Amino acid 1,2-diketo derivatives as renin inhibitors

Compounds of the formula ##STR1## are disclosed. These compounds interevene in the conversion of angiotensin to angiotensin II by inhibiting renin and thus are useful as anti-hypertensive agents.

FIELD OF THE INVENTION 
The present invention relates to amino acid derivatives and more 
particularly concerns 1,2-diketo derivatives useful, for example, as renin 
inhibitors. 
BACKGROUND OF THE INVENTION 
Szelke et al., in European Patent Application No. 0,104,041 A1, disclose 
various polypeptide analogues. These analogues, useful as renin 
inhibitors, include polypeptide 1,2-ketoamides wherein the amide group 
comprises a peptidic function. 
In Australian Patent Abstract No. AU-A-52881/86, Kolb et al. disclose new 
activated electrophilic ketone-bearing peptidase inhibitors. Among the 
analogues disclosed are polypeptidyl 1,2-hydroxy esters and 1,2-keto 
esters useful for renin inhibition. 
Kubota et al., in European Patent Application No. 0,190,891 A2, disclose 
amino acid derivatives of the formula 
##STR2## 
wherein when n=0, polypeptidyl 1,2-hydroxy esters are provided. These 
compounds are also disclosed as having activity as renin inhibitors. 
Matsueda et al., in Japanese Patent No. J6 1078-795-A, disclose peptides of 
the formula 
##STR3## 
When X is 
##STR4## 
Y is hydroxy, A is a single bond, and R.sub.3 is optionally protected 
carboxy, acyl; 1,2-hydroxy esters and 1,2-hydroxy ketones, useful as renin 
inhibitors, are provided. 
SUMMARY OF THE INVENTION 
In accordance with the present invention new diketone derivatives useful as 
renin inhibitors are disclosed. These compounds have the formula 
##STR5## 
wherein X is R.sub.6 --(CH.sub.2).sub.m --, 
##STR6## 
R.sub.1 is hydrogen, alkyl, arylalkyl, aryl, heteroalkyl or a fully 
saturated, partially saturated, or unsaturated monocyclic heterocyclic 
ring of 5 or 6 atoms. The heterocyclic ring is attached to 
##STR7## 
by way of an available carbon atom. 
##STR8## 
represents a heterocyclic ring of the formula 
##STR9## 
wherein Y is --CH.sub.2, O, S, or N--R.sub.9, a is an integer from 1 to 
4, and b is an integer from 1 to 4 provided that the sum of a plus b is an 
integer from 2 to 5; 
R.sub.3, R.sub.4, R.sub.5 and R.sub.10 are independently selected from 
hydrogen, lower alkyl, halo substituted lower alkyl, --(CH.sub.2).sub.n 
-aryl, --(CH.sub.2).sub.n -heterocyclo, --(CH.sub.2).sub.n --OH, 
--(CH.sub.2).sub.n --O-lower alkyl, --(CH.sub.2).sub.n --NH.sub.2, 
--(CH.sub.2).sub.n --SH, --(CH.sub.2).sub.n --S-lower alkyl, 
--(CH.sub.2).sub.n --O--(CH.sub.2).sub.g --OH, --(CH.sub.2).sub.n 
--O--(CH.sub.2).sub.g --NH.sub.2, 
##STR10## 
and --(CH.sub.2).sub.n -cycloalkyl; R.sub.6 and R.sub.6 ' are 
independently selected from lower alkyl, cycloalkyl, aryl and heterocyclo; 
p is zero or one; 
q is zero or one; 
m and m' are independently selected from zero and an integer from 1 to 5; 
n is an integer from 1 to 5; 
g is an integer from 2 to 5; 
R.sub.7 is 
##STR11## 
R.sub.8 is 2,4-dinitrophenyl, 
##STR12## 
R.sub.9 is hydrogen, lower alkyl, 
##STR13## 
or --(CH.sub.2).sub.n -cycloalkyl. 
DETAILED DESCRIPTION OF THE INVENTION 
This invention in its broadest aspects relates to the compounds of formula 
I above, to compositions and the method of using such compounds as 
antihypertensive agents. 
The term lower alkyl used in defining various symbols refers to straight or 
branched chain radicals having up to seven carbons. Similarly, the terms 
lower alkoxy and lower alkylthio refer to such lower alkyl groups attached 
to an oxygen or sulfur. The preferred lower alkyl groups are straight or 
branched chain of 1 to 5 carbons. 
The term cycloalkyl refers to saturated rings of 4 to 7 carbon atoms with 
cyclopentyl and cyclohexyl being most preferred. 
The term halogen refers to chloro, bromo and fluoro. 
The term halo substituted lower alkyl refers to such lower alkyl groups 
described above in which one or more hydrogens have been replaced by 
chloro, bromo or fluoro groups such as trifluoromethyl, which is 
preferred, pentafluoroethyl, 2,2,2-trichloroethyl, chloromethyl, 
bromomethyl, etc. 
The term aryl refers to phenyl, 1-naphthyl, 2-naphthyl, mono substituted 
phenyl, 1-naphthyl, or 2-naphthyl wherein said substituent is lower alkyl 
of 1 to 4 carbons, lower alkythio of 1 to 4 carbons, lower alkoxy of 1 to 
4 carbons, halogen, hydroxy, amino, --NH-alkyl wherein alkyl is of 1 to 4 
carbons, or --N(alkyl).sub.2 wherein alkyl is of 1 to 4 carbons, di or tri 
substituted phenyl, 1-naphthyl or 2-naphthyl wherein said substituents are 
selected from methyl, methoxy, methylthio, halogen, and hydroxy. 
The term heterocyclo refers to fully saturated or unsaturated rings of 5 or 
6 atoms containing one or two O and S atoms and/or one to four N atoms 
provided that the total number of hetero atoms in the ring is 4 or less. 
