US 4,929,641 AGrant

Mercapto-Acylamino Acid Antihypertensives

Issue Date:1990-05-29

•20 Claims

Abstract

Novel mercapto-acylamino acids useful in the treatment of hypertension and combinations of mercapto-acylamino acids and atrial natriuretic factors or angiotensin converting enzyme inhibitors useful for treating hypertension are disclosed.

Metadata

Assignee

Schering Corporation

Inventors

Martin F. Haslanger
Bernard R. Neustadt
Elizabeth M. Smith

Application Information

Application Number:US 1924354

Filing Date:1988-05-11

Priority Date:1988-05-11

Art Unit:116

Classifications

IPC:

C07C14940C07C15600C07C15709

Field of Search:

558564560562514254;417153;15410;16;17;18426;427;432506;513;522;529;532;540;562

Patent Drawings

This patent does not have any drawings.

Description

EXAMPLE 1

N-(2-Benzyl-3-Mercaptopropionyl)-S-(4-Methylbenzyl)-L-Cysteine (Isomers A and B)

Step 1: N-(3-Acetylthio-2-Benzylpropionyl)-S-(4-Methylbenzyl)-L-Cysteine Methyl Ester (Isomers A & B): Add S-(4-methylbenzyl)-L-cysteine methyl ester, hydrochloride (1.85 g, 0.77 mmole) to 3-acetylthio-2-benzyl propionic acid (1.93 g, 0.81 mmole), DEC (1.46 g, 0.76 mmole), HOBT (1.18 g, 0.76 mmole) and NMM (2.30 g, 2.5 ml, 2.27 mmole) in DMF (20 ml) and stir the resulting mixture at room temperature for 20 hours. Concentrate the reaction mixture in vacuo and partition the residue between EtOAc and water. Concentrate the dried (MgSO.sub.4) ethyl acetate solution in vacuo to give an amber oil (3.85 g). Chromatograph the oil on silica gel (Baker, 60-200 mesh) (1.5L) using EtOAc:hexane 4:21 as eluent to give Isomer A, white solid (0.64 g), m.p. 101.degree.-104.degree., [.alpha.].sub.D.sup.26 =-76.2.degree. (MeOH); overlap Isomer A and Isomer B (0.40 g); and Isomer B, white solid (0.67 g), m.p. 52.degree.-55.degree. [.alpha.].sub.D.sup.26 =-4.9.degree. (MeOH).

Step 2: N-(2-Benzyl-3-Mercaptopropionyl)-(S)-(4-Methylbenzyl)-L-Cysteine (Isomer B): Dissolve Isomer B (0.66 g, 1.6 mmole) in methanol (20 ml) under a nitrogen atmosphere, cool to 0.degree.-5.degree., add 1N sodium hydroxide (4.8 ml), stir the mixture at 0.degree.-5.degree. for 6 hours and then keep at that temperature for 18 hours. Concentrate the reaction mixture under nitrogen, dilute the resultant oil with water (200 ml) and ethyl acetate (200 ml) and acidify to pH 2-4 with 1N hydrochloric acid. Dry (MgSO.sub.4) the ethyl acetate solution and concentrate in vacuo to give the title compound (Isomer B), a viscous oil (0.45 g), [.alpha.].sub.D.sup.26 =-56.3.degree. (MeOH).

Step 3: N-(2-Benzyl-3-Mercaptopropionyl)-(S)-(4-Methylbenzyl)-L-Cysteine (Isomer A): By a procedure similar to that of Step 2 react Isomer A (0.63 g) and 1N sodium hydroxide (4.5 ml) to give the title compound (Isomer A), a viscous clear oil (0.165 g), [.alpha.].sub.D.sup.26 =-8.8.degree. (MeOH).

In a similar manner, according to Example 1, Step 1, using the appropriate propionic acid, prepare:

N-[3-Acetylthio-2-(.alpha.-naphthylmethyl)propionyl]-S-(4-methylbenzyl)-L-c ysteine ethyl ester, Isomer A, m.p. 71.degree.-74.degree., [.alpha.].sub.D.sup.26 =-40.6.degree. (MeOH);

N-[3-Acetylthio-2-(.alpha.-naphthylmethyl)propionyl]-S-(4-methylbenzyl)-L-c ysteine ethyl ester, Isomer B, m.p. 88.degree.-90.degree., [.alpha.].sub.D.sup.26 =-58.8.degree. (MeOH);

N-[3-Acetylthio-2(.beta.-naphthylmethyl)propionyl]-S-(4-methylbenzyl)-L-cys teine ethyl ester, Isomer A, m.p. 74.degree.-77.degree., [.alpha.].sub.D.sup.26 =-61.0.degree. (MeOH);

N-[3-Acetylthio-2(.beta.-naphthylmethyl)propionyl]-S-(4-methylbenzyl)-L-cys teine ethyl ester, Isomer B, m.p. 86.degree.-88.degree., [.alpha.].sub.D.sup.26 =-20.7.degree. (MeOH);

N-[3-Acetylthio-2-(4-chlorobenzyl)propionyl]-S-benzyl-L-cysteine ethyl ester (Isomer A), m.p. 89.degree.-90.degree.;

N-[3-Acetylthio-2-(4-chlorobenzyl)propionyl]-S-benzyl-L-cysteine ethyl ester (Isomer B), m.p. 103.degree.-4.degree.; and

N-[3-Acetylthio-2-(4-chlorobenzyl)propionyl]-L-tryptophan methyl ester (Isomers A and B).

Using the procedure of Example 1, Step 2, treat the above 3-acetylthio compounds to obtain the following 3-mercaptopropionyl compounds:

N-[2-(.alpha.-Naphthylmethyl)-3-mercaptopropionyl]-S-(4-methylbenzyl)-L-cys teine Isomer A, m.p. 70.degree.-75.degree., [.alpha.].sub.D.sup.26 =+18.3.degree. (MeOH);

N-[2-(.alpha.-Naphthylmethyl)-3-mercaptopropionyl]-S-(4-methylbenzyl)-L-cys teine Isomer B, m.p. 48.degree.-55.degree., [.alpha.].sub.D.sup.26 =-102.3.degree. (MeOH);

N-[2-(.beta.-Naphthylmethyl)-3-mercaptopropionyl]-S-(4-methylbenzyl)-L-cyst eine, Isomer A, a white foam, [.alpha.].sub.D.sup.26 =+9.9.degree. (MeOH);

N-[2-(.beta.-Naphthylmethyl)-3-mercaptopropionyl]-S-(4-methylbenzyl)-L-cyst eine, Isomer B, a white foam, [.alpha.].sub.D.sup.26 =-50.1.degree. (MeOH);

N-[2-(4-chlorobenzyl)-3-mercaptopropionyl]-S-benzyl-L-cysteine (Isomer A), [.alpha.].sub.D.sup.26 =-3.0.degree. (EtOH, c=1);

N-[2-(4-chlorobenzyl)-3-mercaptopropionyl]-S-benzyl-L-cysteine (Isomer B), [.alpha.].sub.D.sup.26 =-48.7.degree. (EtOH, c=1);

N-[2-(4-chlorobenzyl)-3-mercaptopropionyl]-L-tryptophan (Isomer A), [.alpha.].sub.D.sup.26 =+18.1.degree. (EtOH, c=0.5); and

N-[2-(4-chlorobenzyl)-3-mercaptopropionyl]-L-tryptophan (Isomer B), [.alpha.].sub.D.sup.26 =-22.5.degree. (EtOH, c=0.5).

EXAMPLE 2

N-(2-Benzyl-3-Mercaptopropionyl)-S-Benzyl-L-Cysteine (Isomers A & B)

Step 1: N-(3-Acetylthio-2-Benzylpropionyl)-S-Benzyl-L-Cysteine, Ethyl Ester (Isomers A & B): React S-benzyl-L-cysteine ethyl ester hydrochloride (1.38 g) and 3-acetylthio-2-benzyl propionic acid (1.19 g) in a procedure similar to that described in Example 1, Step 1 to give a yellow oil. Chromatograph the oil on silica gel (1.5L, 60-200 mesh) using CH.sub.2 Cl.sub.2 :ethyl acetate 98:2 as eluant to give Isomer A, white solid (0.49 g), m.p. 83.degree.-5.degree., [.alpha.].sub.D.sup.26 =-73.5.degree. (MeOH); overlap Isomer A and B (0.66 g); and Isomer B, white solid, m.p. 72.degree.-4.degree., [.alpha.].sub.D.sup.26 =-9.4.degree. (MeOH).

