DE1941021A1 - Phloroglucin derivatives and processes for their preparation - Google Patents

Description

PattntanwShe
Dlpl.-lng.R.Beetiu.

Dipl.-Ing. Lamprecht 96-14.846P August 12, 1969

LABORATOIRE L. LAPON, Paris (France)

Phloroglucine derivatives and processes for their

Manufacturing

The invention relates to new derivatives of phloroglucin, which are therapeutically active and of the general formula:

-0-CH- (CHOH) ₅ -CH-CH ₂ OH 0

suffice, in which R stands for a hydrogen atom or a low molecular weight Alkyl radical, in particular a methyl radical.

The new derivatives leave you ingenious produce »that one phlorogluoinderivate of the general Formula:

96- (H 655S) -DfE (6)

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-OH

in which R is again either a hydrogen atom or a lower alkyl radical, in particular a methyl radical, IaBt ₄ reacts with aoetobromoglucose in the presence of alkali, resulting in an acetyl derivative which can be saponified to obtain the monogluooside.

To further explain the invention are the following some exemplary embodiments are described in more detail, which, however, do not imply any restriction for the scope of the invention:

Example 1;

Phloroglucin d, fl-Glucoald
HO

-0-CH- (CHOH), - CH-CH ₂ OH 0

In a three-necked flask of 5 liters, equipped with a stirrer and a Felkinsöhen RüokfluBkühler "154 g of phloroglucinol are {1 * 065 mol) and 850 csa ^ in-Hatronlauge

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give. Then until the product is completely dissolved - optionally with cooling - stirred.

In addition, 550 g (0.85 mol) of acetobroraglucose are in Dissolved 2.45 liters of sulfuric acid ether.

Next, add the essential solution to the caustic soda solution is added, followed by rapid stirring to mix the two phases together and this stirring becomes constant maintained. ·

After 24 hours, 107.5 errr in sodium hydroxide solution added and after 48 hours another 107 * 5 cnr.

The mixture is then further stirred for a total of 120 hours (5 days). The stirring is then stopped and the mixture is poured into a sedimentation vessel.

An ether layer is obtained on 250 g of sodium sulfate, which is stirred and then left to stand overnight.

Then it is filtered, the ether to about 800 cnr (about 1/3) concentrated and in a refrigerator for 4 hours held at 5 ° C.

The product formed then crystallizes in excess in the form of small, round particles. Then will filtered under normal pressure and finally under vacuum

"5 dries. Then it is washed with twice 1/2 inch ice ether, dried and sealed.

A cake is obtained and is dried in for 4 hours

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a drying cabinet under vacuum (8 cm mercury column 37 ° C).

70 g of gross product are obtained with a melting point of about 75 ° C, this is allowed to recrystallize in 1050 ctir boiling water, Then the light product, which is insoluble in the heat, is filtered according to the Büchner method and the piltrate is caught hot in an Erlenmeyer flask.

The mixture is allowed to crystallize out with stirring and is then rapidly cooled using ice.

Then leave the product over Naoht in the refrigerator, then the product is filtered, washed with water and dried.

The drying takes place in a drying cabinet under vacuum (8 cm mercury column at 37 ° C). 40.7 g of the acetylated product are obtained (yield 10.5 %) with a melting point of up to 110 ° C. (not very hot).

40 g of the acetylated product are added together with 800 enr of water and 155 g of baryta (Ba (OH) _2, 8HgO) in an Erlenmeyer flask of 1 liter capacity, and then stirred rapidly overnight at 37 ° C.

Concentrated sulfuric acid is then added dropwise with stirring until the pH is 2.5-3.

The next step is centrifugation for 10 minutes at JOOO revolutions per minute.

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It is then decanted, the baryium sulphate base is washed out with a little water and the aqueous solution brought to a pH value of 4 with sodium hydroxide solution.

The mixture is then cooked with the addition of charcoal and then filtered and concentrated under reduced Druok at a temperature below 50 ⁰ C temperature.

The next step is steam drying twice with absolute ethyl alcohol.

The product is then dissolved in 400 cnr absolute ethyl alcohol added, cooled, any sodium sulfate present was filtered off and the alcohol evaporated under reduced pressure.

The next step is vacuum drying with KOH and HpSC. 20.8 g of product (yield based on the phloroglucinol: 8.65 %) are obtained in the form of amorphous, slightly cream-colored and very hygroscopic crystals.

The melting point of the product obtained in this way is around 140 ° C., the melting point of that which has been completely dehydrated by acetone Product at 228 ° C.

Its elemental analysis leads to the following result ι

theoretical values: _{cn Λ c} cc iiu in = nc u found values: 50.2 5.9 43.9 36.0

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The product obtained is soluble in water and in alcohol, Slightly soluble in acetone and insoluble in ether.

