GB2077719A - (N-(Cycloalkyl)amino acid compounds and compositions containing same - Google Patents

Abstract

N-(Cycloalkyl)amino acid compounds of the formula: <IMAGE> in which: R1 is hydrogen or a lower alkyl group, R2 is hydrogen, acetyl or benzoyl, A is cyclopentyl, cyclohexyl or cycloheptyl, m is 0 or 1 p is 1 or 2, and DCHA is dicyclohexylamine or nil, and their salts, have activity in inhibiting angiotensin I converting enzyme. The compounds may be formulated as pharmaceutical compositions.

Description

SPECIFICATION N-(Cycloalkyl)amino acid compounds and compositions containing same This invention is concerned with certain novel N-(cycloalkyl)amino acid compounds, and with compositions containing them.

We have found that N-(cycloalkyl)amino acid compounds of the formula:

in which: R, is hydrogen or a lower alkyl group, R2 is hydrogen, acetyl or benzoyl, A is cyclopentyl, cyclohexyl or cycloheptyl, m is O or 1, p is 1 or 2, and DCHA is dicylohexylamine or nil, and salts thereof, are potent inhibitors of the enzyme responsible for converting the decapeptide angiotensin I to the octapeptide angiotensin II. Angiotensin II is the powerful pressor agent implicated as the causative agent in some forms of hypertension.

Of late, it has been recognized that a substance capable of interrupting the pathway whereby angiotensin II is produced, viz., the conversion hereabove referred to, presents a useful and effective means of combatting hypertension associated with that pressor agent.

The compounds of formula I and their salts are novel and constitute one aspect of the present invention.

The activity of these compounds has been demonstrated by in vitro techniques. For example, they inhibit the pure converting enzyme isolated from rabbit lung tissue at levels from about 0.041 ym to 0.248 ym. They are, therefore, notable angiotension I converting enzyme inhibitors.

The compounds of this invention are not limited to in vitro manifestations of their converting enzyme inhibiting activity. Upon oral administration, a dose-dependent antihypertensive effect in acute aortic coarctation hypertensive rats is elicited. Oral dosages of from 1 mg/kg to 200 mg/kg administered as a suspension in 0.5% Methocel solution achieve a reduction of 30 mm Hg in mean arterial blood pressure in such rats.

The present invention also comprises a pharmaceutical composition comprising at least one compound according to the invention and an inert, physiologically acceptable carrier or excipient.

Such compositions may be formulated in a variety of dosage forms such as tablets, capsules, solutions and the like for convenient administration employing classical excipients and adjuvants with which there is no incompatibility. Such dosage forms suitably contain from 10 to 500 mg of a compound of formula I or a salt thereof in a unit dosage form.

In order that the invention may be more fully understood, the following examples describing currently preferred methods for the preparation of the novel compounds are given by way of illustration.

Example I N-[3-(Benzoylthio)- 1 -oxopropyl]-N-cycloh exylglycin e A. N-cyclohexylglycine Glycine (37.5 g, 0.5 m) was dissolved in a solution of MeOH (400 ml) and NaOH (20 g, 0.5 m). To this mixture was added cyclohexanone (49.0 g, 0.5 m) and the resulting mixture was stirred for 0.5 hr. Thereafter palladium on charcoal (5%) (15 g) was added and this was hydrogenated on the Parr shaker for 6 hr. An additional 0.5 m of cyclohexanone was added, and the mixture was stirred for 0.5 hr, and then placed back on the Parr shaker for 8 hr.

Catalyst was filtered and the solution was evaporated to a slurry that was dissolved into H20 (500 ml), extracted with EtOAc (2 > c X 150 ml), acidified to pH = 6 with 6 N HCI, and evaporated to a solid. Recrystallization with hot H20 yielded 22 g (28%) of the title compound, m.p.

217-220"C; Rf-0.4 (silicagel, CHCL3, MeOH, HOAc: 8.5, 1.0, 0.5).