Step 2: Using the procedure described in Example 1, Step 2, separately treat the Isomers of Step 1 above to obtain Isomers A and B of the title compound: Isomer A, a colorless oil, [.alpha.].sub.D.sup.26 =-2.1.degree. (MeOH), and Isomer B, a colorless oil, [.alpha.].sub.D.sup.26 =-46.7.degree. (MeOH).

EXAMPLE 3

N-(2-Benzyl-3-Mercaptopropionyl)-S-Benzyl-D-Cysteine (Isomers A and B)

Step 1: N-(3-Acetylthio-2-Benzylpropionyl)-S-Benzyl-D-Cysteine, Ethyl Ester (Isomers A and B): React S-benzyl-D-cysteine ethyl ester hydrochloride (2.05 g) and 3-acetylthio-2-benzylpropionic acid (1.77 g) in a manner similar to that described in Example 1, Step 1 to give a light amber oil. Place the oil on a column of silica gel (2 L, 60-200 mesh) and elute with CH.sub.2 Cl.sub.2 :ethyl acetate 98:2 to give Isomer A, white solid (0.70 g), m.p. 84.degree.-85.degree.; [.alpha.].sub.D.sup.26 =+75.9.degree. (MeOH); overlap Isomer A and Isomer B (0.85 g); and Isomer B, white solid (0.33 g), [.alpha.].sub.D.sup.26 =+15.6.degree. (MeOH).

Step 2: Using the procedure described in Example 1, Step 2, separately treat the Isomers of Step 1 above to obtain Isomers A and B of the title compound: Isomer A, a colorless oil, [.alpha.].sub.D.sup.26 =+13.5.degree. (MeOH); and Isomer B, a colorless oil, [.alpha.].sub.D.sup.26 =+38.2.degree. (MeOH).

EXAMPLE 4

N-(2-Benzyl-3-Mercaptopropionyl)-S-(4-Methoxybenzyl)-L-Cysteine (Isomers A and B)

Step 1: N-(3-Acetylthio-2-Benzylpropionyl)-S-(4-Methoxybenzyl)-L-Cysteine Methyl Ester (Isomers A and B) React S-(4-methoxybenzyl)-L-cysteine methyl ester hydrochloride (1.85 g) and 3-acetylthio-2-benzylpropionic acid (.95 g) in the manner described in Example 1, Step 1 to give an amber oil. Chromatograph this oil on a column of silica gel (2 L, 60-200 mesh) and elute with ethyl acetate:hexane 5:20 to give Isomer A, a clear oil (0.63 g), [.alpha.].sub.D.sup.26 =-66.5.degree. (MeOH), overlap Isomer A and Isomer B (0.28 g); and Isomer B, a clear oil (0.67 g), [.alpha.].sub.D.sup.26 =+3.0.degree. (MeOH).

Step 2: Using the procedure described in Example 1, Step 2 separately treat the isomers of Step 1 above to obtain Isomers A and B of the title compound: Isomer A, a viscous oil, [.alpha.].sub.D.sup.26 =-19.3.degree. (MeOH); and Isomer B, a viscous oil, [.alpha.].sub.D.sup.26 =-44.2.degree. (MeOH).

EXAMPLE 5

N-(2-Benzyl-3-Mercaptopropionyl)-S-(3,4-Dimethylbenzyl)-L-Cysteine (Isomers A and B)

Step 1: N-(3-Acetylthio-2-Benzylpropionyl)-S-(3,4-Dimethylbenzyl)-L-Cysteine Ethyl Ester (Isomers A and B): React S-(3,4-dimethylbenzyl)-L-cysteine ethyl ester hydrochloride (2.20 g) and 3-acetylthio-2-benzylpropionic acid (1.74 g) in the manner described in Example 1, Step 1 to give an amber oil. Place the oil on a column of silica gel (1 L) and elute with ethyl acetate:hexane 25:170 (4 L) and then methanol:hexane 25:170 to give a light orange oily solid. Repeat the chromatography to give Isomer A, a white solid (0.52 g), m.p. 89.5.degree.-92.5.degree., [.alpha.].sub.D.sup.26 =-71.1.degree. (MeOH) and Isomer B, a white solid (0.60 g), m.p. 51.degree.-55.degree., [.alpha.].sub.D.sup.26 =-8.4.degree. (MeOH).

Step 2: Using the procedure described in Example 1, Step 2, separately treat the Isomers of Step 1 above, to obtain Isomers A and B of the title compound: Isomer A, a clear viscous oil, [.alpha.].sub.D.sup.26 =-18.0.degree. (MeOH); and Isomer B, a clear viscous oil, [.alpha.].sub.D.sup.26 =-56.5.degree. (MeOH).

EXAMPLE 6

N-(2-Benzyl-3-Mercaptopropionyl)-S-Phenethyl-L-Cysteine (Isomers A and B)

Step 1: N-(3-Acetylthio-2-Benzylpropionyl)-S-Phenethyl-L-Cysteine Ethyl Ester, (Isomers A and B): React S-phenethyl-L-cysteine ethyl ester hydrochloride (2.85 g) and 3-acetylthio-2-benzylpropionic acid, (2.38 g) in a manner similar to that described in Example 1, Step 1 to give an amber oil. Chromatograph this oil on Prep 500 (2 silica gel cartridges) and elute with CH.sub.2 Cl.sub.2 (4 L) and then CH.sub.2 Cl.sub.2 :ethyl acetate 100:2 to give Isomer A, a white solid (1.32 g), m.p. 63.degree.-64.degree., [.alpha.].sub.D.sup.26 =-51.2.degree. (MeOH); overlap Isomer A and Isomer B (0.63 g); and Isomer B, white solid (b 1.14 g), m.p. 84.degree.-86.degree., [.alpha.].sub.D.sup.26 =+5.3.degree. (MeOH).

Step 2: Using the procedure described in Example 1, Step 2, separately treat Isomers A and B of Step 1 above to obtain Isomers A and B of the title compound. Isomer A, a colorless oil, [.alpha.].sub.D.sup.26 =+4.8.degree. (MeOH); and Isomer B, a colorless oil, [.alpha.].sub.D.sup.26 =-39.7.degree. (MeOH).

EXAMPLE 7

N-(2-Benzyl-3-Mercaptopropionyl)-S-(t-butyl)-L-Cysteine (Isomers A and B)

Step 1: N-(3-Acetylthio-2-Benzylpropionyl)-S-(t-Butyl)-L-Cysteine Methyl Ester (Isomers A and B): React S-(t-butyl)-L-cysteine methyl ester (2.32 g) and 3-acetylthio2-benzylpropionic acid (3.22 g) in the manner described in Example 1, Step 1 to give an orange solid. Chromatograph this solid on a column of silica gel (2L, 60-200 mesh) and elute with ethyl acetate:hexane 3:17 to give Isomer A, a clear oil (1.09 g), [.alpha.].sub.D.sup.26 =-44.9.degree. (MeOH); overlap Isomer A and Isomer B (0.52 g); and Isomer B, a clear oil (0.75 g), [.alpha.].sub.D.sup.26 +8.3.degree. (MeOH).

Step 2: Using the procedure described in Example 1, Step 2, separately treat the Isomers above to obtain Isomers A and B of the title compound; Isomer A, a clear viscous oil, [.alpha.].sub.D.sup.26 =+0.4.degree. (MeOH), and Isomer B, a white solid, m.p. 68.degree.-75.degree., [.alpha.].sub.D.sup.26 =-32.3.degree. (MeOH).

