GB2212804A - N-heterocyclic alcohol derivatives - Google Patents

Description

RA432 2212804 N-HETEROCYCLIC ALCOHOL DERIVATIVES The present invention is

directed to N-heterocyclic alcohol derivatives, and more particularly concerns such compounds useful as renin inhibitors.

In accordance with the present invention novel compounds which are inhibitors of renin, and therefore useful as cardiovascular agents, are disclosed. These compounds have the formula is RA432 R5 0 R4 0 R3 1 11 1 11 1 X-112 -t;ki-C-NH-CH-C-lmki-kjti-cH-Rl 1 0H including pharmaceutically acceptable salts 0 thereof, wherein X is R6- (CH2)M-A-N-C-, 0 0 RIO R6-(CH2)m -A-8 -, R6-(CH2)m -A-0-C-, R6-(CII2)M-A-S-, R6-(CH2)M-A-SO-, R6(CH2)M-A-SO2i 0 11 R6-(CH2) -A-N-SO2-, RG-(CH2) -A-C-S-, m RIO 0 11 m 0 11 is R6-(CH2) -A-(0) -JJ-,CN-C-; m p 1 (0)p 1 1 1 (CH2)M? 1 R6' R, is a fully saturated, partially saturated, or unsaturated monocyclic N-heterocyclic ring of 5 or 6 atoms containing at least one N atom or a bicyclic ring in which such N-heterocyclic ring is fused to a benzene ring. The N-heterocyclic ring can also include an 0 or S atom or up to three additional N atoms. The N-heterocyclic ring is attached to -CH- by way_of an available carbon atom.

OH An available N atom in the Nheterocyclic ring can be substituted with an N-protecting group suchas X 1 i HA432 - -CH2-0-CI12-0 or loweralkyl, -(CH2),7 or -(CH2)n-cycloalkyl.

0 -S02 -0- CH3, or 2,4-dinitrophenyl, Similarly, an available C atom in the monocyclic ring or an available C atom in the benzene portion of the bicyclic ring can be substituted with lower alkyl, -(CH2)rj- 5 COD, 0 or -(CH2)n-cycloalkyl.

Preferred Nheterocyclic rings are R2 1 N R R9, R9, R9, R9 N N-N NL- N "' 1 1 12 S- - \\ - - R9, 1 N-==-1 R9 R9 R2 1 -(,5::N-R2 1 -r S N N j R9 R9 S N R9 R9, N 1 R2 lp- R9, R2 1 N R9, N 0 1 J_ R9 511 Rg, N1 R2 p R9 is RA432 0 - and J R2 iS -CK2-0-CI12- R9 1 -S02- 0- CH3 p 2,4-dinitrophenyl, hydrogen, lower alkyl, -(CH2)H-0 or -(CE2)n-cycloalkyl; CN- represents a heterocyclic ring of the f ormula (C12 Y (CH2)b )a N- wherein Y is -CH2, 01 S, or N-R9, 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 and such heterocyclic rings wherein one carbon atom has a lower alkyl substituent; R3 and R5 are independently selected from hydrogen, lower alkyl, halo substituted lower alkyl, -(CH2)n- aryl, -(CH2)n -heterocyclo, -(CH2)n-OH' -(CH2)n-o-"ower alkyl, -(CH2)n-NH2, -(CH2)n- SH, -(CH2)n- S-lower alkyl, t (CH2)n-O-(CH2) 9 -OHI -(CH2)n -0-(CH2) -NH21. 9 0 -(CI'2)n-S-(CE2)g-OH, -(CH2 )n-C-OH' (CE2) -S-(CH2) -NH2t -(CH2) -NH-C // n 9 n RA432 NH NH2 0 0 11 (CH2) -C-NH2 (CH2 IN-R71 -(CI2 N, n n and -(CH2)n_cycloalkyl; R4 is selected from hydrogen, lower alkyl, halo substituted lower alkyl, (CH2)n_ aryl, -(CI-I2) -heterocyclo, -(CH2) -OH, -(CH2) -0-lower n n n alkyl, -(CH2)n-NI120 -(CH2)n-SK1 -(CI2)n_ S-lower alkyl, -(CH2)n-o-(CI2)g-OH, -(CH2)n-0- (CH2)g-NI42, 0 11 CI"I2) n_ S CI"I2) g-OH, CI"I2) n_ C-OH, -(CH2)n-S-(CH2)g-NH2i _(CE2)n -NH-C \ n NH NE2 1 11 -(CH2) -C-NH2. -(CH2) N-R7o -(CH2)n N, n n -Nj 1 R7 K8 (CH2)n_cycloalkyl, -(CH2)n N:1 n n-- '1 (CH2) (CH2) j N ---J N- NH S- - (CH2) n_ \ 1 N- and, (CH2) r-(\Noj 0 - (CH2 is HA432 R6, R61 and R611 are independently selected from hydrogen, alkyl, aryl, pyridyl and cycloalkyl, or R6 and R61 taken together with the atom to which they are bonded may form a ring of 3 to 5 carbons; m, m' and W' are zero or an integer from 1 to S; n is an integer from 1 to 5; p and p' are zero or 1; g is an integer from 2 to 5; R7 is -CH2-0-CH2-0 or -CH Z-no 0 11 R8 is 2,4-dinitrophenyl, -C-O-CH2 -0 -S02-0-CH3, or -CH2-0-CH2 R9 is hydrogen, lower alkyl, -(CH2), or -(CH2)n_ cycloalkyl; R10 is -(CH2)mj-Rrl; A and A' are a single bond or -(CH)-(CH2)mti-Rr,".

RA432 This invention in its broadest aspects relates to the compounds of formula I above, to compositions and the method of using such compounds 5 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 f luoro.

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, l-naphthyl, 2-naphthyl, mono substituted phenyl, l-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)2 wherein alkyl is of 1 to 4 RA432 carbons, di or tri substituted phenyl, l-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 0 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 2thiazolyl, 2- and 4-imidazolyl, 2- and 3-thienyl, 2- and 3-furyl, 2-, 3- and 4-pyridyl. The term hetero also includes bicyclic rings wherein the five or is six membered ring containing 0, S and N atoms as defined above is fused to a benzene ring. The preferred bicyclic ring is benzimidazolyl.

i HA432 The compounds of formula I are prepared by coupling an amine of the formula II R4 0 R3 1 11 1 H2 N-CH-C-NH-t;ki-uki-Rl 1 Uki with the compound of the formula Rs 0 1 11 X-CH2-CH-C-OH is IV in a solvent, e.g. dimethylformamide, and in the presence of a coupling agent, e.g. dicyclohexylcarbodiimide.

To make the amine of formula II, a starting material, H-R,, is treated with n-butyl lithium to obtain a compound of the formula Li-Rl.

Compound IV is thereafter reacted with an aldehyde of the formula V R3 0 11 Prot-NH-H-CH (wherein Prot is an amino protecting group, e.g. t-butoxycarbonYl) HA432 to provide the protected amine of the formula VI R3 1 Prot-NH-Cli-t M-Rl Ull Compound VI, in a solvent such as ethyl acetate, can be deprotected by means known in the art, e.g. by treatment with hydrogen chloride, to 10 provide an amine of the formula VII is Rs 1 H2N-CH-CH-Rl 1 OH The amine of formula II can then be prepared by reacting the deprotected amine of formula VII with an N-protected amino acid of the formula VIII R4 0 1 11 Prot-NH-CH-C-OH in the presence of a coupling agent, such as dicyclohexylcarbodiimide, and thereafter removing the protecting group by known means, e.g. treatment with hydrogen chloride in the case of a t-butoxycarbonyl protecting group.

To make the compounds of formula I wherein X 0 is R6-(CH2)m-A-C-, a compound of the formula t:

t 0 11 R6-(CH2)m-A-C-CH2Br HA432 (the preparation of which has been described, for example, in Tetrahedron Letters, 26, 5611-5615, 1970) is coupled with a diethyl malonate derivativ having the formula X R5 0 1 11 HC-C-OCH2CH3 1 L;=U 1 U-;112 (;H3 in a solvent, e.g. tetrahydrofuran, and in the presence of a base, e.g. sodium hydride, to provide a compound of the formula XI 0 R,5 0 1 11 R6-(CH2) -A--CH2-C-C-OCH2CH3 m 1 C=0 Compound XI in a solvent, e.g. aqueous ethanol, is treated in a strong base, such as sodium hydroxide, and thereafter with hydrochloric acid and heat to provide the compounds of formula III where 0 X is R6-(CH2)m-A-C-. Reaction with compound II, as above, provides the corresponding compounds of formula I.

RA432 To make the compounds of formula I where X 0 11 0 11 is R6-(CH2) -A-N-C- or CN-C-, and m 1 R10 R5 is -(CH2)n_ aryl and n = 1, a compound of the formula XII is Ar 11.

CH 0 11 11 C-C-OCH2CH3 1 CH2-C-OH 11 U (the preparation of which has been described in J. Amer. Chem. Soc., 90, 3495, (1968)), is hydrogenated in the presence of a palladium on carbon catalyst to provide a compound having the formula XIII R.5 0 1 11 CI-C-OC92CH3 0 Compound XIII is reacted with a compound of the formula XIV R6-(CH2)m-A-NH 1 R1 0 or XV HA432 CNH in the presence of a catalyst, such as hydroxybenzotriazole, and dicyclohexylcarbodiimide to provide the ethyl ester of the formula M or 0 Rs 0 11 1 11 R6 - (CH2)m-A-N-C-CH2 -CH-C-OCH2 CH3 1 K1O 0 R.5 0 if 1 11 M I CN- C - CH2 - CH- C - OCH2 CH3.

Compound XVI or XVII, in a solvent such as aqueous ethanol, is treated with a strong base, e.g. sodium hydroxide to provide the compounds of formula 0 0 11 m 1. or CN-C-, X1 0 and R.5 is -(CH2)n_ aryl and n = 1. Reaction with compound II, as above, provides the corresponding compounds of formula I.

