IL30369A - Aralkylthioamino acids,their preparation and pharmaceutical compositions containing them - Google Patents

Description

7Π33Π , i -t'DKi'n 'p'ysTK mxsin jnis o'^aon ninpn 'B3ni Aralkylthioamino acida, their preparation and pharmaceutical compositions containing them MERCK & CO., INC. 30369/2 2 This invention relates to certain 0-aralkyl- 3 thio-substituted-a-araino acids and their corresponding 4 esters and amides. 8 More 9 particularly, the invention relates to mono, di and 0 tri aralkyl) thio-substituted-a-amino acids and their 1 derivatives and to their pharmaceutical preparations. 2 Still more particularly, this invention is concerned in animals 3 with a method of treating inflammation/with compounds 14 ; of the following general formula: wherein R may be hydrogen, mercapto, cyano, lower alkyl- 16 sulfonyl (methylsulfonyl , propyl∑;ulfonyl) , trifl oroacetyl, j•il .'l.i.;i.o <'i; iiJkylo.irbnmyl (dimoth lcnr- 22 bumyl, othylbutylcarbamyl) , hydroxy, huioyon (cUloro, 23 bromo, fluoro) , lower alkylthio (mobhylthio, propylthio, b U iuli a) , i,c>wetf olkoxy (mevfchox , ethoxy, butoxy, - ia_ 30369/2 pentoxy) , anisyl, phenyl, nitre-, phenethyl, lower ethyl, propyl, pentyl) , methylene . N-lower alkylanilino (N-methyl, N-propyl, N-butyl) , lower alk lphenyl (methylphenyl, propylphenyl, pentylphenyl) , phenoxy or amino.

The substituent may be attached to any one or more of the available positions of a phenyl or naphthyl moiety.

R_ may be hydroxy, lower alkoxy (methoxy, ethoxy, butoxy) , lower alkenyloxy (prop-2-enoxy, but- 3-enoxy) , lower alkynyloxy (prop-l-ynoxy, .pent-2-ynOxy) , cyclopropylmethyloxy , lower alkoxy lower alkoxy (methoxymethoxy, ethoxypropoxy, methoxybutoxy) , polylowoag lltOKy lower alkoit —(ouoh ao the polyalkyl ofehogft dorivod from sorbitol, mannitol oar othor cugar alooholo oontaining up to 6 oarbon atoroG in tho baoio chain) , dilower alkylamino lower alkoxy (dimethylaminoethoxy, dipropylaminopropoxy) , piperidino lower alkoxy (such as ethoxy, propoxy, pentoxy), 1-pyrrolidinyl lower alkoxy (such as ethoxy, propoxy, pentoxy) , morpholino lower alkoxy (such as ethoxy, propoxy, pentoxy) , 1-lower alkyl-2-pyrrolidinyl lower alkoxy (such as the methyl- methoxy, eth l-propoxy, pr.opyl-ethoxy or methyl-butoxy . radicals) , 1-lower alkyl-2-piperidinyl lower alkoxy (such as the methyl-methoxy, ethyl-propoxy, propyl- ethoxy or methyl-butoxy radicals), N ' -lower alk l-N- piperazinyl lower alkoxy (such as the methyl-methoxy ethyl-propoxy, propyl-ethoxy or methyl-butoxy radicals) , phenoxy, p-lower alkanoylamino phenoxy (acetamido phenoxy) , phenyl lower alkoxy (phenylmethoxy , phenyl-ethoxy, 2-phenylpropoxy) , carbamyl phenoxy, lower alkoxyphenyl lower alkoxy (such as the methoxy-ethoxy, ethoxy-propoxy or ethoxy-ethoxy substituents) , phenyl lower alkenyloxy (such as phenyl ethylenoxy, phenyl prop-2-enoxy) , tetrahydrofurfuryloxy, dilower alkylamino cyclohexyloxy (3-dimethylamino-cyclohexyloxy, 2-ethylbutylamino-cyclohexyloxy) , amino, lower alkylamino (meth lamino, propylamino, butylamino) , dilower alkylamino (methylethylamino, ethylpropylamino, dimethyl-amino) , glucosamino, glycosylamino, lower alkenylamino (prop-2-enamino, but-3-enamino) , phenyl lower alkylamino (phenethylamino, phenyl propylamino) , haloanilino (chloroanilino, bromoanilino) , (1-lower alkyl piperi-dinyl-2) -lower alkylamino (such as the methyl-methyl, methyl-ethyl, propyl-propyl groups of this radical) , tetrahydrofurfurylamino, 1,2,5,6-tetrahydropyridino, morpholino, ' -lower alkyl-N-piperazinyl (N-methyl, N-propyl, N-butyl) , piperazino, N-phenyl piperazino, piperidino, benzylamino, anilino, lower alkoxyanilino (ethoxy, propoxy, butoxy) , cyclo lower alkylamino (cyclobutylamino, cyclohexylamino) , pyrrolidine, N-hydroxy lower alkyl piperazino (N-hydroxymethyl, N-hydroxypropyl, N-hydroxypentyl) , Ν,Ν-dilower alkyl carbamyl lower alkylamino (such as dimethyl, methyl-ethyl, propylbutyl for the dilower alkyl, and methyl, ethyl, butyl, pentyl for the lower alkyl) , N,N-dilower alkylamino lower alkylamino (such as dimethyl, methyl- 30369/2 '· ethyl, propylbutyl for the dilower alkyl, and methyl, ethyl, butyl, pentyl for the lower alkyl) , 1-lower alkyl pyrrolidino-2-lower. alkylawino (such as methyl, ethyl, propyl, butyl for the lowor alkyl groups) , N-carbobenzyloxy lower alkylamino (such as methyl, ethyl, butyl for the lower alkyl); 2.may also include ; metal ·■ . · / · 0Z where Z is a/cation (such as iron, aluminum, magnesium, potassium, sodium, and the like) and the symmetrical anhydrides of the acids. and may be hydrogen, lower alkyl (methyl, ethyl, propyl, pentyl, butyl) or phenyl.

R, may be hydrogen, lower alkyl (methyl, propyl, pentyl, butyl) or phenyl.

R. and R_ ,may be hydrogen, lower alkyl (methyl, 1 lofjer alkanoylj I propyl, pentyl butyl) ,/ phenyl o guanyl when R,. is ! hydrogen. .. ■ ■ g and may be hydrogen, lower alkyl (methyl, propyl, butyl), 1 phenyl,' naphthyl, thienyl, pyridyl or a substituted phenyl and naphthyl in which the substituents may be and that Rg and Rg may be the same or different.

The novel compounds of this invention have the general formula A, where the various definitions are as shown above with the exception of ithose compounds in whichJ 30369/2 Rg and Rg , are eac a phenyl group and each of R,- R^, ^ R^, ^ and R-. is hydrogen; or R is hydrogen or a inono-alkox , nono-nitro, mono-halo, or mono-alkenyi s bstituent and each of R^, R-j, R^, ^, R^., Rg and g is hydrogen; or One of g and R is phenyl or 4-methoxy-phenyl and the other is hydrogen, R is hydrogen or a methoxy group in the 4-position and each of ^ R^, R^, R^ and R-. is hydrogen or One of Rg and R is 3,4-diinethoxyphenyl and the other is hydrogen, R represents two methoxy groups in the 3- and 4-positions, R2 is hydroxy and each of R^, R^, ^ ' , and Rc is hydrogen; or One of. ^ and R_. is a.lkanoyl and the other is hydrogen and each of R, R. , R,, R' R, and R' is hydrogen. 30369/2 In its more preferred aspects, this invention is directed to the compounds of this invention as shown above in formula A, and have the following particularly preferred substituents : R may be hydrogen, halogen, trifluoromethyl, methyl- thio, trifluoroacetyl, dimethylcarbamyl or methoxy; may be hydrogen, methyl or phenyl; R2 may be hydroxy, ethoxy, or 0M where M is a pharma- - . ceutically acceptable metal ion such as sodium, magnesium, calcium, aluminum, copper, zinc or choline; R3 and R^ may be hydrogen, methyl or phenyl; ^ and ^ may be' hydrogen, methyl or guanyl; and Rg and Rg may be hydrogen, phenyl, naphthyl or sub- stituted phenyl, and g and g may be the same or different. ■ The most preferred aspects of this invention are directed to compounds of formula A where: R may be hydrogen or halogen; -^ may be hydrogen or methyl 2 is hydroxy; ' - > R3, ^, R^ and R,. are hydrogen; and Rfi and RI may be hydrogen, phenyl, naphthyl or halo- phenyl, provided that at least one of R, R^, R^, R^, R^ and Rj. is other than hydrogen when Rg and Rg are both phenyl.

