NL8302562A - SUBSTITUTED PEPTIDE COMPOUNDS. - Google Patents

Description

... f ____; ft

Substituted Peptide Compounds

The invention relates to substituted peptide compounds of formula 1 and salts thereof, wherein X is an amino or imino acid of formula 2h, formula 25, formula 26, formula 27, formula 28, formula 29, formula 30, formula 31, formula 32, formula 33, formula 3 **, or formula 35.

R 1 is hydrogen, halogen, a short chain alkyl, keto, hydroxy, -UH-C (O) - short chain alkyl, azido, amino, a group of formula 36, formula 37, formula 38, formula 39,; formula 1 * 0, formula 1 * 1, a 1- or 2-naphthyl group of formula 41a, 10 a group of formula 1 * 2, formula 1 * 3, formula U *, formula 1 * 5 »a 1- or 2- naphthyloxy group of formula 1 * 6, a group of formula 1 + 7, formula 1 * 8, or a 1- or 2-naphthylthio group of formula 1 + 9,

Rg is halogen, a keto group, a group of formula 15 50, formula 1 + 5, formula M1, a 1- or 2-naphthyloxy group of formula 1 * 1, a group of formula 1 * 7, formula 1 * 8, or a 1- or 2-naphthylthio group of formula 1 * 9.

is a keto group or a group of formula 38.

R10 is halogen or a group of formula 51 · 20 R ^, R ^ ', R ^ g and R ^' are independently hydrogen or a short chain alkyl group or R '^, and ® * 12 z ^ n ^ 3 ^ 31, 3 ^ 0 ^ and Rjj is a group of formula 52.

R ^ is hydrogen, a short chain alkyl group of 1 to 1 * carbon atoms, a short chain alkoxy group of 1 to 25 carbon atoms, a short chain alkylthio group of 1 to 1 * carbon atoms, chlorine, bromine, fluorine, a trifluoromethyl, hydroxy, phenyl, phenoxy, phenylthio or phenylmethyl group.

R ^ is hydrogen, a short chain alkyl group of 1 to 1 * carbon atoms, a short chain alkoxy group of 1 to 1 * 30 carbon atoms, a short chain alkylthio group of 1 to k carbon atoms, chlorine, bromine, fluorine, a trifluoromethyl or 8302562 2 - 1 r hydroxy group.

m is 0, 1, 2, 3 or 1+.

p is 1, 2 or 3, provided that p is greater than 1 only when either H * is hydrogen, chlorine, fluorine or a methyl or methoxy group.

R ^ is hydrogen or a short chain alkyl group of 1 to 1+ carbon atoms.

Y is oxygen or sulfur.

R ^ is a short chain alkyl group of 1 to 1+ carbon-10 atoms, a group of formula 38, or the Rg groups join to form an unsubstituted 5 "or 6-ring or said ring in which one or more of the carbon atoms as a substituent carries a short chain alkyl group of 1 to k carbon atoms or a di- (short chain alkyl group of 1 to carbon atoms).

R ^ is hydrogen, a short chain alkyl group or a group of formula 39 »formula if0, formula if 1, formula if2, formula 53» formula 5if or formula 55. is hydrogen, a short chain alkyl group, a group of formula 56, formula 57, formula 58, formula 59, formula 60, formula 61, formula 62, formula 63, formula 6U, formula 65, or formula 66.

r is an integer from 1 to if.

R is a short chain alkyl, benzyl or phenethyl group.

f'j R 20 is hydrogen, a short chain alkyl, benzyl or phenethyl group. R hydrogen, a short chain alkyl group, cycloalkyl group, a group of formula 56, formula 58a, formula 58b, formula 58c, formula 62a, formula 62b, formula 62c, formula 63a, formula 63b or formula 63c. R ^ is hydrogen, a short chain alkyl group, a halogen-substituted short chain alkyl group, a group of formula 56, formula 57, formula 58, formula 59, formula 60, formula 61, formula 62, formula 63, formula 61f, formula 65 or formula 66, provided that R ^ 35 is hydrogen only if R is not hydrogen.

R2 is a group with formula 67, formula 39, formula 1 + 0 8302562 k .......

3 —V Ο.

Or formula.

R ^ is hydrogen, a short chain alkyl group, a group of formula 67, formula 39 »formula HO, formula M, formula k2, a halogen-substituted short chain alkyl group, a group of formula 58, formula 59» formula 60, formula 61, formula 62, formula 63, formula 6k, formula 65 or formula 66, wherein m, R 1, p and r are as mentioned above.

Rg is hydrogen, a short chain alkyl, benzyl, or benzhydryl group or a group of formula 68, formula 69, formula 70 or formula 71.

R 1 is hydrogen, a short chain alkyl, cycloalkyl, or phenyl group.

R <0 is hydrogen, a short chain alkyl, short chain {) 18 alkoxy or phenyl group or R 2 and together form a group of formula 72, formula 73, formula Jb or formula 75

Rg1 and R22 are independently hydrogen or a short chain alkyl group.

R22 is a short chain alkyl group.

The invention in its broadest sense relates to the substituted peptide compounds of formula 1, to compositions containing these compounds and the method of using such compounds as pharmaceuticals and to intermediates useful for the preparation of these compounds.

The term "short chain alkyl" used in defining the various symbols refers to straight or branched chain groups with up to 7 carbon atoms.

The preferred short chain alkyl groups contain up to h carbon atoms, most preferred are methyl and ethyl. Accordingly, the terms "short chain alkoxy" and "short chain alkylthio" refer to such short chain alkyl groups attached to an oxygen or sulfur.

The term "cycloalkyl" refers to saturated rings of 3 to 7 carbon atoms, the largest being

__J

8302562 t "*" i S.

I prefer cyclopentyl and cyclohexyl.

The term "halogen" refers to chlorine, bromine and fluorine.

The term "halogen-substituted short chain alkyl" refers to such short chain alkyl groups as described above, wherein one or more hydrogen atoms are replaced by chlorine, bromine or fluorine atoms, such as preferred trifluoromethyl, pentafluoroethyl, 2, 2,2-trichloroethyl, chloromethyl and bromomethyl.

10 The groups of formula 39 »formula ^ 0 and formula M

indicate that the alkylene bridge is bonded to an available carbon atom.

The compounds of formula I, wherein R is hydrogen, can be prepared by converting a carboxymethyl peptide ester of formula 2 into its acid chloride and then reacting it with an oxazolone of formula 3, wherein R 1 q and Rg (in the description of X) protection groups are as eg wherein R ^ is benzyloxycarbonyl and R8 is benzyl. Removal of the RQ and Rg protecting group, e.g. by hydrogenation gives the products of formula 1 wherein Rg is hydrogen.

The carboxymethyl peptide ester of the formula 2 is prepared by reacting the peptide ester of the formula with tert-butyl bromoacetate and then introducing the R 2 protection group, e.g. by treatment with benzyl chloroformate.

The compound of formula 1 can also be prepared by a ketone of formula 5, wherein halogen represents Cl or

Br to react with the peptide ester of formula 6 in the presence of a base, such as sodium bicarbonate, followed by removal of the Rg ester group.

The ketone intermediate of formula 5 can be prepared by treating a ketone of formula 7, wherein R 1 is a protecting group, such as benzyloxycarbonyl, with bromohydrogen and acetic acid, followed by reaction with the acid halide of formula 8, in the presence of a base, such as sodium bicarbonate.

The compounds of the formula I can also be prepared by reacting an amino ketone of the formula 9, in particular its hydrochloride salt, with the halogen acetylamino or imino acid ester of the formula 10, using Rg in the description of X is an easily removable ester protection-5 group and halogen represents Cl or Br.

The compounds of formula 1 may also be prepared by coupling an amino ketone carboxylic acid of formula 11 with the amino or imino acid ester of formula 12 in the presence of a coupling agent, such as dicyclohexylcarbodiimide, wherein Rg in the description of X is an easily removable protecting group . Removal of Rg protecting group yields the products of formula 1 wherein Rg is hydrogen.

(The aminoketone of formula 9 can be prepared by converting the carboxyalkylamine of formula 13, wherein R 1 q protecting group, such as benzyloxycarbonyl, into its acid chloride and then reacting with an oxazolone of formula 3 to a compound of formula 1k is obtained.

Removal of the protecting group, such as by hydrogenation, yields the reaction participant of formula 9 · 20 The anino ketone of formula 9, wherein R is other than hydrogen, can also be prepared by reacting the ketone of formula 5 with substituted amine of formula 15 · The amino ketone carboxylic acid of formula 11 can be prepared by reacting the amine ketone of formula 9 with a haloacetic acid ester of formula 16, wherein Prot is an easily removable ester protecting group, such as tert-butyl, to give the ester of formula 17.

Removal of the ester protecting group yields the reaction participant of formula 11. In the above reactions 30, if one or all of the groups R, R 1, R 1 and R 1 represent formula 57, formula 58, formula 59, formula 61, formula 62, formula 63, formula 65, the hydroxy, amino, imidazolyl, mercaptan or guanidinyl group must be protected during the reaction. Suitable protecting groups are e.g. benzyloxy-35 carbonyl, tert-butoxycarbonyl, benzyl, benzhydryl, trityl, and 9302562 --------—-- ^ 6 t 1 nitro in the case of guanidinyl. The protecting group is removed by hydrogenation, acid treatment or other known method upon completion of the reaction.

The ester products of formula 1, wherein Rg is a short chain alkyl, benzyl or benzhydryl group, may be chemically treated, such as with sodium hydroxide in aqueous dioxane or with trimethylsilyl bromide, to give the products of formula 1 wherein Rg is hydrogen. The benzyl and benzhydryl esters can also be hydrogenated, e.g. by treatment with hydrogen in the presence of palladium on a carbon catalyst.

The ester products of formula 1, wherein Rg is a group of formula 68, can be obtained by using the peptide of λγ '} using formula k or formula 6 or the haloacetylamino or imino acid ester of formula 10 in the above reactions with such an ester group already in the right place. Such ester reactants can be prepared by treating peptide of formula U or formula 6 with the haloacetylamino or imino acid ester of formula 10, wherein Rg is hydrogen, with an acid chloride, such as of formula 76 or formula 77-20 to give the H atom to protect. The protected compound is then reacted in the presence of a base with a compound of formula 18, wherein L is a removable group, such as chlorine, bromine, or tolylsulfonyl, followed by removal of the N-protecting group, such as by acid treatment or hydrogenation.

The ester products of formula 1 wherein Rg is a group of formula 68 may also be obtained by treating the product of formula 1 wherein Rg is hydrogen with a molar excess of a compound of formula 18.

The ester products of formula 1 wherein Rg is a group of formula 69 can be prepared by treating the product of formula 1 wherein Rg is hydrogen with a molar excess of the compound of formula 19

The ester products of formula 1, wherein Rg is a group 35 of formula 70 or formula 71, can be prepared by 8302562 7 * 1 t

C

the product of formula 1, wherein Eg is hydrogen, to couple with a molar excess of the compound of formula 20 or formula 21 in the presence of a coupling agent, such as dicyclohexylcarbodiimide, followed by removal of the hydroxy protecting group.

The esters of formula 1, wherein Eg is a short chain alkyl group, may be obtained from the carboxylic acid compounds, i.e., wherein Eg is hydrogen, the usual esterification methods, e.g. treatment with an alkyl halide of the formula Eg-halogen, or an alcohol of the formula Bg-OH.

The peptide esters of formula b and formula 6 can be obtained by coupling the hydrochloride salt of the amino or imino acid ester of formula 12, wherein Eg eg is benzyl, with the N-protected amino acid of formula 22, wherein Prot protection group, such as a group of formula 78.

This reaction is preferably carried out in the presence of a coupling agent, such as dicyclohexylcarbodiimide. Removal of the N-protecting group, e.g. by treatment with trifluoroacetic acid, yields the peptide esters of formula b and formula 6.

The haloacetylamino or imino acid ester of formula 10 can be prepared by reacting the amino or imino acid ester of formula 12 with a haloethyl ether halide of formula 23.

The products of formula 1, wherein Ej is an amino group 25, can be obtained by the corresponding products f of formula 1, wherein Βγ. is an azido group.

Preferred compounds of the invention with respect to the peptide portion of the structure of formula 1 are the compounds wherein: 30 B is hydrogen, a straight or branched chain short chain alkyl group with 1-U carbon atoms or a phenyl group.

Ej hydrogen, a straight or branched chain short chain alkyl group of 1-U carbon atoms, -CF ^, a group of formula 62, wherein r is an integer from 1 to k, a group of formula 56, formula 57, formula 58 , formula 59, formula 60, 8302562 8 T 'i * / formula 61, formula 62, wherein r = 1, a group of formula 6ka, formula 65a, -CHg-C 10 -JOHG or - (CHgJg-CCoJ-NHg, provided that R ^ is only hydrogen if R is other than hydrogen.

R ^ is hydrogen, a cyclohexyl or phenyl group, R ^ is hydrogen, a straight or branched chain short chain alkyl group having 1 to k carbon atoms, a group of formula 56, formula 5T »formula 58, formula 59, formula 6o , formula 61, formula 63, wherein r = 1, a group of formula 6Ua, formula 10 65a, -CH 2 -C (O) -HH 2 or - (CH 2 -C 1)

Rg is hydrogen, a straight or branched chain short chain alkyl group of 1 to 1+ carbon atoms, an alkali metal (1 salt), a group of formula 68, formula 69a, formula 70 or, formula 71.

R 23 is a straight or branched chain short chain alkyl group, especially -C 1 CH 3 R 5 R is hydrogen, a straight or branched chain short 17 chain alkyl group containing 1 to 1 + carbon atoms or a cyclohexyl group.

R ^ is a straight or branched chain short chain 20 alkyl group with 1-1 + carbon atoms or a phenyl group.

R is a straight or branched chain short chain alkyl group of 1 to 1+ carbon atoms, especially -CCCH ^) ^ R ^ is hydrogen.

R ^ is hydroxy.

f. Rj is a straight or branched chain short chain alkyl group of 1 to 1 + carbon atoms or a cyclohexyl group.

R ^ is an amino group.

R1 is an -O-short chain alkyl group, wherein the short-chain alkyl group has a straight or branched chain with 1 to 1+ carbon atoms.

R ^ is a group of formula 38 wherein p = 1, wherein m is 0, 1 or 2 and R ^ is hydrogen, chlorine, bromine, fluorine, a methyl, methoxy, methylthio or hydroxy group.

R ^ a group of formula 1 + 5, wherein p = 1,1-naphthyl-35 oxy or 2-naphthyloxy, wherein m is 0, 1 or 2 and R ^ 8302562 “ί ί τ 9 hydrogen, chlorine, bromine , fluorine, is a methyl, methoxy, methyl-thio or hydroxy group.

is a -S short chain alkyl group, wherein the short chain alkyl group is a straight or branched chain having 1 to 5 carbon atoms.

Bj is a group of formula U8, where p = 1, a 1-naphthylthio or 2-naphthylthio group, where m is 0, 1 or 2 and is hydrogen, chlorine, bromine, fluorine, a methyl, methoxy, methylthio or hydroxy group .

Rq is an -O-short chain alkyl group, wherein the short chain alkyl group has a straight or branched chain with 1 to carbon atoms.

* * Rg is a group of formula U5 wherein p = 1, m is 0, 1 or 2 and is hydrogen, chlorine, bromine, fluorine, a methyl, methoxy, methylthio or hydroxy group.

Rg is a -S-short chain alkyl group, wherein * short chain alkyl group has a straight or branched chain of 1 to U carbon atoms.

Rg is a group of formula U8 wherein p = 1, m is 0, 1 or 2 and Rg is hydrogen, chlorine, bromine, fluorine, a methyl, methoxy, methylthio or hydroxy group.

Rp is a phenyl, 2-hydroxyphenyl or b-hydroxyphenyl group.

R10 are both fluorine or chlorine.

R ^ 0 are both -YR ^ g, where Y is oxygen or sulfur, R ^ g is a straight or branched chain short chain alkyl group having 1 to k carbon atoms, or the R ^ groups unite to form an unsubstituted 5 ”or 6- to form a ring in which one or more of the available carbon atoms carries a methyl or dimethyl substituent.

R ^, R ', R12 and R * 12 are all hydrogen, or R ^ λ is a phenyl, 2-hydroxyphenyl or U-hydroxy phenyl group and R'^, R12 and R * are hydrogen.

With regard to the peptide portion of the structure of formula 1, most preferred are compounds according to the invention wherein X is a group of formula 2h, formula 27a, formula 3¾ or formula 35.

R is hydrogen or a methyl group.

R 1 is hydrogen, a methyl group or - (CH 2, especially a methyl group, provided that R 1 is only hydrogen if R is other than hydrogen.

Rg is hydrogen, a straight or branched chain short chain alkyl group with 1 to U carbon atoms or an alkali metal salt.

R 1 is a cyclohexyl or phenyl group.

R ^ is hydrogen, a cyclohexyl group, a short chain alkoxy group with 1 to U carbon atoms, a group of formula f 33, formula 1 * 5 or formula 1 * 8 in which p - 1, and in which 9 is equal to 0, 1 or 2 and is hydrogen, chlorine, bromine, fluorine, a methyl, methoxy, methylthio or hydroxy group, with particular preference being given when R 1 is hydrogen.

t is equal to 2 or 3, especially when t is equal to 2.

Preferred compounds of the invention with respect to the keto portion of the structure of formula 1 are the compounds wherein R 1 is a group of formula 67, wherein p = 1, wherein p = 1, wherein m is 1.1 or 2 and R 1 is hydrogen, chlorine, bromine, fluorine, a methyl, methoxy, methylthio or hydroxy group, in particular a phenyl group.

R1 is a straight or branched chain short-chain alkyl group containing 1 to U carbon atoms, a group of formula 62, formula 67 wherein p-1 or a group of formula U 1 wherein m is 0, 1 or 2, R 1 is hydrogen, chlorine, bromine, fluorine, a methyl, methoxy, methylthio or hydroxy group and r is an integer from 1 to in particular benzyl.

The compounds of formula 1 wherein Rg is hydrogen form salts with a variety of inorganic or organic bases. The non-toxic pharmaceutically acceptable salts are preferred, although other salts are also useful for isolating or purifying the product. Such pharmaceutically acceptable salts include metal salts such as sodium, potassium or lithium, alkaline earth metal salts such as calcium or magnesium and salts derived from amino acids such as arginine and lysine. The salts are obtained by reacting the acid form of the compound with an equivalent of the base providing the desired ion in a medium in which the salt precipitates or an aqueous medium followed by lyophilization.

Accordingly, in particular, wherein Rg is an ester group, the compounds of formula I, 10 form salts with a variety of inorganic and organic acids. Again, preference is given to the non-toxic pharmaceutical! acceptable salts, although other salts are also useful for isolating or purifying the product. Such pharmaceutically acceptable salts include salts formed with hydrochloric acid, methanesulfonic acid, sulfuric acid, maleic acid. The salts are obtained by reacting the product with an equivalent amount of the acid in a medium in which a salt precipitates.

As indicated above, the peptide portion of the molecule of the products of formula 1 is represented by formula 79j in the L configuration. A center of asymmetry is also present in the keto portion of the molecule, when R ^ is other than hydrogen. Therefore, the compounds of formula I can exist in diastereoisomeric forms or in mixtures thereof.

The methods described above may use racemates, enantiomers or diastereomers as starting materials.

When diastereomeric products are prepared, they can be separated by conventional chromatographic fractional crystallization methods.

The products of formula 1, in which the amino acid ring is monosubstituted, give rise to cis-trans isomerism.

The configuration of the final product will depend on the configuration of the R 1, R 8 and R 2 substituent in the starting material of formula 12.

6302562 12 'f' 1 "i

The compound of formula 1 and the pharmaceutically acceptable salts thereof are hypotensive agents. They prevent the conversion of the decapeptide angiotensin I to angiotensin II and are therefore useful for reducing or alleviating angiotensin-related hypertension. The action of the enzyme renin on angiotensinogen, a pseudoglobulin in blood, forms angiotensin I. Angiotensin I is converted into angiotensin II by angiotensin converting enzyme (ACE). The latter is an active pressurizing agent, which has been considered the causative agent in various forms of hypertension in different mammalian species, e.g. people.

The compounds according to the invention interrupt the angio-tens') tensinogen -> (renin) - * angiotensin I -> angiotensin II

series by inhibiting angiotensin converting enzyme and reducing or excluding the formation of the pressure-causing agent angiotensin II. For example, administration of a compound containing one (or combination) of the compounds of the invention alleviates angiotensin-induced hypertension in a mammalian species (e.g., humans) leading thereto.

A single dose, or preferably two or four daily doses, provided on a basis of 0.1 to 100 mg, preferably 1 to 50 mg, per body weight per day is suitable for lowering blood pressure. Preferably the fabric turns 25. administered orally, but parenteral routes such as the subcutaneous, intermuscular, intravenous or intraperitoneal routes may also be used.

The compounds of the invention can also be formulated in combination with a diuretic for the treatment of hypertension. A combination product containing a compound of the invention and a diuretic can be administered in an effective amount containing a total daily dose of 30 to 600 mg, preferably 30 to 330 mg of a compound of the invention and up to 300 mg, preferably 35 to 200 mg, of the diuretic, for a mammal species in need thereof 8302562 "13". Examples of the diuretics contemplated for use in combination with the compound of the invention are the thiazide diuretics , eg chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methyclothiazide, trichloromethiazide, polythiazide or banzthiazide, as well as ethacrynic acid, ticrynaphene and triamonorimide, aminolimine, bumethetamine, bumethetamine.

The compounds of formula 1 crowns are formulated for use for lowering blood pressure in compositions such as tablets, capsules or elixirs for oral administration, or in sterile solutions or suspensions for parenteral administration. 10 to 500 mg of a compound of formula 1 are mixed with physiologically acceptable carrier, excipient, binder, preservative, stabilizer, flavoring agent and the like, in unit dosage form as required by accepted pharmaceutical practice. The amount of active ingredient in these compositions or preparations is such that the appropriate dosages achieve the indicated range.

