MXPA96006031A - Inhibitors of elastase perfluoroalquilic cetone and processes to manufacture - Google Patents

Abstract

The present invention relates to compounds that are inhibitors of elastase, particularly human neutrophil elastase, and to novel processes for making them. As inhibitors of human neutrophil elastase, the compounds are useful in the treatment of a patient afflicted with an inflammatory disease associated with neutrophil.

Description

ELABTABA PERFLUOROALOUILICA CETONE INHIBITORS AND PROCESSES TO MANUFACTURE THEM BACKGROUND OF THE INVENTION This invention relates to compounds that are inhibitors of elastase, particularly human neutrophil elastase, useful for a variety of physiological and end-use applications, and to processes for making these * inhibitors. Human neutrophil elastase has been implicated as an agent that contributes to tissue destruction associated with a number of inflammatory diseases, such as chronic bronchitis, cystic fibrosis, and arthritis. rheumatoid J.L. Malech and J.I. Gallin, Neu 'Engl. J. Med. , 317 (11), 687 (1987). Elastase has a wide range of proteolytic activity against a number of connective tissue acromoléculas, including elastin, fibronectin, collagen, and proteoglycan. The presence of the elastase enzyme can contribute to the pathology of these diseases. • Normal plasma contains large amounts of protease inhibitors that control a variety of enzymes involved in connective tissue change and inflammation. For example, the a-1-proteinase inhibitor (a-l-25 Pl) is a serine protease inhibitor that blocks the activity of elastase. A-l-PI has received considerable interest because the reduction in plasma levels to less than 15 percent of normal is associated with the early development of emphysema. In addition to plasma-derived protease inhibitors, secretory fluids, including bronchial, nasal, cervical, and seminal fluid, contain an endogenous protease inhibitor called secretory leukoprotease inhibitor (SLPI), which can inactivate elastase, and it is believed to have an important role in maintaining the integrity of the epithelium in the presence of the inflammatory cell proteases. In certain disease states, the α-l-proteinase inhibitor and the secretory leukoprotease inhibitor are inactivated by neutrophil oxidative mechanisms, allowing neutrophil proteases to function in an environment essentially free of inhibitor. For example, it has been found that bronchial lavage fluids of patients with adult respiratory distress syndrome (ARDS) contain active elastase and α-l-proteinase inhibitor, which had been inactivated by oxidation. In addition to oxidative mechanisms, neutrophils possess non-oxidative mechanisms to bypass inhibition by antiproteases. Neutrophils from patients with chronic granulomatous disease are able to degrade endothelial cell matrices in the presence of an excess of a-l-proteinase inhibitor. There is considerable in vitro evidence that stipulated neutrophils can bind tightly to their substrates, so that antiproteases from ambient micro-environment serum from close cell-substrate contact are effectively excluded. The influx of large numbers of neutrophils to an inflammatory site can result in considerable tissue damage due to proteolysis occurring in this region. Applicants have determined that elastase is one of the primary neutrophil proteases responsible for the degeneration of the cartilage matrix, as measured by the ability of neutrophil lysate, purified elastase, and stimulated neutrophils, to degrade matrix proteoglycan. of the cartilage. In addition, applicants have previously discovered peptide derivatives useful as elastase inhibitors, which exert valuable pharmacological activities. For example, peptide derivatives useful as elastase inhibitors, wherein the terminal carboxyl group has been replaced by a pentafluoroethylcarbonyl group (-C (0) C2F5), and wherein the N-terminal amino acid is substituted with different protecting groups, are described in the European Patent Application OPI Number 0529568, by the inventors Peet et al., with a publication date of March 3, 1993, and in the European Patent Application OPI Number 0410411, by the inventors Bey et al., with a publication date of January 3-0 1991. Due to the new processes for manufacturing perfluoroalkylcarbonyl peptides, applicants have recently discovered the heptafluoropropylcarbonyl and nonafluorobutylcarbonyl fractions of the elastase inhibitors.

COMPENDIUM OF THE INVENTION The present invention relates to compounds having the following formula I: K-P4-P3-P2-NH-CH (R1) -C (= 0) -XI (I) (SEQ ID NO.l) or a hydrate, isoester, or a pharmaceutically acceptable salt thereof, wherein: P4 is Ala, bAla, Leu, Lie, Val, Nva, bVal, Nle, or a bond; P3 is Ala, bAla, Leu, Lie, Val, Nva, bVal, Nle, or a derivative of N-methyl, Pro, Ind, Tic, or Tea, or Lys substituted on its epsilon-amino group, with a morpholino- B or Orn substituted on its delta-araino group with a morpholino-B group; P2 is Pro, Ind, Tic, Pip, Tea, Pro (4-Obzl), Aze, Pro (4-OAc) or Pro (4-OH); R2 is a side chain of Ala, Leu, Lie, Val, Nva or bVal; X 'is -CF2CF2CF3 or -CF2CF2CF2CF3; K is hydrogen, formyl, acetyl, succinyl, benzoyl, tertiary butyloxycarbonyl, carbobenzyloxy, tosyl, dansyl, isovaleryl, methoxysuccinyl, 1-adamantanesulfonyl, 1-adamantanacetyl, 2-carboxybenzoyl, phenylacetyl, tertiary butyl acetyl, bis ( -naphthyl) methyl) acetyl, -C (= 0) N- (CH 3) 2, -A-R, where: 0 0 0 H 0 Rz is an aryl group containing 6, 10, or 12 carbon atoms suitably substituted by 1 to 3 members independently selected from the group consisting of fluorine, chlorine, bromine, iodine, trifluoromethyl, hydroxy, alkyl containing 1 to 6 carbon atoms, alkoxy containing from 1 to 6 carbon atoms, carboxy, alkylcarbonylamino wherein the alkyl group contains from 1 to 6 carbon atoms, 5-tetrazolyl, and acylsulfonamido containing from 1 to 15 carbon atoms, that, the acyl sulfonamide contains an aryl, the aryl may be further substituted by a member from fluorine, chlorine, bromine, iodine, and nitro; or HH - B - z or \ / where: Z is N or CH, and B is a group of the formulas: i- C- CH - C "f- - C CH 4 R 'R' 0 0 0 NH c- S02 (the wavy line? is the union with the rest of the molecule, that is, not with Z) and wherein R1 is hydrogen or an alkyl group of 1 to 6 carbon atoms; They are useful as elastase inhibitors. The compounds of formula I exhibit an anti-inflammatory effect useful in the treatment of gout, rheumatoid arthritis, and other inflammatory diseases, such as adult respiratory distress syndrome, septicemia, disseminated intravascular coagulation, cystic fibrosis, chronic bronchitis, chronic obstructive pulmonary disease Inflammatory bowel disease (particularly ulcerative colitis or Crohn's disease), and in the treatment of emphysema. In a further embodiment, the present invention provides a novel process for the preparation of a compound of the formula: K'-P4-P3-P2-NH-CH (R1) -C (= 0) -X (II) (SEQ ID NO: 2) where: P4 is Ala, bAla, Leu, lie, Val, Nva, bVal, Nle, or a link; P3 is Ala, bAla, Leu, Lie, Val, Nva, bVal, Nle, or a derivative of N-methyl, Pro, Ind, Tic, or Tea, or Lys substituted on its epsilon-amino group with a morpholino-B group , or Orn substituted on its delta-amino group with a morpholino-B group; P2 is Pro, Ind, Tic, Pip, Tea, Pro (4-OBzl), Aze, Pro (4-0Ac), or Pro (4-0H); R-L is a side chain of Ala, Leu, Lie, Val, Nva or bVal; X is -CF2CF3, -CF2CF2CF3, or -CF2CF2CF2CF3; K 'is hydrogen, formyl, acetyl, succinyl, benzoyl, tertiary butyloxycarbonyl, carbobenzyloxy, tosyl, dansyl, isovaleryl, methoxysuccinyl, 1-adamantanesulfonyl, 1-adamantanacetyl, 2-carboxybenzoyl, phenylacetyl, tertiary butyl acetyl, bis (( l-naphthyl) ethyl) acetyl, -C (= 0) N- (CH 3) 2, 0 -A-R_, wherein: H 0 Rz is an aryl group containing 6, 10, or 12 carbon atoms, suitably substituted by 1 to 3 members independently selected from the group consisting of fluorine, chlorine, bromine, iodine , trifluoromethyl, hydroxy, alkyl containing 1 to 6 carbon atoms, alkoxy containing 1 to 6 carbon atoms, carboxy, alkylcarbonylamino wherein the alkyl group contains 1 to 6 carbon atoms, 5-tetrazolyl, and acylsulfonamido containing from 1 to 15 carbon atoms, since when the acyl sulfonamide contains an aryl, the aryl may be further substituted by a member selected from fluorine, chlorine, bromine, iodine , and nitro; which comprises the steps of: (a) coupling an amino acid ester of the formula NH2-CH (R1) C (= 0) OR2, wherein R2 is alkyl (of 1 to 6 carbon atoms) or cycloalkyl (of 3 to 12 carbon atoms), with a suitably N-protected peptide of formula K '-P4-P3-P2-0H, in the presence of a suitable coupling agent, and in the presence of an appropriate coupling solvent, to give a suitably N-protected peptide ester; (b) reacting the suitably N-protected peptide ester with a suitable perfluorinating agent in the presence of a suitable alkali metal base and an appropriate anhydrous solvent.

The present invention further provides a novel process for the preparation of a compound of the formula: K'-P4-P3-P2-NH-CH (R1) -C (= 0) -X (III) (SEQ ID NO: 3) where: P4 is Ala, bAla, Leu, lie, Val, Nva, bVal, Nle, or a link; P3 is Ala, bAla, Leu, Lie, Val, Nva, bVal, Nle, or a derivative of N-methyl, Pro, Ind, Tic, or Tea, or Lys substituted on its epsilon-to-ino group with a morpholino- B, or Orn substituted on its delta-amino group with a morpholino-B group; P2 is Pro, Ind, Tic, Pip, Tea, Pro (4-OBzl), Aze, Pro (4-OAc), or Pro (4-OH); R-L is a side chain of Ala, Leu, Lie, Val, Nva or bVal; X is -CF2CF3, -CF2CF2CF3, or -CF2CF2CF2CF3; K '' is , / \ ° -T-B-Z O where: Z is N or CH, and B is a group of the formulas: OR - c- - CH - C -f- - C CH c R 'R' O O O OR and wherein R 'is hydrogen or an alkyl group of 1 to 6 carbon atoms; which comprises the steps of: (a) coupling an amino acid ester of the formula NH-j-CHfR-L) C (= 0) OR 2, wherein R 2 is alkyl (of 1 to 6 carbon atoms) or cycloalkyl (of 3 to 12 carbon atoms), with a suitably N-protected peptide of the formula K '-P4-P3-P2-0H, in the presence of a suitable coupling agent, and in the presence of an appropriate coupling solvent, to give a suitably N-protected peptide ester; (b) reacting the suitably N-protected peptide ester with a suitable perfluorinating agent in the presence of a suitable alkali metal base and an appropriate anhydrous solvent, to give a properly N-protected perfluoroalkyl peptide; (c) deprotecting the appropriately N-protected perfluoroalkyl peptide with a suitable deprotection agent in the presence of an appropriate organic solvent to give a perfluoroalkyl peptide; (d) reacting the perfluoroalkyl peptide with a compound of the formula: HH c: - B - z or \ / wherein B and Z are as defined above, in the presence of a suitable non-nucleophilic base and an appropriate organic solvent. The present invention further provides a novel process for the preparation of a compound of the formula (II), which comprises the steps of: (a) reacting a suitably protected amino acid ester of the formula Pg-NH-CHIRi) C ( = 0) 0R2, wherein R2 is alkyl (of 1 to 6 carbon atoms), or cycloalkyl (of 3 to 12 carbon atoms), and Pg is a suitable protecting group, with a suitable perfluorinating agent in the presence of a suitable alkali metal base and an appropriate anhydrous solvent, to give a properly N-protected perfluoroalkyl ketone; (b) deprotecting the appropriately N-protected perfluoroalkyl ketone with a suitable deprotection agent in the presence of an appropriate organic solvent, to give a perfluoroalkyl ketone; (c) coupling the perfluoroalkyl ketone with a suitably protected peptide of the formula K ', in the presence of a suitable coupling agent, and in the presence of an appropriate coupling solvent. The present invention further provides a novel process for the preparation of a compound of the formula (III), which comprises the steps of: (a) reacting a suitably protected amino acid ester of the formula Pg-NH-CH (R1) ) C (= 0) 0R2, wherein R2 is alkyl (of 1 to 6 carbon atoms) or cycloalkyl (of 3 to 12 carbon atoms), and Pg is a suitable protecting group with a suitable perfluorinating agent, in the presence of a suitable alkali metal base, and an appropriate anhydrous solvent, to give a properly N-protected perfluoroalkyl ketone; (b) deprotecting the appropriately N-protected perfluoroalkyl ketone with a suitable deprotection agent in the presence of an appropriate organic solvent, to give a perfluoroalkyl ketone; (c) coupling the perfluoroalkyl ketone with a suitably protected peptide of the formula K '-P4-P3-P2-OH, in the presence of a suitable coupling agent, and in the presence of an appropriate coupling solvent. The present invention also provides novel compounds having the following formula (IV): - P4 - P3 - P2 - P, - CF2CF3 (SEQ ID No. 4) (iv; where: P: is Ala, Val, Nva, bVal, Leu, lie, or Nle; P2 is Ala, bAla, Leu, Lie, Val, Nva, bVal, Met, Nle, Gly, Phe, Tyr, Trp, or Nal (l), wherein the nitrogen of the a-amino group can be substituted with a group R , wherein R is an alkyl (of 1 to 6 carbon atoms), cycloalkyl (of 3 to 12 carbon atoms), cycloalkyl (of 3 to 12 carbon atoms) -alkyl (of 1 to 6 carbon atoms), bicycloalkyl (from 4 to 11 carbon atoms), bicycloalkyl (from 4 to 11 carbon atoms) -alkyl (from 1 to 6 carbon atoms), aryl (from 6 to 10 carbon atoms), aryl (from 6 to 10) carbon atoms) -alkyl (from 1 to 6 carbon atoms), heterocycloalkyl (from 3 to 7 carbon atoms), heterocycloalkyl (from 3 to 7 carbon atoms) -alkyl (from 1 to 6 carbon atoms), heteroaryl (from 5 to 9 carbon atoms), heteroaryl (from 5 to 9 carbon atoms) -alkyl (from 1 to 6 carbon atoms), aryl (from 6 to 10 carbon atoms) -cycloalkyl (from 3 to 12 atoms) carbon) molten, aryl (6 to 10 carbon atoms) -ci chloroalkyl (3 to 12 carbon atoms) -fused alkyl (1-6 carbon atoms), heteroaryl (5 to 9 carbon atoms) -fused cycloalkyl (3 to 12 carbon atoms), or heteroaryl (from 5 to 9 carbon atoms) -cycloalkyl (from 3 to 12 carbon atoms) -fused alkyl (from 1 to 6 carbon atoms), or P2 is Pro, Ind, Tic, or Tea; P3 is Ala, bAla, Leu, lie, Val, Nva, bVal, or Nle; P4 is Ala, bAla, Leu, lie, Val, Nva, bVal, Nle or a link; or a pharmaceutically acceptable hydrate, isoester, or salt thereof.

