US 3271416 A
Description (OCR text may contain errors)
United States Patent 3,271,416 INDOLYIL ALIPHATIC ACIDS Tsung Y. Shem, Westfield, and Lewis H. Sarett, Princeton,
N.J., assignors to Merck & Co., line, Railway, N.J., a corporation of New Jersey No Drawing. Filed Get. 241, 19b1, Ser. No. 147,161 The portion of the term of the patent subsequent to July 20, 1982, has been disciaimed 8 Claims. (Cl. 260326.13)
This application is a continuation-in-part of our copending application, Serial No. 837,775, filed September 3, 1959, now abandoned.
This invention relates to new chemical compounds. More particularly, it relates to a new class of compounds of the indole family. Still more particularly, it is concerned with new a- (3-indolyl)-lower aliphatic acids. Still more specifically, it is concerned with a-(3-indolyl)-lower aliphatic acids having a benzyl radical attached to the nitrogen atom of the indole ring and a nitrogen or sulfur functional group in the 5 and/ or 6 position, and with salts and esters of such compounds.
For several years the management of arthritic and related conditions has been carried out with steriods such as cortisone, prednisone and the like. These substances are efficacious but suffer, in varying degrees, the disadvantage of causing certain undesirable side-effects. The non-steroidal anti-inflammatory agents known heretofore have not been entirely satisfactory since they also are prone to cause undesirable side-effects in many instances. Consequently, there has been considerable research toward the discovery of active anti-inflammatory agents which lacked such disadvantages.
In accordance with the present invention, it has been found that certain a(3-iDd01Yl)-1OW61 aliphatic acids possess anti-inflammatory activity and are effective in inhibiting or preventing formation of granuloma tissue. Certain of the compounds of the invention demonstrate a high degree of such activity and are of importance in the treatment of arthritic and dermatological disorders and of like conditions which respond to treatment with anti-inflammatory agents. Certain of them in addition exhibit strong antipyretic action.
The new a-(3-indolyl)-lower aliphatic acids described herein are also useful as sun-screening agents, and as intermediates in syntheses of substituted tryptamines and tryptamine derivatives which counteract the pressor activity of serotonin. They are also useful as intermediates in syntheses of derivatives and analogs of reserpine.
It is an object of this invention, therefore, to provide a new series of tx-(3-indolyl)-aliphatic acids. It is a further object to provide oc-(3-i11d0lYD-1OW6I aliphatic acids having a benzyl radical at the N1 position of the indole ring system and a nitrogen or sulfur functional group at the 5 and/or 6 position. It is a still further object to provide salts and esters of such acids. An additional object is provision of syntheses of these new compounds. Other objects will be apparent from the ensuing discussion of our invention.
The new compounds of this invention have the general structural formula where C is a benzyl radical, B is hydrogen, a lower alkyl or a lower alkenyl radical, B is "a hydrogen or together with B a cycloalkyl group, and M is hydroxy, hydrocarbonoxy,
3,271,416 Patented Sept. 6, 1966 0 metal, NH The sixmembered ring of the indole nucleus are substituted in the 5- and/or 6-positions by a nitrogen or sulfur functional group, and in the preferred compounds D in the above formula is hydrogen or a hydrocarbon radical containing less than nine carbon atoms. These substances may be considered as functionally substituted indoles. Alternatively, and preferably, they are described as an a-S-substituted (3-indolyl)- lower aliphatic acid having a benzyl radical. at the l-position (i.e., the nitrogen atom) of the indole nucleus. All of the compounds of our discovery have both the benzyl radical at the 1-position, the lower aliphatic acid residue at the 3-position of the indole nucleus and the nitrogen or sulfur functional groups at the 5 and/ or 6 position.
In its more narrow aspects, our invention embraces indolyl aliphatic acids having the structural formula Ra R5 and the salts, esters and amides of such acids.
The a-(3-indolyl)-aliphatic acids described herein are lower aliphatic acids such as a-(3-indolyl) derivatives of acetic, propionic, valeric, ,B-halo propionic, acrylic, 4-pentenoic acid and like acids. Thus, R is preferably hydrogen or a lower alkyl or lower alkenyl group, e.g., methyl, propyl, methylene and the like. However, if desired, R together with R may be part of a cycloalkyl substituent such as a cyclopropyl ring.
One of the hydrogen atoms in the methylene group of the N- l benzyl radical may, if desired, be replaced with a lower alkyl or a lower alkenyl group such as methyl, ethyl, propyl, allyl or vinyl radical.
The substituent at the 2-position of the indole ring nucleus in the compounds of the invention may be hydrogen or a hydrocarbon radical. In the preferred compounds, R is a hydrocarbon group having less than nine carbon atoms. This may be a lower alkyl radical such as a methyl, ethyl, propyl, butyl, isopropyl, .amyl or hexyl group, a cycloaliphatic residue such as cyclohexyl, an unsaturated aliphatic group such as allyl or vinyl, an aryl or aralkyl radical such as phenyl, benzyl or phenethyl. Alternatively, R may represent a substituted hydrocarbon of the type represented by haloalkyl, hydroxylalkyl, halophenyl, alkoXy-phenyl, benzylthioalkyl and the like. Specific examples of such substituted hydrocarbon radicals are p-methoxy-phenyl, p-chlorphenyl, benzylmercaptomethyl, fluoromet-hyl and hydroxymethyl.
The indole ring must carry a nitrogen or sulfur functional group at the 5 and/or 6 position (R and R By such groups is meant substituents having a nitrogen or sulfur atom directly attached to the indole homocyclic ring at those positions or at most one carbon removed in a side chain at those positions. Such groups include nitro, amino, lower alkylamino, bis( lower alkyl) amino such as dimethylamino, etc. lower alkanoylamino, amine oxide, cyclic amines such as N-pyrrolidinyl, N-piperazinyl, N- morpholinyl, aryl and aryl alkylamino such as anilino and N-methylanilino, aralkylamino such as benzylamino and phenethylamino, N-substituted carboxamidino such as N- phenylcarboxamidino, aminomethyl and substituted aminomethyl in which any of the above substituents has its nitrogen separated by a -CH from the indole homo- 3. cyclic ring, mercapto, alkylthio, arylthio, aralkylthio, sulfamyl, mercaptomethyl, alkylthiomethyl, arylthiomethyl, aralkylthiomethyl and the like.
Included within this invention, in addition to the 06-(1- benzyl-S-nitrogen or sulfur substituted 3-indolyl)-lower aliphatic acids themselves, are salts and esters of the free acids, and the amides thereof. As is discussed more fully hereinbelow, the esters are important intermediates in one synthesis of the free acids, and in some instances possess the physiological activity of the acids. Lower alkyl esters such as the methyl, ethyl, propyl or t-butyl compounds are preferred although others such as the benzyl, p-halobenzyl, naphthyl, phenyl and like esters are satisfactory and may be employed if desired, as may be heterocyclic esters such as the furoate and pyrazinoate or cyclic esters such as the cyclohexoate.
