DE2909829A1 - ALUMINUM ACETYL SALICYLATE GLUTAMINATE, THE METHOD OF MANUFACTURING IT, ITS USE AND MEDICINAL PRODUCTS - Google Patents

Description

The invention relates to the subject matter characterized in the claims.

Acetylsalicylic acid is known as an anti-inflammatory compound under the trademark Aspirin (Bayer AG). Acetylsalicylic acid is widely used as an antipyretic, anaige ™ and anti-inflammatory agent. It However, it is also known that acetylsalicylic acid often has various side effects, such as gastrointestinal upsets, caused.

Many attempts have been made to reduce the harmful side effects decrease in acetylsalicylic acid. For example, it is known to aluminum acetyl salicylate or a Use a mixed form of acetyl salicylate and an amino acid.

On the other hand, it is known to use glutamine for the treatment of gastric ulcers. Furthermore, the use of Aluminum acetyl glutaminate, which is produced by reacting N-acetyl glutamine is obtained with aluminum alkoxide, known for the same purpose.

Although other compounds besides acetylsalicylic acid are known that have anti-inflammatory and analgesic properties there is nevertheless a great need for compounds which have the activity described above and at the same time have fewer side effects.

Surprisingly, this applies to the aluminum acetyl salicylate glutaminate of the general formula I according to the invention (hereinafter referred to as Compound I).

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The compound I according to the invention can be a the following three compounds Ia, Ib or Ic act:

Aluminum bisacetyl salicylate glutaminate (Ia)
O

(H ₉ NCCH CH CHCO ₂ ) '2 2 2 1 *

NH "

OCOCH _3/2

Aluminum acetyl salicylate bisglutaminate (Ib)

0.

H ₂ NCCH ₂ CH ₂ CHCO ₂ NH _n

AJL-

• ft! ·

OCOCH ₃

(Ia)

(Ib)

Monohydroxy aluminum acetyl salicylate glutaminate (Ic)

I!

H _n NCCHCH ₄ CHCO 2 -2- λ j

NH ₂

'AJL ■ ·

O ₂ C

(OH)

OCOCH,

(Ic)

According to the invention, the compounds I are prepared according to the following two manufacturing variants made;

1. It is produced by reacting acetylsalicylic acid with aluminum alkoxide, whereby an intermediate product (1) is formed, which is then reacted with glutamine.

2. The production can also be carried out by reacting glutamine with aluminum alkoxide to form an intermediate (2) and then reacting the intermediate (2)
done with acetylsalicylic acid.

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The preparation of the individual compounds according to the invention Ia, Ib and Ic are carried out by reacting the starting compounds in the corresponding required addition ratios:

The preparation according to the invention of the compound Ia takes place by reacting acetylsalicylic acid, glutamine and aluminum alkoxide according to one of the process variants described above in a molar ratio of 2: 1: 1. The compound is obtained at a molar ratio of 1: 2: 1 Ib and at a molar ratio of 1: 1: 1, the compound Ic according to the invention is obtained. The implementations are by using slight excesses of starting compounds relieved.

in the 1st Process variant is the reaction mixture the reaction of acetylsalicylic acid with aluminum alkoxide without prior separation of the intermediate (1) from the it is believed to consist of an aluminum complex with added glutamine. Then the implementation continued.

In the 2nd variant of the process, acetylsalicylic acid is added to the reaction mixture from the reaction of glutamine with aluminum alkoxide without prior separation of the intermediate (2), which is regarded as an aluminum complex, whereupon the reaction is continued. Specific examples of preferably employed in the inventive process is aluminum alkoxide Aluminiumi isopropyl-loxid, aluminum methoxide, Aluminiumäthoxid and aluminum tert-butoxide.

The reaction of the aluminum alkoxide with the acetylsalicylic acid in a suitable solvent is preferred in methanol, ethanol, isopropanol, benzene, toluene, chloroform, or dimethyl sulfoxide carried out.

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The reaction of the aluminum alkoxide with glutamine is carried out in a suitable solvent, preferably in water, methanol, Ethanol, isopropanol, acetone, Dimethylsulfoxxd or ethylene glycol carried out.

Likewise, the further reaction of one of the two intermediates (1) or (2) with the remaining reaction partner, i.e. with acetylsalicylic acid or with glutamine, preferably carried out in the same solvent system. A reaction mixture is obtained in which the inventive Compound (I) is preferably precipitated.

Glutamine is usually used as a solution in water, since it ^is insoluble in organic solvents ·

The reaction takes place at temperatures from 0 to 90 ° C and is finished in a short time. Usually the one that is desirable according to the present invention falls Compound from the reaction mixture.

The compound according to the invention is isolated by filtration. If the compound according to the invention does not precipitate, it is made by adding ethanol or isopropanol or the like precipitated to the reaction mixture or obtained by concentrating the reaction mixture.

