DE2824056A1 - PHARMACOLOGICALLY ACTIVE ESTERS, THE PROCESS FOR THEIR MANUFACTURING AND PHARMACEUTICAL COMPOSITIONS CONTAINING THESE ESTERS - Google Patents

Description

The present invention relates to pharmacologically active esters, in particular substituted acetic acid esters, processes for their manufacture and pharmaceutical compositions containing these esters.

Analgesics are widely used today and many compounds of various types have been suggested and used for this purpose has been put on the market. One of the most effective and fast-acting analgesics is 4-acetamidophenol of the structural formula

(D

However, despite its effectiveness as an analgesic, 4-acetamidophenol is not commonly used in the treatment of chronic conditions such as rheumatism and arthritis, except perhaps occasionally for pain relief, because in addition to its analgesic activity, it has no anti-inflammatory effects.

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Hence, used to treat chronic arthritis, rheumatic and similar complaints nowadays usually one of the known anti-inflammatory substituted acetic acid analgesics used.

A class of anti-inflammatory analgesics widely used today is that of the well-known substituted Q ^ - (2-methylind [en / oll-3-yl) acetic acids of the general formula

y-lc ^ oQ ,, / \

wherein A is one of the groups ^ CCl, ^ N, ^ CH or ^ C-SO-CH ₃ and R is a fluorine atom or a methoxy group, η is 0 or 1 and either X is a nitrogen atom and Y is a -CO group or X is C atom and Y represent a = CH group, in the latter case the dotted line is intended to mean a second CC bond, as well as their normal, pharmacologically active salts.

The following are some examples of these known anti-inflammatory Called analgesics:

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1- (p-chlorobenzoyl) ^ - methyl-S-methoxy-indol-S-yl-acetic acid;

1- (p-Methylsulfinyl-benzylidene) -2-methyl-5-fluoro-inden-3-ylacetic acid;

1- (3-Phenyl-acryloyl) ^ - methyl-S-methoxy-indol-S-yl-acetic acid and

1-Isonicotinyl-2-methyl-5-methoxy-indol-3-yl-acetic acid.

Unfortunately, these become substituted acetic acids which have the desired anti-inflammatory and analgesic properties their applicability has been questioned by their tendency to cause gastric disorders. It is believed that this is due to the acidic nature of their carboxyl functions. But this explanation is not convincing in that little or no mitigation of this adverse tendency is observed when this anti-inflammatory analgesics are administered in the form of their salts.

Surprisingly, it has now been found that through education an ester linkage between the carboxyl group in the substituted acetic acid of formula II and the hydroxyl group of 4-acetamidophenol compounds are obtained which are excellent have anti-inflammatory and analgesic effects, but also largely or almost completely free from undesirable side effects on the digestive tract

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by which they are largely or completely unchanged into the body.

The present invention accordingly relates to 4-acetamidophenyl-oti- (2-methyl-ind [en / olJ-3-yl) acetates general formula

Il

(III)

C ~ 0 - / y MH -CO-CK

wherein A, R, η, X and Y have the meanings given above, as well as their acid addition salts.

Of these compounds according to the invention, the following are particularly preferred:

4-acetamidophenyl-1 '- (p -chlorobenzoyl) -2'-methyl-5'-methoxyindol-3'-yl-acetate the structural formula

-Cl

(IV)

> -f ^ U-CC <"H-

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4-acetamidophenyl-1'-isonicotinyl-2'-methyl-5'-methoxy-indol-3'-yl-acetate the structural formula

cc

\: -rrv

οφ

-MH- «-CH,

4-acetamidophenyl-1 '- (3-phenyl-aeryloyl) -2'-methyl-5'-methoxyindol-3'-yl-acetate the structural formula

_m ££ x

- only M _{1 -}

4-acetamidophenyl-1 '- (p-methyl-sulfinyl-benzylidene) -2'-methyl-5'-fluoro-inden-3'-yl-acetate the structural formula

Λ-CU.,.

L- (I V / -HC C C M-,

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The acid addition salts of the invention are all for preparative purposes useful, expediently for pharmacological applications should the salts with pharmacological compatible acids are formed. A large number of pharmacologically acceptable acids are available for this purpose, for example Hydrochloric acid, hydrobromic acid, acetic acid, methanesulfonic acid, tartaric acid, succinic acid, phosphoric and sulfuric acid.

The invention also relates to a process for the preparation of the 4-acetamidophenyl-od- (2-methyl-ind (jen / olj-3-yl) acetates according to the invention of the general formula III or its corresponding acid addition salts, which is characterized by that 4-acetamidophenol is reacted with the corresponding substituted acetic acid chlorides. In particular, this implementation with substituted acetic acid chlorides of the general formula

(VIII)

wherein A, R, n, X and Y have the meanings given above, or carried out with the corresponding acid addition salts.

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The reaction between 4-acetamidophenol and the acid chloride of the general formula VIII is advantageously carried out in an anhydrous, inert, organic solvent. as Solvent will advantageously be a substituted aromatic hydrocarbon such as toluene, or one of the many halogenated ones aromatic solvent, an aliphatic hydrocarbon, a halogenated aliphatic hydrocarbon such as chloroform, or an ether such as diethyl ether is used.

Since the reaction proceeds relatively violently, it can be carried out at room temperature without the supply of heat or, if the Reaction becomes very violent, can be carried out with cooling.

The reaction is preferably in the presence of a base, in particular in the presence of a nitrogen-containing aromatic heterocyclic compound. Particularly pyridine is preferably used as the base.

The process according to the invention advantageously also comprises the preliminary stage for the preparation of the substituted acetic acid chlorides of the general formula VIII, which can be obtained by reacting a solution and / or suspension of a substituted acetic acid of the general formula II or one of its salts in an anhydrous inert solvent with thionyl chloride.

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The pyridine salt is preferably used as the salt of the substituted acetic acid of the general formula II.

The reaction with thionyl chloride can be carried out at any suitable temperature ranging between room temperature and reflux temperature of the solvent are carried out, usually it is carried out in the temperature range between about 40 and 65 C.

