GB1583554A

GB1583554A - Quaternary derivatives of sandwicin and a method of producing them

Info

Publication number: GB1583554A
Application number: GB10521/77A
Authority: GB
Original assignee: Kali Chemie Pharma GmbH
Current assignee: Abbott Products GmbH
Priority date: 1976-03-17
Filing date: 1977-03-11
Publication date: 1981-01-28
Also published as: ES456755A1; DK143602C; FI770855A; BE852493A; CA1072959A; IN146149B; IL51630A; GR62637B; IT1084656B; JPS52113988A; DK114677A; IL51630A0; PT66298A; FR2344557A1; DK143602B; FR2392995B1; DD128774A5; CS197287B2; MX4788E; DE2611162A1

Abstract

Novel sandwicinium salts of the formula I <IMAGE> in which R represents an alkyl group having up to 5 carbon atoms, are obtained by reacting sandwicin with an appropriate alkyl halide. In order to convert the halide into another salt of the formula I', in which X denotes the anion of an organic or inorganic acid, the halide is converted with alkali into the corresponding, open-ring, aldehyde base, which, together with an appropriate acid, yields the desired salt. The novel salts exhibit adrenolytic and cardiac-rhythm-promoting activity. <IMAGE>

Description

(54) QUATERNARY DERIVATIVES OF SANDWICIN AND A METHOD OP PRODUCING THEM (71) We, KALI-CHEMIE PHARMA GMBH, a body corporate organise under the laws of the German Federal Republic, of Hans-Btickler-Allee 20, D-3000 Hannover, German Federal Republic, do hereby declare the invention for which we pray that a patent may be granted to us, and rhe method by which it is to be performed, to be particularly described in and by the following statement :- This invention relates to quaternary derivatives of sandwicin and to methods of producing them.

The new sandwicin derivatives have the general formula;

in which R is a straight-chain or branched alkyl radical containing up to 5 carbon atoms, preferably a methyl, ethyl, or propyl radical, and X is the physiologically compatible anion of an inorganic or organic acid. The anion of the inorganic or organic acid is preferably the anion of oxalic acid, citric acid, tartaric acid, or ortho phosphoric acid.

The new compounds are prepared by reacting sandwicin with an alkyl halide in which the alkyl radical is a straight chain or branched alkyl radical containing up to 5 carbon atoms, and optionally converting the resulting sandwicinium halide by treatment with an alkali into the corresPonding open ring aminoalde- hyde of the following general formula II ;

in which R is as defined above.

The open ring aminoaldehyde is then cyclise with an organic or inorganic acid the anion of which is physiologically compatible, and which provides the anion X in the compound of Formula I.

These open ring aminoaldehydes of the general formula II are described and claimed in our copending Patent Application No.

41140/79 (Serial No. 1583 555).

In this process, the starting substances are reacted in equimolar amounts, but the alkyl halide may also be used in excess, in which case it simultaneously serves the function of a solvent. Alternatively it is expedient for the quatemisanon to be effected at reflux tem- perature in an organic solvent which is inert in relation to the reactants. The temperature may however also be below boiling point. Suitable solvents are for example acetonitrile, chloroform, and dimethyl formamide.

The corresponding open ring aminoaldehyde is obtained either, as in Examples 1B and 2B hereafter, by reacting the sandwicin halide with a 10% aqueous sodium hydroxide solution or by reacting it with another aqueous alkali solution, such as for example a solution of sodium bi-carbonate or of sodium carbonate. It is expedient to work in the presence of a suitable extraction medium which may be any inert water-immiscible solvent, such as chloroform or diethyl ether, in which the base has adequate solubility. After the extraction medium has been distilled off, preferably by vacuum distillation, the base is obtained in an amorphous form.

The base produced in this manner (i. e. an open ring aminoaldehyde) is finally reacted with a physiologically compatible inorganic or organic acid, preferably tartaric acid, oxalic acid, citric acid or phosphoric acid.

It has been found that the quaternary derivatives prepared from sandwicin have adrenolytic and cardiac rhythmising actions.

Surprisingly, however, the new compounds have substantially greater activity and physiological compatibility than the known epimers of sandwicin derivatives. Thus in comparison with the known epimeric ajmaline derivatives the new sandwicin derivatives have comparable activity on the isolated papillary muscle of the guinea pig with a dose reduced by the factor 10. Furthermore the undesirable negative inotropy, such as is observed with the epimeric aimaline derivatives, is weaker, with at the same time a greater therapeutic breadth.

These results permit the conclusion that the steric arrangement of the hydroxyl group at the Cl, atom is of particular importance for the pharmacological action of the new sandwicinium compounds, since this is the sole difference in configuration from the epimers of sandwicin. Sandwicin, which belongs to the group of rauwolfia alkaloids, has been described in detail in Tetrahedron 1, 328 (1957) by M. Gorman et al.

The present sandwicin quaternary derivatives are stable and durable both in aqueous solution and in solid form and can therefore be used therapeutically in suitable medicinal administration forms. They can thus be mixed with conventional solid or liquid carriers and put up into forms suitable for medical administration, including dosage unit forms such as tablets, capsules and solutions and suspensions.

The pharmacological data used for comparison were obtained in known manner by measuring the functional refractory time and the contractive force in the prepared lefthand papillary muscle of guinea pig (male and female of 300-350 g.) The invention will now be illustrated by the following Examples : Example 1 A: N-methyl-sandwicinium iodide.

