DE1620441C3 - i-Acyl ^ -methyl-S-methoxy-a-indolylcarboxylic acids and medicaments containing these compounds - Google Patents

Description

CH ₃ O

CH ₂ - (CH ₂ J _n -COOH

(D

in which R denotes an unsubstituted or halogen-substituted alkyl or alkenyl radical with up to 10 carbon atoms and η has the value 0, 1, 2 or 3.

CH ₃ O

The compounds of the general formula I can be prepared in various ways; a new one The process for their preparation is shown in the following reaction scheme:

N • NH ₂ + CH ₃ -CO-CH ₂ CH ₂ - (CH ₂ ) ,, - COOR ₁ CO

HCl

(H)
CH ₃ O

(III)

N-N = C

ι \

CO

CH ₂ CH ₂ - (CH ₂ ) ,, - COOR ₁

(I)

(IV)

R ₁ denotes a hydrogen atom or an alkyl radical having 1 to 4 carbon atoms.

The process goes smoothly even in the absence of a solvent, but in some cases it is Use of solvents is preferred. Suitable solvents in the condensation of the free aliphatic carboxylic acids are, for. B. organic acids such as acetic acid, formic acid, propionic acid, Lactic acid or butyric acid, non-polar organic solvents such as cyclohexane, η-hexane, benzene and Toluene, as well as polar solvents such as dioxane and dimethylformamide. For condensation of the ketocar

In addition to the solvents mentioned, alcohols are also preferably used. The reaction temperature is about 50 to 200 ^° C., preferably 65 to 90 ^° C. Condensation agents are not always required, but the use of inorganic acids, such as hydrochloric acid, sulfuric acid and phosphoric acid, generally leads to more favorable results.

If a ketocarboxylic acid compound of the general formula V is used with a hydrazine compound of the general formula II or its salt, in some cases the l-acylindolyl- (3) -carboxylic acid compound obtained decarboxylated, so that compounds of the general formula VI according to the invention are formed. This response is as follows Scheme explained:

CH ₃ O

CH ₃ O

COOH

N-NH ₂ + CH ₃ -CO-CH ₂ CH ₂ - (CH ₂ ) ,,.! - CH CO COOH

CH ₂ - (CH ₂ ) ^ ₁ -CH ₂ COOH (V)

(VI)

The working temperature in this case is between 60 and 200 ⁰ C, preferably 80 and 140 ° C. The solvents used are organic acids such as acetic acid, propionic acid and lactic acid, nonpolar solvents such as benzene and toluene, or polar organic solvent such as acetonitrile and butanol , used. Inorganic acids, such as hydrochloric acid and sulfuric acid, or Lewis acids, such as zinc chloride or boron fluoride, are suitable as condensing agents.

The compounds of the general formula I can also be prepared by reacting N'-acylphenylhydrazone compounds of the general formula VII

(VII)

in which R has the above meaning and B is the residue of a ketone or aldehyde, can be prepared with a ketocarboxylic acid compound of the general formula III or V. The radical B should preferably not take part in the ring closure reaction. Suitable radicals for B are e.g. B. the CH ₃ CH = -, C ₂ H ₅ CH = -, C ₆ H ₅ -CH = - or CCl ₃ CH = group. Organic acids such as formic acid, propionic acid, lactic acid or butyric acid, non-polar organic solvents such as cyclohexane, η-hexane, benzene and toluene, or polar organic solvents such as alcohols are used as solvents. The reaction temperature is in the range of 50 to 200 ⁰ C, preferably 65 to 95 ° C. As the condensing agent, inorganic acids such as hydrochloric acid and sulfuric acid, Lewis acids, eg. B. metal halides such as zinc chloride and copper chloride, heavy metal powder, boron fluoride or polyphosphoric acids can be used.

The compounds of general formula I can also be prepared by using phenylhydrazones of the general formula VIII

45 CH ₁ O

CH ₂ - (CH ₂ J _n -COOR ₁

NHN = C

(VIII)

CH,

in which R ₁ and η have the above meaning, condensed in a suitable solvent with an acyl compound of the general formula IX,

Y-C-R

Il ο

(K)

in which R has the above meaning and X represents a halogen atom or an ester radical.

Suitable solvents in this process are, for. B. non-polar solvents, organic acids and Ester. Specific examples of inert solvents are benzene, toluene, xylene, cyclohexane, hexane and tetrahydrofuran, Examples of organic acids are acetic acid, chloroacetic acid, propionic acid, butyric acid, Caproic acid and caprylic acid; Examples of esters are ethyl chloroacetate, methyl butyrate, Acrylic acid methyl ester, valeric acid methyl ester and sorbic acid methyl ester.