B. N-[3-(Benzoylthio)-1-oxopropyl]-N-cyclohexylglycine N-Cyclohexylglycine (11 g, 0.069 m) was dissolved in 1 N NaOH (69 ml) and then this solution was cooled to O"C with an ice salt bath. To this cooled solution was added 3 bromopropionyl chloride (11.8 g, 0.069 m) and 2 N NaOH (34.5 ml) dropwise, simultaneously over 1 5 min. The resulting mixture was stirred at room temperature for 4 hr. At this time a solution of potassium thiobenzoate (12.2 g, 0.069 m) in H20 (69 ml) was added dropwise to the reaction mixture. Stirring was continued overnight.The reaction was then cooled in an ice bath and acidifed with conc. HCI to a pH--2. The product oiled and was extracted with EtOAc (3 x 200 ml).EtOAc extractions were combined; washed 2 X 1 50 ml 1 N HCI, 2 X 1 50 ml H20, 2 X 1 50 ml sat. NaCI, and 1 x 1 50 ml H20; dried (MgSO4); filtered, and evaporated to an oil. The oil was triturated with hexanes to give a white solid which was filtered and recrystallized with EtOAc/hexanes to yield 3.8 g (15%) of the title compound; mp. 118-120 C; TLC: Rf 0.55 (75:25, toluene:acetic acid); IR and PMR were consistent with structure.

Anal. Calcd. for C18H23NG4S: C, 61.87%; H, 6.63% N, 4.01% Found: C, 61.91%, H, 6.70%; N, 3.85%.

Example II N-Cyclohexyl-N-(3-m ercapto- 1 -pxoprnpyl)glycine The solution of the compounds of Example 1 (4.0 g, 0.01 m) in concentrated ammonium hydroxide (15 ml) was stirred at ambient temperature, under a nitrogen atmosphere, for 4 hr.

The resulting mixture was filtered and washed with ethyl acetate (4 X 50 ml) to remove benzamide side product. The aqueous phase was acidified to pH 2 with concentrated hydrochloric acid and extracted 3 X 50 ml ethyl acetate. Ethyl acetate extractions were combined, washed with 100 ml water, dried (MgSO4), and evaporated to an oil.

This oil was dissolved in 5 ml chloroform: methanol: acetic acid (64:1:1) and passed through a column (1.5 cm X 60 cm) packed with 30 g silicagel in CHCl3: MeOH:HOAc (64:1:1).

Fractions of 6-7 ml were collected. TLC's were used to determine which fractions contained product. Those fractions were combined and evaporated to an oil which was triturated with hexanes to a solid. Solid was filtered and dried to yield 0.7 g (30%) of the title compound; m.p.

115-116 C; Ref=0.5 (silicagel, CHCL3;MeOH:HOAc, 64:1:1); PMR and IR are consistent with structure.

Anal. Calcd. for CHagNO3S C, 53.85; H, 7.81; N, 5.71 Found: C, 53.93; H, 7.60; N, 5.53.

Example III (SJ(-)-N-[3-(Acetylthio)- 1 -oxopropyU-N-cyclohexylalanin a A. L-N-Cyclohexylalanine Alanine (22.5 g, 0.25 m) was added to a solution of MeOH (400 ml) and NaOH (10 g, 0.25 m). Cyclohexanone (24.5 g, 0.25 m) was added and the mixture was stirred for 0.5 hr.

Thereafter palladium on charcoal (5%) (7.5 g) was added and this was hydrogenated on the Parr shaker for 4 hr. An additional 0.25 m of cyclohexanone was added, mixture was stirred for 0.5 hr, then placed back on the Parr shaker for overnight. Catalyst was filtered and solution was evaporated to a slurry that was dissolved in H20 (400 ml), extracted with EtOAc (3 X 100 ml) and acidified with 6 N HCI to pH = 6. Precipitate was filtered to give 24 g dried product; m.p.

275-280"C (dec.). Filtrate was evaporated to 1/2 its volume, cooled and precipitate was filtered to given an additional 9 g of product; m.p. 275-280"C (dec.). The two crops were combined to give 33 g (77%) of the title compound; Rf-0.35 (silica gel, CHCl3; MeOH:HOAc; 8.5:1:0.5).