The hetero ring is attached by way of an available carbon atom. Preferred 
hetero groups include 2- and 3-thienyl, 2- and 3-furyl, 2-, 3- and 
4-pyridyl. The term hetero also includes bicyclic rings wherein the five 
or six membered ring containing O, S and N atoms as defined above is fused 
to a benzene ring. The preferred bicyclic ring is benzimidazolyl. 
The compounds of formula I wherein X is 
##STR14## 
can be prepared by treating a compound of the formula 
##STR15## 
with n-butyl lithium and thereafter reacting same with the starting 
material of the formula 
EQU R.sub.1 -Halogen III 
to provide a compound having the formula 
##STR16## 
An N-protected amino acid ester of the formula 
##STR17## 
(wherein Prot is an amino protecting group such as t-butoxycarbonyl) is 
treated with lithium borohydride to give the alcohol of the formula 
##STR18## 
Treatment of the alcohol of formula VI with pyridine-sulfur trioxide 
complex or with periodinane reagent (see Dess et al., J. Org. Chem., Vol. 
48, p. 5155-5156 (1983)) produces an aldehyde of the formula 
##STR19## 
The aldehyde of formula VII is thereafter reacted with the compound of 
formula IV in the presence of n-butyl lithium to provide a compound of the 
formula 
##STR20## 
which can be deprotected such as by treatment with hydrochloric acid to 
provide the alcohol of the formula 
##STR21## 
The alcohol of formula IX is thereafter coupled with a peptide of the 
formula 
##STR22## 
preferably in a solvent such as tetrahydrofuran or dimethylformamide and 
in the presence of hydroxybenzotriazole, a base such as N-methylmorpholine 
or diisopropylethyl amine, and a coupling agent such as 
dicyclohexylcarbodiimide to provide 
##STR23## 
Compound XI is treated with an oxidizing agent, such as ammonium ceric 
nitrate or thallic nitrate to provide the hydroxy keto compound of the 
formula 
##STR24## 
Treatment of the compound of formula XII with, for example, the 
periodinane reagent (cited above in the formation of compound VII) 
provides 
##STR25## 
that is, compounds of formula I wherein X is 
##STR26## 
and p is one. 
To prepare the compounds of the invention wherein X is 
##STR27## 
and p is zero, the amino alcohol of formula IX can be reacted with the 
amino acid of the formula 
##STR28## 
to yield the compounds of the formula 
##STR29## 
Compound XV is thereafter treated as compounds XI and XII above to provide 
the diketone derivatives wherein p is zero. 
The compound of formula I wherein X is other than 
##STR30## 
can be prepared by using compounds of formula XI wherein 
##STR31## 
is either t-butoxycarbonyl or benzyloxycarbonyl as the starting material. 
Removal of the t-butoxycarbonyl or benzyloxycarbonyl by standard amine 
deprotecting means provides the intermediates of the formula 
##STR32## 
The amine of formula XVI is treated with the halide of the formula 
EQU R.sub.6 --(CH.sub.2).sub.m -halo, XVII 
particularly where halo is bromine, to provide the product 
##STR33## 
Compound XVIII is thereafter treated as compounds XI and XII above to 
provide the diketone derivative of formula I wherein p is one and X is 
R.sub.6 --(CH.sub.2).sub.m --. 
Similarly, by starting with compound XV where 
##STR34## 
is either t-butoxycarbonyl or benzyloxycarbonyl, and carrying out standard 
amine deprotection, intermediates XIX can be obtained, 
##STR35## 
The amine of formula XIX can thereafter be reacted with the halide of 
formula XVII to provide a compound of the formula 
##STR36## 
Compound XX is thereafter treated as compounds XI and XII above to provide 
the products of formula I wherein X is R.sub.6 --(CH.sub.2).sub.m -- and p 
is zero. 
The compounds of formula I wherein X is 
##STR37## 
can be prepared by treating the amine of formula XVI or XIX with the acid 
chloride of the formula 
##STR38## 
in the presence of a base such as triethylamine, followed by treatment as 
with compounds XI and XII above. 
The compounds of formula I wherein X is R.sub.6 --(CH.sub.2).sub.m 
--SO.sub.2 -- can be prepared by treating the amine of formula XVI or XIX 
with the substituted sulfonyl chloride of the formula 
EQU R.sub.6 --(CH.sub.2).sub.m --SO.sub.2 --Cl, XXII 
followed by treatment as with compounds XI and XII above. 
The compounds of formula I wherein X is 
##STR39## 
can be prepared by treating the amine of formula XVI or XIX with the acid 
chloride of the formula 
##STR40## 
in the presence of triethylamine, followed by treatment as with XI and 
XII. Alternatively, these compounds can be prepared by coupling the 
carboxylic acid of the formula 
##STR41## 
to the amine of formula XVI or XIX in the presence of a coupling agent, 
such as dicyclohexylcarbodiimide, and 1-hydroxybenzotriazole hydrate, 
followed by treatment as with compounds XI and XII. 
The compounds of formula I wherein X is 
##STR42## 
and q is one can be prepared by acylating the amino acid of the formula 
##STR43## 
with the acid chloride of formula XXIII in the presence of a base, such as 
sodium hydroxide, and in a solvent, such as tetrahydrofuran, and water to 
give the acylated amino acid of the formula 
##STR44## 
The amino acid of formula XXVI is then coupled to the amine of formula XVI 
or XIX in the presence of dicyclohexylcarbodiimide and 
1-hydroxybenzotriazole hydrate followed by treatment as with compounds XI 
and XII to give the desired compounds of formula I. 
The compounds of formula I wherein X is 
##STR45## 
and p is one can be prepared by coupling an amino acid of the formula 
##STR46## 
to the amine of formula XIX in the presence of a coupling agent, such as 
dicyclohexylcarbodiimide, and 1-hydroxybenzotriazole hydrate, followed by 
treatment as with compounds XI and XII. 
