CH644594A5 - 4-Acetamidophenyl alpha-(2-methyl-ind-[en/ol]-3-yl)acetates - Google Patents

Description

644 594

2nd

PATENT CLAIMS

1,4-Acetamidophenyl-a- (2-methyl-ind- [en / ol] -3-yl) acetate of the general formula III:

and the resulting compound of formula VIII, in which A, R, n, X and Y have the same meaning as in claim 1, is reacted with 4-acetamidophenol.

5. A process for the preparation of a 4-acetamidophenyl-a- (2-methyl-ind- [en / ol] -3-yl) acetate of the general formula III, characterized in that a mixed anhydride of the general formula

.nh-co - ch,

[iii]

in which

A a 3 = C.C1-. 5 = -N-, 3 = C.H- or 5 = C-SO.CH3 group, R is a fluorine atom or a methoxy group,

n is 0 or 1 and either X is a nitrogen atom and

Y represents a -CO bond or X represents a carbon atom and Y represents a = CH bond and the dashed line denotes a second C-C bond,

or their acid addition salts.

2,4-acetamidophenyl-1 '- (para-chlorobenzoyl) -2'-methyl-5'-methoxy-indole-3' -yl-acetate, 4-acetamidophenyl-1 '-isonicoti-noyl-2'-methyl-5' -methoxy-indol-3'-yl acetate, 4-acetamidophenyl-l '- (3-phenyl-acryloyl) -2'-methyl-5'-methoxy-indol-3'-yl acetate and 4- Acetamidophenyl-1 '- (para-methylsulfinyl-benzyl-den) -2'-methyl-5'-fluoro-inden-3'-yl acetate as compounds according to claim 1.

3. Process for the preparation of a 4-acetamidophenyl-a- (2-methyl-ind- [en / ol] -3-yl) acetate of the general formula III, characterized in that 4-acetamidophenol with a substituted acetic acid chloride of the general formula VIII :

20th

25th

30th

ch2_c_ci

[VIII]

45

in which A, R, n, X and Y have the same meaning as in claim 1, or an acid addition salt thereof is reacted to give the corresponding 4-acetamido-cc- (2-methyl-ind- [en / ol] -3- to form yl) acetate.

4. A process for the preparation of a 4-acetamidophenyl-a- (2-methyl-ind- [en / ol] -3-yl) acetate of the general formula III, characterized in that a solution or suspension in an anhydrous inert solvent a substituted acetic acid of the general formula II:

ch2_c_oh

[ii]

65

in which A, R, n, X and Y have the same definition as in claim 1, or a salt thereof with thionyl chloride

CH C 0_ Q [0] —Ayl n [ix]

in which A, R, n, X and Y have the same definition as in claim 1, ayl is an alkyl group having 1 to 20 carbon atoms, an alkaryl group having 7 to 20 carbon atoms or an aralkyl group having 7 to 20 carbon atoms, m 0 or 1 and Q. Carbon atom or, if m is 0, represent a sulfonyl group, is reacted with 4-acetamidophenol.

6. A process for the preparation of a 4-acetamidophenyl-a- (2-methyl-ind- [en / ol] -3-yl) acetate of the general formula III, characterized in that substituted acetic acid of the general formula II, in which the Symbols which already have the meaning given in patent claim 4, or a salt thereof with a reactive organic chloride of the general formula X:

35

Ayl [0] m - Q - Cl

[x]

40 in which Ayl, m and Q have the same definition as in claim 5, in the presence of a base and the resulting mixed anhydride of the formula IX, in which the symbols have the meaning given in claim 5, is reacted with 4-acetamidophenol.

7. A process for the preparation of a 4-acetamidophenyl-a- (2-methyl-ind- [en / ol] -3-yl) acetate of the general formula III, characterized in that a compound of the general formula XI:

[xi]

60

in which A, R, Y, X and n have the same meaning as in claim 1, with an acetylating agent.

8. A process for the preparation of a 4-acetamidophenyl-a- (2-methyl-ind- [en / ol] -3-yl) acetate of the general formula III, characterized in that a para-nitrophenol compound of the general formula XII:

644 594

12. Means for carrying out the method according to claim 7 in the form of a para-aminophenyl compound of the general formula XI, in which the symbols have the same meaning as in claim 1.

5 13. Pharmaceutical preparation, characterized in that it contains as active ingredient one or more 4-acetamidophenyl-a- (2-methyl-ind- [en / ol] -3-yl) acetates of the general formula III according to claim 1 together containing a pharmaceutical [XII] vehicle.

io

in which A, R, Y, X and n have the same meaning as in claim 1, reduced and the resulting compound of formula XI, in which the symbols have the same meaning as in claim 1, is reacted with an acetylating agent.

9. A process for the preparation of a 4-acetamidophenyl-a- (2-methyl-ind- [en / ol] -3-yl) acetate of the general formula III, characterized in that a compound of the general formula II in which the Symbols in claim 4 20

have given meaning, or a salt thereof, with bis- (4-nitrophenyl) sulfite of the formula XIII:

Analgesics are widely used today and numerous compounds of various types have been proposed and put on the market for this purpose. Among the most effective and fastest-acting analgesics currently used is 4-acetamidophenol of the structural formula:

CD

o = s

25th

30th

[XIII]

implemented and the compound of formula XII obtained further processed by the method according to claim 8.

10. A process for the preparation of 4-acetamidophenyl-a- (2-methyl-ind- [en / ol] -3-yl) acetate of the formula III, characterized in that 4-acetamidophenol with a solution in a water-immiscible Solvent of a symmetrical a- (2-methyl-ind- [en / ol] -3-yl-acetic anhydride of the general formula XIV:

35

Despite its effectiveness as an analgesic, 4-acetamido-phenol is generally not used for the treatment of chronic conditions, such as. As rheumatism and arthritis, with the exception, perhaps, occasionally to alleviate the pain, because it has no anti-inflammatory effect in addition to its analgesic effectiveness.