The reactions in the preliminary stage and in the subsequent stage are preferably carried out in the same solvent. Usually an organic solvent, preferably a substituted aromatic hydrocarbon, is used for this like toluene, one of the many halogenated aromatic solvents, an aliphatic hydrocarbon, a halogenated one aliphatic hydrocarbons such as chloroform or dichloromethane or an ether such as diethyl ether are used.

Preferably, the reaction is then advantageously carried out under reflux at about 41 ⁰ C is used as solvent of anhydrous dichloromethane. About 1 mole of thionyl chloride per mole of the substituted acetic acid of the general formula II is preferably used for the reaction.

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It was also found that it is advantageous to implement between the substituted acetic acid of the general formula II and the thionyl chloride in the presence of a catalytic Amount of N, N-dimethylformamide to be carried out.

According to a further embodiment of the invention, the 4-acetamidophenyl- QC- (2-methyl-ind [en / ol] -3-yl) acetates of the general formula III are prepared in such a way that a mixed anhydride of the general formula

-l-c

wherein A, R, n, X and Y have the meanings given above, "AyI" is an alkyl group with 1 to 20 carbon atoms, an aryl group with 6 to 20 carbon atoms, an alkaryl group with 7 to "20 carbon atoms or is an aralkyl group having 7 to 20 carbon atoms, m is 0 or 1 and Q is a carbon atom or, if m is 0, a sulfinyl group represents

with 4-Acetamidopheno1 of the formula I to the corresponding acetate of the general formula III is implemented.

The reaction between the mixed anhydride and 4-acetamidophenol can and should if possible in an anhydrous

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inert solvent, preferably in one of those described above organic solvents.

The reaction can be carried out in the presence of a base, preferably a tertiary amine such as triethylamine or pyridine.

The mixed anhydride of the general formula IX is preferably obtained by reacting a substituted acetic acid of the general formula II or one of its salts with a reactive organic chloride compound of the general formula

AyI- [o] _m -Q-ci (X)

wherein "AyI", m and Q have the meanings given above, in Presence of a base.

The following can be used as the reactive organic chloride of the general formula X:

(a) an alkyl, aralkyl, aryl or alkaryl chloroformic acid ester the general formula

0
AyIO-C-Cl (Xa)

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(b) a sterically hindered alkyl, aralkyl, aryl or alkaryl acid chloride of the general formula

O
AyI-C-Cl (Xb)

or

(c) an alkyl, aralkyl, aryl or alkarylsulfonyl chloride of the general formula

AyI-S-Cl (Xc)

in which, as in general formula IX, "AyI" is an alkyl, aralkyl, aryl or alkaryl group with up to 20 carbon atoms
means.

The reaction between the substituted acetic acid and the reactive chloride compound becomes particularly advantageous carried out in an anhydrous solvent, preferably in one of the above-mentioned organic solvents.

The reaction must be carried out in the presence of a base, preferably a tertiary amine, particularly preferably in the presence of triethylamine or pyridine.

The mixed anhydride of the general formula IX formed need not be isolated from the reaction mixture.

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Rather, the reaction mixture containing the mixed anhydride can advantageously be subjected to the second process stage without removing the base and in the same reaction vessel
will.

According to another embodiment of the invention, this is done
Process for the preparation of the 4-acetamidophenyl-Q £ - (2-methylindjen / ol3 ~ 3-yl) -acetate of the general formula III in the
Way that you can get a p-aminophenyl compound of the general
formula

ι 1 ^{ i γ

CW _x -COJ

in which A, R, n, X and Y have the meanings given above, reacts with an acetylating agent.

The acetylation can be carried out with any suitable acetylating agent, for example with acetic anhydride.

The p-aminophenyl compound of the general formula XI can
advantageously by reducing a p-nitrophenyl compound of the general formula

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(XII)

in which A, R, η, X and Y have the meanings given above, getting produced. The reduction is best carried out with nascent hydrogen, for example through The action of an acid on iron powder is generated. The acid used here is advantageously hot acetic acid.

The p-nitrophenyl compound of the general formula XII can by reaction of a substituted acetic acid of the general formula II or one of its salts with bis (4-nitrophenyl) sulfite the formula

(XIII)

getting produced. This reaction is advantageously carried out in a tertiary amine solvent, preferably in pyridine, carried out at or near room temperature.

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According to a further embodiment of the invention, the 4-acetamidophenyl-Q <i: - (2-methyl-ind [en / olj-3-yl) acetates of the general formula III can also be produced by a process in which 4-acetamidophenol with a solution of a symmetrical OC- (2-methyl-ind [en / olJ-3-yl) acetic anhydride of the general formula

wherein A, R, η, X and Y have the meanings given above, is reacted in a water-immiscible solvent in the presence of a strong aqueous base, so that the reaction mixture forms a two-phase system which, with stirring, is 4-alkyl -3,5-dioxo-pyrazolidinyl- OC- (2-methyl-ind [en / olj-3-yl) acetate forms.

The reaction between 4-acetamidophenol and the acid anhydride of the general formula XIV gives the corresponding o £ - (2-methylind [en / ol] -3-yl) acetic acid as a by-product and must therefore be in the presence of a strong base, for example an organic Base such as triethylamine, but preferably an aqueous one

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Sodium hydroxide. The anhydride is quite unstable in the presence of water and therefore becomes in one with water Immiscible solvent brought to reaction. Such a solvent can advantageously be an anhydrous, inert one organic solvent, for example benzene, toluene, chloroform, dichloromethane or ethers such as diethyl ether is used will. The reaction is carried out with stirring in a two-phase system, causing decomposition of the anhydride before it took part in the intended reaction is restricted to a minimum. The reaction will be beneficial at Room temperature or approximately room temperature, but not above 30 ° C.

This fourth process advantageously also comprises the preliminary stage for the preparation of the acid anhydride of the general formula XIV, in which one o £ - (2-methyl-ind [en / ol] -3-yl) acetic acid the general formula II with a carbodiimide in an anhydrous one containing no hydroxyl groups and otherwise inert solvent at room temperature or approximately room temperature, but usually not above 30 ° C, is reacted.

In principle, any carbodiimide can be used, provided it is sufficiently stable. Accordingly, they are best suited N, N'-di [alkyl / aryIJ-carbodiimides of the general formula

C (XV)

Z "N

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2B2A056

where Z ¹ and Z "each denote an alkyl, cycloalkyl, alkaryl, aryl or aralkyl group having 6 to 20 carbon atoms. For economic reasons, in particular because of its low price, the use of N, N ¹ -dicyclohexyl -carbodiimide particularly preferred in the context of this invention.