DETAILED DESCRIPTION OF THE INVENTION Isoesters of the compounds of the formulas (I) - (IV), include those wherein (a) one or more of the a-amino residues of the P2-P4 substituents are in their unnatural configuration (where there is a natural configuration), or (b) when the normal peptide amide bond [-C (= 0) NH-] is modified, such as, for example, to form -CH2NH- (is reduced), - COCH2- (keto), -CH (OH) CH2- (hydroxy), -CH (NH2) CH2- (amino), -CH2CH2- (hydrocarbon), -CH = CH- (alkene). Preferably, a compound of the invention should not be in an isothermal form; it is particularly preferred that there is not a modified peptide amide group, but if there is, it is preferable to keep the isothermal modifications to a minimum. As used herein, the term "alkyl" (from 1 to 6 carbon atoms) "means a straight or branched group of 1 to 6 carbon atoms, such as methyl, ethyl, normal propyl, isopropyl, normal butyl, tertiary butyl, normal pentyl, secondary pentyl, isopentyl, and "normal hexyl" The term "cycloalkyl (from 3 to 12 carbon atoms)" means a cyclic alkyl group consisting of a 3- to 8-membered ring which may be substituted by a lower alkyl group, for example, cyclopropyl, cyclobutyl cyclopentyl, cyclohexyl, 4-methylcyclohexyl, 4-ethyl-cyclohexyl, cycloheptyl, and cyclooctyl The term "cycloalkyl (from 3 to 12 carbon atoms) -alkyl (from 1 to 6 carbon atoms)" means a alkyl group (of 1 to 6 carbon atoms) substituted by a cycloalkyl group (of 3 to 12 carbon atoms), such as a cyclohexylmethyl or cyclopentethylethyl group The term "bicycloalkyl (of 4 to 11 carbon atoms)" means an alkyl group containing a pair of carbon atoms p uenteados, such as 2-bicyclo [l.1.0] butyl, 2-bicyclo [2.2. l] hexyl, and l-bicyclo [2.2.2] octane. He ~~ * term "bicycloalkyl (4 to 11 carbon atoms) -alkyl (from 1 to 6 carbon atoms) "means an alkyl (of the ß carbon atoms) substituted by a bicycloalkyl (of 4 to 11 carbon atoms), such as 2-bicyclohexylmethyl.The term" aryl (from 6 to 10 carbon atoms) "means a cyclic aromatic assembly of conjugated carbon atoms, by For example, phenyl, 1-naphthyl, and 2-naphthyl. The term "aryl (from 6 to 10 carbon atoms) -alkyl (from 1 to 6 carbon atoms)" means an alkyl (from 1 to 6 carbon atoms) substituted by an aryl (from 6 to 10 carbon atoms), such as benzyl, phenethyl, and 1-naphthylmethyl. The term "heterocycloalkyl (from 3 to 15 carbon atoms)" means a cyclic group containing non-aromatic carbon, which contains from 1 to 3 heteroatoms selected from oxygen, nitrogen, and sulfur, such as morpholinyl and piperidinyl. The term "heterocycloalkyl (from 3 to 7 carbon atoms) -alkyl (from 1 to 6 carbon atoms)" means an alkyl group (from 1 to 6 carbon atoms) substituted by a heterocycloalkyl group (give from 3 to 7 atoms) carbon), for example, morpholinomethyl. The term "heteroaryl (from 5 to 9 carbon atoms)" means a cyclic or bicyclic aromatic assembly of conjugated carbon atoms, and from 1 to 3 nitrogen, oxygen, and sulfur atoms, for example, pyridinyl, - Quinoxalinyl, and quinolinyl. The term "heteroaryl (from 5 to 9 carbon atoms) -alkyl (from 1 to 6 carbon atoms)" * * * "means an alkyl group (from 1 to 6 carbon atoms) substituted by a heteroaryl group (from 5 to 9 carbon atoms), such as 3-quinolinylmethyl. The term "fused aryl (from 6 to 10 carbon atoms) -cycloalkyl (from 3 to 12 carbon atoms)" means a group "cycloalkyl (from 3 to 12 carbon atoms)" having one or more sides shared with A group "aryl (from 6 to 10 carbon atoms)", and may include, for example, groups derived by the fusion of benzene and cyclopentane, ie, 2-indanyl. The term "aryl (from 6 to 10 carbon atoms) -cycloalkyl (from 3 to 12 carbon atoms) -alkyl (from 1 to 6 carbon atoms) "Melted" means an alkyl (of the β carbon atoms) substituted by a fused aryl group (from 6 to 10 carbon atoms) - cycloalkyl (from 3 to 12 carbon atoms) The term "heteroaryl" (from 5 to 9) carbon atoms) -cycloalkyl (3 to 8 carbon atoms) "means a heteroaryl group (from 5 to 9 carbon atoms) having one or more sides shared with a cycloalkyl group (of 3 to 8 carbon atoms), and may include, for example, groups derived by the fusion of cyclohexane and pyridine, i.e. , tetrahydroquinoline. Finally, the term "heteroaryl (from 5 to 9 carbon atoms) -cycloalkyl (from 3 to 8 carbon atoms) -alkyl (from 1 to 6 carbon atoms)" means an alkyl substituted by a heteroaryl group of to 9 carbon atoms) -fused cycloalkyl (3 to 8 carbon atoms). The compounds of the formulas (I) - (IV), can form pharmaceutically acceptable salts with any non-toxic organic or inorganic acid. Illustrative inorganic acids which form suitable salts include hydrochloric, hydrobromic, sulfuric, and phosphoric acid, and acid metal salts, such as sodium monoacid orthophosphate, and potassium hydrogen sulfate. Illustrative organic acids that form suitable salts include mono-, di-, and tri-carboxylic acids. Illustrative of these acids are, for example, acetic, glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic acids; tartaric, citric, ascorbic, maleic, hydroximic, benzoic, hydroxybenzoic, phenylacetic, cinnamic, salicylic, 2-phenoxybenzoic, and sulphonic, such as methanesulfonic acid and 2-hydroxyethanesulfonic acid. Each α-amino acid has a characteristic "R group", the R group being the side chain, or residue, attached to the α-carbon atom of the α-amino acid. For example, the side chain of the R group for glycine is hydrogen, for alanine it is methyl, for valine it is isopropyl. (Accordingly, throughout this specification, fraction R2 is the group R for each indicated a-amino acid). For the specific R groups or the side chains of the α-amino acids, reference is made to the text of A.L. Lehninger de Biochemistry (see particularly Chapter 4). Natural amino acids, with the exception of glycine, contain a chiral carbon atom. Unless specifically indicated otherwise, the preferred compounds are the optically active amino acids of the L configuration; however, applicants contemplate that the amino acids of the compounds of the formulas (I) - (IV) can be of the D or L configuration, or can be mixtures of the D and L isomers, including racemic mixtures. Table I stipulates the abbreviations recognized for the α-amino acids.

In addition, the abbreviations recognized for the a-amino acids denoted by the structures and names given below, are as follows: 1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid O (Tea H - N OH thiazolidin-4-carboxylic acid O Aze H- N C -OH acetylcarboxylic acid pipecolinic acid OH 4 - . 4-hydroxyproline 4-acetoxyproline 4-benzyloxyproline As with any group of structurally related compounds possessing a particular generic utility, certain groups and configurations are preferred. Preferred compounds of the formula (I) include the following groupings. With respect to the substituent P4, the compounds of the formula (I) wherein P4 is Ala or a bond are preferred. Particularly preferred are the compounds of the formula (I) wherein P is a bond. With respect to the substituent P3, the compounds of the formula (I) wherein P3 is Lie, Val, or Ala are preferred. Particularly preferred are the compounds of the formula (I) wherein P3 is Val. With respect to substituent P2, l.? compounds of the formula (I), wherein P2 is Pro, Tic, Tea, Pro (4-OBzl), Aze, Pro (4-0Ac) or Pro (4-OH). Particularly preferred are the compounds of the formula (I) wherein P 2 is Pro. With respect to the substituent R 1 f, the compounds of the formula (I) wherein R 1 is CH (CH 3) 2 or CH 2 CH 2 CH 3, which are the "groups", are preferred. R "characteristic of the amino acids Val and Nva respectively. Particularly preferred are the compounds of the formula (I) wherein R x is -CH (CH 3) 2. With respect to the substituent K, the compounds of the formula (I) are preferred, wherein K is benzoyl, tertiary butyloxycarbonyl, carbobenzyloxy, isovaleryl, -C (= 0) N- 4-B- where; \ / Z is N, and B is a group of the formulas: 0 0 or o - C -H CH - C f - C CH c- R 'R' O O or o - (O c-4- '° Oh c-t and wherein R' is hydrogen or an alkyl group (of 1 to 6 carbon atoms). Particularly preferred are the compounds of the formula I wherein K is HH -f- B - Z 0 \ / and where Z is N, and B is a group of the formulas: 0 0 - CH c-f C - CH C 4 R 0 and wherein R 'is hydrogen or an alkyl group of 1 to 6 carbon atoms. Specific examples of the preferred compounds of the formula (I) include: N- [4- (4-morpholinylcarbonyl) benzoyl] -L-valyl-N '- [3,3,4,4,5,5,5-heptafluoro-1- (1-methylethyl) -2-oxopentyl] - L-prolinamide; N- [4- (4-morpholinylcarbonyl) benzoyl] -L-valyl-N '- [3, 3,4,4,5,5,6,6,6,6-nonafluoro-1- (1-methylethyl) - 2-oxohexyl] -L-prolinamide; N- [(-1,1-dimethylethoxy) carbonyl] -L-vali1-N'- [3, 3,4,4,5,5,5-heptafluoro-1- (1-methylethyl) -2-oxopentyl] -L-prolinamide; N- [(1,1-dimethylethoxy) carbonyl] -L-valyl-N '- [3,3,4,4,5,5,6,6,6-nonafluoro-1- (1-methylethyl) -2 -oxohexyl] -L-prolinamide; N- [4- (4-morpholinylcarbonyl) benzoyl] -L-valyl-N '- [3,3,4,4,5,5,5-heptafluoro-l- (1-methylethyl) -2-oxopentyl] - L-2-acetamide; N- [4- (4-morpholinylcarbonyl) benzoyl] -L-valyl-N 1 - [3, 3,4,4,5,5, -6,6, 6-nonafluoro-1- (1-methylethyl) -2 -oxohexyl) -L-2-acetamide; N- [(1,1-dimethylethoxy) carbonyl] -L-valyl-N '- [3,3,4,4,5,5,5-heptafluoro-l- (1-methylethyl) -2-oxopentyl] - L-2-acetamide; N- [(1,1-dimethylethoxy) carboni1] -L-valyl-N '- [3, 3,4,4,5,5,6,6,6-nonafluoro-1- (1-methylethyl) -2 -oxohexyl] -L-2-acetamide; N- [4- (4-morpholinylcarbonyl) benzoyl] -L-valyl-N '- [3,3,4,4,5,5,5-heptafluoro-1- (1-methylethyl) -2-oxopentyl] - D, L-2-pipecolinamide; N- [4- (4-morpholinylcarbonyl) benzoyl] -L-valyl-N '- [3,3,4,4,5,5,6,6,6-nonafluoro-l- (1-methylethyl) - 2-oxohexyl] -D, L-2-pipecoline-mide; N- [(1,1-dimethylethoxy) carbonyl] -L-va1i1-N '- [3, 3,4,4,5,5,5-heptafluoro-1- (1-methylethyl) -2-oxopentyl] - D, L-2-pipecolinamidp; N- [(1-1, 1-dimethylethoxy) carbonyl] -L-valyl-N '- [3,3,4,4,5,5,6,6,6-nonafluoro-1- (1-methylethyl ) -2-oxohexyl] -D, L-2-pipecoline-mide; N- [4- (4-morpholinylcarbonyl) benzoyl] -L-valyl-N '- [3,3,4,4,5,5,5-heptafluoro-l- (1-methylethyl) -2-oxopentyl] - D, L-1, 2,3,4-tetrahydro-3-isoquinolinamide; N- [4- (4-morpholinylcarbonyl) benzoyl] -L-valyl-N '- [3, 3,4,4,5,5,6,6,6,6-nonafluoro-1- (1-methylethyl) - 2-oxohexyl] -D, L-1, 2,3,4-tetrahydro-3-isoquinolinamide; N- [(1,1-dimethylethoxy) carbonyl] -L-valyl-N '- [3,3,4,4,5,5,5-heptafluoro-l- (1-methylethyl) -2-oxopentyl] - D, L-1, 2,3,4-tetrahydro-3-isoquinolinamide; N- [(1,1-dimethylethoxy) carbonyl] -L-valyl-N '- [3,3,4,4,5,5,6,6,6-nonafluoro-1- (1-methylethyl) -2 -oxohexyl] -D, L-1, 2,3,4-tetrahydro-3-isoquinolinamide; N- [4- (4-morpholinylcarbonyl) benzoyl] -L-valyl-N 1 - [3, 3, -4,4,5,5,5-heptafluoro-1- (1-methylethyl) -2-oxopentyl] -L-thiazole-din-4-carboxylic acid; N- [4- (4-morpholinylcarbonyl) benzoyl] -L-valyl-N '- [3, 3, -4,4,5,5,6,6,6-nonafluoro-l- (1-methylethyl)] -2-oxohexyl] -L-thiazolidin-4-carboxylic acid; N- [(1,1-dimethylethoxy) carbonyl] -L-valyl-N '- [3,3,4,4,5,5,5,5-heptafluoro-l- (1-methylethyl) -2-oxopentyl] ] -L-thiazolidin-4-carboxylic acid; N- [(1,1-dimethylethoxy) carbonyl] -L-valyl-N '- [3,3,4,4,5,5,6,6,6-nonafluoro-l- (1-methylethyl)] -2-oxohexyl] -L-thiazolidin-4-carboxylic acid.

Preferred compounds of the formula (II) include the following groupings. With respect to the substituent P4, the compounds of the formula (II) wherein P4 is Ala or a bond are preferred.

Particularly preferred are the compounds of the formula (II) wherein P is a bond. With respect to the substituent P3, the compounds of the formula (II) wherein P3 is Lie, Val, or Ala are preferred. Particularly preferred are the compounds of the formula (II) wherein P3 is Val. With respect to the substituent P2, the compounds of the formula (II) wherein P2 is Pro, Tic, Pip, are preferred.

Pro (4-0Bzl), Aze, Pro (4-0Ac) or Pro (4-OH). Particularly preferred are the compounds of the formula (II) wherein P 2 is Pro. With respect to the substituent R 1 t, the compounds of the formula (II) wherein R 1 is -CH (CH 3) 2 or CH 2 CH 2 CH 3, which are the R groups "characteristic of the amino acids Val and Nva respectively. Particularly preferred are the compounds of the formula (II) wherein R? is -CH (CH3) 2. With respect to the substituent K ', the compounds of the formula (II) wherein K' is benzoyl, tertiary butyloxycarbonyl, carbobenzyloxy, isovaleryl, -C (= 0) N (CH 3) 2, are preferred; Specific examples of the preferred compounds of the formula (II) include: N- [(1,1-dimethylethoxy) carbonyl] -L-valyl-N '- [3,3,4,4,4-pent-fluoro-1- (1-methylethyl) -2-oxobutyl] -L- prolinamide; N- [(1,1-dimethylethoxy) carbonyl] -L-valyl-N '- [3,3,4,4,5,5,5-heptafluoro-l- (1-methylethyl) -2-oxopentyl] - L-prolinamide; N- [(1,1-dimethylethoxy) carbonyl] -L-valyl-N '- [3,3,4,4,5,5,6,6,6-nonafluoro-l- (1-methylethyl) -2 -oxohexyl] -L-prolinamide.