Representative compounds of this invention are as follows: S- (3 , 4-dichlorobenzyl) -L-cysteine S- (3 , 4-dichlorobenzyl) -a-methylcysteine S- (3 , 4-dichlorobenzyl) -a-phenylcysteine S- ( 4 , 4-dichloro) -trity1-L-cysteine S-tris (4-fluorophenyl)methy1-L-cysteine S-tris (m-fluorophenyl) methyl-p-ethyl-DL-^cysteine S-tris (m-fluorophenyl) methyl-p-ethyl-a-phenyl-DL-cysteine S- (p-chlorophenyldiphenylmethyl) -L-cysteine S- (a-naphthyldiphenylmethyl) -L-cysteine S- (p-chlorophenyldiphenylmethyl) -L-cysteineamide S- (p-chlorophenyldiphenylmethyl) -L-cysteine methyl ester S- (2 '-thienyldiphenylmethyl) -L-cysteine S- ( 4 ' -pyridyldiphenylmethy1) -L-cysteine S- (a-naphthylphenylmethyl) -L-cysteine It has been found that compounds of the above structure have a high degree of anti-inflairanatory activity and are effective in the prevention and inhibition of delayed hypersensitivity. The compounds of this invention possess a favorable degree of activity and are of value in the treatment of arthritic and dermatological disorders which are responsive to treatment with anti-inflairanatory agents. For these purposes, the compounds may be administered in tablets or capsules, or other pharma-ceutical preparations, the optimum dose depending upon the activity of the particular compound used and the 30369/2 1 severity and type of infection being treated. Although 2 the optimum dose will depend upon the particular compound 3 and the particular disease being treated, oral dose 4 levels of 10-5000 mg. per day may be usefully employed -but dose levels of 50-1000 mg. are generally preferred.

Preferably a dosage unit will comprise from 5 to 500 mg of the active a-amine acid compound.

(, The a-amino acid compounds of this invention 7 may also be employed in pharmaceutical preparations with 8 various salicylates, such as aspirin. These preparations 9 may .contain 0.1-8.0 gms. of aspirin and 0.5-10.0 gms. of the a-amino acid compound. Preferably, these prepara- 11 tions may contain ca. 250 mg. of the a-amino acid 12 compound and ca. 300 mg. of aspirin, together with 13 excipients. These excipients may be, for example, inert 14 diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulat- 16 ing and disintegrating agents, for example, maize . 17 starch or alginic acid; binding agents, for example, 18 starch, gelatin or acacin; and lubricating agents, for 19 example, magnesium stearate, stearic acid, or talc.

The anti-rheumatic property of penicillamine .21 has been described in the literature. The mechanism of (22. action is still not fully understood. According to 23 A. Lorber [Nature, 210, 1235 (June 18, 1966)3, chelation 24 with divalent metals, such as copper, and participation of the free sulfhydryl group in an exchange dissociation 26 with disulfide linked immune globulins in vivo are two 27 possible modes of action. It is well-known that a free - 28 sulfhydryl group is generally preferred than thioethers 29 as metal complexing ligands and thioethers are incapable of forming disulfide bonds in vivo. Thus, it was unexpected to find that a number of aralkyl thioethers, which are not known to form sulfhydryl metabolites in vivo, actually possess superior anti-rheumatic activities than that of penicillamine.

Accordingly, this invention is directed to novel aralkyl thioethers as well as known aralkyl thio-ethers which possess this unexpected anti-inflammatory property.

The compounds of this invention exist as racemates or their optically active -1 or +d form. For the purposes of this invention, the compounds may be employed as their racemates or optically active forms. Detailed Description The a-amino acids of the present invention are conveniently prepared by the following methods.

Method I From the corresponding g-aminonitriles a-Aminonitriles may be hydrolyzed to the desired free a-amino acids. This reaction may be carried out by any well-known hydrolysis reaction for nitriles, for example, with an acid in the presence of water (preferably a mineral acid) at elevated temperatures (preferably at or near the reflux temperature of the system.) Any acid, both organic or inorganic, which is soluble in water may be used. Representative acids of this class are hydrochloric, sulfuric, and the like. The following equation illustrates this method of preparation: where R, R^, R3 R^ 4, 5 g and Rg are as previously defined.

Method II From the corresponding hydantoin compound Hydrolysis of hydantoin compounds under well- known conditions to a-amino acids, is effected by various reagents in acid or basic mediums. Treatment with most alkali or alkaline earth hydroxides or strong acids, using mild reaction conditions, will afford the desired products. The following equation illustrates this method of preparation: where R, ^, R3, R^, Rg and R are as previously defined and R^ and R^ are hydrogen.

Method III From an a-substituted benzylmercaptan Reaction of an a-.substituted benzylmercaptan with the proper halo a-amino propionic acid at elevated temperatures, preferably at or near the reflux tempera- ture of the system, in a solvent (preferably a polar solvent such as DMF, liquid ammonia, etc) . The follow- where R, R^, R3, R^, R4, R5, Rg and R are as previously defined, and X is halogen.

Method IV From an g-substituted benzyl halide Reaction of an a-substituted benzyl halide with the proper cysteine at elevated temperatures/ preferably at or near the reflux temperature of the system, in a solvent (preferably a polar solvent such as DMP, liquid ammonia, etc.). The following equation illustrates this method of preparation: where R, R1# R3, R^, 4, ¾, Rg and Rg are as previously defined, and X is halogen.

A general method for making a-tris (aryl) thio- substituted-a-amino acids is to condense an appropriate triaryl alcohol with β-mercapto-a-amino acids directly in the presence of a Lewis acid such as BF^ etherate in glacial acetic acid at elevated temperatures.

A convenient method for preparing an R^-a-di- methyl amino acid is by reaction of the corresponding a-amino compound with formaldehyde in the presence of / hydrogen over palladium. Alternatively, when an R,-a-alkylamino acid is desired, another suitable process is the reaction of an appropriate a-amino acid with ammonia and sodium and a trace of ferric chloride. The product thus formed is treated with p-toluenesulfonyl chloride to form an a-toluenesulfonyl amino acid compound. This compound is then reacted with a base and an alkyl halide, followed by sodium and ammonia and an appropriate arylmethyl halide to form the desired a-amino acid final compound with the appropriate a-alkyl substituent.

The racemates may be converted to their -1 or +d form by any conventional method, such as forming a salt of the racemic amino acid with an optically active base or acid such as a-phenethylamine or tartaric acid. These optically active salts may be separated by frac-tional crystallization and converted back to the optically active a-amino acid by treatment with acid or base.

A general method of synthesis particularly use-ful in making the optically active isomers of the a-amino acids is the reductive transamination of an a-keto acid with an optically active amine. This procedure is more fully described in J. Org. Chem. 32, 1790-1794 (1967) . Further, the method described may also be used to prepare the racemic a-amino acid by reductive transamination of an a-keto acid with ammonia. The method described in the above-stated article employs palladium-on-charcoal as the reducing agent; however, it is to be understood that other chemical reducing agents may similarly be employed.

The starting materials used in these foregoing methods can be conveniently prepared by the following FLOW SHEET where R, R^ R3, R^, R4, R5# and R are as previously defined; R? is a lower alkyl, preferably methyl; and X is The reaction conditions for these process steps are as follows: Step (1) - reaction with hydrogen sulfide in the presence of an alkali or alkali earth hydrosulfide (preferably sodium hydrosulfide) in an inert solvent (preferably lower alkanols) at elevated temperatures, preferably at or near the reflux temperature of the system; Step (2) - reaction with sodium in a lower alkanol followed by addition of a halo acetal of the formula preferably a chloro acetal where ^ is methyl, and re-action at elevated temperatures (preferably at or near the reflux temperature of the solvent) ; Step (3) - hydrolysis, by any well-known methods for the conversion of acetals to their corresponding aldehydes.

For example, reaction with a mineral acid (i.e. HC1, H2S0^) at elevated temperatures (preferably at or near the reflux temperature of the systems; ^ of compound IV thus formed must be hydrogen.

