium. 4. Method according to claim 3 characterized in that <EMI ID = 56.1> ethanolic KOH solution. 5. Method according to claim 3 characterized in that decarboxylation is carried out by treating with an aqueous solution of HCl 0.2 to 6N. 6. Method according to claims 4 or 5 characterized in what saponification and / or decarboxylation are <EMI ID = 57.1> do reflux of the reaction medium for 10 minutes to 6 hours. <EMI ID = 58.1> general formula <EMI ID = 59.1> optionally in the form of an addition salt, with a mineral or organic acid, and in their different <EMI ID = 60.1> and R2 independently represent a hydrogen atom <EMI ID = 61.1> <EMI ID = 62.1> 8. Sccoyohimbancs according to claim 7 characterized <EMI ID = 63.1> of hydrogen in position 3 occupies configuration a. 9. Medicines used in human or veterinary medicine characterized in that it contains as active ingredient at least one of the compounds defined in claims 1, 2, 7 and 8, in the form of the base or in the form of an addition salt with a pharmaceutically acceptable mineral or organic acid . Patent application "New pentacyclic indole derivatives, process for obtaining them and pharmaceutical compositions containing them. " tabled November 5, 1979 on behalf of the so-called OMNIUM CHIMIQUE S.A. -The general formula of claim 7 is inaccurate and must be replaced by the following general formula: <EMI ID = 64.1> The undersigned is aware that no document attached to the file of an invention patent can be of a nature to make, either in the description or in the drawings, substantive modifications and declares that the content of this note does not bring about such modifications and has no other object than to report one or more material errors. He acknowledges that the content of this note cannot have the effect of making it totally or partially valid. <EMI ID = 65.1> this was not in whole or in part under the legislation currently in force. <EMI ID = 66.1> patent file and to deliver a photocopy.