EXAMPLE 8

N-(2-Benzyl-3-Mercaptopropionyl)-L-Ethionine (Isomers A and B)

Step 1: N-(3-Acetylthio-2-Benzylpropionyl)-L-Ethionine Ethyl Ester (Isomers A and B): React L-ethionine ethyl ester (3.51 g) and 3-acetylthio-2-benzylpropionic acid (4.37 g) in a manner similar to that described in Example 1, Step 1 to give a yellow residue. Chromatograph the yellow residue on the Waters Prep 500 (2 silica gel cartridges) and elute with ethyl acetate:hexane 2:18 (16L), then ethyl acetate:hexane 3:17. Repeat chromatography of the fractions using ethyl acetate:hexane as eluant to give Isomer A, a white solid (0.89 g), m.p. 84.degree.-90.degree., [.alpha.].sub.D.sup.26 =-60.6.degree. (MeOH) and Isomer B (0.82 g), m.p. 79.degree.-84.degree., [.alpha.].sub.D.sup.26 =-0.3.degree. (MeOH).

Step 2: Using the procedure described in Example 1, Step 2, separately treat the Isomers of Step 1 above to obtain Isomers A and B of the title compound; Isomer A, a milky viscous oil, [.alpha.].sub.D.sup.26 =-41.8.degree. (MeOH); and Isomer B, a milky viscous oil, [.alpha.].sub.D.sup.26 =-66.0.degree. (MeOH).

EXAMPLE 9

N-(2-Benzyl-3-Mercaptopropionyl)-O-Benzyl-L-Tyrosine (Isomers A and B)

Step 1: N-(3-Acetylthio-2-benzylpropionyl)-O-benzyl-L-tyrosine Methyl Ester (Isomers A and B): React O-benzyl-L-tyrosine methyl ester hydrochloride (2.77 g) and 3-acetylthio-2-benzylpropionic acid (2.05 g) in a manner similar to that described in Example 1, Step 1 to give a yellow-orange oil. Chromatograph this oil on a column of silica gel (2.5L) and elute with CH.sub.2 Cl.sub.2 : ethyl acetate 98:2 to give Isomer A, a white solid (0.84 g) m.p. 108.degree.-109.degree.; [.alpha.].sub.D.sup.26 =-39.8.degree. (MeOH); overlap Isomer A and Isomer B (0.80 g); and Isomer B, white solid (0.45 g), m.p. 92.degree.-93.degree., [.alpha.].sub.D.sup.26 =+19.2.degree. (MeOH).

Step 2: Using the procedure described in Example 1, Step 2, separately treat the Isomers of Step 1 above to obtain Isomers A and B of the title compound: Isomer A, an off-white solid, [.alpha.].sub.D.sup.26 =+4.8.degree. (MeOH); and Isomer B, a viscous colorless oil [.alpha.].sub.D.sup.26 =+2.4.degree. (MeOH).

EXAMPLE 10

N-(2-Benzyl-3-Mercaptopropionyl)-(S)-Bishomophenyl Alanine (Isomers A and B)

Step 1: N-(3-Acetylthio-2-Benzylpropionyl)-(S)-Bishomophenylalanine t-Butyl Ester (Isomers A and B): React (S)-bishomophenylalanine t-butyl ester hydrochloride (2.49 g) and 3-acetylthio-2-benzylpropionic acid (2.39 g) in the manner described in Example 1, Step 1 to give a yellow oil. Chromatograph this oil on Waters Prep 500 (2 silica gel cartridges) and elute with CH.sub.2 Cl.sub.2 (4L) and then CH.sub.2 Cl.sub.2 : ethyl acetate 100:2 to give Isomer A, a colorless oil (0.99 g), [.alpha.].sub.D.sup.26 =-54.7.degree. (MeOH), overlap Isomer A and Isomer B (0.62 g); and Isomer B, a colorless oil (0.79 g), [.alpha.].sub.D.sup.26 =+5.1.degree. (MeOH).

Step 2: N-(3-Acetylthio-2-Benzylpropionyl)-(S)Bishomophenylalanine (Isomer A and B): To Isomer A of the product of Step 1 (0.97 g, 0.21 mmole) in CH.sub.2 Cl.sub.2 (10 ml) at 0.degree.-5.degree., add dropwise trifluoroacetic acid (10 ml). Warm the resulting mixture to room temperature, stir for 18 hours, and concentrate in vacuo. Dissolve the residue in CH.sub.2 Cl.sub.2 (10 ml) and concentrate in vacuo. Treat the residue with diethyl ether (10 ml) and concentrate in vacuo to give Isomer A of the title compound, a light amber oil (0.87 g), [.alpha.].sub.D.sup.26 =-43.0.degree. (MeOH).

By this same method, convert Isomer B of Step 1 to N-(3-acetylthio-2-benzylpropionyl)-(S)-Bishomophenylalanine Isomer B, a light amber oil, [.alpha.].sub.D.sup.26 =+19.6.degree. (MeOH).

Step 3: N-(2-Benzyl-3-Mercaptopropionyl)-(S)-Bishomophenylalanine (Isomers A and B): Dissolve Isomer A of Step 2 in methanol (15 ml) at 0.degree.-5.degree. under a nitrogen atmosphere and treat with 1N sodium hydroxide (6.3 ml). Treat the resulting mixture as described in Example 1, Step 2, to give Isomer A of the title compound, a pale yellow viscous oil (0.69 g), [.alpha.].sub.D.sup.26 =-25.4.degree. (MeOH).

By this same method, convert Isomer B of Step 2 to N-(2-benzyl-3-mercaptopropionyl)-(S)-bishomophenylalanine Isomer B, a pale yellow viscous oil, [.alpha.].sub.D.sup.26 =-50.0.degree. (MeOH).

In a similar manner, substitute (S)-(4-methylbenzyl)-L-cysteine t-butyl ester (Preparation 6) for (S)-bishomophenylalanine in Example 10, Step 1 to obtain

N-(3-acetylthio-2-benzylpropionyl)-(S)-(4-methylbenzyl)-L-cysteine t-butyl ester, Isomer A, [.alpha.].sub.D.sup.26 =-82.8.degree. (MeOH); and

N-(3-acetylthio-2-benzylpropionyl)-(S)-(4-methylbenzyl)-L-cysteine t-butyl ester, Isomer B, [.alpha.].sub.D.sup.26 =-23.5.degree. (MeOH).

Treat the above esters in a manner similar to that described in Example 10, Step 2 to obtain

N-(3-acetylthio-2-benzylpropionyl)-(S)-(4-methylbenzyl)-L-cysteine, Isomer A, [.alpha.].sub.D.sup.26 =-58.8.degree. (MeOH); and

N-(3-acetylthio-2-benzylpropionyl)-(S)-(4-methylbenzyl)-L-cysteine, Isomer B, [.alpha.].sub.D.sup.26 =-6.6.degree. (MeOH).

EXAMPLE 11

N-[3-MERCAPTO-2(R,S)-BENZYLPROPIONYL]-L-METHIONINE

Step 1: N-[3-Acetylthio-2(R,S)-Benzylpropionyl)-L-Methionine Methyl Ester: Add methionine methyl ester (2.00 g, 1.23 mmole) to 3-acetylthio-2-benzylpropionic acid (3.01 g, 1.26 mmole), DEC (2.34 g, 1.22 mmole), HOBT (1.88 g, 1.23 mmole) and NMM (2.34 g, 2.31 mmole) in DMF (12 ml), and treat the resulting mixture as described in Example 1, Step 1 to give an amber oil (4.36 g). Chromatograph the oil on a column of silica gel (1 L 60-200 mesh) elute with CH.sub.2 Cl.sub.2 (1 L) and then CH.sub.2 Cl.sub.2 : ethyl acetate 99:1 to give the title compound, a clear oil (2.61 g), [.alpha.].sub.D.sup.26 =-38.9.degree. (MeOH).

Step 2: N-[3-Mercapto-2(R,S)-Benzylpropionyl]-L-Methionine: Dissolve the product of Step 1 in methanol (20 ml) and treat with 1N NaOH (20.4 ml) as described in Example 1, Step 2 to give the title compound, a white solid, m.p. 132.degree.-5.degree., [.alpha.].sub.D.sup.26 =-34.6.degree. (MeOH).