The compounds I according to the invention are valuable medicaments with analgesic, antipyretic and anti-inflammatory effects. In the experiments below, the described effectiveness is explained in more detail.

Attempt a

Analgesic effectiveness of acetylsalicylic acid and the Compounds Ia, Ib and Ic

10 male dd mice weighing 20 + 1 g in a group with the above-mentioned compounds

r 909839/080 6

15 20 25 30 35

■ 9:

(Method by Koster et al., Fed. Proc., Vol. 18 (1959), p. 412). The test compounds are administered orally to the test animals. 60 minutes after administration an intraperitoneal injection of 0.2 mm of a 0.7 percent aqueous acetic acid solution into the test animals. Ten minutes after the administration of acetic acid, the number of convulsive movements occurring during ten minutes is determined counted.

A group of test animals similar to the one above is used for comparison but were not administered the test compounds. In of Table I below are the percentages of suppressed pain responses for the group of test animals that the test compounds administered are summarized.

The doses of the test compounds are 200 mg / kg for acetylsalicylic acid, 300 mg / kg for compound Ia, 600 mg / kg for compound Ib and 400 mg / kg for compound Ic. These latter doses each correspond to 200 mg / kg acetylsalicylic acid .

Table I.

Test compound administered 300 mg / kg Suppression rate Acetylsalicylic acid 200 600 mg / kg 30.3% Connection Ia 400 mg / kg 32.5% Connection Ib mg / kg 29.6% .Connection Ic 31.0%

Attempt B

Antipyretic properties of acetylsalicylic acid and the compounds Ia, Ib and Ic

In this experiment 10 males are found in a group Wistar rats weighing 90 to 100 g by subcutaneous injection in the back with a suspension of

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2.5 ml / rat of a brewer's yeast in physiological saline solution

according to the method of Gleen et al. (J. Pharma. Exp. Therp.

155 (1967), p. 157), followed by fasting Laboratory animals.

Those test animals that show an increased rectal temperature of at least 38 ^{° C. after 17 hours are selected for the experiment.} A solution or suspension of the test compounds in predetermined amounts is then administered to the test animals.

In another group, laboratory animals are only with treated with distilled water.

After administration of the test compounds, the rectal temperature is measured after certain periods of time. The result is shown in Table II below.

Table II

administered
Test connection read "rectal temperature, ⁰ C 0 ι ·. 2 ■ 4 6th control
Acetylsalicylic
acid
200 mg / kg
Connection Ia
300 mg / kg
Connection Ib
600 mg / kg
Connection Ic
400 mg / kg Lapse of time after administration, hours; 38 _r 4 + O ₇ I.
38/2 + 0.1
38.4 + 0.1
38 _? 4 + 0 _r 1
38 j 2 + 0j I 38.4 + 0.1
37.2 + O ₁ L.
3 7 _f 1 + 0.1
37.2 + O ₇ I.
37/1 + 0.1 38 _r 0 + 0 _f l
37j0 + 0 _f l
36.8 + 0 _f 1
37.0 + 0 _r 1
37 _r 0 + 0.1 3 7.8 + 0 _r l
37.4 + 0.2
37.5 + 0.1
37/3 + O ₇ I.
37 4 + 0.2 38, Q + 0 _; 1
37.5 + 0.1
37.7 + 0.0
35 _; 5 + O ₇ 1
³⁷ J ⁶ I ⁰ F ¹

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TSD

Attempt C

■ 40-

Anti-inflammatory activity of acetylsalicylic acid and the compounds Ia, Ib and Ic according to the invention In this experiment, 6 male Wistar rats weighing 140 + 10 g are tested in a group according to the method of Yamasaki et al., (Folia Farm, Jap., Vol . 63 (1967), p. 302) treated with the respective test compounds.

1 hour after oral administration of test compounds the animals are treated with a phlogistic agent (subcutaneous injection of 0.1 ml of a 1% carrageenin solution in the rear paw). The swelling of the paw is measured and the corresponding time is counted.

As a control, the test animals in a different group are subjected to the same treatment, but no administration takes place of the test compounds given above. The suppression rate of the group tested is in the following Table III summarized.

Table III

test compound administered 200 mg / kg suppression rate,% 5 hours 300 mg / kg Time after administration 34 600 mg / kg 3 hours 39 Acetylsalicylic acid 400 mg / kg 43 42 Connection Ia 52 37 Connection Ib 52 Connection Ic 50

Attempt D

Ulcer formation due to acetylsalicylic acid and compounds Ia, Ib and Ic

In this experiment, 10 male Wistar rats are used a weight of 190 + _ 10 g who have fasted for 24 hours, used in a group. After ligating the pylorus

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INSPECTED

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according to the standard method of Shay et al. the test compounds are administered orally. 6 hours after administration the test animals are killed and the stomachs are opened. The length of the lesions is measured. The result is summarized in Table IV below. The expression "ulcus index in mm" denotes the sum of the measured lesions in each group studied.