Example 2;

Phloroglucin aono-Qlucosid-3j 5-Dlmethyl ether

-O-CH- (CHOH) ₅ -CH-CH ₂ OH

0 - y

In a reactor with a capacity of 6 liters "the one with a cooler" a circulating stirrer, a stirrer and a dropping funnel are 6l, 6 g (0.4 mol) of dimethoxy-3,5-pnenol and 320 cnr acetone entered.

The mixture is then stirred until the product has completely dissolved. 400 ear In potassium hydroxide solution added dropwise, then stirring is continued, placed the whole in an ice-water bath and bubbled nitrogen through the apparatus. A weak stream of nitrogen is maintained throughout the synthesis.

In addition, 529 g of acetobromoglueose (0.8 mol) in Dissolved 580 cnr acetone and added to the reactor.

The pH value of the hydroaeetonic solution is 11 »5 ·

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While the solution is being stirred, 400 ml of ln potassium hydroxide solution are added added in small amounts of about JO cnr.

This addition may only be made when the pH value decreases and moves away from 11.5. It is to be avoided that the pH value becomes greater than 11.5 or less than 10.

The additions require a total time of about 6 hours. As soon as all of the potassium hydroxide has been added stirring continued for another 50 minutes. The pH is then at 10.

The mixture is then kept in the refrigerator overnight.

The next day the pH is between 5 and 6.

Then 2 liters of ice water are added, the pH becomes brought back to 11.5 by adding aqueous potassium hydroxide solution, and then initially twice with one liter each Benzene and then extracted again with 500 cnr benzene.

The benzene extracts are mixed five times with 500cc 5 # sodium carbonate washed and rinsed with 1 liter of water. The benzene layer is then dried using calcium chloride, filtered and distilled under reduced pressure.

The residue is heated in 1 liter of a boiling point Mixture of water and alcohol in a ratio of 1: 1 collected and then kept in the refrigerator overnight.

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The resulting crystals are filtered off and washed twice with 60 cnr of a mixture of alcohol and water in a ratio of 1: 2. It is then filtered, centrifuged and dried _{under vacuum with P 2} ⁰ C ^^ ^K0H.

The filtrate is concentrated to one third and then kept in the refrigerator overnight. A second set of crystals crystallizes out. Ss is filtered again, washed with a mixture of ethyl alcohol and water in a ratio of 1: 2 and dried. Then the new crystals are combined with the previously obtained crystals.

50 g of the acetylated product are obtained in the form of fine, pale yellow needles. The melting point is (yield for the product acetyiierte # 25.8) at 120 ⁰ C.

Then you take a saponification with sodium methylate.

50 g of the acetylated product (0.103 mol) are placed in a 1 liter Erlenmeyer flask with a magnetic stirrer. and entered 200 enr chloroform.

The mixture is stirred and placed in a fresh water bath so that the temperature reaches a value of -10 ° C, and it is kept at this temperature for the entire duration of the saponification.

103 cnr of a methanolic solution of In sodium methylate was added.

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The mixture is then stirred for 1 1/2 hours. With further rapid stirring, 500% ice water and 100% ln sulfuric acid are added admitted.

The solution is poured into a 1 liter decanting flask and decanted. An aqueous layer is obtained.

The chloroform layer is washed with 100 cubic meters of water added to the aqueous layer.

Then the aqueous solution is filtered and in a rotating evaporator concentrated at a temperature less than 55 ° C.

It is then dried under vacuum with KOH and P ₂ O, -.

The residue is taken up in 500 cnr anhydrous methanol. The solution is cooled and filtered, the insoluble Sodium sulfate is washed out with 100% anhydrous methanol. Then the methanol is concentrated in the rotating evaporator

This is followed by drying under vacuum using potassium hydroxide solution and calcium chloride.

31.8 g of product are obtained (efficiency compared to the diraethoxy-3,5 phenol 25.1 #).

The product obtained is obtained in the form of white crystals which have a melting point of 166 ° C. The elemental analysis leads to the following result:

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- ίο -

theoretical value 55.2 6.3 40.5 19 * 6 21.5 found value 52.8 6.5 41, 2 19.4 20.9

The product obtained is soluble in water, methanol and ethanol, but insoluble in chloroform, acetone and Ether.

The compounds obtained according to the invention can be used as medicaments, with the properties of the Phlorogluoins show, but have a retarding effect. It is to be hoped that if taken orally it will relieve itself break down by the digestive tract, releasing the phloroglucinol and its own effect on the organism can exercise. This hypothesis could be confirmed.

A "pharmacological investigation has shown that that the products show no digestive activity without their dissolution.

In the following some animal experiments will be described which prove the activity of the compound obtained according to Example I.

I. Aggravated toxicity in mice:

When administered intravenously, the product according to Example 1 showed no toxic effect up to a dose of 1 g / k « No symptoms of poisoning were observed.

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■ j "i

II. Antispasmodic effect:

1) in vitro

A) isolated duodenum from rats:

The experiments were carried out on 8 different organs. Non-cramped organs: The product of Example 1 changed normal tone up to a dose of 1 mg / cnr of the organ not ..