Alternatively, to make the compounds of 0 0 formula I where X is R6. (CE2)m-AN-C11-, CNC-, or 0 410 R6(CH2)mAO-C-, and R5 is -I(CH2)n_ aryl and n = 1 to 5, a dialkylmalonate of the formula if III wherein X is R6-(CH2) -A-N-C- RA432 z a XVIII 0 11 CH2-C-Oalkyl 1 C=0 f Oalkyl in a solvent, such as tetrahydrofuran, is treated with sodium hydride and thereafter reacted with a compound of the formula xix Rs-Cl or R5-Br to provide a compound having the formula XX Rs 0 1 fl CH-C-Oalkyl Oalkyl Compound XX, in a solvent such as aqueous ethanol, is treated with a strong base, e.g. sodium hydroxide, and thereafter with hydrochloric acid to provide M RS 0 1 11 CH2 -C-OH Compound M is treated with benzyl alcohol and 4-dimethylamino pyridine in a solvent, e.g. methylene chloride, in:the presence of dicyclohexyl30 carbodiimide to provide the ester of the formulg -15 M I Rs 0 1 11 LH2 -C-OCH2-0 RA432 1 which is treated with diisopropylamine and n-butyl lithium in a solvent such as tetrahydrofuran, and thereafter reacted with t-butyl bromoacetate to provide xXIII 0 RS 0 1 1 11 t-BuO-C-CH2-CH-C-OCH2 Compound XXIII, in a solvent, such as methylene chloride, is treated with a strong acid, e.g. trifluoroacetic acid, to provide a compound of the formula xxIV 0 Rs 0 H 1 11 HO-C-CH2-CH-C-OCH2 -0 Compound XXIV, in a solvent, such as tetra hydrofuran, is coupled with R6-(Cl12) -A-NH, M I R10 CN-H or R6-(CH2)m-A-OH in the presence of a catalyst, such as hydroxybenzotriazole or dimethyl- aminopyridine, and dicyclohexylcarbodiimide to provide the compounds of formula III where X is 0 R6-(CH2) -A-N-C-, 0 0 11 11 m CN-C-, or R6-(C112)m-A-0-C- X1 0 and R,5 is -(CH2)n_ aryl and n = 1 to 5. Reaction with compound II, as above, provides the corresponding compounds of formula I.

HA43 2 To make the compounds of formula I where X is R6 -(CH2)m-A-S-, a compound of the formula xxV 0 5 0 11 M HO-C-CH-C-OH is reacted with dimethylamine in the presence of formaldehyde to provide a compound of the formula xXVI 0 R5 0 if 1 11 HO-C-C-C-OH j k12 1 N CH3 CH3 Compound XXVI is heated to provide the acrylic acid of the formula xxVII RS 0 1 11 H2 C"C-C-OII.

Compound XXVII, in a solvent such as piperidine, is reacted with a compound of the formula xxvi I I to provide MIX Z 1 RG-(CH2)M-A-SH RS 0 1 11 R,s-(CI"I2)m-A-S-CE2-CH-C-OE, 17- RA43 2 that is, the compounds of formula.III wherein X i R6-(CH2),-A-S-. Reaction with compound II, as above, provides the corresponding compounds of formula I.

Alternatively, a compound of the formula XXVII may be esterified by reaction with ethanol in the presence of dicyclohexylcarbodiimide and a catalyst such as dimethylaminopyridine to give a compound of the formula XXVIIa RS 0 1 11 H2C=C-,-C-OCH2CH3 Compound XXVIIa, in a solvent such as ethanol is then reacted with a compound of the formula XXVIII in the presence of a base such as sodium ethoxide to give a compound of the formula R,s 0 1 11 XXIXa R6-(CI2)m-A-S-C"2-CH-C-OCH2CH3 Compound XXIXa is treated with sodium hydroxide to give compound XXIX.

When X is R6-(CH2),-A-SO-, compound XXIX in a solvent, e.g. methanol, is treated with hydrogen peroxide. When X is R6- (CH2)m-A-SO2-1 compound XXIX, in a solvent such as methanol, is treated with potassium monopersulfate. The res ulting species of formula III can be reacted with compound 11, as above, to provide the compounds of formua I wherein X is R6-(CH2),- A-SO- and R6-(CH2)m-A-SO2-r respectively.

HA432 To make the compounds of formula I where X 0 11 -A- (0) -P- is R6-(CH2)M p 1 is and p and plare 1, a (0) 1 i p A ' 1 compound of the formula U 1;112)M? R69 0 11 xXX Rr,-(CH2)m-A-(0)p-P-H (0 1 1 p A' k 1.I12)Me K6 ' is reacted with the acrylic acid of formula XXVII in dichloromethane and in the presence of bis- (trimethylsilyl)acetamide to provide the compound 0 11 -A- (0) -p of formula III where X is Rr,-(C112), p (U) 1 P, A v 1 (CH2)MY 1 R69 Reaction with compound II, as above, provides the corresponding compounds of formula 1.

To make compouds.of the formula I where X is 0 11 R6-(CH2) M-A-(0) -pp 1 (0) 1 P1 A 1 (CH2)M1 1 X6 and p and/or pI are 0,.a i 1 HA432 compound of the formula XXX wherein p and p, are is reacted with a compound of the formula xxxi RE;-(CH2)m-A-MgBr The resulting species is then reacted with the acrylic acid of the formula XXVII to provide the compound of the formula III where X is 0 11 R6 - (CH2) -A- (0) -P- and either p or p' or m p 1 (0) 1 P, A 1 1 (k12)M I R6 both are 0. Reaction with compound II, as above, provides the corresponding compounds of formula I To make compounds of the formula I where X 0 is R6-(CH2)m-A-C-S-, a compound of the formula 0 fl xxxii R6-(CH2)m-A-C-SH is reacted with an acrylic acid of formula XXVII to give a compound of the formula 0 Rs 11 1 MIII R6-(C112),-A70-S-;k12-n-CO2H Reaction of compound XXXIII with compound II, as above, provides the corresponding compounds of formula I.

A RA432 To make compounds of the formula I where X HS, a compound of the formula I where X 0 R6-(C112)M-A-C-S- is treated with ammonium hydroxide solution.

To make compounds of the formula I where X R6-(CI"I2) -A-N-SO2-, a compound of formula XXXIII is m 1 R10 treated with ammonium hydroxide solution to give a compound of the formula R,5 1 =IV HS-CH2-1-;n-U211 The compound of formula XXXIV is esterified, for example, by treatment with ethanol and dicyclohexylcarbodiimide in the presence of a catalyst, such as dimethylaminopyridine, to give a compound of formula RS 0 1 11 xxxv HS-CH2-CH-COCII2C113 The compound XXXV is treated with chlorine gas in a solvent such as aqueous acetic acid, to give the compound 0 RS 0 11 1 11 xxxvi Cl-S-CH2-CH-C-OCH2CH3 11 0 is which is reacted with an amine XMVII R6-(C112) -A-NH m 1 X1 0 to give a compound of the formula HA432 0 R.S 0 11 1 11 - XXXVIII R6-(CH2)M-A-N-S-CH2-CH-C-OCH2CH3 1 11 M1 0 0 Compound XXXVIII is saponified with a strong base, such as sodium hydroxide, to give a compound of the formula 0 R 5 fl 1 XX= R6-(CB2) -A-N-.b--;M2;n-CO2H m 1 11 Rio U Reaction of compound XXXIX with compound II, as above, provides the corresponding compounds of formula I.

In the above reactions, if any of R3, R4 and R.5 are -(CI42)n_ aryl wherein aryl is phenyl, l-naphthyl, 2-naphthyl substituted with one or more hydroxy or amino groups, -(CH2) n -heterocyclo wherein heterocyclo is an imidazolyl, -(CH2)n-NH2P NH (CH2) - SHf -(CH2) -OH, -(CH2) -NH-C or n n n N52 HA432 0 -(CH2)n-C-OH, 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 10 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 15 Peptide Bond Formation", Academic Press (1979).

Preferred compounds of this invention are those of formula I wherein 0 IISC20 0 0 11 \II 4 X is 011'-C-, P-or S-; C; 1 ISC20 0 R, is -(\N.

N C7 Or -(N R3 is straight or branched chain lower alkyl 25 of 3 to 5 carbons, - (C12)n-cycl opentyl, (CH2) -cyclohexyl, or -(CH2),-<(5 wherein n n n D 1 is an integer from 1 to 3; R4 is hydrogen, straight or branched chain lower alkyl of up to 5 carbons, -(CH2)4-NH2, -CH2 NH, -CH2 - N-CH2 -0-CH2 - J 001 Wj -CH27C p -CH2 1 H -Cl12nO N p - ( CH2) 2- on is HA43 2 f -CH2--OH, -CH2-CON, -CH2-CO5 F S (CH2) n - - F or -CH - N and, 2 N, 1 02 N02 /Nj - (CI"I2) n - \ - 1 N p -(CH2)n- \7; N - R.5 is straight or branched chain lower alkyl of up to 5 carbons, -CH2-0) 1 - (CH2) 2 --CO)), 1 RA432 -CI12-C-OCH3. -CH2-(a-naphthyl), -CB2-(0-naphthyl), -CHZ-C- OH, -CH2-cyclopentyl, -CH2-cyclohexyl, -C12nO 1 -C112J:0:141 -CI42-QIN, N -C112 NI"It Or -CH2 7WJ0 1 ri Most preferred are those compounds of formula I wherein R6 is cycloalkyl, morpholinyl, ethyl or ethoxy; N:3 1; -NH R, is or \N.4 N ---J N R3 i S -C112 -0 Or-CI-I2-CH CI"I3 R4 is -CI12-CH C113 CH3 or -CI:12 NH; and, CH3 TI -NIJI RS is -CH2--a or -CH2---( Q The compounds of-formula I form salts with a variety of inorganic and organic acids. The nontoxic pharmaceutically acceptable salts are preferred, although ot_her salts are also useful in 1 1 RA43 2 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 R3, R4 and R5 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. Angiotepsin 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 RA432 species, e.g., humans. The compounds of this invention intervene in the angiotensinogen -)(renin) - angiotensin I (ACE) - 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 25 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 RA432 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 is 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