To facilitate chronic arthritis, rheumatism and the like, it is therefore currently common to use one of the known anti-inflammatory substituted acetic acid analgesics.

A class of existing anti-inflammatory analgesics, which is currently used very heavily, are the known substituted a- (2-methyl-ind- [en / ol] -3-yl) -acetic acids of the general formula

40

[XIV]

in which A, R, n, X and Y have the same meaning as in claim 1, is reacted in the presence of a strong aqueous base, so that the reaction mixture forms a two-phase system which is shaken to give the desired 4-acetamidophenyl-a- ( To give 2-methyl-ind- [en / ol] -3-yl) acetate.

11. A process for the preparation of a 4-acetamidophenyl-a- (2-methyl-ind- [en / ol] -3-yl) -acetate of the general formula III, characterized in that an a- (2-methyl-ind - [en / ol] -3-yl) -acetic acid of the general formula II, in which the symbols have the meaning given in claim 4, with a carbodiimide in solution in an anhydrous, hydroxyl-free and inert organic solvent at room temperature and the resulting Acid anhydride of the formula XIV further processed by the process according to claim 10.

55

60

65

(II)

in which

A is a> C.C1, S = N, S = C.H or SsC.SO.CH3 group, R is a fluorine atom or a methoxy group,

n represents 0 or 1 and either X is a nitrogen atom and

Y is a -CO bond, the dashed line has no meaning, or X is a carbon atom, Y is a = CH group and the dashed line is a further C-C bond and their normal pharmacologically acceptable salts.

The following compounds are examples of these known anti-inflammatory analgesics of general formula II:

1- (para-methylsulfinyl-benzylidene) -2-methyl-5-fluoro-inden-3-yl-acetic acid;

1- (3-phenyl-acryloyl) -2-methyl-5-methoxy-indol-3-yl-acetic acid, and l-isonicotinyl-2-methyl-5-methoxy-indol-3-yl-acetic acid.

Unfortunately, however, the desired anti-inflammatory and analgesic properties of this substituted vinegar

644 594

Acids of general formula II are affected by their tendency to cause digestive disorders. It was suspected that this was due to the acidic nature of the carboxyl function; however, this explanation is not entirely accurate since little or no reduction in this tendency occurs when these anti-inflammatory analgesics are administered in the form of salts.

It is therefore particularly surprising that it was not only possible to form an ester bond between the carboxyl group present in the substituted acetic acid of the general formula II and the hydroxy group of 4-acetamidophenol, but that the resulting esters were also largely or practically completely free are of undesirable side effects on the intestine, but nevertheless are assimilated into the body to a large extent or completely unchanged by the intestine, whereby they prove to be effective and exceptionally anti-inflammatory analgesics.

The present invention relates to new compounds with anti-inflammatory and / or analgesic activity, namely 4-acetamidophenyl-a- (2-methyl-ind- [en / ol] -3-yl) -acetates of the general formula:

x.

.CH

3rd

.NH-CO-CH.

in which A, R, n, X and Y have the same meaning as above, and their acid addition salts.

Specifically preferred 4-acetamidophenyl-a- (2-methyl-ind- [en / ol] -3-yl) acetates of the present invention, which fall under the general formula III, are for example:

4-acetamidophenyl-1 '- (para-chlorobenzoyl) -2'-methyl-5'-methoxy-indol-3'-yl acetate of the formula:

co.

.egg

N,

ch.

'3

NH-CO-CH.

CH, 0

4-acetamidophenyl-l'-isonicotinyl-2'-methyl-5'-methoxy-indol-3'-yl acetate of the formula:

co cu cn.-c-o.

■ NIl-CO-CII

CI-I.0-

4-acetamidophenyl-1 '- (3-phenyl-acryloyl) -2'-methyl-5'-methoxy-indol-3'-yl acetate of the formula:

CO-CII = CII.

, N,

CH

3rd

IH-CO-CH.

CH ^ O

(vi)

and

4-acetamidophenyl-1 '- (para-methyl-sulfinyl-benzylidene) -2'-methyl-5'-fluoro-inden-3'-yl acetate of the formula:

CH

CH

.CI!, - C-0-

NH-CO-CH.

(vii)

All of the acid addition salts of the compounds of Formula III are useful for preparative purposes, but the salts should be formed with pharmacologically acceptable acids for pharmaceutical applications. There are a large number of pharmacologically acceptable acids with which the acid addition salts can be formed. These can include, for example, hydrochloric acid, hydrobromic acid, acetic acid, methanesulfonic acid, tartaric acid, succinic acid, phosphoric acid and sulfuric acid.

It was also found that the 4-acetmidophenyl-a- (2-methylind- [en / ol] -3-yl) acetates of the general formula III can be prepared in a convenient manner and in good yields by reacting 4 Acetamidophenol with the corresponding substituted acetic acid chloride.

Another object of the present invention is therefore a process for the preparation of 4-acetamidophenyl-a- (2-methyl-ind- [en / ol] -3-yl) acetates of the general formula III, in which 4-acetamidophenol of the general Formula I with a substituted acetic acid chloride of the general formula:

Y- / CH = CII /

CH

X,

3rd

CH2-C -Cl in which A, R, n, X and Y have the same meaning as above, or an acid addition salt thereof, is reacted to give the desired corresponding 4-acetamidophenyl-cx- (2-methyl-ind- [en / ol ] -3-yl) acetate of the general formula III to give.