Among the acyl compounds of the general formula IX, acyl chlorides are preferred; acyl bromides are also used and acid anhydrides are well suited.

The reaction temperature is in the range of 30 to 150 ⁰ C, preferably 80 to 120 ⁰ C. The reaction is generally within several-Stunden'beendet; then the solution is

evaporates or mixed with acetic acid, water or petroleum ether, whereby the desired product precipitates. If the solution is evaporated, the residue is extracted with ether, benzene or chloroform and the purified product is obtained from the extract.

Another process for the preparation of the compounds of general formula I consists in Compounds of the general formula X

CH ₃ O

CH ₂ - (CH ₂ ) "- COR ₂

(X)

IO

> 5

in which R and η have the above meaning and R _{2 is} an alkoxy, amino or benzyloxy group, to be converted into the free carboxylic acids of the general formula VI.

By hydrogenating the benzyl ester of the compound of general formula X in the presence of a metal catalyst, like palladium, one obtains z. B. the free indolyl (3) carboxylic acid. If a tert-butyl ester is the 'Indolyl (3) carboxylic acid with an aryl sulfonic acid, e.g. B. p-toluenesulfonic acid treated, then saponification takes place. In some cases, the desired product is created as soon as the is heated and melted tert-butyl ester.

When converting an indolyl (3) carboxamide in an inert solvent in the presence of a suitable amount of nitrous acid is obtained also the free indolyl (3) carboxylic acid. Another method of making compounds of the General formula I consists in the elimination of water and simultaneous hydrolysis of l-acyl-3-hydroxy-2,3-dihydroindolyl- (3) -acetic acid compounds of the general formula XI

CH, O

OH
CH ₂ COOR ₁

CH ₃
H

(XI)

40

45

50 in which R and R _{1 have} the above meaning. This reaction is generally carried out by heating the compounds in an inert solvent with stirring. The reaction temperature here is 70 to 200 ° C. If the reaction does not proceed smoothly, the compound is either boiled under reflux, the water being distilled off azeotropically with a solvent such as benzene, toluene or xylene, or heated in the presence of one dehydrating agent, e.g. B. anhydrous sodium sulfate. If the radical R _{1 is} a tert-butyl radical, the compound is saponified in the presence of an arylsulfonic acid without cleaving the acid amide bond. Finally, l-acylindolyl- (3) -carboxylic acid compounds of the general formula I can be prepared by adding an l-acyl-2,3-dihydroindolyl- (3) -carboxylic acid compound of the general formula XII

CH ₁ O

(XII)

in which R has the preceding meaning, dehydrated. The dehydration can e.g. B. in the presence of non-polar Solvents such as benzene, xylene or toluene and various other organic solvents be carried out, e.g. B. in acetone, acetic acid, chloroform, ethanol and methanol. For dehydration Oxidizing agents such as chloranil, selenium dioxide or halogens are suitable.

The compounds of the invention are valuable drugs with anti-inflammatory, analgesic and antipyretic effect. They also work against arteriosclerosis and lower blood cholesterol levels.

The table below shows the results of 'edema tests (rat paw test; cf. Ch. A. Winter et al, Proc, Soc. exp. Biol. Med., Vol. 111, [1962], P. 547) summarized. ■.,,

'~~ - ^^^'Effects'
Connection ^^^^ Inhibition of
Carrageenin
edema on the
Riittenpfotc '),
ED ₅₀ , mg / kg,
'p- ⁰ LD ₅₀ Ra I te ' ² ),
po; ''·
(mg / kW •
LD ₅₀ VED ₅₀ Toxicity ³ ) 1 -p-chlorobenzoyl ^ -methyl-S-methoxy-S-indolylessig-
acid (indomethacin). ;.
3,5-Dioxy-1 ^ -diphenyl ^ -n-butyl-pyrazblidine
(Phenylbutazone) '7.5
145 25th
'680 3.3
4.7

') The rat hind paw was injected with 0.05 ml of a 1% carrageenin solution in sterile 0.9% saline.

² ) Calculated from the number of animals that died within 4 days after the administration of the test compound.

³ ) Measured by the blood content of the faeces according to the Carragcenin test; the body weight was determined daily for the following 4 days.

+ + = Blood in the faeces, body weight decreases. .:.