RA432 N-[(S)-2-cyclohexyl-l-[(R)-hYdroxy(1Himidazol-2-yl)methyllethyll-N2-[4(4morpholinyl)-1,4-dioxo-2-(phenylmethyl)- butyll-L-histidinamide, isomer B, dihydrochloride A. (Phenylmethyl)butanedoic acid, 1-ethyl ester A mixture of a-ethyl-a-benzal succinate (16.3 g, 70 mmols; prepared as described by Cohen and Milovanovic, J. Amer. Chem. Soc., 90, 3495, (1968)) and 10% palladium on carbon (1.2 g) in absolute ethanol (250 mL) was hydrogenated at 30 psi on a Parr apparatus for 24 hours, after which it was filtered and concentrated. The residue was dissolved in ether, dicyclohexylamine (70 mmols) was added, and the mixture was filtered. Hexane was added to the filtrate and the crystals which formed on cooling to -300C were collected. The solid product was recrystallized from ethyl acetate to give the title A dicyclohexylammonium salt (10.7 g). The salt was dissolved in ethyl acetate and washed with aqueous 1N hydrochloric acid. The ethyl acetate layer was dried and concentrated. The residue was dissolved in ether and was extracted with sodium bicarbonate solution. The combined aqueous layers were acidified by addition of concentrated hydrochloric acid and extracted with ethylene acetate. The extract was dried lover anhydrous magnesium sulfate and concentrated to give the title A compound as a pale yellow oil which solidified on standing overnight (6.2 g, 38% yield).

RA432 B. a-(Phenylmethyl)-y-oxo-4-morpholinebutanoic acid, ethyl ester To a mixture of the title A compound (3.05 g, 15 mmol) and morpholine (1.3 mL, 15 mmol) in tetrahydrofuran (50 mL) and dimethy1formamide (5 mL) were added 1- hydroxybenzotriazole hydrate (2.1 g, 15 mmol) and dicyclohexylcarbodiimide (3.1 g, 15 mmol). The mixture was stirred at 250C for 16 hours, after which it was filtered and concentrated. The residue was dissolved in ethyl acetate, washed sequentially with 1N hydrochloric acid and saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, and concentrated. The residue (3.6 g) was flash chromatographed on Merck sil ica gel (180 g), eluting with 1:1 hexane:ethyl acetate to give the title B compound as a clear, colorless oil (3.4 g, 75%), R f 0.25.

C. a-(Phenylmethyl)-y-oxo-4-morpholinebutanoic acid A mixture of the title B compound (3.3 g, 10.8 mmol) and 1N aqueous sodium hydroxide solution (11 mL, 11 mmol) in absolute ethanol (11 mL) was stirred for 22 hours at 250C, after which it was concentrated in vacuo. The residue was dissolved in water, washed with ether, acidified by addition of 1N hydrochloric acid (50 mL), and extracted three times with ethyl acetate. The combined extract was dried over anhydrous magnesium sulfate and concentrated and the residue was crystallized from ethyl acetate/hexane to give the title C compound as a white solid (2 g, 67%), m.p. 133-1340C.

RA432 D. (S)-2-[[(1,1-Dimethylethoxy)carbonyllamino]-2phenylmethyl-l-ethanol To a solution containing N-[(1,1-dimethylethoxy)carbonyl]-Lphenylalanine (10 g, 37.7 mmole) in dimethylformamide (40 ml) is added solid sodium bicarbonate (4.75 g, 56.6 mmole) and iodomethane (16 g, 113 mmole). The mixture is heated at 40' under argon for 12 hours, the cooled and the reaction mixture partitioned between water (150 ml) and ether (250 ml). The organic layer is rinsed with 2% aqueous sodium bicarbonate (2 x 100 ml), 2% aqueous sodium bisulfite (100 ml), water (2 x 100 ml), and brine, dried over magnesium sulfate, and concentrated in vacuo to give 10.5 g of N-[(1,1-dimethylethoxy)carbonyl]-L-phenylalanine, methyl ester as an oil.

To a solution containing N-[(1,1-dimethylethoxy)carbonyl]-L-phenylalanine, methyl ester (10 g, 35.8 mmole) dissolved in a mixture of tetrahydrofuran (190 ml) and absolute ethanol (190 ml) is added lithium chloride (6.09 g, 143.2 mmole). The resulting homogeneous solution is treated with sodium borohydride (5.42 g, 143.2 mmole) and the reaction is stirred at room temperature under argon for 24 hours. The reaction mixture is next filtered using ether (-700 ml) to rinse the filter cake., The resulting filtrate is rinsed with water (3 X 200 ml) and brine (200 ml), dried over magnesium sulfate, and concentrated in vacuo to give 9 g of crude product. RecrystalL lization from ether/hexane gives 7.59 g of the title D compound,; m.p. 94-960. Analysis calcId for C14H21NO3:

C, 66.90; H, 8.42; N, 5.57; Found: C, 66.80; H, 8.57; N, 5.38.

HA43 2 E. [(S)-2-Cyclohexyl-l-(hydroxymethyl)ethyll- carbamic acid, 1,1-dimethylethyl ester A solution of the title D compound (7 g, 27.8 mmole) in methanol (70 ml) is hydrogenated at 55 psi on a Parr Shaker using 5% rhodium on alumina (500 mg) as catalyst. After 17 hours, the reaction mixture is filtered and concentrated in vacuo to yield 7.36 g of the title E compound as an oil.

Analysis calcId for C14H27NO3:

C, 65.33; H, 10.57; N, 5.44 Found: C, 64.94; H, 10.55; N, 5.23.

F. (S)-(2-Cyclohexyl-l-formylethyl)carbamic acid, 1,1-dimethylethyl ester 15 A solution of the title E compound (4.6 g, 17.9 mmole) in methylene chloride (40 ml) is added to a mixture of Dess-Martin periodinane reagent (8 g, 19 mmole) [prepared according to Dess et al., J. Org. Chem., vol. 48, p. 4155 (1983)l and t-butanol 20 (1.5 g, 19 mmole) in methylene chloride (70 ml) which had been stirred at room temperature before the addition. A slight exotherm (to 320) results. After 30 minutes, the reaction mixture is quenched in ether (800 ml), resulting in the separation of a white solid. A mixture of sodium thiosulfate pentahydrate (31.3 g, 126 mmole) in saturated sodium bicarbonate solution (200 ml) is added, with stirring. The resultin' two-phase mixture is 9 separated and the organic phase is washed with water, saturated sodium bicarbonate (2 x 100 ml), water, and brine, dried over magnesium sulfate, and concentrated in vacuo to give 3.8 g of the title F compound as a colorless oil.

G.

RA432 [(lS)-l-(Cyclohexylmethyl)-2-hydroxy-2-[l[(phenylmethoxy)methyll-lHimidazo1-2-yllethyllcarbamic acid, 1,1-dimethylethyl ester 2.5 M nButyllithium solution in hexane (12 ml, 31 mmole) is added to a solution of 1-[(phen'ylmethoxy)methyl]-lH-imidazole (5.3 g, 28 mmole) in tetrahydrofuran (90 ml) at -70 under argon. After stirring for 15 minutes, the title F compound (3.6 g, 14 mmole) in tetrahydrofuran (36 ml) is added dropwise over a period of 5 minutes at a reaction temperature of -65 to 700. After 2 hours at -700, the bath is warmed to 0 and saturated ammonium chloride (25 ml) is added followed by ether (300 ml) and water (2 x 50 ml) and brine, dried over magnesium sulfate, and concentrated in vacuo. The resulting crude product (8.4 g) is flash chromatographed eluting with acetone:petroleum ether (1:4) to give 580 mg of the title G (fast moving isomer), 370 mg of a mixed fraction and 2 g of a slow moving isomer.

H..[R-(R,S)]-a-(1-Amino-2-cyclohexylethyl)-1.[(phenylmethoxy)methyll-1H-imidazole-2-methanol A solution of the title G compound (3.92 g, 25 8.83 mmols) in ethyl acetate (200 mL) was cooled to OIC and hydrochloric acid gas was bubbled through the solution for 30 minutes. The mixture was then stirred for 3.5 hours as it.warmed to room temperature, after which it was concentrated in vacuo to give the title H compound as a white power (3.56 g 97%).

HA43 2 L-Histidine, methyl ester, dihydrochloride To a stirred solution (ice- bath) of L-histidine (38.75 g, 240 mmol) in methanol (500 ml), thionyl chloride (27.2 ml, 375 mmol) was added in drops. After fifteen minutes the ice bath was removed and the reaction mixture was stirred at room temperature for one hour. Then after refluxing for 48 hours, it was concentrated in vacuo. The separated crystals were filtered using methanol for washing (48.93 g). The methanolic solution on dilution with ether afforded additional 10 g of the title I compound, m.p. 208-2090.

J. N,1-Bis[(1,1-dimethylethoxy)carbonyll-L- histidine, methyl-ester To a suspension of the title I compound (24.2 g, 100 mmol) in methanol (80 ml) were added triethyl amine (28 ml, 200 mmol) and di-tert-butyl dicarbonate (48 g, 220 mmol). After 3.5 hours, it was filtered and the methanolic solution concentrated in vacuC. The residue was taken into chloroform and washed with 10% citric acid. The crude product on crystallization from iospropyl ether afforded 23.1 g of the title J compound, m.p.