12.0 g of sandwicin are heated under reflux for about 7 to 9 hours with 12.0 ml. of methyl iodide in 500 ml. of acetonitrile and then evaporated to dryness. 16.0 g. of N-methyl- sandwicinium iodide in the form of an amorphous yellow product are obtained.

Yield: 93% of theory.

B: Open ring aldehyde base 16.0 g. of N-methyl-sandwicinium iodide are suspended in 500 ml. of water, 12.0 ml. of 10% sodium hydroxide solution are added, and the mixture is stirred for 30 minutes with 1000 ml. of chloroform. After separation of the chloroform phase, the aqueous phase is stirred again with 500 ml. of chloroform. The chloroform phases are united and dried over sodium sulphate. An amorphous residue of 11.5 g. of open ring aldehyde base of Formula II (R=CH,) is obtained.

Yield: quantitative.

C: N-methyl-sandwicinium hydrogen tartrate 11.5 g. of open ring aldehyde base are dissolved in 150 ml. of methanol, mixed with 4.1 g. of L-tartaric acid are dissolved in a little methanol, and the mixture is introduced into 1500 ml. of acetic ester while thoroughly stirring. After the light-coloured precipitate has been sucked off and the product washed with ethyl acetate, it is dried at 50 C. until a constant weight is obtained.

Melting point: 135-137 C. (decomposition) Yield: 11.4 g. =69% of theory.

Example 2.

A: N-propyl-sandwicinium bromide 22. 0 g. of sandwicin are heated under reflux for about 7 to 9 hours with 20 ml. of n-propyl bromide in 1000 ml. of acetonitrile, whereby a light-coloured precipitate is formed. The precipitate is sucked off, washed with acetonitrile, and dried at 50 C. 20.8 g. of N-propyl-sandwicinium bromide, MP. 314- 316 C. are obtained.

Yield : 69% of theory.

B: Open ring aldehyde base 20.8 g. of N-propyl-sandwicinium bromide are suspended in 200 ml. of water, 20 ml. of 10% sodium hydroxide solution are added, and the mixture is stirred with 200 ml. of chloroform for 30 minutes. After separation of the chloroform phase, the product is stirred twice with 200 ml. of chloroform. The chloroform phases are united, dried over sodium sulphate, and evaporated in vacuo.

Residue: 16. 2 g. of amorphous aldehyde base of Formula II (R=QH,) Yield: quantitative.

C: N-propyl-sandwicinium hydrogen tartrate 16.2 g. of open ring aldehyde base are dissolved in 50 ml. of methanol and mixed with 7.0 g. of L-tartaric acid dissolved in a little methanol. The mixture is introduced into 2000 ml. of acetic ester with vigorous stirring.

The resulting white precipitate is sucked off after being allowed to stand for a short time, washed with ethyl acetate, and dried to a constant weight of 50 C., 21.5 g. N-propyl- sandwicinium hydrogen tartrate are obtained, MP 205-207 C. (The N-propyl-sandwicinium hydrogen tartrate obtained contains small amounts of the corresponding iso form).

Yield: 94 % of theory.

Claims

WHAT WE CLAIM IS :-

1. A quaternary derivative of sandwicin of the general formula I :

wherein R is a straight chain or branched alkyl radical containing up to 5 carbon atoms, and X is the physiologically compatible anion of either an inorganic or an organic acid.

2. A derivative as claimed in claim 1, wherein R is a methyl, ethyl or propyl radical.

3. A derivative as claimed in claim 1 or 2, wherein X is the anion of oxalic, citric or ortho phosphoric acid.

4. A derivative as claimed in claim 1 or 2, wherein X is a tartrate ion.

5. A quaternary derivative of sandwicin of the general formula defined in claim 1 sub stantially as hereinbefore described in either of the fioregoing Examples.

6. A pharmaceutical composition comprising as an active ingredient a quaternary derivative of sandwicin as claimed in any preceding claim and a solid or liquid carrier.

7. A process for the preparation of a quaternary derivative of sandwicin of the general formula defined in claim 1, wherein sandwicin is reacted with an alkyl halide of which the alkyl radical is a straight chain or branched alkyl radical containing up to 5 carbon atoms, and the resulting sandwicinium halide is optionally converted into the corresponding open ring aldehyde base of the general formula II

wherein R is a straight chain or branched alkyl radical containing up to 5 carbon atoms, by treatment with an alkali, and wherein the said aldehyde base of Formula II is cyclised with a physiologically compatible organic or inorganic acid which provides the anion X in the compound of Formula I.

8. A process as claimed in claim 7, wherein R is a methyl, ethyl or propyl radical.

9. A process as claimed in claim 7 or 8, wherein the acid is oxalic, citric, tartaric or ortho phosphoric acid.

10. A process as claimed in any one of claims 7 to 9, wherein the reaction with the alkyl halide is effected at reflux in an inert organic solvent.

11. A process as claimed in any one of claims 7 to 9, wherein the rection with the alkyl halide is effected with a excess of the alkyl halide which serves as a solvent.

12. A process as claimed in any one of claims 7 to 10, wherein the alkali is sodium hydroxide, sodium bicarbonate or sodium carbonate.

13. A process for the preparation of a quaternary derivative of sandwicin of the general formula defined in claim 1 substan- tially as hereinbefore described in either of the foregoing Examples.