DE2151054A1 - New chemical compounds from alkaloids of cinchona bark and alkane sultones and processes for the production of the same - Google Patents

Description

Patent attorneys

Dipl.-Ing. Leo Fleuchaus
D r. - I η g. Hans L eyh
8 Munich 7i, fAeichiorstr. 42

October 11, 1971

A 12 344 / ln / fi / leC / R

SOGERAS company
France, Paris

New chemical compounds from alkaloids of cinchona bark and alkane sultones and methods of making the same

The invention relates to a new group of chemical compounds which are particularly valuable in human therapy with indications common for alkaloids of cinchona bark such as quinine, quinidine and similar compounds. These connections result from the conversion of alkaloids of the cinchona bark with alkane sultones and therefore form a special one Category of sulfobetaines. Their advantage is that they take into account the pharmacodynamic properties of the Retain alkaloids as a whole, but show the disadvantages of the latter to a lesser extent, especially a reduced one Toxicity.

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Alkane sultones of the general formula
Ό

and, in particular, the propane sultone of the formula
GH ₉ - CH ₉ - OH ₉ - SO ₉

I I

ο 1

and the butane sultone of the formula
I ₂ - GH ₂ - CH ₂ - GH ₂ - SO ₀

0

have been "known for more than 15 years" compounds that can react with compounds that have Ή ζΞ or OH groups, forming compounds with very different properties.

A conversion of this kind with the alkaloids of the cinchona bark
has not yet been tried, but has proven to be very good
Proven to be profitable and results in compounds of greater solubility, greater activity and reduced toxicity compared to the parent alkaloids.

The reaction of the alkaloid with the alkane sultone is expedient in the presence of an inert solvent such as acetone
or methyl ethyl ketone at room temperature or above, using an excess of alkane sultone with respect to the alkaloid of the cinchona bark. You also have

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found that methyl ethyl ketone can be used more advantageously than acetone and leads to better yields.

As mentioned above, the novel compounds of the invention show interesting pharmacological properties in that they in a general way retained the effect of the starting alkaloid, but at the same time improved properties and in particular have reduced toxicity.

According to a further feature of the invention, these latter therefore result in pharmaceutical preparations which contain a novel compound of the invention together with a carrier or pharmaceutical "diluent. The Pharmaceutical preparations of the invention are normally produced in the classical form, for example in i'orm an injectable solution containing the active ingredient in a suitable, sterile and apyrogenic solvent contains dissolved. The preparations according to the invention can also be in the form of oils, pills, coated tablets, lozenges or else be provided as syrup.

The derivatives of the invention can whatever their chemical structure concerns, exist in two forms.

According to a first form corresponding to the derivatives of quinine, quinidine and hydroquinidine, the inventive Represent compounds by the following formula

CHOH. ,

OH ₃ O -

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where η = 3 for the propyl sulfonate derivatives and η = 4 for

is
the butyl sulfonate derivatives), while R means CH = CHp for the quinidine and ohinine radicals and CHp - CH ^ for the hydro "quinidine radical.

In this pail the derivatives are in the form of internal sulfo-

naten of a quaternary ammonium, from which the

on
Designation of the inner sulphate of the H-propyl-chinin, for example

for the quinidine results.

According to a second i'orm, corresponding to the derivatives of Quinicines leave the compounds according to the invention represent by the formula

(GH ₂ J _n - SO ₃ HIT

. CO

-CH = CH,

where η = 3 for the propyl sulfonate derivatives and η = 4 for is the butyl sulfonate derivative.

The following examples are intended to explain the invention:

example 1

16 g of propane sultone are dissolved in 0.400 liters of methyl ethyl ketone and 21 g of quinine base are added. The mixture is stirred on a water bath at 4O ⁰ C until the dissolution of quinine and filtered

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the warm solution. After resting for one night begins the desired product, the internal sulfonate of the Separate N-propyl-quinine by crystallization. One lets the mixture is still at least 5 days to crystallize the desired product. Then the crystals are dried under vacuum, wash it with a little methyl ethyl ketone and then dry it again.