Using the method of Example 11, Step 1, other N-[3-(R,S)-Acetylthio-2-benzylpropionyl]amino acid esters are prepared:

N-[3-Acetylthio-2(R,S)-benzylpropionyl]-S-methyl-L-cysteine ethyl ester, a clear oil, [.alpha.].sub.D.sup.26 =-25.9.degree. (MeOH);

N-[3-Acetylthio-2(R,S)-benzylpropionyl]-S-trityl-L-cysteine methyl ester, an amber oil, [.alpha.].sub.D.sup.26 =+5.9.degree. (MeOH); and

N-[3-Acetylthio-2(R,S)-benzylpropionyl]-(S)-tryptophan methyl ester, a colorless oil, [.alpha.].sub.D.sup.26 =-14.7.degree. (MeOH).

Similarly, from 3-benzoylthio-2(S)-benzylpropionic acid, prepare N-(3-benzoylthio-2(S)-benzylpropionyl)-S-methionine methyl ester, a white solid, m.p. 78.degree.-80.degree. C., [.alpha.].sub.D.sup.26 =-67.9.degree. (EtOH, c=1).

Using the procedure of Example 11, Step 2, convert the above acetylthio and benzoylthio compounds to the following 3-mercaptopropionyl compounds:

N-[2(R,S)-Benzyl-3-mercaptopropionyl]-S-methyl-L-cysteine, a clear viscous oil, [.alpha.].sub.D.sup.26 =-31.1.degree. (MeOH);

N-[2(R,S)-Benzyl-3-mercaptopropionyl]-S-trityl-L-cysteine, a white solid, [.alpha.].sub.D.sup.26 =+10.5.degree. (MeOH);

N-[2(R,S)-Benzyl-3-mercaptopropionyl]-(S)-tryptophan, a white foam, m.p. 68-69.degree., [.alpha.].sub.D.sup.26 =-0.5.degree. (MeOH); and

N-[2(S)-Benzyl-3-mercaptopropionyl]-S-methionine, a white solid, m.p. 88.degree.-89.degree..

EXAMPLE 12

N-[2-(4-Phenylbenzyl)-3-Mercaptopropionyl]-S-(4-Methylbenzyl)-L-Cysteine (S,R AND R,R Diastereomers)

Step 1: 3-Acetylthio-2-(4-Phenylbenzyl)Propionyl Chloride: To 3-acetylthio-2-(4-phenylbenzyl)propionic acid (3.39 g, 10.8 mmole) in toluene (25 ml) add 1% DMF in toluene (2 drops) and thionyl chloride (1.2 ml, 1.65 g, 13.8 mmoles) and stir the resulting solution at room temperature for 18 hours. Concentrate the reaction mixture in vacuo, dissolve the residue in toluene (100 ml) and concentrate the solution in vacuo to give the title compound, a light brown oil (3.37 g).

Step 2: N-[3-Acetylthio-2-(4-Phenylbenzyl)Propionyl]-S-(4-Methylbenzyl)-L-Cysteine (S,R and R,R diastereomers): Add the acid chloride (3.37 g) from Step 1 in acetonitrile (25 ml) dropwise to S-(4-methylbenzyl)-L-cysteine hydrochloride (2.62 g, 10 mmol) in acetonitrile (30 ml), water (15 ml) and triethylamine (2.8 ml), and stir the resulting mixture at room temperature for 4 hours. Concentrate the reaction mixture in vacuo and partition the residue between ethyl acetate (700 ml) and water (2.times.200 ml) and then saturated sodium chloride solution (100 ml). Dry the ethyl acetate solution (MgSO.sub.4) and concentrate in vacuo to give a brown solid. Chromatograph this solid on a column of silica gel (2L, 60-200 mesh) and elute with CH.sub.2 Cl.sub.2 :methanol:glacial acetic acid (97.5:2.5:0.25) to give a white foam (2.45 g). Chromatograph this white foam on a column of silica gel (1.2L, 60-200 mesh) and elute with CH.sub.2 Cl.sub.2 :methanol:glacial acetic acid (97.5:2.5:0.25) to give the S,R-diastereomer of title compound, a white solid (1.04 g), m.p. 123.degree.-125.degree., [.alpha.].sub.D.sup.26 =-45.5.degree. (EtOH) and the R,R-diastereomer of the title compound, a white solid (0.86 g), m.p. 131.degree.-135.degree., [.alpha.].sub.D.sup.26 =-7.1.degree. (MeOH).

Using a similar procedure, prepare the diastereomers of the following:

N-[3-acetylthio-2-benzylpropionyl]-S-(4-methylbenzyl)-L-cysteine: the S,R-diastereomer, a colorless oil, [.alpha.].sub.D.sup.26 =-23.0.degree. (MeOH) and the R,R-diastereomer, a yellow oil, [.alpha.].sub.D.sup.26 =-1.3.degree. (MeOH);

N-(2-acetythiomethyl-3-(4-methylphenyl-propionyl)-S-methionine: the S,S-diastereomer, a white solid, m.p. 90.degree.-93.degree., [.alpha.].sub.D.sup.26 =-32.2.degree. (EtOH, c=1) and the R,S-diastereomer, a white solid, [.alpha.].sub.D.sup.26 =+13.0.degree. (EtOH, c=1);

N-(2-acetylthiomethyl-3-phenylpropionyl)-S-methionine: the S,S-diastereomer, a white solid, m.p. 95.degree.-98.degree., [.alpha.].sub.D.sup.26 =-36.6.degree. (EtOH, c=1).

Step 3: N-[2-(4-Phenylbenzyl)-3-Mercaptopropionyl]-S-(4-Methylbenzyl)-L-Cysteine (S,R and R,R-diastereomers): Dissolve the S,R-diastereomer of Step 2 in methanol saturated with ammonia (50 ml) at 0.degree.-5.degree. under a nitrogen atmosphere. After 35 minutes, bubble nitrogen through the reaction mixture. Dilute the reaction mixture with water and acidify to pH 2-4 with 1N hydrochloric acid. Extract the acidic solution with ethyl acetate, dry the organic layer (MgSO.sub.4) and concentrate in vacuo to give the S,R-diastereomer of the title compound, a white solid (0.73 g). Purify the S,R-diastereomer by flash chromatography on silica gel (Baker flash silica gel, 40 .mu.M) (25 g) eluting with CHCl.sub.2 :MeOH:gl.AcOH, 97.5:2.5:0.25, to obtain a white solid (0.549 g), [.alpha.].sub.D.sup.26 =-2.2.degree. (MeOH).

In a similar fashion, prepare the R,R-diastereomer of the title compound, a white solid, [.alpha.].sub.D.sup.26 =-62.2.degree. (MeOH).

EXAMPLE 13

N-[2-Benzyl-3-Mercaptopropionyl]-L-Methionine Amide

Step 1: N-(3-Acetylthio-2-Benzylpropionyl)-L-Methionine Amide: In similar fashion to that described in Example 12, Step 2, convert L-methionine amide to N-(3-acetylthio-2-benzylpropionyl)-L-methionine amide. Recrystallize from hexane:CH.sub.2 Cl.sub.2 to obtain a solid, m.p. 101-3.degree.. Chromatograph on silica gel with 4% methanol/CH.sub.2 Cl.sub.2 to obtain the S,S-diastereomer, m.p. 149.degree.-51.degree., [.alpha.].sub.D.sup.26 =-87.5.degree. (CHCl.sub.3) and the R,S-diastereomer, m.p. 119.degree.-21.degree., [.alpha.].sub.D.sup.26 =+5.0.degree. (CHCl.sub.3).

Step 2: N-(2-Benzyl-3-Mercaptopropionyl)-L-Methionine Amide: Treat each of the 3-acetylthio diastereomers of Step 1 with NH.sub.3 /MeOH for 4 hours as in Example 12, Step 3, to give the S,S-diastereomer of the title compound, [.alpha.].sub.D.sup.26 =-67.8.degree. (EtOH, c=1), and the R,S-diastereomer of the title compound, m.p. 153.degree.-6.degree., [.alpha.].sub.D.sup.26 =+9.7.degree. (EtOH, c=1).