88-950C. After evaporation and redissolution of the mother liquor (15.75 g) in methanol (50 ml) di-tert-butyl dicarbonate (10 g, 45.9 mmol) was added. After stirring the reaction mixture overnight it was evaporated, taken into chloroform and washed with 10% citric acid. The residueafter chromatography over silica gel yielded 6.4 g of homogeneous title J compound.

HA432 K. N-[(1,1-Dimethylethoxy)carbonyl]-3-[(phenylmethoxy)methyll-L-histidine, methyl ester, monohydrochloride To a solution of the title i compound (24.7 g, 66.9 mmol) in dry methylene chloride (156 ml), benzylchloromethyl ether (11.6 ml, 88.6 mmol) was added and the reaction mixture stirred at room temperature for 5 hours. After concentration in vacuo and on dissolution in ethyl acetate (100 ml), the title K compound crystallized out (17.85 g, 65%), m.p. 152-1530C.

L. N-[(1,1-Dimethylethoxy)carbonyll-3-[(phenylmethoxy)methyll-L-histidine The title K compound (18.66 g, 43.8 mmol) was dissolved in methanol (50 ml). Aqueous sodium hydroxide (1N, 92 ml) was added followed by water 83 ml). After keeping the reaction mixture at room temperature for 90 minutes it was further diluted by the addition of water (650 ml) and acidified to pH 4.5 using aqueous hydrochloric acid. The aqueous solution was extracted with chloroform. The chloroform solution was evaporated and the residue was crystallized from ethyl acetate (15.13 g, 92%), m.p.. 155-1570C.

M.

[(1,1-Dimethylethoxy)carbonyll-N-[(1S,2R)-'-(cyclohexylmethyl)-2-hydroxy2-[l-[(phenylmethoxy)methyll-1H-imidazol-2-yllethyl]3[(phenylmethoxy)methyll-L-histidinamide To a solution of the title H compound (3.06 g, 7.35 mmols), 1-hydroxybenzotriazole hydrate (1.13 g, 7. 35 mmols), and the title L compound (2.76 g, 7.35 mmols) in tetrahydrofuran (20 mL) were added triethylamine (2.06 mL, 14.7 mmol) and HA432 dicyclohexylcarbodiimide (1.52 g, 7.35 mmol). mixture was stirred for 18 hours at 25'C, after which it was filtered. The filtrate was diluted with ethyl acetate, washed with saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate and concentrated. The residue (4.92 g) was chromatographed on Merck silica gel, eluting with ethyl acetate:pyridine:acetic acid:water (80:20:6:11) to give the title M compound as the major product (3.98 g, 77%).

N.

N-[(1S,2R)-1-(Cyclohexylmethyl)-2-hydroxy-2[1-[(phenylmethoxy)methyll-1Himidazol-2-yllethyll-3-[(phenylmethoxy)methyll-L-histidinamide A solution of the title M compound (3.88 g, 5.53 mmol) in ethyl acetate (200 rnL) was cooled to OIC in an ice bath and hydrochloric acid gas was bubbled through the solution for 30 minutes. The resulting mixture was then stirred for 2.5 hours as it warmed to 250C, after which it was concentrated to small volume. The resulting white precipitate was collected on a PTFE filter to give the title N compound as a white powder (3.33 g, 85%), m.p. 143-1570C.

0.

[4-(4-Morpholinyl)-1,4-dioxo-2-(phenylmethyl)butyll-N-[(1S,2R)-1(cyclohexylmethyl)-2hydroxy-2-fl-f(phenylmethoxy)methyll-1H-imidazol2yllethyll-3f(phenylmethoxy)methyll-Lhistidinamide, isomer B To a mixture of the title C compound (610 mg, 2.2 mmols), 1- hydroxybenzotriazole hydrate (337 mg, 2.2 mmols) and the title N compound (1.47 g, 2 mmols) in tetrahydrofuran (8 mL) at OOC were added 35 triethylamine (0.84 mL, 6 mmols) followed by HA432 dicyclohexylcarbodiimide (453 mg, 2.2 mmols). The resulting mixture was stirred for 18 hours as it warmed to 250C, after which it was fitered. The filtrate was diluted with ethyl acetate, washed with saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate and concentrated. The mixture (1.64 g) was chromatographed on Merck silica gel (165 g), eluting with ethyl acetate:pyridine:acetic acid:water (80:20:6:11) to give isomer A of the title 0 compound (550 mg, 32%) and isomer B of the title 0 compound. The B isomer of the title 0 compound was further purified-by preparative HPLC to give 580 mg of the title 0 compound.

P. N-[(S)-2-Cyclohexyl-l-[(R)-hydroxy(1Himidazol-2-yl)methyl]ethyll-N2-[4(4morpholinyl)-1,4-dioxo-2-(phenylmethyl)- butyl]-L-histidinamide, isomer B, dihYdrochloride A mixture of the title 0 compound (isomer B) (580 mg, 0.53 mmols) 20% palladium hydroxide on carbon (120 mg), and 1 N aqueous hydrochloric acid (1.17 mL, 1.17 mmols) in methanol (15 mL) was hydrogenated under a slow stream of hydrogen for 19 hours. The mixture was then filtered and concentrated to dryness. The residue (350 mg) was dissolved in 1N aqueous hydrochloric acid (10 mL) and concentrated to dryness in vacuo. The residue was redissolved in 1N hydrochloric acid and concentrated to dryness again, then was dissolved in water, millipore filtered and lyophilized to give the title compound as a fluffy white solid (330 mg, 90%).

Example 2

RA432 [4-(4-Morpholinyl)-1,4-dioxo-2-(1-naphthalenylmethyl)butyl]-N-[(1S,2R)-1(cyclohexylmethyl)-2-hydroxy-2-(1H-imidazol-2yl)ethyll-L-histidinamide, isomer B, dihydrochloride A. (1-Naphthalenylmethyl)propanedioic acid diethyl ester To a suspension of sodium hydride (8 g of 60% dispersion in mineral oil, 200 mmols) in tetrahydrofuran (200 mL) was added diethyl malonate (30.5 mL, 200 mmols) dropwise over 15 minutes; gas evolution was observed. When the addition was complete, the mixture was stirred for 10 minutes at 250C. A solution of 1-chloromethyl naphthalene (35.5 g, 200 mmols) in tetrahydrofuran (20 mL) was added dropwise over 15 minutes, after which the mixture was heated at reflux under argon for 18 hours. Excess 1N hydrochloric acid was then added and the mixture was extracted with ether. The extract was washed with saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was transferred to a flask fitted with a vacuum distillation head. Unreacted diethyl malonate (bp 45-550C/0.2 torr) and 1- chloromethyl naphthalene (bp 120-130OC) were distilled off and the residue was recooled to 250C. The distillation residue (43.5 g) was crystallized from petroleum ether at -30C to give the title A compound as a low melting (mp about 30OC) solid (27.3 g, 46%)- 38B..1-Naphthalenepropanoic acid A solution of the title A compound (10 g, 33.3 mmols) in ethanol (70 mL) and 1 N aqueous sodium hydroxide solution (70 mL, 70 mmols) was stirred for 2 hours at 25C then for two hours At reflux. The ethanol was removed in vacuo and the remaining aqueous mixture was diluted with water and washed with ether. The aqueous layer was acidified by addition of 1N hydrochloric acid (100 mL). Dioxane (100 mL) was then added (for solubility) and the mixture was heated at reflux for 18 hours, after which it was concentrated in vacuo. Water and ethyl acetate were added to the residue and the mixture was extracted three times with ethyl acetate. The extract was washed with 1N hydrochloric acid, dried over anhydrous magnesium sulfate, and concentrated. The residue was triturated with ether to give the title B compound as a white solid (4.6 g, 60%), m.p. 151-1530C.

RA432 c.

2-Naphthalenepropanoic acid, phenylmethyl ester To a solution of the title B compound (7 g, 35 mmol), benzyl alcohol (3.8 mL, 37 mmol), and 4dimethylamino pyridine (420 mg, 3.5 mmol) in methylene chloride (175 mL) at OOC was added dicyclohexylcarbodiimide (7. 6 g, 37 mmol). The resulting mixture was stirred for 2 hours at OOC then for 18 hours at 250C, after which it was filtered. The filtrate was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated. The residue (10.9 g) was dissolved in benzene and filtered through a pad of coarse silica gel (180 g). The filtrate was concentrated to give the title C compound as a clear, colorless 35 oil (9.66 g, 95%).

HA432 D. (2-Naphthalenylmethyl)butanedioic acid, 4-(1,1-dimethylethyl) 1(phenylmethyl ester To a solution of diisopropyl amine (4.4 mL) in tetrahydrofuran (58 mL) at -10C under argon was added n-butyllithium (11.3 mL) of 2.6 M solution in hexane). The mixture was stirred at that temperature for 15 minutes, then was cooled to -780C. A solution of the title C compound (8.5 g, 29 mmols) in tetrahydrofuran (10 mL) was added dropwise to the cold solution, after which the solution was stirred for 15 minutes at -780C. Tert-butyl bromoacetate (5.2 mL, 32 mmol) was then added and the mixture was stirred for 15 minutes at -780C, then for 2 hours as it slowly warmed to 250C. The mixture was then poured into excess 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with saturated sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, and concentrated. The residue (8.06 g) was flash chromatographed on silica gel (500 g), eluting first with benzene:hexanes (2:1) to bring off a yellow colored band then with benzene and finally with benzene:ethyl acetate (4:1), to give the title D compound as a colorless oil which crystallized on standing (6.62 g, 56%), m.p. 64-660C.

E. (2-Naphthalenylmethyl)butanedioic acid, 1- (phenylmethyl) ester To a solution of the title D compound (9.5 g, 23.5 mmols) in methylene chloride (50 mL) at OOC was added trifluoroacetic acid (50 mL). The mixture was stirred for 2 hours at CC, after which HA432 it was concentrated to dryness. The residue was crystallized from acetonitrile to give the title E compound (6.89 g, 84%), m.p. 124-1260C.

