DE1944758C3 - 1 -Cinnamoyl ^ -methyl-S-methoxy-Sindolylessigsäureester, process for their preparation and medicinal products - Google Patents

Description

N CH ₁

ί
CO

CH CH C ₁₁ II,

in which R denotes the / J-dimethylaminoethyl, jJ-piperidinoethyl, γ-piperidinopropyl, / J-morpholinoethyl, ^{γ-morpholinopropyl or ß- (N 4} -benzylpiperazino) ethyl group, and their salts with acids.

2. Process for the preparation of the compounds according to claim 1, characterized in that one a 3-indolylacetic acid in a manner known per se

CH, COOH

N CIl ₁
CO

CW CH C _t , U,

or its reactive derivative with a Alcohol of the general formula III

HO R

(NU

in which R has the meaning given in claim 1, or its reactive ester is condensed and optionally converting the free base obtained into its salt with an acid.

3. Medicinal preparations with an anti-inflammatory effect, containing a compound according to claim 1.

It is known that some indolyl carboxylic acid derivatives have valuable anti-inflammatory properties. However, these compounds have the disadvantage that they have a fairly high toxicity and occult bleeding frequently in animal studies at high doses cause. The invention is based on the object of 1 -Cinnamoyl ^ -methyl-S-methoxy-S-indolylacetic acid ester to create, which is characterized by a high anti-inflammatory effect, but at the same time a lower one Toxicity and the absence of side effects are characterized. This object is achieved by the invention solved.

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

The salts of the 3-indolylacetic acid derivatives are derived of mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid or Phosphoric acid, or organic acids such as maleic acid, tartaric acid, fumaric acid, succinic acid, Citric acid or acetic acid.

Examples of reactive derivatives of 3-indolylacetic acid of the formula II which can be used according to the process are the acid halides, such as the acid chloride or acid bromide, the acid anhydride, esters, such as the methyl, Ethyl, tosyl, benzyl or p-nitrophenyl esters, and the Metal salts.

The 3-indolylacetic acid of the formula II or its reactive derivative, e.g. B. the acid halide, the Ester or the acid anhydride is condensed with the alcohol of the general formula III, or the metal salt the 3-indolylacetic acid is treated with a reactive ester of the alcohol of the general formula III, e.g. B. with an alkyl halide, alkyl sulfate or alkyl aryl sulfonate.

The aforementioned reactions are in the presence or absence of a condensing agent such as Sodium hydroxide, potassium hydroxide, sodium carbonate, pyridine, triethylamine or dicyclohexylcarbodiimide accomplished. A condensing agent is preferably used for the reaction. The implementations are usually in the presence of a solvent such as diethyl ether, tetrahydrofuran, dioxane, acetone, Benzene, toluene, chloroform, pyridine or dimethylformamide. The use of a solvent is preferred. The reaction is usually carried out at room temperature, but it can also be carried out at elevated temperature or with cooling.

The compounds of the invention are valuable medicinal substances which not only have excellent antipyretic, analgesic and anti-inflammatory effects, but also have very low toxicity and are notable for the absence of gastrointestinal side effects. They can be used to treat rheumatic and other inflammatory diseases, as well as to prevent or suppress inflammatory processes. The compounds of the invention are less toxic than the corresponding free carboxylic acids. Even at high doses of 400 mg / kg when administered orally, they rarely cause occult bleeding in animal experiments. The experimentally produced carrageenin edema on the rat paw is strongly suppressed by the compounds prepared according to the invention. The therapeutic quotient ¹ . of the compounds of the invention is significantly larger than that of the best known anti-inflammatory drugs, such as indomethacin, phenylbutazone and the 1 - (2 ', 4-hexadienoyl) -2-methyl-5-methoxy-3-indolylacetic acid known from DL-PS 63,373 . This is shown in Table I.

■ J

3 4

1 abcllr 1

Aniiphliigistic activity (a)

Compound D ,, _MS Inhibition dc ·. I »xi / itäi [D.