Similarly, the compounds of formula I wherein X is 
##STR47## 
and p is zero can be prepared by coupling an amino acid of the formula 
##STR48## 
to an amino alcohol of formula IX in the presence of a coupling agent, 
such as dicyclohexylcarbodiimide, and 1-hydroxybenzotriazole hydrate to 
provide a compound of the formula 
##STR49## 
Compound XXIX can thereafter be treated as compounds XI and XII above to 
provide the diketo compound of formula I wherein X is 
##STR50## 
and p is zero. 
The compounds of formula I wherein X is 
##STR51## 
and p is one can be prepared by coupling an amino acid of the formula 
##STR52## 
to the amine of formula XIX in the presence of a coupling agent and 
1-hydroxybenzotriazole hydrate, followed by treatment as with compounds XI 
and XII. Similarly the compound of formula I wherein X is 
##STR53## 
and p is zero can be prepared by coupling an amino acid of the formula 
##STR54## 
to the amino alcohol of formula IX in the presence of the above-described 
coupling agent and hydrate to provide a compound of the formula 
##STR55## 
Compound XXXII is thereafter treated as compounds XI and XII above to 
provide the diketone compounds of formula I wherein X is 
##STR56## 
and p is zero. 
The amino acid intermediates of formulas XXVII, XXVIII and XXXI can be 
prepared by treating an amine R.sub.6 --(CH.sub.2).sub.m --NH.sub.2 or 
##STR57## 
with phosgene and N-methylmorpholine followed by reaction with an amino 
acid methyl ester hydrochloride salt of the formula 
##STR58## 
or of the formula 
##STR59## 
in the presence of N-methylmorpholine. Removal of the methyl ester group 
by treatment with aqueous sodium hydroxide gives the desired intermediate. 
The products of formula I wherein X is 
##STR60## 
can be prepared by coupling the carboxylic acid of the formula 
##STR61## 
to the amine of formula XVI or XIX in the presence of 
dicyclohexylcarbodiimide and 1-hydroxybenzotriazole hydrate, followed by 
treatment as with compounds XI and XII. Alternatively, the acid of formula 
XXXV can be converted to the acid chloride and this acid chloride can then 
be coupled to the amine of formula XVI or XIX in the presence of 
triethylamine and tetrahydrofuran and followed by treatment as with 
compounds XI and XII. 
The compounds of formula I wherein X is 
##STR62## 
can be prepared by acylating proline with the acid chloride of formula 
XXIII in the presence of base such as sodium hydroxide, i.e., a pH of 
about 8, and a solvent mixture of tetrahydrofuran and water to give 
##STR63## 
The acylated amino acid of formula XXXVI is then coupled to the amine of 
formula XVI or XIX in the presence of a coupling agent such as 
dicyclohexylcarbodiimide and 1-hydroxybenzotriazole hydrate, followed by 
treatment as with XI and XII. 
In the above reactions, if any of R.sub.3, R.sub.4, R.sub.5 and R.sub.10 
are --(CH.sub.2).sub.n -aryl wherein aryl is phenyl, 1-naphthyl, 
2-naphthyl substituted with one or more hydroxy or amino groups, 
--(CH.sub.2).sub.n -heterocyclo wherein heterocyclo is an imidazolyl, 
--(CH.sub.2).sub.n --NH.sub.2, --(CH.sub.2).sub.n --SH, --(CH.sub.2).sub.n 
--OH, 
##STR64## 
then the hydroxyl, amino, imidazolyl, mercaptan, carboxyl, or guanidinyl 
function should be protected during the reaction. Suitable protecting 
groups include benzyloxycarbonyl, t-butoxycarbonyl, benzyl, benzhydryl, 
trityl, tosyl, etc., and nitro in the case of guanidinyl. The protecting 
group is removed by hydrogenation, treatment with acid, or by other known 
means following completion of the reaction. 
The various peptide intermediates employed in above procedures are known in 
the literature or can be readily prepared by known methods. See for 
example, the Peptides, Volume 1, "Major Methods of Peptide Bond 
Formation", Academic Press (1979). 
Preferred compounds of this invention are those of formula I wherein 
X is 
##STR65## 
R.sub.6 is selected from straight or branched chain lower alkyl of up to 5 
carbons, cycloalkyl of 4 to 6 carbons, phenyl, 1-naphthyl, and 2-naphthyl; 
m is selected from zero, one and two; 
R.sub.1 is alkyl, arylalkyl, aryl, or heteroaryl; 
R.sub.3 is straight or branched chain lower alkyl of 3 to 5 carbons, 
--(CH.sub.2).sub.n -cyclopentyl, --(CH.sub.2).sub.n -cyclohexyl, or 
##STR66## 
wherein n is an integer from 1 to 3; R.sub.4 is hydrogen, straight or 
branched chain lower alkyl of up to 5 carbons, --(CH.sub.2).sub.4 
--NH.sub.2, 
##STR67## 
R.sub.5 is straight or branched chain lower alkyl of up to 5 carbons, 
##STR68## 
Most preferred are those compounds of formula I wherein 
##STR69## 
The compounds of formula I form salts with a variety of inorganic and 
organic acids. The nontoxic pharmaceutically acceptable salts are 
preferred, although other salts are also useful in isolating or purifying 
the product. Such pharmaceutically acceptable salts include those formed 
with hydrochloric acid, methanesulfonic acid, sulfuric acid, acetic acid, 
maleic acid, etc. The salts are obtained by reacting the product with an 
equivalent amount of the acid in a medium in which the salt precipitates. 