The compounds of formula 1, wherein X is a group of formula 80, also have some nephalinase inhibitory activity and are useful as analgesics. Thus, the administration of a composition or a combination of such compounds of formula 1 or containing a pharmaceutically acceptable salt thereof relieves pain in the mammalian host. A single dose, or preferably two or more divided daily doses, provided on a basis of 0.1 to 100 mg per kg body weight per day, preferably 1 to 50 mg per kg 30 per day, provides the desired analgesic activity. The composition is preferably administered orally, but parenteral routes, such as subcutaneous, can also be used.

The examples below serve to illustrate the invention. Temperatures are stated in ° C. Li-20 refers to a Sephadex chromatography gel commercially available from 830 2 5 62 '1 * 1' 1 * from Pharmacia Fine Chemicals.

Example I

1 "/" "r3" (benzoylamino) -2-oxo - ^ - phenylbutyL7-L-alanyl7-L-nroline, monohydrochloride_ 5 a) L-alanyl-L-proline, phenylmethyl ester, p-toluene sulfonic acid salt N-ƒ ( 1,1-dimethylethoxy) carbonyl J-L-alanine (310.7 g), L-proline, phenyl methyl ester, hydrochloride (396.2 g), dicyclohexyl carbodiimide (338.6 g), hydroxybenzotriazole hydrate (251.5 g), Diisopropylethylamine (285.7 ml) and tetrahydrofuran (5 L) are combined at 0 ° (dicyclohexylcarbodiimide is added last) and stirred overnight at room temperature (1). The reaction mixture is filtered and concentrated.

The residue is dissolved in 1 ethyl acetate and washed with 5% sodium dicarbonate (2 x 2 L), 5 # potassium bisulfate (2 x 2 L) and water. The ethyl acetate layer is dried (MgSO4) and concentrated, the residue is dissolved in 3 L of diethyl ether and left at 0 ° overnight. The mixture is filtered and the filtrate concentrated to give 620 g of crude 11- (71.1-dimethylethoxy) carbonyl / -L-alanyl-L-proline, phenylmethyl ester.

N - / (1,1-dimethylethoxy) carbonyLf-L-alanyl-L-proline, phenylmethyl ester (275 g) is cooled in an ice bath and treated with 500 ml of cold trifluoroacetic acid (freshly distilled) under argon 25 and at room temperature for 1 hour stirred. The mixture is concentrated in vacuo and azeotroped 2x with toluene. The crude trifluoroacetic acid salt, an oil, is dissolved in 500 ml of ether and slowly treated with stirring with a solution of p-toluenesulfonic acid hydrate (1 equivalent) in 6 1 of ether. The precipitate obtained is collected by filtration. The solid is dissolved in 11 methanol and treated with b 1 ether and cooled. The resulting precipitate is collected and dried to yield 300 g of L-alanyl-L-proline, phenylmethyl ester, p-toluenesulfonic acid salt; m.p. 156 -1580 are obtained.

35 8302562 15 1 1 · i • (b) 1- / ϊί- / 2- (1,1-dimethylethoxy) -2-oxoethyl7-N - / '(phenyl methoxy) carionyl J-L-alanyl J-L-proline, phenylmethyl ester_ ... ____________

A mixture of L-alanyl-L-proline, phenylmethyl ester, 5 p-toluenesulfonic acid salt (32.16 g, 72 mmol), tert-butyl bromoacetate (1.2 g, 72 mmol), triethylamine (20.1 mL, 1¼ nmol), and tetrahydrofuran (290 ml) is stirred at room temperature for 72 hours. Benzyl chloroformate (12 ml, 87.8 mmole) and triethylamine (12.5 ml, 87.8 mmole) are added and the mixture is stirred overnight. The reaction product is evaporated and partitioned between water and ethyl acetate. The substances soluble in ethyl acetate are washed with dilute hydrochloric acid and then with water. The ethyl acetate solution is then evaporated and chromatographed on silica gel (230-U00 mesh) using the solvent system ethyl acetate / hexane (1: 1 (0.7 kg / cm 2 pressure) to give 19.5 g of 1 / 11- / 2 - (1,1-dimethyl-ethyl-hoxy) -2-oxoethyl7-H - / (phenylmethoxy) carbonyl7'-alanyl7-L-proline, phenylmethyl ester are obtained.

c) 1- / 11- (carboxymethyl) -N - / * (phenylmethoxy) carbonyl-L-20-alanyl-7-nroline, phenylmethyl ester-1- / 11- / 2- (1,1-dimethyl-ethoxy) -2- oxo-hyl / -H- / 1 [phenylmethoxy) carbonyl7-L-alanyl7-L-proline, phenylmethyl ester (18 g, 3, 3.3 mmol) is dissolved in trifluoroacetic acid (50 ml) and left at room temperature for 15 hours. The mixture is evaporated and filtered through a small column of silica. Gel (200 g) using the solvent mixture chloroform / methanol / acetic acid (9.6: 0.2: 0.2) to give 11 µ g of 1 / t- (carboxymethyl) -N- / X phenylmethoxy) carbonyl7 -L-alanyl7 "L-proline, phenylmethyl ester.

D) 1- / li- / 2- (benzoylamino) -2-oxo-1 + -phenylbutyl / -N- [{phenylmethoxy) carbonyl7-L-alanyl7-L-proline, phenylmethyl ester 1- / N- (carboxymethyl) -H - / (phenylmethoxy) carbonyl7-L-alanyl7-L-proline, phenylmethyl ester (7.0 g, 15.0 mmol) is dissolved in dry tetrahydrofuran (50 ml) and cooled in an 8302562 • T; f -.

16 ice bath, oxalyl chloride (1.57 ml, 18 mmol) is added, followed by U drops of dimethylformamide. After 15 min, the reaction mixture is stirred at room temperature for an additional 1 hour. The mixture is evaporated, redissolved in tetrahydrofuran 5 (30 ml) and the solution is cooled in an ice bath The solution is added dropwise over 5 min to an ice cold solution of 2-phenyl-1 - (phenylmethyl) -5 () - oxazolone (3, 98 g (15 »75 mmol) in tetrahydrofuran (2 ml) Triethylamine (2.5 ml, 17» 1 mmol) is added to the reaction mixture and is stirred overnight at room temperature The mixture is filtered to give triethylamine hydro chloride salt and the filtered tetrahydrofuran solution is evaporated and redissolved in pyridine (16 ml). U-dimethylaminopyridine (50 mg) is added and the solution is stirred at room temperature for 3 hours Glacial acetic acid (16 ml) is added and the reaction mixture is heated at 100 ° for 5 min heated. The reaction mixture is then cooled, evaporated in vacuo, dissolved in ethyl acetate and extracted with aqueous sodium bicarbonate and dilute hydrochloric acid. The ethyl 20 acetate extract is chromatographed on silica gel (230-UOO mesh) after evaporation using the ethyl acetate / benzene (U: 6) solvent system to yield U, 9 g 1 "/ S" Z3- (benzoylamino) -2-oxo -Uf enylbutyl7 "N- (phenylmethoxy) -carbonyl7-L-alanyl7-L-proline, phenylmethyl ester.

Analysis calculated for Cj ^ Hj ^ N ^ O ^. 0.02 H 2 O: C 70.31; N 6.15; H 6.17. Found C 70.31; N 6.13; H 6.08 e) 1- / N- / 3- (benzoylamino) -2-oxo-U-phenylbutyl7-L-alanyl? -L-proline, monohydrochloride_ 30 1 - / N-Z3- (benzoylamino) -2- oxo-Uf-enylbutyl / -N- (phenyl-methoxy) carbonyl7-L-alany-7-L-proline, phenylmethyl ester (1.0 g) is dissolved in absolute ethanol (30 ml) and 1N hydrochloric acid (2, 25 ml). Palladium carbon catalyst (10%, 200mg) is added and the solution is stirred under a hydrogen blanket overnight. The catalyst is filtered off and the 8302562 * f

IT

solution is evaporated. The crude product (700 mg) is combined with 300 mg of crude product from a small-scale preliminary reaction and passed through a column of LH-20 (2.5 cm x 38.1 cm) in methanol. The fractions containing the desired product are collected, evaporated, dissolved in water and filtered. The clear aqueous solution is lyophilized to give 800 mg of 1 - / - H - / 3 - (benzoylamino) -2-oxo - phenylbutyl7-L "alanyl7" L-proline, monohydrochloride; = "59 * 8 (c = 1, *; methanol); m.p. 98-130 ° (dec.) 10 are obtained.

Tic (silica gel, n-butaiiol / acetic acid / water, 1+: 1: 1)

Bf = 0, ¾¾.

f} Analysis calculated for. 0.75 HgO: C 59.88; H 6.33; If 8.38; Cl 7.07. Found: C 59.82; H, 6.30; H 8 ^ 2; Cl 6.85

Example II

1 - ^ "ZT" amino-3 "(benzoylamino) -2-oxoheptyl7-L-alanyl-L-proline, dihydrochloride_ a) N ^ -benzoyl-N - / Ifenylmethoxy) carbonyl7-L" lysine

Benzoyl chloride (5 ml, ¾3.2 mmol) and aqueous sodium hydroxide (ta, 10.8) are added to an ice-cold solution of N - / (phenylmethoxy) carbonyl 7-lysine (10.09 g, 36 mmol) in aqueous sodium hydroxide. ml) added simultaneously in 5 portions over a period of 30 min. The ice bath becomes PC? and stirring is continued for an additional hour at room temperature. The reaction mixture is then extracted with ethyl acetate (discarded), the aqueous mother liquor is acidified with dilute hydrochloric acid and extracted with ethyl acetate.

The ethyl acetate extract is concentrated and the residue crystallized from ethyl acetate-hexane to give 12.9 g of N 2 -benzoyl-Sph 2 -phenylmethoxy) carbonyl-7-L-lysine; m.p. 110-112 ° (109 °).

b) 2-phenyl-A / Z (phenylmethoxy) carbonyl-7-amino-butyl-7-5 (te) -oxazolone 35 26 N-benzoyl-N (phenylmethoxy) carbony] J-Irlysine 8302532 18 t! 1; (11.53 g, 30 mmol) is dissolved in tetrahydrofuran (55 ml) and stirred in an ice city. To this reaction mixture, a solution of dicyclohexylcarbodiimide (6.8g, 33mmol) in tetrahydrofuran is added dropwise over a 15 minute period. The ice bath is removed after one hour and stirring is continued for an additional 18 hours at room temperature.

Dicyclohexylurea is filtered off and tetrahydrofuran is concentrated in vacuo. The residue is crystallized from ethyl acetate-hexane to yield 9.5 g of 2-phenyl ~ - - / - / 7 '(phenyl-10-methoxy) carbonyl-7-amino / butyl / "5 (te) -oxazolone; mp 72-73 ° ( 68 °).

c) 1- / -1- / 3- (benzoylamino) -7 "ZT (phenylmethoxy) -carbonyl / amino-2-oxoheptyl7" H - / '(phenylmethoxy) carbonyl7-L-') alanyl7-L-proline, phenylmethyl ester-1 / N- (carboxylethyl) -i- / tf-enylmethoxy) -carbonyl / -L-15 alanyl7-L-proline, phenylmethyl ester (2.82 g, 6 mmol) from Example 1 c), dissolved in tetrahydrofuran (20 ml) and the solution is stirred in an ice bath. Oxalyl chloride (0.63 ml, 7.2 mmol) is added followed by U drops of dimethyl formamide. 11a stirring this reaction mixture for 20 min.

It is then stirred at room temperature for an additional hour in an ice bath. The solvents are removed in vacuo and the residue is redissolved in tetrahydrofuran (10ml) and cooled in an ice bath. To this cold stirred solution is added a cold solution of 2-phenyl-1- / 1- / 77-phenylmethoxy) carbonyl / amino / butyl / -5 (1H) -oxazolone (2.2 g, 6 mmol) in tetrahydrofuran ( 11 ml), added with triethylamine (0.85 ml, 6 mmol). The ice bath is removed and the reaction mixture is stirred at room temperature overnight.

The precipitated triethylamine hydrochloride is removed by filtration and the mother liquor is concentrated in vacuo.

It is then redissolved in pyridine (6 ml), 1-dimethylaminopyridine (30 mg) is added and the solution is stirred at room temperature for 3 hours. Acetic acid (6 ml) is added and the reaction mixture is heated to 105 ° 35 for 15 min. It is then evaporated, taken up in ethyl acetate 8302562 [---------- • ï; * 19 and washed with water, dilute hydrochloric acid and aqueous sodium bicarbonate. After evaporation of the solvent, the crude product (3.8 g) is chromatographed (silica gel, 230 g) using ethyl acetate-hexane (1 *: 3), followed by 5 ethyl acetate-hexane (2: 1) for elution to give 1 8 g of 1 - / N- / 3- (benzoylamino) -7 - // (phenylmethoxy) carbonyl / amino / -2-oxoheptyl7 "N - / (phenylmethoxy) carbonyl7-L-proline, phenylmethyl ester.

d) 1- / II-ZY-amino-3- (benzoylamino) -2-oxoheptyl / -L-alanyl-7-Tiroline, dihydrochloride-10 (benzoylamino) -7-^ (phenylmethoxy) -carbonyl /-amino7 "2- oxoheptyl / -N - / '(phenylmethoxy) carbonyl / -L-alanyl / -L- "proline, phenylmethyl ester (1.3g, 1.6mmol) is dissolved in ethanol (75ml) and aqueous hydrochloric acid (1N, 5 ml). Paladium on carbon catalyst (10 ¢, 1 * 50 mg) is added and the mixture is hydrogenated overnight at atmospheric pressure. The catalyst is filtered off and the solution is evaporated in vacuo. The residue is dissolved in water and lyophilized. The lyophilate is triturated with ether to give 0.6 g of 1- / tt- / Y-amino-3 "(benzoylamino) -2-oxoheptyl7-L-2 O20 alanyl7-L-proline, hydrochloride; m.p. 80-155 °; / <* = -50 (c = 1.1; methanol). 0.09 (silica gel, n-butanol / acetic acid / water, 1 *: 1: 1).

Analysis calculated for. 2HC1. 1.5 HgO:

C 1 * 9.63; H 7.00; N 10.52; Cl 13.55. Found: C 1 * 9.63; H 6.82; N 10.1 * 8; Cl 13.36 Example III

1 "Z & - / 3- (benzoylamino) -2-oxoheptyl7-L-alanyl / -L- • proline, monohydrochloride a) N-benzoyl-DL-norleucine 30 D, L-norleucine (39.3 g, 300 mmol) is taken up in sodium hydroxide (2n, 150ml) and with stirring in an ice bath, sodium hydroxide (2n, 150ml) and benzoyl chloride (330mmol, 38.3ml) are added over a 30 minute period.

The bath is removed and the reaction mixture is extracted with ether for one hour. The aqueous portion is acidified

____J

8302562 20% with 2N hydrochloric acid and the crystals filtered to melt 68.9g of N-benzoyl-D, L-norleucine. 131-133 ° (125 °) are obtained, b) U-butyl-phenyl-5 (1 * H) -oxazolone N-benzoyl-D, L-norleucine (1 * 0 g, 170 mmol) is taken up in intetrahydrofuran (300 ml) with stirring in an ice bath.

To this reaction mixture, a solution of dicyclohexyl carbodiimide (38.52g, 187mmol) in tetrahydrofuran (195ml) is added dropwise over a 15 minute period.

The ice bath is removed and stirring is continued for an additional 18 hours at room temperature. Dicyclohexylurea is filtered off and the tetrafuran is concentrated in vacuo.

The residue (31.7 g) is purified on silica in hexane: ether (2: 1) to give 32.1 g of 1 * -butyl-2-phenyl-5 (1 * H) -oxazolone. v c) 1 "/ N- / 3" (benzoylamino) -2-oxoheptyl7-N - / (phenyl-15 "methoxy) carbonyl7" L-alanyl7-L-proline, phenylmethyl ester_

A solution of 1- / N- (earboxymethyl) -N- (phenyl-methoxy) carbonyl-L-alanyl-L-proline, phenylmethyl ester (1.1 * 1 g, 3 mmol) from Example 1 (c), in tetrahydrofuran (10ml) 20 is cooled in an ice bath, oxalyl chloride (0.32ml, 3.7mmol) is added with stirring followed by four drops of dimethylformamide. The reaction mixture is stirred in the ice bath for 20 minutes and then at room temperature for 1 hour. It is evaporated in vacuo, redissolved in tetrahydrofuran 25 (5 ml) and cooled in an ice bath. A cold solution of 1 * -butyl-2-phenyl-5 (11H) -oxazolone (0.65g, 3mmol) in tetrahydrofuran (5ml) is added dropwise, followed by triethylamine (0.1 * 3ml, 3 , 1 mmol). The reaction mixture is stirred at room temperature overnight. After filtering off triethylamine hydrochloride, the tetrahydrofuran solution is concentrated in vacuo. The residue is redissolved in pyridine (3ml), 1 * dimethylarninopyridine (15mg) is added and the reaction mixture is stirred at room temperature for 3 hours. Acetic acid (3 ml) is added and the reaction mixture is heated at 100 ° for 1 * 0 min. It is then evaporated, again 8302562 '' *; * 21 dissolved in ethyl acetate and washed with water, saturated sodium bicarbonate, dilute hydrochloric acid and water. After evaporation, the residue is chromatographed on silica gel using the solvent system ethyl acetate-5 benzene (4: 6) to give 0.8 g of 1 / N-3 (benzoylamino) -2-oxoheptyl-7-N-ƒ (phenylmethoxy) carbonyi / -L-alanyl / -L-proline, phenylmethyl ester.

d) 1- / N- / 3- (benzoylamino) -2-oxoheptyl7-L-alanyl7-L-proline, monohydrochloride_ 1 - / N "/ 3- (benzoylamino) -2-oxoheptyl7" N- (phenylmethoxy) 10 carbonyl7 "L-alanyl7" L "proline, phenylmethyl ester (0.96g, 1.5mmol) is dissolved in ethanol (75ml) · Hydrochloric acid (in, 2ml) is added followed by palladium on carbon catalyst f '(10 JS, 200 mg) The solution is stirred under a hydrogen blanket overnight, The catalyst is filtered off, the ethanolic solution is evaporated and the residue is dissolved in water and lyophilized to give 0.62 g of 1-7%. 3 ”(benzoylamino) -2-oxoheptyl7-L-alanyl7” L-proline, monohydrochloride; mp 86-123 °; / c - -62.9 ° (c = 1.05; methanol). 0.57 (silica gel , n-butanol / acetic acid / water; 4: 1: 1).

Analysis calculated for ¢ ^ 22 ^ 31 ^ 3 ^ 5 · HCl. 21: 0: C 53.85; H7, U0; N 8.57; Cl 7.23 Found: C 53.85; H 7.20; N 8.73; Cl 7.29.

Example IV

25 1 - / N ~ Z "3- (benzoylamino) -2-oxo-4- (pyridin-3-yl) butyl7-v. L-alanyl7-L-proline, dihydrochloride_ a) 2-benzoylamino) -3- (pyridin-3-yl) -2-propenoic acid 2-phenyl-4- (3-pyridinylmethylene) -5 (4H) -oxazolone (3 g, 12 mmol) (see Griffith et al., J. Org. Chem., Vol. 29, 30, p. 2659) is dissolved in acetic acid (24 ml) and aqueous hydrochloric acid (0.5 n, 150 ml). The reaction mixture is stirred at room temperature overnight, it is evaporated and evaporated again from absolute ethanol. triturated with tetrahydrofuran, filtered and the filtered solid 35 is triturated again with absolute ethanol to yield 2.8 g of 8302562 22 1 1

J

2- (benzoylamino) -3- (pyridin-3-yl) -2-propenoic acid; m.p. 215-216 ° (203 °).

Ta) 2- (benzoylamino) -3- (pyridin-3-yl) -2-propanoic acid 2- (benzoylamino) -3 ”(pyridin-3-yl) -2-propenoic acid 5 (iH g, U6 mmol) is dissolved in water (500ml) and hydrogenated overnight using palladium on carbon catalyst (10%, 1.8g). The catalyst is filtered off and the reaction mixture is evaporated to a small volume (100 ml) and lyophilized to give 13 µg of product. The lyophilate is triturated with an absolute ethanol-ether mixture and filtered to give 12 g of 2- (benzoyl-amino) -3- (pyridin-3-yl) -2-propanoic acid; m.p. 99 - 115 ° are obtained.

c) 1- / N- / 3- (benzoylamino) -2-oxo-U- (pyridin-3-yl) -15 butyl7-N - / (phenylmethoxy) carbonyl / p \ L-alanyl7-L-proline, phenylmethyl ester -1- / Ir- (carboxymethyl) -N -. / (phenylmethoxy) carbonyl-7-L-alanyl-L-proline, phenylmethyl ester (6.2 g 13.1 mmol) from Example 1 (c), is dissolved in tetrahydrofuran (20 ml) and the solution is stirred in an ice bath. Oxalyl chloride is added followed by U drops of dimethylformamide. After stirring this reaction mixture in an ice bath for 20 minutes, it is then stirred for an additional hour at room temperature.

The solvents are removed in vacuo and the residue is redissolved in tetrahydrofuran (20 ml).

2- (benzoylamino) -3 ~ (gyridin-3-yl) -2-propanoic acid (1 * g, 13 mmol) is suspended in tetrahydrofuran (1 * 5 ml) and triethylamine (1.96 ml) is stirred in an ice bath , 1¾ mmol) and dicyclohexylcarbodiimide (2.96 g, 1U mmol). The reaction mixture is stirred at room temperature overnight. It is then filtered and the filtrate is evaporated to dryness. This residue is dissolved in tetrahydrofuran (30 ml) and stirred in an ice bath. To this solution, the above solution of 1 - / ΪΊ- (carboxymethyl) -N - / (phenylmethoxy) -35 carbonyl7-L-alanyl7 "L-proline, phenylmethyl ester, an acid 8302562 23 τ * f chloride in tetrahydrofuran ( 20 ral) added. Triethylamine (1.9 ml, 13.6 mmol) is added and the reaction mixture is stirred overnight at room temperature. It is filtered to remove triethylamine hydrochloride.