The salts of these a-(-indolyl)-lower aliphatic acids represent an additional, and in some cases a preferred, aspect of the invention. Many of the salts are more water soluble than the corresponding acids and esters and in many instances are more suitable physiologically than the acids. Examples of salts within the purview of the invention are those of alkali salts such as sodium, potassium, lithium, alkaline earth metals such as the barium and calcium salts, the aluminum or magnesium salts, those of organic amines such as glucosamine, morpholine, choline or diethylamine and salts of heavy metals such as zinc and iron. When such compounds are to be used as anti-inflammatory or antipyretic agents, or administered to animals for other purposes, it is of course necessary to employ a non-toxic salt. The salts are conveniently prepared in pure form from the free acid by treating the acid in solution with a base such as an alkali or alkaline earth metal hydroxide, a sulfate such as aluminum sulfate, or by exposing the acid to an anion exchange resin on the salt cycle.
In addition, the acids of Formula I above may be converted to the corresponding amides by reaction with urea. Alternatively, amides may be obtained by reacting the acid halide with ammonia or an alkylamine. When alkylamines are used, an N-alkylamide will be formed.
Representative of the new ot-(l-substituted benzyl-3- indolyl)-lower aliphatic acid compounds within the scope of our invention are the following:
a-( l-benzyl-2-methyl-5-amino-3-indolyl) -propionic acid;
oc-( l-benzyl-2-methyl-S-nitro-3-indolyl -propionic acid;
oc-( 1-benzyl-2-methyl-5 -dimethylamino-3-indolyl) -propionic acid;
a-(1-benzyl-2-methyl-5-dimethylaminomethyl-3-indolyl)- propionic acid;
a-( 1-benzyl-2-methyl-5 -dimethylamino-3-indolyl -propionic acid;
a-( 1-benZyl-2-methyl-5-N-pyrrolidinyl-3 -indolyl -propionic acid;
al-benzyl-Z-methyl-S- (4-methy1-1-piperazinyl -3 -indolyl -propionic acid;
lX-( l-benzyl-Z-methyl-S-l'-morpholinyl-3-indolyl) -propionic acid;
a-( 1-benzyl-2-methyl-5-acetamido-3 -indolyl propionic acid;
a-( 1-benzyl-2-rnethyl-5-N-methylacetamido-3 -indolyl butyric acid;
a-( 1-benzyl-2-methyl-5-N-methylanilino-3 -indolyl) -butyric acid;
a- 1 benzyl-Z-Inethyl-S-benzylami-no-3 -indolyl -acetic acid;
Ot-( l-benzyl-2-rnethyl-5-methylamin0-3-indolyl) -acetic acid;
oc- 1-benzyl-2-propyl-5 -N-phenylcarb oxamidino-B-indolyl) propionic acid;
oc-( 1-benzyl-2-ally1-5-aminomethyl-3-ind0lyl -propionic acid;
a-(1-benzyl-2-ethy1-5-N-morpholinylmethyl-3-indolyl)- acetic acid;
oc- 1-benzyl-2-rnethyl-S-acetylaminornethyl-3-indolyl propionic acid;
a-(1-benzyl-Z-methyl-5-oXidodimethylamino-3-indolyl)- acetic acid;
a-( 1-benzy1-2-methyl-5 -N,N-dimethylsulfamyl-3-indolyl) acetic acid;
a-(1-benzyl-2-phenyl-5phenylthio3 -indolyl) -acetic acid;
ac- 1-benzyl-2-phenethyl-6-phenylthio-3-indolyl -propionic acid;
OL-( 1-benzyl-2-me-thyl-6-mercapto-3-indolyl) -propionic acid;
04-- l-benzyl-2-rnethyl-6-methylthiomethyl-3 -indolyl -propionic acid;
Or.( l-benzyl-2-propyl-5mercapto-3-indolyl) -propionic acid;
a-( 1-benzyl-2-methyl-5-phenylthiomethyl-3 -indolyl -propionic acid;
o( 1-benzyl-2-methyl-5-methylthio-3 -indolyl -propionic acid;
0H( l-benzyl-2-methyl-5 -benzylthiomethy1-3-indolyl -propionic acid;
oc-( 1-benzyl-2-methyl-5-propylamino-3 -indolyl propionic acid;
a-( 1-benzyl-2-methyl-S butyrylamino-3-indolyl) -propionic acid;
a- 1-benzyl-2-methyl-5rnethylethy1amino-3-indolyl acetic acid;
a-( 1-benzyl-2-ethyl-S-u-methylbenzylamino-3 -indolyl acetic acid;
oc- 1-benZy1-5-methylthio-3-indolyl) -acetic acid;
oc-( 1-benzyl-2-methyl-5-sulfo-3-indolyl -propionic acid;
a-(1-benzyl-2-methyl-6-dimethylan1ino-3 -i-ndolyl) -propionic acid.
The salts, esters and amides of the above-mentioned free acids may be obtained by appropriate treatment of the acids.
The u-(l-benzyl-5-nitrogen or sulfur substituted-3-indolyl)-lower aliphatic acids described herein may be synthesized by various methods, the method of choice in any particular instance depending to a large extent on the nature of R According to one process, there is first prepared an a-(S-indolyD-aliphati acid, or an ester thereof, having the desired substituents at the 2, 5 and 6 positions of the indole nucleus, and this substance is then aralkylated to produce the corresponding u-(l-benzyl-3- indolyl)-lower aliphatic acid or ester. When an ester is employed, it is readily saponified to the free acid with a base such as an alkali metal hydroxide or carbonate.
The aralkylation is conducted by intimately contacting the indoyl aliphatic acid or ester thereof with the benzyl ester of a strong inorganic acid or of an organic sulfonic acid in the presence of a strongly basic condensing agent such as sodium hydride, potassium hydride, sodamide, an alkyl lithium or an alkali metal oxide, in a suitable solvent medium. The metallo derivative of the indole reactant forms firs-t, and this in turn reacts with the functionally substituted ester. Suitable benzyl esters are the chlorides, bromides, benzene-sulfonates, p-toluene-sulfonates or methanesulfonates, with benzyl chloride or bromide being preferred. The reaction medium is not unduly critical, and dimethylformamide, dimethylf-ormamide-benzene, aromatic hydrocarbons such as benzene, toluene or xylene, and lower alkanols such as methanol, ethanol, t-butanol, isopropanol, tetrahydrofuran, diphenyl ether and nitrobenzene are representative of satisfactory solvent media that may be employed. When an indolyl aliphatic acid ester is one of the reactants, it is preferred to employ essentially equimolar amounts of the ester and alkaline condensing agent, and a slight molar excess of the functionally substituted benzyl halide. However, in those cases where the free acid is aralkylated, we use two moles of condensing agent per mole of indolyl acid since an acid salt is formed in the reaction mixture.
The temperature at which the aralkylation is conducted is not critical. It is convenient to carry out the process at about room temperature, under which condition it is ordinarily substantially complete in about one hour. Longer reaction times are not harmful and may be used if desired.
This arakylation reaction may be pictured structurally in the following mannerwherein R R R R R and R are as previously defined, Y is hydrogen or lower alkyl, and X is halogen. When Y is hydrogen, a metal salt is formed under the reaction conditions.