The compounds of formula I contain asymmetric centers when any or all of 
R.sub.3, R.sub.4, R.sub.5 and R.sub.10 are other than hydrogen and at the 
carbon to which the --OH group is attached. Thus, the compounds of formula 
I can exist in diastereoisomeric forms or in mixtures thereof. The 
above-described processes can utilize racemates, enantiomers or 
diastereomers as starting materials. When diastereomeric products are 
prepared, they can be separated by conventional chromatographic or 
fractional crystallization methods. 
The compounds of formula I, and the pharmaceutically acceptable salts 
thereof, are antihypertensive agents. They inhibit the conversion of 
angiotensinogen to angiotensin I and therefore, are useful in reducing or 
relieving angiotensin related hypertension. The action of the enzyme renin 
on angiotensinogen, a pseudoglobulin in blood plasma, produces angiotensin 
I. Angiotensin I is converted by angiotensin converting enzyme (ACE) to 
angiotensin II. The latter is an active pressor substance which has been 
implicated as the causative agent in several forms of hypertension in 
various mammalian species, e.g., humans. The compounds of this invention 
intervene in the angiotensinogen.fwdarw.(renin).fwdarw.angiotensin 
I.fwdarw.(ACE).fwdarw.angiotensin II sequence by inhibiting renin and 
reducing or eliminating the formation of the pressor substance angiotensin 
II. Thus by the administration of a composition containing one (or a 
combination) of the compounds of this invention, angiotensin dependent 
hypertension in a species of mammal (e.g., humans) suffering therefrom is 
alleviated. A single dose, or preferably two to four divided daily doses, 
provided on a basis of about 100 to 1000 mg, preferably about 250 to 500 
mg per kg of body weight per day is appropriate to reduce blood pressure. 
The substance is preferably administered orally, but parenteral routes 
such as the subcutaneous, intramuscular, intravenous or intraperitoneal 
routes can also be employed. 
The compounds of this invention can also be formulated in combination with 
a diuretic for the treatment of hypertension. 
A combination product comprising a compound of this invention and a 
diuretic can be administered in an effective amount which comprises a 
total daily dosage of about 1000 to 6000 mg, preferably about 3000 to 4000 
mg of a compound of this invention, and about 15 to 300 mg, preferably 
about 15 to 200 mg of the diuretic, to a mammalian species in need 
thereof. Exemplary of the diuretics contemplated for use in combination 
with a compound of this invention are the thiazide diuretics, e.g., 
chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, 
bendroflumethiazide, methylclothiazide, trichloromethiazide, polythiazide 
or benzthiazide as well as ethacrynic acid, tricrynafen, chlorthalidone, 
furosemide, musolimine, bumetanide, triamterene, amiloride and 
spironolactone and salts of such compounds. 
The compounds of formula I can be formulated for use in the reduction of 
blood pressure in compositions such as tablets, capsules or elixirs for 
oral administration or in sterile solutions or suspensions for parenteral 
administration. About 100 to 500 mg of a compound of formula I is 
compounded with physiologically acceptable vehicle, carrier, excipient, 
binder, preservative, stabilizer, flavor, etc., in a unit dosage form as 
called for by accepted pharmaceutical practice. The amount of active 
substance in these compositions or preparations in such that a suitable 
dosage in the range indicated is obtained.

The present invention will now be described by the following examples, 
however, the invention should not be limited to the details therein. 
EXAMPLE 1 
(S)-[(1,1-Dimethylethoxy)carbonyl]-L-phenylalanyl-N-[1-(cyclohexylmethyl)-2 
,3-dioxohexyl]-L-leucinamide 
A. 2-Propyl-1,3-dithiane 
n-Butyl lithium (2.5M, 56.32 ml, 141 mmol) was added dropwise to a 500 ml 
tetrahydrofuran solution of 1,3-dithiane (15.42 g, 128 mmol) at 
-20.degree.. After stirring for 2.5 hours at -20.degree., the solution was 
cooled to -78.degree. and 1-iodopropane (12.5 ml, 128 mmol) was added to 
it in one portion. The reaction mixture was left for gradual warming 
(-78.degree. to 0.degree. C.) and overnight stirring (19 hours). 
Tetrahydrofuran was removed on the rotary evaporator, residue taken in 
ether (250 ml) and washed with water (200 ml). The aqueous layer was 
reextracted with ether (250 ml). Combined ethereal extracts were washed 
sequentially once with water, once with saturated sodium chloride, dried 
over anhydrous sodium sulfate and concentrated to give a yellow oil which 
on distillation under vacuum yielded 19.310 g of the title A compound. 
B. 
[(1S)-1-(Cyclohexylmethyl)-2-hydroxy-2-(2-propyl-1,3-dithian-2-yl)ethyl]ca 
rbamic acid, 1,1-dimethylethyl ester 
n-Butyl lithium (2.5M, 11.76 ml, 29.4 mmol) was added dropwise at 
-25.degree. to a 40 ml tetrahydrofuran solution of 2-n-propyl-1,3-dithiane 
from part A (4.536 g, 28.0 mmol). After stirring for 2 hours at 
-20.degree. to -25.degree., the solution was cooled to -78.degree. and 
(S)-&lt;.alpha.-[[(1,1-dimethylethoxy)carbonyl]amino]cyclohexanepropanal 
(3.57 g, 14.0 mmol) was added as a 20 ml tetrahydrofuran solution. A 
chromatography check after 1 hour revealed the formation of a complex 
reaction mixture. It was warmed gradually from -78.degree. to -50.degree. 
over a period of 18 hours, quenched with saturated ammonium chloride (50 
ml) and the two layers separated upon warming to room temperature. The 
aqueous layer was diluted with water (75 ml, to dissolve the precipitated 
ammonium chloride) and reextracted with ethyl acetate (2.times.50 ml). 