B. (S) (-)-NI3-(Acetykhio)-1 -oxopropyl]-N-cyclohexylalanine L-N-Cyclohexylalanine (10 g, 0.06 m) was dissolved in pyridine (120 ml). This solution was cooled to -15", then 3-acetylthio-propanoyl chloride (8.0 ml, 10 g, 0.06 m) was added dropwise at a rate to maintain the temperature between 1 5-1 8". The ice bath was then removed and reaction was stirred at room temperature overnight.

The reaction mixture was added to 140 ml ice water, acidified with conc. HCI to a pH of 1-2 and extracted with 3 x 1 50 ml ether. The combined ether extracts were washed with 2 X 100 ml water, dried over MgSO4, treated with Darco, filtered and evaporated to a light yellow oil (wt.

9.5 g).

The oil was dissolved in 20 ml 5% HoAc/toluene and passed through a column (2.5 X 60 mm) packed with 1 50 g silica gel in 5% HOAc/toluene. The product was eluted from the column with 5% HOAc/toluene while collecting 7 ml fractions on a fraction collector. The fractions were checked by TLC (5% HOAc/toluene) and those fractions containing product were combined and evaporated to an oil, triturated with hexanes to a solid. Solid was recrystallized twice with nitromethane to yield 2.2 g (12%) of the title compound; m.p. 140-141 "C; TLC RfO.l (silica gel, 5% HOAc/toluene); [a0= -0.4" (C = 1, MeOH); IR and PMR were consistent to assigned structure.

Anal. Calcd. for C,4H23NO4S: C, 55.78; H, 7.69; N, 4.65 Found: C, 56.05; H, 7.88 N, 4.54.

Example IV (S)(-)-No-[3-(Acetylthio)- 1 -xopropylj-N-cyclopentylalanine A. L-N-Cyclopentylalanine Alanine (22.5 g, 0.25 M) was added to a solution of MeOH (400 ml) and NaOH (10 g, 0.25 m). Cyclopentanone (21 g, 22.1 ml, 0.25 m) was added and the mixture was stirred for 0.5 hr.

Thereafter palladium on charcoal (5%, 7.5 g) was added and this was hydrogenated on the Parr shaker for 4 hr. An additional 0.25 m of cyclopentanone was added, mixture was stirred for 0.5 hr, then placed back on the Parr shaker for overnight. Catalyst was removed by filtration and filtrate was evaporated to a slurry which was dissolved in H20 (500 ml), extracted with ethyl acetate (2 X 150 ml), and acidified with 6 N HCI to pH = 6. Solution was evaporated to a slurry, triturated with isopropanol, solid was filtered and dried to given 36.5 g (92%) of the title compound; m.p. 240"C (dec.); Rf-0.38 (silica gel, CHCL2:MeOH:HOAc; 8.5:1:0.5).

B. (S)(-)-N-[3-(Acetylth io)-1 -oxopropyl]-N-cyclopentylalanine L-N-Cyclopentylalanine (9.4 g, 0.06 m) was dissolved in pyridine (120 ml). This solution was cooled to 1 5", then 3-acetylthiopropanoyl chloride (8.0 ml, 10 g, 0.06 m) was added dropwise at a rate to maintain the temperature between 15-18". The ice bath was then removed and reaction was stirred at room temperature overnight.

The reaction mixture was added to 300 ml ice water, acidified with conc. HCI to a pH of 1-2 and extracted with 3 x 200 ml ether. The combined ether extracts were washed with 2 X 1 50 ml water, dried over MgSO4, treated with Darco, filtered and evaporated to an oil which crystallized upon standing. This solid was triturated with cold ether, filtered and recrystallized with ethyl acetate to yield 1.8 g (10%) of the title compound; m.p. 123-1 24"C; Rf-0.19 (silica gel, 9:1; toluene:acetic acid); [a]23 5 = - 0.6 (C = 2, HOAc); IR and PMR were consistent to assigned structure.

Anal. Calcd. for C,3H2lNO4S: C, 54.33; H, 7.37; N, 4.87 Found: C, 54.36; H, 7.32; N, 4.83.