The substituted acetic acid chlorides of the general formula VIII, the mixed anhydrides of the general formula IX and the symmetrical anhydrides of the general formula XIV were described in British parallel application No. 23260/77 (S.N.) described. In contrast, the present invention comprises the p-nitrophenyl compounds of the general formula XII, the p-aminophenyl compounds of the general formula XI and the end products of the general formula III and the processes to make these connections.

The 4-acetamidophenyl-Qci- (2-methyl-ind [en / olj -3-yl) acetates of the general formula III and in particular the preferred compounds of the formulas IV to VII are distinguished by outstanding properties anti-inflammatory and analgesic effects, such as corresponding, in general for the examination of anti-inflammatory effects Have shown recognized test methods for medicinal products. The preliminary investigations also suggest this indicate that these compounds, when administered orally, have essentially no undesirable gastrointestinal side effects cause.

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The 4-acetamidophenyl- ^c t- (2-methyl-ind [en / olJ-3-yl) acetates of the general formula III according to the invention are expediently used as anti-inflammatory analgesics in human and veterinary medicine in the form of suitable pharmaceutical compositions compatible pharmaceutical carrier materials.

The term "pharmaceutical" is used here in the sense that that no such carrier materials (pharmaceutical vehicles) are to be used that are related to the intended Form of administration of the composition unsuitable or even can be harmful. The selection of a suitable carrier for any desired purpose and mode of administration is readily possible for one of ordinary skill in the art.

The invention accordingly further relates to pharmaceutical compositions, the one or more of the acetates of the general formula III according to the invention as the active ingredient component with suitable pharmaceutical carriers included.

Although these pharmaceutical compositions according to the invention are primarily for administration via the digestive tract, including rectal use, but they can also be administered parenterally. Preferably these compositions are administered orally.

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Because of the various possible modes of application, the following are desirable for the pharmaceutical carrier To shape:

(a) an ingestible excipient in the form of tablets, coated tablets, sublingual tablets or pills; a ingestible carrier in the form of a capsule or cachet; an ingestible powdery solid carrier in the form of a powder, or an ingestible liquid medium in the form of a syrup, solution, suspension or elixir;

(b) a solid or liquid medium in the form of a paste, lotion, ointment, ointment base or a propellant-containing medium Medium in the form of an aerosol;

(c) a sterile, injectable liquid solution or suspension, or

(d) a base in the form of suppositories.

The forms of application mentioned above are the most common used, but the list is by no means exhaustive.

The amount of the dosage of the anti-inflammatory according to the invention Analgesics in the pharmaceutical compositions depend to some extent on the way in which the composition is

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genes are to be administered, and of course on the individual treatment case. In general, the appropriate dose for adults is a range of 30 to 750 mg (divided into Dosages) of the analgesic active ingredient per day, with a dosage unit usually between 10 and 250 mg, preferably contains about 50 mg.

The invention is further illustrated below by way of examples in order to cover some further aspects of the invention and in particular various To show production methods and formulations for the active ingredients according to the invention.

example 1

Preparation of 4-acetamidophenyl-i '- (p-chlorobenzoyl) -2'-methyl-5'-methoxy-indol-3'-yl acetate (Formula IV)

Level a

A solution of 6.0 g of thionyl chloride in 10 ml of dichloromethane was slowly stirred into a solution of 7.9 g of 1- (p-chlorobenzoyl) -2-methyl-5-methoxy-indol-3-yl-acetic acid and 4.8 g of pyridine in 80 ml of dichloromethane. The resulting red solution was refluxed for 15 minutes and contained 1- (p-chlorobenzoyl) ^ - methyl-S-methoxy-indol-S-yl-acetyl chloride, that was not normally isolated during the manufacturing process. Only for the purpose of his analysis was a minor one Amount of acid chloride isolated and examined. It was

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found a melting point of 107-109 ° C.

Level B.

A suspension of 7.55 g of 4-acetamidophenol in 5.0 g of pyridine and 10 ml of dichloromethane was carefully added to a solution from Step A which was refluxed. The received The mixture was then refluxed for 10 minutes, cooled, twice with 2 molar hydrochloric acid and once with 20% sodium carbonate solution and then washed over magnesium sulfate dried.

The dichloromethane solution was concentrated under reduced pressure and gave a solid, yellow substance which crystallized from aqueous acetone as cream-colored needles. Yield: 11.6 g, that is 48% of the theory; Melting point: 198 to 199 ° C.

Example 2

Preparation of 4-acetamidophenyl-1 '- (p-chlorobenzoyl) -2'-methyl-5-methoxy-indol-3'-yl acetate (Formula IV) via the p-nitrophenyl ester

Level a

A solution of 10 g of bis (4-nitrophenyl) sulfite in 60 ml of pyridine became a solution of 4.0 g of i- (p-chlorobenzoyl) -2-methyl-5-methoxy-indol-3-yl-acetic acid given in 50 ml of pyridine.

The mixture was left at room temperature overnight under a

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Maintained nitrogen atmosphere and then under reduced Focused pressure.

The residue was triturated with 200 ml of ethyl acetate and the Mixture filtered. The filtrate was washed with 100 ml of dilute hydrochloric acid, then with 50 ml of saturated aqueous sodium carbonate solution and finally washed with water and then dried over magnesium sulfate.

The ethyl acetate solution was concentrated to give a yellow solid which was triturated with 50 ml of ether and then filtered off became. In this way, the p-nitrophenyl ester was obtained in a yield of 5.0 g (93%). Melting point: up to 154 C. The substance was pure enough to be used in the next stage without further purification.

Level B.

A solution of 1.0 g of p-nitrophenyl-1 '- (p-chlorobenzoyl) -2 '-methyl-5'-methoxy-indol-3'-yl acetate in 100 ml of ethyl acetate was hydrogenated under a pressure of 2 atmospheres shaken in the presence of 500 mg of catalyst (5% palladium on charcoal) for 5 hours.