Preferred compounds of the formula (III) include the following groupings. With respect to the substituent P4, the compounds of the formula (III) wherein P4 is Ala or a bond are preferred. Particularly preferred are compounds of the formula (III) wherein P4 is a bond. With respect to the substituent P3, the compounds of the formula (III) wherein P3 is Lie, Val or Ala are preferred.

Particularly preferred are the compounds of the formula (III) wherein P3 is Val. With respect to the substituent P, the compounds of the formula (III) wherein P is Pro, Tic, Pip, Tea, Pro (4-0Bzl), Aze, Pro (4-0Ac), or Pro (4-OH) are preferred. ). Particularly preferred are the compounds of the formula (III) wherein P2 is Pro. With respect to the Rx substituent, the compounds of the formula (III) wherein R is -CH (CH3) 2 or -CH2CH2CH3, which are the "R groups" characteristic of the amino acids Val and Nva, respectively. Particularly preferred are the compounds of the formula (III) wherein R? is -CH (CH3) 2. With respect to substituent K ", particularly preferred are compounds of formula (III) wherein K1 'is HH • f B-Z' 0 / and where Z is N, and B is a group of the formulas: 0 0 0 or - - CH c-t - c CH c4 R 'R' and wherein R1 is hydrogen or an alkyl group of 1 to 6 carbon atoms. Specific examples of the preferred compounds of the formula (III) include: N- [4- (4-morpholinylcarbonyl) benzoyl] -L-valyl-N '- [3,3,4,4,4'-pentafluoro-1- (1-methylethyl) -2-oxo-butyl] -L-prolinamide; N- [4- (4-morpholinylcarbonyl) enzoyl] -L-valyl-N '- [3, 3,4,4,5,5,5-heptafluoro-1- (1-methylethyl) -2-oxopentyl] - L-prolinamide; N- [4- (4-morpholinylcarbonyl) benzoyl] -L-valyl-N '- [3, 3,4,4,5,5,6,6,6,6-nonafluoro-1- (1-methylethyl) - 2-oxopentyl] -L-prolinamide.

Preferred compounds of the formula (IV) include the following groupings. With respect to the substituent P4, the compounds of the formula (IV) wherein P is Ala or a bond are preferred. Particularly preferred are the compounds of the formula (IV) wherein P is a bond. With respect to the substituent P3, the compounds of the formula (IV) wherein P3 is Lie, Val or Ala are preferred. Particularly preferred are the compounds of the formula (IV) wherein P3 is Val. With respect to the substituent P2, the compounds of the formula (IV) wherein P2 is Pro, Ind, Tic, or Tea are preferred. Particularly preferred are the compounds of the formula (IV) wherein P2 is Pro. With respect to the substituent P1; particularly preferred are compounds of the formula (IV) wherein P? is Val or Nva. Specific examples of the preferred compounds of the formula (IV) include: N- [3- (3-pyridyl) propanoyl] -L-valyl-N '- [3,3,4,4,4-pentafluoro-1- (1-methylethyl) -2-oxo-butyl] -L-prolinamide; N- [3- (3-pyridyl) propanoyl] -L-valyl-N '- [3,3,4,4,4-pentafluoro-1- (1-methylethyl) -2-oxobutyl] -D, L- 1, 2,3, 4-tetrahydro-3-isoquinoline ida; N- [3- (3-pyridyl) propanoyl] -L-valyl-N '- [3, 3, 4,4,4-pentafluoro-1- (1-methylethyl) -2-oxobutyl] -Lt-iazole idin -4-carboxylic acid In general, the compounds of the formulas (I) - (IV) can be prepared using conventional chemical reactions in a manner analogous to that known in the art and as illustrated in scheme A.

Scheme A H2N-CH (1) -C (= O) -X (1) ?2. P3. K- 4 Pair (SEQ ID NO.1) K-P4-P3-P2- HN-CH (R1) -C (= 0) -X. { I KNOW THAT. ID NO. 2) . { I KNOW THAT. ID NO. 3) l-IV (SEQ ID NO 4) Groups P2, P3, and K-P can be linked to the free amino group of the amino acid derivative of structure (1). Note that structure (1) represents the fraction of P-_ where the free carboxylic acid group has been substituted with an "X" fraction as defined above. P2, P3, and K-P4 can be linked to the unprotected free amino compound (Pi ~ X) by well-known peptide coupling techniques. In addition, the groups P ?, P2, P3, and K-P4 can be linked together in any order, provided that the final compound is K-P4-P3-P2-P1-X. For example, K-P4 can be linked to P3 to give K-P4-P3 which is linked to P2-P1-X; or K-P4 binds to P-3-P2 and then binds to an appropriately protected P1 with C-terminal, and the C-terminal protecting group is converted to X. In general, the peptides are elongated by deprotection of the amine of the N-terminal residue, and coupling the next N-protected amino acid suitably via a peptide bond, using the methods described. This deprotection and coupling procedure is repeated until the desired sequence is obtained. This coupling can be performed with the constituent amino acids in a stepwise fashion, as illustrated in Scheme A, or by fragment condensation (from 2 to several amino acids), or a combination of both processes, or by peptide synthesis in phase solid according to the method originally described by Merrifield, J. AM. Chem. Soc. 1963, 85, 2149-2154, the disclosure of which is incorporated herein by reference. When the synthetic approach is used in solid phase, the C-terminal carboxylic acid is bound to an insoluble vehicle (usually polystyrene). These insoluble carriers contain a group that will react with the aldehyde group to form a bond that is stable to the elongation conditions, but readily dissociates thereafter. Examples of these are: chloro- or bromo-methyl resins, hydroxymethyl resin, and aminomethyl resin. Many of these resins are commercially available with the desired C-terminal amino acid already incorporated. Alternatively, the compounds of the invention can be synthesized using automated peptide synthesizing equipment. In addition to the above, peptide syntheses are described in Stewart and Young, "Solid Phase Peptide Synthesis", 2 & Edition, Pierce Chemical Co., Rockford, IL (1984); Gross, Meienhofer, Uden-friend, Eds., "The Peptides: Analysis, Synthesis, Biology", Volumes 1, 2, 3, 5 and 9, Academic Press, New York, 1980-1987; Bodanszky, "Peptide Chemistry: A Practical Textbook", Springer-Verlag, New York (1988); and Bodanszky et al., "The Practice of Peptide Synthesis" Springer-Verlag, New York (1984), whose descriptions are incorporated herein by reference. The coupling between two amino acids, an amino acid and a peptide, or two peptide fragments, can be carried out using conventional coupling methods, such as the azide method, the mixed carbonic acid-carboxylic anhydride method (isobutyl chloroformate), the carbodiimide method (dicyclohexyl carbodiimide, diisopropyl carbo-diimide, or water-soluble carbodiimide), the active ester method (p-nitrophenyl ester, N-hydroxysuccinic imidoester), the oodward K reagent method, the carbonyldiimidazole method, the phosphorus reagent methods such as B0P-C1, or oxidation-reduction. Some of these methods (especially the carbodiimide method) can be improved by the addition of 1-hydroxybenzotriazole, N-hydroxysuccinimide, dimethylaminopyridine, or the like. These coupling reactions can be carried out either in the solution phase (liquid phase) or in the solid phase. The functional groups of the constituent amino acids generally must be protected during the coupling reactions to avoid the formation of undesired bonds. Protective groups that can be used are mentioned in Greene, "Protective Groups in Organic Chemistry," John Wiley & amp;; Sons, New York (1981), and "The Peptides: Analysis, Synthesis, Biology", Volume 3, Academic Press, New York (1981), whose description is incorporated herein by reference. The α-carboxyl group of the C-terminal residue is normally, but not necessarily, protected with an ester that can be dissociated to the carboxylic acid. Protecting groups that can be used include: 1) alkyl esters such as methyl and tertiary butyl, 2) aryl esters such as benzyl and substituted benzyl, or 3) esters that can be dissociated by treatment with weak base or weak reducing elements, such as trichloroethyl and phenacrylic esters. The a-amino group of each amino acid that is to be coupled with the growing peptide chain must be protected. Any protecting group known in the art can be used. Examples of these include: 1) acyl types, such as formyl, trifluoroacetyl, phthalyl, and p-toluenesulfonyl; 2) the aromatic carbamate types, such as benzyloxycarbonyl (Cbz or Z), and substituted benzyloxycarbonyls, 1- (p-biphenyl) -l-methylethoxycarbonyl, and 9-fluoro-nylmethyloxycarbonyl (Fmoc); 3) the aliphatic carbamate types such as tertiary butyloxycarbonyl (Boc), ethoxycarbonyl, diisopropylmethoxycarbonyl, and allyloxycarbonyl; 4) the cyclic alkyl carbamate types such as cyclopentyloxycarbonyl and adamantyloxycarbonyl; 5) alkyl types such as triphenylmethyl and benzyl; 6) trialkyl silane such as trimethylsilane; and 7) thiol-containing types, such as thiophenylcarbonyl and dithiasuccinoyl. The preferred a-amino protecting group is Boc or Fmoc, preferably Boc. There are many amino acid derivatives suitably protected for the synthesis of commercially available peptides. The protecting group of the a-amino group of the newly added amino acid residue is dissociated before coupling the next amino acid. When the Boc group is used, the methods of choice are trifluoroacetic acid, clean or in dichloromethane, or HCl in dioxane-diethyl ether, or ethyl acetate. The resulting ammonium salt is then neutralized either before coupling or at the site with basic solutions such as aqueous pH regulators, or tertiary amines in dichloromethane or dimethyl formamide. When the Fmoc group is used, the reagents of choice are piperidine or substituted piperidine in dimethyl formamide, but any secondary amine or aqueous basic solutions can be used. The deprotection is carried out at a temperature between 0 ° C and room temperature. Any of the amino acids that carry side chain functionalities must be protected during the preparation of the peptide, using any of the groups described above. Those skilled in the art will appreciate that selection and use of appropriate protecting groups for these side chain functionalities depend on the amino acid and the presence of other protecting groups in the peptide. The selection of these protective groups is important because they should not be removed during deprotection and coupling of the a-amino group. For example, when Boc is used as the a-amino protecting group, the following side chain protecting groups are suitable: the p-toluenesulfonyl (tosyl) moieties can be used to protect the chains of amino acids such as Lys. and Arg; the p-methylbenzyl, acetamidomethyl, benzyl (Bzl), or tertiary-sulfonyl butyl fractions can be used to protect the sulfide-containing side chains of amino acids such as cysteine, and benzyl ether (Bzl) can be used to protect to the hydroxy-containing side chains of the amino acids such as Ser or Thr. When Fmoc is selected for a-amine protection, tertiary butyl-based protecting groups are usually acceptable. For example, Boc can be used for lysine, tertiary butyl ether for serine and threonine, and tertiary butyl ester for glutamic acid. Once the elongation of the peptide is complete, all protecting groups are removed. When a liquid phase synthesis is carried out, the protecting groups are removed in any manner that is dictated by the selection of the protecting groups. These methods are well known to those skilled in the art. When a solid phase synthesis is used, the peptide is dissociated from the resin usually in a simultaneous manner with the removal of the protecting group. When the Boc protection scheme is used in the synthesis, treatment with anhydrous hydrofuran containing additives such as dimethyl sulfoxide, anisole, thioanisole, or p-cresol at 0 ° C, is the preferred method to dissociate the peptide from the resin. The dissociation of the peptide can also be carried out by other acid reagents, such as mixtures of trifluoromethanesulfonic acid / trifluoroacetic acid. If the Fmoc protection scheme is used, the N-terminal Fmoc group dissociates with the reagents described above. The other protecting groups and the peptide are dissociated from the resin using a solution of trifluoroacetic acid and different additives such as anisole, and the like. Alternatively, the compounds of formulas (I) - (IV) can be prepared using conventional chemical reactions in a manner analogous to what is known in the art, and as illustrated in Scheme B. Scheme B H2N-CH (R,) - CH (OH) -X (2) P2 p3, K-P4 Pair K-P4-P-P2- HN-CH (R,) - CH (OH) -X (3) (SEQ ID No. 5) Oxidation (SEQ ID No. 1) K-P4-P3-P2- HN-CH < R1) -C (= O) -X (SEQ ID NO: 2), _ | V (SEQ ID NO 3) (SEQ ID NO 4) Scheme B provides an alternative general synthetic scheme for the preparation of the compounds of the formulas (I) - (IV). The groups P, P3, and KP can be linked to the free amino group of the amino alcohol derivative of structure (2), as described above in Scheme A, to give the peptide alcohol of structure (3) . The alcohol functionality of the peptide alcohol of structure (3) is then oxidized by techniques and procedures well known and appreciated by one of ordinary skill in the art, such as Swern Oxidation using oxalyl chloride or trifluoroacetic anhydride and dimethyl sulfoxide. , to give the compounds of the formula I. The starting materials to be used in the Schemes A and B are readily available to an ordinary expert in this field. For example, the amino acids P2, P3, and K-P, where K is hydrogen, are commercially available, and the linker compound of the structure (Ll) is described in J. Am. Chem. Soc. f 114, 3157-59 (1992). In addition, the substituted amino acids KP, wherein K is acetyl, succinyl, benzoyl, tertiary butyl-carbonyl, carbobenzyloxy, tosyl, dansyl, isovaleryl, methoxysuccinyl, 1-adamantanesulfonyl, 1-adamantanacetyl, 2-carboxybenzoyl, phenylacetyl, tertiary butyl- acetyl, bis [(1-naphthyl) -methyl] acetyl, or -A-Rz where: ooo A is -C-. -N-C- -O-C- or -í - and II 0 Rz is an aryl group containing 6, 10, or 12 carbon atoms suitably substituted by 1 to 3 members independently selected from the group consisting of fluorine, chlorine, bromine, iodine, trifluoromethyl, hydroxy, alkyl containing 1 to 6 carbon atoms, alkoxy containing from 1 to 6 carbon atoms, carboxy, alkylcarbonylamino wherein the alkyl group contains from 1 to 6 carbon atoms, 5-tetrazolyl, and acylsulfonamido (ie, acylaminosulfonyl and sulfonylaminocarbonyl) containing 1 to 15 carbon atoms, since when the acylsulfonamido contains an aryl, the aryl may be further substituted by a member selected from fluorine, chlorine, bromine, iodine, and nitro; and the other amino terminal protecting groups that are functionally equivalent thereto are described in European Patent Application OPI No. 0363284, April 11, 1990. The starting amino compounds of structure (1) are readily available. available to an ordinary expert in this field. For example, the amino compounds of structure (1) wherein X is -CF2CF3 are described in European Patent Application OPI Number 0503203, September 16, 1992. In addition, the amino compounds of structure (1) wherein X is CF2CF3, are described in European Patent Application OPI Number 0410411, January 30, 1991. In addition, other starting materials may be prepared for use in Schemes A and B by the following synthetic procedures, which They are well known and appreciated by an ordinary expert in this field. The substituted amino acids K-P of the structure where K is \ where: Z is N or CH, and B is a group of the formulas: 0 0 0 CH - C - CH c - R R ' 0 0 or OR wherein R1 is hydrogen or an alkyl group of 1 to 6 carbon atoms are prepared using conventional chemical reactions in a manner analogous to that known in the art. The process for the preparation of the substituted amino acids K-P4 wherein K is -Z O where: B is a -C (= 0) -, are illustrated in Scheme C, where P and Z are as defined above, or are the functional equivalents of these groups.