The reaction between 3-acetamidophenol and the acid chloride of the general formula VIII is advantageously carried out in an anhydrous inert solvent. The inert solvent is usually an organic solvent and advantageously a substituted aromatic hydrocarbon such as toluene, one of the many halogenated aroma4

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60

65

table solvent, an aliphatic hydrocarbon, a halogenated aliphatic hydrocarbon such as chloroform, or an ether such as diethyl ether.

Since the reaction is fairly lively, it can be carried out at room temperature without heating, or, if the reaction is very lively, which occasionally occurs, even with cooling.

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

The process according to the invention can advantageously comprise the precursor for the preparation of the substituted acid chloride starting material of the general formula VIII by reacting a solution and / or suspension of a substituted acetic acid of the general formula II or a salt thereof, in an anhydrous inert solvent with thionyl chloride.

If a salt of the substituted acetic acid of the general formula II is used, this is preferably the pyridine salt.

The reaction with thionyl chloride can be carried out at any suitable temperature between room temperature and the reflux temperature of the solvent; It is usually carried out at a temperature in the range between approximately 40 ° C. and approximately 65 ° C.

The solvent used in the reaction is advantageously the same as that used in the subsequent step described above. Usually it is an organic solvent and preferably a substituted aromatic hydrocarbon such as toluene, one of the many halogenated aromatic solvents, an aliphatic hydrocarbon, a halogenated aliphatic hydrocarbon such as chloroform or dichloromethane, or an ether such as diethyl ether.

Preferably the solvent used is anhydrous dichloromethane and the reaction is then best carried out under reflux at a temperature of about 41 ° C. The proportions of the reactants preferably correspond to about 1 mole of thionyl chloride per mole of the substituted acetic acid of the general formula II.

It has proven advantageous to carry out the reaction 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.

Another object of the invention is a further process for the preparation of 4-acetamidophenyl-a- (2-methyl-ind- [en / ol] -3-yl) acetates of the general formula III, in which a mixed anhydride of the general formula :

x.

, CH

3rd

in which A, R, n, X and Y have the same meaning as above, ayl 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 an aralkyl group with 7 to 20 Carbon atoms, m 0 or 1 and Q represent a carbon atom or, if m is 0, a sulfinyl group, is reacted with 4-acetamidophenol of the formula I to give the desired corresponding 4-acetamidophenyl-a- (2-methyl-ind- [ en / ol] -3-yl) acetate of the general formula III to form.

644 594

The reaction between the mixed anhydride of general formula IX and 4-acetamidophenol can and should preferably be carried out in an aqueous inert solvent, and this solvent is preferably an organic solvent as described in connection with the first method.

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

The mixed anhydride of the general formula IX is prepared by reacting a substituted acetic acid of the general formula II or a salt thereof with a reactive organic chloride of the general formula:

0

r- II

Ayi / oym-Q-ci cx)

in which Ayl, m and Q have the same meaning as above, in the presence of a base, to give the corresponding mixed anhydride of the general formula IX.

The reactive organic chloride of the general formula X can be, for example:

(a) an alkyl, aralkyl, aryl or alkaryl chloroformate of the general formula

0 -

II

AylO-C-Cl (xa)

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

0

Ayl-Ü-Cl (Xb)

or

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

0. o

Ayl-S-Cl (Xc)

in which, as in the general formula IX, ayl denotes an alkyl, aralkyl, aryl or alkaryl group with up to 20 carbon atoms.

The reaction between the substituted acetic acid of general formula II and the reactive chloride of general formula X (or Xa, b or c) is conveniently carried out in an anhydrous solvent, and this is preferably an organic solvent, as described above in connection with the subsequent step described the procedure.

The reaction must be carried out in the presence of a base which is advantageously a tertiary amine and preferably either triethylamine or pyridine.

It is unnecessary to isolate the mixed anhydride of the general formula IX from the reaction mixture in which it is obtained. The solution of the mixed anhydride obtained, which is obtained in the first stage of the process, can advantageously be subjected to the second stage of the process in the same reaction mixture without eliminating the base and in the same reaction vessel.

Another object of the invention is yet another process for the preparation of 4-acetamidophenyl-a- (2-methyl-ind- [en / ol] -3-yl) acetates of the general formula III, in which a para-aminophenyl compound of general formula

5

5

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20th

25th

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55

60

65

644 594

R ^

(xi)

Y- £ CU = CllJ

10th

(XIV)

in which A, R, n, X and Y have the same meaning as above, is reacted with an acetylating agent to give the desired 4-acetamidophenyl-a- (2-methyl-ind / en / ol-3-yl) acetate to give general formula III. 15

This acetylation can be done with any suitable acetylating agent, e.g. B. with acetic anhydride.

The para-aminophenyl compound of general formula XI can be conveniently prepared by using a para-nitrophenyl compound of general formula 20

Y- / CII-CII7n- ^ A

25th

30th

(XII)

in which A, R, n, X and Y have the meanings given above, reduced to obtain the corresponding para-aminophenyl compound of the general formula XI.

The reduction of the para-nitrophenyl compound of general formula XII can best be done using nascent hydrogen, e.g. produced using iron powder and an acid. The acid is advantageously hot acetic acid.

The para-nitrophenyl compound of the general formula XII can in turn be prepared by reacting a substituted acetic acid of the general formula II or a salt thereof with bis- (4-nitrophenyl) -su! Fit of the formula

35

40

45

in which A, R, n, X and Y have the same meaning as above, in the presence of a strong aqueous base, so that the reaction mixture forms a two-phase system which is shaken to give the desired 4-alkyl-3,5-dioxopyrazole to give -dinyl-a- (2-methyl-ind- [en / ol] -3-yl) acetate.