, .'-Dimethylaminoethyl-1-cinnanioylO-methyl-20 46 - · 1000

5-methoxy-3-indi> lylacciai-hydroi; chloride

,; - Morpholinoethyl-l-cinnamovl-2-mcth \ l-5-incthi) xy- 5 39.2 -> HXX)

3-indolylaci:! Ai hydrochloride

; -Morpholinopropyl-l-cinnamoyl-2-mi: thyl-5-metht) xy- 5 34.8 - > 1000

3-indolylacctate hydrochloride

, / - Piperidinoethyl-l-cinnamoyl ^ -methyl-S-methoxy- 5 40.6 - > 1000

3-indolylacetate hydrochloride

■ -Piperidinopropyl-1-cinnamoyl ^ -methyl-S-melhoxy- 5 38.9 - > 1000

3-indolylacctate hydrochloride

, (- (N ⁴ -Benzylpiperazino) -ethyl-1-cinnamoyl-2-methyl-5 23.3 -> 1000

5-methoxy-3-indolylacetate dihydrochloride

, i-morpholinoethyl-l-lp-chlorobenzoyl ^ -methyl- 5 38.6 - > 1000

5-methoxy-3-indolylacctate hydrochloride (US-PS 32 71 394)

1- (p-Chlorobenzoyl) -2-methyl-5-methoxy-3-indolyl acetic acid-5 39.8-25

acid

(Indomethacin)

1- (p-Chlorobenzoyl) -2-methyl-5-methoxy-3-indolyl-1 11.5 - > 500

ethyl acid ester

(US-PS 32 71 394)

Phenylbutazone 50 30.4-680

1- (2 ', 4'-hexadienoyl) -2-methyl-5-methoxy-3-indolyl-50 40.9-1000

acetic acid

(a) The anti-inflammatory activity was determined on the basis of the suppression of the by injection of 0.05 ml of a carrageenin solution determined to produce edema in sterile 0.9% saline in the calf paw.

(b) The compounds were administered orally one hour before the carrageenin injection. 3 to 6 rats were used at each dose.

(c) The paw volume was measured 3, 4 and 5 hours after the carrageenin injection. The mean of these measurements was calculated for each rat. The inhibition of the edema is expressed by (1 - T ^: C) χ 100. where T is the mean edema volume of the treated group and C is the mean volume of the comroll group.

I)> 'ΜΊ Inhibition de-, loxi / ilul Carraticcnn ιημ kii tJdeirTr. (H, IcI (d! 20th 46 _ 50 50 - 2 (K) 56 _ 5 39.2 - 20th f. · :. 5 - 50 72.8 - 200 74.6 5 34.8 _ 10 46.1 _ 21) 48.0 - 50 61.3 _ 200 63.7 4- 5 40.6 - 2'.i 44.6 - 50 74.1 - 200 78.1 + 5 38.9 _ 20th 42.5 - 50 68.1 - 200 72.4 + 5 23.3 _ 20th 55.3 - 200 74.3 - 400 72.9 - 5 38.6 - 10 50.9 - 50 74.5 + 5 39.8 _ 10 56.6 4- + 20th 57.6 + V + 1 11.5 _ 5 32.2 - 10 45.0 - 50 65.1 + 50 30.4 - 100 40.6 - 200 51.2 + + 50 40.9 - 100 62.1 4- 200 69.0 4- 4-

no blood in the tacs, normal body weight gain.

no blood in the faces, body weight is decreasing.
Blood in the faces, body weight is decreasing,

Symptoms of ++, some animals die on the fourth day after compound administration,
(e) rat, po, mg / kg.

In Tabcllell are more Higebnisse phaimakoloüischer Untersuelnmuen with ^v 'erliiiuliiniieii the I irll IIUE in 11 · and known compounds / usammengefaüt.

Table 11

Connection!