Combined organic extracts were washed with saturated ammonium chloride 
(1.times.75 ml), dried over anhydrous sodium sulfate and concentrated to 
give 7.9 g crude product which upon flash chromatographic purification 
yielded 1.517 g of the title B compound. 
C. 
.alpha.-[(S)-1-Amino-2-cyclohexylethyl]-2-propyl-1,3-dithiane-2-methanol, 
monohydrochloride 
The title B compound (533 mg, 1.278 mmol) was dissolved in ethyl acetate 
(20 ml), cooled to 0.degree. and the solution saturated by hydrogen 
chloride by bubbling the gas through it for a period of .about.5 minutes. 
A chromatography check revealed total disappearance of starting material. 
Ethyl acetate was removed on the rotary evaporator and the resulting 
yellow solid triturated with ether and filtered to give the title compound 
(370 mg) which looked pure by .sup.13 C NMR. 
D. t-Butyloxycarbonylphenylalanyl leucine, methyl ester 
To a mixture of t-butyloxycarbonyl-L-phenylalanine (13.265 g, 50 mmol), 
L-leucine methyl ester (9.085 g, 50 mmol) and hydroxybenzotriazole hydrate 
(7.65 g, 50 mmol) in 100 ml tetrahydrofuran at 0.degree. was added 
dropwise a solution of diisopropylethylamine (8.7 ml, 50 mmol) in 50 ml 
tetrahydrofuran. This was followed by addition of dicyclohexylcarbodiimide 
(10.315 g, 50 mmol). The reaction was stirred at 0.degree. for 2 hours and 
then left for overnight stirring at room temperature. The precipitated 
urea was filtered off, solvents stripped down and the residue diluted with 
ethyl acetate (200 ml). The organic solution was washed sequentially with 
saturated aqueous sodium hydrogen carbonate (2.times.100 ml), saturated 
aqueous sodium chloride (2.times.100 ml), dried over sodium sulfate, 
filtered and concentrated to give crude product which on crystallization 
from ethyl ether gave 7.05 g pure product. Concentration of the mother 
liquor solution afforded 4.57 g crystalline product. An additional 1.35 g 
product was obtained by chromatographic purification of the crude product 
obtained from the left over mother liquors (40 g silica gel, 4:1 
hexane/ethyl acetate). Thus, a total of 12.96 g of the title D compound 
was obtained. m.p.=104.degree.-105.degree., [.alpha.].sub.D =-17.5.degree. 
(c=1.2, MeOH). 
Elemental analysis calc'd for C.sub.24 H.sub.32 N.sub.2 O.sub.5 : C, 64.30; 
H, 8.15; N, 7.14; Found: C, 64.12; H, 8.16; N, 7.02. 
E. t-Butyloxycarbonylphenylalanyl leucine 
Sodium hydroxide (1N; 12 ml, 12 mmol) was added to a 40 ml methanol 
solution of 
(S)-&lt;.alpha.-[[(1,1-dimethylethoxy)carbonyl]amino]cyclohexanepropanoic 
acid, methyl ester (3.92 g, 10 mmol) and a chromatography check after one 
hour revealed total disappearance of starting material. The solvents were 
removed on rotary evaporator. The resulting white solid was suspended in 
10 ml of water and 50 ml of ethyl acetate, acidified to pH=3.5 using 1N 
hydrochloric acid and the two layers separated. The aqueous layer was 
reextracted with ethyl acetate (3.times.30 ml), combined organic extracts 
dried over sodium sulfate and concentrated to give 3.54 g of the title E 
compound. 
F. 
[(1,1-Dimethylethoxy)carbonyl]-L-phenylalanyl]-N-[(1S)-1-(cyclohexylmethyl 
)-2-hydroxy-2-(2-propyl-1,3-dithian-2-yl)ethyl]-L-leucinamide 
The title E compound (415.8 mg, 1.1 mmol) and the title C compound (388.9 
mg, 1.1 mmol) were dissolved in 5 ml dimethylformamide and cooled to 
0.degree.. N,N-diisopropylethylamine (191.4 .mu.l, 1.1 mmol) was added and 
after 5 minutes, this was followed by sequential addition of 1-hydroxy 
benzoatriazole hydrate (168.3 mg, 1.1 mmol) and dicyclohexylcarbodiimide 
(227 mg, 1.1 mmol). The reaction was left for gradual warming and 
overnight stirring. Next day, the reaction mixture was diluted with ethyl 
acetate (35 ml), the urea filtered off and the filtrate washed 
sequentially with water (2.times.20 ml), saturated sodium hydrogen 
carbonate (2.times.20 ml), 10 percent citric acid (1.times.20 ml), and 
saturated sodium chloride (1.times.20 ml). Drying with anhydrous sodium 
sulfate and concentration afforded 821 mg of crude product which upon 
chromatographic purification yielded 621 mg of the title F compound, 
m.p.=87.degree.-92.degree., [.alpha.].sub.D =-35.0.degree. (c=0.34, MeOH). 
Elemental analysis calc'd for C.sub.36 H.sub.59 N.sub.3 O.sub.5 
S.sub.2.0.6H.sub.2 O: C, 62.77; H, 8.81; N, 6.10; S, 9.31; Found: C, 
62.84; H, 8.60; N, 6.00; S, 9.13. 
G. 
[(1,1-Dimethylethoxy)carbonyl]-L-phenylalanyl-N-[(1S)-1-(cyclohexylmethyl) 
-2-hydroxy-3-oxohexyl]-L-leucinamide 
The title F compound (338.5 mg, 0.5 mmol) was dissolved in 12 ml 
acetonitrile and diluted with 3 ml water. Ammonium ceric nitrate (1.096 g, 
2.0 mmol) was added to this solution and after 20 minutes, the reaction 
mixture was diluted with water (40 ml) and extracted with ether 
(3.times.30 ml). The combined organic extracts were dried over anhydrous 
sodium sulfate and concentrated to give 378 mg of residue which upon 
chromatographic purification yielded 140 mg of the title G compound, 
m.p.=149.degree.-152.degree.. 