Scheme C O Cl (4) s \ or (5) \ / Specifically, the amino acids K-P where K is B ~ ZO \ / where: B is -C (= 0) -, are prepared by coupling the amino acid K-P4, where K is hydrogen, with 'n acid chloride of the structure (4), in the presence of one to four molar equivalents of a suitable amine, which can act as a hydrogen halide acceptor. Suitable amines for use as hydrogen halide acceptors are tertiary organic amines, such as triamines (lower alkyl), for example, triethyl amine, or aromatic amines such as picolines, collidine, and pyridine. When pyridines, picolines, or collidines are used, they can be used in a high excess, and can therefore also act as the solvent of the reaction. N-methyl morpholine ("NMM") is particularly suitable for the reaction. The coupling reaction can be carried out by the addition of an excess, such as from 1 to 5 times, preferably a molar excess of about 4 times of the amine, and then the acid chloride of the structure (4), to a solution of the amino acid K-P4 where K is hydrogen. The solvent can be any suitable solvent, for example, petroleum ethers, a chlorinated hydrocarbon such as carbon tetrachloride, ethylene chloride, methylene chloride, or chloroform; a chlorinated aromatic such as 1,2,4-trichlorobenzene or o-dichlorobenzene; carbon disulfide; an ether solvent such as diethyl ether, tetrahydrofuran, or 1,4-dioxane, or an aromatic solvent such as benzene, toluene, or xylene. Methylene chloride is the preferred solvent for this coupling reaction. The reaction is allowed to proceed for from about 15 minutes to about 6 hours, depending on the reagents, the solvent, the concentrations, and other factors, such as temperature, which may be from about 0 ° C to about 60 ° C, conveniently at about room temperature, that is, 25 ° C. The N-protected amino acids K-P4, where K is wherein: B is a -C (= 0) -, can be isolated from the reaction mixture by any suitable techniques, such as by chromatography on silica gel. The substituted K-P amino acids where K is where: B is different from -C (= 0) -, they can be prepared in an analogous way, merely substituting the appropriate intermediary A - B ~ ZO ^ where: B is different from -C (= 0) -, and A is Cl or OH (the corresponding acid, acid chloride, or sulfonyl chloride) for the compound of the structure (5) in Scheme C. The acid chloride of structure (4), and the appropriate intermediate of the formula / \ A - B - ZO \ / wherein: B is different from -C (= 0) -, and A is Cl or OH (the corresponding acid, acid chloride, or sulfonyl chloride), are commercially available, or can be easily prepared by well-practiced techniques and procedures known and appreciated by an ordinary expert in this field. - For example, the appropriate intermediaries of the formula they can be prepared as illustrated in Scheme D, wherein all substituents are as defined above.

Scheme D ruro (6) Amidation (7) (9) 0 (10) Scheme D provides a general synthetic procedure for the preparation of the appropriate intermediates of the formula: where: Z is as defined above. In step a, the carboxylic acid functionality of the appropriate 2, 5-pyridinedicarboxylic acid 2-methyl ester (6) (Nippon Kagaku Zaeshi, 1967, 8J3, 563), is converted to its acid chloride using techniques and procedures. well known and appreciated by one of ordinary skill in the art, such as thionyl chloride, to give the corresponding 6-carbomethoxynicotinoyl chloride (7). In step b, the acid chloride (7) is amidated with morpholine (8) by techniques and procedures well known and appreciated by one of ordinary skill in the art, to give the methyl ester of 5- (morpholin-4) acid -carbonyl) -2-pyridinecarboxylic (9). In step c, the methyl ester functionality (9) is hydrolyzed by techniques and procedures well known and appreciated by one of ordinary skill in the art, for example, with lithium hydroxide in methanol, to give 5- (morpholin-4) acid -carbonyl) -2-pyridinecarboxylic (10). In addition, the appropriate intermediary of the formula: 0 it can be prepared as illustrated in Scheme E, wherein all substituents are as defined above.

Scheme E (6) Amidation (eleven) (12) (13) Scheme E provides a general synthetic procedure for the preparation of the appropriate intermediates of the formula: where: Z is as defined above, In step a, the free carboxylic acid functionality of 2-methyl-5-pyridinedicarboxylic acid ester (6) (Nippon Kagaku Zasshi, 1967, 88./563), is converted to its tertiary butyl ester using techniques and procedures well known and appreciated by one of ordinary skill in the art, such as the adduct of tertiary carbodiimide butyl dicyclohexyl alcohol (Synthesis, 1979, 570), to give the tertiary 5-butyl ester of 2-methyl 2-methyl 2-methyl ester corresponding pyridinedicarboxylic acid (11). For example, the 2-methyl ester of 2,5-pyridinedicarboxylic acid (6) is combined with a molar excess of the dicyclohexyl carbodiimide tertiary butyl alcohol adduct in an appropriate organic solvent, such as methylene chloride. The reaction is typically conducted on a temperature scale of 0 ° C to room temperature, and for a period of time of 2 to 24 hours. The 2-methyl-5-pyridinedicarboxylic acid tertiary 2-methyl ester ester (11) is isolated from the reaction mixture by conventional extraction methods, as is known in the art, and can be purified by crystallization. In step b, the methyl ester functionality of (11) is amidated with morpholine (8) to give the corresponding tertiary butyl ester of 6- (morpholin-4-carbonyl) nicotinic acid (12). For example, the 5-butyl tertiary ester of 2-methyl-2-pyridinedicarboxylic acid ester (11) is contacted with a molar excess of morpholine in an appropriate organic solvent, such as tetrahydrofuran. The reaction is typically conducted on a temperature scale from room temperature to the reflux temperature, and for a period of time from 5 hours to 3 days. The tertiary butyl ester of 6-morpholin-4-nicotinic acid (12) is isolated from the reaction mixture by conventional extraction methods, as is known in the art, and can be purified by crystallization. In step C, the tertiary butyl ester functionality of (12) is hydrolysed, for example, with HCl in nitromethane, to give the corresponding 6- (morpholine-4-carbonyl) nicotinic acid (13).

In Scheme F alternative routes are shown for the preparation of the compounds of structure (1) wherein X = -CF2CF3.

Scheme F Rl -.CH, i P4P3P2NH-CH_ "N O-CH3 PgNH-CH, 0 (SEQ ID NO 6) 0 Ri i KP4P 3, PP2, NHH - CCfK / CF2CF3 (SEQ ID NO.7) (18) The required starting material defined by the compound (14) is readily available, either commercially or by the application of known prior principles and techniques. The term "Pg" refers to a suitable protecting group, as defined more fully in the foregoing. In Scheme F, step A, the protected amino acid (14) is transformed into the hydroxamate (15). This amidation can be carried out using a coupling reaction as between two amino acids, using the protected amino acid (14) and the N-alkyl O-alkylhydroxylamine. The conventional coupling reaction can be performed using conventional coupling methods as described above for coupling between two amino acids, to provide the hydroxamate (15). In step b, the protected hydroxamate (15) is transformed into the protected pentafluoroketone (157) [or (18)]. This reaction can be carried out using a reaction of the type described in the following reference: M.R. Angelastro, J.P. Burkhart, P. Bey, N.P. Peet, Tetrahedron Letters, 3 (1992), 3265-3268. In step c, hydroxamate (15) is deprotected under conditions well known in the art, as described by T.H. Green "Protection Groups in Organic Synthesis", John Wiley and Sons, 1981, Chapter 7, to provide the deprotected hydroxamate. The deprotected hydroxamate is lengthened by coupling the next suitably protected amino acid through a peptide bond, using the methods previously described in Scheme A, or by fragment condensation, or a combination of both processes, to provide the elongated peptide ( 16). In step d, the ketone (17) is deprotected under conditions as described above. The deprotected ketone (17) is lengthened by coupling the next suitably protected amino acid through a peptide bond, using the methods previously described in Scheme A, or by a fragment condensation, or a combination of both processes, to provide the elongated ketone (18). Alternatively, the corresponding N-protected amino acid ester of (14) [ie, PgNH-CH (R1) C - (= 0) OR2, (15a), wherein R and Pg are as defined above] , can be used to replace hydroxamate (15). The corresponding protected amino acid esters of (14) are commercially available, or can be easily synthesized from (14) by methods well known to one of ordinary skill in the art. In step b, the amino acid ester (15a) is transformed into the N-protected pentafluoroketone (17) [or (18)], in a manner directly analogous to that employed for the corresponding hydroxamate. Steps c and d should be the same as those used when hydroxamate was used (15). Scheme F is also applicable for the preparation of the compounds of structure (1) wherein X is -CF2CF2CF3, the amino acid ester (15a) being reacted with a suitable perfluorinating agent, such as from 4 to 8 equivalents of iodide of perfluoropropyl or perfluorobutyl iodide, although equivalent bromides can also be used. This reaction is carried out in the presence of a suitable alkali metal base, for example, from 4 to 8 equivalents of MeLi / LiBr in an appropriate anhydrous solvent (or mixed solvents), such as ether, tertiary butyl methyl ether, or toluene . Other examples of suitable alkali metal bases include t-BuLi, EtMgBr, PhMgBr, n-BuLi, and the like. The reaction is carried out at a reduced temperature of -100 ° C to 0 ° C, preferably -30 ° C to -80 ° C, to provide the protected perfluoropropyl amino ketone and the protected perfluorobutyl aminoce-tone., respectively. Steps c and d would be the same as those used when hydroxamate was used (15). Alternatively, the N-protected amino acid ester (15a) could be first deprotected and coupled with a suitably N-protected peptide in the presence of a suitable coupling agent, and in the presence of an appropriate coupling solvent. The N-protected peptide ester subsequently formed [KP4P3P2NH-CH (R?) C (= 0) 0R2, (16a)] would then be perfluorinated in a manner directly analogous to that employed for the corresponding hydroxamate. Steps c and d would be the same as those used when hydroxamate was used (16). For the purposes of this invention, the terms "suitable coupling agent" and "appropriate coupling solvent" include any of the conventional coupling reagents and solvents used in the conventional coupling processes used in the conventional coupling procedures defined above. In a similar manner, the terms "suitable deprotection agent" and "appropriate organic solvent" are intended to include any of the conventional deprotection agents and solvents used in the conventional deprotection procedures described above. The related procedures are described in Gassman, P.G. , O'Reilly, N.J., J. Org. Chem. 1987, 52, 2481 and Portella, C., Doussot, P., Dondy, B., Synthesis 1992, 995. All the amino acids used in the synthesis of formula I are commercially available or are easily synthesized by a person skilled in the art. relevant. For example, the amino acid derivative: C - CH3 defined in P2, it can be done by esterifying: OH by employing techniques well known to one of ordinary skill in the art.

The following examples present typical syntheses as described in Schemes A to F. It is understood that these examples are illustrative only, and are not intended to limit the scope of the present invention in any way. As used herein, the following terms have the indicated meanings: "g" refers to grams; "mmol" refers to millimoles; "my" refers to milliliters; "pe" refers to boiling point; "° C" refers to degrees Celsius; "mm Hg" refers to millimeters of mercury; "μL" refers to microliters; "μg" refers to micrograms; and "μM" refers to micromolar; "DME" refers to 1,2-dimethoxyethane; "DCC" refers to carbodiimide dicyclohexyl-ca; "h" refers to hour; "DMF" refers to formamide N, N'-dimethyl; "conc." refers to concentrate; "NMM" refers to N-methyl morpholine; "vacuum" refers to the removal of the solvent under reduced pressure; "GC" refers to gas chromatography; "Rt" refers to retention time.

EXAMPLE 1 Preparation of N-f (1,1-dimethylethyl) c-nyl ^ -L-valyl-N, -f3-methoxy-1- (1-methylethyl) -2-oxopropyl-T-L-prolinamide DL 104,259 To a solution of N- (tertiary butyloxy-carbonyl) -L-valyl-L-proline (from Advanced ChemTech, 3.1 grams, 0.01 moles) and N-methyl morpholine (1.10 milliliters, 0.01 moles) in CH2C12 (100 milliliters) , at -20 ° C, isobutyl chloroformate (1.30 milliliters, 0.01 mol) was added at -20 ° C. After stirring for 20 minutes, an additional equivalent of N-methyl morpholine (1.10 milliliters, 0.01 mol) was added, followed by the addition of L-valine methyl ester hydrochloride (1.67 grams, 0.01 mol, Aldrich), as a solid in one portion. The reaction was stirred at -20 ° C for an additional 1 hour, and then allowed to warm to room temperature. Then the reaction mixture was diluted with additional CH C12 (50 milliliters), and washed with IN HCl (3 x 50 milliliters), saturated NaHCO 3 (2 x 50 milliliters), and brine (1 x 50 milliliters). The resulting organic extract was dried (MgSO4) and concentrated in vacuo to give the desired product (MDL 104259) (4.27 grams, 100 percent) as a soft foam. TLC Rf 0.33 (3: 1 Et20-hexane); FT-IR (KBr) 3553, 3537, 3520, 3510, 3310, 2968, 2935, 2876, 1741, 1687, 1631, 1527, 1440, 1390, 1367, 1338, 1309, 1244, 1203, 1172, 1114, 1093, 1043, 1016, 962, 923, 883, 831, 754, 665, 628, 603 cm "1; 1 H NMR (300 MHz, CDC13) d 7.22 (br d, 1 H, J = 8.4 Hz, NH), 5.24 (br d, 1H, J = 11.0 Hz, NH), 4.62 (dd, 1H, J = 8.2, 2.9 Hz, CH of Val), 4.43 (app.dd, 1H, J = 8.6, 5.1 Hz, CH of Pro), 4.30 (dd, 1H, J = 9.5, 6.4 Hz, CH of Val), 3.75-3.70 and 3.63-3.59 (pr m, 2H, CH2N), 3.7 (s, 3H, Ome), 2.36 (m, 1H, ß -CH of Val), 2.17-1.9 (m, 5H, CH2CH2 and ß-CH of Val), 1.43 (s, 9H, t-Bu), 1.00 (d, 3H, J = 6.7 Hz, CH3), 0.95- 0.90 (m, 9H, 3 X CH3), 13C CMR S 172.5, 172.1, 170.9, 155.8, 79.5, 77.4, 771., 76.9, 76.8, 76.5, 59.9, 57.5, 56.7, 52.0, 47.6, 31.4, 31.0, 28.3 , 28.2, 27.1, 25.1, 19.5, 18.9, 17.8, 17.3; MS (CI / CH4) m / z (relative intensity) 428 (MH +, 22), 372 (68), 328 (100). Analysis Calculated for C21H37N306; C, 58.99, H, 8.72; N, 9.83. Found: C, 58.68; H, 8.79; N, 9.55.