Step (4) - same as Step (2) , using equivalent amounts of ketones of the formula in place of the acetal, where X is a halogen (preferably chloro) and R^ is as defined above, but other than hydrogen. Step (5) - reaction by the well-known Strecker reaction, alkali cyanide and ammonia, lower alkylamines (ethyl- amine, butylamine and the like) , dilower alkylamino (dimethylamine, ethylpropylamine and the like) , phenyl- amine, or phenyl lower alkylamines (phenethylamine, phenyl-methylamine) at any suitable temperature, preferably at or near room temperature; Step (6) - reaction under the well-known conditions for preparing a hydantoin compound from the corresponding aldehyde or ketone; for example, reaction in an inert solvent such as lower alkanols with a mixture of an alkali cyanide and ammonium carbonate at elevated temperatures.

The trityl carbinols are easily prepared by hydrolysis of the corresponding halo compounds with water or dilute bases following conventional techniques. The mono-, di- and triarylmethyl halides and the halo and mercapto cysteines are known.

The intormodiato compoundo III; IV# V and VI are now compoundc and an additional aspect of this invention.

The desired a-amino acid esters may be directly prepared from the nitrile by using the proper alcohol in place of water in Method I. For example, if ethyl alcohol were used, the a-amino acid ethyl ester would be obtained. Furthermore, if desired, the corresponding primary amide may be obtained directly from the corresponding nitrile by carrying out the hydrolysis in water at temperatures at or below room temperature.

Alternatively, the desired esters or amides of this invention may be obtained by esterification of the corresponding free acid using the appropriate alcohol to obtain the desired ester moiety or by amidation of the ester compound with the appropriate amine to obtain the desired amide moiety. Any well-known reaction conditions may be used to prepare these esters or amides such as reaction of the a-amino acid with alcohol in the presence of the mineral acid at elevated temperature or reaction of an a-amino acid ester (such as an alkyl ester) with ammonia or an appropriate R2 amine at temperatures at or below room temperature.

Desired esters and amides of this invention may further be prepared directly by methods III and IV.

Another convenient method for preparing an a-dimethylamino ester or amide is by reaction of the corresponding a-amino compound with formaldehyde in the presence of hydrogen over palladium as the a-dimethyl-amino acid is prepared.

The a-guanidino amino acid compounds of this invention may be prepared by reacting the appropriate a-amino acid compound with S-methylisothiourea sulfate in the presence of ammonia.

The following examples are given by way of illustration.

Example 1 Tri- (m-fluorophenyl) methyl mercaptan To a solution of sodium hydrosulfide prepared by saturating with hydrogen sulfide at room temperature, a solution of 1.15 grams (0.05 mole) sodium in 200 cc. isopropanol is added with cooling 0.05 mole of chloro-tris (m-fluorophenyl) methane. The reaction mixture is stirred at room temperature overnight while hydrogen sulfide is slowly bubbled through it at a slow rate.

The reaction mixture is heated to reflux for 15 minutes, cooled, poured into water and extracted well with chloroform. The combined chloroform extracts are washed well with water, dried over sodium sulfate, and con-centrated. Chromatography of the residue on 1500 grams of silica gel and elution with ether-petroleum ether (0-80%) gives tris- (m-fluorophenyl) methyl mercaptan.

(A) When the triarylmethyl halides of Table I below are used in place of chlorotris (m-fluorophenyl) -methane in the above example, the corresponding triaryl-methyl mercaptans are obtained.

Table I ~¾io chlorobis ( 5-chloro-2-methylrooroaptophenyl) henyl methane thio chlorobis (o-methylmoroaptophenyl) phenyl methane thio . chlorobis (p-methylmGrcaptophenyl) phenyl methane chloro (2, 4-dimethoxyphenyl) diphenyl methane chlorodiphenyl (p-tolylphenyl) methane thio chloro (p-methylmoroaptophenyl) diphenyl methane thio chlorotris ( 5-chloro-2-methylmeroaptopheny1) methane thio chlorotris [o- (ethylmoroapto) -phenyl] methane chlorotris (2-methyl-p-anisyl) methane thio chlorotris o-meth linoiroa to hen l) methane thio chlorotris (p-methylntercaptophenyl) methane chlorotris (p-phenylphenyl) methane chlorobis (2 , 4-dimethoxyphenyl) phenyl methane chlorobis (p-nitrophenyl) phenyl methane chloro (p-chlorophenyl) diphenyl methane chloro (a-naphthyl) diphenyl methane chloro (β-naphthyl) diphenyl methane chloro (2 ' -thienyl) diphenyl methane chloro (4 ' -pyridyl) diphenyl methane chlorodiphenyl (phenylphenyl) methane chloro (p-nitrophenyl) diphenyl methane chloro (o-phenethylphenyl) diphenyl methane chlorotris (p-ethylphenyl) methane chlorotris (p-isobutylphenyl) methane chlorotris [p- (p-phenoxyanilino) phenyl] methane chlorotris [p- (p-phenylanilino) henyl] methane thio chlorotris [p- (p-phenylmoroaptoanilino) phenyl] methane chlorotris (p-propylphenyl) methane bis (p-bromophenyl) chloro (p-chlorophenyl) methane bis (p-bromophenyl) chlorophenyl methane bis (p-sec-butylphenyl) chlorophenyl methane bis (p-tert-butylphenyl) chlorophenyl methane bis (p-tert-butylphenyl) chloro-m (and o) -tolyl methane bis (p-tert-butylphenyl) chloro-p-tolyl methane bromo (o-methoxyphenyl) - (p-methoxyphenyl) phenyl methane bromo (4-methoxy-m-tolyl) diphenyl methane bromo (m-nitrophenyl) diphenyl methane (m-bromophenyl) -bis (p-tert-butylphenyl) chloro methane (o-bromophenyl) chlorodiphenyl methane bromotris (4-biphenylyl) methane bromotris (4 · -methyl-4-biphenylyl) methane chlorobis (m-chlorophenyl) phenyl methane chlorobis (p-chlorophenyl) phenyl methane chlorobis (p-diphenylaminophenyl) phenyl methane chlorobis (m-fluorophenyl) phenyl methane chlorobis (p-fluorophenyl) phenyl methane chlorobis (o-methoxyphenyl) phenyl methane chlorobis (N-methylanilinophenyl) phenyl methane chloro (m-chlorophenyl) diphenyl methane chloro (o-chlorophenyl) diphenyl methane chloro-p-cumyldiphenyl methane chloro-p-cumyl (p-ethylphenyl) p-tolyl methane chloro (p-dimethylaminophenyl) - (p-diphenylaminophenyl) - phenyl methane chloro (p-dimethylaminophenyl) - (p-N-methylanilinophenyl) - phenyl methane chlorodiphenyl (p-propylphenyl) methane chlorodiphenyl-m-tolyl methane chlorodiphenyl-o-tolyl methane chlorodiphenyl-2, 5-xylyl methane chloro (o-ethylphenyl) diphenyl methane chloro (p-ethylphenyl) phenyl-p-tolyl methane chloro (m-fluorophenyl) diphenyl methane chloro (o-fluorophenyl) diphenyl methane chloro (p-fluorophenyl) diphenyl methane chloro (p-iodophenyl) diphenyl methane chloro (p-isobutylphenyl) diphenyl methane chloro (o-methoxyphenyl) - (p-methoxyphenyl) phenyl methane chloro (3 , 4-methylenedioxyphenyl) diphenyl methane chlorophenyldi-m-tolyl methane chlorophenyldi-o-tolyl methane chloro-m-tolyldi-p-tolyl methane chlorotri-p-cumyl methane chlorotriphenyl methane chlorotris (m-chlorophenyl) methane chlorotris (m-fluorophenyl) methane chlorotris (p-fluorophenyl) methane chlorotris (m-methoxyphenyl) methane chlorotris (p-N-methylanilinophenyl) methane chlorotris (4 '-methyl-4-biphenylyl) methane chlorotri-m-tolyl methane chlorotri-o-tolyl methane chlorotri-p-tolyl methane chlorotri-2, 3 (2, 4-, 2,5- and 3,5)-xylyl methane chlorotri-3 , 5-xylyl methane 3 (and 4) -biphenylylchlorodiphenyl methane bis [3 (and 4) -biphenylyljchlorophenyl methane bis (4-biphenylyl) chlorophenyl methane (p-bromophenyl) bis (tert-butylphenyl) chloro methane chloro (o-chlorophenyl) di-p-tolyl methane chloro (p-chlorophenyl) di-p-tolyl methane chlorodiphenyl-p-tolyl methane chloro (p-nitrophenyl) diphenyl methane chlorophenyldi-p-tolyl methane chlorotris (p-cyclohexylphenyl) methane chlorotris (o-ethylphenyl) methane chlorotris (p-methoxyphenyl) methane chlorotris (p-chlorophenyl) methane chlorotris (p-nitrophenyl) methane bromobis (p-methoxyphenyl) henyl methane chloro (o-chlorophenyl) bis (p-chlorophenyl) methane chloro (p-neopentylphenyl) diphenyl methane (B) When the diarylmethyl halides of Table II below are used in place of chlorotris (m-fluorophenyl) methane in the above example, the corresponding diarylmethyl mercaptans are obtained.