In a similar manner to that described in Example 13, Step 1, substitute the appropriate acetylthio compounds and amides and separate by chromatography to obtain:

N-(3-Acetylthio-2-benzylpropionyl)-S-(4-methylbenzyl)-L-cysteine amide, Isomer A, [.alpha.].sub.D.sup.26 =-38.2.degree. (MeOH);

N-(3-Acetylthio-2-benzylpropionyl)-S-(4-methylbenzyl)-L-cysteine amide, Isomer B, [.alpha.].sub.D.sup.26 =-1.6.degree. (MeOH);

N-[3-Acetylthio-2-(4-chlorobenzylpropionyl)]-L-methionine amide, Isomer A;

N-[3-Acetylthio-2-(4-chlorobenzylpropionyl)]-L-methionine amide, Isomer B, m.p. 166.degree.-9.degree.;

N-(3-Acetylthio-2(S)-phenylpropionyl)-S-3-(2-thienyl)alanine amide, a white solid, TLC R.sub.f =0.35 (1% EtOH/EtOAc); and

N-(3-Acetylthio-2(R)-phenylpropionyl)-S-3-(2-thienyl)alanine amide, TLC R.sub.f =0.30 (1% EtOH/EtOAc).

Treat the amides obtained above in a manner similar to that described in Example 13, Step 2 to obtain:

N-[2-(4-Chlorobenzyl)-3-mercaptopropionyl]-L-methionine amide, Isomer A, m.p. 194.degree., [.alpha.].sub.D.sup.26 =+1.2.degree. (MeOH);

N-[2-(4-Chlorobenzyl)-3-mercaptopropionyl]-L-methionine amide, Isomer B, [.alpha.].sub.D.sup.26 =-65.2.degree. (MeOH);

N-(2-Benzyl-3-mercaptopropionyl)-S-(4-methylbenzyl)-L-cysteine amide, Isomer A, m.p. 130.degree.-2.degree., [.alpha.].sub.D.sup.26 =-4.2.degree. (MeOH);

N-(2-Benzyl-3-mercaptopropionyl)-S-(4-methylbenzyl)-L-cysteine amide, Isomer B, [.alpha.].sub.D.sup.26 =-29.0.degree. (MeOH);

N-(2(S)-Benzyl-3-mercaptopropionyl)-S-3-(2-thienyl)alanine amide, a white solid, TLC R.sub.f =0.40 (4% MeOH/CH.sub.2 Cl.sub.2); and N-(2(R)-Benzyl-3-mercaptopropionyl)-S-3-(2-thienyl)alanine amide, TLC R.sub.f =0.35 (4% MeOH/CH.sub.2 Cl.sub.2).

EXAMPLE 14

N-(3-Benzoylthio-2-Benzylpropionyl)-L-Methionine Amide

Prepare the R and S enantiomers of 3-benzoylthio-2-benzylpropionic acid according to the procedure described in U.S. Pat. No. 4,329,495, herein incorporated by reference.

In a manner similar to that described in Example 1, Step 1, condense each acid separately with L-methionine amide to obtain

N-(3(S)-benzoylthio-2-benzylpropionyl)-L-methionine amide, m.p. 178.degree.-180.degree., [.alpha.].sub.D.sup.26 =-97.6.degree. (MeOH); and

N-(3(R)-benzoylthio-2-benzylpropionyl)-L-methionine amide, m.p. 145-9.degree., [.alpha.].sub.D.sup.26 =+32.9.degree. (CHCl.sub.3).

EXAMPLE 15

N-[2-Benzyl-3-Mercaptopropionyl]-L-Aspartic Acid .beta.-Benzyl Ester

In similar fashion to that described in Example 12, Step 2, convert L-aspartic acid .beta.-benzyl ester to N-(3-acetylthio-2-benzylpropionyl)-L-aspartic acid, .beta.-benzyl ester.

Treat with NH.sub.3 /MeOH as in Example 12, Step 3 to give the title compound, [.alpha.].sub.D.sup.26 =-5.7.degree. (EtOH, c=0.5).

EXAMPLE 16

N-[N-(2-Benzyl-3-Mercaptopropionyl)-L-Phenylalanyl]-L-Alanine

Using the procedure of Example 1, convert L-phenylalanyl-L-alanine benzyl ester hydrochloride to N-(N-(3-acetylthio-2-benzylpropionyl)-L-phenylalanyl]-L-alanine, benzyl ester.

Treat with NaOH as in Example 1, Step 2 to give the crude title compound. React the product (0.62 g) with zinc powder (0.5 g) and 5N HCl (10 ml) in 20 ml MeOH for 1 hour. Concentrate the mixture, extract with CH.sub.2 Cl.sub.2, dry, and remove the solvent to give the title compound, [.alpha.].sub.D.sup.26 =-23.1.degree. (EtOH, c=0.5).

Use the same procedure to prepare N-(N-(2-benzyl-3-mercaptopropionyl)-L-phenylalanyl-L-leucine, [.alpha.].sub.D.sup.26 =-20.8.degree. (EtOH, c=0.5).

EXAMPLE 17

N-[N-(2-Benzyl-3-Mercaptopropionyl)-L-Alanyl]-L-Proline

Step 1: N-[N-(3-Acetylthio-2-Benzylpropionyl)-L-Alanyl]-L-Proline: Using the procedure of Example 12, Step 2, convert L-alanyl-L-proline to N-[N-(3-acetylthio-2-benzylpropionyl)-L-alanyl]-L-proline, a white foam, [.alpha.].sub.D.sup.26 =-81.8.degree. (MeOH).

Step 2: N-[N-(2-Benzyl-3-Mercaptopropionyl)-L-Alanyl]-L-Proline: Treat the product from Step 1 with methanol saturated with ammonia as described in Example 12, Step 3 (before chromatography). Treat the resultant residue with zinc powder as described in Example 17. Chromatograph the product on flash grade silica gel using CH.sub.2 Cl.sub.2 MeOH:NH.sub.4 OH (97.5:2.5:0.25) to give the title compound, [.alpha.].sub.D.sup.26 =-118.2.degree. (MeOH).

EXAMPLE 18

N-(2(R,S)-Acetylthiomethyl-3-Phenylpropionyl)-S-Methionine Piperidine Amide

Step 1: Combine N-(t-butoxycarbonyl)-S-methionine (1.50 g, 6.0 mmol), piperidine (0.51 g, 6.0 mmol) and HOBT (0.91 g, 6.0 mmol) in DMF (40 ml). Add DEC (1.15 g, 6.0 mmol). Stir 5 hours, concentrate in vacuo, and partition between EtOAc and H.sub.2 O. Wash with aqueous NaHCO.sub.3, dry, and concentrate to obtain the piperidine amide as a colorless oil (TLC single spot R.sub.f =0.6 in 5% MeOH/CH.sub.2 Cl.sub.2).

Step 2: Treat the amide of Step 1 with 6M HCl/dioxane (25 ml). After 0.5 hr., concentrate in vacuo to obtain the amine hydrochloride as a foam.

Step 3: Treat the above amide hydrochloride of Step 2 with triethylamine (1.35 g, 15 mmol) in CH.sub.3 CN:H.sub.2 O 2:1 (60 ml). Add 2-acetylthiomethyl-3-phenylpropionyl chloride (1.37 g, 5.4 mmol), stir 1 hr., add 1N HCL (15 ml), and extract with EtOAc. Dry and concentrate to obtain a brown oil. Chromatograph on silica gel (2% MeOH/CH.sub.2 Cl.sub.2 as eluent) to obtain the product, a 3:2 mixture of S,S- and R,S-diastereomers, as a yellow oil, [.alpha.].sub.D.sup.26 =-31.7.degree. (EtOH, c=1).