When the compound being synthesized has a basic nitrogen or a substituent containing an active hydrogen, in the 5-position of the indole nucleus, the aralkylation in the l-position must be carried out before the basic nitrogen is present in the 5 or 6 position. This can be done while the 5 or 6 substituent is a ni-tro or similar group, followed by further transformation of the 5 or 6 substituent into the desired group. In the latter step, nitro can be reduced to amino which can be alkylated to alkyl and dialkylamino or built into heterocyclic rings (e.g. by hydroxyethylating and ring-closing the bis(hydroxy ethyl)amino intermediate. Similarly, 5 or 6 cyano compounds can be reduced and alkylated to N-substituted carboxamidino and arninomethyl derivatives. Details of such transformations are shown in the examples.
Free mercapto groups likewise will interfere with the aralkylation and should be formed after such a step or protected by conversion to an alkyl or aralkylthio group, e.g.
The indoyl aliphatic avids employed as starting material in the process discussed above, and having the formulamay be obtained in various Ways. When R is hydrogen, methyl, aryl or aralkyl it is preferred to form such compounds by reacting together an appropriately substituted phenylhydrazine (II) and a compound of Formula III to form an intermediate phenyl-hydrazone which cyclizes under the reaction conditions to the indole compound R R 3 5 R4 NHNHz i Rr-C 0112C COOY R CCOOY Re Re N Rz (III) (IV) where R R R R and Y are as above, and R is hydrogen, methyl, aryl or aralkyl.
The reaction is normally carried out in aqueous acid or in a lower alkanol such as methanol, ethanol, isopropanol or butanol containing an acid such as hydrochloric, hydrobromic, sulfuric or acetic acid. The acid serves as a catalyst in the condensation and ring-closure reactions leading to the indole Compound IV. When Compound III is an ester, the nature of the ester is not critical, although it is preferred to utilize a lower alkyl ester, e.g.., the methyl, ethyl, propyl, isobutyl or isopropyl compound. To avoid the possibility of transesterification the alcohol used as the solvent medium is preferably the same as the alcohol moiety of the ester. When R is hydrogen, it is convenient to employ the aldheyde in the form of an acetal, e.g. methyl v,v-dimethoxy butyrate. An acid addition salt of the phenylhydrazine reactant, for example the hydrochloride, is normally preferred over the free base for practical reasons, although such salts and the base are equivalent in the reaction itself.
Formation of the a-(3-indoyl)-aliphatic acid, or ester thereof, is brought about at elevated temperatures, good results being obtained by refluxing the reaction mixture for at least about 15 minutes. Longer reaction times are not harmful and may be used if desired. The desired compound is recovered from the reaction mixture and purified by techniques such as solvent extraction, chroma tography and/or distillation. Since the esters of Formula IV are generally low melting solids, they are conveniently purified by distillation under reduced pressure, and may be saponified if desired by treatment with an alkali metal hydroxide.
The substituted phenylhydrazines employed as one of the starting materials in this synthesis are prepared by known methods. One convenient method is via diazotization of the appropriately substituted aniline to give the diazo compound, treatment of the latter with stannous chloride to form a tin complex, and decomposition of this complex to the phenylhydrazine with sodium hydroxide.
Alternatively, it is possible to first produce an indole of the formula- Where R R and R have the same meaning as set forth previously, and subsequently introduce the carboxylic acid residue at the 3-position, either before or after the N-1 aralkylation step discussed above. This is accomplished by treating the indole of Formula V under Mannich reaction conditions with formaldehydedialkylamine to produce a substituted grarnine, subsequently reacting this latter compound with an alkali metal cyanide in a lower alkanol, and finally hydrolyzing with a strong base such as sodium or potassium hydroxide.
While this method of introducing the aliphatic acid residue at the 3-position after elaboration of the indole ring is, of course, generally applicable to compounds having the structure shown above, it is particularly useful for making compounds of this invention wherein R is an alkyl radical other than methyl, such as. the 2-ethyl, 2-propyl, 2-allyl and like substances.
Compounds of Formula V are readily prepared following the procedures set forth in columns 2 and 3 of US. Patent No. 2,825,734, products where R; and/ or R represent cyano or nitro being prepared via the synthesis beginning from a substituted Z-nitrobenzaldehyde or 2-nitrotoluene.
According to a further aspect of this invention, there are provided novel a-(I-benzyl-S-nitrogen or sulfur sub- 7 stituted-2,3-dihydro-3-indolyl)-loWer aliphatic acids having the general formula Ra Ra l R4 O O O H L. R6 \N/ R3 where R R R R R and R have the same values as in Formula I above. These dihydro compounds are synthesized by reacting the corresponding indole having a double bond in the 2:3 position with tin in hydrochloric acid. The reduction is carried out at elevated temperature for about 8-20 hours. Preferably, however, they are obtained by reducing the N-l unsubstituted indole ester of the formula with the metal-hydrochloric acid reducing agent to form the corresponding 2,3-dihydro compound, and aralkylating this reduced material with the functionally substituted benzyl halide by the method described above. When R is hydrogen, an alternate synthesis of the 2,3-dihydro derivatives comprises reduction of an indole of the structure- Rr- 0 C O 0 lower alkyl N II where R R R and R are as defined above, with hydrogen in the presence of Raney nickel catalyst. The resulting 2,3-dihydro compound is aralkylated as previously described. As will be understood by those skilled in the art, when R, and/ or R represent reducible groups that would be affected by the reaction conditions, they are suitably protected by known methods prior to the reduction of the indolyl 'aliphatic acid ester.
It will be appreciated that the compounds of Formula I above possess a center of asymmetry when R or R are other than hydrogen. In the syntheses described above such substances are obtained as racemic mixtures. Since the anti-inflammatory activity of our a-(1-benzyl-5 or 6-substituted-3-indolyl)-aliphatic acids is in one stereoisomer, it is sometimes desirable to resolve the racemic mixtures into their optically-active isomers and use the active stereoisomer in treating inflammatory conditions. This resolution may be accomplished using an optically-active salt of a-phenethylamine. When the 5 or 6 substituent contains a basic nitrogen, the resolution can be carried out by using as the resolving agent L-tartaric acid, D-camphorsulfonic acid or other optically-active acids and making their salts with the basic nitrogen substituent of the racemate.
Our invention can be illustrated by the following examples:
EXAMPLE 1 A. A solution of 40 g. of levulinic acid in 300 ml. of hot water is added to a solution of 65 g. of p-nitrophenylthydiazine hydrochloride in 700 ml. of hot water with stirring. After about one-half hour, the hydrazone derivative is collected in a filter, washed with water and dried at 110 in vacuo. The yield is 84 g., M.P. 175- An amount of 42 g. of the abovehydrazone is added to a solution of 120 g. of fused zinc chloride in 100 ml. of absolute ethanol and the mixture is refluxed for 18 hours. The cooled solution is poured into dilute hydrochloric acid with stirring, and the insoluble gummy material separated is extracted with hot ethanol. The ethanolic extract is evaporated in vacuo to a syrup, which is redissolved in ether. The ether solution is extracted With 10% sodium carbonate several times. Acidification of the aqueous solution gave a crude produce which recrystallizes from chloroform to give 2-methyl-(5-nitro-3-indolyl)acetic acid, M.P. 238.
The above acid is treated with a mixture of 3 g. of sulfuric acid and 40 ml. of methanol at the reflux temperature for 6 hours. The methyl ester is obtained as a yellow crystalline product, M.P. 132-40 after recrystallization from benzene.
