CH557815A - Alpha- 1-acyl-3-indolyl aliphatic acid derivs - Google Patents

Abstract

Indole derivs. R1 = opt. substd. aryl, heteroaryl (opt. substd.) R2 = H, lower alkyl/alkenyl, aryl (opt. substd.), aralkyl, alkaryl, substd. alkyl R3 = H, lower alkyl/alkenyl R4 = HO, NH2 (opt. substd.) and salts, lower alkoxy, aralkoxy, OM(M=cation) R5 = H, halogen, lower alkyl/alkoxy, haloalkyl, NO2, NH2 (opt. substd.), CN, NH2CH2 (opt. alkylated on N), HS, (alkyl)2NSO2, PhCH2S. The cpds. have anti-inflammatory activity. Prevent granuloma tissue formn. Also possess useful antipyretic action.

Description

  

  
 



   The present invention relates to a process for the preparation of 3-indole-aliphatic acids of the formula
EMI1.1
 wherein
R, aryl, substituted aryl, heteroaryl or substituted heteroaryl radical,
R2 is a hydrogen atom or lower alkyl, lower alkenyl, aryl, aralkyl, alkaryl, substituted alkyl or substituted aryl radical, R3 is a hydrogen atom or lower alkyl or lower alkenyl radical, and
R5 denotes a hydrogen or halogen atom or lower alkyl, lower alkoxy, haloalkyl, nitro, amino, di-lower alkyl amino, cyano, aminomethyl, alkyl-substituted aminomethyl, mercapto, dialkylsulfonamide or benzyl-mercapto radical.



   This process is characterized in that a compound of the formula
EMI1.2
 heated with an acid anhydride of the formula (R1CO) 2O above 150 ° C. in a high-boiling inert solvent, the acylation also being accompanied by pyrolytic cleavage of the t-butyl ester group.



   For example, the process can conveniently be carried out by heating the starting material with an anhydride of the formula mentioned to 180 ° C. in camphor or a similar boiling inert solvent.



   The esters, aldehydes, acetals, alcohols and ethers are in many cases important intermediate products in the preparation of free acids according to the invention and in many cases they are just as important as the desired end products. In addition to the - (3-indolyl) acetic acids produced according to the invention, the production of the esters or salts of the abovementioned acids should also be classified under the present invention.



   The 3-indolyl acids produced according to the invention can be used to prepare amides and N-substituted amides according to conventional techniques. For example, the corresponding acid can be converted into a symmetrical anhydride in the presence of a mild dehydrating agent such as dicyclohexylcarbodiimide and then treated with ammonia, whereby the corresponding amine is obtained or is reacted with a primary or secondary amine which has the desired substituents in an inert solvent to give the corresponding substituted amides.

  In another alternative, the acid in question can be converted into a mixed anhydride in such a way that this acid is first treated with a non-hydroxy base, e.g. a tertiary alkylamine, pyridine and the like., to obtain an acid salt, and then the same with an acid halide such as. an alkyl or aryl chloroformate, phosphorus oxychloride, thionyl chloride and the like., A mixed anhydride is obtained which is then converted into the corresponding amides by treatment with ammonia, primary amines or secondary amines.

  Among the primary and secondary amines applicable here are the alkylamines such as methylamine, ethylamine, isopropylamine, butylamine, diethylamine, ethyl-sec-butylamine, diisopropylamine and the like, alkanolamines such as ethanolamine, diethanolamine, 2-amino-1 -butanol, morpholine and the like., arylamines, such as aniline, diphenylamine and the like., mixed aromatic-aliphatic amines, such as monomethylaniline, mono-ethylaniline and the like, aralkylamines, such as benzylamine, 9-phenylethylamine and the like Amines, such as p-chloroethylamine, para-chloroaniline, para-chlorobenzylamine and the like., And other substituted aliphatic or aromatic amines, such as B-methoxyethylamine, para-tolylamine,

   para-methoxyaniline and Ähal. to call. In some cases the amides can be generated directly from the intermediate products occurring in the process according to the invention.



   As mentioned above, the corresponding esters can be obtained from the 3-indolylacetic acids obtained according to the invention. For example, the corresponding acid can first be converted into symmetrical or mixed anhydrides, as described above, and then with a desired alkyl or araikyl alcohol, in the presence of a non-hydroxy containing base, e.g. with a tertiary alkylamine, pyridine and the like., Reacted, whereby the corresponding alkyl or aralkyl ester is obtained. Among the esters preferably produced are the lower alkyl esters, such as methyl, ethyl, propyl or t-butyl esters, and the aralkyl esters, such as the benzyl, p-halobenzyl and the like. Esters with fewer than 9 carbon atoms.