F. (2-Naphthalenylmethyl)butanedioic- acid, 1 (phenylmethyl) ester, (+)-isomer The title E compound (5.8 g, 16.6 mmol) was dissolved in ether (100 mL) and (-)-ephedrine (2.75 g, 16.6 mmol) was added. The mixture was stored at -300C for three days resulting in a waxy solid which was collected. The solid was recrystallized twice from 35 mL of ethyl acetate and 165 mL of ether, then twice more from 50 mL of ethyl acetate and 150 mL of ether, resulting in a solid of constant melting point and specific rotation (3.0 g, m.p. 114.5-115.50C, [a] D =+31.70). The crystalline solid was then partitioned between ethyl acetate and 1N hydrochloric acid and was extracted with ethyl acetate. The extract was dried and concentrated to give the title F compound, [a) D =+54.80 (methanol), (1.89 g).

G.

a-(2-Naphthalenylmethyl)-y-oxo-4-morpholine- butanoic acid, phenylmethyl ester, (+)-isomer To a mixture of the title F compound (1.89 g, 5.4 mmol, [a] D =+54.81), morpholine (0.525 mL, 6 mmols), and 1-hydroxybenzotriazole (730 mg, 5.4 mmol) in tetrahydrofuran (15 mL) was added dicyclohexylcarbodAmide (1.1 g, 5.4 mmol). The resulting mixture was stirred at 250C for 20 hours, after which it was filtered. The filtrate was diluted with ethyl acetate, washed with 1N HA432 hydrochloric acid and saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate, and concentrated to give the title G compound (2.1 g, 93%). [a] D'+32.10 (c 4, methanol).

H. u-(2-Naphthalenylmethyl)-y-oxo-4-morpholinebutanoic acid, (-)-isomer A mixture of the title G compound (2.1 g, 5 mmol) and 1 N sodium hydroxide solution (5 mL) in dioxane (10 mL) was stirred at 250C for 16 hours, after which it was diluted with water and washed with ether. The aqueous layer was acidified (HC1) and extracted three times with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated to give the title H compound as a colorless glass (1.58 g, 97%).

[R-(R,S)]-N-[1-(Cyclohexylmethyl)-2-hydroxy2-(lH-imidazol-2-yl)ethyll-L-histidinamide A mixture of the title M compound from Example 1 (1.46 g, 2 mmols), 20% palladium hydroxide on carbon (350 mg, Aldrich), and 1 N hydrochloric acid (4 mL, 4 mmols) in methanol (15 mL) was hydrogenated under a slow stream of hydrogen for 20 hours at 250C, after which it was filtered (PTFE filter) and concentrated to dryness.. The residue (1.1 g) was dissolved in acetic acid (30 mL) and dry hydrochloric acid gas was bubbled through the solution for 30 minutes at 25C. The mixture was then stirred at 250C for two hours, after which it was concentrated in vacuo. The residue was RA432 triturated with acetonitrile to give a white solid (833 mg). The solid was dissolved in excess 1N hydrochloric acid and wag concentrated to dryness; the process was repeated a total of three times to give the title I compound as a white solid.

J.

[4-(4-Morpholinyl)-1,4-dioxo-2-(1-naphthalenylmethyl)butyll-N-[(1S,2R)-1(cyclohexylmethyl)-2-hydroxy-2-(1H-imidazol-2Y1)ethyll-L-histidinamide, isomer B, dihydrochloride To a solution of the title H compound (164 mg, 0.5 mmol), 1- hydroxybenzotriazole hydrate (84 mg, 0.55 mmol) and the title I compound (276 mg, 0.55 mmol) in dimethy1formamide (2.5 mL) at OOC were added triethylamine (0.24 mL, 1.65 mmol) and dicyclohexylcarbodiimide (113 mg, 0.55 mmol). The resulting mixture was stirred for 18 hours as it warmed to 250C, after which the mixture was concentrated to dryness in vacuo. The residue was dissolved in a mixture of methanol (3 mL) and 1N hydrochloric acid (2 mL), filtered, and concentrated. The residue (814 mg) was chromatographed on Merck silica gel, eluting with ethyl acetate:pyridine:acetic acid:water (50:20:6:11). Fractions containing the major product (R f 0.25) were' combined and concentrated. The residue was dissolved in excess 1N hydrochloric acid and concentrated to dryness three times. 'The reddish residue (295 mg, 74%) was chromatographed on HP-20, eluting with a gradient from 0.01N hydrochloric acid to methanolic hydrochloric acid (0.01N). Fractions containing the major product HA432 were combined and partially concentrated, then lyophilized to dryness. The residue was relyophilized from water to give the title compound as a fluffy white solid (120 mg, 29%).

Example 3 [4-Cyclohexyl-1,4-dioxo-2-(phenylmethyl)butyll-N-[(2S,3R)-1(cyclohexylmethyl)-2hydroxy-2-(1H-imidazol-2-yl)ethyll-L- histidinamide, isomer B, dihydrochloride A. (2-Cyclohexyl-2-oxoethyl)(phenylmethyl)propanedioic acid, diethyl ester To a suspension of sodium hydride (8 g, 0.2 mole) in tetrahydrofuran (200 mL) under argon was - added diethylbenzyl malonate (50 g, 0.2 mole).

The mixture was stirred for 30 minutes at 2SIC after the addition was complete, resulting in a homogeneous solution. Bromomethyl cyclohexyl ketone (20.5 g, 0.1 mole; the preparation of which has been described in Tetrahedron Letters, 26, 5611-5615, (1970)) was then added over 10 minutes, after which the mixture was warmed to 500C and stirred at that temperature for 16 hours. The mixture was then poured into excess 1N hydrochloric acid and the resulting mixture was extracted with ether. The extract was washed once in 1N hydrochloric acid and twice in sodium hydrogen carbonate, dried over anhydrous magensium sulfate and concentrated to a yellow oil. The oil was distilled and the residue passed through a short RA43 2 column of silica gel, using stepwise gradient elution. Elution with 1:1 hexane:ethyl acetate gave the title B compound as a yellowish oil (28 g, 75%).

B. a-(Phenylmethyl)-y-oxocyclohexanebutanoic acid A mixture of the title A compound (28 g, 0.075 mmol) and 1 N sodium hydroxide solution (150 mL, 0.15 mole) in ethanol (150 mL) was stirred at 750C for 15 hours, after which it was diluted with water (500 mL) and washed with ether. The aqueous solution was then acidified in concentrated hydrochloric acid and extracted twice with ethyl acetate. The extract was dried and concentrated to a yellow oil (18 g). The residue was dissolved in dioxane (180 mL), concentrated hydrochloric acid (1 mL) was added, and the mixture was stirred at 1000C for 22 hours. The mixture was then concentrated to an orange oil. The oil was dissolved in 1N sodium hydroxide solution (125 mL) and the mixture was stirred for 18 hours at 750C, after which it was diluted with water and washed with ether. The aqueous solution was-made acidic with hydrochloric acid and extracted twice with ether. The extract was dried over anhydrous magnesium sulfate and concentrated to give a yellow oil (12 g). After standing at 250C for one week, the compound crystallized. The crystals were triturated with petroleum ether to give the title B compound as a white powder (8.4 g, 41%), m.p. 71-730C.

HA432 [4-Cyclohexyl-1,4-dioxo-2-(phenylmethyl) butyll-N-[(2S,3R)-l(cyclohexylmethyl)-2hydroxy-2-(lH-imidazol-2-yl)ethyll-Lhistidinamide, isomer B, dihydrochloride To a solution of the title I compound from Example 2 (754 mg, 1.5 mmols) 1-hydroxybenzotriazole hydrate (230 mg, 1.5 mmols), and the title B compound (230 mg, 1.5 mmols) in dimethy1formamide (7 mL) at OOC were added triethylamine (0.68 mL, 4.9 mmols) and dicyclohexylcarbodiimide (309 mg, 1.50 mmols). The resulting mixture was stirred for 18 hours at 25C, after which it was concentrated to dryness. Methanol (9 mL) and 1 N hydrochloric acid (6 mL) were added to the residue. The resulting solution was filtered and the filtrate was concentrated to dryness. The residue (2.56 g) was chromatographed on Merck silica gel; fractions containing the major product (R f 0.2) were collected and concentrated.

The residue (640 mg) was further purified by preparative HPLC. Two major fractions (Isomer A and Isomer B) were separately collected and concentrated. The resulting trifluoroacetate salts were not water soluble, thus the residues were separately dissolved in excess 1 N hydrochloric acid and reconcentrated three times to convert to the soluble hydrochloride salts. The residues were then dissolved in water, charcoal filtered, and lyophilized to give Isomer A (162 mg, 16%) and Isomer B (134 mg, 13%) of the title compound.

RA432 Example 4 [3-[(Cyclohexylthio)methyl]-1-oxo-3-phenylpropyll-N-[(1S,2R)-1(cyclohexylmethyl)-2- hydroxy-2-(1H-imidazol-2-yl)ethyll-Lhistidinamide, dihydrochloride A. a-Methylenebenzenepropanoic acid Benzyl malonic acid (13 g, 0.067 mole) was mixed with aqueous dimethylamine (7.6 g, 0.068 mole, 40%) and formalin (5-4 g, 0.068 mole, 37%) in water (150 ml). The voluminous solid which formed in 15 minutes was filtered after 2 hours, washed with water and dried partially in air to give 20.8 g. The solid was melted in a 1700 oil bath and heated for 10 minutes, until amine evolution had stopped and bubbling had virtually ceased. The cooled product, a mobile liquid, was acidified with 10% potassium hydrogen sulfate, extracted with hexane, dried over sodium sulfate and evaporated to give 6.3 g of solid. The aqueous filtrates from the Mannich reaction were allowed to stand overnight and were then heated at 1000C on a steam cone until bubbling ceased. Cooling, acidification and extraction as above gave another 1.2 g of solid for a total of 7.5 g of benzyl acrylic acid.