Using a similar procedure, prepare the following mixtures of diastereomers:

N-(2(R,S)-acetylthiomethyl-3-phenylpropionyl)-S-methionine 4-methylbenzyl amide, a 1:1 mixture of diastereomers, a colorless foam, [.alpha.].sub.D.sup.26 =-18.6.degree. (EtOH, c=1);

N-(2(R,S)-acetylthiomethyl-3-phenylpropionyl)-S-methionine 2-hydroxyethyl amide, a 3:2 mixture of the S,S- and R,S-diastereomers, [.alpha.].sub.D.sup.26 =-31.1.degree. (EtOH, c=1); and

N-(2(R,S)-acetylthiomethyl-3-phenylpropionyl)-S-methionine morpholine amide, a 1:1 mixture of diastereomers, a yellow oil, [.alpha.].sub.D.sup.26 =-30.0.degree. (EtOH, c=1).

Using a similar procedure, prepare N-(2(R,S)-acetylthiomethyl-3-phenylpropionyl)-S-methionine pyrrolidine amide. Chromatograph on silica gel (elute with diethylether) to obtain the S,S-diastereomer as a yellow solid, [.alpha.].sub.D.sup.26 =-49.4.degree. (EtOH, c=1) and the R,S-diastereomer as a white solid, [.alpha.].sub.D.sup.26 =-6.1.degree. (EtOH, c=1).

Again, using a procedure similar to Example 18, prepare N-(2(S)-acetylthiomethyl-3-phenylpropionyl)-S-methionine 2-dimethylaminoethyl amide, a beige solid, [.alpha.].sub.D.sup.26 =-58.3.degree. (EtOH, c=1). Dissolve in CH.sub.2 Cl.sub.2, add HCl/Et.sub.2 O and concentrate to obtain the hydrochloride salt as a yellow gum.

EXAMPLE 19

N-(2(S)-Acetylthiomethyl-3-Phenylpropionyl)-S-Methionine 2-(2-Chloroethoxy)ethyl Ester

Step 1: Combine N-(t-butoxycarbonyl)-S-methionine (2.0 g, 8.0 mmol), 2-(2-chloroethoxy)ethanol (0.99 g, 8.0 mmol) and 4-dimethylaminopyridine in CH.sub.2 Cl.sub.2 (35 ml). Add DEC (1.54 g, 8.0 mmol). Stir 1 hour, concentrate, and partition between Et.sub.2 O and 1N HCl. Dry and concentrate to obtain the ester as an oil.

Step 2: Treat the ester of Step 1 with 6M HCl/dioxane (25 ml). After 35 min., concentrate and triturate the residue with Et.sub.2 O to obtain the amine hydrochloride as a solid.

Step 3: Treat the hydrochloride of Step 2 (1.30 g, 4.5 mmol) with triethylamine (0.90 g, 8.9 mmol) in CH.sub.3 CN:H.sub.2 O 2:1 (60 ml). Add 2-acetylthiomethyl-3-phenylpropionyl chloride (1.14 g, 4.5 mmol), stir 1 hour, add 1N HCl (13 ml), and extract with EtOAc. Dry and concentrate. Chromatograph on silica gel (Et.sub.2 O/hexane 6:4 as eluent) to obtain the title compound as a yellow solid, m.p. 58.degree.-63.degree., [.alpha.].sub.D.sup.26 =-44.7.degree. (EtOH, c=1).

In a similar manner, prepare mixtures of esters and separate by chromatography to obtain:

N-(2(S)-acetylthiomethyl-3-(4-methyphenyl)propionyl)-S-methionine 2-(2-chloroethoxy)ethyl ester, a yellow solid, [.alpha.].sub.D.sup.26 =-47.7.degree. (EtOH, c=1);

N-(2(R)-acetylthiomethyl-3-(4-methyphenyl)propionyl)-S-methionine 2-(2-chloroethoxy)ethyl ester, a yellow solid, [.alpha.].sub.D.sup.26 =-2.5.degree. (EtOH, c=1);

N-(2(S)-acetylthiomethyl-3-(2-methylphenyl)propionyl)-S-methionine 2-(2-chloroethoxy) ethyl ester, a yellow solid, [.alpha.].sub.D.sup.26 =-46.4.degree. (EtOH, c=1); and

N-(2(R)-acetylthiomethyl-3-(2-methylphenyl)propionyl)-S-methionine 2-(2-chloroethoxy) ethyl ester, a yellow solid, [.alpha.].sub.D.sup.26 =-17.7.degree. (EtOH, c=1).

EXAMPLE 20

N-(2(R,S)-ACETYLTHIOMETHYL-3-PHENYLPROPIONYL)-S-METHIONINE DIETHYLAMINOCARBONYLMETHYL ESTER

Step 1: Combine N-(t-butoxycarbonyl)-S-methionine (1.50 g, 6.0 mmol), N,N-diethylbromoacetamide (1.16 g, 6.0 mmol) and Cs.sub.2 CO.sub.3 (0.97 g, 3.0 mmol) in DMF (40 ml), stir 18 hours, and partition between EtOAc and H.sub.2 O. Wash with 1N NaHCO.sub.3, dry and concentrate to obtain the ester as an oil.

Step 2: Treat the ester as in Example 19, Steps 2 and 3, to obtain the title compound as a 3:2 mixture of S,S- and R,S-diastereomers, yellow oil, .alpha.].sub.D.sup.26 =-30.4.degree. (EtOH, c=1).

EXAMPLE 21

N-(2(S)-BENZOYLTHIOMETHYL-3-PHENYLPROPIONYL)-S-METHIONINE 2-(2-CHLOROETHOXY)ETHYL ESTER

Combine the product of Example 19, Step 2 (1.00 g, 3.4 mmol) with 2(S)-benzoylthiomethyl-3phenylpropionic acid (see U.S. Pat. No. 4,329,495) (1.03 g, 3.4 mmol), HOBT (0.52 g, 3.4 mmol) and triethylamine (0.86 g, 8.6 mmol) in DMF (35 ml). Add DEC (0.65 g, 3.4 mmol) and stir 18 hours. Concentrate and partition between EtOAc and H.sub.2 O. Wash with 1N NaHCO.sub.3, dry and concentrate. Chromatograph the resultant oil on silica gel (Et20:hexane 3:1 as eluant) to obtain the title compound, a white solid, [.alpha.].sub.D.sup.26 =-50.6.degree. (EtOH, c=1).

The R,S-diastereomer of the title compound may be prepared in a similar manner.

In a similar manner, prepare the following esters of N-(2(S)-benzoylthiomethyl-3-phenylpropionyl)-S-methionine:

2-(ethoxy)ethyl ester, a yellow solid, [.alpha.].sub.D.sup.26 =-49.9.degree. (EtOH, c=1);

2-(2-methoxyethoxy)ethyl ester, a white solid, [.alpha.].sub.D.sup.26 =-48.9.degree. (EtOH, c=1);

2,2-dimethyl-1,3-dioxolan-4-yl-methyl ester, a white solid, m.p. 76.degree.-78.degree., [.alpha.].sub.D.sup.26 =-58.6.degree. (MeOH, c=1).

The last compound may be converted to the 2,3dihydroxypropyl ester by hydrolysis with AGW-50 resin (H.sup.+ form) in CH.sub.3 CN:H.sub.2 O 2:1 for 20 hours and subsequent silica gel chromatography. The product ester is a white solid, [.alpha.].sub.D.sup.26 =-57.4.degree. (MeOH, c=1).

EXAMPLE 22

N-(3-PHENYL-2(S)-(4-PYRIDYLCARBONYLTHIOMETHYL) -PROPIONYL)-S-METHIONINE AMIDE AND

N-(3-PHENYL-2(R)-(4-PYRIDYLCARBONYLTHIOMETHYL) -PROPIONYL)-S-METHIONINE AMIDE

To N-(2(R,S)-mercaptomethyl-3-phenylpropionyl)-S-methionine amide (0.32 g, 1.0 mmol) and triethylamine (0.19 g, 1.9 mmol) in CH.sub.2 Cl.sub.2 (30 ml), add isonicotinoyl chloride hydrochloride (0.19 g, 1.1 mmol). After 3 hours, concentrate and chromatograph on silica (6% MeOH/CH.sub.2 Cl.sub.2 as eluent) to obtain:

the S,S-diastereomer, a yellow solid, m.p. 157.degree.-160.degree., [.alpha.].sub.D.sup.26 =-68.3.degree. (EtOH, c=1); and

the S,R-diastereomer, a white solid, [.alpha.].sub.D.sup.26 =+27.6.degree. (EtOH, c=1).