The reaction between 4-acetamidophenol and the acid anhydride of the general formula XIV generates the corresponding a- (2-methyl-ind- [en / ol] -3-yl) -acetic acid as a by-product and must therefore be carried out in the presence of a strong base, which can be an organic base, such as triethylamine, but preferably aqueous sodium hydroxide. The anhydride is somewhat unstable in the presence of water and is therefore in solution in a water-immiscible solvent and preferably an anhydrous inert organic solvent, e.g. B. benzene, toluene, chloroform, dichloromethane or ether, such as diethyl ether, brought to reaction. The reaction is carried out with stirring in a two-phase reaction system, thereby minimizing any disintegration of the anhydride before it has participated in the intended reaction. This reaction can advantageously be carried out at room temperature or approximately room temperature not above 30 ° C.

This fourth method can also advantageously include the further precursor for the preparation of the acid anhydride of the general formula XIV by reacting a- (2-methyl-ind- [en / ol] -3-yl) acetic acid of the general formula II with a carbodiimide in solution in an anhydrous, hydroxyl group-free and otherwise inert organic solvent at room temperature or near room temperature, usually not above 30 ° C.

In principle, any carbodiimide can be used, but in practice the carbodiimide used must be stable and therefore the most suitable carbodiimide is an N, N'-di- [alk / ar] -yI-carbodiimide of the general formula:

0 = s

50

(XIII) 55

The reaction between the substituted acetic acid of the general formula II and the bis- (4-nitrophenyl) sulfite of the formula XIII is advantageously carried out in solution in a tertiary amine, preferably pyridine, and at room temperature or approximately room temperature.

Yet another object of the present invention is a fourth process for the preparation of 4-acetamidophenyl-a- (2-methyl-ind- [en / ol] -3-yl) acetates of the general formula III, in which 4-acetamidophenol is the Formula I with a solution in a water-immiscible solvent of a symmetrical a- (2-methyl-ind- [en / ol] -3-yl) acetic anhydride

-N II

C.

II

■ N

(XV)

60

65

general formula:

in which Z 'and Z "each represents an alkyl, cycloalkyl, alkaryl, aryl or aralkyl group with 6 to 20 carbon atoms. It must also be mentioned that currently the only carbodiimide commercially available, at least in Great Britain, with an acceptable price N , N'-dicyclohexyl-carbodimide, which is therefore preferably used in this invention.

The substituted acetic acid chloride of the general formula VIII, the mixed anhydride of the general formula IX and the symmetrical anhydride of the general formula XIV are described in British patent application no. 23 260/77. The para-nitrophenyl compound of the general formula XII and the para-aminophenyl compound of the general formula XI are new compounds, and the present invention provides these compounds per se. The invention also extends to the end products of the general formula III, prepared according to • one of the procedures described here.

The 4-acetamidophenyl-a- (2-methyl-ind- [en / ol] -3-yl) acetates of the general formula III and in particular the preferred compounds of the formulas IV to VII appear to have excellent anti-inflammatory and analgesic activity if they be tested for generally accepted tests for anti-inflammatory drugs; the preliminary investigations indicate that these compounds, administered orally, are practically free of side effects in the stomach.

For use in human and veterinary medicine as anti-inflammatory analgesics, however, the 4-acetamidophenyl-a- (2-methyl-ind- [en / ol] -3-yl) acetates of the general formula III should of course first be added corresponding pharmaceutical preparations are processed by combination with suitable pharmaceutical vehicles.

The term "pharmaceutical" is used here to rule out any possibility that the nature of the vehicle (considered, of course, with reference to the mode of administration) could be harmful. The selection of a suitable vehicle for each selected mode of administration and form of presentation lies in the component of the person skilled in the art.

The present invention further relates to pharmaceutical preparations which, as an active ingredient, contain one or more 4-acetamidophenyl-a- (2-methyl-ind- [en / ol] -3-yl) acetates of the general formula III together with a pharmaceutical Vehicle included.

Although the preparations of the present invention are primarily intended for administration via the digestive tract, including rectal administration, they can also be administered parenterally. The preparations are preferably administered orally, including perlingual administration. With respect to these different types of preparations, the pharmaceutical vehicle is preferably:

(a) the ingestible excipient of a tablet, a coated tablet, a sublingual tablet or pill; the ingestible container of a capsule or cache; the ingestible powdery solid carrier of a powder or the ingestible liquid medium of a syrup, a solution, a suspension or an elixir;

(b) the solid or liquid medium of a paste, lotion, ointment, balm or cream or the propellant of an aerosol;

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

(c) the basis of a suppository.

The forms of presentation mentioned above are the most used, but they do not exhaust all possibilities.

The anti-inflammatory analgesics of general formula III, according to the present invention, including the preferred compounds of formulas IV, V, VI and VII, are most often administered in the form of tablets, capsules and other solid dosage forms.

As a general indication, although the dosage of the anti-inflammatory analgesics of the general formula III depends to a certain extent on the route of administration and of course also on the disease to be treated, the useful dose can be between 30 mg and 750 mg (in divided doses) of the active analgesic per day for an adult, with a unit dose usually containing 10 to 250 mg and preferably about 50 mg.

The following examples and preparations explain some aspects of the present invention and in particular various preparations and recipes for the new 4-acetamido-phenyl-a- (2-methyl-ind- [en / ol] -3-yl) acetates of the formulas IV , V, VI and VII.

example 1

Preparation of 4-acetamidophenyl-1 '- (para-chlorobenzoyl) -2'-methyl-5'-methoxy-indol-3'-yl acetate of the formula IV

644 594

Level A:

A solution of 6.0 g of thionyl chloride in 10 ml of dichloromethane slowly became a stirred solution of 7.9 g of l- (para-chlorobenzoyl) -2-methyl-5-methoxy-indol-3-yl-acetic acid and 4.8 g Added pyridine in 80 ml dichloromethane. The red solution obtained was heated under reflux for 15 minutes and contained 1- (para-chlorobenzoyl) -2-methyl-5-methoxy-indol-3-yl-acetyl chloride, which, however, was not isolated for the present purpose. When this compound is isolated for characterization, the acid chloride is found to have a melting point of 107 to 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 the refluxed solution from Step A. This mixture was then refluxed for 10 minutes, cooled, washed twice with 2M hydrochloric acid and once with 20% sodium carbonate solution and then dried over magnesium sulfate.