B. a-[(Cyclohexylthio)methyllbenzenepropanoic acid To a solution of the title A compound (8.1 g, 50 mmol) in piperidine (16 mL) under argon was added cyclohexyl mercaptan (6 mL, 50 mmol). The mixture was stirred under argon at 1000C for 24 hours, after which it was cooled to 25C and acidified by addition of concentrated HA432 hydrochloric acid. The mixture was then saturated with sodium chloride and was extracted twice with ether. The ether extracts were combined and extracted with 1 N sodium hydroxide solution. The basic aqueous extract was made acidic by addition of concentrated hydrochloric acid and was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated. The residue (4 g) was purified by flash chromatography 10 on silica gel, eluting with 1:1 ethyl acetate:hexanes, to give the title B compound as a colorless oil.

C. [3-[(Cyclohexylthio)methyl]-1-oxo-3-phenylpropyll-n-[(1S,2R)-1(cyclohexylmethyl)-2- hydroxy-2-(1H-imidazol-2-yl)ethyll-Lhistidinamide, dihydrochloride To a solution of the title B compound (557 mg, 2 mmol), 1-hydroxybenzotriazole hydrate (337 mg, 2.2 mmol) and the title I compound from Example 2 (1.1 g, 2.2 mmol) in dimethylformamide (8 mL) at CC were added triethylamine (0.92 mL, 2.2 mmol) and dicyclohexylcarbodiimide (453 mg, 2.2 mmol). The resulting mixture was stirred for 18 hours at 250C, after which it was concentrated to dryness. The residue was dissolved in a mixture of methanol (9 mL) and 1 N hydrochloric acid (6 mL), filtered, and the filtrate was concentrated to dryness. The residue (3.68 9) was flash chromatographed on. silica gel, eluting with ethyl acetate:pyridine: acetic acid:water (80:20:6:11) to yield a major fraction having R f = 0.31 (940 mg). This pinkish material was further purified by chromatography on HP-20 (400 mL), eluting with a gradient from 0.01 N HA432 hydrochloric acid to 0.01 N hydrochloric acid in methanol. Fractions were monitored by HPLC analysis; those containing the desired products (7-1 min and 8.3 min. YMC S-ODS column, 4.6 x 150 mm, 1.0 mL/min of 66% aqueous methanol containing 0.01% phosphoric acid, h = 220 nm) were combined and partially concentrated in vacuo to remove methanol, then frozen and lyophilized. The-residue was relyophilized from water to give the title compound as a fluffy, off-white (pinkish) solid (386 mg, 28%).

Ex le 5 is [2-[(Cyclohexylsulfinyl)methyl]-1-oxo-3phenylpropyl]-N-[(1S,2R)-1(cyclohexylmethyl)-2-hydroxy-2-(1H-imidazol-2-yl)- ethyl]-L-histidinamide, isomer 2B, trifluoroacetate (1:2) salt A. u-[(Cyclohexylsulfinyl)methyl]benzenepr panoic acid, isomers 1 and 2 A solution of the title B compound from Example 4 (1.95 g, 7 mmol) and hydrogen peroxide 25 (4.76 mL, 42 mmol) in methanol (35 mL) was stirred at 250C for two hours, after which additional hydrogen peroxide was added (0.45 mL). The mixture was stirred for 1.5 additional hours (3.5 hours total), then made acidic by addition of sulfuric acid (35 mL). The mixture was checked for presence of peroxides using starch-iodine test paper (positive test). Saturated aqueous sodium thiosulfate solution was added until a positive peroxide test was no longer obtained. The mixture was then diluted with an equal volume of ethyl HA432 acetate and stirred for 10 minutes, after which it was filtered and extracted with ethyl acetate. The extracts were combined, dried over anhydrous magnesium sulfate, and concentrated. The residue (2.3 g) was crystallized from 95% ethanol to give isomer 1 of the title A compound (670 mg, 32%, m.p. 153-1540C). The mother liquor was diluted with ether and cooled to give a white solid (m.p. 118-1200C) which was recrystallized from ethanol to give isomer 2 of the title A compound (365 mg, 18%, m.p. 123-1240C).

B. [2-[(Cyclohexylsulfinyl)methyll-l-oxo-3phenylpropyll-N-[(1S,2R)-1(cyclohexylmethyl)-2-hydroxy-2-(1H-imidazol-2-yl)ethyl]-L-histidinamide, isomer 2B, trifluoroacetate (1:2) salt To a solution of the isomer 2 of the title A compound (539 mg, 1.83 mmol), 1-hydroxybenzo- triazole hydrate (306 mg, 2 mmol), and the title I compound from Example 2 (998 mg, 2 mmol) in dimethylformamide (7 mL) at 011C were added triethylamine (0.85 mL, 6 mmol) and dicyclo- hexylcarbodiimide (412 mg, 2 mmol). The resulting mixture was stirred for 19 hours at 250C, after which it was concentrated to dryness. The residue was dissolved n a mixture of methanol (10 mL) and 1 N hydrochloric acid (7 mL), filtered and concentrated. The residue (3.6 g) was flash. chromatographed on silica gel, eluting with ethyl acetate:(pyridine:acetic acid:water) 2:1(20:6:11). Fractions containing the major "product" (R f 0.30) were combined and concentrated to give an isomeric 1 r% HA432 mixture (720 mg). The isomers were separated by preparative HPCL to give isomer 2A of the title B compound (280 mg, 31%) and isomer 2B of the title B compound (150 mg, 17%).

Example 6 [2-[(Cyclohexylsulfonyl)methyll-l-oxo-3Dhenylpropyl]-N-[(1S,2R)-1(cyclohexylmethyl)-2-hydroxy-2-(1H-imidazol-2-yl)- ethyl]-L-histidinamide, isomer B, trifluoroacetate (1:2) salt A. a-[(Cyclohexylsulfonyl)methyllbenzene- propanoic acid To a solution of the title B compound from Example 4 (2.78 g, 10 mmol) in methanol (40 mL) at OOC was added a solution of potassium monopersulfate (9.21 g, 30 mmol) in water (40 mL). The resulting mixture was stirred for 2 hours as it warmed to 25C, after which it was extracted with chloroform. The extract was dried over anhydrous magnesium sulfate and concentrated. The residue (3.02 g) was crystallized from ethyl acetate/hexanes to give the title A compound (2.90 g, 94%), m.p. 109- 1110C.

B. [2-[(Cyclohexyldulfonyl)methyll-l-oxo-3phenylpropyll-N-[(1S,2R)-1-(cyclohexylmethyl)-2-hydroxy-2-(1H-imidazol-2yl)ethyl]-L-histidinamide, isomer B, trifluoroacetate (1:2) salt To a solution of the title A compound (1.24 g, 4 mmol), 1-hydroxybenzotriazole hydrate (612 mg, 4 mmol)-and the title I compound from HA432 Example 2 (2 g, 4 mmol) in dimethylformamide (15 mL) at CC were added triethylamine (1.76 mL, 12.6 mmol) and dicyclohexylcarbodiimide (824 mg, 4 mmol).

After being stirred for 18 hours at 250C, the mixture was concentrated to dryness. To the residue were added methanol (20 mL) and 1 N hydrochloric acid (14 mL). The mixture was filtered and the filtrate was concentrated to dryness. The residue was chromatographed on silica gel to give an isomeric mixture R f 0.28 (1.54 g).

The isomers were separated by preparative HPLC.

Fractions containing the individual isomers were partially concentrated and lyophilized. The residues were relyophilized from water to give isomer A of the title B compound (730 mg, 21%) and isomer B of the title B compound (520 mg, 15%).

Example 7 [2-[(Diethoxyphosphinyl)methyll-l-oxo-3phenylpropyll-N-[(2S,3R)-1(cyclohexúlmethyl)-2-hydroxy-2-(1H-imidazol-2-yl)ethylL-histidinamide, isomer B, trifluoroacetate (1:2) salt A. a-[(Diethoxyphosphinyl)methyllbenzenepr panoic acid Bis(trimethylsilV1)acetamide (5 g, 0.024 mole, 6 ml) was added, at room temperature, to a solution of benzyl acrylic acid (2 g, 0.012 mole) and diethyl phosphite (3.3 g, 0.024 moles) in dichloromethane (30 ml). The mixture was stirred at ambient temperature for 30 minutes, concentrated in vacuo at room temperature, and the residue was heated at a bath temperature of 100-1101 for 16 HA432 hours. The colorless oil reaction mixture was dissolved in ethyl acetate and extracted with 5% sodium bicarbonate (pH 9-10). The aqueous alkaline solution was washed with ether and acidified to a pH of 1-2 with concentrated hydrochloric acid. The colorless oil that separated was extracted into ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to give a colorless oil (3.6 g).

B. [2-[(Diethoxyphosphinyl)methyll-l-oxo-3phenylpropyl]-N-[(1S,2R)-1(cyclohexylmethyl)2-hydroxy-2-[1-[(phenylmethoxy)methyll-1Himidazol-2-yllethyl]-3-[(phenylmethoxy)methyllL-histidinamide, isomers A and B To a solution of the title J compound from Example 1 (1.46 g, 2.0 mmols), 1-hydroxybenzotriazole hydrate (337 mg, 2.20 mmols), and the title A compound (600 mg, 2.20 mmols) in tetrahydrofuran (8 mL) at OOC were added triethylamine (0.92 mL, 6.6 mmols) and dicyclohexylcarbodiimide (453 mg, 2.20 mmols). The resulting mixture was stirred for 18 hours at 25C andfiltered. Ethyl acetate was added to the filtrate and the resulting solution was washed with saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate and concentrated. The residue (1.75 g) was flash chromatographed on Merck silica gel, eluting with ethyl acetate:pyridine:acetic acid:water (100:20:

6:11), to give isomer A of the title B compound (680 mg, 38%) and isomer B of the title B compound (620 mg, 35%).