To purify the product, the dried crystals are added to 200 ml of a mixture of equal volumes of methanol and water and the whole is heated on a water bath to 60 ^° C. until the product has dissolved. The solution is then filtered to obtain a completely clear solution and 300 ml of demineralized water are added dropwise with stirring. The resulting mixture is left to rest at about 4 ° C. for the next day, the resulting precipitate is dried under vacuum, washed with a little water and finally dried under vacuum at about 50 ° C., 21 g of product being obtained.

This product is a white, crystalline powder that is insoluble in water, acetone, chloroform and ether and is soluble in methanol, ethanol and dilute acidic and alkaline solutions. This product is a monopropyl sulfonate with the molecular formula Cp ^ H ^ NpOj-S. Its theoretical quinine content is 72.7 ^c / o (found 72.4 %) and its theoretical sulfur content is 7.1 ^c / <> (found: 7.3 ^c / o) .

■ Example 2

24 g of propane sultone are dissolved in 0.450 l of methyl ethyl ketone and 32 g of quinidine base are added to the solution. The reaction mixture is stirred on a water bath at 40 ° C. until the Quinidines. The reaction mixture is then filtered while warm and left to precipitate the crystals for at least 5 days of the internal sulfonate of N-propyi-quinidine,

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of a precipitate, which after a day of rest of the üeaktions - mixture occurs. They are collected in the reaction mixture precipitated crystals, wash them with a little methyl ethyl ketone and dry them under vacuum.

To purify the product, the crystals are dissolved in 300 ml of methanol on a water bath at about 40 ° C. One filters the Solution and slowly add 50 ml of demineralized liquid to the clear water Add water with moderate stirring. The mixture is left to rest at about 4 G for the product to crystallize, dry the crystals under vacuum, washes them with something demineralized Water and finally dry them again at a temperature of about 50 ° G, giving 33 g of the product:.

The product obtained is a white, crystalline, in water: ~ v, Acetone, chloroform and ether insoluble and laudable in methanol, Easily soluble in ethanol, in dilute alkaline Solutions insoluble but powder soluble in acidic batches.

This product is a mono-propyl sulfonate and has the molecular _formula G ox H ^ _n N _o 0 _K S.

d? 3U d ο

±) s has a theoretical quinidine content of 72.7 7 ° (found 72.6% ) and a theoretical sulfur content of 7.17 % (found 7.25%).

example 3

Dissolve 16 g hydroquinidine base and 12 g of propane sultone in 0.480 1 of methyl ethyl ketone on water bath at 40 ⁰ G. Filter the reaction mixture, leaving them in the dark for 5 days at room temperature are provided. The precipitate is then dried under vacuum, washed with a little methyl ethyl ketone and dried again. For purification, this product is dissolved in a mixture of ethanol (200 ml) and

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Water (60 ml) on the water bath at 7O ⁰ G, the reaction mixture is then left to rest at room temperature until the next day, the precipitate formed is dried in the air (essorer) and dried (dessecher) it under vacuum at about 60 0, whereby 14 g of the product are obtained.

The product obtained is a white crystalline powder which is insoluble in water, ethanol, acetone and ether, partially soluble in methanol, readily soluble in chloroform and soluble in Athano ± or aqueous methanol.

The product is a mono-propyl sulfonate and has the molecular formula C ₂₅ H ₅₂ N ₂ O ₅ S.

ils has a theoretical hydroquinidine content of 69.4 % (found 69.2%) and a theoretical sulfur content of 7.14 ^c / o (found 7.2 96).

Example 4

9 g of quinicine base are dissolved in 10 ml of methyl ethyl ketone and 6.5 g of propane sultone are dissolved in 5 ml of methyl ethyl ketone. The two solutions are mixed with cooling, because the reaction between the two reactants is exothermic. The reaction mixture is left to rest for 5 days, after which the precipitate which forms is decanted off and taken up again with> 0 ml of diethyl ether. The product which forms is filtered under vacuum and ^{dried at about 0} ° C. under reduced pressure, 11 g of the product being obtained.

The product is a yellow powder that is soluble in water and methanol, insoluble in acetone and ether. It has the molecular formula C ₂₅ H ₅₀ NpO ₁ -S.

Its theoretical quinicine content is 72.7 ° / ° (found 7'd, t>>) and its theoretical sulfur content 7.17 %

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(found 6.9 ^c / o) .