Table II chloro (3 , 4-dimethoxyphenyl) -(2,4, 6-trimethoxyphenyl) methane chlorobis (p-chlorophenyl) methane chlorobis (p-phenylphenyl) methane chloro (m-chlorophenyl) -phenyl methane chloro (a-naphthyl) phenyl methane chloro (β-naphthyl) phenyl methane chloro (p-chlorophenyl) phenyl methane chlorodi-p-tolyl methane chloro (p-ethylphenyl) phenyl methane chloro (p-phenoxyphenyl) phenyl methane chlorophenyl (p-phenylphenyl) methane chlorophenyl-m-tolyl methane bromo- (m-fluorophenyl) phenyl methane bromo (o-fluorophenyl) phenyl methane chlorobis (p-methoxyphenyl) methane chlorobis (2, 4, 6-triethylphenyl) methane chlorodimesityl methane chlorodiphenyl methane chlorodi-m-tolyl methane chlorodi-o-tolyl methane chlorodi-2, 4-xylyl methane chlorodi-2, 6- (3, 5) -xylyl methane chloromesityl-o-tolyl methane chloromesity1-2, 6-x lyl methane chloropheny1 (2,3,4, 6-tetramethyIpheny1) methane chlorophenyl-p-tolyl methane chloro-o-toly1-2, 6-xylyl methane bromobis (p-bromophenyl) methane bromobis (p-fluorophenyl) methane bromo (o-bromophenyl) phenyl methane bromo (p-bromophenyl) phenyl methane (p-bromophenyl) chloro (p-chlorophenyl) methane (p-bromophenyl) chlorophenyl methane bromophenyl-p-tolyl methane bromophenyl-2,3 (2, 4-, 2,5-, 3,4-)-xylyl methane chloro (p-chlorophenyl) -(2, 4-dichlorophenyl) methane chloro (o-chlorophenyl) phenyl methane chloro (chlorophenyl) -p-tolyl methane chloro [2, 4 (and 3 , 4) -dichlorophenyljphenyl methane chloro (3 , 4-diethyIpheny1) phenyl methane chloro (p-iodophenyl) phenyl methane chloromesityIpheny1 methane chloro (p-nitrophenyl) phenyl methane bromodi-2 , 5-xylyl methane chlorobis (3 , 4-dimethoxyphenyl) methane chlorobis (p-nitrophenyl) methane chloro-m-cumenyIpheny1 methane chloro-o-cumenylphenyl methane chloro-p-cumenylphenyl methane chloro (m-ethylphenyl) phenyl methane chloro (o-ethylphenyl) phenyl methane chloro (p-fluorophenyl) henyl methane chloro (p-hexyIpheny1) phenyl methane chlorophenyl-o-tolyl methane chlorophenyl (3 , 4, 5-trimethyIpheny1) methane chlorophenyl-2, 6-xylyl methane chlorophenyl-3 , 5-xylyl methane chloro-o-tolyl-p-tolyl methane chloro-p-toly1-2 , 6-xylyl methane chlorobis (2 , 6-diethyIpheny1) methane chlorobis (2 , 6-diisopropylphenyl) methane chlorobis (o-ethylphenyl) methane chloro-o-cumeny1 ( 2 , 6-diisopropylphenyl) methane chlorodi-o-cumenyl methane chloro (2, 6-diethylphenyl) - (o-ethylphenyl) methane chloro ( 2 , 6-diethylphenyl) phenyl methane chloro (2, 6-diisopropylphenyl) phenyl methane chloro (o-chlorophenyl) - (p-chlorophenyl) methane chlorobis (2, 4, 6-trichlorophenyl) methane chloro (p-chlorophenyl) - (p-nitrophenyl) methane chloro (p-fluorophenyl) - (p-nitrophenyl) methane chloro (p-methoxyphenyl) - (p-phenoxyphenyl) methane chloro (p-nitrophenyl) -p-tolyl methane bromo (o-nitrophenyl) phenyl methane Example 2 2- [Tris- (m-fluorophenyl) methylthio] -1, 1-dimethoxybutane To a solution of 1.15 grams of sodium (0.05 mole) in 100 cc. of absolute ethanol which is stirred under nitrogen, is added 0.05 mole of tris-(m-fluorophenyl) methyl mercaptan. The reaction mixture is then cooled and added to it is 0.05 mole of 2-chloro-1 , 1-dimethoxybutane . The reaction mixture is slowly heated to reflux and is then refluxed for three hours. The reaction mixture is cooled, concentrated, treated with 300 cc. of water and extracted well with chloroform. The combined chloroform extracts are washed well with water, dried over sodium sulfate and concentrated.

Chromatography of the residue on 1500 grams of silica gel and elution with ether-petroleum ether (0-90%) gives 2- [tris- (m-fluorophenyl) methylthio] -1, 1-dimethoxy-butane.

(A) When 2-chloro-l, 1-dimethoxybutane in the procedure above is replaced by the haloacetals of Table I below, the corresponding arylmethylthio acetals are obtained.

Table I 2-bromo-l, 1-dimethoxypropane 2-chloro-l, 1-dimethoxybutane 2-bromo-l, l-dimethoxy-2-phenylethane 2-bromo-l, l-dimethoxy-2-methylpropane 2-bromo-l, l-dimethoxy-2-phenylpropane (B) When tris- (m-fluorophenyl) methyl ercaptan in the procedure above is replaced by the triarylmethyl mercaptans described in Example 1, or by the diary1-methyl mercaptans described in Example 1, or by the benzyl mercaptans from Table II below, the corresponding arylmethylthio acetals are obtained.

Table II The following benzyl mercaptans are prepared from the corresponding halide according to the procedure described in Example 1. benzyl mercaptan m-nitrobenzyl mercaptan p-nitrobenzyl mercaptan o-methylbenzyl mercaptan m-methylbenzyl mercaptan p-methylbenzyl mercaptan 2, 4-dimethylbenzyl mercaptan 3 , 4-dimethylbenzyl mercaptan o-chlorobenzyl mercaptan m-chlorobenzyl mercaptan p-chlorobenzyl mercaptan 2, 4-dichlorobenzyl mercaptan 3 , 4-dichlorobenzyl mercaptan 2,4, 5-trichlorobenzy1 mercaptan 2-chloro-5-nitrobenzyl mercaptan -amino-2 , 4-dichlorobenzyl mercaptan p-bromobenzyl mercaptan o-bromobenzyl mercaptan o-aminobenzyl mercaptan 3-amino-4-methoxybenzyl mercaptan o-methylaminobenzyl mercaptan p-methoxybenzyl mercaptan 4-methoxy-3-nitrobenzyl mercaptan 3 , 4-dimethoxybenzyl mercaptan 3 , 4-methylenedioxybenzyl mercaptan; or 4-phenylbenzyl mercaptan p-chloro-a-phenethyl mercaptan p-trifluoromethylbenz 1 mercaptan p-cyanobenzyl mercaptan p-dimethylsulfonylbenzyl mercaptan V Ρ -trifluoroacet Ibenzy1 mercaptan 4 -benzyloxybenzyl mercaptan 2 -hydroxy-4-nitrobenzyl mercaptan 2 ,3,4,5, 6-pentafluorobenzyl mercaptan 2 -methylbenzyl mercaptan 3 -methyIbenzy1 mercaptan 4 -methylbenzyl mercaptan 2 , 5-dimethylbenzyl mercaptan 3 , 4-dimethyIbenzy1 mercaptan 3 , 5-dimethylbenzyl mercaptan 2· -nitrobenzyl mercaptan 4--nitrobenzyl mercaptan 2· -fluorobenzyl mercaptan 3--fluorobenzyl mercaptan 4--fluorobenzyl mercaptan 4· -bromobenzyl mercaptan 4--phenylbenzyl mercaptan 4--carboxybenzyl mercaptan ο--methoxybenzyl mercaptan m--methoxybenzyl mercaptan p-methoxybenzyl mercaptan 2, , 3-diraethoxybenzyl mercaptan 3, , 4-dimethoxybenzyl mercaptan α--naphthylbenzyl mercaptan α--naphthylmethyl mercaptan 4--mercaptomethyl-ci-phenyl pyridine 2--mercaptomethy1-a-pheny1thiophene 2--mercaptomethyl-a-phenyl pyridine t ■ Example 3 2- [Tris- (m-f luorophenyl)methylthio] -butyraldehyde A mixture of 0.05 mole of 2- [tris- (m-fluoro-phenyl) methylthio] -1, 1-dimethoxybutane and 300 cc. of I sulfuric acid is refluxed under nitrogen for three hours. The reaction mixture is cooled, and extracted well with chloroform. The combined chloroform extracts are washed well with water, dried over sodium sulfate and concentrated. Chromatography of the residue on 1600 grams of silica gel and elution with ether-petroleum ether (0-90%) gives 2- [tris- (m-fluorophenyl) methylthio] -butyraldehyde.

