MXPA96006030A - Novedous elast inhibitors - Google Patents

Abstract

This invention relates to compounds that are inhibitors of elastase, particularly human neutrophil elastase. The inhibitors are short synthetic peptides in which the P2 portion is substituted with several heterocyclic nitrogen-containing groups, as human neutrophil elastase inhibitors, the compounds are useful in the treatment of a patient suffering from an inflammatory disease associated with neutrophil.

Description

INNOVATIVE ELASTASE INHIBITORS BACKGROUND OF THE INVENTION This invention relates to compounds that are both elastase inhibitors, particularly human neutrophil elastase, useful for a variety of physiological and end-use applications. Neutrophil elastase from humans 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 rheumatoid arthritis. J.L. Malech and J.l. Gallin, New Engl. J. Med., Zll (11), 687 (1987). Elastase has a broad scale of proteolytic activity against a number of connective tissue macromolecules including elastin, fibronectin, collagen, and proteoglycan. The presence of the enzyme elastase, 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 disorder and inflammation. For example, the a-1-proteinase (a-1-PI) inhibitor is a serine protease inhibitor that blocks elastase activity. a-1-PI has received considerable interest since the reduction in plasma levels is less than 15% of normal if it is associated with the early development of emphysema. In addition to the plasma-derived protease inhibitors, secretory fluids, including bronchial, nasal, cervical, and seminal fluid contain an endogenous protease inhibitor called leukoprotease secretory inhibitor (ISLP) that can inactivate elastase and is thought to play an important role in maintaining the integrity of the epithelium in the presence of cell proteases inflammatory In certain disease states, a-1-PI and SLPI are inactivated by the neutrophilic oxidizing mechanisms that allow neutrophil proteases to function in an essentially uninhibited environment. For example, it has been found that bronchial wash fluids of patients with respiratory distress syndrome in adults (STRA), contain active elastase and a-1-PI that has been inactivated by oxidation. In addition to the oxidizing mechanisms, neutrophils have non-oxidizing mechanisms to elute inhibition by antiproteases. Neutrophils from patients with chronic granulomatous disease are able to degrade endothelial cell matrices in the presence of excess a-1-PI. There is considerable in vitro evidence that stimulated neutrophils can be tightly bound to their substrates in such a way that serum antiproteases are effectively excluded from the close contact microenvironment of cellular substrates. The influx of large numbers of neutrophils to an inflammatory site can result in considerable tissue damage due to the proteolysis that occurs in this region.

Applicants have determined that elastase is one of the primary proteases of neutrophils responsible for the degeneration of cartilage matrix as measured by the ability to lyse neutrophils, purified elastase and stimulated neutrophils to degrade proteoglycan from cartilage matrix. In addition, applicants previously discovered that peptide derivatives useful as elastase inhibitors exert valuable pharmacological activities. For example, peptide derivatives useful as elastase inhibitors in which the carboxyl terminal group carboxy has been replaced by a pentafluoroethylcarbonium group (-C (O) C2F5) and in which the amino terminal amino acid is protected by several groups containing heterocycles such as a 4-morpholinocarbonyl group, are described in European Patent Application OPI No. 0529568, Peet et al., with a publication date of March 3, 1993. Applicants have recently discovered elastase inhibitors of peptidyl in which the P2 portion is substituted with several heterocyclic groups containing nitrogen. COMPENDIUM OF THE INVENTION The present invention relates to compounds having the following formula 1. or a hydrate, isostere, or pharmaceutically acceptable salt thereof wherein P4 is Ala, bAla, Leu, Me, Val, Nva, bVal, Nle