The filtrate is evaporated in vacuo, redissolved in pyridine (15 ml), k-dimethylaminopyridine (65 mg) is added and the reaction mixture is stirred at room temperature for 3 hours.

Acetic acid (16 ml) is added and the reaction mixture is heated to 100 ° for 15 min. It is then evaporated, redissolved in ethyl acetate and washed with aqueous sodium bicarbonate and water. After evaporation, the ethyl acetate extract is chromatographed on silica gel using ethyl acetate for elution to give 3.3 g of 1 - / N - / - 3 - (benzoyl-amino) -2-oxo - (pyridin-3-yl) ) butyl 7-N- / T phenylmethoxy) carbonyl 7-L-15 alanyl 7-L-proline, phenyl methyl ester.

d) 1- / ft - / "3" (benzoylamino) -2-oxo-U- (pyridin-3-yl) -butyl7-L-alanyl7-L-proline, dihydrochloride The phenylmethyl ester product of part (c) (2, 6g, 3.8¾mmol) are dissolved in ethanol (75ml) and aqueous hydrochloric acid 20 (1η, 8ml) is added followed by palladium on carbon catalyst (10% t 0.6g) After hydrogenation for 16 hours an additional 0.5 g of catalyst is added and hydrogenation is continued for a further 6 hours The mixture is filtered, evaporated and combined with such a reaction product obtained by hydrogenation of 0.8 g of ester product from part (c).

v ··. The hydrogenated material is then chromatographed on LH-20 in water to give the homogeneous product.

An aqueous solution of this material is treated with aqueous hydrochloric acid (1η, 3 ml) and the solution is lyophilized to give 1.0 g of 1- / ft- / 3- (benzoylamino) -2-oxo-U- (pyri din-3-yl) butyl7 "L" alanyl7-L-proline, dihydrochloride; mp 120-135 °; fa - -55.5 ° (c = 1.1, methanol). Rf 0.11 (silica gel; n -butanol / acetic acid / water; h: 1: 1).

Analysis calculated for ^ 1 ^ 28¾ ^ 5 * 2H 2 O: 35 C 51.35; H 5.75; N 9.98; Cl 12.63

Found: C 51.35; H 5.8¾¾ N 9.96; Cl 12.8¾ 8302562 i; j: 2k

Example V

1- / N- / 3- (benzoylamino) -k - (-hydroxyphenyl) -2-oxo-butyl-L-alanyl] -L-proline. monohydrochloride a) 2-phenyl-i + - / Z1 + - (phenylmethoxy) phenyl7methyl7-5 C UH) -5 oxazolone 0-benzyl-L-tyrosine (11.0 g, * + 0.5 mmol) is taken up in 0.5 n sodium hydroxide (81 ml) and water (81 ml) with vigorous stirring in an ice bath. To this are added in 5 equal amounts a total of 52 ml of benzoyl chloride, 10 * + 5 ml of 1N sodium hydroxide and an additional 100 ml of water over 25 minutes. The bath is removed and the reaction is carried out at room temperature for 2 hours. The mixture is extracted 2x with ethyl acetate. The aqueous portion is filtered, acidified with 1N hydrochloric acid and the crystals are filtered to give 12.9 g of N-benzoyl-O-benzyl-L-tyrosine; m.p. 166-168 ° (162 °) are obtained.

This U-benzoyl-O-benzyl-L-tyrosine (12.76 g, 35 mmol) is taken up in dry tetrahydrofuran (50 ml) with stirring in an ice bath. To this is added dicyclohexylcarbodi-20 imide (7.7 g, 37 * + mmol) in tetrahydrofuran (18 ml) dropwise. The ice bath is removed after 20 minutes and the reaction continues overnight at room temperature.

The dicyclohexylurea is filtered off and the filtrate is concentrated to dryness. The crude product is crystallized with ether / hexane to give 10.26 g of 2-phenyl-WA ”(phenylmethoxy) -phenyl / methyl / -5 (* + H) -oxazolone; m.p. 85-87 ° (83 °).

b) 1- / 3- (benzoylamino) -2-oxo-U-JU- (phenylmethoxy) -phenyl7butyl7-N - / '(phenylmethoxy-4-carbonyl7 "L-alanyl7" L-proline-phenylmethyl-ester-1- / 11 - (carboxymethyl) -N - / "(phenylmethoxy) -carbonyl7" L-alanyl7-L-proline, phenylmethyl ester (2.82 g, 6 mmol), from Example I (c) is dissolved in tetrahydrofuran (20 ml) and the solution is stirred in an ice bath Oxalyl chloride (0.63 ml, 7.2 mmol) is added, followed by * + drops of dimethyl-35 formamide, stirring this reaction mixture for 20 min.

8302562 i i 25

It is then stirred for an additional hour at room temperature in an ice-bath. The solvents are removed in vacuo and the residue is redissolved in tetrahydrofuran (10ml) and cooled in an ice bath. To this cold stirred solution, a cold solution of 2-phenylphenylmethoxy J-phenyl / methyl / -5 (te) -oxazolone (2.1½g, 6mmo 1) in tetrahydrofuran (50ml) is added. Triethylamine (0.8½ ml, 6 mmol) is added and a basic medium is maintained during the reaction by adding additional necessary amounts of triethylamine. The reaction mixture is stirred at room temperature overnight. It is then filtered and the filtrate is evaporated and redissolved in pyridine (7 ml), dimethyl. Aminopyridine (30 mg) is added and the reaction mixture is stirred at room temperature for 3 hours. Acetic acid (7 ml) is added and the reaction mixture is heated to 100 ° for ½5 min. It is then evaporated and the residue is redissolved in ethyl acetate and washed with saturated sodium bicarbonate and dilute hydrochloric acid. The neutral ethyl acetate extract is evaporated and chromatographed on silica gel (300 g) using the solvent system ethyl acetate: benzene (6.5: 3.5) to give 2.7 g of 1-ZI- / 3- (benzoylamino) - 2-οχο- ^ 2Ά (phenylmethoxy) -phenyl-7-butyl / -Nf-enylmethoxy) carbonyl-7-L-alanyl / -L-proline, phenylmethyl ester.

c) 1 (benzoylamino) -½- (^ hydroxyphenyl) -2-25oxobutyl7-L-alanyl7-L-proline, monohydrochloride

The ester product from part (b) (1.8 g, 2.26 mmol) is dissolved in ethanol (150 ml) containing aqueous hydrochloric acid (in, 3.5 ml). Palladium on carbon catalyst (10 #, 500 mg) is added and the solution is stirred under a hydrogen blanket overnight. It is evaporated, dissolved in water and lyophilized to give 1- / U- / 3- (benzoylamino) ^ - (hydroxy-phenyl-2-oxobutyl-7-alanyl-7-L-proline, monohydrochloride, mp 118-152 °; / a7 ^ -63.1 ° (c = 1.07; methanol), Rf 0 ^ 7 (silica gel, n-butanol / acetic acid / water; 35 ^ 1: 1).

8302562 2 6 ^ Λ t '* *

Analysis calculated for 0._Η.ηΝ_0 ^. HCl. H 2 O 2 O 2 O 2 C 57.22; H 6.16; N 8.0U; Cl 6.78 Found C 57 * 2; H 6.03; 21 8.0ll; Cl 7.11.

Examples VI - LXII

5 Following the procedure of Examples I-III and V

the peptide ester shown in column 1 is treated to yield the carboxymethyl peptide ester shown in column 2. Conversion to its acid chloride and further reaction with the oxazolone from column 3 yields the N-protected ester-10 product from column h. Removal of the N-protecting group and the ester group yields the final product of column 5S wherein Rg is hydrogen. Column 1 gives compounds of formula U, column 2 gives compounds of formula 2a, column 3 gives compounds of formula 3 »column U gives compounds of formula 1a and column 5 gives compounds of formula 1b.

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The protecting groups in Examples XX, XXXVT-XXXIX and XLI, the protecting groups in Examples XLIII and XLIV and the R <_ protecting groups in Examples XLIX, L and LII - LV are removed as the last step in the synthesis.

The Rg ester groups shown in Examples LVH-LXII are not removed.

Example LXIII

1-fft-flS) -3- (benzoylamino) -2-oxo-U-phenylbutyl7 "L" alanyl7-L-proline. monohydrochloride 10 a) (S) -3-amino-1-chloro-phenyl-butan-2-one, hydrobromide (S) - / "3-chloro-2-oxo-1 - (phenylmethyl) propyl-7-carbamine" acid, phenylmethyl ester (51 µg) is dissolved in a mixture of acetic acid (252 ml) and hydrobromic acid in acetic acid (3, 5n, 15 3 ^ 8 ml) and kept at room temperature for 1 hour. concentrated in vacuo and precipitated with ether to give 36.6 g of (S) -3-amino-1-chloro-U-phenyl-but an-2-one, hydrobromide, mp (175 °), 177-179 °.

b) (S) -N- / 3-chloro-2-oxo-1- (phenylmethyl) propyl-7-benzamide (S) -3-amino-1-chloro-U-phenyl-butan-2-one, hydrobromide ( 36.3 g, 130.3 mmol) is suspended in 520 ml dry tetrahydrofuran and 18.2 ml triethylamine (130.3 mmol) for 10 min with stirring. The mixture is placed in an ice bath and 15.2 ml of benzoyl chloride are added, followed by 10.95 g of sodium bicarbonate. After 5 minutes, the ice bath is removed and the reaction mixture is kept at room temperature for 1 hour. The reaction mixture is then concentrated in vacuo and the residue is taken up in 1 L of aqueous methanol (10 * water).

The precipitate is collected, filtered and washed with methanol to give 25.3 g of (S) -N- / 3-chloro-2-oxo-1- (phenylmethyl) -propyl7-benzamide; m.p. (160 °) 170 ° -172 ° (dec.); fa = -129 (c 1.7; dimethylformamide) is obtained.

c) 1- / 11- / 7 S) -3- (benzoylamino) -2-oxo-U-phenylbutyl7-L-35 alanyl7-L-proline, 1,1-dimethylethyl ester_

_A

8302562 1 * 6 r *! * * L-alanyl-L-proline, 1,1-dimethylethyl ester (2.1 * 2 g, 10 mmol), sodium bicarbonate (81 * 0 mg) and (S) -N- / 3-chloro-2-oxo- 1- (phenylmethyl) propylbenzamide (3.01 g) are combined in 50 ml dimethylformamide under an argon blanket at room temperature and stirred overnight. The reaction mixture is then concentrated in vacuo to about half its original volume and the residue is taken up in ethyl acetate and washed with saturated sodium bicarbonate to give 2.25 g of crude product. This material is taken up in ethyl acetate: methanol (9515) to give 860 mg of 1- / 11 / (S) -3- (benzoyl-amino) -2-oxo-1 * -phenylbutyl-L-alanyl / -L-proline 1.1-dimethyl ethyl ester.

d) 1- / lT-Z '(S) -3- (benzoylamino) -2-oxo-1 * -phenylbutyl7-L-alanyl7-L - proline, monohydrochloride 15 1S) -3- (benzoylamino) -2 -oxo-1 * -phenylbutyl7 "L-alanyl7" L-proline, 1,1-dimethylethyl ester (7 ** 0 mg, 1.1 * 6 mmol) is dissolved in a solution of hydrogen chloride in acetic acid (1.5 n , 10 ml) and kept at room temperature for 30 min. It is then concentrated, taken up in water, filtered and lyophilized to give 600 mg of 1- / N- (S) -3 "(benzoylamino) -2-oxo-1 * -phenylbutyl7" L-alanyl7 "L-proline, monohydrochloride; m.p. 83 -163 °; Aa = -109 ° (c = 1.0l *; methanol) are obtained.

0.6 (silica gel; butanol / acetic acid / water, U: 1: 1).

Analysis calculated for C_ ϋϊ ,, -. Ν., Ο-. . HCl. 1.65 H 2 O: 5 έ 25 C 57.99; H 6.1 * 8; N 8.12; Cl 6.85

Found: C 57.99; H 6.39; H 8.09; Cl 6.95-

Example LXIV

• P

(S) -1- / N - / 5- (benzoylamino) -2-oxo-1 * -phenylbutyl7-L-

Lysyl7-L-proline, dihydrochloride -30 a) 1- / H6- / T1,1-dimethylethoxy) -carbony] JN2 - / '(phenyl-methoxy) carbonyl7-L-lysyl7-L-proline, 1,1-dimethyl- ethyl ester-N ^ - / (1,1-dimethylethoxy) carbonyl7-N2 - / (phenylmethoxy) carbonyl7-L-lysine (9.51 g) and hydroxybenzotriazole (3.825 g) are taken up in 25 ml dimethylformamide with stirring in an ice bath 8302562 '! n ^ 7 under an argon blanket. To this is added L-proline, 1,1-dimethylethyl ester (U, U9 g), followed by N, 1P-diisopropylethyl amine (2.2 ml) and dicyclohexylcarbodiimide (5.15 g). After 15 min. the bath is removed and the reaction is allowed to proceed for 6 hours at room temperature. The dimethylformamide is removed in vacuo. The residue is taken up in ethyl acetate and the dicyclohexylurea is filtered off. The filtrate is washed neutral with 10% potassium bisulfate and saturated sodium bicarbonate The crude product (13.26 g) is purified on silica gel column by eluting with ethyl acetate: hexane (2: 1) to give 13.0 g of 1 - / - - / - 1,1-dimethylethoxy) carbonyl 7 'N 2 - / (phenylmethoxy) carbonyl7-L-lysyl7-L-proline, 1,1-dimethylethyl ester.

b) (S J-1-Zi ^ -Zs-fbenzoylaminoJ-S-oxo - ^ - phenylbutylJ- 15 N ^ -Z (1,1-dimethyl ethoxy) carbonyl7 ~ L-lysyl7 ”L- • proline. 1.1-dimethylethyl ester

The ester product from part (a) is reduced in ethanol with palladium on a carbon catalyst (10 JS) to give 3.99 g of 1/6 '/ 1-dimethylethozy) -carbonyl-7-lysyl / -L-proline, 20 1 1,1-dimethylethyl ester are obtained. This material is taken up in UO ml of dimethylformamide and treated with (s) -N- / 3 "chloro-2-oxo-1- (phenylmethyl) propyl / benzamide (3.01 g), from example LXIII (b), and sodium bicarbonate (8U0 mg). After stirring at room temperature for 18 hours, the reaction mixture is concentrated in vacuo, taken up in ethyl acetate and washed with saturated sodium bicarbonate. The crude product (7.0 g) is purified on a silica gel column and eluted with ethyl acetate: 1% methanol to yield 1.7 g (Ξ) -1- / Ν2- £ 3- (Κβηζογΐ8Μίηο) -2-oxo-b- phenylbutyl / -N2 - (1,1-dimethylethoxy) carbonyl-7-lysyl-7-L-proline, 1,1-dimethylethyl ester.

c) (S) -1 (benzoylamino) -2-oxo-U-phenylbutyl7-L-lysyl-L-proline, dihydrochloride_

The ester product from part (b) (1.6 g) is treated for 30 min at room temperature with 20 ml of 1.5 N hydrochloric acid: acetic acid, concentrated to dryness and triturated to a solid 3302562 Η8 τ V ·

* I

with ether to yield 1.37 g of product. This material is taken up in water, filtered on millipore and lyophilized to yield 1.28 g of product. Further purification is performed on an LH20 column in water yielding 7 ^ -0 mg

O

5 (S) -1- / ¾ - / 3- (benzoylamino) -2-oxo-U-phenylbutyl7-L-lysyl / "L- o 25 proline, dihydrochloride; m.p. 120-180; /a / ? -8H.8 (c = 1.05; methanol) are obtained. 0.61 (trace he 0.9) (silica gel, chloroform / methanol / acetic acid, 60, Uo, 38 # 20). Analysis calculated for C28H3A ° 5 · 21101 * 3H 2 O: 10 C 52.98; H 6.98; N 8.83; Cl 11.17

Found: C 52.98; H 6.93; N 8.66; Cl 11.31

Example LXV

. % N- / ÏT - // (S) -3- (benzoylamino) -2-oxo-U-phenylbutyl7-L-alanyl7-N-cyclohexylglycine, monohydrochloride 15 a) N-cyclohexylglycine, 1,1-dimethylethyl ester

Cyclohexylamine (70.35 ml) and sodium bicarbonate (12.9 g) are suspended with stirring in 200 ml of absolute ethanol with stirring in an ice bath. Bromoacetic acid 1,1-dimethylethyl ester (20.78 ml) is added dropwise to this.

The ice bath is removed. After 2 hours at room temperature, the reaction mixture is concentrated to dryness, taken up in chloroform and washed with water. The crude product (to g) is chromatographed on silica gel and eluted with ethyl acetate: hexane (2: 1 to give 27 µg of N-cyclohexylglycine, 1,1-dimethyl ethyl ester.

b) N-cyclohexyl-N- / N - / ((phenylmethoxy) carbonyl7-L-alanyl-7-glycine, 1,1-dimethylethyl ester 11- / (phenyl-methoxy) carbonyl-7-alanine g), N-cyclohexyl-glycine, 1,1-dimethylethyl ester (k, 26 g), hydroxy-30 benzotriazole (3.06 g), dicyclohexylcarbodiimide 12 g) and triethylamine (2.8 ml) are stirred in 1 * 0 ml dimethylformamide at room temperature for 20 hours. The reaction mixture is then concentrated in vacuo, taken up in ethyl acetate, the dicyclohexyl urea is filtered off and the filtrate is washed neutral with 10% potassium bisulfate and saturated sodium bicarbonate 8302562: 5.9 g of crude product. Crystallization from ether: hexane gives 3.97 g of N-cyclohexyl-N- / (phenylmethoxy) carhonyl] L-alanyl glycine, 1,1-dimethyl ethyl ester; m.p. 10¾ - 105 ° c) N- (L-alanyl) -N-cyclohexylglycine, 1,1-dimethylethyl ester

The ester product from part (b) (3.9 g) is taken up in methanol with palladium on carbon catalyst (10%, 700 mg) and stirred under a hydrogen blanket for one hour. The reaction mixture is filtered and concentrated to dryness to yield 2.65 g of crude 10 IT- (L-alanyl) -N-cyclohexylglycine, 1,1-dimethylethyl ester, d) S) -3 “(benzoylamino) -2-oxo ^ -phenylbutyi-L-alanyl / Hicyclohexylglycine, 1,1-dimethylethyl ester 15 The crude ester product from part (c) (2.6 g), sodium bicarbonate (76 µmg) and (S) -N - / '3- chloro-2-oxo-1- (phenylmethyl) -propyl-benzamide (2.75 g) from Example LXIIl (b) is stirred in 25 ml of dimethylformamide for 20 hours. The reaction mixture is concentrated to dryness, taken up in ethyl acetate, and washed with saturated sodium carbonate to give bt7 g of crude product. Purification on a silica gel column and eluting with ethyl acetate: methanol (99: 1) provides 1.5 g of N-1-f-f ((s) -3- (benzoylamino) -2-oxo-phenyl-butyl-7-Lanyan) 7-N-cyclohexylglycine, 1,1-dimethylethyl ester.

E) H- / IT - # (S) -3- (benzoylamino) 2-oxo-U-phenylbutyl7-L-alanyl7-H-cyclohexylglycine, monohydrochloride

The ester product from part (d) (500 mg) is treated with 5 ml of 1.5 N hydrochloric acid: acetic acid for 30 min and then concentrated to dryness at room temperature. The crude product is taken up in methanol and purified on an LH20 column to yield 113 mg of product. This is made semi-crystalline in acetonitrile: ether to yield N- / ft - / "/, (S) -3" (benzoylamino) -2-oxo-U-phenylbutyl7-L-alanyl-N-cyclohexylglycine, monohydrochloride; m.p. 15¾ - 157 ° (132 °); fa = -67, ¾0 (c = 1.35, methanol). R ^ 0.60 (low impurity at 0.92) 8302562 r 50 *: *: (silica gel, chloroform: methanol: conc. Ammonia, 30: 10: 2).

Analysis calculated for C ^ gH ^ N ^ O2. , HCl. H 2 O C 61.35; H 6.99; N 7.67; Cl 6.17. Found: C 61.08; H 6.79; N 7.65; Cl 6, U6.

Example LXVI

N- / N- / (S) -3- (benzoylamino) -2-oxo-ii-phenylbutyl7-L-alanyl-N-phenylglycine, monohydrochloride_ a) N-phenylglycine, 1,1-dimethylethyl ester 10 A solution of triethylamine (11.25 g, 0.11 mol) and aniline (9.3 g, 0.10 mol) in ether (100 ml) under an argon blanket are added. an ice bath cooled to 0 °. Bromoacetic acid 1,1-dimethylethyl ester (18 g, 0.093 mol) is added thereto over a period of 30 minutes. The resulting mixture is stirred at 0 ° for 1 hour, then warmed to room temperature and stirred overnight. The solution is filtered and rinsed with ether and the filtrate concentrated to give 6.9 g of yellow oil. R ^ 0.6; 0.7 (silica gel, ethyl acetate). Chromatographing on LPS-1 using hexane: ethyl acetate (7: 3) as the eluent provides 2.3 g of N-phenylglycine, 1,1-dimethyl ethyl ester as a pale yellow liquid. R ^ 0.7 (silica gel, ethyl acetate).

b) N-phenyl-N-ZiT-Z-phenylmethoxy) carbonyl / -L-alanyl 7 "glycine, 1,1-dimethylethyl ester. A solution of 11- (phenylmethoxy) carbonyl 7" L-alanine (2.8 g, 12.7 mmol) in dry tetrahydrofuran (50 ml) under argon is cooled in a dry ice-ethanol bath. N-methyl morpholine (1.28 g, 12.7 mmol) and isobutyl chloroformate (1.73 g, 12.7 mmol) are added thereto. After 20 min. N-phenylglycine, 1.1-30 dimethylethyl ester (3.7 g, 12.7 mmol) is added. The resulting mixture is stirred at -20 ° for 1 hour and then at room temperature overnight. The mixture is partitioned between ethyl acetate and 1N hydrochloric acid. The organic layer is washed successively with 1N hydrochloric acid and 10% sodium bicarbonate, dried (MgSO 2), and concentrated. Chromatograph on LPS-1 and elute 8302562 Μ-. 51:51 with a gradient of ethyl acetate-hexane (3: 1 -> 1: 1) yields Π.Ο g of N-phenyl-N- / N - / (phenylmethoxy) carbonyl / -L-alanyl / glycine, 1.1 dimethyl ethyl ester as a clear oil. R ^ 0, ¾ (silicon dioxide gel, ethyl acetate).