Similarly, methyl-a-(2-methyl-5-nitro-3-indolyl) propionate is prepared by using an equivalent amount of tat-methyl levulinic acid as the starting material.
B. A solution of 5.8 g. (0.021 mole) of methyl-w (2-methyl-5-nitro-3-indolyl) propionate in 20 ml. of dimethylformamide is added dropwise to a cold suspension of 1.0 g. (0.022 mole) of sodium hydride (52% dispersion in mineral oil) and 25 ml. of dimethylformamide. The mixture is stirred at room temperature for 20 minutes, cooled and treated with 2.54 ml. (0.0222 mole) of benzyl chloride. The reaction mixture is stirred at room temperature for about 16 hours and poured into 260 ml. of ice water. The aqueous mixture is extracted with three 250-ml. portions of ether. The ether extract is washed with 100 ml. of potassium bicarbonate solution and three 100-ml. portions of water. The ether layer is dried and concentrated at reduced pressure to give 6.9 g. of crude product. Crystallization of this oil from petroleum-ether (B.P. 60-80) yields methyl a (1 benzyl-Z-methyl-S- nitro-3-indolyl) propionate.
C. A solution of 5.0 g. of methyl-a-( l-benzyl-Z-methyl- 5-nitro-3-indolyl) propionate, 16 ml. of 34% aqueous sodium hydroxide and ml. of ethanol is refluxed for 2 hours. The solution is concentrated at reduced pressure to a volume of about 25 ml. and diluted with 150 ml. of water. The aqueous solution is extracted twice with ml. portions of ether, acidified and filtered. The crystal line product thus obtained is dried and recrystallized from 20 ml. of benzene to yield u-(1-benzyl-2-methyl-5-nitro- 3-indolyl) propionic acid.
D. 0.05 M of o-(1-benzyl-2-methyl-5-nitro-3-indolyl) propionic acid in 200 ml. of ethanol is hydrogenated in the presence of 250 mg. of 10% palladium or charcoal catalyst at 40 p.s.i. at room temperature. After 0.15 M of hydrogen has been consumed, the hydrogenation is stopped, and the solution filtered to remove the catalyst. The filtrate is concentrated to dryness in vacuo to give u-(1-benzyl-2-methyl-5-amino-3-indolyl) propionic acid.
EXAMPLE 2 Ethyl-u-(I-benzyl-Z-methyl-5-amin0-3-ind0lyl) propionate A. 0.025 M of ethyl-0M1-benzyl-2-methyl-5-nitro-3- indolyl) propionate in 100 m1. of ethanol is hydrogenated in the presence of mg. of 10% palladium or charcoal catalyst at 40 p.s.i. at room temperature. After 0.075 M of hydrogen has been consumed, the hydrogenation is stopped, and the solution filtered to remove the catalyst. The filtrate is concentrated to dryness in vacuo to give ethyl 0c (l-benzyl-2-methyl-5-amino-3-indolyl) propionate.
B. The same ester is obtained when the zx-(I-bfil'lZYl-Z- methyl-5-amino-3-indolyl) propionic acid prepared in Example 1 is treated with a mixture of 3 g. of sulfuric acid and 40 ml. of ethanol at reflux for 6 hours. When the ethanol is replaced by methanol, the corresponding methyl ester is obtained as a yellow crystalline product after recrystallization from benzene.
9 EXAMPLE 3 Ethyl-ot-(1-benzyl-2-methyl-5-acetamid0-3-ind0lyl) propionate 0.01 M of the ethyl ester produced in Example 1 is added to 20 ml. of dry pyridine, and this solution is treated with 2 g. of acetic anhydride at room temperature for about 18 hours. The reaction mixture is then poured in 100 ml. of cold water. An immediate precipitate of ethyl-a41-benzyl-2-methyl-5-acetamido-3-indolyl) propionate forms which may be recovered by filtration and purified by recrystallization from ethyl acetate-benzene.
EXAMPLE 4 a-(1-bcnzyl-2-methyl-S-acetamid0-3-indolyl)-pr0pi0nic acid The ethyl ester obtained in Example 4 is converted to the free acid by refluxing 0.01 M of the ester with 200 ml. of 0.1 N sodium hydroxide in 90% ethanol for three hours. The resulting solution is concentrated to a volume of about 50 ml, diluted with 200 ml. of water and extracted with two 100-ml. portions of ether. The aqueous layer is separated and acidified with 2.5 N hydrochloric acid. The m-(1-benzyl-2-methyl-S-acetamido-S-indolyl) propionic acid which precipitates is purified by recrystallization from ethanol.
In like manner, a-(1-benzyl-2-methyl-5-p-chlorobenzamido-3-indolyl)propionic acid is prepared, via the ethyl ester, by reacting ethyl ot-(1-benzyl-2-methyl-5-amino-3 indolyl) propionate with p-chlorobenzoyl chloride.
EXAMPLE E tlzyl-w l -bcnzyl-2-methyl-5 -dimethylamin0-3-ind0lyl propionate Ethyl a (1 benzyl-2-methyl-5-dimethylamino-3-in dolyl) propionate is obtained from the corresponding S-amino compound (prepared in Example 3) by treating g. of the latter material with 20 ml. of dimethyl sulfate in solution in 100 ml. of 30% aqueous dioxane containing g. of sodium bicarbonate. The dimethyl sulfate is added over minutes to the solution. After 3 hours the solution is then brought to 7080 to decompose excess dimethyl sulfate. The solution of crude ethyl u-(lbenzyl-Z-methyl-5-dimethylamino-3-ind0lyl) propionate is carefully evaporated to dryness in vacuo.
The residue is treated with a solution of 5 g. of sodium in 300 ml. n-propyl alcohol at reflux for 18 hours. The solution is concentrated in vacuo to a small volume, diluted with water and allowed to stand at room temperature overnight. The mixture is extracted with ether and acidified to a pH of 6 to give ot-(1-benzyl-2-methyl-5- dimethylamino-3-indolyl) propionic acid.
EXAMPLE 6 Methyl-a-[l-l7enzyZ-2-methyl-5-(N-methyl-acelamido)- 3-indolyl] propionate Methyl 1 benzyl 2 methyl-5-acetamido-3-indolyl-otpropionate is added to a suspension of sodium hydride in dimethylformamide with stirring and ice-cooling. After one hour methyl iodide is added and the mixture is stirred overnight. The reaction mixture is poured into icedwater and extracted with ether. Evaporation of the ethereal solution and chromatography of the residual oil on an alumina column, using 15-25% (v./v.) ether in petroleum ether as the eluent, gives methyl l-benzyl-Z- methyl-S- N-methyl acetamido -3 -indolyl-2-propionate.
Saponification of the ester with 0.1 N sodium hydroxide in 90% aqueous ethanol at room temperature for 18 hours gives the corresponding acid.
When the methyl iodide is replaced with the equivalent amount of benzylchloride in the above procedure, the corresponding S-(N-benzylacetamido) compound is produced.
10 EXAMPLE 7 Ot-(l -benzyl-2-methyl-5-methylamin0-3-ind0lyl) propionic acid Methyl ot-(1-benzyl-2methyl-5-(N-methylacetamido)- 3-indolyl) propionate, produced in Example 6, is refluxed 8 hours in 2 N solution of NaOH in aqueous ethanol. The reaction mixture is poured into ice water and acidified to pH 6-6.5. The precipitated m-(1-benzyl-2- methyl5-methylamino-3-indolyl) propionic acid can be recrystallized from organic solvents (e.g., benzene or ether).