Concentration of the dichloromethane solution under reduced pressure gave a yellow solid which crystallized from aqueous acetone in the form of cream-colored needles; Yield 11.6 g, 48%; Melting point 198 to 199 ° C.

Example 2

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

Level A:

Preparation of the para-nitrophenyl ester

A solution of 10 g bis- (4-nitrophenyl) sulfite in 60 ml pyridine became a solution of 4.0 g l- (para-chlorobenzoyl) -2-methyl-5-methoxy-indol-3-yl-acetic acid added in 50 ml of pyridine. The mixture was left at room temperature overnight under a nitrogen atmosphere and then concentrated under reduced pressure.

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

Concentration of the ethyl acetate solution gave a yellow solid which was triturated with 50 ml ether and filtered. In this way a yield of 5.0 g (93%) of the para-nitrophenyl ester of melting point 153 to 154 ° C. was obtained, which was sufficiently pure to be used in the next step without further purification.

Level B:

Preparation of the 4-acetamidophenyl ester

A solution of 1.0 g para-nitro-phenyl-1 '- (para-chlorobenzoyl) -2'-methyl-5'-methoxy-indol-3'-yl acetate in 100 ml of ethyl acetate was made under hydrogen under two atmospheres Shaken pressure with 500 mg of 5% palladized carbon catalyst for 5 h.

The catalyst was filtered off through a bed of Celite and the ethyl acetate solution was concentrated under reduced pressure. 2 ml of acetic anhydride was added to the remaining oil and, after the exothermic reaction was complete, chloroform was added until the entire contents of the flask were in solution.

The chloroform was removed under reduced pressure and the remaining oil was triturated with 50 ml of ether and filtered quickly. The addition of a small amount of petroleum ether (40 to 60 °) led to the crystallization of 4-acetamidophenyl-l '- (para-

7

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644 594

chlorbenzoyl) -2'-methyl-5'-methoxy-indol-3'-yl-acetatin Form cream-colored needles. Yield: 0.75 g. The product was found to be identical to the sample obtained from the acid chloride in Example 1.

Example 3 5

Preparation of 4-acetamidophenyl-1 '- (para-chlorobenzoyl) -2'-methyl-5'-methoxy-indol-3'-yl acetate of the formula IV

A mixture of 3.58 g of l- (para-chlorobenzoyl) -2-methyl-5-methoxy-indol-3-yl-acetic acid and 1.9 g of para-toluenesulfonyl-10 chloride in 20 ml of dichloromethane was stirred and slowly added Treated 1.01 g of triethylamine in 5 ml of dichloromethane and stirred for a further 10 min.

A solution of 1.51 g of 4-acetamidophenol and 1.0 g of pyridine in 30 ml of dichloromethane was then added and the 15th

The mixture was heated at reflux for 10 min and then cooled to room temperature. The dichloromethane solution was washed first with 2M hydrochloric acid, then with 20% sodium carbonate solution and dried over magnesium sulfate.

Concentration of the dichloromethane solution under reduced pressure gave a yellow solid which crystallized from aqueous acetone in the form of cream-colored needles. Yield: 3.51 g, 71%. This product was found to be identical to the sample obtained from the acid chloride in Example 1.

25th

Example 4

Preparation of 4-acetamidophenyl-1 '- (para-methylsulfinyl-benzylidene) -2'-methyl-5'-fluorinden-3'-yl acetate of the formula VII. A mixture of 1.1 g of triethylamine and 10 ml of dichloromethane was slowly added added to a stirred mixture of 3.56 g of l- (para-methylsulfinyl-benzylidene) -2-methyl-5-fluoro-inden-3-yl-acetic acid and 1.91 g of para-toluenesulfonyl chloride in 50 ml of dichloromethane. After 10 minutes, 1.51 g of 4-acetamidophenol and 1.0 g of pyridine in dichloromethane were added and the mixture was refluxed for 3 minutes for 10 minutes and then cooled. The dichloromethane solution was washed with 50 ml of 2M hydrochloric acid and twice with 50 ml of 20% aqueous sodium carbonate solution and then dried over magnesium sulfate. Concentration of the dichloromethane solution under reduced pressure gave an oil which could not be crystallized. Thin layer chromatography showed that the oil contained the substituted acetic acid used as the starting material, the desired product of formula VII and three components which ran against the solvent front. 4J The oil was chromatographed over 110 g of silica gel and eluted first with chloroform and then with a mixture of 95: 5 chloroform / methanol. The formula VII product thus obtained was contaminated with starting acid, but this could be removed by redissolving in chloroform and washing with 20% aqueous sodium carbonate solution. The desired product was crystallized from acetone-petroleum ether (40:60) in the form of small, lime-colored needles; Yield: 0.5 g; Melting point: 230 to 233 ° C.