C) N- (L-alanyl) -N-phenylglycine. 1,1-dimethyl ethyl ester

A solution of the ester product from part (b), 0.05 g 9S7 mmol) in ethanol (125 ml) and 10% palladium on carbon catalyst is stirred under hydrogen flow for 18 hours.

The solution is filtered, concentrated, dissolved in ethyl 10 acetate and extracted with 1N hydrochloric acid. The aqueous layer is treated with sodium bicarbonate to basic and extracted with ethyl acetate. The combined ethyl acetate extracts are (dried (MgSO4) and concentrated to give 1.3 g of IT- (L-alanyl) -N-phenylglycine, 1,1-dimethyl ethyl ester as a white solid. R ^ 0.52, slight stain at 0.6¾ (silica gel, ethyl acetate: methanol; 1: 1).

d) Ή- £ §- ££ (S) -3 ~ (benzoylamino) -2-oxo-U-phenylbutyl7 "

11-alanyl7 ~ N-phenylglycine, 1,1-dimethylethyl ester

To a stirred solution of (S) -N- / 3-chloro-2-oxo-20 1- (phenylmethyl) propylbenzamide (1.1 g, ^ 7 mmol) from Example LXIII (b) and N- (L-alanyl ) -N-phenylglycine, 1,1-dimethylethyl ester (1.3 g, ¾, 7 mmol) in dry dimethylformamide, become sodium bicarbonate (θ, 3θ g, ¾, 7 mmol) and sodium iodide (0.7 g, ¾, 7 mmol) ) added. After stirring overnight at room temperature, the mixture is concentrated, dissolved in ethyl acetate and filtered. The filtrate is washed with 10% sodium bicarbonate, dried (MgSO4) and concentrated to a gel. Chromato graphing on LPS-1 and eluting with a gradient of ethyl acetate and formed hexane (1: 1) to ethyl acetate yields 1.8 g of 30 N- / II - / "/ tS) -3" (benzoylamino) -2-oxo -U-phenylbutyl7-L-alanyl7 "N-phenylglycine, 1,1-dimethylethyl ester. R ^ 0.3¾ (silica gel, ethyl acetate).

e) l / IT / V "CS) -3- (benzoylamino) -2-oxophenylbutyl7" L-alanyl7-IT-phenylglycine, monohydrochloride "A solution of the ester product from part (d) 8302562 52 ** »1 * * (1.6 g, 2.9 mmol) in hydrochloric acid / acetic acid (1.77 n, 17.0 ml) is stirred at room temperature for 30 min. The solution is concentrated and the residue is triturated with ether to give a pale yellow solid Recrystallization from methanol / ether gives 0.8 µg of TT-0- / f (S) -3- (benzoylamino) -2-oxo-1 + -phenylbutyl7-L-alanyl7 "N-phenylglycine, monohydrochloride as a white crystalline solid, mp. 1 ^ 7" 159 ° (dec.)

Rf 0.8 (silica gel, butanol: acetic acid water; 1: 1: 1). faJ-Q ~ 12.7 ° (c = 1.5; methanol).

Analysis calculated for C28H29W305 * HCl * 20: C 62.77; H 5 * 89; N 7.8U; Cl 6.62 Found: C 62.77; H 5.70; N 7.81+; Cl 6.12

Example LXVII

(1 - (S) -1 - / K- / 75- (benzoylamino) -2-oxo-U-phenylbutyl ^ -N- methyl-L-alanyl7-L-proline, monohydrochloride_ a) N- / Tphenylmethoxy) carbonyl7 -L-alanine L-alanine (89.1 g, 1 mol) is dissolved in 2N sodium hydroxide (500 ml) and cooled to 0 °. To this are added dropwise benzyl-20 chloroformate (20H, 5 g, 1.2 mol) and Un sodium hydroxide (250 ml) dropwise over 1 hour. The reaction mixture is stirred overnight (0 ° to room temperature) and washed with ethyl acetate (2x 500ml). The aqueous portion is acidified to pH 2.0 with 6N hydrochloric acid and extracted with ethyl acetate (3x 600ml).

The combined ethyl acetate extracts are dried (Na 2 SO 4),; concentrated on a rotary evaporator and the solid residue is triturated with petroleum ether to obtain 19.0 g of II-ƒ (phenylmethoxy) carbonyl] L-alanine as a white solid.

B) N-methyl-11 - / (phenylmethoxy) carbonyl7'-L-alanine

A cold (0 °) solution of H - / (phenylmethoxy) carbonyl-L-alanine (22.3 g, 0.1 mol) and methyl iodide (50 ml, 0.8 mol) in tetrahydrofuran (50 ml) is added sodium hydride dispersion (11.25 g, 0.3 mol) was added carefully with gentle stirring. The suspension is stirred under a nitrogen blanket (0 ° -> room temperature) overnight, slowly poured into 8302562, 1 53 saturated sodium bicarbonate (200 ml), diluted with ethyl acetate (300 ml) and the layers are separated. The organic layer is extracted one more time with saturated sodium bicarbonate. The combined aqueous layers are acidified to pH 2.0 with 10% potassium bisulfate and extracted with ethyl acetate. The combined ethyl acetate extracts are dried (Ha 2 SO 4) and concentrated in vacuo to a dark oily residue (23.0 g).

The crude acid is treated with dicyclohexylamine (20 ml) in ether (150 ml). The crude d-cyclohexylamine-10 salt obtained is collected (37 * 0 g), recrystallized from chloroform / ether (35 * 0 g) and converted back into the acid by partition between 1N hydrochloric acid / ethyl acetate to give a pale yellow oil, which crystallizes when standing (17 »^ g)

Recrystallization (11.2 g) from ethyl acetate / petroleum-15 ether gives 0.0 g of 11-methyl-T- (phenylmethoxy) -carbonyla 3 -7-L-alanine & O C a as a white crystalline product; m.p. 65 - 66.5 ° fa - -31.1 ° (c = 2, acetic acid) c) 1 - / TJ-methyl-NA phenylmethoxy) c arbonyi / -L-al anyl7 “L-alanvU-L-proline - 1,1-dimetyl ethyl ester. 20 To a solution of 1-methyl-1-yl / 7-phenylmethoxy) -carbony] J-alanine (U, 7 µg, 20 mmol) in distilled tetrahydrofuran (50 ml) are L -proline, 1,1-dimethylethyl ester (3 µg 2 g, 20 mmol), hydroxybenzotriazole hydrate (3.06 g, 20 mmol) and dicyclohexylcarbodiimide (U, 12 g, 20 mmol). The reaction mixture is stirred overnight, the precipitated dicyclohexylurea is filtered off and the filtrate is concentrated. The residue is dissolved in ethyl acetate (50ml) and washed with saturated sodium bicarbonate (2x), 10% potassium bisulfate (2x) and water (2x), dried (Ha 2 SO 4) and 3O concentrated to give 6.0g 1 / H methyl-H-phenylmethoxy) -carbonyl-7-alanyl-L-proline, 1,1-dimethyl ethyl ester are obtained as an oily residue.

d) 1- (U-methyl-L-alanyl) -L-proline, 1,1-dimethylethyl ester_ 35 A mixture of the ester product from part (c) (6, hg, 8302562): 16.1 *. mmol) and 0.8 g of 10% palladium on carbon catalyst in ethanol (95% 150 ml) are hydrogenated overnight at atmospheric pressure. The catalyst is removed by filtration and the filtrate is evaporated. The resulting oily residue solidifies on drying in high vacuum to an oily solid residue (3.8 g). Trituration with ether gives 1.5 δ 1- (N-methyl-L-alanyl) -L-proline, 1,1-dimethyl ethyl ester, monohydrochloride as a white solid; Rf 0. HU (silicon dioxide gel, 20% methanol / chloroform). fa = -102.1 °

10 (c = 2, acetic acid). The ether filtrate provides 2.3 g of 1 - (N-methyl-L-alanyl) -L-proline, 1,1-dimethyl ethyl ester as an oil; R_ 0, UU

pr ^ - (silica gel, 20% methanol / chloroform). fa = -101.6 '') (c = 2, acetic acid) e) (S) -1 - £ & -fB- (benzoylamino) -2-oxo-U-phenylbutyl / - 15 N-with hyl-L -alanylJ-L-proline, 1,1-dimethylethyl ester_

A reaction mixture of 1- (N-methyl-L-alanyl) -L-proline, 1,1-dimethylethyl ester (2.1 g, 8.19 mmol), (s) -N- / 3-chloro-2-oxo -1- (phenylmethyl) propyl / benzamide (2.16g, 8.19mmol), 20 from Example LXIIl (b), excess sodium bicarbonate and sodium iodide (1.22g, 8.10mmol) in dimethylformamide ( 15 ml) is stirred overnight at room temperature under a nitrogen blanket.

The reaction mixture is concentrated, the residue is partitioned between water / ethyl acetate, the layers are separated, the aqueous layer is extracted again with ethyl acetate. The combined 1 ^ organic extracts are washed with saturated sodium bicarbonate and water, dried (Na ^ SO ^) and concentrated to an oily residue (3.5 g) · Rapid chromatography (200 g silica gel, 1% methanol / ethyl acetate ) yields 2.8 g (S) -1- / 11-30 Z "/ 3- (benzoylamino) -2-oxo-U-phenylbutyl] -N-methyl-L-alanyl7-L-proline, 1,1-dimethyl ethyl ester like a yellow oil.

f) (S) -1- / 1J- / Y "3- (benzoylamino) -2-oxo-phenylbutyl7-N-methyl-L-alanyl7-L-proline, monohydrochloride

The ester product from part (e) (1g, 2.7mmol) is treated with 2N hydrochloric acid / acetic acid (20ml). After stirring for 2 hours at 8302562: *: <55 room temperature, the reaction mixture is concentrated under reduced pressure and the resulting oily residue is triturated with ether (kx) to yield 1.05 g (S) -1 - / ΪΓ- / Ζ3- (benzoylamino) -2-oxo-k-phenylbutyl-7-N-methyl-L-alanyl / -L-proline, monohydrochloride 5 as an off-white solid; m.p. 125 ”135 °; R ^ Q, 2h (silica gel, n-butanol / acetic acid / water; lt: 1: 1).

Ca = -8 ° (c = 1, methanol).

Analysis calculated for. SCI. 0.7 H 2 O: C 60.68; H6, U1; N 8.16; Cl 6.38. Found: C 60.68; H 6.36; H 7.95; Cl 6.1 * 8

Example LXVIII

* (S) -1-i & - / '3- (benzoylamino) -2-oxo-k-phenylbutylJ-h- () phenylglycyl7-Lt> roline, hydrochloride (20: 3) __ a) 1-bromoacetyl) -L -proline. 1.1-dimethylethyl ester 15 To a cooled (-10 °) solution of L-proline, 1.1-dimethylethyl ester (3 µg, 2 g, 0.2 mol) in methylene chloride (250 ml), diisopropylethylamine (38.3 ml, 0.22 mol) and bromoacetyl chloride (16.5 ml, 0.2 mol) added dropwise over 20 min while keeping the temperature between -10 ° to -5 °. The dark reaction mixture is stirred overnight (-10 ° to room temperature) and concentrated under reduced pressure. The oily residue is redissolved in ethyl acetate, washed with saturated sodium bicarbonate (2x), 10% potassium bisulfate (2x) and water (2x), dried (lia ^ SO ^) and concentrated to a dark oily residue (20.0 g) . Rapid chromatography (LPS-1, silica gel, 10% ethyl acetate / methylene chloride) provides 11.0 g of 1-bromoacetyl) -L-proline, 1,1-dimethyl ethyl ester as a pale yellow oil.

b) 1- (N-phenylglycyl) -L-proline, 1,1-dimethylethyl ester 30 To a solution of 1- (bromoacetyl) -L-proline, 1,1-dimethyl ethyl ester (2.1 g, 7.5 mmol) in distilled tetrahydrofuran (1 * 0 ml), aniline (1.5 g, 15 mmol) is added and the reaction mixture is stirred under nitrogen blanket overnight.

The reaction mixture is diluted with ethyl acetate (200ml), washed with saturated sodium bicarbonate (2 x 50ml) and water 8302562 56 (2 (), dried (Na 2 SO 4), and concentrated in vacuo to a dark oily residue (U, 0 g). Rapid chromatography (LPS-1 dilicidal dioxide gel, 10% ethyl acetate / methylene chloride) yields 2.2 g of 1- (N-phenylglycyl) -L-proline, 1,1-dimethyl ethyl ester which it dries in a high vacuum.

c) (S) -1- / -; f3 “(benzoylamino) -2-οχο-1 * -phenylbutyl / -N-phenylglycyl7-L-proline, 1,1-dimethylethyl ester

A reaction mixture of 1- (1-phenylglycyl) -L-proline, 1,1-dimethylethyl ester (1.06 g, 3.5 mmol), (S) -N- / 3-chloro-2-oxo-10 1- (phenylmethyl) propyl7henzamide (1.06g, 3.5mmol), from Example LXIIl (b), excess sodium bicarbonate and sodium iodide (0.52g, 3.5mmol) in dimethylformamide (10ml) overnight stirred at room temperature under a nitrogen blanket. The reaction mixture is poured into water (50 ml) and extracted with * 15 ethyl acetate (3 x 50 ml). The combined ethyl acetate extracts are washed with saturated sodium bicarbonate (2x) and water (3x), dried (NagSO 2), and concentrated under reduced pressure to give a dark oily residue (2.0 g). Rapid chromatography (LPS-1 silica gel, 5% ethyl acetate / methylene-20 chloride to 15% ethyl acetate / methylene chloride) provides 0.3 g (S) -1- /--Z3- (benzoylamino) -2-oxo-1 | - phenylbutyl / -N-phenyl-glycyl7 "L-proline, 1,1-dimethylethyl ester as a pale yellow foam.

d) (S) -1 - / N- / 3 -. (benzoylamino) -2-oxo-U-phenylbutyl / -N- phenylglycyl7-L-proline, hydrochloride (20: 3) _

The ester product from part (c) (0.28 g, 0.1 * 9 mmol) is treated with 2N hydrochloric acid / acetic acid. After stirring for 1 hour at room temperature, the reaction mixture is concentrated under reduced pressure and the resulting oily residue is triturated with ether (hx) to yield 1.0 g (S) -1- / -1- / * 3- (benzoyl-amino) -2-oxo-1 * -phenylbutyl / -H-phenylglycyl7-L-proline, hydrochloride (20: 3) as an off-white solid; m.p.

110 - 11 * 0 °; 0.76 (slight stain at 0.53) (silica gel, n-butanol / acetic acid / water; 3: 1: 1) are obtained.

3302562; v:, 57

Analysis calculated for ^ 30 ^ 31 ^ 3 ^ 5. 0.15 HCl, 0.5 HgO: C 68.22; H 6.13; 11 7.95; Cl 1.00 Found: C 68.22; H 6.00; N 8.25; Cl 0.99-

Examples LXIX - XC

Proceeding by the method of Examples LXIII to LXVIII but using the ketone as shown in column 1, the acid chloride as shown in column 2 and the peptide ester as shown in column 3, the ester product as shown in column is obtained. of the 10 Rg ester group and any other protecting groups, the corresponding end product yields in acid form.

Column 1 gives formula 7a again, column 2 formula 8a, column 3 formula Ua and column U formula 1b.

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The R1 protecting groups in Examples LXXIV, LXXVI and LXXVII, and the R ^ protecting groups in Examples LXXVIII and LXXX and the R ^ protecting groups in Examples LXXXI and LXXXIII to LXXXV are removed as the last step in the synthesis. The Rg ester groups shown in examples LXXXVII to XC are not deleted.

Example XCI

(+) -1 - / R- / 3- (benzoylamino) -2-oxo-U-phenylbutyl7-R-methylglycyl / -1-proline, monohydrochloride_ 10 a) / 3- (benzoylamino) -2-oxo-U- phenylbutylmethyl carbamic acid, phenylmethyl ester R-methyl-R - / (phenylmethoxy) carbonyl / glycine (2.23g, 10mmol) is dissolved in 30ml tetrahydrofuran and cooled in an ice bath. Oxalyl chloride (1ml, 11.5mmol) is added followed by two drops of dimethylformamide. After stirring in the ice bath for 30 minutes, the mixture is then stirred at room temperature for one hour. 0.25 ml of oxalyl chloride are added thereto. The mixture is evaporated, redissolved in 15 ml of tetrahydrofuran and stirred in an ice bath. A solution of 2-phenyl-U-20 (phenylmethyl) -5 (te) -oxazolone (3.1 g, 12, U mmol), dissolved in 15 ml of tetrahydrofuran, is added to the above solution with stirring in the ice bath . Triethylaraine (1.1 ml, 10 mmol) is added and the solution is stirred at room temperature overnight. The precipitated triethylamine hydrochloride salt is filtered off. Tetrahydrofuran is removed from the residue and then redissolved in pyridine (6ml) and p-dimethylaminopyridine (20mg) is added. After stirring at room temperature for 3 hours, acetic acid (5 ml) is added and the reaction mixture is kept at 105 ° 30 for 30 min. The reaction mixture is then evaporated, the residue is dissolved in ethyl acetate and washed with aqueous sodium bicarbonate and water. Trituration with ethyl acetate / hexane gives 2.2 g of homogeneous / 3- (benzoylamino) -2-oxo-U-phenylbutyl / methyl carbamic acid, phenylmethyl ester; slaps. Ik0-lkl °.

35 8302562> 66 * b) (+) - N- / 3- (methylamino) -2-oxo-1- (phenylmethyl) -propyl / benzamide, hydrochloride_ [2> - (benzoylamino) -2-oxo - ^ - phenylbutyl with hylcarbamic acid, phenylmethyl ester (0.5 g) is dissolved in ethanol (50 ml) containing 1N hydrochloric acid (2 ml). Carbon palladium catalyst (10%, 100mg) is added and hydrogenation is continued overnight. The reaction mixture is then filtered, evaporated, dissolved in water and lyophilized to give 300 mg (10-N- <f3- (methylamino) -2-oxo-1- (phenylmethyl) propyl] benzamide, hydrochloride as a homogeneous white powder .

c) (+) - 1 - / N- / 3- (benzoylamino -oxo - ^ - phenylbutyl / -N-with hylglycyl-L-nroline. 1,1-dimethylethyl ester j A reaction mixture of (+) - ïï- 3- (methylamino) -2-oxo-1 - (phenylmethyl) propylbenzamide, hydrochloride (1.65 g, 15 mmol), 1- (bromoacetyl) -L-proline, 1,1-dimethyl ethyl ester (2.9 g , 10 mmol) from example LXVII1 (a), and diisopropylethyl amine (1.7 µl, 10 mmol) in dimethylformamide (20 ml) stir stirred nitrogen at room temperature overnight.

The reaction mixture is partitioned between water / ethyl acetate and the aqueous layer is extracted one more time with ethyl acetate. The ethyl acetate extracts are dried (100 SO 4) and concentrated to a yellow oily residue (U, 0 g). Rapid chromatography (150 g on Merck silica gel 6θ) yields 0.7 g (+) * 1 (benzoylamino) -2-oxo-1 + -phenylbutyl7-i-methyl-glycyl] -L-proline, 1,1-dimethyl-ethyl ester as a yellow foam.

d) (+) -1-1 / -1- / 3 "(benzoylamino) -2-oxo-phenylbutyl7" H-methylglycyl7-L-proline. monohydrochloride

The ester product from part (c) (0.1 µg, 0.79 mmol) is treated with 2N hydrochloric acid / acetic acid (5 ml). Ha U5 min.

While stirring at room temperature, the reaction mixture is concentrated under reduced pressure and the resulting oily residue is triturated with ether (3x) to yield 0.28 g (+) - 1 - / H - / 3 - (benzoylamino) -2-oxo-2. phenylbutyl7 "H-methylglycyl7" L-proline, monohydrochloride are obtained as a white solid; m.p. 125-130 °. R 0.73 (silica gel, n-butanol / 8302562 r 1 6j acetic acid / water; 3: 1: 1).

