DE1965217A1 - New 21-esters of triamcinolone and process for their preparation - Google Patents

Description

DR ₁ -ING-RICHARDGLAWe DIPL-ING. KLAUS DELFS · DIPL-PHYS. DR. WALTER MOU

MDNCHEN HAMBURG MUNICH

8000 Munich 22 Uebherrstrasse 20. Tel. (0811} 22 05 43 2000 Hamburg 52 · Walzstrasse 12 ■ Tel. (0411} 89 22 55

! - J

li «SIGN YOUR MESSAGE FROM OUR SIGN MONKS

SHRIFTS:

Laboratoire MARSAN

3, rue de 1'Industrie _s Monaco-Fontvieille

Monaco

"New 21-ester of triamcinolone and method for _Λ

their manufacture "

The present invention relates to new 21-esters of 'triamcinolone and triamcinolone acetonide, respectively the general formula

34/1944

A 7

-OCO-R or

_r CO-CI ^ -OCO-R

and a method for their production. In this formula, R

1,4-dioxybenzene

Trimethoxy-1,3, SH

OCH.

Triraetiioxy-1,2 »I * -benzene

OCH, OCH,

• OCH

009834/1944

or an alkylamino dialcohol of the general formula

CH ^ -CH ₀ -HH-CO-CH-- G -

ir
OH CH.

CHpOH

The new products according to the invention have very interesting ones therapeutic properties especially as anti-inflationary agents.

The preparation of these esters is carried out by the following ^ " Examples which, however, have no Bes ^ -hrclnlii-rc of Erf -> - Vmr: should represent., explained.

B e i s "O i

Triamcinolone gentisate;

CO-CH ₂ GH

CO-CH ₂ OCO

009834/1944

COOH

In a 300 ml flask fitted with a stirrer, a Thermometer, a dropping funnel for bromine and a cooler are placed:

3.7 g of pure gentisic acid (20% excess) 120 ml of anhydrous tetrahydrofuran

2.5 g of anhydrous triethylamine. A reading is obtained with gentle warming. It is cooled to -5 ⁰ C, and slowly dropped a solution at this temperature

26 g of freshly distilled ethyl chloroformate and Add 50 ml of anhydrous tetrahydrofuran.

After the addition is complete, the mixture is left to rest at -5 ° C. for 1 hour and then add:

8 g of triamcinolone alcohol-21 with gentle introduction of nitrogen.

The mixture is stirred under a nitrogen atmosphere for 1 hour at 0 ° C. and then for 6 hours at room temperature. The mixture is then left to stand overnight, stirring and the introduction of nitrogen are restarted and the mixture is heated to reflux temperature for 10 hours. After the reaction has ended, the solvent is removed first at normal pressure and then under vacuum. Han takes up the distillation residue in 100 ml of water and 100 ml of crushed ice, stirs for 1 hour, centrifuges, washes and dries to constant weight. 9 _S 7 β of a very impure crude product is obtained.

00983 4 / 19U - 5 -

BATH ORIGINAL

! ■ lan carries out a first crystallization in a mixture of water alcohol with 68% _{alcohol and obtains a product 3} which melts at 237 to 238 ° and which, after recrystallization from 80/6 strength tetrahydrofuran, 5 g of triamcinolongentisate with a p. Of 263 ° C results.

Example 2 2.4 _I- 6-trimethoxybenzoate of triamcinolone

CO-CILOCO

OCH,

In a 250 ml flask, equipped as in Example 1, placed v / earth:

2.2 g of 2,4,6-trimethoxybenzoic acid (0.01 mol)

50 ml of anhydrous acetone 1 * 3 S anhydrous triethylamine.

There is immediate dissolution. It is cooled to -5 ° C and drips slowly at this temperature

13 g of freshly distilled ethyl chloroformate are added. Precipitation occurs. The mixture is stirred for 1 hour at -5 ° C, then it is out

0091134/1844

2 g of triamcinolone alcohol-21 50 ml of anhydrous acetone.

Han stirred for 1 hour at 0 ⁰ C, then for 6 hours at room temperature and then kept it at reflux temperature for 9 hours on.