   The salts of these new & - (1- aroyl- or heteroaroyl-3-indolyl) acetic acids produced according to the invention can be obtained by treating the free acid with a base under mild conditions. In this way, the salts of the alkali metals, such as lithium, sodium and potassium, the aluminum or magnesium salts or the salts of the alkaline earth metals, such as barium and calcium, can be obtained. Salts of organic amines, such as alkylamine, morpholine, choline, methylcyclohexylamine or glucosamine, can be produced by reacting the acid obtained according to the invention with the corresponding organic base. The preparation of the heavy metal salts such as zinc and iron also fall within the present inventive method.



   The production according to the invention of various compounds which have a 5-substituent on the indole ring system, which substituent has a nitrogen attached to the homocyclic ring of the indole, is generally based on the use of the 5-nitro compound, which is subsequently converted into the desired t- Substituents can be converted.



  Such conversion can be accomplished in a number of ways. Reduction of the 5-nitro groups yields a 5-amino group, and reaction of the amino group with alkyl halides results in mono- and dialkylamine groups. If the alkyl halide is a dihaloalkylene group, e.g. 1,4-dibromobutane, a heterocyclic ring is formed, e.g. a pyrrolidino ring. Similarly, bis (n-chloroethyl) ether will give an N-morpholine compound. An alkylation can also take place simultaneously with the reduction, e.g. using formaldehyde and Raney nickel and hydrogen. The 5-amino compounds or the 5-nitro compounds can also be acylated at the same time, with simultaneous reduction, and give 5-acylamido compounds.

  Furthermore, the 5-amino group can be reacted with isocyanates, and 5-ureido compounds are obtained.



   The following compounds produced according to the invention are listed as representative compounds: methyl -a- (l-p-chlorobenzoyl-2-methyl-5-methoxy-3-indoi) acetate, cc- (lp-chlorobenzoyl-2,5-dimethyl -3-indolyl) acetic acid, methyl, c - (1 -p-methylthiobenzoyl-2-methyl-5-methoxy-3-indolyl) acetate, (1 -p-chlorobenzoyl-2-methyl-5-methoxy- 3 -indolyl) -propionic acid, α- (1-p-chlorobenzoyl-2-methyl-5-methoxy-3-indolyl) -acetamide, α- (1-benzoyl-2-methyl-5-methoxy-3 -indolyl) -acetamide, ethyl-?

  ; - [1- (2,4-dichlorobenzoyl) -2-methyl-5-methoxy-3-indolyl] acetate, ethyl - [1 - (2,4-dichlorobenzoyl) -2- methyl-5- methoxy-3-indolyl] -propionate, methyl-cc- [1- (2'-then-oyl) -2-methyl-5-methoxy-3-indolyl] -acetate, benzyl-α- [1- (4 '- -thiazolyl-carbonyl) -2-ethyl-5-methyl-3-indolyl acetate, benzylla- [l - (4'-thiazolyl-carbonyl) -2-ethyl-5-methyl-3-indolyl] - propionate, benzyl- [1 - (2'-furoyl) -2,

   S-dimethyl-3-indolyl- acetate, benzyl, x-P1- (2'-furoyl) -2,5-dimethyl-3-indolyl] propionic acid, propylnsc- (l-nicotinoyl-2-methyl- 5-methoxy-3-indolyl) acetate, a- (1-naphthoyl-2-methyl-5-methoxy-3-indoWi) -acetic acid, benzyl - (1-naphthoyl-2-methyl-5 -methoxy-3-indolyl) acetate, [1 - (4'-thiazolyl-carbonyl) -2-methyl-5-methoxy--3-indolylj-acetamide, α - [1- (4'-thiazolyl carbonyl) -2-methyl-5-methoxy-3-indolyl] -propionamide, methyl-ia- (1-naphthoyl-2-methyl-5-methoxy-3-indolyl) acetate, (1-p-methylthiobenzoyl -2-methyl-5-methoxy-3-indolyl) -acetic acid and 0c- (lp-methylthiobenzoyl-2-methyl-5-methoxy-3-indolyl) -acetic acid and the like.