Analysis calculated for. HCl. 0.23 H 2 O: C 61.01; H 6.2k, N 8.5¼

Found: C 61.01; H 6.10; N 8.36

5 Example XCII

(S) -7 - // 73 "(benzoylamino) -2-oxo-U-phenylbutyl-methyl-amino / acetyl / -1, -dithia-7-azaspi.ro A s k7-nonane-8-carboxylic acid» trifluoroacetate salt (1: 1) _ a) (S) -7- (bromoacetyl) -1, ^ - dithia-7 ~ azaspiro 10 A A7 nonane-8-carboxylic acid__ (s) -1 A-ditbia-7 ~ azaspiroA j ^ / nonane-S-carboxylic acid, hydrochloride (2.1 g, 8.7 mmol) is dissolved in 1N sodium hydroxide (25 ml), cooled to 0 ° and bromoacetyl bromide (2.1 g, 0.91 ml, 10, ¼ mmol) is added dropwise over 15 min. The reaction mixture is stirred (0 ° to room temperature) for 2 hours, washed with ethyl acetate (2x) and the aqueous layer is acidified to pH 2 and extracted with ethyl acetate ( 3x) The combined organic extracts are dried (HagSO4) and concentrated to give 2.25 g of 20 (S) 7-(bromoacetyl) -1A-dithia-7-azaspiroA, k / nonane-8 carboxylic acid.

b) (S) “7” (bromoeetyl) -1, U-dithia-7 ~ azaspiroA »k7 ~ nonane ~ 8 ~ carboxylic acid diphenylmethylester_ (S)“ 7 ~ (bromoeetyl) -1, U-dithia-7 ~ azaspiroAA-7nonane -25--carboxylic acid (2.25 g, 6.9 mmol) is dissolved in ethyl acetate (150 ml). Diphenylazomethane (1.3 g, 6.9 mmol) is added and the reaction mixture is stirred at room temperature overnight. The decolorized reaction mixture is washed with saturated sodium bicarbonate (2x), 10% potassium bisulfate (2x) 3P and water, dried (Ha 2 SO 4) and concentrated to give 2.5 g (3) -7 ~ (bromoacetyl) -1 U ditia-7-a-zaspiroA, by nonan-3-carbonic acid, diphenylmethyl ester are obtained as a white solid residue.

c) (S) -7 - // 73- (benzoylamino) -2-oxo-U-phenylbutyl / -35 methylaminojacetyl-1, U-dithia-7 "azaspiroA, k7nonane-8-carboxylic acid, diphenylmethyl ester_ 8302562 68": > '

A mixture of the ester product from part (b) (2.0 µg, U, 87 mmol), (+) -N- / 3- (methylamino) -2-oxo-1- (phenylmethyl) propyl / benzamide (0, 81g, 2.1 * 3mmol) prepared as set forth in Example XCl (b), and diisopropylethylamine (0.85ml, h, 87mmol) in dimethylformamide (20ml) are stirred at room temperature overnight. The reaction mixture is poured into water (50 ml) and extracted with ethyl acetate (3x 100 ml).

The combined organic extracts are washed with saturated sodium bicarbonate, 10% potassium bisulfate and water, dried (NagSO4), and concentrated to a dark oily residue (2.8 g). Rapid chromatography (200 g Merck silica gel, 10% ethyl acetate / methylene chloride, 20% methanol / ethyl acetate) yields 1.1 g (S) -? "// (benzoylamino) -2-oxo-U-phenylbutyl / methylamino / acetyl / -1, U-dithia-7 ~ azaspiro A A7 “15 'nonane-8-carboxylic acid, diphenylmethyl ester as a yellow oil.

d) (S) -7 - /// 3- (benzoylamino) -2-oxo-U-phenylbutyl / -methylamino / acetyl / ~ 1, - dithia-7 "azaspiro A A7 ** nonane-8-carboxylic acid, trifluoroacetate salt (1: 1)

The ester product from part (c) (10.5 g, 0.72 mmol) 20 is added to cooled (0 °) trifluoroacetic acid (2 ml) containing anisole (0.1 ml). After stirring for 1 hour, the volatiles are removed in vacuo and the residue is rinsed with toluene (2x). The oily residue is triturated with ether (kx) to yield 0.36 g (S) -7 - /// 3- (benzoylamino) -2-οχο-Π-25-phenylbutyl / methylamino / acety] / - 1.1 * ditia-7-azaspiroA A7 "nonane-8-carboxylic acid, trifluoroacetate salt (1: 1); m.p. 120-125 ° are obtained. 0.1 * 5 (run-out) (silica gel, n-butanol / acetic acid / water; 1 *: 1: 1).

Analysis calculated for C ^ H ^ H ^ O ^. CgHF 4 Ogi 30 C 53.11; HI *, 92; H 6.1 * 0; S 9.78

Found: C 52.68; H 5.03; H 6.53; S 9.97-Example XCIII

(S) -2 - /// 3- (benzoylamino) -2-oxo-i + -phenylbutyl / methylamino / acetyl / -1,2,3,1-tetrahydro-3-isoquinoline-35 carboxylic acid, monohydrochloride 8302562 * 3 69 a) 2- (bromoacetyl) -1,2,3 i -tetrahydro-S-isoquinolinecarboxylic acid, 1,1-dimethylethyl ester

To a cooled solution of 1,2,3,1-tetrahycLro-3-isoquinolinecarboxylic acid, 1,1-dimethylethyl ester (7.7 g, 33 mmol) 5 in methylene chloride (100 ml), is diisopropylethylamine (6.23 ml, 36, 3 mmol) and finally in a time frame of 15 min.

bromoacetyl bromide (6.6 g, 2.87 ml, 33 mmol), while keeping the temperature at 5 °. The reaction mixture is stirred overnight (-5 ° to room temperature), concentrated 10 to about 33 1/3% of its volume, diluted with ethyl acetate (100ml), washed with saturated sodium bicarbonate (2x), 10% potassium bisulfate (2x ) and water (2x), dried (NagSQ ^) and concentrated to a dark yellow semi-solid residue (11.0 g).

Recrystallization from ethyl acetate / hexane provides 2 g of 2- (bromoacetyl) -1,2,3,3 "tetrahydro-3" isoquinoline carboxylic acid, 1,1-dimethyl ethyl ester as a cream solid; m.p.

92-95 ° (85 °).

b) (S) -2- / 7 / 3- (benzoylamino) -2-oxo-U-phenylbutyl / -methylamino / acetyl-1,2,3, Ut et rahy dro-3-i-soquinoline carboxylic acid, 1 , 1-dimethylethyl ester

To a solution of 2- (bromoacetyl) -1,2,3,3-tetra-hydro-3-isoquinoline carboxylic acid, 1,1-dimethylethyl ester (2.12 g, 6 mmol) in dimethylformamide (20 ml) (+ JN -73- (methylamino) -2-oxo-1 - (phenylmethyl) propyl-7-benzamide (2.0 g, 6 mmol), prepared as set forth in Example XCl (b), and \ diisopropylethylamine (0.77 g> 1.0U ml, 6 mmol).

The reaction mixture is stirred overnight, poured into water (50 ml) and extracted with ethyl acetate (3x 50 ml).

The combined ethyl acetate extracts are washed with saturated sodium bicarbonate (2x) and water (2x), dried (Na 2 SO 4) and concentrated to a yellow oily residue (2.9 g).

Rapid chromatography (200 g Merck silica, 2% methanol / chloroform) yields 0.68 g (S) -2- / 773- (benzoylamino) -2-oxo-U-phenyl-butyl / with hyl amino / acetyl / -1,2,3,1-tetrahydro-3-isoquinoline-35 carboxylic acid, 1,1-dimethylethyl ester as a yellow dried foam.

8302562 70 tc) (S) -2 - /// 3- (benzoylamino) -2-oxo-4-phenylbutyl-methylamino / acetyl / -1,2,3,1,6-tetrahydro-3-isoquinolinecarboxylic acid, monohydrochloride_

The ester product from part (b) (1.67g, 1.17mmol) is treated with 2N hydrochloric acid / acetic acid (5ml). After stirring for 1 hour at room temperature, the reaction mixture is concentrated under reduced pressure and the resulting oily residue is triturated with ether (bx) to yield 0.55 g (S) -2 - /// 3- (benzoyl-amino) -2-oxo phenylbutyl / methylaminoacetyl / "1,2,3,4-t et rahydro-10 3" isoquinoline carboxylic acid, monohydrochloride obtained as an off-white substance; m.p. 123-126 °. 0.1 * 7 (silica gel, n-butanol / acetic acid / water; 1 *: 1: 1).

(^ Analysis calculated for ^ 30 ^ 3 'C1' ° '^ 2 H 2 O: C 64.82; H 5.92; N 7.56; Cl 6.38 15 Found: C 6 ^, 82; H 6.22 H 7.55 Cl 6.13.

Example XCIV

/ 1 (+), bsj-1- / N- / 3- (benzoylamino) -2-oxo-1 * -phenylbutyl / -N-methylglycyl / -l + - (phenylthio) -L-proline, monohydrochloride_20 a) ( Us) -1- (bromoacetyl) -U- (phenylthio) -L-proline

To a suspension of (1 * S) -! * - (phenylthio) -L-proline (2.2 g, 10 mmol) in methylene chloride (50 ml, freshly distilled), di (trimethylsilyl) acetamide (7.35 ml, 30 mmol). The reaction mixture is stirred at room temperature for 2 hours until it becomes almost clear. The reaction mixture is then cooled to -5 ° and bromoacetyl chloride (1.9 g, 1.0 ml, 12 mmol) is added dropwise while keeping the temperature at -5 °. After stirring overnight (-5 ° to room temperature), the reaction mixture is concentrated 30 to about 50% of its volume, partitioned between saturated sodium bicarbonate / ethyl acetate and the layers are separated.

The organic layer is extracted one more time with saturated sodium bicarbonate. The combined aqueous layers are acidified at pH 2.0 with 10% potassium bisulfate and extracted with ethyl acetate (3x). The ethyl acetate fractions are combined, 3302562 t t

t X

Π dried (Na ^ SO ^) and concentrated to give 3.5 g (Us) -1- (bromoacetyl) -1 (- (phenylthio) -L-proline as a viscous oil b) (Us) -1 - (bromoacetyl) -U- (phenylthio) -L-proline, 5 diphenylmethyl ester

A solution of diphenyldiazomethane (2.0 g, 10.2 mmol) in ethyl acetate (50 ml) is added dropwise to a solution of (IfS) -1- (bromoacetate) -4- (phenylthio) -L-proline (3, 5 g, 10.2 mmol) in ethyl acetate (50 ml). The purple solution is stirred at room temperature overnight.

The decolorized reaction mixture is washed with saturated sodium carbonate (2x) and water (2x), dried (NagSO ^) and concentrated to give 1 (-, 73 g (Us) -1- (bromoacetyl) -k- (phenylthio) - L-proline, diphenylmethyl ester are obtained as a yellow viscous oil.

c) β (+), ltsJ-1- / III-3- (benzoylamino) -2-oxo-U-phenyl-butyl7 "H-methylglycyl / -U- (phenylthio) -L-proline, diphenylmethyl ester_

To a solution of (tó) -1- (bromoacetyl) - ^ - (phenyl-20 thio) -L-proline, diphenylmethyl ester (U, 78 g, 9, b mmol) in dimethylformamide (20 ml) (+ ) -N- / 3 ”(methylamino) -2-oxo-1- (phenyl-methyl) propybenzamide (2.1 (-2 g, 7 * 2 mmol), prepared as outlined in example XCl (b), and diisopropylethylamine (0.93 g, 1.25 ml, 7 2 2 mmol). After stirring overnight at room temperature, the reaction mixture is poured into water (50 ml) and extracted with ethyl acetate (3x). The combined ethyl acetate extracts are washed with saturated sodium bicarbonate (2x) and water (2x), dried (Na 2 SO 4) and concentrated to a yellow oil (6.2 g) Rapid chromatography (Merck Silicon-30 dioxide gel, 2% methanol / methylene chloride yields 3, 2 g of β (+), ksj-1 (benzoylamino) -2-oxo-H-phenylbutyl-7-methyl-glycyl / - (phenylthio) -L-proline, diphenylmethyl ester as a pale yellow foam.

8302562 72 * v * ►. 1.

d) / 1 (+), US / -1- / H - ^ - (benzoylamino) -2-oxo-U-phenyl-buty] J-U-with hylglycyl7 -! + - (phenylthio) -L-proline, monohydrochloride____

The ester product from part (c) (1.6 g, 2.2 nmol) is treated with 2N hydrochloric acid / acetic acid (20 ml). After stirring for 2 hours at room temperature, the reaction mixture is concentrated under reduced pressure and the oily residue is triturated overnight with ether to give 1.2 g / Ί (+), Us7-1-ZIT - /! 3- (benzoylamino) -2 -oxo - ^ - phenylbutyl / -H-methylglycyl7 * * * (phenyl-10 thio) -L-proline, monohydrochloride are obtained as an off-white solid; mp 131-133 ° R ^ 0.38 (silicon dioxide gel, n-butanol / acetic acid / water; U: 1: 1).

's Analysis calculated for Ο ^ Η ^ Η ^ Ο, -δ. HCl. 0.9 HgO: C 60.82; H 5.90; N 6.87; S 5.2U; Cl 5.79. Found: C 60.82; H 5.7¾. N 6.9 ^; S 5.25; Cl 5.75.

Example XCV

(US) -1 - / ϊί- / 5 "(benzoylamino) -2-oxo-U-phenylbutyl-7-methyl-methyl-glycyl - - - (H-fluorophenoxy) -L-proline, monohydrochloride_ 20 a) (Us) - 1- (bromoacetyl) -U- (fluorophenoxy) -L-proline, 1,1-dimethylethyl ester_

Bromoacetic acid (1.0 ^) is added to a solution of (S) - ^ + - (fluorophenoxy) -L-proline, 1,1-dimethylethyl ester (2.1 g, 7.5 mmol) in distilled tetrahydrofura (50 ml). g, 7.5 mmol), hydroxybenzotriazole hydrate (1.1 µg, 7.5 mmol) and dicyclohexyl carbodiimide (1.5 µg, 7.5 mmol). The reaction mixture is stirred overnight, the precipitated dicyclohexyl urea is filtered off and the filtrate is concentrated.

The residue is dissolved in ethyl acetate (50 ml) and washed with saturated sodium bicarbonate (2x), 10% potassium bisulfate (2x) and water (2x), dried (252 SO4) and concentrated to give 3.1 g () -1- (bromoacetyl) -1 * - (fluorophenoxy) -L-proline, 1,1-dimethylethyl ester, are obtained as an oily residue.

35 8302562 73 I'll b) (l | -S) -1- / If-Z3- (benzoylamino) -2-oxo-U-phenylbuty3j-N-methylglycy257-U - (^ - fluorophenoxy) -L-proline, 1,1-dimethyl ethyl ester there

To a solution of (^ S) -1- (bromoacetyl) -U- (fluoro-5-phenoxy) -L-proline, 1,1-dimethylethyl ester (3.0 g, 3.5 mmol) in dimethylformamide (20 ml) (+) - N- / 3 "(methylamino) -2-oxo-1- (phenylmethyl) propyl / composition (2.83 g, 8.5 mmol) are prepared as set forth in Example XCl (b) and diisopropylethylamine (1 3 g, 1.92 ml, 11.0 mmol). After stirring overnight at room temperature, the reaction mixture is poured into water (100 ml) and extracted with ethyl acetate (3x). The combined ethyl acetate extracts are washed with saturated sodium bicarbonate (2x), 10% potassium bisulfate (2x) and water (2x), dried (Na ^ SO ^) and concentrated to a dark residue (5 »5 g) · Fast chromato-15 graph (LPS-1 silica gel, 50% ethyl acetate / methylene chloride) gives 1.2 g (US) -1- / 11- / 3- (benzoylamino) -2-oxo-U-phenylbutyl7 “H-methylglycyl / -U - (1,1-Fluorophenoxy) -L-proline, 1,1-dimethylethyl ester as a pale yellow foam.

c) () -1- / IT- / 3- (benzoylamino) -2-oxo-U-phenylbutyV "20 N-methylglycyl] -4 - (^ - fluorophenoxy) -L-proline, monohydrochloride

The ester product from part (b) (1.2 g, 1.95 mmol) is treated with 2N hydrochloric acid / acetic acid (20 ml). After stirring at room temperature for 2 hours, the reaction mixture is concentrated under reduced pressure and the oily residue is triturated overnight with ether to yield 0.92 g (1 ^) - 1 / 11- / 3- (benzoylamino) -2-oxo -Uf enylbuty3s7-N-methylglycy3] - (U-fluoro-phenoxy) -L-proline, monohydrochloride are obtained as an off-white solid; m.p. 131-1 ^ 0 °. R ^ 0.5 ^ (silica gel, n-butanol / acetic acid / water; 3: 1: 1).

Analysis calculated for * HCl * °> 55 HgO: C 61.2U; H 5.65; N 6.91; Cl 5.83 Found C 61.2 * :; H 5.66; N T, 09; Cl 5.70

Likewise, the method of Examples XCI to XCV can be used to prepare 8302562 i * t f t '*

7U

the compounds of Examples I to XC.

Example XCVI

N- / N- / 3 ”(benzoylamino) -2-oxo-U-phenylbutyl / -N-methyl-glycyl / -N-cyclohexylglycine, monohydrochloride_ 5 a) (+) - N- / 3 ~ (benzoylamino) -2 -oxo-U-phenylbutyl7-N-methylglycine, 1,1-dimethylethyl ester_

To a solution of (+) - N- / 3- (methylamino) -2-oxo-1- (phenylmethyl) propylbenzamide (5.0 g, 15 imnol), prepared as outlined in Example XCI (b) in dimethylformamide (20 ml), bromoacetic acid 1,1-dimethylethyl ester (13.8 g, 3.15 ml, 19.5 mmole) and diisopropylethylamine (2.5 g, 3 ml, 19.5 mmole) are added. After stirring overnight at room temperature, the reaction mixture is poured into water (100 ml) and extracted with ethyl acetate (3x). The combined ethyl acetate extract and 15 are washed with saturated sodium bicarbonate (2x), 10% potassium bisulfate (2x), and water (2x), dried (Na 2 SO 4) and concentrated to a yellow oil, which becomes a dried foam when dried in high vacuum to give 5 µg (+) - N- / 3- (benzoylamino) -2-oxo-it-phenylbutyl7-N-methylglycine, 1,1-dimethyl and ethyl ester.

b) (+) - 11 - / ^ - (benzoylamino) -2-oxo-U-phenylbutyl7-N-methylglycine, monohydrochloride_

The ester product from part (a) (k, 51 g, 11 mmol) is treated with 2N hydrochloric acid / acetic acid (20 ml). After stirring at room temperature for 22 hours, the reaction mixture is concentrated under reduced pressure and the oily residue is triturated with ether to give 3.3 g (+) - 11- / 3- (benzoylamino) -2-oxo-U- phenylbutyl7-N-methylglycine, monohydrochloride are obtained as an off-white solid.

C) N- / li- / 3- (benzoylamino) -2-oxo-U-phenylbuty] 1 / ”N-methylglycyl7-N-cyclohexylglyeine, 1,1-dimethyl ethyl ester_

To a solution of (+) - N- / 3- (benzoylamino) -2-oxo-H - f eny lb ut yl / -IT-with hyl glycine, hydrochloride (1.0 g, 2.6 mmol) 35 in distilled tetrahydrofuran (50 ml), N-cyclohexyl-3302562 75 ', "V, * glycine, 1,1-dimethylethyl ester (0.55 g, 2.6 mmol)" are prepared as set forth in Example LXV (a), hydroxybenzotriazole- hydrate (0.39 g, 2.6 mmol) and dieyclohexylcarbodiimide (0.55 g, 2.6 mmol) are added The reaction mixture is stirred overnight, the precipitated dicyclohexyl urea is filtered off and the filtrate is concentrated. dissolved in ethyl acetate (50 ml) and washed with saturated sodium bicarbonate (2x), 10% potassium bisulfate (2x), and water (2x), dried (lia 2 SO 4) and concentrated to an oily residue (1.5 g). Rapid chromatography (100 g, Merck silica gel 60) gives 0.69 g of 11- / 11- / 3- (benzoylamino) -2-oxo-h-phenylbutyl / -N-with hylglycyl / -N-cyclohexylglycine, 1 , 1-dimethyl ethyl ester as a foam.

d) N- / li- / 3 "(benzoylamino) -2-oxo-U-phenylbutyl / -IT-15 methylglvyl / -N-cyclohexylglycine, monohydrochloride

The ester product from part (c) (0.1 * 8 g, 0.87 mmol) is treated with 2N hydrochloric acid / acetic acid (10 ml). After stirring for 2 hours at room temperature, the reaction mixture is concentrated under reduced pressure and the oily residue is triturated overnight with ether to yield 0.32 g of N - / - 1 - / 3 - (benzoyl-amino) -2-oxo-hf enylbutyl-7-N-methylglycyl / -N-cyclohexylglycine, monohydrochloride obtained as an off-white solid; m.p. 131-1 ^ 5 °. Rj 0.36 (silica gel, n-butanol / acetic acid / water; 1 *: 1: 1).

25 Analysis calculated for. HI . 0.7 H 2 O: C 61.95; H 6.95; N 7.7fc; Cl 6.53

Found: C 61.95; H 6.7 ^; H 7.71; Cl 6.23 Example XCVII

(S) ~ 7- / 71 ((+) - 3- (benzoylamino) -2-oxo-1 * -phenylbutyl7-30 methylaminq / acety2j-1,1 * -dithia-7 ~ azaspiro / l *, k7- nonane-8-carboxylic acid, methyl ester_

To a solution of (+) - H- / 3- (benzoylamino) -2-oxo-4-phenylbutyl-7-methyl-glycine, monohydrochloride (1.0 g, 2.5 mmol), prepared as outlined in Example XCV1 (b ), In distilled tetrahydrofuran (50 ml), (S) -1,1-dithia-7-3302562 ► 7 6 azaspiroA 4-nonan-8-carboxylic acid. methyl ester, monohydrochloride (0.66 g, 2.5 mmol), dicyclohexylcarbodiimide (0.5 µg, 2.5 mmol), hydroxyhenzotriazole hydrate (0.39 g, 2.5 mmol) and diisopropyl ethylamine (0.9 ml, 5 mmol). The reaction mixture is stirred overnight, the precipitated dicyclohexyl urea is filtered off and the filtrate is concentrated.

The residue is dissolved in ethyl acetate (100ml) and washed with saturated sodium bicarbonate (2x) and water (2x), dried (low SO2) and concentrated to a yellow oily residue (1.3g). Rapid chromatography (Merck silica gel, 25% ethyl acetate / methylene chloride, 1% methanol / methylene chloride) yields 0.53 g (S) -7- / 777 +) “3- (benzoylamino) -2-oxo-1-4-phenylbutyl / methylamino / -acetyl / -1, U-dithia-7-azaspiroA, Vnonane, 8-carboxylic acid, methyl ester as a white foam; m.p. 60-62 °. 0.52 15 (silica gel, 5% methanol / methylene chloride).