The above experiment is repeated, but male Donryu rats are used instead of the Wistar rats. The results are also summarized in Table IV below.

Table IV

test compound administered 300 mg / kg Ulcer Index, mm Donryu rats 600 mg / kg Wistar rats 49.3 η 400 mg / kg 32.8 + _ 5.0 14.9 η Acetylsalicylic acid 200 mg / kg 0.1 + ^ 0.4 7.2 π Connection Ia 11.7 + _ 2.0 10.2 η Connection Ib 6.7 + 1.5 κ 8.1 Connection Ic I ₁ 3.3 H ₁ 1.4 η 2.5

Try

LDc ^ values of the compounds Ia and Ib

OU

In this experiment, 10 male dd mice with a Weight of 20 + 1 g used. The compounds I are administered orally.

The number of animals that died within a 7 day period after dosing is shown in Table V. emerged.

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Table V

test compound administered Dose, g / kg 1 3 1Q Connection Ia
Connection Ib O 8th
O 9

10

20th

The LDj. Values of compounds Ia and Ib are as follows:

1 g / kg <c LD ₅₀ <3 g / kg

Ib: 3 g / kg K LD ₅₀ <10 g / kg

The LD ₅ value of acetylsalicylic acid is 1.6 g / kg.

From the above experiments it appears that when administered of the compounds Ia, Ib or Ic according to the invention, the antipyretic, analgesic and anti-inflammatory Properties of the compounds according to the invention are comparable to those of acetylsalicylic acid, but the former cause stomach lesions to a lesser extent than acetylsalicylic acid.

The medicaments according to the invention can be used in the usual dosage forms administered, preferably orally, but also parenterally, intraperitoneally, subcutaneously, intramuscularly or intravenously.

The drugs can be in the form of tablets, pills, suspensions, Powders, elixirs, suppositories, syrups, filled into capsules or as injection preparations.

A dosage unit preferably contains about 0.1 to 1 g Drug. Depending on the dosage form and the frequency of administration, the daily dosage for treatment is adult humans preferably about 0.5 to 2 g.

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The examples illustrate the invention.

Example i

9.0 g of acetylsalicylic acid and 10.2 g Aluminxumisopropyloxid are dissolved at 5 ⁰ C in 150 ml of methanol and stirred. After the reaction has ended, the reaction mixture is filtered to remove a small amount of insoluble constituents. A solution of 14.6 g of glutamine in 200 ml of water is then added to the filtrate. Shortly after the start of the addition of the solution, a white precipitate separates out. After the addition has ended, the mixture is stirred for a further 30 minutes and then the resulting reaction mixture is filtered off. The precipitate is dried. 22.4 g of a white powder with the following physicochemical properties are obtained

15 properties:

Elemental analysis _{C 10} H ₀ JN ₄ O _{1 Al.2H 9} O

CH calc .: 42.9 5.5

found: 42.8 5.5 20

Water content: 6.8%.

Infrared absorption spectrum, as KBr pellets (characteristic absorptions at the following wave numbers in cm " ¹ ) 3410, 1685, 1630, 1588, 1487, 1450, 1414, 1330 and 1200.

The results confirm that the white powder obtained Represents aluminum acetyl salicylate bisglutaminate. Yield: 84.1%.

Example 2 .. ■.

18.0 g of acetylsalicylic acid and 10.2 g Aluminxumisopropyloxid are dissolved at 5 ⁰ C in 50 ml of methanol and stirred. After the reaction has ended, a solution of 7.3 g of glutamine in 100 ml of water is added to the reaction mixture. Shortly after the start of the addition, a white precipitate separates out. The reaction mixture is stirred for a further 30 minutes while cooling with ice, until the reaction and crystallization have ended

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N , 5 Al 1 N (Amide) 10 , 4 5, 2 5.3 10 5, 5.2

are. The resulting reaction mixture is then filtered. The residue is washed and dried. 21.0 g of a white powder are obtained which has the following physicochemical properties:
Elemental analysis: C ₂₃ H ₂₃ O ₁₁ Al ^ H ₂ O

CHN Al N (Amid) calc .: 48.8 4.8 5.0 4.8 2.5 found: 48.9 4.7 4.9 4.7 2.4 Water content: 6.4%
The IR spectrum is recorded in a KBr pellet. It shows characteristic absorption maxima at the following wave numbers (cm)
3410, 1755, 1690, 1632, 1610, 1570, 1490, 1457, 1427, 1200.