or a ligation; P3 is Ala, bAla, Leu, He, Val, Nva, bVal, Nle, or a derivative of methyl, Pro, Ind, Tic, or Tea, or Lys substituted in their amino group epsilon with a group B morpholino or Orn substituted in its amino delta group with a morpholino B group; P2 is Pip, Aze, Pro (4-OH), Pro (4-Oac) or Pro (4-Obzl); R, is a side chain of Ala, Leu, II, Val, Nva or bVal; is -CF3, -CF2H, -CFH2, -C (= O) Y, -C (= O) P2'-Y, -FC2C) = O) P2'-Y, -CF2CF (R1 ') C (= O ) P2, -Y, CF2CH (R1 ') NHC (= O) P2'-Y, -CF2CH (R1') NHC (= O) R3, CHFCH (R? ') NHC (= O) R3, -CHFCH ( R1 ') NHC (= O) R3, -H, -C (= O) R3 > -CH (R1) C (= O) P2'-Y, -CF2CF3, -CF2 (CH2) TCH3, - CF2 (CH2) tC.OOR4, -CHF (CH2) tCH3, -CF2 (CH2) tCONHR4, - CF2 (CH2), CH2OR4, -CF2 (CH2) VCH = CH2, -CH2CI or -C (= O) -C (= O) -Y; R: is H, d-e alkyl, phenyl, benzyl, cyclohexyl, cyclohexylmethyl; R 4 is -H or C 6 alkyl; R? ' it is a side chain of Ala, Leu, lie, Val, Nva or bVal; it is a ligature, Ala, or Val; And it is -NHR3, OR3; t is 2, 3, or 4; is 1, 2 or 3; is hydrogen, formyl, acetyl, succinyl, benzoyl, tertiary butyloxycarbonyl, carbobenzyloxy, tosyl, dansyl, isovaleryl, methoxysuccinyl, 1-adamantanesulfonyl, 1-adamantanoacetyl, 2-carboxybenzoyl, phenylacetyl, tertiary butylacetyl, bis ((1-naphthyl) methyl) acetyl, -C (O) N- (CH3) 2, -A-R2 where A i -C-, -N-C- -O-C-L or -S-; HO Rz is an aryl group containing 6, 10 or 12 carbons suitably substituted by 1 to 3 members independently selected from the group consisting of fluoro, chloro, bromo, iodo, trifluoromethyl, hydroxy, alkyl containing from 1 to 6 carbons, akoxy containing from 1 to 6 carbons, carboxy, alkylcarbonylamino wherein the alkyl group contains from 1 to 6 carbons, 5-tetrazolyl, and acylsulfonamido containing from 1 to 15 carbons, with the proviso that when the acylsulfonamido contains an aplo, the it can also be replaced by a selected member of fluoro, chlorine, bromine, iodine and nitro, where is N or CH, and B is a group of the formulas (the wavy line being the binding to the rest of the molecule, ie, not Z) and wherein R 'is hydrogen or an alkyl group of d.6; useful as elastase inhibitors. The compounds of formula 1, exhibit an anti-inflammatory effect useful in the treatment of gout, and other inflammatory diseases, such as respiratory distress syndrome in adults, septicemia, chronic bronchitis and inflammatory bowel disease, disseminated intravascular coagulation, cystic fibrosis , and in the treatment of emphysema. DETAILED DESCRIPTION OF THE INVENTION Isosters of the compounds of the formula I include those wherein (a) one or more residues of α-amino acids of the P2-P4 substituents are in their non-natural configuration (when there is a natural configuration) or (b) ) when the normal peptide amine ligation [-C (= O) NH-] is modified, such as for example, to form -CH2NH- (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 isostere form; it is particularly preferred that the peptide amide group is not modified, but if it is, it is preferable to keep the isosteric modifications to a minimum. It is considered a group of C? .6, includes straight or branched alkyl groups, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, isopentium, sec-pentyl, cylcopentyl, hexyl, isohexium, cyclohexyl and cydopentylmethyl. The compounds of the formula I 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 monohydrogen orthophosphate and potassium hydrogen sulfate. Illustrative organic acids that form suitable salts include mono acids, di and tricarboxylic. Illustrative of said acids are, for example, acetic, glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxyloalleric, benzoic, hydroxybenzoic, phenylacetic, cinnamic, salicylic acids 2- phenoxy-benzoic, and sulphonic such as methanesulfonic acid and 2-hydroxyethanesulfonic acid. The compounds of the formula Y wherein X is -C (= o) -C (= O) -Y, can exist in a hydrated or dehydrated form. The hydrates of these triceate compounds of the formula I are much more chemically stable than the dehydrated triceate compounds of the formula I wherein X is -C (= O) -C (= O) -Y. For this reason, hydrates