Analysis calculated for C28 ^ 33 ^ 3 ° 5S2 "^" 33 H ^ O:

C, 59.87; H 6.0 * 4; N 7, 8; S11.22 Found: C, 59.87; H 5.9 **; N 7.56; S 11.36 Example XCVIII

20 (S) -7-f +) - 3- (benzoylamino) -2-oxo- * 4-phenylbutyl / - methylaminoj acetyl7 “1,4-dithia-7-azaspiro A A] nonane-8-carboxylic acid, methyl ester, monohydrochloride

The methyl ester product from Example XCVII (0.26 g, 0.16 mmol) is treated with 2N hydrochloric acid / acetic acid to homogeneous (2 min), concentrated under reduced pressure, and the oily residue is triturated with ether (2x) to give 0, 26 g (S) -7 "/ T / 7 ±)" 3 "(benzoylamino) -2-oxoA-phenylbutyl / methyl-amino Ljac etyl7 ~ 1, * 4-dit hia-7-az aspiro A, k / nonane -8-carboxylic acid, methyl ester. monohydrochloride are obtained as a white solid; m.p. 79 ° 85 ° Rf 0.53 (silica gel, 5% methanol / methylene chloride).

Analysis calculated for. HCl. 0.56 HgO: C 55.8%; H 5.88; N 6.98; S 10.61+; Cl 5.88 Found: C 55.8 * 4; H 5.95; N 6.78; S 10.1 + 3; Cl 5.66 8302562 * r 1 77

Example XCIX

(4s) -1 ** Zn_ / 3- (benzoylamino) -2-oxo-4-phenylbutyl7 "N-methylglycyl7-4- (4-fluorophenoxy) -L-proline, methyl ester, monohydrochloride 5 a) (4S) -4- (fluorophenoxy) -L-proline, methyl ester, monohydrochloride

To a suspension of (4S) -4- (fluoropheno: ^) -L-proline (2.5 g, 11 mmol) in methanol at -30 ° under an argon blanket, thionyl chloride (8.09 ml, 11 mmol) is added . The reaction mixture is stirred at -20 ° for 2 hours, then at room temperature for 16 hours. The solvent is removed under reduced pressure and the residue is redissolved in methylene chloride (150 ml) and washed with 1N sodium carbonate (2x) and water (2x). After drying (MgSO4), excess hydrochloric acid / methanol 15 is added and the solvent is removed under reduced pressure.

Addition of ether gives a light brown solid (2.6 g). Recrystallization from methanol / ether gives 1.49 g of (4S) -4- (fluoro-phenoxy) -L-proline, methyl ester, monohydrochloride as a light brown solid; m.p. 147 ”148 °; [q / ^ = + 6.96 ° 20 (c * 1.55; methanol).

h) (4s) -1- / 11- / 3 "(benzoylamino) -2-oxo-4-phenylbutyl / -N-methylglycyl] -4- (4-fluorophenoxy) -L-proline, methyl ester_

To a solution of (+) - H- / 3- (benzoylamino) -2-oxo-25 4-phenylbutyl7-H-methylglycine, monohydrochloride (1.17 g, 3 mmol) prepared as set forth in Example XCV1 (b), in distilled tetrahydrofuran (20 ml), (4s) -4- (fluorophenoxy) -L-proline, methyl ester, monohydrochloride (θ ', 82 g, 3 mmol), hydroxy-benzotriazole hydrate (0.46 g, 3 mmol) and dicyclohexylcarbo -30 diimide (0.62 g, 3 mmol) was added. The reaction mixture is stirred overnight, the precipitated dicyclohexylurea is filtered off and the filtrate is concentrated. The residue is dissolved in ethyl acetate (50ml) and washed with saturated sodium bicarbonate (2ml) and water (2ml), dried (Ha 2 SO 2) and concentrated to an oily residue (1.1g).

8302562 ► 78 (i t

Rapid chromatography (200 g Merck silica gel 60; 3% methanol / chloroform) yields 0.15 g () -1 - / U - / * 3- (benzoyl-amino) -2-oxo-Uf enylbutyl7 "N-methyiglycyl / - 11 · - (1-Fluorophenoxy) -L-proline, methyl ester as a foam.

5 c) (Us) -1- / IT- / 3 "(benzoylainino)" 2-oxo-U-phenylbuty: i7 "i-methylglycyl7" ii "(1i-fluorophenoxy-2-proline, methyl ester. Monohydrochloride_

The methyl ester product from part (h) (0.15 g, 0.26 mmol) is treated with 2N hydrochloric acid / acetic acid to homogeneous (2 min.), Concentrated under reduced pressure, and the oily residue is triturated with ether (2x) yielding 0.1¾g (hS) -1 - / - - 73- (benzoylamino) -2-oxo-U-phenylbutyl / -N-methyl - {''> glycyl7 ~ ^ - (^ - fluorophenoxy) -L-proline , methyl ester, monohydrochloride as an off-white solid are rained. 105-125 °. 0.27 (silica gel, 5% methanol / chloroform).

Analysis calculated for. HCl C 62.79; H 5.76; H 6.86; F 3.10; Cl 5.79 Found C 62.78; H 5.73; 6.87; F 2.83; Cl 5.33.

Example C

(hS) -1- (e) (S) -3 ~ (benzoylamino) -2-oxo-U-phenylbutyl7 ~ L-alanyl7 ~ 1 | - (^ -fluorophenoxy) -L-proline, monohydrochloride_a) ( S) -11 / 3- (benzoylamino} -2-oxo-U-phenylbutyl7-L-25 alanine. 1,1-dimethylethyl ester V. / To a stirred solution of (S) -i- / 3-chloro-2-oxo -1- (phenylmethyl) propylbenzamide (10.0g, 33.1mmol) in dimethylformamide (80ml) to become L-alanine, 1,1-dimethylethyl ester, hydrochloride (6.0g, 33.1mmol), sodium bicarbonate (6.1 g, 72 mmol) and sodium iodide (U, 9 g, 33.1 mmol) were added.

The resulting solution is stirred at room temperature overnight, poured into ether and washed with water (2x) and 10 µg sodium bicarbonate. The ethereal solution is extracted with 1N hydrochloric acid (3x), the combined extracts are made basic by the addition of solid 8302562 79 1 1 1, 1 sodium bicarbonate and extracted with ethyl acetate (bx). The organic extracts are combined, dried (MgSO4) and concentrated to yield 8.9 g of pale yellow solid. Part of this material is recrystallized from ethyl acetate to give (S) -11- / 3- (benzoylamino) -2-oxo-phenylbutyl7 "L-alanine, 1,1-dimethyl ethyl ester as a white solid; m.p. 106.5 "110 °.

b) (S) -11- / 3 "(benzoylamino) -2-oxo-U-phenylbutyl7-L-alanine, monohydrochloride_ 10 A solution of the ester product from part (a) (2.95 g, 5Λ mmol) in 1 Hydrochloric acid in acetic acid (39 ml) is stirred at room temperature for 2 hours. The white (x precipitate obtained) is collected, rinsed with ether and dried to give 2.27 g of (S) -N- / 3- (benzoylamino) -2-oxo-U-phenylbuty3i-L-15 alanine, monohydrochloride, mp 208 -209 ° (dec.); Fa = -71 ° (c = 0.38% in methanol). 0.51 (silica gel; chloroform / methanol / acetic acid; b: 1: 1).

Analysis calculated for ^ 20 ^ 22¾ ^ ¾ *: C 61.6U; H 5.93; N 7.17; Cl, 9.07. Found: C, 61.33; H 5.97; N 7.17; Cl 8.79 c) (S) -II- / ÏT- (benzoylamino) -2-οχο - ^ - ίenylbutyl7 “N” f [phenylmethoxy) carbonyl7 ~ L-alanine_

Triethylamine (2.1 ml, 15 mmol) is added to a mixture of (S) -11- / 3- (benzoylamino) -2-oxo -) + - phenylbutyl7-L-25 alanine, monohydrochloride (2.0 g , 5.1 mmol), benzyl chloroformate (730yl, 5.1 mmol), water (7 ml) and dioxane (7 ml) at 25 °

The resulting mixture is stirred at 25 ° for 3 hours, after which it is poured into 5% aqueous sodium bicarbonate solution and washed with ether. The aqueous layer is acidified (HCl) and extracted with ethyl acetate (3x). The extract is dried (MgSQ 4) and concentrated to give a colorless oil. Trituration with ether yields a white granular solid (150 mg) which is collected and discarded.

The mother liquor is concentrated in vacuo to yield 1.75 g of 35 (S) -ΙΙ- / ΪΓ- (benzoylamino) -2-oxo-U-phenylbutyl / -If (phenylmethoxy) -8302562. 180 carbonyl J-L-alanine are obtained as a white glass.

d) (US) -1S) -3 "(benzoylamino) -2-oxo-U-phenyl-butyl7-N - / '(phenylmethoxy) carbony37" L-alanyl / -U- (fluorophenoxy) -L-proline phenylmethyl ester 5 A mixture of (S) -N- / II- (benzoylamino) -2-oxo-U-phenylbutyl-7-phenylmethoxy) carbonyl-7-L-alanine (300mg, 0.62mmol), ( 1 * S) -U - (! + - fluorophenoxy) -L-proline, phenylmethyl ester, p-toluenesulfonic acid salt (300mg, 0.62mmol), triethylamine (90yl, 0.62mmol), dicyclohexylcarbodiimide (130mg, 0 , 62 mmol) 10 and hydroxybenzotriazole hydrate (90 mg, 0.62 mmol) in tetrahydrofuran (7 ml) is stirred at 25 ° C for 20 hours, the mixture is then filtered and diluted with ethyl acetate. washed with 1n, hydrochloric acid and 10% aqueous sodium bicarbonate solution, dried 15 (MgSO4), filtered and concentrated to give 500 mg (Us) -1-βΧ-Π S) “3” (benzoylamino) -2-oxo-Uf enylbutyl7 ”' H - / '(phenylmethoxy) carbonyl7-L-alanyl7-1 + - (U-fluorophenoxy) -L-proline, phenyl with methyl ester obtained as a whitening gel e oil ..

e) (bS) -1- / 11-7 (8) -3 "(benzoylamino) -2-oxo-H-phenyl-butyl7-L-alanyl7_J +" (^ -fluorophenoxy) -L-proline, monohydrochloride_

A mixture of the ester product from part (d) (500mg, 0.6mmol), palladium on carbon catalyst (10 #, 100mg), absolute ethanol (15ml) and 1.0n aqueous hydrochloric acid (800µl, 0.05g). 8 mmol) is hydrogenated at 1 at 25 ° C for 17 hours, after which it is filtered and concentrated. The residue is chromatographed on HP-20 with a linear gradient from (9: 1, 0.01 n aqueous hydrochloric acid: methanol) to (1: 1, 0.01 n aqueous hydrochloric acid: methanol). Fraction containing the desired product (TLC) is combined and concentrated. The residue is dissolved in a minimum amount of methanol. Ether is added to form a white precipitate, which is collected and dried in vacuo, yielding 200 mg (! + S) -1- / -1- / "(S) -3" (benzoylamino) -2-oxo- -phenylbutyl / -L-alanyl- (U-fluorophenoxy) -35 L-proline, monohydrochloride; mp 152-153 ° (dec.); £ 7 = 8302562; * 81 "50 ° (c = 0.5; methanol). R 0.75 (silica gel, chloroform / methanol / acetic acid, U; 1: 1) are obtained.

Analysis calculated for ^ 31 ^ 32 ^ 3 ^ 6 * ^ Cl1.5 H ^ O: C 59.57; H 5.80; n 6.72; ci 5.67 Found: C 59.68; Η 5.5β; N 6.67; Cl 5.99 Example Cl ^ (S), Ur / - 1 - / & - / 3- (benzoylamino) -2-oxo-phenyl-butyl-L-alanyl-7-phenyl-Ir-proline, monohydrochloride_ a) ( S) -N- / IT- (benzoylamino) -2-oxo-phenylbutyl / -N- 10 H phenylmethoxy) carbonyl / L-alanine succininidoester

A mixture of (S) -Ν- / ΪΓ- (benzoylamino) -2-oxo-U-phenyl-butyl7 "I- / T phenylmethoxy) carbonyl7-L-alanine (800 mg, 1.6 mmol) prepared as set forth in Example C (c), dicyclohexylcarbo-15 diimide (3 mg, 1.6 mmol) and N-hydroxysuecinimide (190 mg, 1.6 mmol) in tetrahydrofuran (5 ml) is stirred at 25 ° for 18 hours. After this time, it is filtered and concentrated to yield 950 mg (s) -N- / N- (benzoylamino) -2-oxo-U-phenyl-butyl / -11- / 7-phenylmethoxy) carbonyl / -L-alanine, suecinimido ester 20 are obtained.

b) / “1 (S), UR / -1- / 11- / 3- (benzoylamino) -2-oxo - ^ - phenyl-butyl / -N - / '(phenylmethoxy) c & rbonylJ-L-alzriylJ-b -phenyl-L-proline _

To a solution of (S) -N- / - (benzoylamino) -2-25 oxo-U-phenylbutyl-7-II- / 7-phenylmethoxy) carbonyl-L-alanine, suecinimido ester (950 mg, 1.6 mmol) in dimethylformamide (5ml), (IfR) -U-phenyl-L-proline, hydrochloride (375mg, 1.7mmol) and triethylamine (b0x1, 3.2mmol) are added. The resulting mixture is stirred at 25 ° for 2 hours, after which it is poured into excess 1N hydrochloric acid and extracted with ethyl acetate (3x). The extracts are combined, dried (MgSO4), filtered and concentrated to give 1.1 g / 1 (S), Ur7-1- / II- / 3- (benzoylamino) -2-oxo-U-phenylbutyl / -II- / (phenylmethoxy) carbonyl] -L-alanyl-7-phenyl-L-proline.

3302562 t ''> 82 c) Z “1 (S), HR / - 1 - / H- £ 3” (benzoylamino) -2-oxo - ^ - phenyl-butyl / -L-alanyl / -H-phenyl- L-proline, monohydrochloride

The product from part (b) (1.0 g, 1.5 mmol), ethanol (20 ml), water (5 ml), 1.0 n hydrochloric acid (1.5 ml, 1.5 mmol), and palladium on a catalyst (10% 3 100 mg) is hydrogenated for 18 hours at 1 at 25 °, after which it is filtered and concentrated. The residue is chromatographed on HP-20 using a linear gradient (0.01n aqueous hydrochloric acid methanol, U0: 60 to 10:90). Fraction containing the desired product (TLC) is combined and concentrated. The residue is dissolved in a minimum amount / methanol. Ether is added and the white precipitate formed is collected and dried to give 300 mg / * 1 (S), Hr / -1 (benzoylamino) -2-oxo-Uf enylbutyl J-L-alanyl-phenyl-L-proline, monohydrochloride; m.p. 160-162 ° (dec.); [α - -57 ° (c = 1.5 µm methanol) are obtained. Rf 0.8 (silica gel; chloroform / methanol / acetic acid; U: 1: 1).

Analysis calculated for ^ 31 ^ 33 ^ 3 ^ 5 · HCl. 1.35 H 2 O: c 63.27; H 6.29; H 7.1 ^; ci 6.02 Found: C, 63.27; H 6.17; H 7.19; Cl 5.97 Example CII

[\ (S), ^ 3 / -1- / ΐΤ- / 3 ”(benzoylamino) -2-oxo-kf-enylbutyl / -L-alanyl-7-phenyl-L-proline, monohydrochloride According to the method of Example C1 but using (Us) -H-phenyl-L-proline, hydrochloride in part (b), Z "1 (S), 1 + S / -1- / -1- / 2- (benzoylamino) -3 is obtained Oxo-U-phenyl-butyl / -L-alanyl / - - - phenyl-L-proline, monohydrochloride; mp 138-1 ^ 3 °; fa ^ * -6l ° (c = 0.3% in methanol) R ^ 0.8¾ (silica gel, chloroform / methanol / acetic acid, U: 1: 1).

Analysis calculated for ^ 31 ^ 33 ^ 30 ^ HCl. 2.13 HgO:

C, 61.80; H 6.35; N 6.98; Cl 5.88 Found: C 61.80; H 6.06; H 7.05; Cl 5.65 Example CIII

/ l (S), i + R / -1 - / 5- / 3- (benzoylamino) -2-oxo - ^ - phenylbutyl / -L-alanyl / -H-cyclohexyl-L-proline, monohydrochloride 8302562, "; 83

According to the method of example C1 but using () - ^ - cyclohexyl-L-proline, hydrochloride in part (b), / 1 (S), UR / -1- / -1- / 3- (benzoylamino) - 2-oxo-1; -phenylbutyl / -L-alanyl / -k-cyclohexyl-L-proline, monohydrochloride j.

5 m.p. 1 ^ 0-15 ^ ° (dec.); / a = * -83 ° (c = 0.36% in methanol).

R ^ 0.8H (silica gel; chloroform / methanol / acetic acid;

Analysis calculated for C-H-II-O-. HCl. 0.79 H2: 31 39 3 5 E C 63.71; H 7.17; S 7.19; Cl 6.06 Found: C 63.71; H 7.21; N 7.05; Cl 5.82

Example CIV

/ ï (s) 1- / ï- / 3- (benzoylamino) -2-oxo-^ -phenylbutyl-L-alanyl-7-cyclohexyl-h-proline, monohydrochloride '} Using the method of Example C1 but using Making (1 * S) -4-cyclohexyl-L-proline, hydrochloride in part (b), / Ms), I + S / -1- / II- / 3- (benzoylamino) -2- oxo-11-phenylbutyl7-L-alanyl / -1-cyclohexyl-L-proline monohydrochloride; m.p. 139 “1 ^ 1 ° (dec.); [mpg] = -80 ° (c = 0.2% in methanol).

R ^ 0.83 (silica gel; chloroform / methanol / acetic acid; 20 U: 1: 1).

Analysis calculated for * HCl 1 »5 ^ H ^ O:

C 62.28; H 7.26; N 7.03; Cl 5.93 Found C 62.28; H 7.01; N 7.02; Cl 6.16 Example CV

25 (S) -7 "/ * (S) -2 - // 3- (benzoylamino) -2-oxo-U-phenylbutyl / - amino / -1-oxopropyl7-1, U-dithia-7" azaspiro A, Non-8-carboxylic acid, monohydrochloride_

According to the method of Example C1 but using (S) -1, U-dithia-7-azaspiroA, 7-nonan-8-carboxylic acid hydrochloride in part (b) for the L-proline reaction participant, (S) ~ 7 is obtained "/ (S) -2 - // 3- (benzoylamino) -2-oxo-U-phenyl-butyl / amino7-1-oxopropyl7-1, ^ -dithia-7 ~ az aspiro [k ^ / ηοηβ ^ Χί- β-25 o carboxylic acid, monohydrochloride; m.p. 170-172 °; / et = -26 ° (c = 1, U% in methanol). R 0.73 (silica gel; 35 chloroform / methanol / acetic acid; 6: 1: 1).

8302562 8¾ * *. Λ 1

Analysis calculated for. HCl. 0.7TH20:

c 5 ^ 77; H 5.71; N 7.10; S 10.83; Cl 5.99 Found: C 5 ^ 77; H 5.70; N 6.9b; S 10.82; Cl 6.07 Example CVI

5 Z "1 (S), 5S7 ~ 1 ~ / tI- / ~ 3 ~ (benzoylamino) -2-oxo-U-phenylbutyl-L-alanyl7-U, 5-dihydro-3" phenyl-1H-pyrazole-5 Carbonic acid, monohydrochloride

According to the method of Example C1 but using (S) -5,5-dihydro-3-, phenyl-1H-pyrazole-5 * -carboxylic acid 10 for the L-proline reaction participant in part (b), the said link.

Example CVII

^ ') (S) -2- / 11- / 7S) -3 ”(benzoylamino) -2-oxo - ^ - phenylbutyl7-L-alanylJ-1,2,3, ^ - tetrahydro-3“ isoquinolinecarbonic acid, * Monohydrochloride

According to the method of Example C1 but using (S) -1,2,3,1-tetrahydro-3-isoquinoline carboxylic acid, hydrochloride in part (b) instead of the proline reaction participant, (s) -2 is obtained - / fr -, / (S) -3 "(benzoylamino) -2-20 oxo-U-phenylbutyl / -L-alanyl-1,2,3, U-tetrahydro-3-isoquinoline carboxylic acid, monohydrochloride.

Example CVIII

1- (II- / TS) -3 ”(benzoylamino) -2-oxo-U-phenylbutyl / -L-alanyl / -2- (2-hydroxyphenyl) —U (R) -thiazolidine carboxylic acid, 25 monohydrochloride - According to the method of Example C1 but using 2- / 7-2-phenylmethoxy) phenylJ-b (R) -thiazolidine carboxylic acid, hydrochloride in part (b) instead of the proline reaction participant is obtained after removal of hydroxy protection group 30 1S) -3 "(benzoylamino) -2-oxo-1 + -phenylhutyl / -L-alanyl / -2-hydro (2-hydroxyphenyl) MR) -thiazolidine carboxylic acid, monchloride

Likewise, the methods of Examples XCVI, XCVII, XCIX and C to CVIII can be used to prepare the compounds of Examples I to XCV.