EXAMPLE 2 Preparation of N-r (1'-dimethylethoxy) oarbonyl-1-L-valyl-N '[3, 3, 4, 4, 4-pentafluoro-l- (1-methylethyl) -2-oxopropyl-1-L-proline MDL 102,051 To a solution at -78 ° C of the product of Example 1 (3.8 grams, 9.0 moles) in Et20 (100 milliliters), condensed pentafluoroethyl iodide (5.5 milliliters, 48.0 mmol) was added. To the mixture was added a complex of lithium methyl-lithium bromide (28.5 milliliters, 42.0 millimoles) at a rate that maintained an internal reaction temperature of less than -70 ° C. The reaction mixture was stirred at -78 ° C for 0.5 hour, the cold bath was removed, and stirring was continued for 5 minutes. The mixture was poured into H20 (100 milliliters), and the aqueous phase was acidified with IN HCl. The aqueous phase was extracted with additional Et20 (100 milliliters), and the combined ether extracts were dried (MgSO4). The solvent was removed in vacuo to give a crude yellow oil which was immediately passed through evaporation chromatography (4.0 x 25 cm column eluted with 3: 1 Et20-hexane), to give the desired product (MDL 102.051) (1.95 grams). , 42 percent) as a white foam; 1 H NMR (300 MHz, CDC13) d 7.60 (br d, 1 H, J = 7.6 Hz, NH), 5.23 (br d, 1 H, J = 9.2 Hz, NH), 4.94 (dd, 1 H, J = 7.6, 4.4 Hz, CH of Val), 4.63 (dd, 1H, J = 8.1, 2.8 Hz, CH of Pro), 4.28 (dd, 1H, J = 9.3, 6.5 Hz, -CH of Val), 3.81-3.69 and 3.64- 3.54 (pr m, 2H, CH2N), 2.44-1.81 (series of m, 6H, ß-CH of Val, CH2CH2), 1.44 (s, 9H, t-Bu), 1.02 (d, 3H, J = 6.8 Hz , CH3), 0.98 (d, 3H, J = 6.8 Hz, CH3), 0.95 (d, 3H, J = 6.8 Hz, CH3), 0.88 (d, 3H, J = 6.8 Hz, CH3); 19F NMR d -82.15 (s, CF3), -121.70 and -122.70 (AB quartet, J = 296 Hz, CF2); MS (CI / CH4) m / z (relative intensity) 516 (MH +, 52), 460 (100), 416 (26).

EXAMPLE 3 Preparation of Nf (1, 1-dimethylethoxy) carbonyl] -L-valyl-N 1 - [3,3,4,4,5,5, S-heptafluoro-l- (1-methylethyl) -2-oxopentyl) -L- Prolinamide MDL 103.830 To a solution at -78 ° C of the product of Example 1 (3.8 grams, 9.0 mmol) in Et20 (100 milliliters), perfluoropropyl iodide (6.6 milliliters, 48.0 mmol, Aldrich, stabilized with Cu). To this mixture was added a complex of lithium methyl-lithium bromide (28.5 milliliters, 42.0 millimoles) at a rate that maintained an internal reaction temperature of less than -70 ° C. The reaction mixture was stirred at -78 ° C for 1 hour, the cold bath was removed, and stirring was continued for 5 minutes. The mixture was poured into H20 (100 milliliters), and the aqueous phase was acidified with 1N HCl. The aqueous phase was extracted with additional Et20 (100 milliliters), and the combined ether extracts were dried (MgSO4). The solvent was removed in vacuo to give a crude yellow oil, which was immediately passed by evaporation chromatography (4.0 x 25 cm column eluted with 3: 1 Et20-hexane), to give the desired product (MDL 103.830) ( 654 milligrams, 13 percent) as a white foam; FT-IR (KBr), 3423, 3292, 2972, 2937, 2879, 2823, 2771, 2253, 1755, 1687, 1635, 1525, 1444, 1392, 1367, 1348, 1313, 1232, 1178, 1126, 1041, 1018 , 966, 922, 910, 877, 837, 798, 756, 736, 667, 650, 632, 596 cm "1; XH NMR (300 MHz, CDC13) d 7.63 (d, 1H, J = 8.2 Hz, NH) , 5.44 (d, 1H, J = 9.2 Hz, NH), 5.02 (dd, 1H, J = 7.8, 4.5 Hz, CH of Val), 4.64 (dd, 1H, J = 8.0, 3.0 Hz, CH of Pro) , 4.30 (dd, 1H, J = 9.2, 6.8 Hz, a-CH of Val), 3.80-3.74 and 3.66-3.60 (pr, 2H, CH2N), 2.31-1.92 (series of m, 6H, ß-CH of Val, CH2CH2), 1.44 (s, 9H, I-Bu), 1.02 (d, 3H, J = 7.0 Hz, CH3), 0.98 (d, 3H, J = 6.9 Hz, CH3), 0.94 (d, 3H, J = 6.7 HZ, CH3), 0.88 (d, 3H, J = 6.9 Hz, CH3): 13C NMR <193.3, 193.0, 192.7, 172.9, 171.1, 155.7, 115.8, 111.3, 108.9, 108.6, 108.2, 105.9 , 79.6, 77.3, 77.2, 76.9, 76.6, 59.7, 59.3, 56.8, 47.8, 31.4, 29.0, 28.3, 26.9, 25.1, 19.9, 19.8, 19.7, 19.5, 19.5, 19.5, 19.5, 19.5, 19.5 376.3 MHz, CDC13) d -80.91 (t, CF3), -119.03 and -120.43 (AB quartet, J = 297 Hz , CF2), -126.62 (s, CF2); MS (CI / CH4) m / z (relative intensity) 566 (MH +, 100). HRMS (C 23 H 34 F 7 N 305) (M +) calculated 566.2492, observed 566.2475.

EXAMPLE 4 Preparation of N ~ r (1 * 1-dimethylethoxy) carbonyl-1-L-valyl-Nt- [3,3,4,4,5,5,6,6,6-nonafluoro-1- (1-methylethyl) -2- oxohexill -L-prolinamide MDL 105,731 To a solution at -78 ° C of the product of Example 1 (3.8 grams, 9.0 mmol) in anhydrous Et20 (100 milliliters), perfluoropropyl iodide (3.6 milliliters, 48.0 mmol, from Aldrich) was added dropwise under N2. ). To this mixture was added an ethyl lithium-lithium bromide complex (28.5 milliliters, 42.0 millimoles) at a rate that maintained an internal reaction temperature of less than -70 ° C. The reaction mixture was stirred at -78 ° C for 1 hour, the cold bath was removed, and stirring was continued for 5 minutes. The mixture was then poured into H20 (100 milliliters), and the aqueous phase was acidified with IN HCl. The aqueous phase was extracted with additional Et20 (100 milliliters), and the combined ether extracts were dried (MgSO4). The solvent was removed in vacuo to give a crude yellow oil, which was immediately passed by evaporation chromatography (4.0 x 25 cm column eluted with 3: 1 Et20-hexane), to give the desired product (MDL 105.731) ( 493 milligrams, 9 percent) as a white foam; FT-IR (KBr) 3421, 3292, 2972, 2937, 2879, 2773, 1755, 1687, 1637, 1525, 1444, 1392, 1367, 1309, 1238, 1174, 1138, 1093, 1043, 1016, 960, 927, 875, 848, 744, 709, 690, 667, 653, 632, 599, 574 cm "1; 13C NMR 173.0, 170.9, 155.7, '79.7, 77.2, 77.1, 76.9, 76.6, 59.7, 59.3, 56.8, 47.8 , 31.3, 28.9, 28.3, 26.7, 26.1, 19.8, 19.5, 17.4, 16.2, 19F NMR (376.2 MHz, CDC13) d -81.35 (s, CF3), -118.27 and -119.91 (AB quartet, J = 297 Hz, CF2), -123.09 (s, CF2), -125.97 (s, CF2), MS (CI / CH4) m / z (relative intensity) 616 (MH +, 68), 560 (100), 516 (31). Calculated for C24H34F9N305: C: 46.83; H, 5.57; N, 6.83 .. Found: C, 46.32; H, 5.65; N, 6.66 HRMS (C24H34F9-N305) calculated 616.2433, observed 616.2435 EXAMPLE 5 Preparation of NL-valil -N'-r3,3,4,4,5,5,5-heptafluoro-1- (l-methylethyl) -2-oxopentyl-L-prolinamide In a stirred solution of the product of Example 3 (0.21 grams, 0.37 mmol) in EtOAc (10 milliliters) cooled in an ice water bath, HCl gas was bubbled for 4 minutes. The bubbling was stopped and the reaction was capped with a drying tube, and allowed to warm to room temperature with stirring. After 1 hour, the reaction was concentrated and azeotroped with CC14, and placed under high vacuum to give the desired product (185 milligrams, 100 percent) as a white solid; NMR (300 MHz, CDC13) d 8.29 (br s, 2 H, NH 2), 7.88 (br s, 1 H, NH), 5.70 (m, 1 H, CH), 4.89 (m, 1 H, CH), 4.16-3.55 ( a series of m, 4H, CH, CH, CH2N), 2.40-1.94 (a series of, 5H, ß-CH of Val and CH2CH2), 1.13 (br s, 6H, 2 x CH3), 1.01 (d, 3H , J = 5.8 Hz, CH3), 0.94 (d, 3H, J = 4.8 Hz, CH3); 19 F NMR d-81.02 (s, CF 3), -120.11 (s, CF 2), -126.75 (s, CF 2).

EXAMPLE 6 Preparation of N- | ~ 4- (4-morpholinylcarbonyl) benzoyl "l-valyl-N '- [3,3,4,4,5,5,5-heptafluoro-l- (1-methylethyl) -2 - oxopentill -L-prolinamide To a stirred suspension of 4- (4-morpholinylcarbonyl) benzoic acid (0.13 grams, 0.53 mmol) and benzyltriethylammonium chloride (1 milligram, 0.004 mmol) in 1,2-dichloromethane (20 milliliters), chloride was added. of thionyl (0.05 milliliters, 0.53 millimoles), and the reaction was heated to reflux. After 2.5 hours, the reaction was allowed to cool to room temperature and concentrated in vacuo. Then the residue was azeotroped with CC14 and placed under a vacuum to give a light orange oil (quantitative), which was used without further purification. In a separate round-bottomed flask, a stirred solution of the product of Example 5 (185 milligrams, 0.37 mmol) in CH2Cl2 (10 milliliters) was cooled to -20 ° C. N-methyl morpholine (0.2 milliliters, 2.0 millimoles) was added, and immediately followed by the dropwise addition of the acid chloride to CH2C12 (5 milliliters), at such a rate that the internal reaction temperature was maintained at -10. ° C or less. After the addition is finished, the reaction mixture was allowed to warm to room temperature. After 1.5 hours at room temperature, the reaction mixture was diluted with CH2C12 (20 milliliters), and washed with IN HCl (2 x 20 milliliters), saturated NaHCO3 (2 x 0 20 milliliters), and brine (1 x 20 milliliters). Drying (MgSO) and concentration in vacuo afforded a crude form of the desired product (260 milligrams). The crude white foam was immediately passed by evaporation chromatography (2 x 15 cm column eluted with 1:27 MeOH-CH 2 Cl 2) 5 to give the desired product (MDL 105,495) (162 milligrams, 64 percent) as a white foam.; IR (KBr) 3431, 3323, 2049, 2970, 2935, 2877, 1755, 1693, 1631, 1529, 1437, 1394, 1346, 1300, 1278, 1259, 1232, 1161, 1118, 1068, 1014, 933, 896, 862, 842, 798, 785, 740, 686, 653, 628, 596'Cm "1; 1 H NMR 0 (300 MHz, CDC13) d 7.86 (d, 2H, J = 8.4 Hz, aryl), 7.52 (d, 1H, J = 8.4 Hz, NH), 7.46 (d, 2H, J = 8.3 Hz, aryl), 7.12 (d, 1H, J = 8.7 Hz, NH), 5.04 (dd, 1H, J = 8.2, 4.2 Hz , a-CH of Val), 4.84 (dd, 1H, J = 8.6, 7.3 Hz, a-CH of Val), 4.62 (dd, 1H, J = 7.9, 2.9 Hz, CH of Pro), 3.94-3.37 ( m, 10H, 2 x 5 NCH2CH20 and NCH2 of Pro), 2.29-1.97 (series of m, 6H, 2 x β-CH of Val and CH2CH2), 1.06 (d, 3H, J = 6.8 Hz, CH3), 1.01 (d, 6H, J = 6.7 HZ, 2 X CH3), 0.86 (d, 3H, J = 6.9 Hz, CH3): 13C NMR d 172.2, 170.9, 169.2, 166.3, 138.5, 135.1, 127.4, 77.4, 77.1, 76.9, 76.5, 66.7, 59.9, 59.3, 55.9, 47.9, 31.8, 29.1, 27.0, 25.1, 19.8, 19.5, 17.8, 16.2; 19F NMR (470.2 MHz, CDC13) d -80.24 (t, J = 9 HZ, CF3 ), -118.39 and -119.87 (dq, J = 295, 9 Hz, COCF2), -125.99 (AB m, CF2); MS (CI / CH4) m / z (int relative density) 683 (MH +, 59), 367 (100). Analysis Calculated for C30H37F7N4O6 * 1.3 H20: C, 51.01; H, 5.65; N, 7.92. Found: C, 51.34; H, 5.27; N, 7.87.

EXAMPLE 7 Preparation of Boc-Val-CF2CF3 MDL 101,286 A solution of Boc-Val-OCH3 (2.27 grams, 9.81 mmol) in Et20 (14 milliliters) / PhMe (11.3 milliliters) was cooled to -50 ° C and treated with CF3CF2I (3.7 milliliters, 31.1 millimoles, 3.2 equivalents) , and then further cooled to -60 ° C and treated by dripping with lithium methyli-co-brobium lithium complex (55 minutes, from -60 ° C to -50 ° C; 1.5 M in Et20, 20 milliliters, 30 millimoles, 3.1 equivalents). The resulting reaction mixture was stirred for 1 hour, and then treated dropwise with isopropanol (20 minutes; <-50 ° C). After stirring for 30 minutes, the reaction mixture was allowed to warm to 0 ° C, and then poured into 1M KHS04 (60 5 milliliters). The phases were separated, and the aqueous phase was extracted with Et20 (1 x 50 milliliters). The organic phases were combined and dried (MgSO 4), filtered, and the filtrate was evaporated in vacuo (room temperature, 15 mmHg), to give a white solid. The raw material showed a proportion of the desired product to the starting material of 3: 1, without other impurities > 1 percent of the total area (gas chromatography). The crude white solid was chromatographed on Si02 (40 grams, 3 x 6.5 centimeters, hexane (400 milliliters), then 400 milliliters of 10 percent EtOAc / -5 hexane), to provide 2.22 grams, 70 percent yield , of the desired product. This solid was recrystallized from hexane (40 milliliters, reflux, and then cooled to 0 ° C), and provided 1.62 grams, 57 percent, of the desired pure product (MDL 101.286) (first crop; mother liquor); Rf = 0.77 in 20% EtOAc / hexane; P.F. 69-70 ° C; XH NMR (CDCl3) 5.0 (m, 1H), 4.8 (m, 1H), 2.3 (m, 1H), 1.44 (s, 9h), 1.1 (D, 3h, j = 6.8 hZ), 0.84 (D, 3h , j = 6.9 hZ), 19f NMR (CDC13) -82.1 (s), -121.4 (d, J = 297 Hz), -122.8 (d, J = 297 Hz): IR (CHC13) vmax 3443, 2976, 1753 , 5 1716, 1500, 1369, 1234, 1197, 1163 can "1; UV (MeOH)? Max 225 nm (- = 754); CIMS (CH4) m / e (percent relative intensity) 320 (M + H +, 100) Analysis calculated for C12H18N03F5: C, 45.14; H, 5.68; N, 4.39, Found: C, 45.28; H, 5.71; N, 4.26.