Similar treatment of the corresponding 5-(N-benzylacetamido) compound yields 0L-( 1 benzyl 2 methyl-5- benzylamino-3-indolyl) propionic acid.
EXAMPLE 8 ot-[1-benZyl-2-methyl-5-(N-methylanilino)-3-il1d0lyl] propionic acid A mixture of 0.05 mole of 1-benzy-l-2-methyl-5-(N- methylanilino)-3-indolyl-a-propionic acid, 20 g. of diphenyliodonium bromide in ml. of 1 N sodium hydroxide is heated under reflux for 24 hours. The solution is extracted with benzene and then neutralized carefully with 0.5 hydrochloric acid to give ot-[1-benzyl-2-methyl- S-(N-methylanilino)-3-indolyl] propionic acid, which is purified by recrystallization.
EXAMPLE 9 oz- (1-benzyl-2methyl-5-diethylamin0-3-ind0lyl) acetic acid A mixture of methyl 1-benzyl-2-methyl-5-amino-3-indolyl acetate (10 g.) and sodium bicarbonate (15 g.) is stirred in 100 ml. of 30% aqueous dioxane as 20 ml. of diethylsulfate is added during 30 minutes. After 3 hours the solution is brought to 7080 to decompose unreacted diethylsulfate, and then acidified with 6 N hydrochloric acid. The solution of crude methyl 1-benzyl-2-methyl-5- triethylammonium-3-indolyl acetate chloride is carefully evaporated in vacuo to dryness and the residue is treated with a solution of 5 g. sodium in 300 ml. n-propyl alcohol at the reflux temperature for 18 hours. The solution is concentrated in vacuo to a small volume, diluted with water and allowed to stand at room temperature overnight. The mixture is extracted once with ether and acidified to a pH of 6 to give 1-benzyl-2-methyl-5-diethylamino-3-indolyl acetic acid.
When ethylene chlorhydrin is used in place of the diethyl sulfate, the corresponding 5-bis(hydroxyethyl) amino compound is obtained.
EXAMPLE 10 otl-benzyZ-Z-methyl-5-N-pyrrolidinyl-3-ind0lyl] acetic acid The procedure of Example 9 is followed using one mole of 1,4-dibromobutane in place of the dicthylsulfate per mole of S-amino indole. The product obtained is a- (1 benzyl 2-methyl-5-N-pyrrolidinyl-3-indolyl)-acetic acid.
EXAMPLE 11 A. Methyl 06- [1 -benzyl-2-methyl-5-bis(fi-hydroxyethyl amin0-3-ind0lyl] propionate A mixture of 0.02 mole of methyl ot-(1-benzyl-2-methyl- 5-amino-3-indolyl) propionate, 0.044 mole of ethylene oxide and 300 cc. of 2 N acetic acid in dimethoxyethane is heated to for 18 hours in an autoclave. The mixture is then diluted with water and filtered to yield crude methyl a-[1-benzyl-2-methyl-5-bis(,B-hydroxyethyl)amino- 3-indolyl] propionate.
B. Methyl a-[1-benzyl-2-methyl-5-(4-melhyl-1'-piperazinyl)-3-indolyl] propionate The product of A is stirred at 0 in pyridine with two mole proportions of p-toluenesulfonyl chloride until the reaction is substantially complete. The mixture is poured into water and the -bis(p-toluenesulfonyloxyethyl)amino compound is isolated. This is dissolved in benzene and one mole proportion of methylamine is added. The mixture is refluxed for 18 hours. The mixture is poured into water containing two equivalents of sodium hydroxide and extracted with ether. Evaporation of the ether yields methyl a-[1-benzyl-2-methyl-5-(4'-methyl-1-piperazinyl)- 3-indolyl] propionate.
Either of the above products, when treated by the procedure of Example 1C, gives the corresponding free acid.
EXAMPLE 12 Methyl a-[l-benzyl-2-methyl-5-(4'-m0rph0linyl)-3- indolyl] propionate A solution of tosyl chloride (0.1 mole) in 200 ml. benzene is added dropwise with stirring to a solution of methyl al-benzyl-Z-methyl-S-bis B-hydroxyethyl) amino- 3-indolyl] priopionate (0.1 mole) and pyridine (0.3 mole) in 300 ml. benzene at room temperature over a period of one hour. The mixture is then heated under reflux for 3 hours, washed with water, dried over sodium sulfate and evaporated to a syrup. Chromatography of the syrup on an alumina column using 3050% (v./v.) ether in petroleum ether as the eluent gives methyl a-[lbenzyl-2'methyl-5-(4'-morpholinyl -3-indolyl] a-propionate.
Saponification by the procedure of Example l-C gives the corresponding acid.
EXAMPLE 13 A. Z-methyl-5-cyano-3-ina'olyl acetic acid methyl ester A solution of p-cyano phenylhydrazine (0.1 mole) and levulinic acid (0.1 mole) in 200 ml. concentrated hydrochloric acid is heated at 90 for minutes and diluted with ice Water (400 ml.). The crude product which separates is extracted with ether and chromatographed on a silica gel column to give 2-methyl-5-cyano-3-indolyl acetic acid using 20-50% (v./v.) ether and petroleum ether as the eluent.
The methyl ester is prepared by treatment with diazomethane in ether until the yellow of diazomethane persists and the mixture is evaporated.
B. Methyl a-(Z-benzyl-2-methyl-5-cyan0-3-ind0lyl) acetate Alkylation of the ester (prepared in Example l3A above) in dimethylformamide with sodium hydride and benzyl chloride, by the procedure of Example 1-B, gives methyl a-(l-benzyl-2-methyl-S-cyano-3-indolyl) acetate C. Methyl a-(1-benzyl-2-methyl-5-amin0methyl-34ndolyl) acetate The S-cyano ester prepared in Example 13-B is hydrogenated in ethanol in the presence of Raney nickel and 3 moles of anhydrous ammonia at 2000 psi. at room temperature to give, after filtration of the catalyst and evaporation of the reaction mixture, methyl x(1-benzyl-2-methyI-S-aminomethyl-3-indolyl) acetate which can be recrystalized from aqueous ethanol.
D. Methyl a-(1-benzyl-2-methyI-S-dimethylaminomethyl- 3-ind0lyl) acetate Treatment of the above a-aminomethyl indole with 2 moles of methyl iodide gives the S-dimethylaminomethyl derivative.
E. When the products of Examples 13-C and 13-D above are used in the procedure of the last paragraph of Example 5, the corresponding free acids are obtained.
EXAMPLE 14 a-[I-benzyl-Z-methyl-S-(N-phenylcarboxamidino)-3- indolyl] propionic acid A mixture of 1-benzyl-2-methyl-5-cyano-3-indolyl-2- propionic acid (3 g.) and 5 g. aniline p-toluenesulfonate is heated for one hour and 200 and the cooled melt is triturated with aqueous ethanol at pH 66.5 to give l-pbenzyl 2-methyl-5-(N-phenyl-carboxamidino)-3-indo1yla-propionic acid. It is further purified by recrystallization from aqueous ethanol as its hydrochloride.