The catalyst was removed by filtration through a bed of celite removed and the ethyl acetate solution obtained under reduced

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Focused pressure. Then 2 ml of acetic anhydride was added to the remaining oil and after the exothermic reaction When it had subsided, chloroform was added until everything was dissolved.

The chloroform was removed under reduced pressure. An oil remained, which was triturated with 50 ml of ether and quickly filtered. An addition of a small amount of petroleum ether (boiling point 40 to 60 ⁰ C) resulted in the crystallization of 4-acetamidophenyl-1 '- (p-chlorobenzoyl) -2'-methyl-5'-methoxyindol-3-yl acetate in cream-colored needles . The yield was 0.75 g. The product was identical to the sample prepared using the acid chloride in Example 1.

Example 3

Preparation of 4-acetamidophenyl-1 '- (p-chlorobenzoyl) -2'-methyls' -methoxy-indol-3'-yl-acetate (formula I)

A mixture of 3.58 g of 1- (p-chlorobenzoyl) -2-methyl-5-methoxyindol-3-yl-acetic acid and 1.9 g of p-toluenesulfonyl chloride in 20 ml of dichloromethane was stirred and slowly treated with 1.01 g of triethylamine in 5 ml of dichloromethane. Afterward was stirred for a further 10 minutes.

A solution of 1.51 g of 4-acetamidophenol and 1.0 g of pyridine in 30 ml of dichloromethane were added, the mixture for 10 minutes

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refluxed and then cooled to room temperature. The dichloromethane solution was washed first with 2 molar hydrochloric acid, then with 20% sodium carbonate solution and then dried over magnesium sulfate.

The dichloromethane solution was concentrated under reduced pressure and gave a yellow, solid substance which crystallized from aqueous acetone as cream-colored needles. One received a yield of 3.51 g, d.s. 71%. The substance was identical to the sample, which, as described in Example 1, via the Acid chloride had been produced.

Example 4

Preparation of 4-acetamidophenyl-i '- (p-methyl-sulfinylbenzylidene) -2'-methyl-5'-fluoro-inden-3'-yl-acetate (Formula VII)

A mixture of 1.1 g of triethylamine and 10 ml of dichloromethane was slowly added with stirring to a mixture of 3.56 g 1- (p-Methylsulfinyl-benzylidene) -2-methyl-5-fluoro-inden-3-ylacetic acid and 1.91 g of p-toluenesulfonyl chloride in 50 ml of dichloromethane given. After 10 minutes, 1.51 g of 4-acetamidophenol and 1.0 g of pyridine in dichloromethane were added. the The mixture was refluxed for 10 minutes and cooled. The dichloromethane solution was mixed with 50 ml of 2 molar hydrochloric acid and twice with 50 ml of 20% aqueous sodium carbonate solution

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washed and then dried over magnesium sulfate. Then the dichloromethane solution was concentrated under reduced pressure, whereby an oil was obtained which could not be crystallized. It was found by thin layer chromatography that the oil is the substituted acetic acid used as the starting product, the desired reaction product of the formula VII and three other compounds running close to the solvent front. The oil was attached to 110 g of silica gel chromatographed and first with chloroform and then with 95: 5 ratio of chloroform / methanol eluted. That on this The product of the formula VII obtained in this way was contaminated with the starting acid, but this was caused by redissolving in chloroform and washing with 20% sodium carbonate solution could be removed. The desired product crystallized from acetone-petroleum ether (40:60) in small needles. The yield was 0.5 g, the melting point 230 to 233 ° C.

Example 5

Preparation of 4-acetamidophenyl-1 '- (p-chlorobenzoyl) -2'-methyl-5'-methoxy-indol-S-yl acetate

Step A Preparation of the symmetrical 1- (p-chlorobenzoyl) -2-methyl-5-methoxy-indol-3-yl-acetic anhydride

16.5 g (0.08 mol) of N ^ '- dicyclohexyl-carbodiimide became one Solution of 28.62 g (0.08 mol) 1- (p-chlorobenzoyl) -2-methyl-5-

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methoxy-indol-3-yl-acetic acid in 150 ml of tetrahydrofuran. The resulting mixture was left to stand at room temperature overnight. It was then filtered, the filtrate evaporated to dryness and the residue taken up in ethanol and recrystallized. A yield was obtained of 6.5 g of the desired 2-acetoxybenzenic anhydride.

Stage B Preparation of 4-acetamidophenyl-i '- (p-chlorobenzoyl) -2'-methyl-5'-methoxy-indol-3-yl acetate

1.51 g (0.01 mol) of 4-acetamidophenol were in 20 ml of 1 molar Dissolved sodium hydroxide. A solution of 6.98 g (0.01 mol) of the anhydride obtained in step A was then added to this solution, dissolved in 20 ml of benzene. The two-phase mixture was shaken vigorously for 30 minutes and then filtered, whereby received the desired product.

Formulation I Pharmaceutical composition in the form of

Tablets

A tablet blend was prepared by intimately mixing the following ingredients:

4-acetamidophenyl-1 '- (p -chlorobenzoyl) -2'-methyl-5'-methoxy-indol-3'-yl-acetate

spray-dried lactose dicalcium phosphate magnesium stearate

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143 G 286 G 563 G 8th G 1000 G

The mixture was then mixed using conventional tabletting equipment Compressed into tablets of 350 mg each, each of which contains 50 mg of 4-acetamidophenyl-1 '- (p-chlorobenzoyl) -2'-methyl-5'-methoxy-indol-3'-yl acetate contained.

Formulation II Pharmaceutical composition in the form of

Capsules

A corresponding mixture was prepared by intimately mixing the following ingredients:

4-acetamidophenyl-1 '- (p -chlorobenzoyl) -2'-methyl-5'-methoxy-indol-3'-yl-acetate

Lactose B.P. Corn starch Magne s iums tearat

250 G 360 G 375 G 15th G 1000 G

The mixture was filled into the capsules in amounts of 200 mg per capsule, corresponding to 50 mg of 4-acetamidophenyl-1 '- (p-chlorobenzoyl) -2'-methyl-5'-methoxy-indol-3'-yl acetate per capsule.

Formulation III Pharmaceutical composition in the form

an injectable suspension

4-acetamidophenyl-1 '- (p-chlorobenzoyl) -2'-

methyl-5'-methoxy-indol-3'-yl-acetate 5.00% w / v.