EXAMPLE 8 Alternative Preparation of Boc-Val-CF2CF3 MDL 101,286 A mixture of 288.0 grams (1.11 moles) of N-methyl-O-methylhydroxamic acid from Boc-Val, and 4.7 liters of anhydrous Et20, was charged into a 12-liter three neck flask adapted with a stirrer, thermometer, condenser dry ice, gas dispersion tube, and purge with continuous N2. The resulting solution was cooled from -60 ° C to -65 ° C. A total of 885.2 grams (3.60 moles) of C2F5I was added via a gas dispersion tube for approximately 30 minutes to the solution of N-methyl-O-methylhydroxamic acid from Boc-Val, while maintaining a temperature about -65 ° C. Immediately upon completion of the gas addition, a total of 2.39 liters of CH3Li »LiBr 1.5M in Et20 (3.59 moles) was added for 1 hour, maintaining a reaction temperature of -52 ° C to -58 ° C. A precipitate formed after approximately one third of the CH3Li »LiBr had been added, but a complete solution was present at the end of the addition. The resulting solution was stirred from -52 ° C to -58 ° C for 1 hour. The reaction was monitored by gas chromatography (Rt of MDL 101.286 = 1.3 minutes, Rt of N-methyl-O-methylhydroxamic acid from Boc-Val = 5.1 minutes), and found to contain 7.2 percent of N-methyl acid -O-methylhydroxamic of Boc-Val. A total of 255 milliliters (3.47 moles) of acetone was added for about 15 minutes, maintaining a reaction temperature of -52 ° C to -58 ° C, and the resulting mixture was stirred for 10 minutes. The mixture was quenched in a 22 liter flask containing 4.7 liters of KHS0 0.75M, which had been cooled to about 0 ° C. The organic layer was separated and washed with 3 liters of H20. The organic layer was dried using 500 grams of MgSO, and filtered to remove the drying agent. The filtrate was concentrated at 40 ° C / 100 torr, until a semi-solid weighing 409 grams was obtained. The crude material was dissolved in 1.2 liters of hexane at 45 ° C, and cooled slowly for about 30 minutes from -25 ° C to -30 ° C. The solid that crystallized was filtered and washed with 250 milliliters of hexane at -30 ° C. The obtained MDL 101.286 was dried under vacuum (25 ° C (100 torr) to give 176.7 grams.) The filtrate was concentrated at 35 ° C / 100 torr until a residue weighing 153.5 grams was obtained. Kugelrohr distillation, and a first test was collected at 40 ° C / 0.6 torr.The receiver was changed, and a total of 100.5 grams of crude MDL 101.286 was collected at 40 ° C-60 ° C / 0.6 torr. dissolved in 500 milliliters of hexane at about 50 ° C. The resulting solution was cooled to -30 ° C. The solid that crystallized was filtered and washed with 100 milliliters of cold hexane (-30 ° C.) The product was dried vacuum at 25 ° C / 100 torr, to give another 68.0 grams of MDL 101,286 for a total yield of 244.7 grams (70 percent yield), which was 99.9 percent pure by gas chromatography.

Analysis calculated for C12H18F5N03 (319.28): C, 45.14, H, 5.68, N, 4.39; Found: C, 45.30, 45.49, H, 5.50, 5.58, N, 4.26, 4.35.

EXAMPLE 9 N- [3- (3-pyridine) propanoyl] -L-valyl-N-r 3, 3, 4, 4, 4-pentaf luoro-1- (1-methylethyl) -2-oxobutyl-L-prolinamide a) Preparation of H-Val-CF2CF3 »hydrochloride Boc-Val-CF2CF3 (350 milligrams, 1.1 mmol) is dissolved in ethyl acetate (50 milliliters), and cooled to 0 ° C. It is treated with hydrogen chloride gas for 5 minutes, and stirred for 30 minutes. The solvent is removed in vacuo to give the title compound. b) Preparation of Boc-Val-Pro-Val-CF CF3 Boc-Val-Pro-OH (314 milligrams, 1.0 millimoles) is dissolved in methylene chloride (4 milliliters), and N-methyl morpholine (252 milligrams, 2.5 millimoles). It is cooled to -22 ° C, and isobutyl chloroformate (136 milligrams, 1.0 mmol) is added. Stir for 20 minutes, and add to H-Val-CF2CF3 »hydrochloride (1.1 mmol). Stir for 1 hour at -22 ° C, allow to warm to room temperature, and stir for 3 hours. Purify by silica gel chromatography (40 percent ethyl acetate / hexane) to give the title compound (405 milligrams). c) Preparation of H-Val-Pro-Val-CF2CF3 »hydrochloride Boc-Val-Pro-Val [CF2CF3] (385 milligrams, 0. 74 mmol) in ethyl acetate (50 milliliters) and cooled to 0 ° C. It is treated with hydrogen chloride gas for 5 minutes, and stirred for 30 minutes. The solvent is evaporated in vacuo to give the title compound (334 milligrams). d) Preparation of N- [3- (3-pyridyl) propanoyl-L-valyl-N- [3,3,4,4,4-pentafluoro-l- (1-methylethyl) -2-oxobutyl] -L-prolinamide Acid is suspended 3- (3-pyridyl) propionic (174 milligrams, 1.15 millimoles, Walker, FA et al., J. Amer. Chem. Soc., 102, 5530-5538 (1980)) in methylene chloride (15 milliliters). N-methyl morpholine (0.38 milliliters, 3.45 millimoles), and triethyl amine (0.32 milliliters, 2.30 millimoles) are added, and the resulting clear colorless solution is cooled to -18 ° C. Isobutyl chloroformate (0.15 milliliters, 1.15 millimoles) is added and stirred for 20 minutes. Subsequently, N-methyl morpholine (0.13 milliliters, 1.15 millimoles) and H-Val-Pro-Val-CF2CF3 »hydrochloride (520 milligrams, 1.15 millimoles) are added and stirred at -20 ° C for 1 hour. Allow the reaction mixture to warm to room temperature, dilute the reaction mixture with additional methylene chloride (35 milliliters), and wash successively with IN HCl (3 x 20 milliliters), saturated NaHCO 3 (2 x 20 milliliters) and brine (1 x 20 milliliters). The crude product is dried and concentrated. The crude product is purified by evaporation chromatography (75:25 acetone: EtOAc) to give the title compound as a white solid foam. (Yield: 470 milligrams, 74 percent, 3: 1:: LLL: LLD).

TLC Rf 0.42 (3: 1:: acetone: EtOAc): 1 H NMR 5. 8.49 (br s, 1H, aryl), 8.45 (br d, 1H, J = 4.2 Hz, aryl), 7.84 (br d,% H, J = 7.7 Hz, NH), 7.53 (dt, 1H, J = 7.8, 1.7 HZ, aryl), 7.50 (br d, 3 / 4H, NH), 7.21 (dd, 1H, J = 7.7, 4.8 HZ, aryl ), 6.31 (br d, 3 / 4H, J = 8.9 Hz, NH), 6.24 (br d,% -H, J = 8.9 Hz, NH), 5.02-4.92 (m, 1H, CH), 4.67 (dd) ,% H, J = 8.1, 2.1 Hz, OR-CH from Pro), 4.63-4.55 (m, 1 3/4 H, OR-CH from Pro and Ó-CH from Val), 3.87-3.72 and 3.70-3.55 (pr m, 2H, CH2N), 3.07-2.87 and 2.63-2.50 (pr m, 4H, aryl CH2CH2CO), 2.50-1.80 (m, 6H, 2? ß-CH and CH2CH2), 1.12-0.79 (series of d , 12H, 4XCH3); 19F NMR d -82.13 (s, CF3, major isomer), -82.17 (s, CF3, minor isomer), -121.53 and 122.71 (AB quartet, J = 295 Hz, CF2, minor isomer), -121.59 and -122.61 ( AB quartet, J = 295 Hz, CF2, major isomer); MS (El) m / z (relative intensity) 548 (M +, 4), 401 (6), 233 (65), 205 (100), 134, (45), 106 (35), 70 (77). Analysis: C25H33F5N4O4 »0.3 H20) C, H, N.

EXAMPLE 10 N-r3- (3-pyridyl) ropanoill -L-valil-N-r3, 3,4,4,5,5,5-heptafluoro-1- (1-methylethyl) -2-oxopentyl-L-prolinamide a) Preparation of Boc-Val-Pro-Val-QCH3 Isobutyl chlorofor-ato (1.30 milliliters, 0.01 mole) is added to a solution of Boc-Val-Pro-OH (3.1 grams, 0.01 mole, Advanced ChemTech) in sodium chloride. methylene (100 milliliters) at -20 ° C, and stirred for 20 minutes. An additional equivalent of N-methyl morpholine (1.10 milliliters, 0.01 moles) is added. L-valine methyl ester hydrochloride (1.67 grams, 0.01 moles, Aldrich) is added as a solid in one portion. The reaction mixture is stirred at -20 ° C for an additional 1 hour, and then allowed to warm to room temperature. Dilute with additional methylene chloride (50 milliliters), and wash with IN HCl (3 x 50 milliliters), saturated NaHCO 3 (2 x 50 milliliters), and brine (1 x 50 milliliters). The resulting organic extract is dried (MgSO4), and concentrated in vacuo to provide the title compound as a white foam. (Yield: 4.27 grams, 100 percent).

TLC Rf 0.33 (3: 1 Et20-hexane); FT-IR (KBr) 3553, 3537, 3520, 3510, 3310, 2968, 2935, 2876, 1741, 1687, 1631, 1527, 1440, 1390, 1367, 1338, 1309, 1244, 1203, 1172, 1114, 1093, 1043, 1016, 962, 923, 883, 831, 754, 665, 628, 603 cm "1; XH NMR (300 MHz, CDC13) d 7.22 (br d, 1H, J = 8.4 Hz, NH), 5.24 (br d, 1H, J = 11.0 Hz, NH), 4.62 (dd, 1H, J = 8.2, 2.9 Hz, CH of Val), 4.43 (app.dd, 1H, J = 8.6, 5.1 Hz, CH of Pro), 4.30 (dd, 1H, J = 9.5, 6.4 Hz, CH of Val), 3.75-3.70 and 3.63-3.59 (pr m, 2H, CH2N), 3.7 (?, 3H, OMe), 2.36 (m, 1H, ß -CH of Val), 2.17-1.91 (m, 5H, CH2CH2 and ß-CH of Val), 1.43 (s, 9H, t-Bu), 1.00 (d, 3H, J = 6.7 HZ, CH3), 0.95- 0.90 (m, 9h, 3 X CH3); 13C CMR Ü 172.5, 172.1, 170.9, 155.8, 79.5, 77.4, 77.1, 76.9, 76.8, 76.5, 59.9, 57.5, 56.7, 52.0, 47.6, 31.4, 31.0, 28.3, 28.2, 27.1, 19.5, 18.9, 17.8, 17.3, MS (CI / CH4) m / z (relative intensity) 428 (MH +, 22), 372 (68), 328 (199) Analysis calculated for C21H37N305: C, 58.99; H, 8.72; N, 9.83, Found: C, 58.58; H, 8.79; N, 9.55. b) Preparation of Boc-Val-Pro-Val-CF CF2CF3 Perfluoropropyl iodide (6.6 milliliters, 48.0 millimoles, from Aldrich, stabilized with Cu) is added dropwise, under N2, to a solution at -78 ° C Boc. Val-Pro-Val-OCH3 (3.8 grams, 9.0 mmol) in anhydrous diethyl ether (100 milliliters). A complex of lithium methyl * lithium bromide (28.5 milliliters, 42.0 millimoles) is added, at a rate that maintains an internal reaction temperature below -70 ° C. The reaction mixture is stirred at -78 ° C for 1 hour, and then the cold bath is removed and stirring is continued for 5 minutes. The reaction mixture is poured into H20 (100 milliliters), and the aqueous phase is acidified with IN HCl. The aqueous phase is extracted with additional diethyl ether (100 milliliters), and the combined ether extracts are dried (MgSO.sub.4). The solvent is removed in vacuo, and the resulting yellow foam is purified by evaporation chromatography (4.0 x 25 cm column eluted with 3: 1 Et20-hexane), to give the title compound as a white foam. Yield: 654 milligrams, 13 percent).

FT-IR (KBr) 3423, 3292, 2972, 2937, 2879, 2823, 2771, 2739, 2253, 1755, 1687, 1635, 1525, 1444, 1392, 1367, 1348, 1313, 1232, 1178, 1126, 1041, 1018, 966, 922, 910, 877, 837, 798, 756, 736, 667, 650, 632, 596 cm "1; 2H NMR (300 MHZ, CDCL3)" 5 7.63 (d, 1H, J = 8.2 Hz, NH), 5.44 (d, 1H, J = 9.2 Hz, NH), 5.02 (dd, 1H, J = 7.8, 4.5 Hz, CH of Val), 4.64 (dd, 1H, J = 8.0, 3.0 Hz, CH of Pro), 4.30 (dd, 1H, J = 9.2, 6.8 Hz, a-CH of Val), 3.80-3.74 and 3.66-3.60 (pr m, 2H, CH2N), 2.31-1.92 (series of m, 6H, ß -CH of Val, CH2CH2), 1.44 (s, 9H, t-Bu), 1.02 (d, 3H, J = 7.0 Hz, CH3), 0.98 (d, 3H, J = 6.9 Hz, CH3), 0.94 (d , 3H, J = 6.7 Hz, CH3), 0.88 (d, 3H, J = 6.9 Hz, CH3); 13C NMR d 193.3, 193.0, 192.7, 172.9, 171.1, 155.7, 118.7, 115.8, 111.3, 108.9, 108.6, 108.2, 105.9, 79.6, 77.3, 77.2, 76.9, 59.7, 59.3, 56.8, 47.8, 31.4, 29.0, 28.3, 26.9, 25.1, 19.9, 19.8, 19.7, 19.5, 19.5, 19.5, 19.4, 19.5 (376.3 MHz, CDC13) d -80.91 (t, CF3), -119.03 and -120.43 (AB quartet, J = 297 H z, CF2), -126.62 (s, CF2): MS (CI / CH4) m / z (relative intensity) 566 (MH +, 100). HRMS (C 23 H 34 F 7 N 305) (M +) calculated 566.2492, observed 566.2475. c) Preparation of H-Val-Pro-Val-CF2CF2CF3 »Hydrochloride HCl gas is bubbled into a stirred solution of Boc-Val-Pro-Val-CF2CF2CF3 (0.21 grams, 0.37 mmol) in ethyl acetate (50 milliliters), and it cools in a bath of ice water. It is treated with hydrogen chloride gas for 4 minutes. The reaction mixture is stirred for 1 hour, and is warmed to room temperature. The reaction mixture is concentrated and azeotroped with CC14. Place under a high vacuum to give the title compound as a white solid (Yield: 185 milligrams, 100 percent).