Elemental analysis calc'd for C.sub.33 H.sub.53 N.sub.3 O.sub.6 : C, 67.43; 
H, 9.09; N, 7.15; Found: C, 67.14; H, 9.40; N, 7.03. 
H. 
(S)-[(1,1-Dimethylethoxy)carbonyl]-L-phenylalanyl-N-[1-(cyclohexylmethyl)- 
2,3-dioxohexyl]-L-leucinamide 
A solution of the title G compound (58.7 mg, 0.1 mmol) in 3 ml methylene 
chloride was added to a suspension of Dess Martin periodinane (65 mg, 0.15 
mmol) and t-butylalcohol (12 mg, 0.15 mmol) in 2 ml methylene chloride. 
The reaction mixture was vigorously stirred. A TLC check after 6 hours 
revealed incomplete reaction; hence excess Dess Martin reagent (153 mg, 
0.45 mmol) and t-butylalcohol (35 mg, 0.45 mmol) was added along with 5 ml 
methylene chloride and the reaction mixture left for overnight stirring. 
Next day, the reaction was judged complete by TLC. The reaction mixture 
was filtered through celite, the filtrate concentrated and the residue 
chromatographed to give 51 mg of the title compound. 
m.p.=134.degree.-143.degree., [.alpha.].sub.D =-36.6.degree. (c=0.61, 
MeOH). 
Elemental analysis calc'd for C.sub.33 H.sub.51 N.sub.3 O.sub.6 : C, 67.66; 
H, 8.78; N, 7.17; Found: C, 67.52; H, 8.71; N, 7.13. 
EXAMPLE 2 
(S)-(Cyclopentylcarbonyl)-L-phenylalanyl-N-[1-(cyclohexylmethyl)-2,3-dioxoh 
exyl]-L-leucinamide 
A. N-(L-Phenylalanyl)-L-leucine, methyl ester, monohydrochloride 
The compound from part D of Example 1 (12.01 g, 31 mmol) was dissolved in 
hydrochloric acid/acetic acid solution (62 mL), reacted for one hour and 
concentrated to give an oily residue. It was triturated with toluene 
(3.times.60 mL), and concentrated yielding 10 g of the title A compound. 
B. N-[N-(Cyclopentylcarbonyl)-L-phenylalanyl]-L-leucine, methyl ester 
Cyclopentane carboxylic acid (1.65 mL, 15.2 mmol) was added to a solution 
of the title A compound (5.0 g, 15.2 mmol) in dimethylformamide (60 mL) 
and cooled to 0.degree. C. 1-Hydroxybenzotriazole (2.33 g, 15.2 mmol), 
N,N-diisopropylethylamine (2.93 mL, 17 mmol) and dicyclohexylcarbodiimide 
(3.14 g, 15.2 mmol) were added sequentially. After 16 hours at 0.degree. 
C., the reaction mixture was filtered and concentrated. The residue was 
taken in ethyl acetate (250 mL), washed with water (3.times.150 mL), 
saturated sodium bicarbonate (150 mL), saturated sodium chloride (150 mL), 
dried and concentrated, yielding 6.0 g of crude product. Purification by 
flash chromatography afforded 3.40 g of the title B compound. 
m.p.=170.degree.-171.degree. C., [.alpha.].sub.D =-23.9.degree. (c=1.18, 
MeOH). 
Elemental analysis calc'd for C.sub.22 H.sub.32 N.sub.2 O.sub.4.0.13H.sub.2 
O: C, 67.60; H, 8.32; N, 7.17; Found: C, 67.57; H, 8.31; N, 7.20. 
C. N-[N-(Cyclopentylcarbonyl)-L-phenylalanyl]-L-leucine 
Sodium hydroxide (1N; 12.36 mL, 12 mmol) was added to a solution of the 
compound of part B (2.04 g, 5.3 mmol) in methanol (20 mL). After five 
hours, the reaction mixture was concentrated and the residue was taken up 
in a mixture of water (20 mL) and ethyl acetate (50 mL) and acidified to 
pH 1.8. The layers were separated and aqueous layer was reextracted with 
ethyl acetate (3.times.75 mL). The combined organic extracts were dried 
and concentrated yielding 1.84 g of product, m.p. 148.degree.-151.degree. 
C. [.alpha.].sub.D =-12.9.degree. (c=1.19, MeOH). 
Elemental analysis calc'd for C.sub.21 H.sub.30 N.sub.2 O.sub.4.1.34H.sub.2 
O: C, 63.28; H, 8.26; N, 7.03; Found: C, 63.32; H, 7.77; N, 7.01. 
D. 
(Cyclopentylcarbonyl)-L-phenylalanyl-N-[(1S)-1-(cyclohexylmethyl)-2-hydrox 
y-2-(2-propyl-1,3-dithian-2-yl)ethyl]-L-leucinamide 
The compound of part C in Example 1 (707 mg, 2 mmol) was added to a 
solution of the title C compound from this Example (748 mg, 2 mmol) in 
tetrahydrofuran (8 mL) and cooled to 0.degree. C. 1-Hydroxybenzotriazole 
(306 mg, 2 mmol), N,N-diisopropylethylamine (383 .mu.l, 2.2 mmol), and 
dicyclohexylcarbodiimide (413 mg, 2 mmol) were added sequentially. After 
16 hours at 0.degree. C., the reaction mixture was filtered and 
concentrated. The reaction was taken up in ethyl acetate (50 mL), washed 
with water (2.times.30 mL), saturated sodium bicarbonate (2.times.40 mL), 
10 percent citric acid (40 mL), saturated sodium chloride (40 mL), dried 
and concentrated. Purification of the crude product (1.2 g) by flash 
chromatography yielded 936 mg of pure product. 