Example 5 55

Preparation of 4-acetamidophenyl-1 '- (para-chlorobenzoyl) -2'-methyl-5'-methoxy-indol-3-yl acetate (IV)

Level A: 60

Preparation of the symmetrical anhydride of l- (para-chloro-benzoyl) -2-methyl-5-methoxy-indol-3-yl-acetic acid

16.5 g (0.08 mol) of N, N'-dicyclohexyl-carbodiimide became a solution of 28.62 g (0.08 mol) of l- (para-chlorobenzoyl) -2-methyl-5-methoxy-indole -3-yl-acetic acid in 150 ml of tetrahydro 65 furan added. The resulting mixture was left to stand at room temperature overnight. It was then filtered and the filtrate was evaporated to dryness and the residue taken up in ethanol and recrystallized to give 6.5 g of the desired 2-acetoxy-benzoic anhydride.

Level B:

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

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

Recipe I:

Preparation in the form of tablets A tablet mixture was prepared by intimately mixing the following components:

4-acetamidophenyl-l '- (para-chlorobenzoyl) -2'-methyl-5'-

methoxy-indole-3'-yl acetate 143 g spray-dried lactose 286 g

Dicalcium phosphate 563 g

Magnesium stearate 8 g LÖÖÖi

The mixture was then compressed into 350 mg tablets in a conventional tablet machine, each 50 mg of 4-acetamidophenyl-1 '- (para-chlorobenzoyl) -2'-methyl-5'-methoxy-indol-3'-yl- contained acetate.

Recipe II:

Capsule preparation A mixture was prepared by intimately mixing the following ingredients:

4-Acetamidophenyl-1 '- (para-chlorobenzoyl) -2'-methyl-5'-methoxy-indol-3'-yl acetate 250 g

LactoseB.P. 360g

Corn starch 375 g

Magnesium stearate 15 g LÖÖÜg

The mixture was then filled into capsules in an amount of 200 mg per capsule, corresponding to 50 mg of 4-acetamodophenyl-1 '- (para-chlorobenzoyl) -2'-methyl-5'-methoxy-indol-3'-yl -acetate per capsule.

50

Recipe HI:

Preparation in the form of injectable suspensions 4-acetamidophenyl-1 '- (para-chlorobenzoyl) -2'-methyl-5'-methoxy-indol-3'-yl acetate 5.00% (w / v)

"Polysorbate 80" 0.15% (w / v)

Thiomersal 0.005% (w / v)

Sodium chloride 0.33% (w / v ol)

Sodium phosphate 1.00% (w / v)

Phosphoric acid . qs to pH 6.0 to 7.0

Water for injections at 100% (w / v)

The isotonic injection vehicle was prepared using 90% water. The 4-acetamidophenyl-1 '- (para-chlorobenzoyl) -2'-methyl-5' -methoxy-indole-3 '-yl-acetate was dispersed in the vehicle and, if necessary, the pH was adjusted using phosphoric acid. The suspension was made up to the final volume.

The whole was sterilized in an autoclave. After sterilization, the product was filled into pre-sterilized multi-dose ampoules using an aseptic transition.

Recipe IV:

Preparation in the form of suppositories 4-acetamidophenyl-1 '- (para-chlorobenzoyl) -2' -methyl-5 '-methoxy-indol-3'-yl acetate 250 g

Suppository base 777.5 g

1027.5 g

The suppository base was melted in a jacketed pan. The 4-acetamidophenyl-1 '- (para-chlorobenzoyl) -2'-methyl-5' -methoxy-indole-3 '-yl-acetate was added to the molten base in finely divided form and the mixture was stirred until the ester was evenly dispersed. The mixture was then poured into 2 g molds, allowed to solidify and then removed from the mold.

The 2 g suppositories contained 500 mg of 4-acetamidophenyl-r- (para-chlorobenzoyl) -2'-methyl-5'-methoxy-indol-3'-yI acetate and 1555 mg of the base.

Finally, certain studies are described below with reference to a preferred 4-acetamido-dophenyl-a- (2-methyl-ind- [en / ol] -3-yl) acetate of the present invention, showing the absence of undesirable side effects is evident in the compounds according to the invention, as is their excellent anti-inflammatory and / or analgesic activity.

Investigation of the Stability of the Compounds In order to examine the stability of the 4-acetamidophenyl-a- (2-methyl-ind- [en / ol] -3-yl) acetates of the present invention in the gastrointestinal tract, simulated gastric and intestinal fluids prepared as follows:

Preparation of simulated gastric fluid 2 g of sodium chloride were mixed with 7.0 ml of concentrated hydrochloric acid and the mixture was then brought to a volume of 1000 ml with distilled water, giving a simulated gastric fluid with a pH of about 1.2.

Preparation of simulated intestinal fluid 6.8 g of monobasic potassium phosphate were dissolved in 250 ml of water and a mixture of 190 ml of 0.2M sodium hydroxide solution and 400 ml of water was added to this solution. The pH of the solution obtained was adjusted to 7.5 with 0.2M sodium hydroxide and the solution was then brought to 1000 ml with distilled water, which gave a simulated intestinal fluid.

Test methods 100 mg of the 4-acetamidophenyl-a- (2-methyl-ind- [en / ol] -3-yl) -acetate investigated were suspended in 5 ml of the simulated liquids and shaken at 37 ° C. for 16 h. The mixture was then left to stand and the supernatant liquid was placed on silicon dioxide thin-layer chromatography plates and developed in 90:10 chloroform / methanol. The mixture was then extracted with 5 ml of chloroform and the chloroform-containing mixture was filtered through phase-separating papers which only allow passage of the chloroform solution. The chloroform solution was also placed on silica thin layer chromatography plates and developed in 90:10 chloroform / methanol.

The results of this procedure, performed for both the simulated gastric and simulated intestinal fluids, show that negligible decomposition in both fluids644 594

occur. This indicates that all 4-acetamidophenyl-a- (2-methyl-ind- [en / ol] -3-yl) acetates that have been investigated are largely or completely free from interfering influences in the gastrointestinal tract. Are tract when administered orally.