+ + + = Blood in the faeces, some animals died on the 4th day after the administration of the compound. The mean dose at which occult bleeding occurred was 6.0 mg / kg for indomethacin and 200 mg / kg for phenylbutazone.

continuation

^ ~ ^ ----_ ^^^ Effects
Connection ^ ~~~~~ --- ~ ^^ _ ^ Inhibition of
Carrageenin
edema on the
Rilttenpfote ').
ED ₅₀ , mg / kg,
po LD ₅₀ rat ² ),
po
(mg / kg) LD ₅₀ / ED ₅₀ Toxicity ³ ) - (2 ', 4'-hexadienoyl) -2-methyl-5-methoxy-
3-indolylacetic acid
-Chloracetyl ^ -methyl-S-methoxy-S-indolylacetic acid
NAcetyl ^ -methyl-S-methoxy-S-indolylacetic acid
-n-Hexanoyl ^ -methyl-S-methoxy-S-indolylacetic acid
- (y-chloro-n-butanoyl) -2-methyl-5-methoxy-
3-indolylacetic acid
- (y-methyl-n-pentanoyl) -2-methyl-5-methoxy-
3-indolylacetic acid
.-n-Decanoyl ^ -methyl-S-methoxy-S-indolylacetic acid
- [I - (2,4-hexadienoyl) -2-methyl-5-methoxy-
3-indolyl] butyric acid 75
160
280
110
150
120
450
290 > 1000
> 1000
> 1000
. > 1000
> 1000
> 1000
> 1000
> 1000 > 13.3
> 6.3
> 3.6
> 9.2
> 6.2
> 8.3
> 3.3
> 3.4 I I I I I I Il

') 0.05 ml of a 1% carrageenin solution in sterile 0.9% saline was injected into the rat's hind paw.

² ) Calculated from the number of animals that died within 4 days after the administration of the test compound.

³ ) Measured on the blood content of the faeces after the carrageenin test; the body weight was determined daily for the following 4 days. - = No blood in the faeces, normal body weight gain.

Among the known anti-inflammatory or anti-inflammatory compounds that are not part of the class ier anti-inflammatory steroids include, indomethacin has the greatest activity, however, too very high toxicity. After oral administration of lur 10 mg / kg of this compound to rats jcculte bleeding observed. All conventional Anti-inflammatory drugs cause bleeding in the digestive tract; it's even about in the literature vascular and intestinal breakthroughs have been reported. Phenylbutazone, i.e. H. 3,5-Dioxy-1,2-diphenyl-4-n-butylpyrazolidine, is one of the z. Currently the most commonly used anti-inflammatory drugs, but it has a very high Because of its acute toxicity, it only has a comparatively negative effect and thus an unfavorable therapeutic effect Quotient.

The compounds of the invention are notable for their low toxicity; even at > After administration of 1000 mg / kg to rats or mice, hardly any toxic symptoms occur. Even Jccult bleeding could not be detected. ) The compounds of the invention are more effective than Phenylbutazone and indomethacin, so that overall the therapeutic quotient is more favorable than that ■ any other known compound with a similar effect.

Most of the compounds of the invention have greater analgesic and antipyretic activity than \ midopyrin and acetylsalicylic acid. They are also suitable I for the prophylactic treatment of experimental arteriosclerosis and cause a considerable Lowering blood cholesterol.

The examples illustrate the invention.

example 1

2.8 g of N ¹ - chloroacetyl - N ¹ - (p - methoxyphenyl) lydrazine hydrochloride and 9.3 g of levulinic acid are heated to 75 ° C. for _{4 hours while stirring.} After cooling, the liquid reaction mixture is poured into cold water, the precipitated crystals are filtered off and dried. 2.2 g of crude 1-chloroacetyl ^ -methyl-S-methoxy-S-indolylacetic acid are obtained, melting point 155 to 156 ° C. after recrystallization from ethanol.

Example 2

Following the procedure of Example 1, the hydrochloride of the corresponding hydrazine compound is heated with an aliphatic carboxylic acid compound 90 minutes to 2.5 hours with stirring at 75 to 8O ⁰ C. The following compounds are obtained in high yield:

l-Acetyl-2-methyl-5-methoxy-3-indoIylessigsäure, F. 163 to 164.5 ⁰ C after recrystallization from acetone,

l- (2 ', 4'-hexadienoyl) -2-methyl-5-methoxy-

3-indolylacetic acid,

F. 157 to 160 ⁰ C after recrystallization
Acetone.

Example 3

4.8 g of N'-acetyl-N'-ip-methoxyphenylJ-hydrazine hydrochloride and 2.5 g of levulinic acid are added to 20 ml of acetic acid, and the mixture is heated to 76 ° C. for 2 hours while stirring. About 60 ml of water are then added to the reaction mixture, and the precipitated crystals are filtered off and dried. There are obtained 4.2 g of crude l-acetyl-2-methyl-5-methoxy-3-indolyIessigsäure, which is recrystallized from acetone, mp 163 to 164.5 ⁰ C.