Example V N-3-(Acetylthio)- 1-oxopropyl-N-cycloheptylalanine A. L-( + )-N-Cycloheptylalanine In methanol (400 ml) was placed a mixture of NaOH (20.0 g, 0.50 mole) and cycloheptanone (56.0 g, 0.50 mole), and the mixture was stirred for 16 hrs. Then 15.0 g of 5% Pd/C was added, and the mixture was subjected to reduction at 40 psi (initial) on a Parr apparatus. After 6 hr, 24 psi of the theoretical 34 psi was taken up. Another 35.0 g (0.31 mole) of cycloheptanone was introduced, and the mixture was let stand for 1 6 hr. The mixture was reduced catalytically for another 20 hrs, and another 1 3 psi was taken up.

The filtered solution was concentrated to a clear syrup. After adding water (500 ml), dissolution was achieved and the basic solution was extracted with ethyl acetate (500 ml). A white, crystalline solid began to precipitate from the aqueous solution and the pH was adjusted to 6 with conc. HCI and 1 N NaOH. The thick mass was filtered and the collected wet solid was stirred in 2-propanol (500 ml), collected, and let air-dry (82.3 g, 89%). A 1.0 g sample was recrystallized by suspension in refluxing absolute ethanol (50 ml) and slow addition of water (30 ml). The hot solution was filtered and allowed to cool, resulting in the title compound as a white solid, m.p. > 300"; a2D0= 11.8 (C = 1, 0.5NHC1).

Anal. Calcd. for C10H19NO2 C, 64.83; H, 10.34; N, 7.56 Found: C, 65.15; H, 10.43; N, 7.29.

B. N-3-(Acetylthio)-1 -oxopropyl-N-cycloheptylalanine A solution containing 1 N NaOH (100 ml), (S)-N-cycloheptylalanine (18.5 g, 0.10 m) and water (500 ml) was maintained at 5" while acetylthiopropionyl chloride (13.0 ml, 0.10 m) and 1 N NaOH (100 ml) were simultaneously added over 10 minutes. The mixture was diluted to 800 ml as solid was separating from solution. Sodium acetate (0.20 m) was added as the solid and another 0.10 m of acid chloride (13.0 m) was rapidly introduced. The mixture was stirred without cooling for 6 hr and was then filtered. The filtrate was acidified with dilute hydrochloric acid, extracted with ethyl acetate (2 X 400 ml) and the combined extract was washed with water (2 X 200 ml) and dried (MgSO4).

The filtered solution was concentrated to an oil which was chromatographed on a 60 X 6 cm column with silica (300 9), using toluene/acetic acid (20:1) as eluent. The UV-positive material at Ref 0.2 (silica gel, same eluent) was collected and evaporation of eluent yielded a solid which recrystallized from acetonitrile to give 4.8 9 of white solid. The sample was stirred in ether (50 ml) and collected, 4.29, 13% yield of the title compound; m.p. 110-111", [a]20=0.l0 (e = 10, DMF).

Anal. Calcd. forC'5H2sNO4S: C, 57.12; H, 7.99; N, 4.44 Found: C, 56.92; H, 8.00; N, 4.38.

Example VI N-[3-Benzoylthio- I -oxopropyl]-N-cyclopen tylglycin e A. N-Cyclopentylglycine Glycine (18.75 9, 0.25 m) was dissolved into a solution of MeOH (400 ml) and NaOH (10 g, 0.25 m). To this solution was added cylopentanone (22.1 9, 0.25 m) and the resulting mixture was stirred for 0.5 hr. Thereafter palladium on charcoal (5%) (7 9) was added and this mixture was hydrogenated on the Parr shaker for 6 hr. An additional 0.25 m of cyclopentanone was added, mixture was stirred for 0.5 hr, then placed back on the Parr shaker for overnight.

Catalyst was filtered, another 0.25 m cyclopentanone was added, mixture was stirred for 0.5 hr, another 7 9 5% palladium on charcoal was added, and mixture was hydrogenated on the Parr shaker for 4 hr (until H2 uptake had stopped). Catalyst was then filtered and filtrate was evaporated to an oil. To this oil was added 300 ml H2D. This resulted in a milky solution which was washed with 3 X 200 ml EtOAc. The pH of the aqueous phase was then adjusted to 6 with conc. HCI and the solution was evaporated to a slurry. The slurry was triturated with ispropanol and the resulting solid was filtered, triturate with cold nitromethane, filtered and dried to yield 22.6 9 (63%) of the title compound; TLC shows 1 major spot Err0.29 and 2 minor spots RfO.38 and 0.51 (silica gel, CHCl3, MeOH, HOAc; 8.5:1.0:0.5).