Polysorbate 80 O, 15% w / v

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Thimerosal Sodium Chloride Disodium Phosphate Phosphoric Acid

Water for injection

0.005% w / v 0.33% w / v 1.00% w / v

Sufficient amount to adjust the pH to 6.0 - 7.0

to 100% w / v

The isotonic injection vehicle contained 20% water. That 4-acetamidophenyl-i '- (p -chlorobenzoyl) -2'-methyl-5'-methoxyindol-3'-yl-acetate was dispersed in the carrier and, if necessary, the pH was adjusted with the aid of phosphoric acid. The suspension was then made up to its final volume.

The entire batch was sterilized in an autoclave. After sterilization, the lot was aseptically sterilized in advance Ampoules filled in dosed portions.

Formulation IV Pharmaceutical composition in the form of

Suppositories

4-acetamidophenyl-1 '- (p -chlorobenzoyl) -2'-methyl-5'-methoxy-indol-3'-yl-acetate

Suppository base

250 g

777.5 g 1027.5 g

The suppository base was melted in a double boiler. The 4-acetamidophenyl-1 '- (p-chlorobenzoyl) -2'-methyl-

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5 '~ -methoxy-indol-3'-yl-acetate was in finely divided form added to the molten base and the mixture stirred until the ester was completely dispersed. The mixture was then poured into 2g molds where it solidified and then demolded.

The suppositories obtained in this way contained 500 mg of 4-acetamidophenyl-i '- (p-chlorobenzoyl) ^{-2'-methyl-5'-methoxyindole-3-1-yl} acetate and 1555 mg of the base fabric.

The following are based on a preferred invention 4-Acetamidophenyl-QcS- (2-methyl-ind [en / ol] -3-yl) -acetate Scientific Compiled evaluations which show that the compounds according to the invention are free from undesirable side effects and have excellent anti-inflammatory and / or analgesic properties.

Assessment of the Stability of the Compounds According to the Invention To assess the stability of 4-acetamidophenyl-o £ - (2-methyl-ind [en / ol] -3-yl) acetates in the gastrointestinal tract, simulated gastric and intestinal fluids were used as follows manufactured:

Preparation of a simulated gastric fluid

2 g of sodium chloride were mixed with 7.0 ml of concentrated hydrochloric acid

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mixed and the mixture made up to 1000 ml with distilled water. A simulated gastric fluid was obtained a pH of about 1.2.

Production of simulated intestinal fluid

6.8 g of monobasic potassium phosphate were dissolved in 250 ml of water and then a mixture of 190 ml 0.2 molar Sodium hydroxide solution and 400 ml of water were added. The pH of the resulting solution was adjusted with 0.2 molar sodium hydroxide solution adjusted to 7.5 and the solution diluted to 1000 ml with distilled water. You got one in this way simulated intestinal fluid.

The stability test was carried out as follows: 100 mg of the above-mentioned acetate according to the invention were suspended in each case in 5 ml of the simulated liquid in question and the suspensions shaken at 37 ° C for 16 hours. The mixture was then left to rest. The protruding Liquid was applied to thin-layer silica gel plates and developed with a 90:10 mixture of chloroform / methanol. The mixture was then with 5 ml Chloroform extracted and the chloroform-containing mixture filtered through phase-separating papers, through which only the chloroform solution could happen. This chloroform solution was also on thin-layer chromatography coated with silica gel.

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~ ⁴³ "2824Q56

graphical plates applied and with chloroform / methanol in the ratio 90:10 developed.

From the experiments carried out in this way with both the simulated gastric and the simulated intestinal fluid it can be seen that only negligible decomposition occurs in both media. It follows that all of the 4-acetamidophenyl- Q ^ - (2-methyl-ind [en / olj-3-yl) -acetate practical do not cause gastric disorders when administered orally.

Assessment of Gastric Compatibility in Rats Gastric intolerance is a particular problem encountered with oral administration of the class of compounds with analgesic and anti-inflammatory properties. The therapeutic index (or safety factor) of such compounds is best demonstrated by the gastric tolerance test in rats.

Accordingly, one of the typical compounds preferred according to the invention, 4-acetamidophenyl-1 '- (p-chlorobenzoyl) -2'-methyl-5'-methoxy-indol-3'-yl acetate (Compound IV), tested for its acute gastric tolerance in rats (duration: 4 hours) by taking the oral administration in two different dosage levels and at the same time with

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compared to an equimolar amount of acetic acid that is one of the two building blocks of the acetate tested according to the invention, namely the building block that is the strongest irritated the stomach.

So that the experiments could be carried out under conditions which make the difference between the compounds according to the invention and to determine the known compounds used as a comparison standard in a reproducible and unambiguous manner allowed, the effect of the comparative active substances in relation to their dose was also shown in a series beforehand checked by preliminary tests to find the appropriate dosage levels.

The examination procedure

Groups of 10 male rats (Charles River) each weighing about 180 to 250 g were given about No more food 21 hours before they were killed. The active ingredients were administered orally as a suspension in 1% gum tragacanth. Four hours after the administration, the animals were sacrificed by bleeding from the neck. then the stomachs were removed, opened, carefully with a saline solution washed and then pinned flat to a board for further examination.

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During the examination, the superficial mucosal hemorrhages were classified according to their severity, their extent and their number, classified into zones of needlepoint, blotchy or more extensive Size.

Bleeding lesions that had penetrated the mucous membrane (submucosal lesions) were considered to be ulcers which were also classified according to their severity according to their extent and their number: spots (1 to 2 mm in size) and Furrows (elongated). Perforations were usually not observed.

The carcasses were then ranked according to the severity of the symptoms present, identifying any ulcers (submucosal Damage) were usually rated as more serious than superficial mucosal bleeding. The control animals regularly showed certain signs of "hyperemia", a condition of the vascular system that causes rush of blood (congestion) at the moment of killing and therefore not to be assigned to a functional (organically caused) hyperemia was. They were therefore not considered to be signs of gastric irritation.

Statistical comparisons between specific test groups were made using the Mann and Whitney unit test method,

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which were based on the graded severity of the damage observed. The results were given as the percentage of the test animals that showed either only superficial mucosal bleeding or submucosal damage (ulcers) usually together with mucosal bleeding, based on the
Total number of test animals in a group, and summarized in a simplified form in Table I.