Example 4

2.7 g of N ¹ - chloroacetyl - N ¹ - (p - methoxyphenyl) hydrazine and 1.6 g of levulinic acid are added to 30 ml of glacial acetic acid. The mixture is treated with about 2 ml of concentrated hydrochloric acid and 2 hours under

409 538/361

Stirring heated to 75 ° C. When the reaction has ended, the crystals which have separated out are filtered off and dried. There are obtained 2.3 g of crude 1-chloroacetyl-2-methyl-5-methoxy-3-indolylacetic acid, F. 155 to 157 ⁰ C after recrystallization.

Example 5

20 g of N ¹ - crotonoyl - N ¹ - (p - methoxyphenyl) hydrazine hydrochloride are introduced into 40 g of levulinic acid, and the mixture is heated to 78 ° C. for 2.5 hours while stirring. After the reaction has ended, the liquid reaction mixture is poured into 200 ml of cold water, the crystals obtained are filtered off, extracted with ether, and then the ether is distilled. What remains is crude crystalline 1 -Crotonoyl ^ -methyl-S-methoxy-S-indolylacetic acid, which is recrystallized from an 85:15 mixture of ether and alcohol. Yield 7.5 g (44% of theory); M.p. 130 to 131 ° C.

Example 6

According to Example 5, 1-decanoyl-2-methyl-5-methoxy-3-indolylacetic acid is used produced, mp 126 ° C after recrystallization from acetone.

Example 7

20 g of N'-caproyl-N ^l - (p-methoxyphenyl) hydrazine hydrochloride are introduced into 40 g of levulinic acid, and the mixture is heated to 75 ° C. for 2 hours while stirring. The liquid reaction mixture is then poured into 100 ml of cold water, and the crystals obtained are filtered off and dried. 13.0 large l-CaproyW-methyl-S-methoxy-3-indolylacetic acid are obtained which, after recrystallization from acetone / water, 8.7 g (37% of theory) of the pure compound, mp 140 to 141 ° C, result.

Example 8

17 g of N ¹ - (2 ', 4' - hexadienoyl) - N ¹ - (p - methoxyphenyl) hydrazine hydrochloride and 10 g of o-acetylvaleric acid are introduced into 35 ml of acetic acid, and the mixture is heated to 70 for 2 hours while stirring heated to 80 ° C. The liquid reaction mixture is then poured into 150 ml of cold water, and the crystalline precipitate obtained is filtered off and dried. 10 g of crude y- [1- (2 ', 4'-hexadienoyl) -2-methyl-5-methoxy-3-indolyl] -butyric acid are obtained which, after recrystallization from acetone / water, 4.6 g of pure product, F. 127 to 129 ° C.

Example 9

Following the procedure of Example 8, prepare the following compounds:

/ J- [l- (2 ', 4'-hexadienoyl) -2-methyl-5-methoxy-

3-indolyl] propionic acid,

F. 166 to 167 ° C after recrystallization aqueous acetone,

l- (4'-methylpentenoyl) -2-methyl-5-methoxy-

3-indolylacetic acid,

F. 135 ° C after recrystallization from aqueous acetone,

l- (4'-chlorobutyroyl) -2-methyl-5-methoxy-

3-indolylacetic acid,

F. 149 to 150 ° C after recrystallization from acetone, u- [l- (2 ', 4'-HexadienoyI) -2-methyl-5-methoxy-

3-indolyl] propionic acid ethyl ester,

F. 57 to 6O ⁰ C.

Example 10

4.7 g of l-decanoyl ^ -methyl-S-methoxy - ^ - indolylacetic acid tert-butyl ester 45 ml of benzene are added. After adding p-toluenesulfonic acid, the mixture is heated to boiling under reflux. The reaction mixture is then diluted with 30 ml of 10% strength aqueous sodium bicarbonate solution and then washed several times with water and then dried. The benzene is then distilled off under reduced pressure and the residue is removed from acetone recrystallized. 1-decanoyl-2-methyl-5-methoxy-3-indolylacetic acid is obtained, 126 ° C.

Example 11

Following the procedure of Example 10, the following compounds are made:

1- (4'-chlorobutyroyl) -2-methyl-5-methoxy-3-indolylacetic acid, m.p. 149 to 150 ⁰ C,
1- (4'-Methylvaleroyl) -2-methyl-5-methoxy-3-indolylacetic acid, mp 135 ° C.