1 c.

HA432 [2-[(Diethoxyphosphinyl)methyll-l-oxo-3phenylpropyll-N-[(2S,3R)-1(cyclohexylmethyl)-2-hydroxy-2-(1H-imidazol-2-yl)ethyl- L-histidinamide, isomer B, trifluoroacetate (1:2) salt A mixture of the isomer B of the title B compound (600 mg, 0.68 mmols), 20% palladium hydroxide on carbon (150 mg), and 1 N hydrochloric acid (1.5 mL, 1.5 mmols) in methanol (15 mL) was hydrogenated under a slow stream of hydrogen for 18 hours at 250C, after which it was filtered and concentrated to dryness. The residue (470 mg) was flash chromatographed on Merck silica gel, eluting with chloroform:methanol:ammonium hydroxide (100:25:1.25). Fractions containing the major component were combined and concentrated. The residue (300 mg) was dissolved in excess 1% aqueous trifluoroacetic acid solution and reconcentrated. The residue was then dissolved in 20 water (50 mL), treated with activated charcoal, millipore filtered, and lyophilized to give the title compound as a fluffy white solid (320 mg, 66%).

Example 8

HA432 [(S)-2-[(Benzoylthio)methyll-l-oxo-3-phenylpropyll-N-[(1S,2R)-1-(cyclohexylmethyl-2hydroxy-2-(1H-imidazol-2yl)ethyll-Lhistidinamide, trihydrochloride A. a-[(Benzoylthio)methyl]benzenepropanoic acid A mixture of the title A compound from Example 4 (13.7 g, 85 mmol) and thiobenzoic acid (15 mL, 127 mmol) in methylene chloride (170 mL) was stirred under argon at reflux temperature for 3 days, after which it was concentrated in vacuo. The residue was crystallized from ether/hexane to give 13.7 g of the title A compound as a colorless solid, m.p. 99-100'C.

B. (S)-a-[(Benzoylthio)methyllbenzene2ropanoic acid A solution of the title A compound (14.5 g, 48.0 mmol) and (R)-(+)-a-methylbenzyl amine (6. 25 mL, 48 mmol) in ether (250 mL) was stored at -40C for two days, resulting in a gummy solid. The solvent was decanted and the solid was recrystallized 3 times from hexane/methylene chloride (1:1) then twice from isopropanol to give a 1:1 salt, m-p- 131-132C, [a) D = -25.00 (c = 1, CHC1.3). The salt was-dissolved in ethyl acetate and washed with 1.0 N hydrochloric acid. The organic layer was dried over anhydrous magnesium sulfate and concentrated to give 1.57 g of the title B compound as a white solid, m.p. 65-660C, [U]D = -53.30 (c = l.- CEC13).

c.

HA432 [(S)-2-[(Benzoylthio)methyl]-1-oxo-3-phenylpropyl]-N-[(1S,2R)-1(cyclohexylmethyl-2hydroxy-2-(1H-imidazol-2-yl)ethyll-Lhistidinamdie, trihydrochloride To a solution of the title B compound (1.42 g, 4.73 mmol), 1-hydroxybenzotriazole hydrate (724 mg, 4.73 mmol) and the title I compound from Example 2 (2.22 g) in dimethylformamide (20 mL) at OOC were added triethylamine (2.2 mL, 16 mmol) and dicyclohexylcarbodiimide (975 mg, 4.73 mmol). The resulting mixture was stirred at 250C for 18 hours, after which it was filtered and concentrated. The residue was chromatographed on silica gel, eluting with ethyl acetate:(pyridine:acetic acid:water) 2:1(20:6:11). Fractions containing the major product were combined and concentrated. The residue was dissolved in excess 1 N hydrochloric acid and concentrated in vacuo. The residue was then lyophilized from water to give the title compound as a fluffy white solid.

Example 9 [(S)-2-(Mercaptomethyl)-1-oxo-3-phenylpropyll-N-[(1S,2R)-1(cyclohexylmethyl)2-hydroxy-2-(1H-imidazol-2-yl)ethyll-L- histidinamide, trifluoroacetate (1:2) salt A mixture of [(S)-2-[(benzoylthio)methyl]-1oxo-3-phenylpropyll-N-[(1S,2R)-1-(cyclohexylmethyl2-hydroxy-2-(1H-imidazol-2-yl)ethyl]-L-histidinamide, RA43 2 trihydrochloride (270 mg, 0.35 mmol) and concentrated ammonium hydroxide solution (1 mL) in methanol (5 mL) was stirred at 500C for 7 days (additional ammonium hydroxide (2 mL) was added. after 2 and 6 days). After 7 days, the mixture was concentrated in vacuo and the residue was purified by preparative HPLC. Fractions containing the major product were concentrated in vacuo. The residue was dissolved in water and lyophilized to give 45 mg of the title compound as a fluffy white powder.

Examples 10-30 Following the procedures of Examples 1-9, is additional compounds within the scope of this invention can be prepared having the formula Rs 0 R4 0 R3 1 11 1 11 1 X-CH2-CH-C-NH-CH-C-NH-CH-CH-RI f Uki wherein the substituents are as defined below.

W W W r') F bi Ul C) Ln C) Ul C) Ul Ex. No. X Rs R4 R3 R, CH3 1 0 -CH2 NH N 2-0 -CHT-0 N (CH3)3-CO-C- -CH H 1 0 -CH2 NIL1 CH3 11 C-CH2-0-C- -CH2 -00 N-J -CH:C-0 0.-CH2t-Ti NH 12 - CH2 -C- -CH2 %;- -CH2CH(CH3)2 N-N 1 ffi H H 0 CH2 N 13 11 -S- - - 1 -fo -CH2CH(CH3)2 1 1 (CH3)3C CH2-( T'l,' N-1 ll D) v 0 H W Un W C> K) Ul C> ILn e-i C) Ul Ex. No. X R5 R4 R3 R, 0 -CH2-"1:,NH 14 0 N-s- -CH2 N) -CH2CH(CH3)2 \--/ 11 -0 0 0 S - 1 11 - -11 - cl is (CH3)2CH-S- CH2 CH2-0 -CH2-0 -CH(CH3)2 co 0 -CH2T1 0 -LA 2CH 0 CH2 -CH N 16 CH 11 2CH(CH:3)2 20-P- OCH2CH3 H 0 -CH2- NH 11 - 17 CH3CH20-P- -CH27 N) -CH2CH(CH3h N 1 00 (CH 2)4 1 W W ri f-i. F Ul 0 Ul C) tn Ul Ex. No. X Rs R4 R3 R, 0 -CH2-C, NH S 18 0 N-C- -CH N -CH2- N 0' 0 1 0 -CH2 NH N- 11 Co 19 CH3CH 0-P- -CH -CH2CH(CH3)2 2 2- 1 6CH2CH3 H CH2 NH S S02- -CH N42 H A -CH2CH(CH3h 4 I-C 2 2-CO -0 CO, - V.

5- N > 0 -CH2 -E b.

11 N X0) - _r 112)2CH(CH3) 21 (CH3)2CHCH2S- -CH 1 CH2CH(CH3)2 N (CH 2 2 H H 0 H W Ul (Ai C) Ln C) Ul C) c_n Ex. No. X R5 R4 R3 RI 0 (CH2) 3_ on 11 1 - 22 CH2CH30-p- (CH2) 4 -NH2 -CII2 NH -CH2CH(CH3)2 OCH2CH3 N- N 1 H 1 1 jr 1 -c TN.:j (3, 0 -CH2 C NII 23 (CH3) 3 C-S- H2- CH2- ---ColCH3 11 0 \k -- Y N 0 H 0 -CH2- -CH2 -17rH k 11 0, - ri - 11 24 S_ ",N' -CH2CH(CH3)2 N 1 CH2- On &II 0' 0 8 CH3 0 -0 -CI12-]l_fH H 11 'N ', 3)2 N-S- -CH2 -CH2CH(CH CH 3 0 N CH2) T(j j 1 1 1 W (Ai N) NJ l-i F Ul C) Ul C) Ul C> Ul Ex. No. X R5 R4 R3 R, 0 -CH2 NH H -CHIr- -CH N 26 CH3CH2-1'- 2CH(CH3b 1 CH2CH3 N - C2H5 -CH2 NH H 1 1 27 H-S -CH2 -CH N 01 -Q-- N - CH3 H 0 0 11 28 C-S -CH2-0-- (CH2) 4 -NH2 -CH2- N (0_ fil^'-1 N -1 -CH NH --IN _) -CH 0 N 29 H-S -CH2-(0 2- J 9 (A) Ul W C) K) ul K) C) Ii-n C) Lrl Ex. No. X R5 R4 R3 RI 0 -CH2 NH -ro 11 -CH - TNJ- -CH N J (CH3M-CH2-P 210 2-0 1 OCH2CH3 1 m N 1 :4 I" W K) ir

Claims (1)

1. A compound having the formula I RS 0 R4 0 R3 1 11 1 11 1 X-CH2-CH-C-NH-CH-C-NH-CH-CH-Rl 1 OH HA432 including pharmaceutically acceptable salts 0 11 10 thereof, wherein X is Re-(CH2)m-A-N-C-, 0 11 0 R10 11 R6-(CH2)M-A-C-, R6-(CH2)M-A-0-C-, R6-(CB2)m-A-S-, R6-(CH2)m-A-SO-, R6(CH2)m-A-SO2t 0 11 Re-(CH2)m-A-N-SO2-1 Re-(CH2) -A-C-S 1 m Rjo 0 H R6-(CH2)m-A-(0) -P-, p i 01)p A' 1 (CH2)M1 1 k(6 R, is a fully saturated, partially saturated, or unsaturated monocyclic N- heterocyclic ring of 5 or 6 atoms containing at least one N atom or a bicyclic ring in which said N-heterocyclic ring is fused to a benzene ring wherein said Nheterocyclic ring can also include an 0 or S atom or up to three additional N-atoms, an available N atom in said N-heterocyclic ring can 0 CH N-C; be substituted with -CI12-0-CH jp -502-<0) -CH3.