EXAMPLE 15 a-(1-benzyl-Z-ethyl-5-nitr0-3-ind0lyl) -acetic acid A. A mixture of 5.4 ml. of 25% aqueous dimethylamine, 3 m1. of acetic acidand 2.25 ml. of 40% aqueous formaldehyde is cooled in an ice bath and added to 4.4 g. of 2-ethyl-5-nitroindole. The indole dissolves gradually and the solution is allowed to stand for 5 hours at room temperature. The addition of 25 ml. of 10% potassium hydroxide to the solution causes precipitation of a gum which is extracted into ether. The ether solution is washed with two 30-m1. portions of 1.25 N hydrochloric acid and the combined acidic extracts are neutralized and extracted with three 50-ml. portions of ether. The combined ether extracts are dried with anhydrous sodium sulfate and evaporated. The crystalline residue is recrystallized once from Skellysolve B (petroleum ether) and once from cyclohexane to give 2-ethyl-5-nitrogramine.
B. A solution of 2.0 g. of 2-ethyl-5-nitrogramine and 4.0 g. of potassium cyanide in 32 m1. of aqueous ethanol is refluxed for 68 hours. After cooling, the solution is neutralized with hydrochloric acid and concentrated under vacuum until most of the ethanol is removed. The residue is diluted with 20 ml. of water and 2.3 g. of potassium hydroxide is added. The resulting solution is refluxed 6 hours, cooled and extracted with ether. The aqueous phase is then acidified with hydrochloric acid and extracted with four 95-ml. portions of ether. The combined ether extracts are dried and evaporated to give 1.1 g. of crystalline acid. On crystallization of this residue from 20 ml. of benzene, u-(2-ethyl-5-nitro-3-indolyl)acetic acid is obtained.
C. 0.005 m. of a-(2-ethy1-5-nitro-3-indolyl)-acetic acid in 5 ml. of dimethylformamide is added to 0.01 m. of sodium hydride (dispersed in mineral oil) in 10 ml. of dimethylformamide. To the resultant sodio derivative of the acid is added 0.0055 m. of benzyl chloride. The reaction mass is stirred at room temperature for minutes, at the end of which time 50 ml. of water is added, and the u-(l-benzyl-2-ethyl-5-nitro-3-indolyl)-acetic acid recovered by drowning in water, extraction of neutral substances with ether, and acidification with hydrochloric acid.
When the procedures of Examples 2, 3, 4, 5, 6, 7, 8, 9, 10, ll, 12, 13 and 14 are followed using this product, the corresponding Z-ethyl indolyl compounds are obtained.
EXAMPLE l6 oc-( l -benzyl-2-methyl-5-nitr0-3-indolyl) -butyric acid When the procedure of Examples 1-A, 1-B, 1C is followed using ethyl a-ethyl levulinate in place of ethyl a-methyl levulinate, there is obtained successively ethyl a-(2-methyl-5-nitro-3-indolyl -butyrate, ethyl al-benzyl- 2-methyl-5-nitro-3-indolyl)-butyrate, and a-(l-benzyl-Z- methyl-5-nitro-3-indolyl)-butyric acid.
When these compounds are used in the procedures of Examples 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 and 14, the corresponding butyric acids are obtained.
The starting ethyl a-ethyl levulinate is prepared by alkylation of the sodio derivative of ethyl acetoacetate in ethanol with l m. of ethyl a-bromobutyrate, followed by hydrolysis and decarboxylation. The a-ethyl levulinic acid obtained is reesterified with 2 N ethanolic hydrogen chloride at reflux temperature for 18 hours.
EXAMPLE 17 a- (I -benzy l-2-phenyl-5-nitr0-3-ind0lyl -acetic acid A mixture of 20 g. of N -benzyl-p-nitrophenyl-hydrazine hydrochloride and 15 g. of ethyl 3-benzyl propionate in 300 ml. of 2 N ethanolic hydrogen chloride is refluxed for 3 /2 hours. The dark solution is filtered, evaporated in vacuo to a syrup, and partitioned between 300 ml. of ether and 600 ml. of Water. The ether solution is washed with sodium bicarbonate and with Water, and dried over sodium sulfate. Evaporation of the dried solution and purification of the residue by chromatography on 1 lb. of acid-Washed alumina, using ether-petroleum ether as eluent, gives ethyl ot-(1-benzyl-2-phenyl-5-nitro-3'indolyl)- acetate.
The ester is s-aponified with l N sodium hydroxide in 90% ethanol at reflux temperature for 2 hours to give ot-(1-benzyl-2-phenyl-5-nitro-3-indolyl)-acetic acid.
When these products are used in the procedures of Examples 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 and 14, the corresponding 2-phenyl indolyl compounds are obtained.
EXAMPLE 18 4.45 g. of a-(1-benzyl-2-rnethyl-5-amino-3-indolyl)- propionic acid is slurried in 12 ml. of methanol and the system purged with nitrogen. One equivalent of sodium methoxide in methanol is then added under a nitrogen atmosphere. The mixture is stirred for a few minutes and then the clear solution is concentrated to a thick syrup. 90 ml. of ethyl ether are added slowly with stirring to cause crystallization of the sodium salt of a-( 1-benzyl-2-methyl-5-amino-3-indolyl) -propionic acid. The resulting slurry is stirred for 1 hour under nitrogen and then the crystals of sodium salt are collected by filtration. They are washed With three S-ml. portions of ether and air dried.
7.4 r g. of ot-(1-benzyl-2-methyl-5-amino-3-indolyl)- propionic acid are added to 50 ml. of water which has been flushed with nitrogen. The slurry is stirred under nitrogen and 20 ml. of 1.05 N sodium hydroxide added with stirring. When a clear solution is obtained, a solution of 2.2 g. of Al (SO .l8H O in 8 ml. of Water is added with vigorous stirring. The mixture is stirred until it is homogeneous and the solid aluminum salt of a-( 1- benzyl-2-methyl-5-amino-3-indolyl)-propionic acid, is recovered by filtration and Washed with Water and with ethanol.
In a similar fashion, there may be prepared the sodium and aluminum salts as well as other salts, such as the potassium, iron and magnesium salts, of the various l-(benzyl-indolyl) aliphatic acids described in the accompanying examples.
EXAMPLE 19 ot-(1-benzyl-Z-metltyl-5-nitr0-3-ind0lyl) -acrylic acid A. 500 ml. of dry ether, 36.02 g. of triphenylphosphonium bromide and 94.36 ml. of 1.10 N n-butyl lithium are stirred for 1 hour at room temperature under nitrogen. 38 g. of ethyl a(1-benzyl-Z-methyl-S-nitro-3-indolyl)- keto acetate in 260 ml. of benzene and 500 ml. of dry ether are added, and stirring continued for 1 hour. The reaction mixture is transferred to a pressure flask and heated in a closed flask at 6570 C. for hours. The liquid is poured from the pressure flask and the gum triturated with 500 ml. of 33% benzene in ether. The solutions are combined and washed with three 500' ml. portions of Water, dried over sodium sulfate, filtered and concentrated in vacuo to a syrup. The syrup is .slurried in benzene and charged onto a 200 g. column of activated alumina. Ethyl a-(l-benzyl-2-methyl-5-nitro-3-indolyl)- acrylate is eluted by washing the column with 30% ether in petroleum ether and removing the eluting solvents by concentration.