EXAMPLE 23

N-(2(R,S)-MERCAPTOMETHYL-3-PHENYLPROPIONYL)-S-TRYPTOPHAN 4-METHYLPIPERAZINE AMIDE HYDROCHLORIDE and N-(2(R,S)-MERCAPTOMETHYL-3-PHENYLPROPIONYL)-S-TRYPTOPHAN 2-(4-PYRIDYL)ETHYL AMIDE HYDROCHLORIDE

Step 1: Using the procedure of Example 18, prepare N-(2(R,S)-acetylthiomethyl-3-phenylpropionyl)-S-tryptophan-4-methylpiperaz ine amide and convert to the hydrochloride, a brown foam, mass spectrum M.sup.+ =506.

Similarly, prepare the hydrochloride of the 2-(4-pyridyl)ethyl amide, an off-white foam, mass spectrum M.sup.+ =528.

Step 2: Using the procedure of Example 12, Step 3, convert the products of Step 1 to the title compounds:

the 4-methylpiperazine amide hydrochloride, an off-white foam, mass spectrum M.sup.+ =486; and

the 2-(4-pyridyl)ethyl amide hydrochloride, a beige foam, mass spectrum M.sup.+ =464.

EXAMPLE 24

N-(2-BENZOYLTHIOMETHYL-3-PHENYLPROPIONYL)-METHIONINE 4-METHYLPIPERAZINE AMIDE HYDROCHLORIDE (S,S- and R,S-diastereomers)

Using procedures similar to Example 18, Step 1 and Example 1, Step 1, prepare the S,S-diastereomer of the title compound, a white solid, m.p. 157.degree.-158.degree.. Similarly, prepare the R,S diastereomer, a white solid, m.p. 114.degree.-116.degree..

In a similar manner prepare the diastereomeric mixture N-[(2(R,S)-benzoylthiomethyl-3-phenylpropionyl]-S-methionine 2-(4-pyridyl)ethyl amide, a white solid, m.p. 108.degree.-110.degree..

EXAMPLE 25

N-(2(S)-BENZOYLTHIOMETHYL-3-PHENYLPROPIONYL)-S-METHIONINE SULFOXIDE 2-(2-CHLOROETHOXY)ETHYL ESTER

To the title compound of Example 21 (1.00 g, 1.86 mmol) in MeOH (25 ml) add 30% H.sub.2 O.sub.2 (0.22 g, 4 mmol), stir 45 min. and concentrate. Triturate the residue with Et.sub.2 O:hexane 3:1 to obtain the title compound, a white solid, as a 1:1 mixture of sulfoxide diastereomers, NMR (CDCl.sub.3) .delta.2.42, 2.45.

In a similar manner, prepare the sulfoxide of the R,S-diastereomer of the title compound, a colorless oil, [.alpha.].sub.D.sup.26 =-2.8.degree. (EtOH, c=1).

Also in a similar manner prepare the sulfoxide of N-(2(S)-acetythiomethyl-3-phenylpropionyl)-S-methionine amide, a beige solid, [.alpha.]hd D.sup.26 =-50.6.degree. (EtOH, c=1).

EXAMPLE 26

N-(2(S)-MERCAPTOMETHYL-3-PHENYLPROPIONYL)-S-METHIONINE SULFOXIDE

Treat the title compound of Example 25 (the S,S-diastereomer) (0.46 g, 1.0 mmol) with MeOH (8 ml) and 1N NaOH (4 ml). Stir 18 hr. under N.sub.2, concentrate and add 1N HCl (4 ml). Extract with EtOAc, dry, concentrate and chromatograph on silica (CH.sub.2 Cl.sub.2 :MeOH:HOAc 90:9:1 as eluent) to obtain the title compound as a white solid, NMR (DMSO) .delta.2.45, 2.46.

EXAMPLE 27

N-[2(S)-ACETYLTHIOMETHYL-3-(2-METHYLPHENYL)PROPIONYL]-(S)-METHIONINE ETHYL ESTER and N-[2(R)-ACETYLTHIOMETHYL-3-(2-METHYLPHENYL)PROPIONYL]-(S)-METHIONINE ETHYL ESTER

Method A:

Combine S-methionine ethyl ester hydrochloride (3.00 g, 14.0 mmol), 2-acetylthiomethyl-3-(2-methylphenyl)propionic acid (Preparation 8) (3.52 g, 14.0 mmol), HOBT (2.14 g, 14.0 mmol) and triethylamine (2.82 g, 28.0 mmol) in dry DMF (60 ml). Add DEC (2.94 g, 15.4 mmol) and stir for 18 hr. Concentrate in vacuo, partition between EtOAc and H.sub.2 O, wash with 1N NaHCO.sub.3, dry and concentrate to obtain an oil. Chromatograph on 520 g Baker 60-200 silica, eluting with Et.sub.2 O: hexane to obtain first the S,S-diastereomer title compound, m.p. 92.degree.-93.degree., [.alpha.].sub.D.sup.26 =-59.9.degree. (MeOH) and then the R,S-diastereomer, m.p. 56.degree.-57.degree., [.alpha.].sub.D.sup.26 =-14.5.degree. (EtOH).

Method B

Step 1: Dissolve the product of Preparation 8 (18.9 g) in EtOAc (75 ml) and add R-(+)-.alpha.-methylbenzylamine (9.7 ml). After 18 hr., filter the solid and wash with hexane. Dissolve the resultant residue in EtOAc (500 ml) at 70.degree. C. and add hexane (500 ml). After 18 hr., filter and wash the solid. Recrystallize from EtOAc (450 ml) and hexane (350 ml) to obtain the salt of the S-acid, m.p. 135.degree.-137.degree.; [.alpha.].sub.D.sup.26 =-29.7.degree. (MeOH). Partition the above salt between EtOAc and 1N HCl. Dry and concentrate to give 2(S)-acetylthio-3-(2-methylbenzyl)propionic acid, m.p. 47.degree.-48.degree., [.alpha.].sub.D.sup.26 =-38.8.degree. (MeOH).

Step 2: Treat the acid from Step 1 with S-methionine ethyl ester hydrochloride as in Method A, conducting the reaction at 0.degree. C. Filter the crude product through silica to obtain only the S,S-diastereomer, m.p. 92.degree.-93.degree., [.alpha.].sub.D.sup.26 =-59.9.degree. (MeOH).

EXAMPLE 28

N-[2(S)-ACETYLTHIOMETHYL-3-(3-METHYLPHENYL)PROPIONYL-(S)-METHIONINE ETHYL ESTER and N-[2(R)-ACETYLTHIOMETHYL-3-(3-METHYLPHENYL)PROPIONYL-(S)-METHIONINE ETHYL ESTER

Using a procedure similar to that described in Example 27, but starting with the (3-methylphenyl) compound of Preparation 7, prepare the title compounds:

S,S-diastereomer: m.p. 71.degree.-76.degree., [.alpha.].sub.D.sup.26 =-63.4.degree. (MeOH);

R,S-diastereomer: m.p. 69.degree.-74.degree., [.alpha.].sub.D.sup.26 =+1.3.degree. (MeOH).

EXAMPLE 29

N-[2(S)-ACETYLTHIOMETHYL-3-(2-METHYLPHENYL)PROPIONYL]-(S)-METHIONINE AND N-[2(R)-ACETYLTHIOMETHYL-3-(2-METHYLPHENYL)PROPIONYL]-S-METHIONINE

Step 1: To 2-acetylthiomethyl-3-(2-methylphenyl)propionic acid (1.80 g, 7.0 mmol) in toluene (50 ml) add thionyl chloride (1.25 g, 10.5 mmol). Stir 18 hr, concentrate, dilute with toluene, concentrate, and repeat to obtain 2-acetylthiomethyl-3-(2-methylphenyl)propionyl chloride, a yellow liquid.