(A) When 2- [tris- (m-fluorophenyl) methylthio] -1, 1-dimethoxybutane is replaced in the procedure described above by the arylthiomethyl acetals prepared in Example 2, the corresponding arylmethylthio aldehydes are obtained.

Example 4 2- [Tris- (m-fluorophenyl) methylthio] -butyrophenone When 2-chlorobutyrophenone is used in place of 2-chloro-1, 1-dimethoxybutane in the procedure of Example 2, there is obtained 2- [tris- (m-fluorophenyl) -methylthio] -butyrophenone.

(A) When 2-chlorobutyrophenone in the procedure above is replaced by the halo ketones of Table I below, and when tris (m-fluorophenyl) methyl mercaptan in the above procedure is replaced by the mercaptans as shown in Example 2, the corresponding thio ketones are obtained. ι Table I l-chloro-2-propanone 3-bromo-2-butanone 3-chloro-2-pentanone l-chloro-l-phenyl-2-propanone l-chloro-2-butanone 2-chloro-3-pentanone 4-chloro-3-hexanone l-bromo-l-phenyl-2-butanone 2-chloroacetophenone 2-bromo-2-phenylacetophenone 3-chloro-3-methyl-2-butanone 2-bromo-2-methyl-3-pentanone 2-chloro-2-methylpropiophenone Example 5 S-tris (m-fluorophenyl)methyl-P-ethyl-DL-cysteine Forty grams (0.10 mole) of 2- [tris- (m-fluoro-phenyl) methylthio] butyraldehyde is added during about 30 minutes to a well-stirred mixture of 11.5 grams of ammonium chloride, 10.4 grams of sodium cyanide, 70 ml. of concentrated aqueous ammonia solution, and 40 ml. of ethanol saturated with gaseous ammonia. Stirring is continued overnight at room temperature. The reaction mixture is extracted with ether, and the ethereal solution evaporated in vacuo, giving the corresponding amino nitrile intermediate as an oily residue. The crude oil is hydrolyzed by refluxing with 60 ml. of concentrated hydrochloric acid for 2.5 hours. The solution is evaporated to dryness, the residue is dissolved in water, and the pH adjusted to about 6 by the addition of concentrated aqueous ammonia . The precipitate is collected by filtration, washed well with cold water, and crystallized from boiling water. On cooling, S-tris- (m-fluorophenyl) methyl-3-ethyl-DL-cysteine is obtained.

(A) When 2- [tris- (m-fluorophenyl) methylthio] -butyraldehyde is replaced in the above procedure by the arylmethylthio aldehydes described in Example 3, or by the arylmethylthio methyl ketones described in Example 4, the corresponding S-arylmethyl cysteines are obtained. For example; S-Benzyl-a-methyl-DL-cysteine, m.p. 233-234°C, 66 .

Example 6 S-tris- (m-fluorophenyl) methyl-3-ethyl-a-phenyl-DL-cysteine A suspension of 47.7 grams (0.10 mole) of 2- [tris- (m-fluorophenyl) methylthio] butyrophenone in 300 ml. of absolute ethanol is stirred at 60° until all the solid dissolves. A solution of 10 grams of potassium cyanide in 100 ml. of water is added with continued stirring, followed by 60 grams of solid ammonium carbonate. The mixture is stirred at 60-70° for 48 hours. The resulting clear, yellow solution is poured on about 400 grams of crushed ice, and the mixture acidified carefully with hydrochloric acid. The precipitated solid is separated by filtration, washed thoroughly with water, and dried. Crystallization from hot ethanol gives 5- (a- [tris- (m-fluorophenyl) methylthio] -propyl) -5-phenyl hydantoin.

A mixture of the hydantoin together with 85 grams of barium hydroxide (dried) and 700 ml. of water is heated at reflux with stirring for 7 days. The hot mixture is acidified carefully with concentrated hydrochloric acid to dissolve precipitated barium salts. The product, S-tris- (m-fluorophenyl) methyl-(3-ethyl-a- phenyl-DL-cysteine, is insoluble in the aqueous medium; after cooling, it is separated by filtration, washed thoroughly with water, and allowed to air-dry.

Purification of the crude solid is effected through f solution in hot, dilute sulfuric acid, filtration to remove insoluble impurities, and reprecipitation by the dropwise addition of concentrated aqueous ammonia.

(A) When 2- [tris- (m-fluorophenyl) methylthio] butyro- phenone is replaced in the above-described procedure by the thio ketones prepared in Example 4, the corresponding S-arylmethyl cysteines are obtained. For example: S-Benzyl-a-phenyl-DL-cysteine, m.p. 227-228 C, 83#.

Example 7 S- (p-chlorophenyldiphenylmethyl) -L-cysteine To a stirred mixture of 6.05 g. (0.05 mole) of L-cysteine in about 150 ml. of refluxing liquid ammonia is added, portionwise, 15.6 grams (0.05 mole) of chloro- (p-chlorophenyl) diphenylmethane. The reaction mixture is stirred until a clear solution results at which time the ammonia is allowed to evaporate. The mixture is then treated with water and the product is separated from the aqueous and washed thoroughly with cold water-ether, and filtered. The product is collected by filtration (m.p. 160-162°C). 1 (A) When the triarylmethyl halides and diar 1- 2 methyl halides from Example 1 are used in place of 3 chloro- (p-chlorophenyl) diphenyl methane in the procedure 4 above, then the corresponding cysteine products are obtained. 6 (B) When the corresponding benzyl halides of the 7 benzyl mercaptans of Example 2 are used in place of 8 chloro- (p-chlorophenyl) diphenyl methane in the procedure 9 above, the corresponding cysteine products are obtained; For example: - 3,4-aichlorobenzyl)-a-methyl~DL-cysteine, m.p. 217-219° , 32%.

S- 3.4-dichlorobenzyl) -a-phenyl-DL-cysteine, m.p. 230-233°, 65%. s- 3-naphthylmethyl)-L-cysteine, dec. 202°, 32%. s- 4-trifluoromethylbenzyi) -L-cysteine, dec. 203°, 49%. s- 5-chloro-2-thienyl) -L-cysteine, dec. 199°, 57%. s- p-methylthi benzyl) -L-cysteine, dec. 198°, 6%. s- o-methylthiobenzyl) -L-cysteine, dec. 195°, 51%. s- p-fluorobenzyl) -L-cysteine, m.p. 189-196°, 19%. ' s- o-chlorobenzyl) -L-cysteine, m.p. 194-200°, 85%. s- 2.6-dichlorobenzyl) -L-cysteine, m.p. 209-212°, 40%. ' s- a-naphthylmethyl) -L-cysteine, m.p. 194-197°, 14%* s- 3-chlorobenzyl) -L-cysteine, m.p. 196-204°, 29%. s- 4-chlorobenzyl) -L-cys^eine, m.p. 199-204°, 20%. s- 3. -dichlorobenzyl) -L-cysteine, m.p. 195-202°, 49%. s- 4-nitrobenzyl) -L-cysteine, m.p. 192-194°, 55%. s- 4-mothoxybenzyl) -L-cysteine, m.p. 212-214°, 77%. 30a S-(3,4-dimethylbenzyl)-L-cysteine, m.p. 195-198°, 71%.

S-(2-methoxybenzyl)-L-cysteine, m.p. 190-191.5°, 68%.

S-(3,4-dimethoxybenzyl)-L-cysteine, m.p. 195-196.5°, 38%.