8302562: * -85

Example CIX

(+.) - 1- / 1- / 3- (henzoylamino) -2-oxo-1 | -f enyrbutyl / -L-alanyl7-L-oroline, methyl ester, monohydrochloride a) 1 - /! T- (2- ethoxy-2-oxoethyl) -IT-phenylmethoxy) -5 carbonyl7-L-alanyl <7-L-proline, 1,1-dimethyl ethyl ester L-alanyl-L-proline, 1,1-dimethylethyl ester (25. g, 105 mmol) is taken up in tetrahydrofuran (0000 ml) with stirring. To this is added bromoethyl acetate (11t6h ml, 105mmol) and diiso-10 propylethylamine (18.3ml, 105mmol). After 6 hours, the reaction mixture is cooled in an ice bath and benzyl chloroformate (16.5ml, 115.5mmol) and diisopropylethylamine (20.1ml, 115.5mmol) are added. After 1 hour, the ice bath is removed and the reaction mixture is kept at room temperature overnight. It is then concentrated to dryness, taken up in ethyl acetate and washed neutral with 10% potassium bisulfate and saturated sodium bicarbonate. The crude product (52.3 g) is purified on a silica gel column and eluted with ethyl acetate-hexane (1: 1) to give k2, hg of 20 l-^ (2-ethoxy-2-oxoethyl) -N - / "(phenylmethoxy) carbonyl7-L-alanyl, 17'-L-proline, 1,1-dimethylethyl ester are obtained.

b) 1 - / & - (carboxymethyl) -11 - / (phenylmethoxy) carbonyl7-L-alanyl7-L-proline, 1,1-dimethylethyl ester_

The ester product from part (a) (21 g, ,5, U mmol) is taken up at room temperature with stirring in methanol (150 ml) V ... and 1N sodium hydroxide (50 ml, 50 mmole). After 5 hours, the methanol is removed in vacuo and the aqueous portion is extracted with ethyl acetate. The aqueous portion is acidified with concentrated hydrochloric acid and extracted with ethyl acetate to give 16.95 g of 1 - / iT - (carboxymethyl) -H- (phenyl methoxy) carbonyl / "L-alanyl7-L-proline, 1,1-dimethyl ethyl ester obtained.

8302562

V

[86 * lic) (+) - 1-4- / 3- (3-benzoylamino) -2-oxo-phenyl-butyl 2-N-phenyimethoxy) carbonyl-7-alanyl-7-proline - 1 „1-dimethylethyl ester_

The ester product from part (b) (10.0 g, 23 mmol) is taken up in tetrahydrofuran (75 µl) with stirring in an ice city.

To this oxalyl chloride (2, k ml, 27.6 mmol) is added dropwise, followed by 15 drops of dimethylformamide. After 20 minutes, the ice bath is removed and the reaction mixture is kept at room temperature for 1 hour. The mixture is then concentrated in vacuo to dryness and taken up in tetrahydrofuran (bo ml) with stirring in an ice bath. To this is added 2-phenyl-U- (phenylmethyl.) 5 (UH) -oxazolone (6g, 23.8mmol) in tetrahydrofuran [) (35ml) dropwise, followed by triethylamine (3.22ml, 23mmol) ). Additional triethylamine is added to maintain a basic environment. After 20 min. The ice bath is removed and the reaction mixture is kept at room temperature overnight. The triethylamine hydrochloride is filtered off and the filtrate is concentrated to dryness in vacuo. The residue is taken up in pyridine (25 ml) and U-dimethylamine pyridine (75 mg) is added and the solution is stirred under an argon blanket for 3 hours. Acetic acid (25 ml) is added and the reaction mixture is stirred at 100 ° under positive argon flow for 5 min. The reaction mixture is concentrated to dryness, taken up in ethyl acetate and washed neutral with saturated sodium bicarbonate and dilute hydrochloric acid. The crude product (12.8 g) is chromatographed on silica gel and eluted with ethyl acetate: hexane (1: 1) to give 9.05 g (+) - 1 / N -, 3 - (benzoylamino) -2- oxo-1-phenylbutyl / -N - / (phenyimethoxy) carbonyl-7-alanyl / -L-30 proline, 1,1-dimethyl ethyl ester are obtained.

d) (+,) - 1 - / II- / N- / 3- (benzoylamino) -2-oxo-1 + -phenylbutyl7-N- / T phenyimethoxy) carbonyl7-L-alanyl7-L-prolxne

The ester product from part (c) (11 µg, 17.7 mmol) is taken up in trifluoroacetic acid (50 ml) and kept at room temperature for 5 min. It is then concentrated to dryness and triturated with ether: hexane to yield 10.3 g of crude product. This material is purified on a silica gel column in benzene / acetic acid (8: 2) to yield 9, T g (+,) - 1 - /?! - /?! - / 3- (benzoylamino) -2-oxo-l + - phenylbutyl-3 (phenyl-5-methoxy) carbonyl-7-alanyl-1-L-proline; mp 70-91 °; [O. = 53.0 (c * 1.22; methanol). R ^. 0.1 + 1 (silica gel, benzene / acetic acid; 8: 2).

Analysis calculated for C 67.68; H 6.02; ff 7.17. Found: C 67.95; H 6.02; ff 6.82 e) (+) -1- / ff- / ff- £ 3 "(benzoylamino) -2-oxo-U-phenylbutyl] - ff- / T phenylmethoxy) carbonyi / -L-al anylj -L- pr ol in e, "j methvlester

The acidic product from part (d) (3.5 g, 6 mmol) is taken up in dimethylformamide (12 ml) with stirring at room temperature. Sodium bicarbonate (630 mg, 7.5 mmol) and methyl iodide (0.1 + 7 ml, 7.5 mmol) are added to this. After 18 hours, additional methyl iodide (T, b mmol) and sodium bicarbonate (7.1+ mmol) are added, stirring for an additional 1+ hours, the reaction mixture is concentrated in a vacuum to dryness, taken up in ethyl acetate and washed with saturated sodium bicarbonate. .

The crude product (3.7 g) is purified on a silica gel column in ethyl acetate: hexane (2: 1) to give 3.5 g (+) -1 £ 3- (benzoylamino) -2-oxo-1 + -phenylbutyl / - ff-, (phenyl-methoxy) carbonyl / -L-alanyl] -L-proline, methyl ester are obtained.

f) (+) "1 (benzoylamino) -2-oxo-1 + -phenylbutyl / -L-alanyl7-L-proline, methyl ester. monohydrochloride

The ester product from (e) (900mg, 1.5mmol) is taken up in ethanol (95ml, 100ml) and 1N hydrochloric acid (1.8ml).

Palladium on carbon catalyst (10%, 180 mg) is added and the reaction mixture is stirred under hydrogen overnight. The reaction mixture is filtered to remove the catalyst, concentrated to dryness and 2x 35 lyophilized from water to yield 700 mg (+) - 1- / S- / 3 "(benzoyl-3302562 0 88 t · 1 amino)" 2 "oxo- H-phenylbutyl7 "L-alanyl7-L-alanyl7" L-proline, 23 methyl ester, monohydrochloride; m.p. 110-128 ° (90 °); [α] “--69 699 ° (c * 1.18, methanol) are obtained. R ^ 0.63 (silica gel, chloroform / methanol / acetic acid; 9: 1: 1).

5 Analysis calculated for ^ 36 ^ 31 ^ 3 ^ 5 * * ^ 2 ^ 2 H 2 O: C 60.22; H 6.58; N 8.11; Cl 6.8k Found: C 60.22; H 6.28; N 8.10; Cl 7.06 «

Example CX

(+) -1 - / ^ - / 3- (benzoylamino) -2-oxo-ii-phenylbutyl / -L-10 alanyl 7-L-proline, methyl ester, monomethanesulfonate (+) -1 - / ^ 1- / 11 - / 3- (benzoylamino) -2-oxo-1 + -phenylbutyl7-11- / (phenylmethoxy) carbonyl / -L-alanyl] -L-proline, methyl ester) (600 mg, 1 mmol) prepared as set forth in Example CIX ( e) taken up in methanol (60 ml) and methanesulfonic acid * 15 / (0.066 ml, 1 mmol). Palladium on carbon catalyst (120 mg) is added and the reaction mixture is stirred under hydrogen for 2 hours. The reaction mixture is filtered to remove the catalyst and then concentrated in vacuo. The crude product is triturated with ether and filtered. The precipitate is taken up in water and lyophilized to give VfO mg (+) -1 - /! L- / 3 "(benzoylamino) -2-oxo - ^ - phenylbutyl7" L-alanyl, 7-L-proline, methyl ester, monomethanesulfonate ; m.p.

80-1i + 0 °; fa = -61, U ° (c = 1.10; methanol) are obtained. Rj 0.63 (silica gel, chloroform / methanol / acetic acid; 9: 1: 1).

f '

K Analysis calculated for ¢ 36 ^ 31 ^ 3 ^ CH ^ O S

C, 56.98; H 6.3 * 1-; H 7.30; S 5.63 Found: C 56.98; H 6.32; N 7, 7; S 5.63 Example CXI

30 (+) -1 - / I- / 3- (benzoylamino) -2-oxo-Uf enylbutyjJ-L-alanyl7-LT> roline, methyl ester, hemisulfate_ (+) -1 - / N- / 5r- / 3 " (benzoylamino) -2-oxo-Uf enylbutyl7-N - / "(phenylmethoxy) carbonyl / -L-alanyl / -L-proline, methyl ester (600 mg, 1 mmol), prepared as set forth in Example CIX (e) .35 is taken up in methanol (10 ml) together with 1 N sulfuric acid 8302562 89. L τ. (0.9 ml). Palladium on carbon catalyst (10 #, 120 mg) is added and the reaction mixture is stirred under hydrogen for 2 hours. The reaction mixture is filtered to remove the catalyst, concentrated to dryness, triturated with ether and filtered The crude product (Mi6 mg) is taken up in water, filtered to millipore, and lyophilized to give U05 mg (+) - 1- / N - / 3 ** (benzoylamino) -2-oxo-k-phenyl-tutyl / -L-alanyl7 "L-proline, methyl ester, hemisulfate; m.p.

98 - 112 ° (85 °); Α = -60.3 ° (c * 1.16; methanol) are obtained. 0.63 (run out) (silica gel, chloroform / methanol / acetic acid; 9: 1: 1).

Analysis calculated for. 0.5 H 2 SO 2. 0.91Hg0:. - C 58.81; Ξ 6, h2; N 7.92; S 3.01 'Found: C 58.81; H 6.11; 7.91; S 3.09

15 Example CXII

(+) - 1-Zfo-Z3- (benzoylamino) -2-oxo-phenylbutyl] -1-alanyl [alpha] -L-proline. propyl ester, monomethanesulfonate a) (+) - 1 - /! i- / li- / 5 "(benzoylamino) -2-oxo-U-phenylbufcyl-7-enylmethexy) carbony3j-L-alanyl7" L-proline, + 20-propyl ester (+ ) -1- / tt-ZS-ZS- (benzoylamino) -2-oxo-U-phenylbutyl7 “H” [{phenylmethoxy) carbonyl / -L-alanyl7-L-proline (1.17 g, 2 mmol) prepared as set forth in Example XCIX (d) under stirring in an ice bath taken up in tetrahydrofuran (2ml). To this is added n-propanol (3.0 ml, U0 mmol), followed by (U-dimethylaminopyridine (122 mg, 1 mmol) and dicyclohexylcarbodiimide (I412 mg, 2 mmol). The reaction is allowed to warm to room temperature and Run overnight The dicyclohexylurea is filtered off and the filtrate is concentrated to dryness in vacuo.

The crude product (1.2 g) is chromatographed on a silica gel column in benzene-acetic acid (9: 1) to give 1.0 g (+) -1- / K-X- / 3- (benzoylmino) - 2-oxo-h-phenyl-butyl-N - [{phenylmethoxy) carbonyl-7-alanyl / -L-proline, propyl ester is obtained.

8302562 / * 1 90 b) (+) - 1 - /! N- / 3 "(benzoylamino) -2" 0X0-U-phenylbutyl7 "L-alanyl7-L-proline, propyl ester, monomethane sulfonate_

The ester product from part (a) (500mg, 0.8mmol) is taken up in methanol (50ml). Methanesulfonic acid (0.72 ml of a 1 n solution in methanol) and palladium on carbon catalyst (10 #, 100 mg) are added and the reaction mixture is stirred under hydrogen overnight. The reaction mixture is filtered to remove the catalyst, concentrated to dryness, triturated with ether and filtered to give 106 mg of crude product. This is taken up in water, filtered with millipore, and lyophilized to give 390 mg (i) -1 ~ ^ "Z3" (t> enzoylamino) "2-oxo" ^ - phenylbutyl7-L-alanyl-L-proline, propyl ester, monomethane-15 sulfonate; m.p. 82-9 ° (69 °); / a = 60.5 ° (c = 0.95; methanol is obtained). 0, H6 (silica gel, chloroform / methanol / acetic acid; 90: 5: 5)

Analysis calculated for · CH ^ O ^ S. 0.5 H2 O: C 58.15, H 6.73; H 7.01; s 5.3¾ 20 Found: C 58.15; H 6.63; H 7.05; S 5.3¾

Example CXII

(+) - 1- / 3- (3-benzoylamino) -2-oxo-U-phenylbutyl7 "L-aanyl-L-nroline, ethyl ester, monomethanesulfate a) (+) -1 (benzoylamino) -2-oxo -H-phenylbutyl7 -25-7- / 7-phenylmethoxy) carbonyl / -L-alanyl7-L-proline, ethyl ester_ (+.) - 1 -ΖΗ- / ΐί-Ζ3 "(benzoylamino) -2-oxo-phenylbutyl-N - / ^ phenylmethoxy) carbonyl / -L-alanyl / -L-proline (1.17 g, 2 mmol), prepared as outlined in example CIX (d), is taken up in tetrahydrofuran (2 ml) with stirring in an ice bath (30 ml) . Absolute ethanol (2.3 ml, 00 mmol) is added thereto, followed by U-dimethylaminopyridine (122 mg, 1 mmol) and dicyclohexylcarbo-diimide (U12 mg, 2 mmol). The reaction is allowed to proceed overnight at room temperature. The dicyclohexylurea is filtered off, the filtrate is concentrated to dryness, the 3302562 rf * 91 residue is taken up in ethyl acetate and washed neutral with 10% potassium bisulfate and saturated sodium carbonate. The crude product (1.2 g) is purified on a silica gel column in henzene: acetic acid (8: 2) to give 1.0 g (+) - 1 ~ / ΪΓ-βϊ- / 3-5 (benzoylamino) -2 -oxo-1 * -phenylbuty] J-1 - / '(phenylmethoxy) carbonyl7-L- - alanylJ-L-proline, ethyl ester.

b) (+) - 1- / Sl- / 3 ~ (benzoylamino) -2-oxo-U-phenylbutyl-L-alanylT-L-nroline, ethyl ester, nonomethanesulfate The ester product from part (a) (500 mg, 0.811 *) 7 mmol) 10 is taken up in 50 ml of methanol-methanolic methanesulfonic acid (1η, 0.733 ml). Palladium on carbon catalyst (100 mg) * is added and the reaction mixture is stirred under a positive hydrogen pressure for 3 hours. The reaction mixture is filtered to remove the catalyst, concentrated to dryness, triturated with ether and filtered. The precipitate (U28 mg) is taken up in water, filtered to millipore and lyophilized to give 3 & 0 mg (+) - 1 - / Η-.Γ3 "(benzoylamino) -2-oxo-1 * -phenylbutyl7" L-alanyl / -L "Proline, ethyl ester, mono-methanesulfonate; mp. 91" 96 ° (72 °) · / et - "57" 2 ° (c = 1.0l *; 20 methanol) are obtained. Rf 0.1 * 1 * (silica gel, chloroform / methanol / acetic acid; 90: 5: 5)

Analysis calculated for ^ 27 ^ 33 ^ 3 ^ 5 * * ^ 1 * ^^ 3 * H ^ O:

C, 57.33; H 6.56; 5 7.17; S 5.37. Found: C, 57.33; H 6.1 * 3; II 7.12; S 5.1 * 7-25 Example CXIV

(j ^) -1 (benzoylamino) "2-oxo-1 * -phenylbutyl-L-alanyl-L-proline, 1-methyl ethyl ester, monomethane sulfonate a) (+) -1 - / 11- / 11- / 3 - (benzoylamino) -2-oxo-1 * -phenylbutyl / -30 phenylmethoxy) carbonyl7-L-alanyl7-L-proline, 1-methyl ethyl ester (+,) - 1 - / & - / H- / 3- (benzoylamino) -2-oxo-1 * -phenylbutyl / -II- / 7-phenylmethoxy) carbonyl7 "L-alanyl7" L "proline (1.17 g, 2 mmol), prepared as outlined in Example CIX (d), and isopropanol 35 (3 .0 ml, 1 * 0 mmol) are taken up in an ice bath with stirring 3302562

? V

92 in tetrahydrofuran (2 ml). Dicyclohexylcarbodiimide (12 12 mg, 2 mmol) is added thereto. The reaction is allowed to proceed overnight at room temperature. It is then concentrated to dryness, taken up in ethyl acetate and the dicyclohexylurea is filtered off. The filtrate is washed neutral with 10% potassium bisulfate and saturated sodium bicarbonate. The crude product (1.2 g) is purified on a silica gel column with benzene: acetic acid (8: 2) to give 1.0 g (+) - 1- $ T- / -1- / 3 "(benzoyl-amino) -2 -oxo-U-phenylbutyl / -N - / (phenylmethoxy) carbonyl7-L-alanyl7-10 L-proline, 1-methyl ethyl ester.

b) (+) - 1 - / ΪΓ- / 3- (benzoylamino) -2-oxo - ^ - phenylbutyl / - L-alanyl7 "L-proline, 1-methyl ethyl ester, monomethane y sulfonate_

The ester product from part (a) (815 mg, 1.3 mmol) is taken up in methanol (20 ml) and methanolic methanesulfonic acid (1η, 1.17 ml) and stirred under hydrogen for 3 hours in the presence of palladium on carbon catalyst ( 10 #, 160 mg).

The reaction mixture is filtered to remove the catalyst and concentrated to dryness in vacuo. The residue is triturated with ether and the precipitate is filtered to give 70 µg of crude product. This is taken up in 35 ml of water (2% solution), filtered on millipore and lyophilized to give 600 mg (+) - 1- / II- / 3 ”(benzoylamino) -2-oxo-^ -phenylbutyl / -L-alanyl7- L-proline, 1-methyl ethyl ester, monomethanesulfonate; m.p. 88-105 °; £ cc ~ ”55 * 2 ° (c = 1.05; (" methanol) are obtained. 0.33 (silica gel, chloroform / methanol / acetic acid; 9: 1: 1) ·

Analysis calculated for C28 ^ 35 ^ 3 ° 5 'Η ,, Ο: c 57.89; H 6.75; N 6.99; s 5.33. Found: C, 57.89; H 6.62; N 6.62; S 5.32

Examples CXV - CXXIII

Following the method of Examples XIX, CXII, CXII and CXIV, (+) - 1- ^ 1- £ $ - (benzoylamino) -2-oxo-U-phenyl-butyl / -U - /? (Phenylmethoxy) carbonyl / -L-alanyl7 "L-proline treated with the reaction participant as shown in column 1 below.

8302562 93

1 A

- V

Removal of the alanyl protecting group yields the ester product as shown below in column 2.

4 8302562. - 9b.-Column 2

The formula 1c on the formula sheet

Example column 1 Rg O o CXV Cl-CH-0-CrC2H5 -ch-o-c-c2H5 ό ό 'o o

8 II

CXVI Cl-CH-O-C-C H -CH-O-C-C H

I I

CH (CH3) 2 CH (CH3) 2 o o ii · i ΠΠ1 ci-ch2-o-c-c (ch3) 3 -ch2-o-c-c (ch3> 3 ’o o

II II

CXVIII Br-CH -O-C-CH, -CH -O-C-CH

8302562 * .1> - - 95 -

Example column 1 Rg o h CXIX C1-CH2-0-C- ^ o) -CH2-0-C- @ o o

ll H

cxx i-ch2-c-oc (ch3) 3 -ch2-c-o-c (ch3) 3 CH O CH o I 3 ll I 0 CXXI I-C- C-0-CH3 -c --C-0-CH3

I I

CH, 'CH,? j * l.

. *.

CXXII CH- (CH2-O-CH2r ^ ©} 2 -CH (CH ^ OH ^

OH

CH, -CH - CH -CH -CH — CH

I I I II

OH O O OH OH

CXXIII | j- * 2C- © H2C- @ 8302562 9β £ v

Example CXXIV

1- / II - / '(S) -3 "(benzoylamino) -2-oxo - ^ - phenylbutyl7- L-alanyl7-L-proline, sodium salt__ 1 - / & * £ (S)" 3 "(benzoylamino) - 2-oxo-H-phenylbutyl-L-5-alanyl7-L-proline, hydrochloride mg, 1 mmol) is dissolved in water (50 ml). Aqueous sodium bicarbonate (0.1 n, 20 ml) is added and the aqueous solution is lyophilized. It is then dissolved in water (10 ml) and applied to a column (5 cm x 60 cm) of Sephadex chromatographic gel 10 G-10 and elute <5 water. Practices containing the desired product are combined and lyophilized to yield 1- / 15- (3) -3- (benzoylamino) -2-oxo-phenylbutyl-7-alanyl-7-proline, sodium salt.

Example CXXV

15 '1000 tablets each containing the following ingredients 1 - / N - / * (S) -3- (benzoylamino) -2-oxo-U-phenylbutyl J-L-alanylZ-L-proline, sodium salt 100 mg 20 corn starch 50 mg gelatin 7.5 mg

Avicel (microcrystalline cellulose) 25 mg of magnesium stearate 2.5 mg are prepared in sufficient amounts by the 1- / N - / "(s) -3" 25 (benzoylamino) -2-oxo-U-phenylbutyl7-L-alanyl7 "L -proline, sodium 1 salt and corn starch to be mixed with an aqueous solution of the gelatin The mixture is dried and ground to a fine powder The Avicel and then the magnesium stearate are mixed under granulation This mixture is then compressed in a tablet press to form 1000 tablets each containing 100 mg of the active ingredient.

In such a manner, tablets containing 100 mg of the product of any of Examples I to CXXIII can be prepared. Such a method can be used to form tablets containing 50 mg of active ingredient 8302562 97 r - 'r' V -.

Example CXXVI

Two-part No. 1 gelatin capsules, each containing 50 mg) -3 "(benzoylamino) -2-oxo-phenylbutyl-L-alanyl7-L-proline, sodium salt, are filled with a mixture of 5 of the following ingredients:) - 3 "(benzoylamino) -2-oxo-U-phenyrbutyl7-L-alanyl7-L-proline, sodium salt 50 mg magnesium stearate 7 - mg 10 lactose 193 mg * 250 mg

In such a manner, capsules containing 50 mg of the product of any of Examples I to CXXIII can be prepared.