B e i s ρ i e 1 12

3.6 g of N ¹ - (2 ', 4' - hexadienoyl) - N ¹ - (p - methoxyphenyl) hydrazine hydrochloride and 2.4 g of acetonylmalonic acid are heated to 85 ° C. for 4 hours in 10 ml of acetic acid while stirring. After cooling, the reaction mixture is poured into cold water.

The precipitated crystals are filtered off and dried. 3.0 large 1- (2 ', 4'-hexadienoyl) -2-methyl-5-methoxy-3-indolylacetic acid are obtained obtained, which on recrystallization from aqueous acetone in yellow needles, mp 162 to 163 ° C, crystallize.

Example 13

Following the procedure of Example 12, the following compounds are prepared:

ln-Hexanoyl ^ -methyl-S-methoxy-S-indolylacetic acid, mp 140 to 141 ° C,
l-chloroacetyl ^ -methyl-S-methoxy ^ -indolylacetic acid, m.p. 156 to 157 ° C.

B e i s ρ i e 1 14

7.5 g of acetaldehyde-N'-chloroacetyl-N'-ip-methoxyphenyl) hydrazone 50 g of levulinic acid are added and 1.45 g of dry acid are obtained while cooling with ice Hydrogen chloride gas initiated. After that, the temperature of the reaction mixture is gradually increased, and finally the mixture is heated to 80 ° C for 3 hours. The mixture is left to stand overnight and then poured into a large amount of water. The amorphous one that fails here Product is repeated from alcohol and acetone together with some activated charcoal to decolorize recrystallized. 1-chloroacetyl-2-methyl-5-methoxy-3-indolylacetic acid is obtained, F. 156 to 157 ° C.

Example 15

Following the procedure of Example 14, the following compounds are prepared:

l-Acetyl-2-methyl-5-methoxy-3-indolyl acetic acid, m.p. 162 to 164 ° C,

ln-hexanoyl ^ -methyl-S-methoxy-S-indolylcssigsäure, F. 138 to 140 C. ^r

Example 16

A mixture of 3.8 g of l-AcetyW-methyW-hydroxy-5-methoxy-2,3-dihydro-3-indolylacetic acid tert-butyl ester, 500 ml of toluene and 3 g of p-toluenesulfonic acid is heated to 100 ° C for 3 hours with stirring. Thereafter, the reaction mixture is three times with Washed water and the toluene solution dried over sodium sulfate. Then the Toluene solution evaporated. Crude crystalline 1-acetyl-2-methyl-5-methoxy-3-indolylacetic acid separates on standing in the refrigerator from, m.p. 167 to 168 ° C after recrystallization from aqueous acetone.

Example 17

According to example 16, the following connections are made:

ji - \ _ 1 - (2 ', 4'-hexadienoyl) -2-methyl-5-methoxy-3-indolyl] propionic acid _; F. 166 to 167 ° C,

y- [1- (2 ', 4'-hexadienoyl) -2-methyl-5-methoxy-3-indolyl] -butyric acid, F. 127 to 129 ° C.

Example 18

3.7 g of l-acetyl ^ -methyl-S-methoxy ^ .S-dihydro-3-indolylacetic acid are introduced into 100 ml of benzene and then treated with 7.5 g of chloranil. That The reaction mixture is refluxed for 3 hours

ίο heated to the boil, after which the solvent Distilled off under reduced pressure, the residue taken up in acetone and insoluble Filtered off substances. The acetone solution is evaporated to dryness. The crude crystalline 1-acetyl-2-methyl-5-methoxy-3-indolylacetic acid is recrystallized from aqueous acetone. The light yellow crystals melt at 163 to 164 ° C.

Example 19

According to Example 18, l-chloroacetyl-2-methyl-5-methoxy-3-indolylacetic acid, M.p. 156 to 157 ° C.

Claims (2)

Patent claims:
1. 1-Acyl ^ -methyl-S-melhoxy-S-indolylcarboxylic acids of the general formula I. CH ₁ O CH ₂ - (CH ₂ ) ,, - COOH (D in which R denotes an unsubstituted or halogen-substituted alkyl or alkenyl radical with up to 10 carbon atoms and η has the value 0, 1, 2 or 3. 2. Medicament, consisting of a compound according to claim 1 and pharmaceutically customary auxiliaries Carriers. The invention relates to new 1-acyl ^ -methyl-S-methoxy-S-indolylcarboxylic acids of the general formula I.