Example 5

5.5 ml of butane sultone are dissolved in 50 ml of methyl ethyl ketone then add 10 g of Ühinidin base and heat the mixture during 16 hours under reflux with stirring. The precipitate is collected by vacuum filtration, washing it with a little methyl ethyl ketone and then drying it again.

To purify the product, the crystalline product is dissolved in 80 ml of methanol, then 65 ml of water are added and the mixture is left Mix "rest at 4 C for one hour. The crystals will dried, washed with a little water and finally dried again under vacuum at 50 ° C., 10 g of des Product receives.

This is a crystalline white powder that is soluble in methanol but insoluble in water, acetone, chloroform and ether. _{Its gross} formula is C _o "H 3O N _o 0r-S and its theoretical quinidine content is 70.5 7 ° (found 70.7 ⁰ Zo) ₁ its theoretical sulfur content is 6.96 ^. (found 6.91 #).

Example 6

8.5 ml of butane sultone are dissolved in 200 ml of methyl ethyl ketone then 7 g of hydroquinidine base are added and the mixture is heated under reflux for 16 hours while stirring. One dries the precipitate that forms, washes it with a little methyl ethyl ketone and then dries it.

To purify the product, dissolve the crystals in 1: .O ml hot methanol and gives 150 ml of water after filtration. The mixture is left to rest at 4 ° C for one night,

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then collecting the crystals by filtration tinter vacuum, washed with a little water, dried again in air and then under vacuum at 50 ⁰ G to give 4 g of the product obtained.

The product is a white crystalline powder that is soluble in methanol, insoluble in water, ether, oleochemical and acetone. Its gross formula is ö _or IL ₂ , N ₀ Or-S

24 94 2 5

and its theoretical hydroquinidine content is 70.6 ⁰ Jo (found 70.6 ^c / o) _t its theoretical sulfur content is 6.92 % (found 6.9 ⁰ J ₀ ).

The piiarmacodynamic properties of these new compounds: The internal sulfonates of N-propyl- or N-butyl-quinidine as well as the corresponding derivatives of hydro-quinidine a significant antagonistic effect compared to the electrocardiographic effects induced by aconitine in the rat Anomalies (Haas and Busch method, Medic. I'orsch. 18, (1960) No. 4).

On the other hand, the acute or rapid (aigue) ΐοχΐζΐtat of the internal sulfonates, determined according to the method of Diechmann (J.Ind. Hyg. Toxical. 25, 415 (1943)) is significantly lower than those of the corresponding alkaloids. The therapeutic index of the products according to the invention is thus clearly more favorable than that of quinidine or hydroquinidine.

In addition, the inner sulfonate of N-propyl-quinine shows a clear antipyretic activity against pyrexia, caused in rabbits by the Cheymol method (O.A. Soc. Biol. 149, 338 (1955)). The by subcutaneous injection The fever curve produced by 150 mg / kg of the product of Example 1 is completely comparable to that of the

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ίο

with an equal dose of the quinine hydrochloride is recorded. Since the theoretical quinine content of the product of Example 1 is 72.4 % , the effectiveness of the product is considerably superior to that of the quinine.

Overall, the products of the invention are pharmacodynamic Properties of the corresponding alkaloids, but usually more effective than these.

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Claims (5)

-AU Claims 1, New chemical compounds - characterized by that they originated from an alkane sultone and an alkaloid of the cinchona bark. 2. Compounds according to claim 1, characterized marked Q z ic Ii et η that the alkaloid quinine, quinidine, hydro-CM ¹ ^ Ti .in, Chiiiiein or one of its salts. ;>. Compounds according to claim 1, characterized in that that the alkane sulton is propane sulton or uutan-oulton. 4. Process for the preparation of the compounds according to Claims 1 to 1 _{-J 1,} characterized in that the alkane sultone is allowed to act in excess on the alkaloid of the quinine bark in solution in methyl ethyl ketone. 5. Pharmaceutical preparations for the areas of application of the alkaloids of cinchona bark, characterized in that that they contain compounds according to claims to 3. 2 0 9 8 1 8/1 1 0 A ORiG (NAL INSPECTED