15 Example CXXVII

An injectable solution is prepared as follows: 1- / II- / t S) -3- (benzoylamino) -2-oxo-U-phenylbutyl / -L-alanyl7-L-proline, sodium salt 500 g 20 methyl paraben 5 g propyl paraben 1 g sodium chloride 25 g water for injection 5 1

The active substance, preservatives and sodium-25 chloride are dissolved in 3 l of water for injection and then the volume is brought to 5 l. The solution is filtered through a sterile filter and aseptically filled into pre-sterilized vials closed with pre-sterilized rubber stopper. Each vial contains 5 ml of solution 30 at a concentration of 100 mg of active ingredient per ml of solution for injection.

In such a manner, an injectable solution containing 100 mg of active ingredient per ml of solution can be prepared for the product of Examples 1 to 35 8302562 98 fc. r * r. * * CXXIIÏ.

Example CXXVIII

1000 tablets, each containing the following ingredients: 5 1- / N- (S) -3 "(benzoylamino) -2-oxo- * H-phenylbutyl / -L-alanyl7-L-proline, sodium salt 100 mg

Avicel 100 mg hydrochloric acid hiazide 12.5 mg 10 lactose 113 mg corn starch 17> 5 mg stearic acid 7 mg 350 mg are prepared in sufficient amounts by the 1-P &-3 (15) (benzoylamino) -2 -oxo-U-phenylbutyl7 "L-alanyl7" L-proline, sodium salt, Avicel and part of the stearic acid to be chopped. The chunks are ground and passed through a No. 2 sieve and then mixed with the hydrochlorothiazide, lactose, corn starch and the rest of the starch The mixture is compressed into 350 mg capsule-shaped tablets in a tableting press The tablets are scored to divide in half.

In such a manner, tablets containing 100 mg of the product of any of Examples I to CXXIII can be prepared.

o 30 8302562

Claims (48)

R 1 is hydrogen, chlorine, bromine, fluorine, a short chain alkyl of 1 to 1 carbon atoms, a short chain alkoxy of 1 to b carbon atoms, a short chain alkylthio of 1 to h carbon atoms, trifluoromethyl or hydroxy group; m equals 0, 1, 2, 3 or U; p equals 1, 2 or 3, provided that 20 p is more than 1 only when R 1 or R 1 is hydrogen, chlorine, fluorine or a methyl or methoxy group; R 1 is hydrogen or a short chain alkyl group having 1 to 1 carbon atoms, Y is oxygen or sulfur; R ^ g is a short chain alkyl group of 1 to U carbon atoms, a group of formula 38 is whether the R ^ g groups 25 combine to form an unsubstituted 5 ”or 6” ring or such ring in one or more of the carbon atoms contain a short chain alkyl of 1 to 4 carbon atoms or a di (short chain alkyl of 1 to b carbon atoms) substituent; R1 is a short chain alkyl, benzyl or phenethyl group; R @ 30 is hydrogen, a short chain alkyl, benzyl or phenethyl group; Rg is hydrogen, a short chain alkyl group, benzyl group, benzhydryl group or a group of formula 68, formula 69, formula 70, formula 71 - formula Ma * or formula 82; R 1 is hydrogen, a short chain alkyl, cycloalkyl or phenyl group; R ^ g hydrogen, a short-chain alkyl, short-chain alkoxy or 8302562 It is - * * <(* phenyl group, or and R ^ g together form a group of formula 72, formula 73, formula? U or formula 75, Rg ^ is hydrogen, a short chain alkyl group or a group of formula 83, formula 8U, formula 85 or formula 86; Rg ^ and Rgg are independently hydrogen or a short chain alkyl group, and Rg ^ is a short chain alkyl group. Peptide compound according to claim 1, characterized in that R is hydrogen, a straight or branched short chain alkyl group having 1 to U carbon atoms or phenyl group 10; Rj water, a straight or branched chain short chain alkyl group having 1 to U carbon atoms, CF ^, or a group of formula 56, 57, 58, 59, 60, 61, 62 or 63, wherein r - 1, or a group with formula 65 wherein r = 3 or a group of formula 87, formula 88 or formula 89, provided that R 1 is only hydrogen when R is other than hydrogen; R1 is hydrogen, a cyclohexyl or phenyl group; R 1 hydrogen, a straight or branched chain short chain alkyl group with 1-U carbon atoms, or a group of formula 56, formula 57, formula 58, formula 59, formula 60, formula 61 or formula 63 with ra 1, or a group 20 with formula 65 wherein r = 3 »or a group of formula 62c, formula 87, formula 88 or formula 89; Rg is hydrogen, a straight or branched chain short chain alkyl group having 1-U carbon atoms, an alkali metal salt ion, a group of formula 68, formula 69a, formula 70, formula 71, formula 82 or formula Ula 25; R 1 is hydrogen, a straight or branched chain short chain alkyl group having 1-U carbon atoms or a cyclohexyl group; Rg is a straight or branched chain short chain alkyl group with 1-U carbon atoms or a phenyl group; Rg ^ is a straight or branched chain short chain alkyl group having 1-U carbon atoms; Rg is a group 30 of formula 67 with p = 1; R 1 is a straight or branched chain alkyl group with 1-U carbon atoms, a group of formula U 1, formula 62, or formula 67 with p = 1; R ^ hydrogen, a hydroxy group, a straight or branched chain alkyl group with 1-U carbon atoms, a cyclohexyl group, an amino group, an -0-short chain alkyl group, in which the short chain alkyl group 8302562 Λ ► a straight or branched chain chain with 1 -1+ carbon atoms, a group of formula 38 or formula 1 + 5, wherein p = 1, 1-naphthyloxy group, a 2-naphthyloxy group, a group of formula 1 * 7 »in which the short chain alkyl group has a straight or 5 branched chain with 1-1 + carbon atoms, a group of formula 1 + 8 wherein p = 1 is a 1-naphthylthio group or a 2-naphthylthio group; Rg is a group of formula 1 + 1 +, formula 1 + 7 »or formula 1 + 5 or formula 1 + 8 wherein p = 1, wherein the short chain alkyl group includes a straight or branched chain having 10 1-1 + carbon atoms; R 1 is a phenyl, 2-hydroxyphenyl or 1 + hydroxyphenyl group; R heather fluoro, heather chloro or heather are a group of formula 51; Y represents 0 or S; Rg is a straight or branched chain short chain alkyl group containing 1 to 1 + carbon atoms or the Rg groups join to form an unsubstituted 5 ”or 6-membered ring or the said ring in which one or more reshuffled carbon atoms methyl or dimethyl substituent; R 1, R 3, R 3, and R 3 are all hydrogen, or R 3 is a phenyl, 2-hydroxyphenyl, or 1 + hydroxyphenyl group, and R 3, R 3, and R 3 are all hydrogen; r is an integer from 1 to 1 +; m is equal to 0, 1 or 2; R1 is hydrogen, chlorine, bromine, fluorine, a methyl, methoxy, methylthio or hydroxy group; R 1 is hydrogen, chlorine, bromine, fluorine, a methyl, methoxy, methylthio or hydroxy group; and Rg ^ is a phenyl group. 3. Peptide compound according to claim 2. characterized in that X is a green of formula 35 wherein R 1 - 5 is hydrogen, formula 2 +, formula 27a or formula 3 * +; R is hydrogen or a methyl group, R ^ is hydrogen, a methyl group or a group - (CHg) - - IJKg, provided that R ^ is only hydrogen when R is other than hydrogen; R1 is a cyclohexyl or phenyl group; Rg is hydrogen, a straight or branched chain alkyl group of 1 to 1 + carbon atoms or an alkali metal salt ion; R 1 is hydrogen, a cyclohexyl group, a short chain alkoxy group of 1-1 + carbon atoms, a group 35 of formula 38, formula 1 + 5 or formula 1 + 8 with p = 1; m equals 8302562 <i * I J> · * is 0, 1 or 2; R. ^ is hydrogen, chlorine, bromine, fluorine or a methyl, methoxy, methylthio or hydroxy group; and t equals 2 or 3k. Peptide compound according to claim 3.5, characterized in that X is a group of formula 35, wherein R 5 is hydrogen, Peptide compound according to claim, characterized in that it is a phenyl group and is a benzyl group. Peptide compound according to claim 5, characterized in that R is hydrogen; R ^ is a methyl group, R ^ is a cyclohexyl group and Rg is hydrogen. Peptide compound according to claim 5, characterized in that R is hydrogen; R ^ is a methyl group, R ^ is a phenyl group and R9 is hydrogen. Peptide compound according to claim 5, characterized in that R is a methyl group; R1 is hydrogen; a cyclohexyl group and Rg is hydrogen. Peptide compound according to claim 3, characterized in that X is a group of formula 27b. Peptide compound according to claim 9, characterized in that R 1 is a phenyl group and R 1 is a benzyl group. Peptide compound according to claim 10, 25, characterized in that R is a methyl group; R 1 is hydrogen and R y is hydrogen. O Peptide compound according to claim 10, characterized in that R is a methyl group; R ^ is hydrogen and Rg is a methyl group. Peptide compound according to claim 10, characterized in that R is hydrogen; R ^ is a methyl group and Rg is hydrogen. 1U. Peptide compound according to claim 3, characterized in that X is a group of formula 3 ^. 15. Peptide compound according to claim 1U, 8302562 Λ? 1 (Α) characterized in that Rg is a phenyl group and Rg is a benzyl group. Peptide compound according to claim 15, characterized in that R is a methyl group; R is hydrogen and Rg is hydrogen. Peptide compound according to claim 15, characterized in that R is hydrogen; R ^ is a methyl group and Rg is hydrogen. Peptide compound according to claim 3, 10, characterized in that X is a group of formula 2k. Peptide compound according to claim 18, characterized in that R 1 is hydrogen. Peptide compound according to claim 19, characterized in that Rg is a phenyl group; R ^ is a group 15 '- (CHgJ ^ -Mg; R is hydrogen; R ^ is a methyl group and Rg is hydrogen. Peptide compound according to claim 19, characterized in that Rg is a phenyl group; R ^ is a group - (CHg ^ "* * ^; R is hydrogen; R ^ is a methyl group and Rg is hydrogen. Peptide compound according to claim 19, characterized in that Rg is a phenyl group, Rg is a group of formula 1 * 1 in which m = 1; R hydrogen; R ^ is a methyl group and R8 is hydrogen. Peptide compound according to claim 19, characterized in that Rg is a phenyl group; R ^ is a group of formula 57 wherein R = 1; R is hydrogen; R ^ is a methyl group and Rg is hydrogen. 2l *. Peptide compound according to claim 19, characterized in that Rg is a phenyl group and Rg is a benzyl group. Peptide compound according to claim 2h, characterized in that R is hydrogen; R ^ is a methyl group and Rg is hydrogen. The peptide compound of claim 25, 8302562, K rtf. / * characterized in that it is 1 - / & - / (S) -3- (benzoylamino) -2-oxo-b-phenyrbutyl7-L-alanyl7-L-proline, monohydrochloride. Peptide compound according to claim 2b, characterized in that R is hydrogen; R ^ is a methyl group and Rg is a methyl group. Peptide compound according to claim 2b, characterized in that R is hydrogen; R1 is a methyl group and Rg is an ethyl group. 29. Peptide compound according to claim 2b, 10, characterized in that R is hydrogen; R ^ is a methyl group and Rg is an n-propyl group. Peptide compound according to claim 2b, characterized in that R is hydrogen; R ^ is a methyl group and Rg is an isopropyl group. Peptide compound according to claim 2b, characterized in that R is a methyl group; R ^ is hydrogen and Rg is hydrogen. Peptide compound according to claim 2b, characterized in that R is hydrogen; R1 is a group - (CHgJ ^ -M ,, 20 and Rg is hydrogen. Peptide compound according to claim 18, characterized in that R 1 is a phenylthio group. 3b. Peptide compound according to claim 3b, characterized in that R 1 is a phenyl group and R 1 is a benzyl-25 group. Peptide compound according to claim 3b, characterized. that R is a methyl group; R ^ is hydrogen and Rg is hydrogen. Peptide compound according to claim 18, 30, characterized in that R1 is a b-fluorophenoxy group. Peptide compound according to claim 36, characterized in that Rg is a phenyl group and Rg is a benzyl group. 38. A peptide compound according to claim 37, characterized in that R is a methyl group; R ^ is hydrogen and S302 5 62 ίο 6 r Λ ►. Rg is hydrogen. Peptide compound according to claim 37, characterized in that R is a methyl group, R 1 is hydrogen and R 9 is a methyl group. 40. Peptide compound according to claim 37, characterized in that R is hydrogen; R1 is a methyl group and Rg is hydrogen. Onion. Peptide compound according to claim 18, characterized in that R 1 is a phenyl group. 10 U2. Peptide compound according to claim Ui, characterized in that R 1 is a phenyl group and R 1 is a benzyl group. v 'U3. Peptide compound according to claim U2, characterized in that R is hydrogen; R ^ is a methyl group and Rg is hydrogen. UU. Peptide compound according to claim 18, characterized in that R 1 is a cyclohexyl group. U5. Peptide compound according to claim UU, characterized in that R2 is a phenyl group and R1 is a benzyl group. U6. Peptide compound according to claim U5, characterized in that R is hydrogen; R ^ is a methyl group and Rg is hydrogen. U7. Peptide compound according to claim 1, characterized in that R is a short chain alkyl group, a cycloalkyl group or a group of formula 53, formula 62a, formula 62b, formula 62c, formula 58a, formula 58b, formula 58c, formula 63a, formula 63b or formula is 63c; and m equals 0, 1, 2, 3 or U. 30 U8. Peptide compound according to claim U7, characterized in that R is a methyl group. U9. Peptide compound of formula 1 or a pharmaceutically acceptable salt thereof wherein X is a group of formula 2U, formula 25, formula 26, formula 27, formula 28, formula 29, formula 30, formula 31, formula 32, formula 33, 8302562. * \ lt> 10T formula 3U or formula 80; R ^ a short chain alkyl group, a halogen-substituted short chain alkyl group, a group of formula p6, formula 57, formula 58, formula 59, formula 6θ, formula 61, formula 62, formula 63, formula 6b, formula 65 or formula 66; R 1 is a group of formula 39, formula Uo, formula Ui or formula 67; Rg hydrogen, a short chain alkyl group, a halogen-substituted short chain alkyl group or a group of formula 39, formula hO, formula Ul, formula b2, formula 58, formula 59, formula 60, formula 61, formula 62, formula 63, Formula 6b is Formula 65 or Formula 66; R 1 is hydrogen, a short chain alkyl group, or a group of formula 56, formula 57, formula 58, x formula 59, formula 60, formula 61, formula 62, formula 63, formula 6b, formula 65 or formula 66; r is an integer from 1 to U; R 1, hydrogen, halogen, a short chain alkyl, keto, hydroxy group, an -ffiW (o) - short chain alkyl group, an azido, amino group, or a group of formula 36, formula 37, formula 38, formula 39, formula Uo, formula Ui, a 1- or 2-naphthyl group of formula Ula, a group of formula b2, formula U3, formula UU, formula U5, a 1- or 2-naphthyloxy group of formula b6, a group of formula bj, formula b8 or a 1- or 2-naphthylthio group of formula U9; Rg is halogen, a keto group, a group of formula UU, formula bp, formula 50, a 1- or 2-naphthyloxy group of formula b6, a group 25 of formula U7, formula U8 or a 1- or 2-naphthylthio group of formula bp ; R1 is a keto group or a group of formula 38, R1q is halogen or a group of formula 51; R 2, R 2, R 2 and R 12 'are independently hydrogen or a short chain alkyl group or R 2', and where R 2 'are and R' is a group of formula 52; Hydrogen, a short chain alkyl group with 1-U carbon atoms, a short chain alkoxy group with 1-b carbon atoms, a short chain alkylthio group with 1-U carbon atoms, chlorine, "bromine, fluorine, a trifluoromethyl, hydroxy, phenyl, tenoxy, phenylthio or phenylmethyl group; Hydrogen, chlorine, bromine, fluorine, a short chain alkyl 8302562 "* ff *". With 1 - 1 carbon atoms, short chain alkoxy with 1 - 1 carbon atoms, short chain alkylthio with 1 - 1) carbon atoms 1) carbon atoms, trifluoromethyl or hydroxy group, m equals 0, 1, 2, 3 or 1); p equals 1, 2 or 3, provided that p is only 5 more than one when or R 1 is hydrogen, chlorine, fluorine is a methyl or methoxy group; R is hydrogen or a short chain alkyl group with 1 to 4 carbon atoms; Y is oxygen or sulfur; R ^ g is a short chain alkyl group with 1 to 1) carbon atoms or a group of formula 38, whether the R 10 g groups combine to form an unsubstituted 5 ”or 6 ring or said ring in which one or more of the carbon atoms is a short chain alkyl of 1-1) carbon atoms or v) di (short chain alkyl of 1 -1) carbon atoms or di (short chain alkyl with 1-1) carbon atoms) substituent; R ^ is a short chain alkyl, benzyl or phenethyl group; R ^ q is hydrogen, a short chain n is alkyl, benzyl or phenethyl group; and R 9 is hydrogen, a short chain alkyl, benzyl or benzhydryl group or a group of formula 68, wherein R 8 is hydrogen, a short chain alkyl, cycloalkyl or phenyl group and R 8 is hydrogen, a short chain alkyl, short chain alkoxy or phenyl group, or R ^ and R18 together form a group of formula 72, formula 73, formula 7 ^ or formula 75 50. Pharmaceutical composition for use in the treatment of hypertension, characterized in that it contains a pharmaceutically acceptable carrier and a hypotension-fighting compound of formula 1, wherein R, R 1, R 8, R 1 and X as in claim 1 to be. 51. A method of treating hypertension in a mammalian host, characterized in that an effective amount of the composition according to claim 50 is administered. 52. A pharmaceutical composition to be used as an analgesic, characterized in that it contains a pharmaceutically acceptable carrier and a single palinase preventive compound of formula 1, wherein X is a group of formula 80, and wherein R, 35 R ^, Rg, R ^, R ,. and Rg are as claimed in claim 1. 8302562 10 9? V, «Vt <* 53. A method of alleviating pain in a mammalian host, characterized in that an effective amount of the composition according to claim 52 is administered. New ketone of formula 5 wherein halogen 5 represents chlorine or bromine; B ^ is a group of formula 39, formula 1 * 0, formula 1 * 1 or formula 6j; R ^ is hydrogen, a short chain alkyl group, one by halogen substituted short chain alkyl group, or a group of formula 39 »formula 1 * 0, formula 1 * 1, formula 1 * 2, formula 58, formula 59» formula 60, formula 61, 10 formula 62, formula 63, formula 61 *, formula 65 or formula 66; R 1 is hydrogen, chlorine, bromine, fluorine, a short chain alkyl with 1 - 1 carbon atoms, a short chain alkoxy with 1 - 1 carbon atoms, a short chain alkylthio with 1-1 * carbon atoms, trifluoromethyl or hydroxy group; m equals 0, 1, 2, 3 15 or 1 *, p equals 1, 2 or 3, provided that p is only more than one as R ^ hydrogen , is chlorine, fluorine or a methyl or methoxy group, and r is an integer from 1 to 1 *. Ketone compound according to claim 5, characterized in that Rg is a group of formula 67 with p = 1; R ^ is a group 20 of formula 67 with p = 1; m is equal to 0, 1 or 2; and R 1 is hydrogen, chlorine, bromine, fluorine or a methyl, methoxy, methylthio or hydroxy group. The ketone compound according to claim 55, characterized in that R 1 is a phenyl group; R 1 is a benzyl group 25; and halogen exists for chlorine. 57 «New amino ketone carboxylic acid of formula 11, wherein R is hydrogen, Prot, short chain alkyl, cycloalkyl or a group of formula 53, formula 90a, formula 90b, formula 90c, formula 91a, formula 91b, formula 91c, formula 92a, 30 formula 92b or formula 92c, R 1 is hydrogen, a short chain alkyl group, a halogen-substituted short chain alkyl group, or a group of formula 56, formula 57a, formula 58a, formula 59a, formula 61a, formula 62a, formula 63a, formula oh, formula 65a or formula 66 is provided that R 1 is only hydrogen when R 1 is other than hydrogen; Prot an easy 8302562 Μ. * · * Removable protection group; R 1 is a group of formula 39, formula Lo, formula 11 or formula 6j; Hydrogen, a short chain alkyl group, a halogen-substituted short chain alkyl group, or a group of formula 39, formula 10, formula 1, formula 12, formula 58, formula 59, formula 60, formula 61, formula 62, formula 63 is Formula 61, Formula 65, Formula 66 or Formula 67; R 1 is hydrogen, chlorine, bromine, fluorine or a short chain alkyl of 1 to 1 carbon atoms, a short chain alkoxy of 1 to 1 carbon atoms, a short chain alkylthio of 1 to 1 carbon atoms, trifluoromethyl or hydroxy group; m equals 0, 1,2, 3 or !; p equals 1, 2 or 3, provided p is only more than one when R 1 is hydrogen, chlorine, fluorine or a methyl or methoxy group; and r is an integer from 1 to 1. 58 · Aminoketone carboxylic acid according to claim 57, characterized in that a group of formula 67 with p = 1, R 1 is a group of formula 67 with p = 1; m 'is equal to 0, 1 or 2, hydrogen, chlorine, bromine, fluorine or a methyl, methoxy, methylthio or hydroxy group; R is a methyl group and R 1 is hydrogen. 59. Amino ketone acarboxylic acid according to claim 58, characterized in that R 1 is a phenyl group and R 1 is a benzyl group. An aminoketone carboxylic acid according to claim 57. S 25 characterized in that R 1 is a group of formula 67 with p = 1; R ^ is a group of formula 67 with p = * 1; m is equal to 0, 1 or 2; R 1 is hydrogen, chlorine, bromine, fluorine or a methyl, methoxy, methylthio or hydroxy group, R 1 is an easily removable protecting group and R 1 is a methyl group. A peptide compound according to claim 50, characterized in that R 2 is a phenyl group, R 1 is a benzyl group and R is a group of formula 93. (! a 8302 5 62