United States Patent (19) 11) 4,374,829 Harris et al. 45) Feb. 22, 1983 54 AMNOACD DERVATIVES AS 51 Int. Cl..................... A61K 37/00; C07C 103/52; ANTHYPERTENSIVES C07D 207/24 52 U.S. C. .............................. 424/177; 260/112.5 R 75 Inventors: Elbert E. Harris; Arthur A. Patchett, 58) Field of Search ..................... 260/326.2, 112.5 R; both of Westfield; Edward W. 424/177 Tristram, Watchung; Matthew J. Wyvratt, Mountainside, all of N.J. (56) References Cited PUBLICATIONS (73) Assignee: Merck & Co., Inc., Rahway, N.J. Theohanson, et al., J. Biol. Chem. 175, (1948) 833–848. 21 Appl. No.: 235,335 Primary Examiner-Delbert R. Phillips Attorney, Agent, or Firm-Salvatore C. Mitri; Martin L. (22) Filed: Feb. 17, 1981 Katz Related U.S. Application Data (57) ABSTRACT 63 Continuation-in-part of Ser. No. 79,898, Oct. 9, 1979, The invention relates to new carboxyalkyl dipeptide abandoned, which is a continuation-in-part of Ser, No. derivatives and related compounds which are useful as 36,279, May 7, 1979, abandoned, which is a continua antihypertensives. tion-in-part of Ser. No. 968,249, Dec. 11, 1978, aban doned. 82 Claims, No Drawings 4,374,829 2 R and R6 are the same or different and are hydroxy, AMNOACD DERVATIVES AS lower alkoxy, ANTHYPERTENSIVES lower alkenoxy, dillower alkylamino lower alkoxy (dimethylaminoe RELATED APPLICATIONS thoxy), This application is a continuation-in-part of U.S. Ser. acylamino lower alkoxy (acetylaminoethoxy), No. 079,898 filed Oct. 9, 1979 which is a continuation acyloxy lower alkoxy (pivaloyloxymethoxy), in-part of U.S. Ser. No. 036,279 filed May 7, 1979, both aryloxy, such as phenoxy, now abandoned, which is a continuation-in-part of U.S. arloweralkoxy, such as benzyloxy, 10 substituted aryloxy or substituted arloweralkoxy Ser. No. 968,249 filed Dec. 11, 1978, now abandoned. wherein the substitutent is methyl, halo or me BACKGROUND OF THE INVENTION thoxy, U.S. Pat. Nos. 4,129,571 and 4,154,960 disclose substi amino, tuted acyl derivatives of amino acids which are useful as loweralkylamino, angiotension converting enzyme inhibitors. More spe 15 diloweralkylamino, cifically, these compounds are mercapto substituted hydroxyamino, acyl amino acids and derivatives thereof including the arloweralkylamino such as benzylamino; clinically effective antihypertensive compound, capto R is hydrogen, pril, i.e., D-3-mercapto-2-methylpropanoyl-L-proline. alkyl of from 1 to 20 carbon atoms which include 20 branched and cyclic and unsaturated (such as allyl) The foregoing prior art compounds are not dipeptide alkyl groups, derivatives as are the compounds of the present inven substituted loweralkyl wherein the substituent can be tion. Furthermore, these prior art compounds contain halo, hydroxy, lower alkoxy, aryloxy such as phe an essential sulfhydryl substituent or derivative thereof noxy, amino, dilloweralkylamino, acylamino, such whereas those of the present invention do not. In addi 25 as acetamido and benzamido, arylamino, tion, the dipeptide compounds of the present invention guanidino, imidazolyl, indolyl, mercapto, loweral are unusual dipeptides whose N-terminus bears a car kylthio, arylthio such as phenlithio, carboxy or boxymethyl group which is preferably further substi carboxamido, carboloweralkoxy, tuted on the methyl group. In addition, the carboxyl aryl such as phenyl or naphthyl, group(s) may also be converted to ester, amide and salt 30 substituted aryl such as phenyl wherein the substitu derivatives. In effect, the compounds of the present ent is lower alkyl, lower alkoxy or halo, invention are hybrids formed by fusing a-amino acids arloweralkyl, arloweralkenyl, heteroarlower alkyl or onto dipeptides by means of a nitrogen shared by these heteroarlower alkenyl such as benzyl, styryl or two part-structures. This structural arrangement is rare indolyl ethyl, in the field of synthetic and natural peptides and is not 35 substituted arloweralkyl, substituted arloweralkenyl, suggested or disclosed by the mercaptoacyl type func substituted heteroarlower alkyl, or substituted tions of the two prior art patents identified above. heteroarlower alkenyl, wherein the substituent(s) is U.S. Pat. No. 4,052,511 discloses N-carboxyalkanoyl halo, dihalo, lower alkyl, hydroxy, lower alkoxy, amino acids which are useful as angiotension converting amino, aminomethyl, acylamino (acetylamino or enzyme inhibitors. Since the compounds of the present benzoylamino) dilloweralkylamino, loweralk invention are dipeptide derivatives, in a formal sense ylamino, carboxyl, haloloweralkyl, cyano or sul they may be considered to be related to some of the fonamido; compounds disclosed in U.S. Pat. No. 4,052,511. How arloweralkyl or heteroarloweralkyl substituted on ever, when a particular one of the methylene groups is the alkyl portion by amino or acylamino replaced by an amino function as in the present inven 45 (acetylamino or benzoylamino); tion, compounds of surprisingly high potency are ob R2 and R7 are the same or different and are hydrogen or tained. For example, the