70 m. of ethyl a-(1-benzyl2-methyl-5-nitro-3-indolyl)- acrylate and 2 ml. of ethanol containing 0.2 ml. of sodium hydroxide are refluxed under nitrogen for 1 hour. Three ml. of water are added and the solution concentrated in vacuo. Seven ml. of Water is added to the concentrate which is then washed with two 5-ml. portions of ether and acidified with 2.5 N hydrochloric acid. The resulting precipitate is recrystallized from ethanol to give substan- 14 tially pure Ot( 1-benzyl-2-methyl-5-nitro-3-i11dolyl) -acrylic acid.
When these products are used in the procedures of Examples 2, 3, 4, 5, 6, 7, 8, '9, 10, 11, 12-B and 14, the corresponding acrylic acid derivatives are obtained.
B. The starting material for the above experiment is prepared in the following manner:
19 g. of oxalyl chloride in 25 ml. of ether is added rapidly to an ice cold mixture of 35.7 g. of l-benzyl- 2-methyl-5-nitro-indole in 900 ml. of ether. The resulting mixture is stirred for 2 hours and the resulting solid recovered by filtration and Washed with cold ether. The solid material is then added to 660 ml. of ethanol and to the resulting solution is added with stirring 0.12 m. of sodium ethoxide. The resulting mixture is stirred for one hour and then poured into an equal volume of Water containing about 10 ml. of acetic acid. The solid material is removed by filtration, washed With sodium bicarbonate and water and then dried. It is recrystallized from benzene-petroleum ether to give ethyl a-(l-benzyl- 2-methyl-5-nitro3-indolyl)-keto acetate.
EXAMPLE 20 a- (I-benzyi-Z-methyl-5-nitr0-3-ind0lyl) cyclopropyl carboxylic acid 1.8 g. of ethyl ct-(1-benzyl-2-methyl-5-nitro-3-indolyl)- acrylate in 10 ml of dry tetrahydrofuran is added to 4 g. of diiodomethane, 1.25 g. of zinc-copper couple and 0.2 g. of iodine in 20 ml. of dry tetrahydrofuran. The mixture is refluxed under nitrogen with stirring for 20 hours. The reaction mixture is then filtered, the filtrate added to ice Water, and the whole extracted With three 50-ml. portions of ether. The combined ether extracts are washed with two 50-ml. portions of water, dried over sodium sulfate, filtered, and concentrated. The syrup thus obtained is poured onto a 60 g. alumina column as a slurry in benzene. Ethyl a-(1-benzyl-2-methyl-5-nitro-3-indolyl)- cyclopropyl carboxylate is collected from the column by elution with 60% ether-petroleum ether, and is hydrolyzed to the free acid without further purification.
640 mg. of ethyl a-(l--benzyl-2-methyl-5-nitro-3- indolyl)-cyclopropyl carboxylate and 20 ml. of 1 N ethanolic sodium hydroxide are refluxed for 2 hours and then poured into ice and water. The aqueous solution is Washed with two 50-ml. portions of ether and acidified with 2.5 N hydrochloric acid. The resulting precipitate of a-(1-'benzyl-2-methyl-5-nitro-3-indolyl)-cyclopropyl carboxylic acid is collected by filtration, Washed with water and dried in vacuo.
When these products are used in the procedures of Examples 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 and 14, the correspondingly substituted cyclopropane carboxylic acids are obtained.
EXAMPLE 21 A. (1-p-benzy[-2-carlJ0xyl-5-lzitr0-3-ind0lyl)-acelic acid A solution of 0.05 m. of N -(benzyl)-p-nitrophenylhydrazine hydrochloride, 0.05 m. of 'y-ketoglutaric acid and 3 ml. of BF -etherate in ml. of acetic acid is heated on a steam bath for 6 hours under nitrogen. The cooled solution is poured into 1 liter of ice Water and the precipitate collected, Washed with water, dried and recrystallized from aqueous dimethylformarnide.
B. (1 -benzyl-2-carb0xy l-5-nitr0-3-ind0lyl) -acetic acid anhydride The acid obtained above is heated in 150 ml. of acetic anhydride at the reflux temperature for 2 hours. On cool ing, (1benzyl-2-carboxyl-5-nitro-3indolyl) )-acetic acid anhydride crystallizes and is collected by filtration.
C. Ethyl-(1-benzyl-Z-czirboxyl-5-nitr0-3-ind0lyl)-acetate The anhydride obtained above is dissolved in 200 ml. of absolute ethanol at 0 C. and one equivalent of sodium ethoxide in ethanol is added dropwise at 0 C. with stirring. After stirring at room temperature for 1 hour the solution is poured into 1 liter of ice water containing a slight excess of dilute hydrochloric acid and the product is collected by filtration and recrystallized.
D. Ethyl-(1-benzyl-2-cl1lorocarbonyl-5-nitr0-3-i/zd0lyl) acetate To a solution of the above ester (0.05 m.) in 200 ml. of benzene is added dropwise a solution of 0.06 m. of thionyl chloride in 20 ml. of benzene with ice-cooling and stirring. The mixture is stirred at C. for 2 hours and at room temperature for 4 hours. The solution is evaporated in vacuo to give the corresponding acid chloride.
To a solution of 0.02 -m. of the above acid chloride in 100 ml. of dry tetrahydrofuran is added dropwise a solution of lithium tri-(tertiary-butoxy) aluminum hydride in tetrahydr-ofuran with ice-cooling and stirring. After 2 hours at 0 C. and 2 hours at room temperature, the mixture is treated with a slight excess of ethanol and then poured into 500 ml. of ice water. The product is extracted with 3 x 300 ml. of ether, washed with sodium bicarbonate and dried over sodium sulfate. Evaporation and chromatography of the residue on alumina using mixtures of 1050% ether-petroleum ether as eluent gives the aldehyde, which is purified by recrystallization from benzene-ether.
F (1bcnzy[-2-hydr0xymcthyl-5-nitr0-3-ind0lyl) -acctic acid To a solution of 0.02 m. of the above aldehyde in 200 ml. of ethanol is added 0.02 m. of sodium borohydride in 20 ml. of ethanol with ice-cooling and stirring. After 1 hour in the ice bath and 4 hours at room temperature, the solution is poured into 1 liter of water containing a slight excess of dilute hydrochloric acid and extracted with 3 x 300 ml. of ether. The ether solution is washed with sodium bicarbonate and dried over sodium sulfate. Evaporation of the solution and purification of the residue by chromatography on a silica gel column using 1050% ether in petroleum ether as eluent yields the lactone of (1-benzyl-2-hydroxymethyl-5-nitro-3-indolyl)-acetic acid.
Treatment of the lactone (0.01 m.) with 0.01 m. of sodium hydroxide in 50 ml. of 90% aqueous ethanol at room temperature for 18 hours, followed by dilution with 300 ml. of ether, affords the sodium salt of (l-benzyl-Z- hydroxymethyl-5-nitro-3-indolyl) -acetic acid.