XH NMR (300 MHz, CDC13), d 8.29 (br s, 2H, NH2), 7.88 (br s, 1H, NH), 5.70 (m, 1H, CH), 4.89 (m, 1H, CH), 4.16-3.55 (a series of m, 4H, CH, CH, CH2N), 2. 40-1.94 (a series of m, 5H, ß-CH of Val and CH2CH2), 1.13 (br s, 6H, 2 X CH3), 1.01 (d, 3H, J = 5.8 HZ, CH3), 0.94 (d, 3H, J = 4.8 Hz, CH3); 19F NMR d-81.02 (s, CF3,), -120.11 (s, CF2), -126.75 (s, CF2). d) Preparation of 3- (3-pyridyl) propanoyl chloride Thionyl chloride (0.05 milliliter, 0.53 millimole) is added to a stirred suspension of 3- (3-pyridyl) propionic acid (80.2 milligrams, 0.53 millimole) and sodium chloride. Benzyltrietyl ammonium (1 milligram, 0.004 mmol) in 1,2-dichloroethane (20 milliliters), and heated at reflux for 2.5 hours. The reaction mixture is cooled to room temperature and concentrated in vacuo. The residue is azeotroped with CC14 and placed under vacuum. The resulting acid chloride is used without further purification. e) Preparation of N- [3- (3-pyridyl) propanoyl) [-L-valyl-N- [3,3,4,4,5,5,5,5-heptafluoro-l- (1-methylethyl) -2] -oxopentyl] - L-prolinamide H-Val-Pro-Val-CF2CF2CF3 »hydrochloride (185 milligrams, 0.37 millimoles) is dissolved in methylene chloride (10 milliliters), and cooled to -20 ° C with stirring. N-methyl morpholine (0.2 milliliters, 2.0 millimoles) is added and immediately followed by a dropwise addition of 3- (3-pyridyl) propanoyl chloride in methylene chloride (5 milliliters) at such a rate as to maintain the internal reaction temperature at -10 ° C or less. After the addition is complete, the reaction mixture is allowed to warm to room temperature. After 1.5 hours at room temperature, dilute the reaction mixture with methylene chloride (20 milliliters), and wash with IN HCl (2 x 20 milliliters), saturated NaHCO 3 (2 x 20 milliliters), and brine (1 x 20 milliliters). Dry (MgSO4) and concentrate in vacuo to give the title product in a crude form. Immediately the crude product was purified by evaporation chromatography (2 x 15 cm column eluted with 1:27 MeOH-CH 2 Cl 2), to give the title compound.

EXAMPLE 11 N- f3- (3-pyridyl) ropanoyl-1-L-valyl-N-T3.3,4,4,5,5.6,6,6-nonafluoro-l- (1-methylethyl) -2-oxohexip-L -prolinamide a) Preparation of Boc-Val-Pro-Val [CF2CF2CF2CF3] Perfluorobutyl iodide (7.6 milliliters, 48.0 mmol), from Aldrich), is added dropwise, under N2, to a solution at -78 ° C of Boc-Val Pro-Val [C02CH3] (3.8 grams, 9.0 mmol) in anhydrous diethyl ether (100 milliliters). A lithium lithium complex "lithium bromide (28.5 milliliters, 42.0 millimoles) is added at a rate that maintains an internal reaction temperature below -70 ° C. The reaction mixture is stirred at -78 ° C for 1 hour, then the cold bath is removed, and stirring is continued for 5 minutes. The reaction mixture is poured into H20 (100 milliliters), and the aqueous phase is acidified with IN HCl. The aqueous phase is extracted with additional diethyl ether (100 milliliters), and the combined ether extracts are dried (MgSO.sub.4). The solvent is removed in vacuo, and the resulting crude yellow oil is purified by evaporation chromatography (4.0 x 25 cm column eluted with 3: 1 Et-0-hexane), to give the title compound as a white foam. (Yield: 493 milligrams, 9 percent).

FT-IR (KBr) 3421, 3292, 2972, 2937, 2879, 2773, 1755, 1687, 1637, 1525, 1444, 1392, 1367, 1309, 1238, 1174, 1138, 1093, 1043, 1016, 960, 927, 875, 848, 744, 709, 690, 667, 653, 632, 599, 574 cm "1; 13C NMR < 5 173.0, 170.9, 155.7, 97.7, 77.2, 77.1, 76.9, 76.6, 59.7, 59.3, 56.8, 47.8, 31.3, 298.9, 28.3, 26.7, 25.1, 19.5, 17.4, 16.2; 19F NMR (376.2 MHz, CDC13) d -81.35 (s, CF3), -118.27 and -119.91 (AB quartet, J = 297 Hz, CF2), -123.09 (s, CF2), -125.97 (s, CF2); MS (CI / CH4) m / z (relative intensity) 616 (MH +, 68), 560 (100), 516 (31). Analysis calculated for C 24 H 34 F 9 N 305: C: 46.83; H, 5.57; N, 6.83. Found: C, 46.32; H, 5.65; N, 6.66. HRMS (C 24 H 34 F 9 N 305) (M +) calculated 616.2433, observed 616.2435. b) Preparation of H-Val-Pro-Val-CF2CF2CF3 «Hydrochloride HCl gas is bubbled into a stirred solution of Boc-Val-Pro-Val-CF2CF2CF2CF3 (245 milligrams, 0.40 millimoles) in ethyl acetate (50 milliliters), and it cools in a bath of ice water. It is treated with hydrogen chloride gas for 4 minutes. The reaction mixture is stirred for 1 hour, and is warmed to room temperature. The reaction mixture is concentrated and azeotroped with Cl 4. It is placed under a high vacuum to give the title compound. c) Preparation of Nf 3- (3-pyridyl) propanoyl ') -L-valyl-N- [3,3,4,4,5,5,6,6,6-nonafluoro-1- (1-methylethyl) -2 -oxohexyl1-L-prolinamide H-Val-Pro-Val-CF2CF2CF2CF3 »'hydrochloride (221.0 milligrams, 0.40 millimoles) is dissolved in methylene chloride (10 milliliters), and cooled to -20 ° C with stirring. N-methyl morpholine (0.2 milliliters, 2.0 mmol) is added, followed immediately by a dropwise addition of 3- (3-pyridyl) propanoyl chloride in methylene chloride (5 milliliters), at a rate that maintains the reaction temperature internal at -10 ° C or less. After finishing the addition, the reaction mixture is allowed to warm to room temperature. After 1.5 hours at room temperature, dilute the reaction mixture with methylene chloride (20 milliliters), and wash with IN HCl (2 x 20 milliliters), saturated NaHCO 3 (2 x 20 milliliters), and brine (1 x 20 milliliters). Dry (MgSO4) and concentrate in vacuo to give the title product in a crude form. Immediately the crude product was purified by evaporation chromatography (2 x 15 cm column eluted with 1:27 of MeOH-CH2Cl2), to give the title compound.

In a further embodiment, the present invention provides a method for the treatment of a patient afflicted with an inflammatory disease associated with neutrophils, which comprises administering thereto a therapeutically effective amount of a compound of the formulas (I) - (IV) ). The term "inflammatory disease associated with neutrophils" refers to diseases or conditions characterized by the migration of neutrophils to the site of inflammation, and their participation in the proteolytic degradation of biological matrices. Associated inflammatory diseases are neutrophils for which treatment with a compound of the formulas (I) - (IV) will be particularly useful including: emphysema, cystia fibrosis, adult respiratory distress syndrome, septicemia, chronic bronchitis, inflammatory bowel disease (particularly ulcerative colitis or Crohn's disease), disseminated intravascular vasculitis, gout, and rheumatoid arthritis. The compounds of the formulas (I) - (IV) which are particularly preferred for the treatment of inflammatory diseases associated with neutrophils include: N- [4- (4-morpholinylcarbonyl) benzoyl] -L-valyl-N '- [3, 3,4,4,5,5,5-heptafluoro-l- (1-methylethyl) -2-oxopentyl] - L-prolinamide; N- [4- (4-morpholinylcarbonyl) benzoyl] -L-valyl-N '- [3,3,4,4,5,5,6,6,6-nonafluoro-l- (1-methylethyl) - 2-oxohexyl] -L-prolinamide; N- [(1,1-dimethylethoxy) carbonyl] -L-valyl-N '- [3,3,4,4,5,5,5-heptafluoro-l- (1-methylethyl) -2-oxopentyl] - L-prolinamide; N- [(1,1-dimethylethoxy) carbonyl] -L-valyl-N '- [3, 3,4,4,5,5,6,6,6-nonafluoro-l- (1-methylethyl) -2 -oxohexyl] -L-prolinamide; N- [3- (3-pyridyl) propanoyl] -L-valyl-N '- [3, 3, 4, 4, 4 -pentaf luoro-1- (1-methylethyl) -2-oxobutyl] -L-prolinamide; N- [3- (3-pyridyl) propanoyl] -L-valyl-N '- [3, 3,4,4,4-pentafluoro-1- (1-methylethyl) -2-oxobutyl] -D, L- 1,2,3,4-tetrahydro-3-isoquinoline-linamide; N- [3- (3-pyridyl) propanoyl] -L-valyl-N »- [3,3,4,4,4-pentafluoro-l- (1-methylethyl) -2-oxo-butyl] -L-thiazolidin -4-sarboxíliso.

As used herein, the term "passer-te" refers to a warm-blooded animal, such as a mammal, that is afflicted with a state of particular inflammatory disease. It is understood that the Indian sonejillos, dogs, cats, rats, mice, horses, cattle, sheep, and humans, are examples of animals within the scope of the meaning of the term. The term "therapeutically effective amount" refers to an amount that is effec- tive, over a single-dose or multiple-dose administration to the patient, to provide relief from the associated symptoms are the as- sociated inflammatory diseases are neutrophils. As used herein, "relief of symptoms" of a respiratory disease, refers to a decrease in severity over that expected in the absence of treatment, and does not necessarily indicate a total elimination or surasion of the disease. In the determination of sanctity or therapeutically effec- tive dose, the assistant who diagnoses considers a number of factors, including, but not limited to: the species of mammal; its size, age, and general health; the involuntary thickened disease; the degree of involussion or the severity of the disease; the response of the individual passenger; the partisular substance administered; the administration mode; the bioavailability sarasteristies of the administered preparation; the selected dosage regimen; the use of a consomiting medication; and other relevant services. A therapeutically effective amount of a compound of the formulas (I) - (IV) is expected to range from about 0.1 milligrams per kilogram of body weight per day (g / kg / day) to about 100 milligrams per kilogram of body weight up to date. The preferred amounts are expected to range from about 0.5 to about 10 milligrams per kilogram of body weight per day. The compounds of this invention are highly potent elastase inhibitors, particularly human neutrophil elastase. It is believed that the compositions of this invention will exert their inhibitory inhibition through the inhibition of the elastase enzyme, and therefore, provide relief for elastase-mediated diseases, including, but not limited to, emphysema, fibrosis, cysts, respiratory insufficiency of adults, chronic bronchitis, inflammatory bowel disease, septicemia, disseminated intravasicular soagulation, gout, and rheumatoid arthritis. However, it is understood that the present invention is not limited by any theory in partiscular or proposed mesanism, to explain its effectiveness in a final use aplissation. When making the. treatment of a patient afflicted with a disease state described above, a compound of the formulas (I) - (IV) can be administered in any form or mode that makes the compound biodisposable in effective amounts, including the oral routes , in aerosol, and parenteral. For example, the compounds of formulas (I) - (IV) can be administered orally by aerosolization, subcutaneously, intramuscularly, intravenously, transdermally, intranasally, restally, locally, and the like. In general, oral or aerosol administration is preferred. An expert in the technique of preparation of formulas can easily selession the form and the appropriate mode of administration, depending on the partisan sarasteristisas of the selected sompuesto and the state of disease to be treated, the stage of the disease, and other relevant cirsunstansias. Remington's Pharmaseutisal Ssienses, 18th Ed., Mask Publishing Co. (1990). The compounds may be administered alone or in the form of a pharmaceutical formulation, in combination with vehicles or excipients that are reasonably assumable, their propulsion and nature being determined by the solubility and chemical properties of the selected formulation, the selected administration route, and the practisa farmaséutisa sonvensional. The compositions of the invention, although effective in themselves, may be formulated and administered in the form of their pharmaceutically acceptable salts, such as, for example, acid adduction salts, for purposes of stability, convenience of crystallization, greater solubility. , and similar. In another embodiment, the present invention provides compositions that comprise a composition of the formulas (I) - (IV) mixed or otherwise in asosiation are one or more inert vehicles. These sompositions are useful, for example, as test standards, as novel elements for bulk shipment, or as pharmaceutical compositions. An assayable amount of a compound of the formulas (I) - (IV), is a sanity that can be measured easily by the sonic test methods and theses well studied and taken by the experts in this field. The assayable sanctities of a set of formulas (I) - (IV) will generally vary from about 0.001 per cent to about 75 per cent of the somposisance in weight. The inert vehicles can be any material that is not degraded or otherwise reacted sovalently are a composition of the formulas (I) - (IV). Examples of inert arsenic vehicles are water; aqueous pH regulators, such as those that are generally useful in the analysis of High Performance Liquid Chromatography (HPLC); organic solvents, such as acetonitrile, ethyl acetate, hexane, and the like; and pharmaceutically insurable vehicles or excipients. More particularly, the present invention provides pharmaceutical compositions comprising a therapeutically effective amount of a compound of the formulas (I) - (IV), mixed or otherwise in asosiation are one or more pharmaceutically acceptable vehicles or excipients. Pharmaceutical sompositions are prepared in a manner well known in the pharmaceutical art. The vehicle or excipient can be a solid, semi-solid, or liquid material, which can serve as a vehicle or medium for the active ingredient. The adesuados vehicles or exsipientes are well sonosidos in the teésnisa. The farmasuccesis somposisance may be adapted for oral, parenteral, or oral use, and may be administered to the patient in the form of tablets, sachets, suppositories, in solution, suspensions, or the like. The compositions of the present invention can be administered orally, for example, they are an inert diluent or they are a somatic vehicle. They can be taught in gelatin sachets, or they can be squeezed into tablets. For the purpose of oral therapeutic administration, the dressings can be insorporated are exsipient, and can be used in the form of tablets, trosissos, sapsules, elixirs, suspensions, syrups, wafers, Massar gums, and the like. These preparations should contain at least 4 percent of the compound of the invention, the active ingredient, but may vary depending on the particular form, and may conveniently be between 4 percent and about 70 percent of the unit's weight. The amount of the compound present in the compositions is such that an adesuada dosifisasión is obtained. Preferred sompositions and preparations of agreement are the present invention are prepared in such a way that a unit dosage oral dosage form is between 5.0 and 300 milligrams of a compound of the invention. The tablets, pills, capsules, trocissos, and-like, may also contain one or more of the following auxiliaries: binders such as microscristalline cellulose, tragasanto gum or gelatin; excipients such as starch or lactose, disintegrating agents such as aldose alginate, Primogel, corn starch, and the like; lubricants such as magnesium stearate or Sterotex; brighteners such as solidal silicon dioxide; and sweetening agents such as sucrose or saccharin, or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring. When the unit dosage form is a capsule, it may contain, in addition to the materials of the above type, a liquid carrier, such as polyethylene glycol or a fatty substance. Other forms of dosage unit may contain other different materials that modify the physical form of the dosage unit, for example, as coatings. For example, tablets or pills can be coated with sugar, shellac, or other enteric coating agents. A syrup may contain, in addition to the present compounds, sucrose as a sweetening agent, and certain preservatives, dyes, and solvents and flavorings. The materials used in the preparation of these different sompositions must be pharmaceutically pure and non-toxic in the sanctities used. For the purpose of parenteral therapeutic administration, the compositions of the present invention can be incorporated into a solution or suspension. These pfeparasions must be kept at least 0.1 per cent of a compound of the invention, but may vary between 0.1 and about 50 per cent of the weight of the same. The sanctity of the composition of the invention present in these compositions is such that an adequate dosifisation is obtained. Preferred compositions and preparations of sonicity are the present invention, are prepared in such a way that a unit of parenteral screening is between 5.0 and 100 milligrams of the invention. The formulations of the formulas (I) - (IV) of the present invention can also be administered in aerosol. The term aerosol is used to denote a variety of systems, from those of a solitary nature, to systems that exist in pressurized packages. The aplissation can be by a gas lysed or squeezed, or by a suitable pump system that doses the active ingredients. The aerosols of the compounds of the formulas (I) - (IV) can be applied in single-phase, difási-sos, or tripásisos systems, they are the object of applying the active ingredient. The application of the aerosol includes the necessary container, the spreaders, the valves, the sub-fillers, and the like. The preferred aerosol can be determined by one skilled in the art. The compounds of the formulas (I) - (IV) of this invention can also be administered locally, and when this is done, the vehicle can suitably comprise a solution, ointment, or gel base. The base, for example, may comprise one or more of the following: petrolatum, lanolin, polyethylene glycols, beeswax, mineral oil, diluents such as water and alsohol, and emulsifiers and stabilizers. Loyal formulas may contain a consension of formula I or its pharmaceutic salt, from about 0.1 to about 10 weight percent / volume (weight per unit volume). Solutions or suspensions may also include one or more of the following auxiliaries: sterile diluents, such as water for injections, saline solution, fixed asbestos, polyethylene glisols, glycerin, propylene glycol, or other synthetic solvents; antibaster agents such somo alsohol bensyliso or methylparaben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents, such as ethylenediaminetetraacetic acid; pH regulators such as asetates, sitrates, or phosphates, and toning agents, such as sodium chloride or dextrose. The parenteral preparation can also be enclosed in ampoules, disposable syringes, or multi-dose vials made of glass or plastic. Human neutrophil elastase is tested in vitro using N-MeOSuc-Ala-Ala-Pro-Val-p-nitroanilide, available somersially, as the substrate. The regulator 'of the test pH, the pH, and the test tissues are similar to the dessritos by Mehdi and co-workers, Biochemical and Biophysical Research Communications, 166, 595 (1990). The enzyme is purified from human sputum, although it has become somersially available. The synsease sarasterization of the immediate inhibitors is by means of the Dixon graph, while the faces of the inhibitors of slow and / or tight binding, used data analysis techniques reviewed by Williams and Morrison. The synthesis and analytical use of a highly sensitive and elastic elastase substrate is discussed by J. Bieth, B. Spiess, and C.G. Wermuth, Biochemical Medicine, 11 (1974) 350-375. Table 2 summarizes the sapacity of the compounds selected from this invention to inhibit elastase. For the purposes of this table, MCBz refers to 4- (4-morpholinylcarbonyl) benzoyl, and Pyr refers to 3- (3-pyridinyl) propanoyl.