It is then concentrated to dryness in vacuo and the residue is taken up in 100 ml of water and 100 g of ice up, stir for 2 hours and set aside for 10 hours. Then it is centrifuged and washed and dried to constant weight. 3 g of a crude product with a pp. Of 250 ° C. are obtained. After recrystallization, the product gives a white product (pp .: 250 to 251 ° C.), the 2,4,6-trimethoxybenzoate of triamcinolone is.

Example 3 Pantothenate of triamcinolone

OH OH

CH I

--CO-CHgOCO-CHg-CHg-NH-CO-CH-C-CHgOH

OH CH-,

3 3? 4 Ί 9 U

BATH

In a 250 ml flask equipped as in Example 1 are brought in:

2.62 g GaTcium pantothenate
34 ml of dimethylformamide

! ■ lan heated and stirred under a nitrogen atmosphere until the solution is obtained, then the mixture is cooled to -5 ° C in an ice mixture and a solution of 25 ml of ethyl chloroformate and 60 ml of tetrahydrofuran is then added drop by drop at this temperature.
The mixture is stirred for a further 30 minutes at -5 ° C and then added:

2 g of triamcinolone alcohol-21

0.5 g triethanolamine.

The mixture is stirred for 1 hour at ⁰ ° C., then for 10 hours at room temperature and then for 5 hours under reflux. When the reaction has ended, the solvent is eliminated by distillation in vacuo and the residue is taken up in 100 ml of water and 100 g of ice. I-Ian stirs for another hour and then leaves in the refrigerator at 2 ° C for 2k hours. It is centrifuged, washed and dried. 3.1 g of a crude product with a mp of 236 to 237 ° C. are obtained.

This product is crystallized from a mixture of Chloroform-i-'iethariol (50/50) to obtain 2.5 g of pure Triamcinolone pantothenate (pp .: 240 ° C).

The anti-inflammatory activity of the invention Medicinal product was made according to the pharmacological method

009834/19 A 4

of carrageenin edema in rats. Male Wistar rats with a mean weight of 125 gj in groups of 6, received an injection of one 1 ^ -igen suspension of carrageenin in an isotonic Sodium chloride solution of 0.05 ml under the soles of the feet.

The test substances were administered orally 1 hour before the carrageenin injection in an amount of 1 ml per 100 g

administered.

The edema volume was plethysmographically 3 hours after the administration of the inflammatory agent is measured.

The results obtained are shown below for two of the medicaments according to the invention.

Tabel

Connection

Ver

size- Inhi

d.Volume d. paw

_Verglelohe .

Triamcinolone
pantothenate 23 20th 65 P ' Triamcinolone
gentisat 20th ■ 19 67 ρ : c 0.05 : 0.01

These KxpGriruental results obtained indicate the high

009834/19 A

BATH ORIGINAL

anti-inflammatory activity of the invention
Compounds which can be administered in human medicine as Compretten, capsules with a coating that dissolves in the gastrointestinal tract, suppositories or ointments.

009 834 / 19U - io -

Claims (8)

-IO - P at ent claims 1.) Compound of the group consisting of new 21-esters of triamcinolone and triamcinolone acetonide of general formula - CO-CH _p -OCO-R or CO-CH ₂ -OCO-R where R ■ 1,4-dioxybenzene Trimethoxy-1,3, ^ - benzene OCH. 00983A / 19A4 Trimethoxy-1,2,3 ~ t> enzene OCH. ^> λ— OCH OCH or an alkylamino dialcohol of the formula CH ₀ -CH ₀ -NH-CO-CH-C-CH ₀ OH 2 2 ι j 2 OH CH, 2. Process for the preparation of 21-esters of triamcinolone and of the triamcinolone acetonide according to claim 1, characterized in that the triamcinolone or its acetonide in the presence of suitable solvents treated with the desired acid. ™ 3. Triarncinolongentisate. k. Process for the production of triamcinolongentisate according to claim 2. 5. 2yh , 6-trimethoxybenzoate of triamcinolone. 009834 / 19AA -12- 6. Process for the preparation of 2,4,6-trimethoxybenzoate des triamcinolone according to claim 2. 7. Triamcinolone pantothenate. 8. A method for the preparation of triamcinolone pantothenate according to claim 2 » 009834/1944 SAD original