IL31570A

IL31570A - Laevorotatory indole derivatives,their production and pharmaceutical compositions containing them

Info

Publication number: IL31570A
Application number: IL31570A
Authority: IL
Original assignee: Sandoz Ag
Priority date: 1968-02-09
Filing date: 1969-02-07
Publication date: 1972-03-28
Also published as: IE32639B1; DE1905881A1; FI50972C; AT299188B; SE340621B; NL6900797A; CH495983A; BE728142A; BR6906200D0; GB1251716A; DK119110B; DE1905881C2; NO125590B; FR8067M; FI50972B; FR1598040A; IL31570A0; GB1252399A

Description

Case IMPROVEMENTS IN OR RELATING TO ORGANIC COMPOUNDS The present invention relates to novel laevorotatory indole derivatives of formula H in which and signify hydrogen or and their salts with inorganic and organic Any methyl radical which may be present in the indole structure may be in the or The novel laevorotatory indole derivatives of formula I and their acid addition salts may be obtained in accordance with the invention by reacting a of formula in which has the above in an alkaline medium and in the absence of with laevorotatory epichlorhydrin or heating the reaction product with an amine of formula in which has the above and j signifies hydrogen or splitting off any benzyl radical which be present in the and optionally converting the resulting compound into an acid addition salt by reaction with an inorganic or organic Various embodiments of the invention are described The of formula II is used in the form of an alkali metal or ammonium preferably as sodium For this purpose it may be added to an equimolar solution of an alkali hydroxide or ammonia for a lower alkanol or or may be reacted in an organic solvent which is inert under the reaction benzene or with an equimolar amount of an alkali metal amide or In accordance with another embodiment of the process an alcoholic solution of an alkali metal salt of the derivative of formula II is evaporated to dryness and the residue is suspended in an organic solvent which is inert under the reaction 1 to equivalents of laevorotatory epichlorhydrin or may be added to the solution or suspension of the salt and the mixture is stirred for an extended 10 to 24 at room The of formula II are extremely sensitive to oxygen in an alkaline so that the reactions described above are effected in the absence of for example in an atmosphere of The resulting product isolated in manner known per optionally purified and subsequently heated to for about 10 to 2 hours with an amine of formula The addition of an an inorganic such as potassium a tertiary organic such as pyridine or or an excess of the amino component may be advantageous but is not a primary amine is used as the amino the reaction is preferably effected in an organic solvent which is inert under the reaction conditions and which has a higher boiling point than the benzene or in a pressure in view of the low boiling point of such an When a secondary amine is used as the amino the reaction may be effected at normal pressure and without a this reaction is also preferably effected in an organic solvent which is inert under the reaction benzene or The subsequent splitting off of any benzyl radical which may be present in the product is for by hydrogenation in the presence of a suitable such as in an organic solvent such as ethanol or ethyl The process of the invention does not lead exclusively to the levorotatory compounds of formula but also yields the corresponding racemic compounds as because they are less these may be separated from the laevorotatory compounds by crystallization from a suitable The laevorotatory compounds of formula I are basic which are practically insoluble in but usually fairly or readily soluble in most organic solvents and in aqueous solutions of organic or inorganic With reagent acetic acid containing and concentrated sulphuric and with Van reagent dehyde and dilute sulphuric they generally tic With inorganic such as hydrochloric hydrobromic acid and sulphuric or with organic such as benzoic or acid and they form stable salts which are usually the duction of which is also included in the present The racemic compounds of formula I are known and are blockers having a strong so that they may be used as The laevorotatory compounds of formula have hitherto not been Racemic compounds of formula I are claimed in Israeli Patents 25527 and but since the specifications thereof were not published prior to the priority date of the present they do not form part of the prior In tests on animals they exhibit interesting dynamic properties and may therefore be used as In they exhibit an antagonistic effect towards the and effect of adrenalin on the spontaneously pig atrium and are therefore characterized as In this respect they are superior to the corresponding racemic they are furthermore distinguished by an especially suitable ratio between the and negative inotropic The new laevorotatoiy compounds are indicated for use in the prophylaxis and therapy of coronary especially Angina in the treatment of the hyperkinetic heart muscular hypertrophic subvalvular as well as in the prophylaxis and therapy of heart rhythm disorders and tachycardiac An average daily dose is from about 1 The new laevorotatoiycompounds of formula I and their physiologically tolerated acid addition salts may be used as medicaments on their own or in the form of appropriate medicinal such as suppositories and injectable for enteral or parenteral Aside from the usual inorganic or pharmacologically inert such as stearic natural or hardened oils and waxes and the these preparations may also contain suitable stabilizing or wetting sweetening or colouring substances and In the following Examples all temperatures are indicated in degrees Centigrade and are EXAMPLE 1 g of are added while stirring in an atmosphere of nitrogen to a solution of 5 g of sodium hydroxide in I50 cc of and g of are subsequently The mixture is stirred at room temperature for a further 14 the reaction mixture is extracted times with methylene and the combined organic layers which have been dried over magnesium sulphate are concentrated by evaporation at reduced The oily residue is taken up in 120 cc of dioxane and 60 cc of isopropylamine and heated to for 20 The mixture is evaporated to dryness at reduced is shaken out thrice between ethyl acetate and a 1 N aqueous tartaric acid and a 5 N caustic soda solution is subsequently added to the combined tartaric acid phases until an alkaline reaction is The mixture is extracted thrice with methylene chloride and the combined organic phases which have been dried over magnesium sulphate are concentrated by evaporation at reduced The residue is taken up in the undissolved material is filtered the filtrate is concentrated by evaporation and the residue is crystallized thrice from The resulting 20 has a of 5 3 in The following compounds may also be produced in analogous From and From and From and From and From and EXAMPLE The process is effected in a manner analogous to that indicated in Example except that is used in place of The title compound is identical with the product produced in accordance with Example 20 crystallizing thrice from in EXAMPLE In a manner analogous to the process indicated in Example 1 is reacted in an aqueous sodium hydroxide solution and in an atmosphere of nitrogen with and the reaction product is heated to for 20 hours with propylamine in 15 g of the resulting product are dissolved in 200 cc of methanol and hydrogenated in the presence of 4 g of a palladium catalyst on aluminium at room temperature until the take up of hydrogen is The catalyst is filtered the filtrate is evaporated to dryness at reduced pressure and the residue is taken up in The undissolved material is filtered the filtrate is concentrated by evaporation and the residue is crystallized thrice from The resulting is identical with the product produced in accordance with Examples 1 and 20 crystallizing thrice from in EXAMPLE Galenic 8 magnesium stearate g polyvinyl pyrrolidone g talc g maize starch g laotose g dimethyl silicone oil g polyethylene glycol 6000 g insufficientOCRQuality