Examination of gastric tolerance in rats

Since gastric intolerance is the major problem with the oral administration of the class of compounds that have analgesic and anti-inflammatory properties, the therapeutic index (or factor) of such compounds is best demonstrated through the gastric tolerance test in rats.

Accordingly, one of the preferred and essentially typical compounds of the present invention, namely 4-acetamidophenyl-l '- (para-chlorobenzoyl) -2'-methyl-5'-methoxy-indol-3'-yl acetate (compound IV) tested for acute (4 h) gastric tolerance in rats following oral administration in two different dose ranges,

while at the same time with a lower (but equimolar)

The amount of the two gastrointestinal irritant anti-inflammatory drugs which form the sections of the analgesic ester examined here was compared.

So that the tests could be carried out under conditions which allow the differences between the new ones

Connections and the known connections as comparison

reproducible and unmistakably observable,

the effect of the reference remedies depending on their dose was also determined in a series of preliminary tests,

which made it possible to set up suitable doses before the investigation of the compounds according to the invention began.

Test procedure

Groups of 10 male rats (Charles River, 180 to 250 g body weight) were fasted overnight and until they were killed (about 21 hours). The remedies were administered orally in the form of a suspension in 1% gum tragacanth. 4 hours after the administration, the animals were sacrificed by cutting their throats and bleeding out; then the stomachs were removed, opened, carefully washed with saline, and nailed flat on a board for examination.

During the examination, superficial mucosal bleeding was classified in order of increasing severity according to its size and number as follows: needle tips, spots or larger zones. Bleeding injuries that penetrate the mucous membrane (submucosal lesions) were considered ulcers and were also classified according to their size and number in terms of severity as follows: spots (1 to 2 mm in size) and crevices (with a longitudinal dimension). Perforations were not usually observed.

The animals were then ranked according to the most severe symptoms, with the ulcers (submucosal lesions) generally considered to be heavier than mucosal bleeding (superficial). Control animals regularly showed a certain degree of «hyperemia», which actually corresponds to a congestive state of the vessels at the moment of killing and not to an existing functional hyperemia. It was therefore not considered a sign of gastric irritation.

Statistical comparisons between specific groups were made using the Mann and Whitney U-test, based on the graded severity of the observations. The results, summarized as a percentage of the rats which had either mucosal (superficial) bleeding alone or submucosal (penetrating) lesions (ulcers) together with mucosal bleeding, are shown in simplified form in Table I.

9

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

644 594

10th

Table I

substance

Dose mg / kg

Number of used

Rats

Number of normal

Stomachs

Number of rats with gastric lesions

Bleeding * ulcer * lesions (mucous (submucos) total skin)

U-test control group

U-test versus connection B

Control group Compound B Compound IV

7

9.6

8 8 8

8 1 6

3 + 3 2

1

0% 87% 25%

P <0.003 NS

P <0.007

Control group Compound B Compound IV

10 13.7

8 8 8

7 5

1

2 + 1 + 1 2 + 1

4th

12% 100% 37%

P <0.001 MS

P = 0.001

Compound B = 1- (para-chorbzoyl) -2-methyl-5-methoxy-indol-3-yl-acetic acid

Compound IV = 4-acetamidophenyl-1 '- (para-chlorobenzoyl) -2'-methyl-5'-methoxy-indol-3'-yl acetate

* The position of the numbers from left to right in the "Bleeding", "Ulcer" columns refers to the increasing strength of the specified symptoms.

The results summarized in Table I show that Compound IV, i.e. H. 4-Acetamidophenyl-l '- (para-chlorobenzoyl) -2'-methyl-5'-methoxy-indol-3'-yl acetate, compared to 25 l- (para-chlorobenzoyl) -2-methyl-5 -methoxy-indol-3-yl-acetic acid has a significantly improved tolerance due to the gastric mucosa. A comparison with the gastric effect of 5 mg / kg l- (para-chlorobenzoyl) -2-methyl-5-methoxy-indol-3-yl-acetic acid suggests that the gastric tolerance, on a 30 molar basis, more than doubles is.

Investigation of the desired pharmacological effects

Three tests are commonly used to test the efficacy of analgesic and anti-inflammatory drugs, and all three have been used to study compound IV and l- (para-chlorobenzoyl) -2-methyl-5-methoxy-indol-3-yl- acetic acid (Compound B). In all of these tests,

which are described in more detail below, the groups of rats used consisted of 10 animals each. 40

1) Adjuvant arthritis test (inclined sieve, included screen)

Rats

Adjuvant diseases were induced in various groups of rats. 45

If adjuvant arthritis is produced in rats (usually with mycobacterial adjuvant), the adjuvant will produce inflamed lesions on parts of the body distant from the injection site after a period of 10-15 days; however, the inflammation began to subside on the thirtieth day.

One group was left untreated as control animals; other groups were treated by oral administration once a day for 18 days with various amounts of the parent compound, namely Compound B, which was used as the standard of comparison, and the compound to be tested, namely Compound IV. The compound was in each case given to the rats in solution in 1 part polyoxyethylene oleic acid glyceride, which was made up to 5 parts with 1% aqueous gum tragacanth solution, to which 1% ethanol was added, if necessary, to make up the 60 solution accomplish, administered. The amount of this solvent vehicle administered was usually 5 ml per kg of rat. The same vehicle (but without the active ingredient) was also administered to the control group of the rats.

The treatment was continued for 18 days, during which time the rats were examined at intervals using the usual “included screen test”. This test judges50

65

shares the rat's grip ability by placing it on a wire screen, which is then tilted to an angle of 90 ° from horizontal to vertical and, if necessary, significantly above. The angle at which the examined rat loses grip and falls off the screen is recorded. If all other conditions are the same, it can be concluded that the greater the angle of inclination at which the rat falls off the screen, the stronger its grip on it, and therefore the less it is affected by the arthritis-like adjuvant disease has been; or maybe a little more precisely, the greater the pain relief of the disease due to the compound examined.