are preferred and any reference to this specification and claims for a tricete compound should be taken into account, since it includes reference to the corresponding hydrated form as allowed by the context. In addition, it is expected that the compounds of this invention will have the hydrated form under normal physiological conditions. Each α-amino acid has a characteristic "R group", the R group being the side chain or residue, attached to the a-carbon atom of the α-amino acid. For example, the side chain of the R group for glycine is hydrogen, for ala ni is methyl, for valine is isopropyl. (Therefore, through this specification, the R portion is the R group for each indicated a-amino acid). For the specific R groups or side chains of the α-amino acids, reference to the text of A. L. Lehninger on Biochemistry (see particularly Chapter 4) is useful. 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 formula I can be either the D- or L- configurations or can be mixtures of the D- and L- isomers, including racemic mixtures. The abbreviations recognized for the α-amino acids are set forth in Table I.

As with any group of structurally related compounds, which possesses a particular generic utility, certain groups and configurations are preferred for compounds of formula i in their end-use application.

With respect to the substituent P, the compounds of the formula i wherein P4 is Ala or a ligation are preferred. Particularly preferred are the compounds of the formula I wherein P is a ligation. 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. As for the substituent R ,, the compounds of the formula I wherein Ri is -CH (CH3) 2 or -CH2CH2CH3 are preferred, the "R groups" being characteristic of the amino acids Vai and Nva, respectively. With respect to the substituent X, the compounds of the formula I wherein x is -XF2CF3, -CF3, -CF2 (CH2) tCH3, -CF2 (CH2) tCOOR4, -CHF (CH2) tCH3, -CF2 (CH2) are preferred , CONHR4, CF2 (CH2) tCH2OR4, or -CF2 (CH2) VCH = CH2. Particularly preferred are the compounds of the formula I wherein X is -CF2CF3. With respect to the K substituent, compounds of the formula I wherein K is benzoyl, tertiary butoxycarbonium, carbobenzyloxy, isovaleryl, -C (= O) N (CH 3) 2, are preferred; where Z is N and B is a group of the formulas R 'R' O or > - ^ and wherein R 'is hydrogen or an alkyl group of C ß Particularly preferred are compounds of formula I wherein K is and where Z is N and B is a group of the formulas O O O O and wherein R 'is hydrogen or an alkyl group of C? .6. Specific examples of preferred compounds include: N- [4- (4-morpholinylcarbonyl) benzoyl] -L-valyl-N '- [3,3,4,4,4-pentafluoro-1- (1-methylethyl) -2- oxobutyl] -L-2-azetamide; N- [4- (4-morpholinylcarbonyl) benzoyl] -L-valyl-N '- [3,3,4,4,4-pentafluoro-1- (1-methylethyl) -2-oxobutii] -D, L- 2-pipecolinamide; N- [4- (4-morfo! Inylcarbonyl) benzoyl] -L-valyl-N '- [3,3,4,4,4- pentafluoro-1- (1-methylthiol) -2-oxobutyl] - rans-4-hydroxyprolinemide; N- [4- (4-morpholinylcarbonyl) benzoyl] -L-vall-N '- [3,3,4,4,4- pen tari uoro- 1- (1-methylethyl) - 2-oxobutii] -frar7s-4-acetoxiprolinam ida; N- [4- (4-morpholinylcarbonyl) benzoyl] -L-vayyl-N '- [3,3,4,4,4-pentaf luoro- 1- (1-methylet? L) -2-oxobu ti ] -frans-4-benzyloxyprolonam ida. In general, the compounds of the formula I can be prepared using normal chemical reaction known analogously in the art and as described in Scheme A. Scheme A H2N-CH (R1) -C (= O) -X 1 P2, P3, K-P4 PAR K-P4-P3-P2-HN-CH (R1) -C (= O) -X1 (SEQ ID NO.5) Scheme A provides a general synthetic scheme for preparing the compounds of formula I. The groups P2, P3 and KP can be linked to the free amino group of the amino acid derivative of structure (1). Note that structure (1) represents the Pt portion where the free carboxylic acid group has been replaced with an "X" portion as defined above. P2, P3, and K-P4 can be attached to the free, unprotected amino compound (Pi-X) by well-known peptide coupling techniques. In addition, groups P P2, P3, and K-P4 can be joined in any order while in compound finai is K-P4-P3-P2-P? - For example, K-P4 