Claims

1. A process for the production of a laevorotatory indole derivative of formula I, in which R^ and R^ signify hydrogen or methyl, and acid addition salts thereof, characterized by reacting a hydroxy- indole of formula II, in which has the above significance, in an alkaline medium and in the absence of oxygen, with laevorotatory epichlorhydrin or epibromhydrin, heating the reaction product with an amine of formula III, in which R2 has the above significance, and signifies hydrogen or benzyl, splitting off any benzyl radical which may be present in the product, and optionally converting the resulting compound into an acid addition salt by reaction with an inorganic or organic acid. ** · - 10 - 10-285^

2. A process for the production of a laevorotatory indole derivative of formula I, stated in Claim 1 , substantially as herein described with reference to any one of Examples 1 to 3.

3. A laevorotatory indole derivative of formula I, stated in Claim 1, whenever prepared by the process claimed in Claim 1 or 2.

4. A laevorotatory indole derivative of formula I, stated in Claim 1.

5. - - ) -4- (2-hydroxy-3-isopropylaminopropoxy)indole .

6. - ) -4- (2-hydroxy-3-isopropylaminopropoxy )-2-methylindole.

7. - ) -4- (2-hydroxy-3-isopropylaminopropoxy) -3-methylindole.

8. - ) -4- (2-hydroxy-3-tert.butylaminopropoxy)indole.

9. (-)-4-(2-hydroxy-3-tert.butylaminopropoxy)-2-methylindole.

10. (-)-4- (2-hydroxy-3-tert.butylaminopropoxy)-3-methylindole.

11. An acid addition salt of a compound claimed in any one of Claims 3 to 10.

12. A pharmaceutical composition incorporating as active ingredient a laevorotatory indole derivative of formula I, stated in Claim 1, or a physiologically acceptable acid addition salt thereof.

13. A pharmaceutical composition according to Claim 12, in unit dosage form, suitable for the administration of a total daily dosage of from 1 to 40 mg of active ingredient. For the Applicant.