I I> ,,, "I ρ

, j-Dimethylanimoalhyl-1-anamoyl-2-methyl-5-methoxy-1-indolvlacetate-hydraehlorid

/ i'-Morpholinoalliyl-1-cinniimoyl-Z-methyl-5-methoxy-3-indolylaciate hydrochloride

; -Morpholinuppropyl-1-ananioyl-2-methvl-5-mcihoxy-3-indolylacetit-hydrochloride

// - (N ⁴ -Benzylpiperazino'i-ethyl-1-cinnamoyl-2-niethyl- ^ -n'.ethoxy ^ -indolylacetate dihydrochloride

/ i-Piperidinoethyl-1-cinnamoyl-2-mcthyi-5-melhi) xy-3-indolylacetate hydrochloride

γ-Piperidinopropyl-1-cinnamoyl ^ -methyl-S-methoxy-S-indolylacetate hydrochloride

L- (p-Chlorobenzoyl) -2-methyl-5-methoxy-ethyl vindolylessius acid ester

(US-PS 32 71 394)

/ i-Morpholinoethyl-1- (p-chlorobenzoyl) -2-methyl-5-methoxy-3-indolylacetate hydrochloride (US-PS 32 71 394)

• 400

200

200

■ 400

200

200

50

50

- S 20 10

.-20 K) K) 3.3

Indomethacin 7.5 10 Phenylbutazone 200 200 1- (2 ', 4'-hexadienoyl) -2-methyl-5-methoxy-
3-indolylacetic acid c
(DL-PS 63 373! 70 100

1.4

*) 50% inhibition of the C'arragccnin edema around the hind foot of the rough.
**) F.rstc signs of gastroinlestinal side effects. Ut / enilionen in Majicn-Darm-1 rakl.

The compounds of the invention powders, suspensions or solutions are administered for therapy preferably orally, preferably in the.

In the form of their salts. The connections The example explains how to make the connections

can be in the form of tablets, coated tablets, capsules, 45 gene of the invention.

example

A solution of 7 g of i-cinnamoyl ^ -methyl-S-methoxy-3-indolylacetic acid in 30 ml of dimethylformamide is added to a mixture of 0.5 g of sodium hydride and 10 ml of dimethylformamide at 5 ° C. After stirring for 30 minutes the reaction mixture with 3.3 g of y-Piperidinopropylchlorid is admixed at 5 ⁰ C and stirred for 1 hour at 50-6O ⁰ C and 1 hour at 60-70 ° C and another 90 minutes at 70-8O ⁰ C. The reaction mixture is then poured into 200 ml of water and extracted with benzene. The benzene extract is washed with water and dried over sodium sulfate. The solvent is distilled off under reduced pressure. The y-piperidinopropyl-1-cinnamoyl ^ -methyl-S-methoxy-S-indolylacetate remains as a yellow oil. Hydrogen chloride is passed into a solution of the free base in diethyl ether. The precipitated hydrochloride is filtered off and recrystallized from ethanol. 144-145 ° C.

Following the procedure described above, the following compounds are made:

) ⁱ -Morpholinopropyl-1-cinnamoyl-2-methyl-S-methoxy-S-inderyl acetate hydrochloride,

M.p. 166-167 ° C; jS-morpholinoethyl-1-cinnamoyl-2-methyl-S-methoxy-S-indolyl acetate hydrochloride,

F. 187-188 ⁰ C; j3- (N ⁴ -benzyl-piperazino) -ethyl-1-cinnamoyl-2-methyl-5-methoxy-3-indolylacetate-dihydrochloride,

188-189 ° C; / J-piperidinoethyl-l-cinnamoyl - ^ - methyl-S-methoxy-S-indolylacetate hydrochloride,

164-165 ° C; ß-Dimethylaminoethyl-1-cinnamoyl-2-methyl-S-methoxy-S-indolylacetate hydrochloride,

F. 194-194.5 ° C.

Claims (1)

Her formula II patent claims: 1. 1-Cinnamoyl-1-methyl-S-methoxy-S-indolylacetic acid ester of the general formula I. CH, COO R CII ₁ O,