S-(3-methoxybenzyl)-L-cysteine, m.p. 200-202°, 90%.

S-(2,4-dlchlorobenzyl)-L-cysteine, m.p. 200-202°, 57%.

The following cysteine derivatives are obtained by using sodium methoxide/dimethylformamide in place of liquid NH^.

S-(3-trifluoromethylbenzyl)-L-cysteine, dec. 180-185°, 43%.

S-(2-pyridylmethyl)-L-cysteine di HC1, dec. 189-190°, 64$.

S-(3,4-methylenedioxybenzyl)-L-cysteine, m.p. 197-199°, 43 .

S-(3-chloro-4-methoxybenzyl)-L-cysteine, dec. 200-203°, 30%.

S-(3,4-dichlorobenzyl)-D-penicillamine, m.p. 174-175°, 12 .

(C) When the cysteines of Table I below are used in place of L-cysteine in Examples 7, 7(A) and 7(B), the corresponding cysteine products are obtained.

Table I , a-methyl cysteine β-methyl cysteine a, -dimethyl cysteine β,β-dimethyl cysteine ·· ' α,β ,β-trimethyl cysteine β-ethyl cysteine a-phenyl cysteine β-phenyl cysteine a-methyl- -phenyl cysteine N-ethyl cysteine Ν,Ν-dimethyl cysteine N-phenyl cysteine N-acetyl cysteine N,N-dimethyl^-phenyl cysteine - 12231 0369 2 (D) When chloro- (2-thienyl) diphenyl methane is used in place of the substituted halo methane in the procedures above, the corresponding (2-thienyl) cysteines are prepared.

Example 8 S~ (p-chlorophertyldiphenylmethyl) -L-cysteine To a stirred mixture of 8.4 grams (0.05 mole) of β-bromo-a-amino propionic acid in about 150 ml. of refluxing liquid ammonia, is added, portionwise, .5 grams (0.05 mole) of mercapto- (p-chlorophenyl) - diphenylmethane. The reaction mixture is stirred until a clear solution results, at which time the ammonia is allowed to evaporate. The mixture is then treated with water and the product is separated from the aqueous and washed thoroughly with cold water-ether and filtered.

, The product is collected by filtration (m.p. lv60-162eC. ) .

(A) When the triarylmethyl mercaptans, diaryl- methyl mercaptans, and benzyl mercaptans of Examples 1 and 2 are used in place of mercapto- (p-chlorophenyl) - diphenyl methane in the procedure above, the corresponding cysteine products are obtained.

Thus, when, β-bromo-oc-amino-propionic acid is reacted with mercapto-bis(p-chlorophenyl)phenyl methane, there is obtained S-[di-(p-chlorophenyl)phenylmethyl]-L-cysteine. This product was tested for its anti-inflammatory activity in the well-known Edema Test, which resulted in an inhibition of 9# at 100 mg per kg.

(B) When the β-halo-a-aminopropionic acids of Table I below are used in place of β-bromo-a-aminopropionic acid in Examples 8 and 8(A), the corresponding cysteine products are . obtained.

(D) When chloro- (2-thienyl) diphenyl methane is used in place of the substituted halo methane in the procedures above, the corresponding (2-thienyl) cysteines are prepared.

Example 8 S- (p-chlorophenyldiphenylmethyl) -L-cysteine To a stirred mixture of 8.4 grams (0.05 mole) of β-bromo-a-amino propionic acid in about 150 ml. of refluxing liquid ammonia, is added, portionwise, .5 grams (0.05 mole) of mercapto- (p-chlorophenyl) -diphenylmethane. The reaction mixture is stirred until a clear solution results, at which time the ammonia is allowed to evaporate. The mixture is then treated with water and the product is separated from the aqueous and washed thoroughly with cold water-ether and filtered. The product is collected by filtration (m.p. ½0-162°C. ) . (A) When the triarylmethyl mercaptans, diaryl-methyl mercaptans, and benzyl mercaptans of Examples 1 and 2 are used in place of mercapto- (p-chlorophenyl) -diphenyl methane in the procedure above, the corresponding cysteine products are obtained.

(B) When the β-halo-a-aminopropionic acids of Table I below are used in place of β-bromo-a-amino-propionic acid in Examples 8 and 8 (A) , the corresponding cysteine products are obtained.

Table I β-chloro-a-dimethylaminopropionic acid β-chloro-a-methyl-a-aminopropionic acid β-bromo-β , β-diethyl-a-aminopropionic acid ^Γοηιο- -ρ1ΐ6ηγ1-α-3ΐηίηορΓορϊοηϊσ acid β-bromo-a-phenyl-a-aminopropionic acid β-chloro-a , -dimethyl-a-aminopropionic acid β-chloro-a-phenyl-a-dimethylaminopropionic acid β-chloro-a-acetamidopropionic acid β-chloro-a-guanidinopropionic acid (C) When mercapto- (4-pyridyl) diphenyl methane is used in place of the substituted mercapto methane in the procedures above, the corresponding (4-pyridyl)-cysteines are prepared.

Example 9 p-Chlorophenyldiphenyl carbinol 18.7 Grams of chloro (p-chlorophenyl) diphenyl methane is refluxed with 8.3 grams of potassium carbonate in 50 ml. of water for 5 hours. The mixture is then evaporated and the residue acidified with dilute HCl. This is then extracted with ether, dried and evaporated to dryness.

(A) When the triarylmethyl halides from Example 1 are used in place of chloro- (p-chlorophenyl) diphenyl methane in the procedure above, the corresponding alcohol products are obtained.

Example 10 S- (p-chlorophenyldiphenylmethyl) -L-cysteine To a stirred solution of p-chlorophenyldiphenyl -33- 30369/2 1 carbinol (2.95 grams, 0.010 mole) in glacial acetic 2 acid (10 ml.), is added anhydrous L-cysteine hydro- 3 chloride (1.58 grams, 0.010 mole). The mixture is 4 heated to 60eC. in an oil bath, and then boron tri- 5 fluoride etherate (1.4 ml., 10% excess) is added. The 6 temperature is raised to 80-85°C, and the reaction 7 is allowed to continue, with stirring, for 45 minutes. 8 The mixture is allowed to cool to room temperature, i 9 and then to stand for 15 minutes longer. 0 The reaction mixture is transferred to a 1 beaker with the aid of cthanol (15 ml.), water (5 ml.) 2 and anhydrous sodium acetate (3 g.) are added with 3 stirring, and the mixture is finally treated slowly 4 with water (100 ml.) to precipitate the product as a tacky, pale yellow gum. The supernate is decanted, and 6 the residue triturated vigorously with ice-water until 17 it solidifies. The solid is transferred to a sintered 18 glass funnel, and washed thoroughly by slurrying with 19 water. After being sucked as dry as possible, it is washed thoroughly with ether. The yield of nearly color- 21 less solid, homogeneous by TLC (Rf 0.85; 311 : 1 w/w 22 n-butanol-acetic acid-water on silica gel G) , is 3.2 g. 23 (80%), m.p. 160-162eC, dec. 24 (A) When each of the triarylmethyl halides from Example 9 are substituted for p-chlorophenyldiphenyl 26 carbinol in the procedure above, then the corresponding 27 cysteine is prepared. For example: r' S- (tri-p-fluorophenylmethyl) -L-cysteine, m.p. 153-156°, 62%.

S- (phenyl-di~p-fluorophenylmethyl) -L-cysteine, m.p. 152-155°, 85 S- (p-fluorophenyldiphenylmethyl) -L-cysteine, no m.p.

S- (1, 1-diphenylethyl) -L-cysteine, m.p. 187-188°, 53%.

S- (a-naphthylphenylmethyl) -L-cysteine, m.p. 189-191°, 62%.

S- (β-naphthylphenylmethyl) -L-cysteine, m.p. 190-192°, 77%.

S- (o-chlorophenyldiphenylmethyl) -L-cysteine, m.p. 162-164°, 76%.

S-(o-fluorophenyldiphenylinethyl)-I eystelne, m.p. 172-173°» 68$. S-(diphenyl-2-thienyl-nethyl)~L-cysteir-ei m.p. 165-166°, 4 $.

S-(phenyl-di-m-chlorophenylmethyl)-Ii-cysteine, m.p. 154-155°» 43$· When HgSO^ is used as the catalyst in place of BF-j-etherate, S-(diphenyl-4-pyridylmethyl)-L-cysteine, dec. 245° is obtained in 83$ yield.