can be attached to P3 to give KP " -P3 which is linked to P2-P1-X; or K-P4 linked to P3-P2 then attached to an appropriately protected C-terminal and the C-terminal protective group converted to X. Generally, the peptides are elongated by the deprotection of α-amine from the N-terminal residue and coupling the next N-protected amino acid suitably via a peptide ligation using the methods described. This deprotection and coupling process is repeated until the desired sequence is obtained. This coupling can be carried out with the constituent amino acids in stages, as described in Scheme A, or by fragment condensation (two to several amino acids), or combination of both processes or by synthesis of solid phase peptides., according to the method originally described by Merrifield, J. Am. Chem. Soc, 1963, 85, 2149-2154, the description of which is incorporated herein by reference. When a synthetic solid-phase approach is employed, the C-terminal carboxylic acid is attached to an insoluble carrier (usually polystyrene). This insoluble carrier contains a group which will react with the carboxylic acid group to form a ligation which is stable to the elongation conditions but is then easily divided. Examples of which are: chlorine or bromomethyl resin, hydroxymethyl resin, and aminomethyl resin Many of these resins are commercially available with the amino acid C-terminai already incorporated For compounds of the formula I wherein X is H, it can also be used in the reaction of Scheme A to bind a resin to the functionality of the amino acid derivative of structure (1) wherein X is H. Examples of suitable linker compounds are L3 Alternatively, the compounds of the invention can be synthesized using automatic equipment to synthesize peptides. In addition to the above, peptide syntheses are described in Stewart and Young, "Solid Phase Peptide Synthesis", 2nd. ed., Pierce Chemical Co., Rockford, IL (1984); Gross, Meienhofer, Udenfriend, Eds., "The Peptides: Analysis, Synthesis, Biology", Vol. 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 and others. "The Practice of Peptide Synthesis" Springer-Verlag, New York (1984), descriptions of which are incorporated herein by reference.The coupling between two amino acids, an amino acid and a peptide, or two peptide fragments, can be Lievar out using normal coupling procedures such as the azide method, carbonic acid-carboxylic anhydride method (isobutyl chloroformate, carbodi-imide method (dicyclohexylcarbodiimide, di-isopropylcarbodiimide, or water soluble carbodiimide), active ester method (p-nitrophenyl ester, n-hydroxysuccinic imido ester), Woodward K reagent method, carboniidi-imidazole method, phosphorus reagent methods, such as BOP-CI or oxidation-reduction. Some of these methods (especially the carbodi-imide method) can be improved by adding 1-hydroxybenzotriazole. These coupling reactions can be carried out in any solution (liquid phase) or solid phase. The functional groups of the constituent amino acids should generally be protected during the coupling reactions to avoid formation of unwanted ligatures. Protective groups that can be used are listed in Greene, "Protective Groups in Organic Chemistry," John Wiley & Sons, New York (1981) and "The Peptides: Analysis, Synthesis, Biology", Vol. 3, Academic Press, New York (1981), the description of which is incorporated herein by reference. The α-carboxyl group of the C-terminal residue, usually, but does not have to be, protected by an ester that can be separated to give 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 divided by moderate base treatment or moderate reductive media , such as tpcloroethyl and phenacyl esters The a-amino group of each amino acid to be coupled to the growing peptide chain, has to be protected Any protecting group can be used in the art Examples of which include 1) types of acyl such as formyl, trifluoroacetyl, phthalyl, and p-toluenesulfonyl, 2) aromatic carbamate types, such as benzyloxycarbonyl (Cbz or Z) and substituted benzyloxycarbonyls, 1- (p-biphenyl) -1-methoxyethoxy? carbonyl, and 9-fluoren? lmet? lox? carbon? lo (Fmoc), 3) types of aliphatic carbamate such as tertiary butyloxycarbonyl (Boc), ethoxycarbonyl, di-isopropylmethoxycarbonyl, and halochloricarbonyl, 4) carbamate types of i the cyclical such as ciclop entyloxycarbonyl and adamantyloxycarbonyl, 5) alkyl types such as tphenylmethyl and benzyl, 6) tpalkylsilane such as tpmethylsilane, and 7) thiol containing types such as phenylthiocarbonyl and dithiasuccinoiio The preferred a-amino protecting group, is either Boc or Fmoc, preferably Boc Many amino acid derivatives suitably protected for peptide synthesis are commercially available The a-amino protecting group of the newly added amino acid residue is split before! coupling of the following amino acid When the Boc group is used, the methods of choice are either trifluoroacetic acid, pure or in dichloromethane, or HCl in aioxane or acetate. The resulting ammonium salt is then neutralized either before coupling or in situ with solutions basic solutions such as pH-regulating aqueous solutions, or tertiary amines in dichloromethane or dimethylformamide. When the Fmoc group is used, the reagents of choice are piperidine or substituted piperidine in dimethylformamide, 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 amino acid having side chain functionalities can be protected during the preparation of the peptide using any of the groups described above. Those skilled in the art will appreciate that the selection and use of appropriate protecting groups for these side chain functionalities depends on the amino acid and the presence of other protecting groups on the peptide. The selection of said protecting groups is important in that it should not be removed during the 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: portions of p-toluenesulfonyl (tosyl), can be used to protect the amino side chains of amino acids such as Lys and Arg; p-methylbenzyl, acetamidomethyl, benzyl (Bzl), or tertiary butylsulfonyl portions can be used to protect the sub-acid containing amino acid side chains such as cysteine; and benzyl ether (Bzl) can be used to protect the hydroxy containing side chains of amino acids such as Ser or Thr. When Fmoc is chosen for a-amino protection, tertiary butyl-based protecting groups are usually accepted. 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 solution phase synthesis is used, the protecting groups are removed in any way as indicated by the selection of protecting groups. These methods are well known to those skilled in the art. When a solid phase synthesis is used, the peptide is split from the resin usually simultaneously with the removal of the protecting group. When a Boc protection scheme is used in the synthesis, treatment with anhydride HF containing additives such as dimethyl sulfide, anisole, thioanisole, or -cresol at 0 ° C is the preferred method for cleaving the peptide from the resin. The cleavage of the peptide can also be achieved by other acidic reagents such as mixtures of trifluoromethanesulfonic acid / trifluoroacetic acid. If the Fmoc protection scheme is used, it is divided into an N-terminal Fmoc group with reagents described above. The other protecting groups and the peptide are divided from the resin using a solution of trifluoroacetic acid and various additives such as anisole, etc.

For the compounds of the formula i wherein X is H, the peptide compound of the formula I can be divided from the linking compound and resin with aqueous acid / formaldehyde. Alternatively, the compounds of formula 4 can be prepared using standard chemical reactions analogously known in the art and as described in Scheme B.

Scheme B H2N-CH (R1) -CH (OH) -X (2) Pair P2, P3, -P4 K-P4-P3-P2- HN-CH (R1) -C (= O) -X I (SEC: ID NO 1) Scheme B provides an alternative general synthetic scheme for preparing the compounds of formula I. Groups P2, P3 and KP can be attached to the free amino group of the amino alcohol derivative of structure (2), as previously described in Scheme A to give the peptide alcohol of the 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 and dimethyl sulfoxide to give the compounds of formula I.