The above analytical values show that the white powder obtained is aluminum bisacetyl salicylate glutaminate dihydrate acts. Yield: 74.2%.

Example 3

9 g of acetylsalicylic acid are dissolved in 100 ml of ethanol. The solution is treated with 10.2 g Aluminiumi s opr opy loxid and the reaction mixture is stirred at 5 ⁰ C. After the reaction has ended, a hot solution of 7.3 g of glutamine in 80 ml of hot water is added to the reaction mixture. The reaction is then ^{stirred at 5 °} C. for 1 hour.

The reaction mixture is then filtered and the resulting precipitate is dried. 16 g of a white powder are obtained with the following physicochemical data: Element ar analysis C ₁ ^ E ^ 7O ₈ N ₃ Al. 2H ₃ O

C. , 6 5 H 6th N Al N (amide) ber .: 41 , 0 5 , 2 7th , 9 6.7 3.5 found: 41 , 3 / 0 6.8 3.5

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• Α5-

The IR spectrum (KBr pellet) shows the following _1

characteristic absorption spectra (wave numbers, cm):

3410, 1753, 1690, 1630, 1610, 1580, 1490, 1450, 1418, 1333, 1200.

From the above results it can be seen that the white powder is monohydroxy aluminum acetyl salicylate glutaminate dihydrate.
Yield: 79.1%.

Example 4

14.6 g of glutamine are dissolved in 190 ml of 85 ^° C. warm water. The solution is mixed with 10.2 g of aluminum isopropyl oxide and stirred. The reaction mixture is then rapidly cooled. A solution of 9 g of acetylsalicylic acid in 50 ml of ethanol is then added to the reaction mixture.

After the reaction has ended, the precipitate formed is filtered off and dried. 19 g of aluminum acetylsalicylate bis-glutaminate are obtained in the form of a white powder.

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Claims (11)

VOSSIUS ■ VOSSlUS · HILTL · IAUCHNER · HEUNEMANN PATENT LAWYERS <. d ü 9 8 2 3 SI E BERTSTRASS E 4 SOOO MÖNCHEN 86 PHONE: (089) 474075 CABLE: BENZOLPATENT MÜNCHEN -TELEX 5-29 45 3 VOPAT D u.z .: P 060 (PT / kä) 13.3.1979 Case: 230-4 KYOWA HAKKO KOGYO CO., LTD.
Tokyo, Japan "Aluminum acetyl salicylate glutaminate, method for its Manufacture, its use and medicinal products " Priority: March 13, 1978, Japan, No. 27 784/78 : Claims ι 1 / Aluminiumacetylsalicylat-glutaminate the general For ^v ~ I iifel (D (H ₂ NCCH ₂ CH ₂ CHCO ₂ ^ -A / - (O ₂ C - / (5)> _y ( NH ", OCOCH" ² · 3 in which χ has the value 1 or 2, y has the value 1 or 2, ζ has the value O or 1 and χ + y + ζ = 3, as well as its hydrates. 2. Process for the production of aluminum acetyl salicylate glutaminate and its hydrates according to claim 1, characterized in that that you can acetylsalicylic acid with an aluminum nium alkoxide brings to implementation and the resulting 35 chemical product reacts with glutamine. 9Q9838 / 0806, 3. The method according to claim 2, characterized in that an aluminum alkoxide with 1 to 6 carbon atoms in the alkyl radical is used. 4. The method according to claim 2, characterized in that the implementation of acetylsalicylic acid with aluminum oxide carried out in a solvent, whereby a reaction mixture containing the intermediate is formed, and one this reaction mixture then with a glutamic acid solution offset. 5. The method according to claim 4, characterized in that the reactions are carried out at temperatures from 0 to 90 ^° C. 6. Process for the preparation of aluminum acetyl salicylate glutaminate and its hydrates according to claim 1, characterized in that that glutamine is reacted with an aluminum alkoxide and the intermediate product formed with acetylsalicylic acid. 7. The method according to claim 6, characterized in that there is an aluminum alkoxide having 1 to 6 carbon atoms in Alkyl radical uses. 8. The method according to claim 6, characterized in that the reaction of the glutamine with the aluminum alkoxide carried out in a solvent, whereby a reaction mixture containing the intermediate product is formed, and this reaction mixture is then mixed with an acetylsalicylic acid solution. 9. The method according to claim 8, characterized in that one carries out the reactions at temperatures of from O to 90 ⁰ C. 909839/0806 1 10. Medicinal product / characterized by a pharmaceutical effective content of a compound according to claim 1 and customary carriers and / or auxiliaries and / or diluents. 11. Use of the compounds according to claim 1 for pain relief, Fight against fever and inflammation. 9098 ^ 9/08 Of * - _, ORiGiNAL iHSPECTED