TABLE 2 LIVE TESTS Intratracheal instillation of human neutrophil elastase in rodents results in acute lung damage, which can be easily quantified by measuring hemoglobin ("Hgb") in the bronchial lavage fluid ("BAL"); Fletcher, D.S. and collaborators, Am. Rev. Resp Dis. 141, 672-677 (1990). The eficasia of the formulations (I) - (IV) in order to reduce pulmonary hemorrhage and / or to show an inhibition of human neutrophil elastase ("HNE") in vivo, can be demonstrated by the pulmonary hemorrhage model. in rodents, this is illustrated in Fletsher, DS and collaborators, Td. and Shah, S.K. and collaborators, J. Med. Chem. 35, 3745-3754 (1992). For example, "pre-treated hamsters" are N- [3- (3-pyridyl) propanoyl] -L-valyl-N '- [3, 3,4,4,4-penta-fluoro-1- -methylethyl) -2-oxobutyl] -L-prolinamide ("Pyr-Val-Pro-Val-CF2CF3") (10, 25, or 50 milligrams per kilogram, oral administration), 30 minutes before assaulting them are human neutrophil elastase (20 misrograms, intratracheal administration) Animals can be sedated 1 hour after aggression For hamsters given an oral dose of 25 milligrams per kilogram of Pyr-Val-Pro-Val-CF2CF3, 30 minutes before the intratracheal aggression are elastase of human neutrophils, an inhibition of 67 ± 6 was noted by feeling of pulmonary hemorrhage induced by human neutrophil elastase, measured by Hgb of the bronchial lavage fluid.

SEQUENCE LIST (1) GENERAL INFORMATION: (i) APPLICANT: (A) NAME: Merrell Dow Pharmaceuticals Inc. (B) STREET: 2110 E. Galbraith Road (C) CITY: Cincinnati (D) STATE: Ohio (E) COUNTRY: United States de Norteamérisa (F) POSTAL CODE: 45215 (G) TELEPHONE: 513-948-7960 (H) TELEFAX: 513-948-7961 (I) TELEX: 214320 (Ü) TITLE OF THE INVENTION: INHIBITORS OF PERFLUOROALQUILICA CETONA OF ELASTASE AND PROCESSES TO MANUFACTURE THEM. (Üi) SEQUENCE NUMBER: 6 (iv) COMPUTER LEGIBLE FORM: (A) TYPE OF MEDIUM: Flexible disk (B) COMPUTER: IBM PC compatible (C) OPERATING SYSTEM: PC-DOS / MS-DOS (D) SOFTWARE : Patentln Relay # 1.0, Version # 1.30 (EPO) (2) INFORMATION FOR SEQ ID NO: l: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 4 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (i) SEQUENCE DESCRIPTION: SEQ ID NO: l: Xaa Xaa Xaa Xaa 1 (2) INFORMATION FOR SEQ ID NO: 2: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 4 amino acids (B) TYPE: aminoaside (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 2 Xaa Xaa Xaa Xaa 1 (2) INFORMATION FOR SEQ ID NO: 3: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 4 amino acids (B) TYPE: amino acid ( D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 3 Xaa Xaa Xaa Xaa 1 (2) INFORMATION FOR SEQ ID NOM: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 4 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 4: Xaa Xaa Xaa Xaa 1 (2) INFORMATION FOR SEQ ID NO: 5: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 4 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 5: Xaa Xaa Xaa Xaa 1 (2) INFORMATION FOR SEQ ID NO: 6: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 4 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (Xi) SEQUENCE DESCRIPTION: SEQ ID NO: 6: Xaa Xaa Xaa Xaa 1

Claims (20)

1. A set of the formula: O / f \ - CH 2 - Cri 2 - C - P? -? 3 - ? - P. - F 7CF 3 N (S EQ I D NO 4) where: P? is Ala, Val, Nva, bVal, Leu, lie, or Nle; P2 is Ala, bAla, Leu, Lie, Val, Nva, bVal, Met, Nle, Gly, Phe, Tyr, Trp, or Nal (l), wherein the nitrogen of the alpha-amino group may be substituted are a group R , wherein R is an alkyl (of 1 to 6 atoms of sarbon), cycloalkyl (of 3 to 12 carbon atoms), cisloalkyl (of 3 to 12 atoms of sarbon) -alkyl (of 1 to 6 atoms of sarbon), bicycloalkyl (from 4 to 11 carbon atoms), bicisloalkyl (from 4 to 11 sarbone atoms) -alkyl (from 1 to 6 atoms of sarbon), aryl (from 6 to 10 atoms of sarbon), aryl (from 6 to 10) carbon atoms) -alkyl (from 1 to 6 carbon atoms), heterocycloalkyl (from 3 to 7 carbon atoms), heterocylisalkyl (from 3 to 7 atoms of sarbon) -alkyl (from 1 to 6 atoms of sarbon), heteroaryl (from 5 to 9 atoms of sarbon), heteroaryl (from 5 to 9 atoms of sarbon) -alkyl (from 1 to 6 atoms of sarbon), aryl (from 6 to 10 atoms of sarbon) -sisloalkyl (from 3 to 12 atoms) of sarbono) molten, aryl (of 6 to 10 atoms of sarbono) -s isloalkyl (from 3 to 12 sarbon atoms) -fused alkyl (from 1 to 6 sarbone atoms), heteroaryl (from 5 to 9 sarbone atoms) -silyloalkyl (from 3 to 12 atoms of sarbon), or heteroaryl (from 5 to 9 atoms of sarbon) -sisloalkyl (from 3 to 12 atoms of sarbon) -alkyl (from 1 to 6 atoms of sarbon) melted, or P2 is Pro, Ind, Tis, or Tsa; P3 is Ala, bAla, Leu, lie, Val, Nva, bVal, or Nle; P is Ala, bAla, Leu, lie, Val, Nva, bVal, Nle or a link; or a hydrate, isoester, or a pharmaceutically acceptable salt thereof.

2. A set of claim 1, where P2 is Val or Nva; P2 is Pro, Tis, or Tsa; P3 is Val, Nva, Ala, or bAla; and P is Ala or a enlase. 3. An inventory of claim 2, where

P1 is Val; P3 is Val, and P4 is a enlase.

4. A composition of claim 1, wherein the compound is N- [3- (3-pyridyl) propanoyl] -L-valyl-N '- [3, 3, -4, 4, 4-pentafluoro-l- (1-methylethyl) -2-oxobutyl] -L-prolinamide.

5. A somposission that somprende a sompuesto of reivindisasión 1, and a vehísulo.

6. A pharmaceutic somposision comprising a compound of claim 1, and a pharmaceutically assumable vehicle.

7. A somo somo in one of the reivindisasiones 1 to 4, to be used as sompuesto farmaséutisamente astivo.

8. The use of a somo moiety in one of claims 1 to 4, optionally in co-biosynthesis, is a pharmaceutically acceptable vehicle for the preparation of an elastase inhibitor of human neutrophils.

9. The use of a somo somoid in one of claims 1 to 4, optionally in combination with a pharmaceutically acceptable vehicle, for the preparation of a pharmaceutic somposision for the treatment of an asosiada inflammatory disease are neutrophils.

10. The use of a compound as in one of claims 1 to 4, optionally in symbiosis, is a pharmaceutically insurable vehicle for the preparation of a pharmaceutic composition for the treatment of emphysema.

11. A statement of the formula: K-P4-P3-P2-NH-CH (R1) -C (= 0) -X '(I) (SEQ ID NO.l) or a hydrate, isoester, or a pharmaceutically acceptable salt thereof, wherein: P4 is Ala, bAla, Leu, Lie, Val, Nva, bVal, Nle, or a bond; P3 is Ala, bAla, Leu, lie, Val, Nva, bVal, or Nle; P2 is Pro, Ind, Tic, Pip, Tea, Pro (4-Obzl), Aze, Pro (4-0Ac) or Pro (4-OH); R-L is a side chain of Ala, Leu, Lie, Val, Nva or bVal; X 'is -CF2CF2CF3 or -CF2CF2CF2CF3; and K is:

12. A compound of claim 11, wherein R? is -CH (CH3) 2; P2 is Pro, Pip, Pro (4-0Bzl), or Aze; P3 is lie, Val, or Ala; and P is Ala or a enlase.

13. A set of claim 12, wherein P2 is Pro; P3 is Val; and P is a link.

14. A farmesuccesis somposision that includes a package of claim 11, and a vehicle that is pharmaceutically assumable.

15. A statement as in one of claims 11 to 13, to be used as a pharmaceutically active substance.

16. The use of a somo moiety in one of claims 11 to 13, optionally in conjunction with a pharmaceutically acceptable carrier, for the preparation of an elastase inhibitor of human neutrophils.

17. The use of a composition as in one of claims 11 to 13, optionally in combination with a pharmaceutical carrier being aseptable, for the preparation of a pharmaceutical composition for the treatment of an inflammatory disease associated with neutrophils.

18. The use of a compound as in one of claims 11 to 13, optionally in symbiosis, is a pharmaceutically acceptable vehicle for the preparation of a pharmaceutic somposision for the treatment of emphysema.

19. A process for the preparation of a compound of the formula: K'-P4-P3-P2-NH-CH (R1) -C (= 0) -X (II) (SEQ ID NO: 2) or a hydrate, isoester, or a pharmaceutically acceptable salt thereof, wherein: P4 is Ala, bAla, Leu, Lie, Val, Nva, bVal, Nle, or a bond; P3 is Ala, bAla, Leu, Lie, Val, Nva, bVal, or Nle, P2 is Pro, Ind, Tic, Pip, Tsa, Pro (4-Obzl), Aze, Pro (4-OAs) or Pro (4 -0H); Rx is a side row of Ala, Leu, lie, Val, Nva or bVal; X 'is -CF2-CF3, -CF2CF2CF3 or -CF2CF2CF2CF3; and K is: which comprises the steps of: (a) coupling an amino acid ester of the formula NH2-CH (R1) C (= 0) OR2, wherein R2 is alkyl of 1 to 6 carbon atoms, with a suitably N- peptide protected from the formula K'-P -P3-P2-0H, in the presence of a suitable coupling agent, and in the presence of an appropriate coupling solvent, to give a suitably N-protected peptide ester; (b) reacting the suitably N-protected peptide ester with a perfluorinated agent adessed in the presensia of a base of alded alsaline metal and an appropriate anhydrous solvent.

20. A process for the preparation of a composition of claim 19, the sual comprises the steps of: (a) making an amino acid ester adesutadamente protected from the formula Pg-NH-CH (R1) C (= 0) 0R2 , wherein R 2 is alkyl of 1 to 6 carbon atoms, and Pg is a suitable protecting group, with a suitable perfluorinating agent, in the presence of a base of alded alsaline metal, and an appropriate anhydrous solvent, to give a perfluoroalkyl. - undesirably N-protected; (b) deprotecting the perfluoroalkyline synthetically N-protected is a deprotection agent adesuado in the presensia of a suitable organoiso solvent, to give a setona perfluoroalquílisa; (c) coupling the perfluoroalkyl ketone with a suitably protected peptide of the formula K * • -P -P3-P2-OH, in the presence of a suitable coupling agent, and in the presence of an appropriate coupling solvent.