preferred compounds of the lower alkyl; present invention can be administered in dosages as low R3 is hydrogen, lower alkyl, phenyl lower alkyl, amino as about 2.5 mg. per patient per day as opposed to the methyl phenyl lower alkyl, hydroxy phenyl lower lowest dosage level of 1 mg. per kg. per day for pre 50 alkyl, hydroxy lower alkyl, acylamino lower alkyl ferred compounds disclosed in the U.S. Pat. No. (such as benzoylamino lower alkyl, acetylamino 4,052,511 patent which is about equivalent to 60 mg. per lower alkyl), amino lower alkyl, dimethylamino patient per day based on an average patient weight of lower alkyl, halo lower alkyl, guanidino lower alkyl, about 150 pounds. imidazolyl lower alkyl, indolyl lower alkyl, mercapto 55 lower alkyl, lower alkyl thio lower alkyl; SUMMARY OF THE INVENTION R is hydrogen or lower alkyl; The invention in its broad aspects relates to carboxy Rishydrogen, lower alkyl, phenyl, phenyl lower alkyl, alkyl dipeptides and derivatives thereof which are use hydroxy phenyl lower alkyl, hydroxy lower alkyl, ful as converting enzyme inhibitors and as antihyperten amino lower alkyl, guanidino lower alkyl, imidazolyl sives. The compounds of this invention can be shown by 60 lower alkyl, indolyl lower alkyl, mercapto lower the following formula: alkyl or lower alkyl thio lower alkyl; R“and R5 may be connected together to form an alkyl O R1 R3 R R5 O. ene bridge of from 2 to 4 carbon atoms, an alkylene II R-C-C-NH-CH-C-N-C-C-R6 bridge of from 2 to 3 carbon atoms and one sulfur 65 atom, an alkylene bridge of from 3 to 4 carbon atoms R2 O R7 containing a double bond or an alkylene bridge as above substituted with hydroxy, loweralkoxy, lower wherein alkyl or diloweralkyl; 4,374,829 3 4. and the pharmaceutically acceptable salts thereof. stituent(s) is halo, dihalo, amino, aminoalkyl, hy The loweralkyl or lower alkenyl groups except droxy, lower alkoxy or lower alkyl. Most preferred where noted otherwise represented by any of the vari ables include straight and branched chain hydrocarbon are compounds of Formula I wherein radicals from one to six carbon atoms, for example, R and R6 are hydroxy, lower alkoxy, aralkyloxy; methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, R2 and R7 are hydrogen; pentyl, isopentyl, hexyl or vinyl, ally, butenyl and the R3 is methyl or amino lower alkyl; like. The aralkyl groups represented by any of the R and Rare joined through the carbon and nitrogen above variables have from one to four carbon atoms in atom to form proline, 4-thiaproline or 4-methoxy the alkyl portion thereof and include for example, ben 10 proline; zyl, p-methoxybenzyl and the like. Halo means chloro, bromo, iodo or fluoro. Aryl where it appears in any of R is alkyl having from 1 to 8 carbon atoms, substituted the radicals except where noted represents phenyl or lower alkyl wherein the alkyl group has 1-5 carbon naphthyl. Heteroaryl groups where they appear include atoms and the substituent is amino, arylthio or aryl for example pyridyl, thienyl, furyl, indolyl, benzthienyl, 15 oxy, aralkyl or heteroaralkyl wherein the alkyl por imidazoyl and thiazolyl. tion has 1 to 3 carbon atoms such as phenethyl or The R1, R3 and R5 substituted lower alkyl moieties indolylethyl or substituted aralkyl (phenyl lower are exemplified by groups such as alkyl or naphthyl lower alkyl) and substituted heteroaralkyl wherein the alkyl groups have 1-3 car 20 bons and wherein the substituent(s) is halo, dihalo, N CH2 CH2 amino, aminoalkyl, hydroxy, lower alkoxy or lower CH2 alkyl. N N The preferred, more preferred and most preferred H H 25 compounds also include the pharmaceutically accept able salts thereof and are exemplified by such com pounds as: N-(1(S)-carboxy-3-phenylpropyl)-L-alanyl-L-proline; NH N-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L- H2N-C-NH-(CH2)3- and the like. 30 proline and its maleate salt; N-(1(S)-ethoxycarbonyl-4-methylpentyl)-L-alanyl-L- Rand R5 when joined through the carbon and nitro proline; gen atoms to which they are attached form a 4 to 6 N-(1-carboxy-5-aminopentyl)-L-alanyl-L-proline; membered ring which may contain one sulfur atom or a 35 N-a-(1(S)-carboxy-3-phenylpropyl)-L-lysyl-L-proline; double bond. Preferred rings have the formulae: N-a(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-lysyl-L- proline; N-a1(S)-carboxy-3-(3-indolyl)propyl)-L-lysyl-L-pro -N OR -N line; N-a-1(S)-carboxy-3-(4-chlorophenyl)-propyl)-L-lysyl L-proline; COOR N-a-1 (S)-carboxy-2-phenylthioethyl)-L-lysyl-L-pro where Y is CH2, S, or CHOCH3. line; Preferred are those compounds of Formula I 45 N-a-1 (S)-carboxy-3-(4-chlorophenyl)-propyl-L-lysyl wherein: L-4-a-methoxyproline; R and R can each independently by hydroxy, lower N-a-1(S)-carboxy-5-aminopentyl-L-lysyl-L-proline; alkoxy, lower alkenoxy, arloweralkyloxy, amino, Ethyl N-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-ala dillower alkylamino lower alkoxy, acylamino lower nyl-L-prolinate hydrochloride; alkoxy, acyloxy lower alkoxy wherein the substituent 50 is methyl, halo or methoxy; and the like.