   The a- [l-aroyl- or l-heteroaroyl) -3-indolyl] -aliphatic acid compounds and their corresponding salts, esters and amides produced according to the invention have a high degree of anti-inflammatory activity and are useful in prophylaxis and prevention the granuloma tissue formation effective. Certain of the compounds produced in accordance with the invention exhibit this activity to a high degree and are therefore useful in the treatment of arthritic and dermatological conditions and similar conditions which are sensitive to treatment with anti-inflammatory agents. In addition, these compounds produced in accordance with the invention have a useful level of antipyretic activity.

  For this purpose they will normally be administered orally in tablets or capsules, the optimal dose of course depending on the particular compound used and the type and severity of the infection being treated. Although the optimal amounts of these compounds produced according to the invention to be used in the manner described above depend on the compound used and the particular type of condition to be treated, the oral dosage levels of the preferred compounds produced according to the invention are in the range of 1.0 - 200 mg per day, which amounts are useful in monitoring arthritic conditions, depending on the potency of the specific compound used and the patient's responsiveness.



   Example I.
A mixture of 2.75 g of t-butyl-2-methyl-5-methoxyindole-3-acetate and 4.5 g of p-chlorobenzoic anhydride is heated with stirring at 180 ° to 1900 ° C. for two hours in an inert atmosphere.



   After cooling to room temperature, the mixture is then treated with 50 ml of methylene chloride. The insoluble (p-chlorobenzoic acid) is filtered and the filtrate is concentrated in vacuo. The residue is then recrystallized from t-butanol and l-p-chlorobenzoyl-2-methyl -5-methoxyindole-3-acetic acid is obtained.



   Example 2
300 ml of p-toluenesulfonic acid monohydrate are added to t-butyl-1- (p-chlorobenzoyl) -2-methyl-5-methoxyindole-3-acetate containing 0.03 moles of benzene and the mixture under reflux and with stirring in a Heated in a nitrogen atmosphere for 40 minutes. During this time, 665 ml of isobutylene develop, according to theory 672 ml. At this point the reaction mixture is diluted with 200 ml of benzene at 55-60 "C and with warm water at 60-65" C to a pH of 4-5 washed. The 60-65 "C warm benzene solution is dried over Na2SO4 and decolorized by adding 1.0 g Darco G-60, filtered while hot and concentrated to a volume of about 70-75 ml.



  The mixture is then cooled to 10 C and aged for 4-5 hours. The crude 1-chlorobenzoyl-2-methyl- <-methoxy-indole-3-acetic acid is filtered, washed twice with 5 ml of benzene petroleum ether 1: 1, then twice with 10 ml of petroleum ether and dried in vacuo at 25 ° C receives 9.7 g of the benzene solvate with F = 110-1150C.

 

   9.7 g of the crude product are dissolved in 38.8 ml of t-butanol at 70 "C. The solution is filtered and 38.8 ml of cyclohexane are added while hot at 60-70" C. The solution is then cooled to 100 ° C. and aged for 1 hour. The product is then filtered, washed twice with 4 ml of cold t-butanol: cyclohexane 1: 1 and then twice with 10 ml of petroleum ether. The product is then dried in vacuo at 80 "C under nitrogen. It has an F = 153-154" C.

 

Claims (1)

PATENT CLAIMS 1. Process for the preparation of a compound of the formula EMI2.1 wherein Rl is aryl, substituted aryl, heteroaryl or substituted heteroaryl radical, R2 is a hydrogen atom or lower alkyl, lower alkaryl, aryl, aralkyl, alkaryl, substituted alkyl or substituted aryl radical, R3 is a hydrogen atom or lower alkyl or lower alkenyl radical and R5 is a hydrogen or halogen atom or lower alkyl, lower alkoxy, haloalkyl, nitro, amino, di-lower alkyl, amino, cyano , Aminomethyl, alkyl-substituted aminomethyl, mercapto, dialkylsulfonamide or benzyl mercapto radical, characterized in that a compound of the formula: : EMI3.1 heated with an acid anhydride of the formula (R1CO) 2O above 1500C in a high-boiling inert solvent, with the acylation also a pyrolytic cleavage of the t-butyl ester group takes place. II. Use of the 3-indolylacetic acids produced with the aid of the process according to claim I for the preparation of amide derivatives, characterized in that the corresponding acid is converted into an anhydride with a dehydrating agent and then treated with ammonia or an amine. SUBCLAIMS 1. The method according to claim I for the preparation of esters of 3-indolyl-lower aliphatic acids, characterized in that the acid obtained is treated with appropriate alcohols. 2. The method according to claim I for the preparation of salts of 3-indolylacetic acids, characterized in that the acid obtained is treated with appropriate bases.