A group of rats serving as controls received only the vehicle in an appropriate amount per day from day 0 to 18 (17 doses). A second group of rats received 1 mg / kg per day of Compound B for 18 days. A third group received 2 mg / kg per day of compound B. A fourth group of rats received 2.7 mg / kg of compound IV. The molar equivalent of a dose of 2.7 mg / kg of compound IV is a dose of approximately 2 mg / kg compound B; if the former proves to be better than the second, its use is therefore appropriate.

The results thus obtained are shown graphically in Figure 1 of the accompanying drawing, in which the line of progressive destruction of the circular function expressed by the angle of inclination of the sieve against time is shown for each of the various compounds examined and for the controls. Note that the observations continued after the eighteenth day.

From Fig. 1 it can be concluded that the compound IV, when examined in an amount of 2.7 mg / kg, is practically equally active, but is perhaps slightly less than half the molar amount of compound B in the gripping function test. There were no deaths in the treated rats.

2) Adjuvant arthritis test (body weight) in rats

The experimental detection of unknown side effects is more difficult than the detection of stomach inflammation; however, their presence can be assumed due to the decrease in body weight. To ensure,

The body weights of the rats suffering from the experimentally produced adjuvant disease • were determined daily and the average weights of that the results obtained in the "included screen test" were not impaired by other side effects of the compound examined

11 644 594

each group of rats in FIG. 2 of the enclosed drawing IV became as active as Vi of the molar amount of the compound

gene recorded. dung B.

From Fig. 2 it can be seen that Compound IV is active in its systemic effects on body weight 4) Randall-Selitto test in rats is half the molar amount (or slightly less) of 5 Using the usual techniques compound B. various compounds tested, as identified below,

administered orally to the rats in each group except

3) Antipyretic test against yeast induced hyperthermia in a control group that received only the vehicle and 30 min

Rats later injected each of the rats' yeast into a hind paw. Using the usual procedure, groups were inoculated with yeast to assess the effect of treatment on the pain threshold of rats. Immediately after the injection check, pressure was applied to the injected hind paw and various doses of Compound IV and other non-injected hind paw were applied. Oral pain relief B to various groups of rats other than the threshold was recorded as the pressure at which control group which received only the vehicle was administered. the rat twitched; the readings, from each rat, were taken as

The body temperature of all rats was carefully compared to the pain threshold pressure for the non- pain threshold pressure for the injected awakening during 8 hours after oral administration of the investigated paw.

connection. The results are expressed graphically in Figure 3 of the injected hind paw.

attached drawing. Compound IV was tested. These pain threshold percentages were tested at 5.5 mg / kg intervals. Compound B was determined at 3, 5, 7 and 24 hours after the injection. The molar amount of 4 mg / kg and the semi-molar amount of 2 20 results of this and the other tests are in Table II

mg / kg tested. As can be seen from the drawing, the connection is compiled below.

Table II

Randall-Selitto test in rats (<î 150 to 170 g)

Pain threshold: percentage of non-inflamed other paw statistics: t-test versus control group

Time after administration of yeast or after administration of the test compound

Substance and dose 3 h

(3/2 h)

Control group: 49 ± 2.1 gum tragacanth

Compound B: 58 ± 4.0 2 mg / kg

Compound B: 64 ± 3.6

4 mg / kg P <0.01

Compound IV: 65 ± 5.0

5.5 mg / kg P <0.05

From Table II it can be seen that Compound IV was examined at 5.5 mg / kg per day and compared with Bmit4mg / kg per day. Based on the results thus obtained, it appears to have the same analgesic effect as Compound B in these molar equivalent doses in this test.

5 h 7 h 24 h (5/2 h) (TA h)

50 ± 3.7 46 ± 3.4 48 ± 4.5

61 ± 5.8 74 ± 3.4 52 ± 3.3 P <0.001

60 + 4.7 65 ± 5.8 60 ± 3.6 P <0.02

71 ± 4.7 63 ± 5.4 49 ± 3.7 PCO, 01 PCO, 02

Determination of the therapeutic index From the relative gastric tolerances, which can be seen from Table I, and the relative anti-inflammatory activities, which can be derived from Fig. 1, it is possible to determine the relative separation of the anti-inflammatory activity and the gastric toxicity of the compound IV in Derive comparison to compound B as shown in Table III.

Table III

Substance reference preparation, Relative Relative gastric Relative harmlessness with which the substance anti-inflammatory toxicity (b) is compared relative to the reference preparation Effectiveness (a) Activity of relative gastric toxicity

Compound IV Compound B <'A molar <' A molar ~ 1

(a) Rat adjuvant arthritis: 17 daily oral doses

(b) Acute (4 h, single oral dose) gastric tolerance in rats

It can therefore be seen that Compound IV is at least as effective (compared on a molar basis), but that it is good as Compound B in terms of its analgesic only a quarter of the activity on a molar basis as an antipyretic

644 594 12

cum and only half of the activity on a molar basis than the remaining compounds of the present invention

anti-inflammatory compound. The important one has not been examined in detail so far, but phar-

However, the point is the lack of gastric toxicity. Though her preliminary macological studies suggest that qualitatively similar analgesic effects may only be as good as that of the results with the other compounds as those

Compound B, Compound IV has a gastric tolerance 5 above for 4-acetamidophenyl-r- (para-chlorobenzoyl) -2'-methyl-

which is greater than twice the molar amount of 5'-methoxy-indole-3 '-yl acetate reported. Compound B.

M

2 sheets of drawings