Elemental analysis calc'd for C.sub.37 H.sub.60 N.sub.3 O.sub.4 S.sub.2 : 
C, 65.83; H, 8.96; N, 6.23; Found: C, 65.62; H, 8.78; N, 6.19. 
E. 
(Cyclopentylcarbonyl)-L-phenylalanyl-N-[(1S)-1-(cyclohexylmethyl)-2-hydrox 
y-3-oxohexyl]-L-leucinamide, isomer A 
A 20 ml methanol solution of thallic nitrate trihydrate (1.05 g, 1.18 mmol) 
was added to a solution of the title D compound (799 mg, 1.18 mmol) in 
methanol (40 mL) and ethyl acetate (20 mL). After 10 minutes the reaction 
mixture was filtered, concentrated and residue was taken in ethyl acetate 
(150 mL) and water (100 mL). The layers were separated and aqueous layer 
was extracted with ethyl acetate (2.times.120 mL). The combined organic 
portions were washed with 10 percent citric acid (150 mL), dried and 
concentrated affording 2.5 g of crude compound. Purification by flash 
chromatography yielded 573 mg pure product, m.p. 169.degree. C. 
[.alpha.].sub.D =-61.3.degree. (c=1.19, CH.sub.3 OH). 
Elemental analysis calc'd for C.sub.34 N.sub.53 N.sub.3 O.sub.5.0.63H.sub.2 
O: C, 68.62; H, 9.19; N, 7.06; Found: C, 68.79; H, 8.92; N, 6.99. 
F. 
(S)-(Cyclopentylcarbonyl)-L-phenylalanyl-N-[1-(cyclohexylmethyl)-2,3-dioxo 
hexyl]-L-leucinamide 
A solution of the hydroxy ketone of part E (268 mg, 0.46 mmol) was added to 
a suspension of Dess Martin reagent (389 mg, 0.91 mmol) and t-butylalcohol 
(68 mg, 0.92 mmol) in methylene chloride (40 mL). After five hours, 
reaction mixture was filtered and concentrated yielding 666 mg of crude 
product which was subjected to chromatographic purification affording 217 
mg of the title compound, m.p.=152.degree.-161.degree. C. [.alpha.].sub.D 
=-59.1.degree. (c=0.45, CHCl.sub.3). 
Analysis calc'd for C.sub.34 H.sub.51 N.sub.3 O.sub.5.1.03H.sub.2 O: C, 
70.19; H, 8.84; N, 7.22; Found: C, 70.12; H, 8.79; N, 7.12. 
EXAMPLE 3 
[(1,1-Dimethoxyethoxy)carbonyl]-N-[(1S)-1-(cyclohexylmethyl)-2,3-dioxohexyl 
]-L-histidinamide 
A. 
N-[(1,1-Dimethoxyethoxy)carbonyl]-1-[(4-methylphenyl)sulfonyl]-L-histidine 
N-[(1,1-Dimethoxyethoxy)carbonyl]-L-histidine (12.7 g, 50 mmol) was 
dissolved in a solution of sodium carbonate (10.6 g, 100 mmol) in 150 ml 
water and cooled to 10.degree.. p-Toluenesulfonylchloride (12.8 g, 67 
mmol) was added in very small portions over a period of 30 minutes while 
maintaining vigorous stirring and controlling the temperature between 
10.degree.-15.degree.. After the addition was complete, the reaction 
mixture was warmed to room temperature and stirring continued for an 
additional 4 hours. The reaction mixture was extracted twice with ethyl 
ether (75 ml) and the organic portions were discarded. The aqueous layer 
was acidified with 1N hydrochloric acid, extracted twice with ethyl 
acetate (150 ml) and the combined organic extracts were dried and 
concentrated to give an oily residue. Crystallization from ethyl acetate 
afforded 9.42 grams of the title A compound. m.p.=120.degree., 
[.alpha.].sub.D =15.3.degree. (c=1.66, CH.sub.3 OH). 
Analysis calc'd for C.sub.18 H.sub.23 N.sub.3 O.sub.6 S.0.14H.sub.2 O: C, 
52.48; H, 5.69; N, 10.20; S, 7.78; Found: C, 52.72; H, 5.70; N, 9.72; S, 
8.09. 
B. 
[(1,1-Dimethoxyethoxy)carbonyl]-N-[(1S)-1-(cyclohexylmethyl)-2-hydroxy-2-( 
2-propyl-1,3-dithian-2-yl)ethyl]-1-[(4-methylphenyl)sulfonyl]-L-histidinami 
de, isomer A 
Triethylamine (108 .mu.l, 0.775 mmol) was added dropwise to a solution of 
the title A compound (133 mg, 0.325 mmol) and 
.alpha.-[(S)-1-amino-2-cyclohexylethyl]-2-propyl-1,3-dithiane-2-methanol, 
isomer A, monohydrochloride (88.4 mg, 0.25 mmol) in 2.5 ml methylene 
chloride at 0.degree.. After 5 minutes diphenylphosphoryl azide (70 .mu.l, 
0.325 mmol) was added, and the reaction mixture was stirred for 2 hours at 
0.degree. and then overnight at room temperature. Next day, the reaction 
mixture was concentratd on a rotary evaporator (to remove excess 
triethylamine), the residue diluted with 15 ml methylene chloride and 15 
ml saturated sodium hydrogen carbonate and the two layers were separated. 
The aqueous layer was reextracted twich with methylene chloride and the 
combined organic extracts were dried over sodium sulfate and concentrated 
to give 292 mg residue. Chromatographic purification yielded 125 mg of the 
title B compound. m.p. 83.degree.-88.degree.; [.alpha.].sub.D 
=-16.5.degree. (c=1.3, MeOH). 