B. N-[3-Benzoylthio-1 -oxopropylj-N-cyclopentylglycine N-Cyclopentylglycine (15 9, 0.1 m) was dissolved in 1 N NaOH (105 ml, 0.1 m) and then this solution was cooled with an ice bath. To this cooled solution was added 3-bromopropionyl chloride (10.6 ml, 0.1 m) and 2 N NaOH (52.5 ml) dropwise, simultaneously over 15 min. The reaction was stirred for 4 hr at room temperature. At this time a solution of potassium thiobenzoate (18.5 9, 0.1 m) in 100 ml H20 was added dropwise to the reaction mixture.

Stirring was continued overnight.

The reaction was cooled in an ice bath and acidified with conc. HCI to pH 2 under a 100 ml layer of EtOAc. The layers were separated and the aqueous layer was extracted 3 x 100 ml Et OAc. The combined EtAOc layers were washed 3 X 1 0O ml 10% HCI, 1 X 100 ml H20, 2 x 100 ml sat. NaCI, 1 X 100 ml H20, dried with MgSO4, treated with Darco, filtered and evaporated to a sticky solid. This solid was triturated with cold Et2O, filtered and dried (wt. 7.2 9).

Recrystallization from hot nitromethane gave light yellow crystals, wt. 6.0 9 (18%) of the title compound; m.p. 151-152"C; TLC, Rf-0.30 (silica gel, 9:1, toluene:HOAc); IR and PMR are consistent with structure.

Anal. Calcd. for C,7H2,NO4S: C, 60.88; H, 6.31; N, 4.18 Found: C, 60.93; H, 6.36; N, 4.18.

Example VII N-[2-(Benzoylthioacetyl]-N-cycloh exylglycin e Dicycloh exyla mine Salt To N-cyclohexylglycine (15.7 g, 0.10 mole) in 100 ml of 1.0 NNaOH was added dropwise chloroacetyl chloride (8.0 ml, 0.10 mole) along with 100 ml of 1.0 N NaOH. Six hours layer potassium thiobenzoate (17.6 g, 0.10 mole) was added rapidly, and the mixture was stirred overnight.

Eighteen hours later the solution was at pH 8. The solution was made acid with dilute hydrochloric acid and extracted with ethyl acetate (200 ml). The organic layer was washed with water (100 ml) and dried (MgSO4).

The concentrated residue was chromatographed (300 g of chromatography grade silica, 60-200 mesh) with 20:1 toluene/acetic acid. The UV-positive spot at Rf = 0.05 on TLC silica plate was isolated after three major impurities were first eluted. The collected product of Rf = 0.05 was dissolved in ether, and addition of dicyclohexylamine yielded the title compound as a solid, m.p. 186-188" (8.2 9, 16% yield).

Anal. Calcd. for C7 H2,NO4S.Cr2H23N: C, 67.41; H, 8.58; N, 5.42 Found: C, 67.40; H, 8.64; N, 5.28.

Example VIII N-f3-(Acetyfthio%2-methyl- 1-oxopropyl]-N-cyclohexylglycine Dicyclohexylamine Salt N-Cyclohexylglycine (12 g, 0.076 m) was suspended in pyridine (150 ml). This mixture was cooled to 1 5"C with an ice bath. (i )-3-Acetylthio-2-mercaptopropanoyl chloride (13.8 g, 0.076 m) was added dropwise at a rate to maintain a temperature of 1 5"C. The mixture was stirred overnight at room temperature.

The reaction mixture was poured into 500 ml ice water and acidified to pH 2 with conc. HCI under a layer of 100 ml ether. The layers were separated and the aqueous layer was extracted with 2 x 200 ml ether. The ether layers were combined, washed with 1 X 150 ml H2O, 3 x 100 ml 10% HCL, 1 X 100 ml H2O, 2 X 150 ml sat. NaCI, 1 X 100 ml H2O, dried (MgSO4), treated with Darco, filtered, and evaporated to an oil.