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substance dose
mg / kg number
the
Attempt
rats number
the
not ge
harmed
Stomachs Table I. 1 total
number
the schä
termination
cases
(in %) Unit
test
against
Control
group Unit
test
against
Connect
dung B Control
group 8th 8th 0% Connect
dung B
Connect
dung IV 7th
9.6 σο oo 1
6th Number of rats with
Stomach damage
Bleeding ^x) ulcer ^x)
(the (sub
Mucous membrane) mucous) 4th 87%
25% P <0.003
NS P <0.007 809850 / Control
group - 8th 7th 12% - _ 6900 Connect
dung B 10 8th 0 3 + 3
2 100% P <0.001 Connect
dung IV 13.7 8th 5 1 37% NS P = 0.001 2 + 1 + 1 2 + 1

Notes: Compound B = 1 - (p-chlorobenzoyl) ^ - methyl-S-methoxy-indol-S-yl-acetic acid

Compound IV = 4-acetamidophenyl-1 '- (p-chlorobenzoyl) -2'-methyl-5'-methoxy-

indol-3'-yl acetate

The position of the digits from left to right indicates the number of increasingly difficult
developing damage.

282A056

A comparison of the results in Table I shows that the invention Compound IV compared to compound B has a significantly better tolerance with regard to the gastric mucosa having. A comparison with the effect on the stomach, the 5 mg / kg 1 - (p-chlorobenzoyl) ^ - methyl-S-methoxy-indole-S-ylacetic acid exercise shows that the gastric tolerance of the compound according to the invention, based on the molar amount, is more than twice as high.

Assessment of the pharmacological effects

Three different types of tests are usually carried out, to assess the effectiveness of analgesic and anti-inflammatory agents. Also in the present case the compound IV = 4-acetamidophenyl-i- (p-chlorobenzoyl) 2-methyl-5-methoxy-indol-3-yl acetate and the compound B = 1- (p-chlorobenzoyl) - ^ - methyl-S-methoxy-indol-S-yl-acetic acid subjected to these three tests to assess their effectiveness, using groups of 10 rats each.

1) Adjuvant Arthritis Test ( Inclined Sieve Test) in Rats The adjuvant arthritis was artificially produced in several groups of rats by injecting mycobacterial adjuvants. In this way, foci of inflammation were produced on parts of the body remote from the injection site about 10 to 15 days after the injection, which again after about 30 days

χ decrease.

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One group of rats was left untreated as a control group. Other groups of rats were given a daily for 18 days Oral dose treated with different amounts of the parent compound, namely compound B, which was used in the experiment served as a standard, and the compound to be tested IV. In each case, the active ingredient was given to the rats in a solution administered, the 1 part polyoxyethylene oleic acid glycerol ester, made up to 5 parts with 1% aqueous tragacanth gum solution, contained, to which 1% ethanol was added if this was necessary for solubility reasons. Of this Solvent vehicles were generally administered at 5 ml per kg rat. The same carrier solution without the active ingredient was made administered in the same amount to the rats of the control group.

The treatment was continued for 18 days during which time the rats were given help at intervals the usual inclined sieve test. In this test, the grasping function of the rats is assessed by touching them on a wire mesh screen at an angle of 90 is rotatably supported from the horizontal to the vertical direction, and if necessary, even beyond. The angle, in which the rat to be tested loses its grip and falls off the sieve is determined. The greater the angle of inclination in which the rat falls from the sieve, the greater the force with which it holds itself on the sieve, and the less

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has its gripping function under the arthritis-like disease suffered or the greater is the alleviation of the pain caused by the disease by the test substance.

The rats of the control group received only the carrier material in an appropriate manner for the corresponding period of time (18 days) Dosage administered. A second group of rats received 1 mg / kg per day of Compound B for 18 days. A third Group were administered compound B corresponding to 2 mg / kg per day. A fourth group of rats received 2.7 mg / kg of compound IV. Here, 2.7 mg / kg of compound IV as a molar equivalent correspond to a dose of about 2 mg / kg the connection B.

The results obtained in this way are shown graphically in Fig. 1, with the curves for the progressive Deterioration of the gripping function as the angle of inclination of the screen against time (in days) for each of the tested connections and for which blanks have been plotted. From Fig. 1 it can be seen that the observations also over continued beyond the 18th day.

From Fig. 1 it can be seen that the curve for compound IV at a daily dose of 2.7 mg / kg approximates the indicates the same activity, such as about half the molar amount of

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Connection B in the gripping function test. All rats survived the treatment.

2) Adjuvant arthritis test (body weight) in rats The experimental determination of unknown side effects is more difficult than the determination of gastric irritation. However, their presence can be assumed by a detected decrease in body weight. Therefore, in order to ensure that the results obtained with the inclined sieve test are not inadmissibly reproduced by other side effects of the compound to be tested, the body weights of the rats tested were determined daily and the average weight of each group of rats was shown in FIG . It can be seen from this figure that the systemic effect of compound IV on body weight is comparable to that of half the molar amount of compound B.

3) Antipyretic test against yeast-induced hyperthermia in rats

The usual method of injecting groups of rats with yeast was used. Immediately after the injection different dosages of compounds IV and B were given to the different groups of rats except the Control group receiving only the pharmaceutical carrier administered orally.

8O98S0 / 69Ö0

The body temperature of the test rats was determined over a period of 8 hours after the oral administration of the drug carefully registered. The results are shown graphically in FIG. It can be seen from this that compound IV as effective as a 1/4 molar amount of compound B is.

4) The Randall-Selitto test in rats

The usual technique was used, in which the various Above test compounds the rats of each group, except the control group, which is only the pharmaceutical Vehicle received, were administered orally. Thirty minutes later, each rat was in one of the hind paws injected with yeast.

To assess the effect of this treatment on the pain threshold To be able to do so, pressure was applied to both the injected and the untreated hind paw of the test animals exercised. The pain threshold was determined as the pressure at which the rat flinched. The values for each rat were expressed in% of the pain threshold pressure on the injected hind paw compared to that on the untreated hind paw.