Analysis calc'd for C.sub.34 H.sub.52 N.sub.4 S.sub.3 O.sub.6 : C, 57.60; 
H, 7.39; N, 7.90; S, 13.57; Found: C, 57.71; H, 7.48; N, 7.64; S, 13.71. 
C. 
[(1,1-Dimethoxyethoxy)carbonyl]-N-[(1S)-1-(cyclohexylmethyl)-2-hydroxy-3-o 
xohexyl]-1-[(4-methylphenyl)sulfonyl]-L-histidinamide, isomer A 
Thallic nitrate trihydrate (844 mg, 1.9 mmol) was added in one portion to a 
40 ml 1:1 methanol/ethyl ether solution of the title B compound (674 mg, 
0.95 mmol) at 0.degree.. After 15 minutes, the reaction mixture was 
filtered through celite and the solids washed twice with ethyl acetate (25 
ml). Concentration of the solid gave a residue which upon chromatographic 
purification yielded 399 mg of the title C compound. m.p. 
67.degree.-76.degree., [.alpha.].sub.D =-42.6.degree. (c=1.21, MeOH). 
Analysis calc'd for C.sub.31 H.sub.46 N.sub.4 O.sub.7 S.2.2H.sub.2 O: C, 
58.85; H, 7.57; N, 8.86; Found: C, 59.09; H, 7.47; N, 8.56. 
D. 
[(1,1-Dimethoxyethoxy)carbonyl]-N-[(1S)-1-(cyclohexylmethyl)-2,3-dioxohexy 
l]-1-[(4-methylphenyl)sulfonyl]-L-histidinamide 
Dess martin periodinane (308.5 mg, 0.73 mmol) was added to a solution of 
the title C compound (300 mg, 0.485 mmol) and t-butanol (53 mg, 0.73 mmol) 
in 5 ml dichloromethane. After 2 hours at room temperature, the reaction 
mixture was diluted with 20 ml dichloromethane and washed with an aqueous 
solution of sodium bicarbonate and sodium sulfite. Drying and 
concentration afforded a residue which upon flash chromatographic 
purification provided 288 mg of the title D compound, m.p. 
60.degree.-67.degree.. 
E. 
[(1,1-Dimethoxyethoxy)carbonyl]-N-[(1S)-1-(cyclohexylmethyl)-2,3-dioxohexy 
l]-L-histidinamide 
1-Hydroxybenzotriazole (12.2 mg, 0.08 mmol) was added in one portion to a 
solution of the title D compound (12.2 mg, 0.02 mmol) in 2 ml methanol. 
After 2 hours at room temperature, solvents were removed on rotary 
evaporator and the residue purified by flash chromatography to provide 10 
mg of the title compound. 
EXAMPLES 4 TO 25 
Following the procedures of Example 1 and outlined above, the following 
additional compounds of formula I within the scope of the present 
invention can be prepared. 
##STR70## 
__________________________________________________________________________ 
Ex. 
No. 
R.sub.1 R.sub.3 R.sub.4 R.sub.5 X 
__________________________________________________________________________ 
4 CH.sub.2CH.sub.2CH.sub.3 
##STR71## 
##STR72## 
##STR73## 
##STR74## 
##STR75## 
##STR76## 
##STR77## 
##STR78## 
6 CH.sub.2CH.sub.2CH.sub.3 
##STR79## 
##STR80## 
##STR81## 
##STR82## 
7 CH.sub.2CH.sub.2CH.sub.3 
##STR83## 
##STR84## 
##STR85## 
##STR86## 
8 CH.sub.2CH.sub.2CH.sub.3 
##STR87## 
##STR88## 
##STR89## 
##STR90## 
9 CH.sub.2CH.sub.2CH.sub.3 
##STR91## 
##STR92## 
##STR93## 
##STR94## 
10 CH.sub.2CH.sub.2CH.sub.3 
##STR95## 
##STR96## 
##STR97## 
##STR98## 
11 CH.sub.2CH.sub.2CH.sub.3 
##STR99## 
##STR100## 
##STR101## 
##STR102## 
12 
##STR103## 
##STR104## 
##STR105## 
##STR106## 
##STR107## 
13 
##STR108## 
##STR109## 
##STR110## 
##STR111## 
##STR112## 
14 
##STR113## 
##STR114## 
##STR115## 
##STR116## 
##STR117## 
15 
##STR118## 
##STR119## 
##STR120## 
##STR121## 
##STR122## 
16 
##STR123## 
##STR124## 
##STR125## 
##STR126## 
##STR127## 
17 
##STR128## 
##STR129## 
##STR130## 
##STR131## 
##STR132## 
18 
##STR133## 
##STR134## 
##STR135## 
##STR136## 
##STR137## 
19 CH.sub.2CH.sub.2CH.sub.3 
##STR138## 
##STR139## 
##STR140## 
##STR141## 
20 CH.sub.2CH.sub.2CH.sub.3 
##STR142## 
##STR143## 
##STR144## 
##STR145## 
21 CH.sub.2CH.sub.2CH.sub.3 
##STR146## 
(CH.sub.2).sub.4NH.sub.2 
##STR147## 
##STR148## 
22 CH.sub.2CH.sub.2CH.sub.3 
##STR149## 
CH.sub.2CO.sub.2 H 
##STR150## 
##STR151## 
23 CH.sub.2CH.sub.2CH.sub.3 
##STR152## 
CH.sub. 2CH.sub.2CO.sub.2 H 
##STR153## 
##STR154## 
24 CH.sub.2CH.sub.2CH.sub.3 
##STR155## 
##STR156## 
##STR157## 
##STR158## 
25 CH.sub.2CH.sub.2CH.sub.3 
##STR159## 
##STR160## 
##STR161## 
##STR162## 
__________________________________________________________________________