The dicyclohexylamine salt was made by dissolving the oil (20 9, 0.06 m) in 300 ml ether, cooling the solution in an ice path, and adding dicyclohexylamine (13 ml. 0.06 m) dropwise (pH = 8). A solid formed; it was filtered, recrystallized with acetonitrile, rinsed with ether, and dried; wt. 7.5 g (20%) of the title compound; m.p. 1 34-1 35"C; TLC: Rf = 0.38 (silica gel, 10% HOAc/toluene); IR and PMR are consistent with structure.

Anal. Calcd. for C,4H23NO4S.C,2H22N: C, 64.69; H, 9.61; N, 5.8 Found: C, 64.39; H, 9.71; N, 5.6.

Example IX N-[2-(Benzoylthio)acetyl]-N-cyclohexylglycine The compound of Example VII (6.0 9, 0.012 mole) was stirred in a mixture of 5% potassium hydrogen sulphate (100 ml) and ethyl acetate (100 ml) for 0.5 hr. The separated aqueous layer was extracted with ethyl acetate (100 ml). The combined organic layers were washed with water (100 ml) and dried (MgSO4).

Evaporation under reduced pressure yielded a clear oil which crystallized upon trituration with hexane (200 ml). The solid was recrystallized from toluene to given 2.6 g (65% yield) of the tiltle compound; m.p. 115-117".

Anal. Calcd. for C,7H2,NO4S: C, 60.88; H, 6.31 N, 4.18 Found: C, 60.86; H, 6.25; N, 4.11.

Example X N-[3-(Benzoylth io)- ? -oxopropyl]-N-cycloh ep tylglycine Sodium hydroxide (20.0 g, 0.5 mole) was dissolved in methanol (400 ml). Glycine (37.5 9, 0.5 mole) and cycloheptanone (56.0 9, 0.5 mole) were added and the solution was stirred 1.0 hr. The solution was reduced on a Parr apparatus with 15.0 g of 5% Pd/C (50% H2O) at an initial pressure of 27 psi. After 2.0 hr the theoretical amount of hydrogen was taken up. The mixture was filtered and concentrated to a slushy material that was dissolved in water (200 ml) and brought to pH = 6.0 with conc. HCI and 1 N NaOH solution. Evaporation left a slushy material which was stirred in 2-propanol (400 ml). Filtration yielded 54.0 9 (63%) of crude Ncycloheptylglycine after air drying.

Water (100 ml) and 1.0 N NaOH (100 ml) were added to 17.1 g (0.10 mole) of the amino acid. The solution was cooled to 1 0", methylene chloride (200 ml) was added, and the stirred mixture was maintained at 5-10" while 3-(benzoylthio)propanoyl chloride (0.080 mole, 18.2 g) was added rapidly. In order to keep the solution pH at 7-8.5, 1.0 N NaOH was added dropwise as required, and 80 ml of the basic solution was added over 1.0 hr. Stirring was continued for 20.0 hr. The solutions were separated. The aqueous phase (pH = 7) was discarded and the wet organic layer was saved. The organic solution was treated with 1.0 N HCI (200 ml), separated, and washed with water (100 ml) and dried (MgSO4). Evaporation under reduced pressure left an oily residue.

The oil was dissolved in ethyl acetate (100 ml), and dicyclohexylamine was added dropwise until wet litmus gave a light green colour test. Light yellow solid slowly formed, and it was collected and recrystallized from nitromethane.

The recrystallized solid was stirred with ethyl acetate (100 ml) and 5% KHSO4 for an hour.

The separated organic layer was washed with water (100 ml) dried (MgSO4), and evaporated under reduced pressure to a solid. This solid was stirred in either (50 ml) and collected to give 2.1 g of the title compound (7.2%, 4.5% overall), m.p. 148-149".

A sample was recrystallized from acetonitrile to m.p. 149-151".