Step 2: To a solution of S-methionine (1.04 g, 7.0 mmol) and triethylamine (0.70 g, 7.0 mmol) in CH.sub.3 CN/H.sub.2 O (2:1) (60 ml), add the chloride, of Step 1 in CH.sub.3 CN (5 ml) dropwise. Stir 30 min., add 13 ml 1N HCl, dilute with H.sub.2 O and extract with EtOAc. Dry and concentrate to obtain a yellow oil. Chromatograph on 500 g Baker 60-200 silica eluting with CH.sub.2 Cl.sub.2 :MeOH:HOAc (190:9:1) to obtain first the S,S-diasteriomer, a solid, m.p. 99.degree., [.alpha.].sub.D.sup.26 =-37.5.degree. (EtOH), then the R,S-diastereomer, a solid, [.alpha.].sub.D.sup.26 =0.0.degree. (EtOH).

EXAMPLE 30

N-[2(S)-ACETYLTHIOMETHYL-3-(2-METHYLPHENYL)PROPIONYL]-(S)-METHIONINE METHYL ESTER and N-[2(R)-ACETYLTHIOMETHYL-3-(2-METHYLPHENYL)PROPIONYL]-(S)-METHIONINE METHYL ESTER

In similar fashion to that described in Example 27, Method A, combine S-methionine methyl ester hydrochloride with the product of Preparation 8 to obtain the S,S-diastereomer of the title product, a solid, m.p. 65.degree., [.alpha.].sub.D.sup.26 =-65.5.degree. (EtOH) and the R,S-diastereomer, a waxy solid, [.alpha.].sub.D.sup.26 =-16.8.degree. (EtOH).

In a similar manner, employing the appropriate acetylthio acid, prepare:

N-[2(S)-acetylthiomethyl-3-(4-methylphenyl) propionyl]-(S)-methionine methyl ester, m.p. 85.degree.-87.degree., [.alpha.].sub.D.sup.26 =-65.0.degree. (EtOH) and the corresponding R,S-diastereomer, m.p. 83.degree.-5.degree., [.alpha.].sub.D.sup.26 =+8.4.degree. (EtOH);

N-[2(S)-acetylthiomethyl-3-(3-methoxyphenyl)propionyl]-(S)-methionine methyl ester, m.p. 58.degree.-59.degree., [.alpha.].sub.D.sup.26 =-65.8.degree. (MeOH) and the corresponding R,S-diastereomer, m.p. 78.degree.-81.degree., [.alpha.].sub.d.sup.26 =-7.8.degree. (MeOH).

EXAMPLE 31

N[2(S)-MERCAPTOMETHYL-3-(2-METHYLPHENYL)PROPIONYL]-(S)-METHIONINE

To N-[2(S)-acetylthiomethyl-3-(2-methylphenyl)propionyl]-(S)-methionine methyl ester (0.60 g, 1.5 mmol) in degassed MeOH (15 ml) add 1.0N NaOH (degassed) (5.0 ml). After 2 hr., concentrate in vacuo to 5 ml., add 5.0 ml 1.0N HCl, and separate the gum. Dissolve this in EtOAc, dry and concentrate to obtain the title compound, m.p. 116.degree.-117.degree., [.alpha.].sub.D.sup.26 =+13.0.degree. (EtOH).

Using the same procedure with the R,S-diastereomer of the starting material, prepare the R,S-diastereomer of the title compound as a solid, [.alpha.].sub.D.sup.26 =-76.8.degree. (EtOH).

In similar fashion, prepare N-[2(S)-mercaptomethyl-3-(4-methylphenyl)propionyl]-(S)-methionine, m.p. 95.degree.-98.degree., [.alpha.].sub.D.sup.26 =+3.4.degree. (EtOH).

Claims

We claim:

1. A compound having the structural formula ##STR54## wherein R.sup.1 is phenyl substituted by alkyl, R.sup.2 is alkyl-S(O).sub.0-2 (CH.sub.2)q, R.sup.3 is OR.sup.7 wherein R.sup.7 is hydrogen or lower alkyl, Q is hydrogen or R.sup.10 CO-- wherein R.sup.10 is alkyl, n is 0-2 and q is 1-4.

2. A compound of claim 1 wherein R.sup.2 is alkyl-S(CH.sub.2)q.

3. A compound of claim 2 wherein n is 1.

4. A compound of claim 2 wherein q is 2.

5. A compound of claim 3 wherein q is 2.

6. A compound of claim 5 wherein R.sup.1 is 2-, 3- or 4-methylphenyl.

7. A compound of claim 6 wherein R.sup.1 is 2-methylphenyl.

8. A compound of claim 6 wherein R.sup.10 is methyl.

9. A compound of claim 6 which is selected from: N-[2-acetylthiomethyl-3-(2-methylphenyl)propionyl]-methionine ethyl ester; N-[2-acetylthiomethyl-3-(2-methylphenyl)propionyl]-methionine; N-[2-mercaptomethyl-3-(2-methylphenyl)propionyl]-methionine; N-[2-mercaptomethyl-3-(4-methylphenyl)propionyl]-methionine; N-[2-acetylthiomethyl-3-(2-methylphenyl)propionyl]-methionine methyl ester; N-[2-acetylthiomethyl-3-(4-methylphenyl)propionyl]-methionine methyl ester; and N-[2-acetylthiomethyl-3-(3-methylphenyl)propionyl]-methionine ethyl ester.

10. A compound of claim 9 which is the (S,S)-diastereomer.

11. A compound of claim 10 which is N-[2(S)-acetylthiomethyl-3-(2-methylphenyl)propionyl]-(S)-methionine ethyl ester.

12. A compound of claim 9 which is the (R,S)-diastereomer.

13. A compound of claim 9 which is a mixture of (S,S) and (R,S)-diastereomers.

14. An antihypertensive composition comprising an antihypertensive effective amount of a compound of claim 9 in a pharmaceutically acceptable carrier.

15. A method of treating hypertension or congestive heart failure comprising administering to a hypertensive human an antihypertensive effective amount of a compound of claim 1.

16. A method of claim 15 wherein the compound is selected from N-[2-acetylthiomethyl-3-(2-methylphenyl)propionyl]-methionine ethyl ester; N-[2-acetylthiomethyl-3-(2-methylphenyl)propionyl]-methionine; N-[2-mercaptomethyl-3-(2-methylphenyl)propionyl]-methionine; N-[2-mercaptomethyl-3-(4-methylphenyl)propionyl]-methionine; N-[2-acetylthiomethyl-3-(2-methylphenyl)propionyl]-methionine methyl ester; N-[2-acetylthiomethyl-3-(4-methylphenyl)propionyl]-methionine methyl ester; and N-[2-acetylthiomethyl-3-(3-methylphenyl)propionyl]-methionine ethyl ester.

17. A method of claim 16 wherein the compound is N-[2(S)-acetylthiomethyl-3-(2-methylphenyl)-propionyl]-(S)-methionine ethyl ester.

18. A method of treating congestive heart failure comprising administering to a human in need of such treatment an amount of a compound of claim 1 effective to treat congestive heart failure.

19. A method of claim 18 wherein the compound is selected from: N-[2-acetylthiomethyl-3-(2-methylphenyl)propionyl]-methionine ethyl ester; N-[2-acetylthiomethyl-3-(2-methylphenyl)propionyl]-methionine; N-[2-mercaptomethyl-3-(2-methylphenyl)propionyl]-methionine: N-[2-mercaptomethyl-3-(4-methylphenyl)propionyl]-methionine; N-[2-acetylthiomethyl-3-(2-methylphenyl)propionyl]-methionine methyl ester; N-[2-acetylthiomethyl-3-(4-methylphenyl)propionyl]-methionine methyl ester; and N-[2-acetylthiomethyl-3-(3-methylphenyl)propionyl]-methionine ethyl ester.

20. A method of claim 16 wherein the compound is N-[2(S)-acetylthiomethyl-3-(2-methylphenyl)propionyl]-(S)-methionine ethyl ester.

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