Example 11 S-tris-(m-fluorophenyl )methyl- -ethyl-BL~cysteine methyl ester hydrochloride To 200 ml. of anhydrous methanol is added 44.6 grams (0.10 mole) of S-tris- (m-fluorophenyl) methyl-β-ethyl-DL-cysteine. A slow stream of dry hydrogen chloride gas is passed in while the miicture is maintained at gentle reflux with stirring for three hours. The resulting solution is evaporated in vacuo, and the residue is crystallized from a mixture of methanol and ether, giving S-tris- (m-fluorophenyl) methyl- -ethyl-DL-cysteine methyl ester hydrochloride.

(A) When methanol is replaced in the procedure described above by an inert solvent such as dimethoxy-ethane, THF and an alcohol such as ethanol, n-propanol, but-2-enol, but-2-ynol, cyclopropylmethanol, 2-ethyl-propanol, 2-dimethylaminoethanol, 2-hydroxymethyl-piperidine, 1-hydroxyethylpyrrolidine, 2-hydroxypropyl-morpholine, l-methyl-2-hydroxymethylpiperidine, N-hydroxy-methyl- 1 -ethylpiperazine, phenol, p-acetamidophenol , 2-phenylpropanol, 2-carbamylphenol, 2- (p-methoxyphenyl) -propanol, 2-phenylbut-3-enol, tetrahydrofurfural, 2-dimethylaminocyclohexanol, and S-tris- (m-fluorophenyl) -methyl- -ethyl-DL-cysteine by the S-arylmethyl cysteines prepared in Examples 5-10, then the corresponding amino acid ester hydrochlorides are obtained.

Example 12 S-tris- (m-fluorophenyl) ethyl-3-ethyl-DL-cysteineamide hydrochloride ■ To 250 ml. of methanol saturated at 0°C. with ammonia, is added 49.6 grams (0.10 mole) of S-tris-(m-fluorophenyl) methyl- -ethyl-DL-cysteine methyl ester hydrochloride. The resulting solution is allowed to stand for 4 days at 20eC. The solvent is evaporated in alcohol and ether, giving S-tris- (m-fluorophenyl)methy1- β-ethyl-DL-cysteineamide hydrochloride.

(A) When ammonia is replaced in the above procedure by methylamine, eth lamine, propylamine, dimethylamine, ethylpropylamine, glucosamine, glycos lamine, 1-amino- but-3-ene, 2-phenylpropylamine, 2-chloroaniline, 3-bromo-aniline, l-methyl-2-aminoethylpiperidine, tetrahydro-furylamine, 1,2, 5, 6-tetrahydropyridine, morpholine, N-methylpiperazine, piperazine, N-phenylpiperazine, piperidine, benzylamine, aniline, 2-methoxyaniline, cyclohexylamine, pyrrolidine, N-hydroxyethylpiperazine, 2-dimethylcarbamylpropylamine, 3-diethylaminopropylamine, l-methyl-2~aminomethylpyrrolidine, carbobenzyloxyethyl-amine, or dibutylamine and S-tris- (m-fluorophenyl)meth 1-0-ethyl-DL-cysteine methyl ester hydrochloride by the amino acid alkyl ester hydrochlorides described in Example 11, then the corresponding amide derivatives are obtained.

Example 13 S-tris- (m-fluorophenyl)methyl-β-ethyl-N,N-dimethy1-DL-cysteine A mixture of 11.1 grams (0.025 mole) of S-trie- (m-fluorophenyl)methyl-β-eth 1-DL-cysteine and 9.0 ml. of 40% aqueous formaldehyde in 200 ml. of water is hydrogenated in the presence of 11 grams of 10% palladium-on-charcoal; the theoretical amount of hydrogen is taken up on shaking overnight at room temperature. The catalyst is removed by filtration, and the filtrate evaporated in vacuo. The residue is taken up in boiling acetone; S-tris- (m-fluorophen l)methy1-B-ethyl-N,N-dimeth 1-DL-c steine deposits on cooling.

(A) When S-tris- (m-fluorophenyl)methyl-fl-ethyl-DL-cysteine is replaced in the above-described procedure by the S-arylmethyl cysteines prepared in Examples 5-10, then the corresponding Ν,Ν-diraethyl derivatives are obtained. For examplet N.N-dimethyl-S-benzyl-I-cysteine, m.p. 138*146°, 26$. S-benzyl-F,N-dimethyl-L-cysteine, m.p. 138-146°, 5 Example 14 a-Guanidino-0- [S-tris- (m-fluorophenyl)methylthio] valeric acid ; A solution of 26.7 grams (0.06 mole) of S-trie- (m-fluorophenyl)methyl-3-ethyl-DL-cysteine in 100 ml. of water and 30 ml. of concentrated aqueous ammonia is treated with 27.8 grams (0.10 mole) of S-methyl isothiourea sulfate, added in small portions with vigorous stirring during about 30 minutes. The resulting solution is stirred for 20 hours at room temperature.

The crystallised product is collected after thorough cooling of the reaction mixture, and is washed with water and alcohol. Crystallization from a mixture of water and alcohol gives pure a-guanidino-0- [S-tris- (m-fluoro-phenyl) raefchylthiol valeric acid.

(A) When the S-tris- (m-fluorophenyl)methyl-0-ethyl-DL-cysteine of the above example is replaced by any of the S-arylmethyl cysteines having » H, prepared in Examples 5 to 10, then the corresponding ct-guanidino-6-(S-arylmethylthio)carboxylic acids are obtained. For example: N-amidino-S-trityl-L-cysteine, m.p. 222-224°, 47$.

Example 15 S-trls- (m-fluorophenyl) methyl-P-eth l-N-methyl-DL-cysteine I. di-p-Toluenesulfonyl-fi-ethyl-DL-cystine To a solution of 0.05 mole of S-tris- (m-fluoro- phenyl) methyl-3-ethyl-DL-cysteine in 400 ml. of liquid ammonia is added small pieces of sodium metal, slowly and with stirring, until a permanent blue color appears. The color is just discharged with ammonium chloride, and then additional ammonium chloride, equivalent to the amount of sodium used, is added. The reaction mixture is left overnight to allow the ammonia to evaporate.

The residue is dissolved in water, and the solution extracted thoroughly with ether. The pH of the aqueous phase is adjusted to about 8, a trace of ferric chloride is added, and the solution is aerated overnight. The pH is then adjusted to 6, and the solution evaporated to small volume when β-ethyl-DL-cystine crystallizes.

A solution of 14.8 grams (0.05 mole) of β-ethyl-DL-cystine in 100 ml. of 1 N aqueous sodium hydroxide is stirred vigorously while a solution of 38 grams of p-toluenesulfonyl chloride in 100 ml. of ether is added in ten portions at 15 minute intervals; each portion is preceded by addition of 10 ml. of 2 N aqueous sodium hydroxide solution. When the addition is complete, the mixture is stirred for 30 minutes more. The ether layer is removed, and the aqueous layer is extracted with 100 ml. of fresh ether. Dissolved ether is removed from the aqueous phase by warming, and then the warm solution is acidified by the addition, with vigorous shaking, of concentrated hydrochloric acid. Di-p-toluenesulfonyl-β-ethyl-DL-cystine crystallizes, and after thorough cooling, is collected by filtration. (Λ) When the S-arylmethyl cysteines prepared in Examples 5 to 10 are used in place of S-tris- (m-fluoro- phenyl) methyl-p-ethyl-DL-cysteine in the procedure above, there is obtained the corresponding di-p-toluenesulfonyl cystines.

II. S-tris-(m-fluorophenyl) methyl-β-ethyl- -methyl- DL-cysteine To 5.5 grams (0.0091 mole) of di-p-toluenesulfonyl-fi-ethyl-DL-cystine, dissolved in 55 ml. of 1 N aqueous sodium hydroxide solution, is added 2.3 ml. of methyl iodide. After being warmed to about 70eC, the mixture is shaken vigorously until the methyl iodide layer disappears. When the solution cools, it is extracted with ether. The aqueous layer is overlaid with 100 ml. of ether and strongly acidified with hydrochloric acid. The aqueous layer is then reextracted with small portions of ether until it gives a negative test for disulfide. The combined ether extracts are washed with water containing a small amount of sodium bisulfite, and evaporated in vacuo.