Anal. Calcd. for CagH25NO4S C, 62.44; H, 7.45; N, 3.83 Found: C, 62.79; H, 6.93; N, 3,85.

Example Xl N-Cyclopentyl-N-[3-merca 1 1 -oxopropyl]glycine The compound of Example VI (2 9, 0.006 m) was dissolved in conc. ammonium hydroxide.

This solution was stirred for 4 hr at ambient temp. The resulting solid was removed by filtration and the filtrate was diluted with water. This solution was washed with 3 X 50 ml of EtOAc.

Then the aqueous layer was acidified to pH = 2 with conc. HCI. The aqueous solution was extracted with 3 X 50 ml EtOAc. The combined extracts were washed (2 X 50 ml H2O), dried (MgSO4), treated with Darco, and evaporated to an oil. After trituration with hexanes, the title compound was filtered off as a solid (1.0 9, 72%); m.p. 105-107"; TLC: Rf-0.5 (silica gel; 25% HOAc/toluene); IR and PMR are consistent with structure.

Anal. Calcd. for C,oH,7NO3S: C, 51.92; H, 7.41; N, 6.06 Found: C, 52.08; H, 7.49; N, 6.03.

Example XII N-Cyclohexyl-N-[3-merca pto-2-methyl- 7 -oxopropyl]glycine N-r3-acetylthio-2-methyl-1-oxopropyl]-N-cycloheXylglycine (1.5 9, 0.005 m) was dissolved in 2.6 ml (0.04 m) conc. ammonium hydroxide. This solution was stirred for 4 hr. at ambient temperature. The solution was diluted with 50 ml of H2O, washed with 3 X 50 ml of EtOAc, and the aqueous layer was acidified with conc. HCI to pH = 2. This layer was extracted with 3 x 50 ml EtOAc. Extracts were combined, washed with 2 X 50 ml H2O, dried (MgSO4) and evaporated to an oil.

After triturating with hexanes, the title compound ws filtered as a solid (0.6 9, 46%); m.p.

83-86"C; TLC: Rr0.61 (75% toluene/HOAc); IR and PMR are consistent with structure.

Anal. Calcd. for C,2H2,NO3S: C, 55.57; H, 8.16; N, 5.40 Found: C, 55.48; H, 8.01; N, 5.27.

Claims (11)

1. Compounds of the formula:

in which: R, is hydrogen or a lower alkyl group, R2 is hydrogen, acetyl or benzoyl, A is cyclopentyl, cyclohexyl or cycloheptyl, m isO or 1, p is 1 or 2, and DCHA is dicyclohexylamine or nil, and their salts.

2. N-[3-Benzoylthio)- 1 -oxopropyl]-N-cyclohexylglycine.

3. N-Cyclohexyl-N-(3-mercapto-l -oxopropyl)glycine.

4. (S)-(-)-N-[3-Acetylthio)-l -oxopropyl]-N-cyclohexylalanine.

5. (S)-(-)-N-[3-Acetylthio)-l -oxopropyl]-N-cyclopentylalanine.

6. N-3-(Acetylthio)- 1 -oxopropyl-N-cycloheptylalanine.

7. N-[3-Benzoylthio- 1 -oxopropyl]-N-cyclopentylg Glycine.

8. N-[2-Benzoylthio)- 1 -acetyl]-N-cyclohexylglycine dicyclohexylamine salt.

9. N-[(3-Acetylthio)-2-methyl- 1 -oxopropyl]-N-cyclohexylglycine dicyclohexylamine salt.

10. N-[2-(Benzoylthio)acetyl]-N-cyclohexylglycine.

11. N-[3-Benzoylthio)- 1 -oxopropyl]-N-cycloheptylglycine.

1 2. N-Cyclopentyl-N-(3-mercapto- 1 -oxopropyl)glycine.

1 3. N-Cyclohexyl-N-(3-mercapto-2-methyl-l -oxopropyl)-glycine.

1 4. A pharmaceutical composition comprising at least one compound as claimed in any of claims 1 to 1 3 and an inert, physiologically acceptable carrier or excipient.

1 5. A composition according to claim 14 which is in unit dosage form and which contains from 10 to 500 mg of said compound(s) per unit dosage.