G. (1-benzyl-2-bcnzylthi0methyl-5-nitr0-3-ind0lyl -acctic acid A solution of 0.02 m. of the above lactone and 0.025 m. of potassium benzylmercaptide in 300 ml. of ethanol is heated under reflux for 18 hours under nitrogen. The solution is concentrated in vacuo to a volume of about 100 ml. and then poured into 500 ml. of ice water containing 0.03 m. of hydrochloric acid. The oily product is extracted with 2 x 200 ml. of methylene chloride, the extracts washed with water and dried over sodium sulfate. The solution is filtered, evaporated and charged on a 1 lb. silica gel column. Elution with ether in petroleum ether removes some unchanged benzyl-mercaptan. (1 benzyl 2 benzylthiomethyl 5 nitro 3 indolyl)- acetic acid is recovered from the column with 50100% ether in petroleum ether. It is recrystallized from ethanol.
H. When the above products are used in the procedures of Examples 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 and 14, the correspondingly substituted 2-substituted-3-indolyl acetic acids are obtained.
EXAMPLE 22 al -bcnzyZ-Z-methyl-5-N,N-dimcthyl-sulfamy l-3-ind0lyl propionic acid The procedure of Example 1 is followed using an equiv- .alent quantity of ethyl-a-(2-methyl-5-N,N-dimethyl-sulfamyl-3-indolyl) propionate as the starting material in place of the S-nitro compound used there. The product is a (1 benzyl 2 methyl 5 N,N dimethyl sulfamyl-3-indolyl) propionic acid.
EXAMPLE 23 a-(Z-benzyl-2-methyl-5-methyltlti0mcthyl-3-ind0lyl) propionic acid The procedure of Example l-B and 1-C is followed using an equivalent quantity of ethyl-a-(2-methyl-5- methylthiomet'hyl-3-indolyl) propionic acid as the starting material in equivalent amounts to the S-nitro compound used in Example 1. The S-methylthiomethyl compound is prepared by reacting p-nitrobenzylchloride with sodium methylmercaptide, reducing the methyl mercaptomethylnitrobenzene with LiAli-L, to the corresponding aniline, diazotizing and reducing the diazo with stannous chloride to obtain p-methylmercaptomethylphenylhydrazine, and using this in the procedure .of Example 1A with a-methyl levulinic acid as the other reactant.
EXAMPLE 24 a-(1-benzyl-2-melhyl-6-nitr0-3-ind0lyl)-pr0pi0nic acid The procedure of Example 1 is followed using mnitrophenylhydrazine as the starting material in place of the p-nitrophenylhydrazine. The product, a-(l-benzyl- 2-rnethyl-6-nitro-3-indolyl) propionic acid, or its immediate precursor the methyl ester, when used in the procedure of Example 2, gives the corresponding 6-amino derivative. This product is acetylated by the procedure of Example 3 and the 6-acetylamido compound, when used in the procedures of Examples 4, 5, 6 and 7 result in the corresponding 6-substituted acids. The 6-amino acid, when used in the procedure of Examples 9, 10, 11 and 12, gives the corresponding 6-substituted compounds.
It is to be appreciated that the a-(1-benzyl-3-indolyl)- lower aliphatic acids of this invention vary in the degree of physiological activity which they possess, and certain of them represent preferred aspects of our discovery. Among the preferred compounds are those wherein R in Formula I is a lower alkyl radical such as methyl or ethyl and R is hydrogen or methyl. Also preferred are those having S-dialkylamino and S-dialkylamino methyl substituents, and the non-toxic salts of such acids, represent preferred aspects of the invention with respect to use in anti-inflammatory agents.
When the compounds of the invention are to be employed for treatment of the disease conditions previously referred to, they may be formulated into unit dosage forms such as tablets or capsules. For instance, tablets containing mg. of the sodium salt of a-(1-benzyl-2- methyl-5-amino-3-indolyl)-propionate and having the following composition per tablet:
Sodium-a-( l-benzyl-Z-methyl-S-amino-3-indolyl)- g propionate 100 Lactose 90 Corn starch 14 Starch-paste 10 Magnesium stearate 1 are prepared by mixing the sodium salt, lactose and 10 mg. of corn starch and grinding to a fine powder. This mixture is granulated with the starch paste and the wet mass passed through a #10 screen. It is dried at F. for about 12 hours and passed through a #20 mesh screen. Then 4 mg. of corn starch and 1 mg. of magnesium stearate are added to the resulting unmixed granulation, and the whole compressed into tablets.
Although the optimum quantities of a-(l-benzyl-S- nitrogen or sulfur substituted-3-indolyl)-lower aliphatic acid, or salt, ester or amide derivative thereof, to be used 17 in the management of arthritic and other inflammatory conditions will depend on the compound employed and the particular type of disease condition being treated, oral dose levels of the preferred compounds in the range of about 1502000 mg. per day are useful in management and control of arthritic conditions.
Any departure from the above description which conforms to the present invention is intended to be included Within the scope of the claims.
1. A compound of the formula:
in which R is selected from the group consisting of lower alkyl,
phenyl, carboxy, carboxy chloride, formyl, hydroxymethyl and benzylthiomethyl;
R is selected from the group consisting of hydrogen, lower alkyl and, together with R methylene and part of a cyclopropane ring;
R is selected from the group consisting of hydrogen and, together with R methylene and part of a cyclopropane ring;
R; is selected from the group consisting of nitro, amino, lower alkanoylamino, lower alkylamino, di(lower alkyl) amino, phenylamino, benzylamino, di(hydroxy lower alkyl)amino, N-pyrrolidinyl, N-piperazinyl, N-morpholinyl, cyano, aminomethyl, di(lower alkyl) 18 aminomethyl, N-phenyl carboxamidino, lower alkylthiomethyl and N,N-di(lower alkyl) sulfamoyl, the said R being on a position selected from the group consisting of the 5 and 6-positions; and
M is selected from the group consisting of OH, NH
and lower alkoxy. 2. a-(l-benzyl 2 methyl 5 dimethylamino-3- indolyl)-propionic acid.
3. a-(1-benzyl 2 methyl 5 dimethylamino-3- indolyl) -acetic acid.
4. a-(l-benzyl 2 methyl 5 nitro-3-indolyl)-propionic acid.
5. a-(l-benzyl 2 methyl 5 cyano 3 indolyl)- propionic acid.
6. oz(1-bnZyl 2 methyl 6 nitro 3 indolyl)- propionic acid.
7. a-(l-benzyl 2 methyl 6 dimethylamino-3- indolyl)-propionic acid.
8. a-(l-benzyl 2 methyl 5 dimethylaminomethyl- 3-indolyl)-propionic acid.
References Cited by the Examiner UNITED STATES PATENTS 2,814,625 11/1957 Specter 260-319 2,825,734 3/ 1958 Specter 260-319 2,890,223 6/1959 Whoolley et a1 260319 3,051,723 8/ 1962 Fritz 2603 19 3,074,960 1/1963 Archer 260-319 OTHER REFERENCES Bergmann, The Chemistry of Acetylene and Related Compounds, page (1948).
Lowy et al., An Introduction to Organic Chemistry, page 213 (1945).
ALEX MAZEL, Primary Examiner.
IRVING MARCUS, Examiner.
EGON E. BERG, Assistant Examiner.