The residue is taken up in about 200 ml. of liquid ammonia, and sodium is added in small pieces with stirring until a permanent blue color remains; excess sodium is destroyed with ammonium chloride [in some cases where the arylmethyl halide is so reactive that solvolysis is the principal reaction in liquid ammonia (notably with trityl halides) , the procedure must be modified at this point by allowing the ammonia to evaporate and replacing it with dimethylformamide] , and 6.7 grams (0.02 mole) of chloro-tris- (m-fluorophenyl) methane is added slowly.

The ammonia is allowed to evaporate, and 50 ml. of ice-water is added to the residue. The resulting solution is extracted twice with ether, and then acidified to pH about 6 with hydrochloric acid. The precipitate of S-tris- (m-fluorophenyl)methyl-3-ethyl- -methyl-DL** cysteine is collected by filtration, and washed successively with water, alcohol, and ether.

(A) When the di-p-toluenesulfonyl cystines prepared in Part I above are used in place of di-p-toluenesulfonyl-3-ethyl-DL-cystine, and when the aryl-methyl halides of Examples 1 and 2 are used in place of chloro-tris- (m-fluorophenyl) methane in Part II above, the corresponding S-arylmethyl- -methyl cysteines are obtained.

(B) When ethyl iodide, propyl iodide or butyl iodide is used in place of methyl iodide in Part II above, the corresponding S-arylmethyl-N-alkyl cysteines are obtained.

Example 16 N,N-diethyl-a-ethyl-S-tris- (m-fluorophenyl) methyl-i>L-cysteine hydrochloride I. a-Diethylamino-a-tris- (m-fluorophenyl) methylthio-methyl butyronitrile , To a concentrated aqueous solution of diethyl-amine hydrochloride is added 0.01 moles of potassium cyanide, followed by 0.01 moles of ethyl-tris- (m-fluoro-phenyl) methyl ketone.

The reaction mixture is shaken for 48 hours at room temperature and then extracted well with ether. The combined ether extracts are dried over a2S04 and concentrated to yield crude α-diethylamino-a-tris- (m-fluorophenyl) methylthiomethy1 butyronitrile.

II. Hydrolysis A solution of 0.1 mole of a-diethylamino-a-tris- (m-fluorophenyl)methylthiomethyl butyronitrile in 100 ml. of concentrated hydrochloric acid is refluxed for 12 hours and then concentrated to yield N,N-diethyl-a-ethyl-S-tris- (m-fluorophenyl) methyl-DL-cysteine hydrochloride.

(A) When dimethylamine hydrochloride, propylethyl-amine hydrochloride, phenylamine hydrochloride or phenylpropylamine hydrochloride is used in the above Example in place of diethylamine hydrochloride, there is obtained the corresponding a-amino substituted compound.

Example 17 A mixture of 250 parts of S-trityl-L-cysteine and 25 parts of lactose is granulated with suitable water, and to this is added 100 parts of maize starch.

The mass is passed through a 16 mesh screen. The granules are dried at a temperature below 60°C. The dr granules are passed through a 16 mesh screen, and mixed with 3.8 parts of magnesium stearate. They are then compressed into tablets suitable for oral administration.

EXAMPLE 18 S- (p-chlorophenyldiphenylmethyl) -L-cysteine sodium salt A solution of 0.01 moles of S- (p-chlorophenyldiphenylmethyl) -L-cysteine and 0.01 moles of sodium hydroxide in 25 ml. of water is allowed to stir at room temperature for 30 minutes and is then concentrated to dryness in vacuo. Trituration with ether followed by filtration gives the sodium salt of S- (p-chlorophenyldiphenylmethyl} -L-c ste 1ne.

Replacement of sodium hydroxide with potassium hydroxide, calcium hydroxide or aluminum hydroxide gives the potassium, calcium or aluminum salt of S- (p-chlorophenyldiphenylmethyl) -L-cysteine.

EXAMPLE 1ft Ethoxyethyl ester of L-cysteine hydrochloride A. mixture of 0.1. moles of L-cysteine and 150 mis. of 2-ethoxy ethanol is saturated with hydrogen chloride gas at 0° and then allowed to stir at ambient temperature for 24 hours. Concentration in vacuo followed by the addition of ether gives the ethoxyethyl ester of L-cysteine hydrochloride.

Using 2-ethoxyethoxy etanol in place of 2-ethoxy ethanol in the procedure of the above example gives the 2-ethoxyethoxy-ethyl ester of L-cysteine hydrochloride.

I^oxycthyl ester of 5- (p-chlorophenyldiphenylmethyl) -L-cystoine To a stirred mixture of 0.05 mole of the ethoxyethyl ester of L-cysteine in about 150 ml* of refluxing liquid, ammonia is added, portionwise, 0.05 mole of chloro- (p-chlorophenyl) diphenylmethane. The reaction mixture is stirred until a clear solution results at which time the ammonia is allowed to evaporate. The mixture is then treated with water and the product is separated. from the aqueous and washed thoroughly with cold water-ether and filtered. The product is collected by filtration.

Uoing an equivalent amount of 2-o¾hoxycthoxyothyl ootor of-L- | -oy-steino hydrochloride in place of othoxyothyl octer of L-cyeteino, yields 2™QthoKyotho..yothyl OPtor of 6" (p-ohl-or-o-^-phonyIda.phenyImpthy1) -L-oyctoino.

Claims (1)

1. A method of treating which comprises administering to patients 5000 per day of a compound of the wherein R is lower lower lower lower or R2 is lower lower lower lower alkoxy lower poly lower lower alkox dilower alkylamino lower piperidino lower lower lower lower lower lower alkanoylamino phenyl lower carbamyl lower alkoxyphenyl lower phenyl lower tetrahydrofurfurylox dilower alkylamino lower dilower glucosamine lower phenyl lower alk alkyl lower cyclolower lower alkyl alkyl lower alkylamino lower alkyl lower or OZ where Z is a metal cation the symmetrical anhydrides of the and are each independently lower alkyl or is lower alkyl or and are each independently lower lower phenyl or guanyl when is and and each independently lower pyridyl or substituted phenyl or naphthyl in which the subs may be and 6 and R may be the same or A method of treating inflammation in animals according to Claim where the dose level is in animals A method of treating ccording to Claim where R is 4 and are all is and and R are naphthyl or substituted in animals A method of treating to Claim which comprises administering to patients per day of Compounds of formula A in Claim excepting those compounds in and Rg are each a phenyl group and each of and is or R is hydrogen or a or and each of g and is or One of and is phenyl or and the other is R is or a methoxy group in the and of is or One of and Rg is and the other is R represents two methoxy groups in the and hydroxy and each of and is or One of and is alkanoyl and the other is hydrogen and each of R g and Rg is 44 A compound according to Claim where R is and are all is and and are naphthyl or substituted cysteine cysteine A process for preparing an acid compound of the formula A in Claim 1 in which is except for the compounds whioh are excluded from Claim which comprises hydrolyzing a corresponding compound of the formula where Ry Ry y Rg and are as defined in Claim to form the desired acid A process according to Claim where R is Ry Ry and are all and Rg and R are naphthyl or substituted A for preparing an acid compound of the formula A in Claiml in which is hydroxy and and are each except for the compounds which are exoluded from Claim which comprises hydrolyzing a corresponding compound of the formula where and are as defined in Claim to give the desired acid A process according to Claim where R is and are all and Rg and are naphthyl or substituted A process for preparing an acid compound of the formula A in Claim 1 in which is except for the compounds which are excluded from Claim which comprises reacting a corresponding benzyl halide of the where Rg and are as defined in Claim and X is with a cysteine compound of the formula where and are as defined in Claim A process according to Claim where R is and are all and and are naphthyl or substituted A process for preparing an acid compound of the formula A in Claim in which is except for the compounds which are excluded from Claim which comprises reacting a corresponding benzyl mercaptan of the where and R are as defined in Claim with a halo propionic acid of the formula X C C COOH 5 where and and are as defined in Claim and X is A process according to Claim where R is halo and are all and and are naphthyl and substituted A process for preparing an acid ester or amide compound of the formula A in Claim in which is other than except for the compounds which are excluded from Claim which comprises esterifying the corresponding free acid to form the desired acid ester if amidating the thus formed acid ester to form the desired acid A pharmaceutical composition in dosage unit form comprising between 5 and 500 mg of a compound of the formula A in Claim A pharmaceutical composition according to Claim 23 where R is and are all is and and are naphthyl and substituted A pharmaceutical composition according to Claim where the active ingredient is A pharmaceutical composition according to Claim where the active ingredient is 48 insufficientOCRQuality