j RA432 is -2,4-dinitrophenyl, lower alkyl, CH2 n or -(CH2)n-cycloalkyl, an available carbon atom in said monocyclic N-heterocyclic ring or in the benzene portion of said bicyclic N-heterocyclic ring can be substituted with lower alkyl, (CE2 r Or - (C52 n \= n-cycloalkyl, and said N-heterocyclic ring is bonded to the -CH- moiety at OH an available carbon atom, CN- represents a heterocyclic ring of the formula (CH2) Y (CH2) b Nwherein Y is -CI42, Or S, or N-Rq, 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 and such heterocyclic rings wherein one carbon atom has a lower alkyl substituent; R3 and R5 are independently selected from hydrogen, lower alkyl, halo substituted lower alkyl, -(CH2) n- aryl, -(CI42)n-heterocyclo, -(CE2)n-OH' -(CH2)n-0- lower alkyl, -(CI42)n-NH2i -(CH2)n- SH, -(CH2)n- S-lower alkyl, -(CH2) -0-(CH2)g-OH, -(CH2)n-o-(CI42)g-NH2r 0 11 -(CH2) n_ S-(CH2)g-OH, -(CH2)n-C-OH, (CH2)nS-(CH2)g-NH2.. -(CH2)n -NH-C \ RA432 NH NH2 g -(CH2) -C-NH2 -(CH2) -R7# -(CH2) -N, n n n 1 N) 1 R8 and -(CH2) n-cycloalkyl; R4 is selected from hydrogen, lower alkyl, halo substituted lower alkyl, - (C112) n_ aryl, -(CH2) n -heterocyclo, -(CH2) JOH' -(CH2) n-o-lower alkyl, -(CH2) n-NH2P -(CH2)n-SH, -(CH2) n_ S-lower alkyl, _(CE2) n-O-M-I2)g-OH, -(CH2) JO(CH2)g-NH2, 0 11 -(C112) -S-(C112) -OIIP -(C112)-C-OHr n n (CH2 S-(C112)g-NE2f _(CH2 NH-C )n-)n- NH NH2 r 0 11 CI.I2 C-NI42 C112) n N-R7. -(C112) n_ N, n_ W.' N' WJ N:] (CI'12) _cycloalkyl, -(CH2)rjn N 0 (CH2 and, -(C112),i- n M R6, R61 and R611 are independently selected from hydrogen, alkyl, aryl, and cycloalkyl, or R6 and R61 taken together with the atom to which they are bonded may form a ring of 3 to 5 carbons; -66 HA43 2 m, m' and m" are zero or an integer from 1 to 5; n is an integer from 1 to 5; p and p' are zero or 1; is R2 1 N g is an integer from 2 to S; R7 is -CI"I2-0-CE2---a or -CHi---W 11 R8 is 2,4-dinitrophenyl, -C-O-CH 2-C -S02 -0- CH3 p Or -C112 -0-CE2 -a R9 is hydrogen, lower alkyl, -(cH,) n -ccl Or -(CH2)n_ cycloalkyl.

Rjo is -(CH2)mj-R61; A and A' are a single bond or -(CH)-(CH2)m,-R611 1 2. A compound of claim 1 wherein R, is R2 1 0 R9 R9 R9, IL_-Rg N-N N 1 R2 R9 -(\N N-N 0 R9 g -f" N N 1 2.2 -11.1 A.

R9 N-R2 N R2. R9 S 0 - r--- S N-=-1 R9 R9 0 11 R9 $ - LI - R9 N r r 1 1 HA432 R2 1 N -11 -t R9, R9 Rg, N 1 N k2 - S - ri 1 R9 and N 0 R9 N A compound in accordance with claim 1 wherein 0 H5C20 0 / --- \ 11 \11 X is 0 N-C-, P or H.SC20 0 11 S-; 0-11 0 is i- NH -(5 R, is - or \ 1 - 1 N 11 N - R3 is straight or branched chain lower alkyl of 3 to 5 carbons, -(CH2)ncyc lopentyl, (CH2) -cyclohexyl, Or -(CH2)---C n n is an integer from 1 to 3; R4 is hydrogen, straight or branched chain 25 lower alkyl of up to 5 carbons, -(C112)4-NI12, wherein n -CH2-1",. -CI12-1N-CH 1LT N" 2-0-CH2 --c 1 -C112 C112 H -CH 00, 2ú0), -CH2 - N N - (CE2) 2 -U 7 177\ -CH2-,r-',,j _ OH, 0 -C112 -col, - (C112) -(\ Nn X_J JI (CH2 (CH2 n n is N RA432 or -CHi -,,N and, Nlij 1 9--mo 2 N02 Rs is straight or branched chain lower alkyl of up to 5 carbons, -CH2-C F -(CH2)2-\0 -CH2- OCH3. -CH2-(a-naphthyl), -CH2-(p-naphthyl), -CH2 OH, -CH2-cyclopentyl, -CI12-cyclohexyl, -CH2- On N -CE2 NH, or -CE2 -'I 1 0 /77\ -CH2--00tl,, -CH2 GN, h::.1 c 1 HA432 4. A compound in accordance with claim 1 wherein ethoxy; R6 is cycloalkyl, morpholinyl, ethyl or N /-NH 1 J.4 R, is "JI; _ 1 or -(\N N S] R3 is -CH2-0or -C142-CE CH3 CH3 CH3 R4 is -CH2-CII is Or -CH2T, --NI-I; and, 14., CH,3 RS is -CH2-C or -CE2 -CP 5. A compound of claim 1 wherein' N] 1 w R, is 1 NH R3 iS -CE2-0 -NH R4 is I-N /J RiS -CH'.'% L2 X is p is 1 0 11 /--\ -C-N 0; and, 6. A compound of claim 1 yherein is N - 1 Tj R, is - 1 R3 is -CH2-0 NH R4 15 -C112 NI R5 is -CHZ-C 0 j i /--\ X is -C-N 0; and, p is 1. \,-/ 7.

A compound of claim 1 wherein _ N:] R, is II R3 iS -CH2-0 NH R4 iS -CH2 N / RS is -CE2-C 0 11.0 X is -C-; and, p is 1.

RA43 2 c z 8. A compound of claim 1 wherein 14 R, is - NH JI R3 iS -CE2-C) NI-I R4 iS -CHi- N R5 is -CH r-.D X is -S-C); and, p is 1. g. A compound of claim 1 wherein _ N:3 R, is i H R3!S -C112 -0 NI-I R4 is -CH2J1 NI R5 is -CH 2-0 0 fl X is -S-0 and, p is 1.

HA432 10. A compound of claim 1 wherein N R 1i 5- 1171 is R3 is -CH2-0 NH R4 is _CH2 N RS is -CE2 0 11-0 X is -S; and, 11 0 p is 1.

11. A compound of claim 1 wherein R, is - 1,11 R3 is -CH2-0 NE R4 is -CH2rRS is -CH2- 00 0 0C2ES X is - 11/; and l\ 0C211S p is 1.

RA432 RA432 12. A compound in accordance with claim 1 having the name [4-(4morpholinyl)-1,4-dioxo-2(1-naphthalenylmethyl)butyl]-N-[(1S,2R)-1-(cyc lohexylmethyl)-2-hydroxy-2-(1H-imidazol-2-yl)ethyl3 5, L-histidinamide, isomer B, dihydrochloride.

13. A compound in accordance with claim 1 having the name N-[(S)-2cyclohexyl-l-[(R)-hydroxy(1H-imidazol-2-yl)methyl]ethyl]-N2-[4-(4morpholinyl)-1,4-dioxo-2-(phenylmethyl)butyl]-L-histi- dinamide, isomer B, dihydrochloride.

14. A compound in accordance with claim 1 having the name [4-cyclohexyl-1, 4-dioxo-2-(phenylmethyl)butyll-N-[(2S,3R)-1-(cyclohexylmethyl)-2hydroxy-2-(1H-imidazol-2-yl)ethyl]-L-histidinamide, isomer B, dihydrochloride.

15. A compound in accordance with claim 1 having the name [3[(cyclohexylthio)methyl]-1-oxo3-phenylpropyl]-N-[(1S,2R)-1(cyclohexylmethyl)-2hydroxy-2-(1H-imidazol-2-yl)ethyll-L-histidinamide, dihydrochloride.

16. A compound in accordance with claim 1 having the name [2[(cyclohexylsulfinyl)methyll-loxo-3-phenylpropyl]-N-[(1S,2R)-1(cyclohexylmethyl)2-hydroxy-2-(1H-imidazol-2-yl)ethyll-L-histidinamide, isomer 2B, trifluoroacetate (1:2) salt.

17. A compound in accordance with claim 1 having the name [2[(cyclohexylsulfonyl)methyll1-oxo-3-phenylpropyll-N-[(1S,2R)-1(cyclohexylmethyl)-2-hydroxy-2-(1H-imidazol-2-yl)ethyl]-L- histidinamide, isomer B, trifluoroacetate (1:2) salt.

Published 1989 atThe Patent Ofnee, State House. 66f7l High Holborn, London W01B 4TP. Further copiesmaybe obtainWrom The Patentomee. Sales Branch., St Mary Cray, Orpington. Kent BR5 3RD. Printed by Multiplex techniques ltd, St Mary Cray, Kent, Con. 1/87