These pain threshold percentages were determined at time intervals of 3, 5, 7 and 24 hours after the injection. the Results are shown in Table II.

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Table II

Randall-Selitto test in male rats (body weight 150 - 170 g each) Pain threshold in% of the untreated hind paw pressure values Statistical evaluation against the control group

Substance and dosage o » O CO CD ot · Control group: tragacanth

rubber

Compound B: 2 mg / kg period since yeast injection (since administration
of the test connections)

Hrs. 5 hrs. 7 hrs.
(3 1/2 hours) (5 1/2 hours) (7 1/2 hours)

- 2.1

- 4.0

- 3.7

- 5.8

- 3.4

- 3.4
P <0.001

24 hours

48 - 4.5

52-3.3

Compound B: 4 mg / kg - 3.6
P <O, O1

- 4.7

- 5.8
P <0.02

60 ^z 3.6

Compound IV: 5.5 mg / kg - 5.0
P <0.05

- 4.7
P <0.01

- 5.4
P <0.02

49 - 3.7

As can be seen from Table II, the compound IV was tested in a dosage of 5.5 mg / kg per day and with Compound B at a dosage of 4 mg / kg per day was compared. The dosages correspond to equimolar amounts. The results show that the compound IV according to the invention has the same analgesic effect as compound B.

Assessment of the therapeutic index

From the relative gastric tolerance, as shown in Table I, and the relative anti-inflammatory effects, which can be derived from Fig. 1, it is possible, in comparison with compound B, a relative separation of the anti-inflammatory To derive effect from the gastric toxicity of Compound IV as indicated in Table III.

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Table III

Active ingredient Comparison relative ent relative active ingredient non-ignition gastric OO Effectiveness (a) Toxicity (b) O CO Ver
binding IV OO Ver
binding B cn
ο <= Molar <-j molar approx ο ο

relative safety advantage compared to the comparative active ingredient:

relative efficacy relative gastric toxicity

(a) Arthritis produced in rats: one oral dose daily for 17 days

(b) acute (4 hours, a single oral dose) gastric tolerability in rats

From this it can be concluded that compound IV in terms of its analgesic effect, compared on a molar basis, at least as good as compound B, whereas it only accounts for fourth part of the antipyretic effect and only half the anti-inflammatory effect of the reference active ingredient on a molar basis. Of particular importance, however, is the low gastric toxicity that allows the Compound IV distinguishes itself. Although the analgesic effect is not greater than that of compound B, the compound shows IV gastric tolerability more than twice that of a comparable molar amount of Connection B.

Pharmacological preliminary tests have shown that the other Active ingredients according to the invention not discussed in detail here, results in qualitatively similar results to 4-acetamidophenyl-1 '- (p-chlorobenzoyl) -2'-methyl-5'-methoxy-indol-3'-yl acetate deliver.

sy: kö

809850/6900

Claims (47)