Compared to barium chloride: Compared to a spasm caused by barium chloride, the product of Example 1 increased in size at a dose of 100 "," / on? the contraction to a small extent * At a dose of 1 rag / cnr a slight antispasmodic effect could be observed, which could not be confirmed by a larger dose (7 * 5 mg / enr).

In these organs, papaverine carbohydrate at a dose of 2 "T / om reduced spasm by $ 69.

B) Isolated guinea pig urethra:

The experiments were carried out with 4 organs.

Up to a dose of 1 mg / cm- ^{5, the} product of Example 1 showed no effect whatsoever either on an organ at rest or on an organ contracted by bariurium chloride.

2) in vivo

Guts of guinea pigs:

The product showed when injected intravenously on three

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Animals at a dose of 100 mg / kg no effect on the Intestinal peristalsis.

In practical tests on humans, the product of Example 1 administered parenterally to volunteers in the following solution:

Tested product (Example 1) 1.25 g sodium disulphite 0.05 g

Sodium chlorine solution of 9 o / oo qsp 250 cm- ⁵

This solution was administered in a 4 cnr ampoule.

Such an ampoule injected into a person had no secondary effects, but it also did not induce any sedation in the event of an attack of pain of spasmodic origin.

This proves that the product is stable under these conditions and does not dissolve in the organism.

• However, once the product was administered orally to humans, a dose of 0.25 g gave in shape tablets had a sedative effect on the pain attack, and the product lasted much longer than the product administered orally Phloroglucine.

The product of Example 2 was also the subject of animal experiments.

The results of these tests are summarized below:

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19A1021

I. Increased toxicity for mice:

The product of Example 2 showed no toxic effects up to a dose of 1 g / kg and intravenous administration,

Mydriatic disease was found in mice given a dose of 1 g / kg of the product intramuscularly Effect and a slight hypothermia (-0.5)

II. Cardiovascular properties when examined in isolated rabbit hearts.

At three sprayed with barium chloride heart the product at doses of 1 Ύ / cnr, 10 T / ^cm and 100] f / onr no effect either on the periphery or on the amplitude or to the rhythm of the heart beat exhibited.

III. Antispasmodic effect - chloleresis

1) Isolated rat duodenum

A) Organs at rest: no effect up to a dose of 250 TVcnr, a slight contraction effect at a dose of 1 mg / cm.

B) Duroh addition of barium chloride contracted organs:

The product showed none up to a dose of 1 mg / onr antispasmodic effect compared to barium chloride

C) Organs contracted by acetylcholine: the product showed no antispasmodic up to a dose of 1 rag / cnr Effect on acetylcholine (4 organs).

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The atropine used as a standard reduced the contractions induced by acetylcholine by an average of 76 # at a dose of 0.005 "f '/ cm (4 organs).

2) Isolated guinea pig urethra:

The product showed none up to a dose of 1 mg / enr antispasmodic effect against barium chloride (4 organs).

3) Isolated ileum from guinea pigs in situ:

The product showed when injected into 4 guinea pigs at a dose of 50 mg / kg intravenously (by solubility of the product limited maximum injectable dose) had no effect on pearlescence in two cases and brought the Peristaltic in the other two cases to a standstill for three and ten minutes, respectively.

A slight and transient decrease in blood pressure was observed in all cases.

4) cholerese,

In anesthetized rats, the product at an intravenous dose of 100 mg enlarged / kg bile production ~ tion to 25 £ zwisohen 50 and 45 minutes and between 45 to JJjL \ and 6o minutes.

This experiment proves that the fixation of a glucose molecule to a dimethylated phloroglucinol opens up the possibility of ■■ {

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to a masking of its usual properties.

An attempt on humans with the oral administration of a Dose of 0.25-0.50 g has the delayed antispasmodic Effect of the product confirmed. A control was carried out beforehand by administering the product by the oral route the duodenum, and it has been observed in guinea pigs a controlled antispasmodic effect in situ on the ileum of the animals at doses of 200 mg / kg and more. The effect developed slowly (between 25 and 60 minutes depending on the attempt); it lasts for a very long time.

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Claims (4)

- 16 claims Phloroglucine derivatives, characterized by the general formula: -0-CH- (CHOH J ₀ in which R stands for a hydrogen atom or for a low molecular weight Alkyl radical. 2. Phloroglucin derivatives according to claim 1, characterized in that both radicals R are hydrogen atoms, J5. Phloroglucin derivatives according to Claim X, characterized in that that both radicals R are methyl groups. 4. Process for the preparation of phloroglucine derivatives according to one of claims 1 to 3, characterized in that Phloroglucine of the general formula -OH 009808/1821 in which R stands for a hydrogen atom or a low molecular weight Alkyl radical, is reacted with acetobromoglucose in the presence of alkali and the acetyl-enriched product obtained for recovery of the desired monoglucose derivative is saponified. 5 Pharmaceutical, especially retardant antispaemodic, characterized by a content of phloroglucin derivatives according to one of claims 1 to 3 009808/1821