UEXKÜLL 4 STOLBERG PATENTANWÄLTE BESELERSTRASSE 4 2000 HAMBURG 52 OR. J.-D. FRHR. by UEXKÜLL DR. ULRICH GRAF STOLBERG DIPL.-ING. JÜRGEN SUCHANTKE Sterwin A.G. (Prio: June 2, 1977 GB 23320/77 - 14974) Zeughausgasse 9 CH - 6300 Zug Hamburg, May 25, 1978 Pharmacologically active esters, processes for their production and pharmaceutical compositions containing these esters 1. 4-Acetamidophenyl- αέ- (2-methyl-ind [en / ol ^ -3-yl) acetates of the general formula (III) 809850/6900 where A is one of the groups ^ CCl, ^ N, ^ CH or ^ C-SO-CH ₃ and R is a fluorine atom or a methoxy group, η is 0 or 1 and either X is a nitrogen atom and Y is a -CO group or X a C atom and Y a = CH group and the dotted line a second CC bond indicates or their acid addition salts. 2. acid addition salts according to claim 1, characterized in that they are formed with a pharmacologically suitable acid will. 3. 4-Acetamidophenyl-1 '- (p -chlorobenzoyl) -2'-methyl-5'-methoxyindol-3'-yl acetate. 4. 4-Acetamidophenyl-1'-isonicotinoyl-2'-methyl-5'-methoxyindol-3'-yl acetate. 5. 4-Acetamidophenyl-1 '- (3-phenyl-acryloyl) -2'-methyl-5'-methoxy-indol-3'-yl-acetate. 6. 4-Acetamidophenyl-1 '- (p-methylsulfinyl-benzylidene-2'-methyl-5'-fluoro-inden-3'-yl-acetate. 8098S0 / 6900 7. Process for the preparation of 4-acetamidophenyl-o ^ - (2-methyl-indren / ol] -3-yl) -acetates of the general formula III or its acid addition salts, characterized in that that 4-acetamidophenol with a substituted acetic acid chloride of the general formula Y- [CH = C h] - / A (VIII) _λ Γ II Il Γ ir. wherein A, R, n, X and Y have the meanings given in claim 1, reacts. 8. The method according to claim 7, characterized in that the reaction in an anhydrous inert solvent is carried out. 9. The method according to claim 8, characterized in that either a substituted one as the inert organic solvent aromatic hydrocarbon or a halogenated aliphatic hydrocarbon are used will. 8098 B D / 6900 -A- 10. The method according to claim 9, characterized in that toluene or chloroform can be used as solvents. 11. The method according to claims 7 to 10, characterized in that that the reaction can be carried out without heating or, if it is necessary, to carry out the reaction at room temperature, is carried out under cooling. 12. The method according to claims 7 to 11, characterized in that that the reaction is carried out in the presence of a base. 13. The method according to claim 12, characterized in that pyridine is used as the base. 14. The method according to claims 7 to 13, characterized in that that the substituted acetic acid chloride of the general formula VIII by reacting a substituted Acetic acid of the general formula (II) 809850/0900 wherein A, R, η, X and Y have the meaning given in claim 1 or their corresponding salt with thionyl chloride in an anhydrous inert solvent. 15. The method according to claim 14, characterized in that the pyridine salt of a substituted acetic acid of the general formula II is used. 16. The method according to claims 14 and 15, characterized in that the reaction is carried out with thionyl chloride
at a temperature in the range between 40 and 65 ° C. 17. The method according to claims 14 to 16, characterized in that either a substituted aromatic hydrocarbon or a halogenated aliphatic hydrocarbon is used as the inert organic solvent
is used. 18. The method according to claim 17, characterized in that anhydrous dichloromethane is used as the solvent and the reaction is carried out under reflux. 809850/6900 19. The method according to claims 14 to 18, characterized in that that the quantitative ratio of the reactants im is essentially 1 mole of thionyl chloride per mole of substituted acetic acid. 20. The method according to claims 14 to 19, characterized in that that the reaction is carried out in the presence of a catalytic amount of N, N-dimethylformamide. 21. Process for the preparation of 4-acetamidophenyl-O £ - (2-methyl-ind Cen / οΓ) -3-yl) acetates of the general formula III, characterized in that a mixed anhydride of the general formula ^v ' - "- \ —J / Ll < ^IX ) W. Il _L ~ c ~ <- in which A, R, n, X and Y have the meanings given in claim 1, "AyI" is an alkyl group with 1 to 20 carbon atoms, an aryl group with 6 to 20 carbon atoms, an alkaryl group with 7 to 20 carbon atoms Means atoms or an aralkyl group with 7 to 20 carbon atoms, m is O or 1 and Q is a carbon atom or, if m is O, a sulfonyl group , is reacted with 4-acetamidophenol. 809850 / (5900 282405S 22. The method according to claims 14 to 21, characterized that the reaction between the mixed anhydride and 4-acetamidophenol in an anhydrous inert organic solvent is carried out. 23. The method according to claims 21 and 22, characterized in that that the reaction is carried out in the presence of a tertiary amine. 24. The method according to claims 21 to 24, characterized in that that the mixed anhydride of the general formula IX by reaction of a substituted acetic acid of the general formula II or one of its salts with a reactive organic chloride of the general Formula _ AyI- [O] -Q-Cl (X) ILL _ψ wherein AyI, m and Q have the meanings given in claim 21 have, in the presence of a base. 25. The method according to claim 24, characterized in that the reaction is carried out in an anhydrous organic solvent is carried out. 26. The method according to claim 25, characterized in that a substituted aromatic carbon is used as the solvent 8098B0 / 6 900 hydrogen or a halogenated aliphatic hydrocarbon is used. 27. The method according to claims 25 or 26, characterized in that that toluene or chloroform are used as solvents. 28. The method according to claims 24 to 27, characterized in that that a tertiary amine is used as the base. 29. The method according to claim 28, characterized in that either triethylamine or pyridine is used as the base will. 30. The method according to claims 24 to 29, characterized in that that the mixed anhydride of the general formula IX is not isolated from the reaction mixture after preparation, but in the reaction mixture is subjected to the further reaction with 4-acetamidophenol without removing the base previously used. 31. Process for the preparation of 4-acetamidophenyl-Q £ - (2-methyl-ind [en / ol] -3-yl) acetates of the general formula III, characterized in that a p-aminophenyl 809850/6900 compound of the general formula wherein A, R, Y, X and η have the meanings given in claim 1 have reacted with an acetylating agent. 32. The method according to claim 31, characterized in that acetic anhydride is used as the acetylating agent. 33. The method according to claims 31 and 32, characterized in that that the p-aminophenyl compound of the general formula XI by reducing a p-nitrophenyl compound the general formula (XII) 609850 / (5900 wherein A, R, Y, X and η have the meanings given in claim 1 have, manufactures. 34. The method according to claim 33, characterized in that nascent hydrogen is used as the reducing agent, which is produced by the action of acid on iron powder receives. 35. The method according to claims 33 and 34, characterized in that that the p-Nitropheny! compounds of the general Formula XII by reacting a compound of the general formula II or a corresponding salt with bis (4-nitropheny1) sulfite of the formula > - / Vm ₀ (XIII) in the presence of a tertiary amine as a solvent. 36. The method according to claim 35, characterized in that pyridine is used as the tertiary amine. 37. Process for the preparation of 4-acetamidophenyl-0 £ - (2-methyl-ind (en / ol3-3-yl) acetates, characterized in that 809880/6900 that 4-acetamidophenol with a solution of a symmetrical ⁰ ^ - (2-methyl-ind {en / olj-3-yl) acetic anhydride of the general formula (XIV) wherein A, R, η, X and Y have the meanings given in claim 1 have, in a water-immiscible solvent in the presence of a strong aqueous base converts, whereby the two-phase system that forms is vigorously stirred. 38. The method according to claim 37, characterized in that sodium hydroxide is used as the strong base. 39. The method according to claims 37 and 38, characterized in that that as a water-immiscible solvent benzene, toluene, chloroform, dichloromethane or Diethyl ether is used. 40. The method according to claims 37 to 39, characterized in that that the reaction at room temperature or at 809850 / Θ900 approximate room temperature, but not above 30 C,
is carried out. 41. Process according to claims 37 to 40, characterized in that the acid anhydride of the general formula
XIV is prepared by reacting a ^ C- (2-methylind [en / olJ-3-yl) acetic acid of the general formula II with a carbodiimide in an anhydrous, no hydroxyl groups containing inert organic solvents at or near room temperature. 42. The method according to claims 37 to 41, characterized in that the carbodiimide is dicyclohexyl-carbodiimide
is used. 43. p-Nitropheny! Compounds of the general formula (XII) wherein A, R, Y, X and η have the meanings given in claim 1 to have. 809850/5900 44. p-Aminopheny! Compounds of the general formula γ-LcvucrtJ wherein A, R, Y, X and η have the meanings given in claim 1 to have. 45. Pharmaceutical composition, characterized in that it contains as active ingredient one or more 4-acetamidophenyl- OC- (2-methyl-ind [en / olJ-3-yl) acetates of the general formula III in conjunction with a pharmaceutical carrier material. 46. Pharmaceutical composition according to claim 45, characterized in that it is effective as at least one Ingredient 4-acetamidophenyl-1 '- (p-chlorobenzoyl) -2'-methyl-5'-methoxy-indol-3'-yl acetate contains. 47. Pharmaceutical composition according to claims 45 and 46, characterized in that it is in the form of dosage units Contains 10 to 250 mg of the active ingredient. 809850/6900