The starting materials for use in Schemes A and B are readily available to one of ordinary skill in the art. For example, amino acids P2, P3 and K-P where K is hydrogen, are commercially available, and the linker compound of the structure (L1) is described in J. Am. Chem. Soc, 114, 3157-59 (1992). In addition, the substituted amino acids K-P4 wherein K is acetyl, succinyl, benzoyl, tertiary butyloxycarbonyl, carbobenzyloxy, tosyl, dansyl, isovaleryl, methoxysuccinyl, 1-adamantanesulfonyl, 1-adamantanacetyl, 2-carboxybenzoyl, phenylacetyl, tertiary butylacetyl, bis [ (1-naphthyl) methyl] acetyl or -A-R2 where O O A is II II C -.- N-C -, - O-C-or-S-; Rz is an aryl group containing 6, 10 or 12 carbons suitably substituted by 1 to 3 members independently selected from the group consisting of fluoro, chloro, bromo, iodo, trifluoromethyl, hydroxy, alkyl containing from 1 to 6 carbons, alkoxy which contains from 1 to 6 carbons, carboxy, alkylcarbonylamino wherein the alkyl group contains from 1 to 6 carbons, 5-tetrazoyi, and acylsulfonamido (ie, acylaminosulfonyl and sulfonylaminocarbonyl) containing from 1 to 15 carbons, with the proviso that when the acyl sulfonamide contains an aryl, the aryl can be further substituted by a member selected from fluoride, chlorine, bromine, iodine and nitro; and said other amino terminal protecting groups, which 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 for someone with ordinary experience in the field. For example, certain protected amino compounds of structure (1) wherein X is H, are well known in the literature and are also described in the European Patent Application OPI No. 0275101, July 20, 1988 and in the application for European Patent OPI No. 0363284, April 11, 1990. In addition, the starting amino compounds, of structure (1), wherein X is -CF3, -CF2 (CH2) tCH3, -CF2CF3, and -CF2 (CH2 ), CH = CH2 are described in European Patent Application OPI no. 0503203, September 16, 1992. The amino compounds of structure (1) wherein X is -CF3, -CF2H, -C (= O) -Y, -CF2CH (R1 ') -C (= O) P2' -Y and -C (= O) -P2'-Y are described in the European Patent Application OPI No. 0195212, September 24, 1986. The amino compounds of the structure () wherein X is -CF2CH (R1 ' ) NHC (= O) R3 are described in OPI No. 0275101, July 20, 1988 and the amino compounds of structure (1) wherein X is -CFCH (R1 ') NHC (= O) R3 can be prepared by analogous procedures using bromo-fluoroacetic acid ethyl ester. The amino compound of structure (1) wherein X is -CFH2, are described in Biochem. J. (1987), 241, 871-5, Biochem. J. (1986), 239, 633-40 and U.S. Pat. No. 4,518,528, May 21, 1985. The amino compounds of the formula (1) wherein X is -CO2R3, C (= O) -R3 and -CH (R1) -C (= O) P2'-Y are described in European Patent Application OPI No. 0363284, April 11, 1990. The amino compounds of structure (1) wherein x is -CF2CH (R1 ') NHC (= 0) -R3 are described in the European Patent Application In addition, amino compounds of structure (15) wherein X is -CF2CF3, are described in European Patent Application No. 0410411, January 30, 1991. The linker compound Benzyl ester of trans-4- (aminomethyl) -cyclohexanecarboxylic acid, used in synthesis of compounds of formula I wherein X is H, is prepared from the corresponding acid as described in J. Am. Chem. Soc. 1992, 114, 3156-3157. In addition, other starting materials may be prepared for use in Schemes A and B, by the following synthetic procedures which are well known and appreciated by one of ordinary skill in the art. 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 O O - CH - C - CH c - - C R ' wherein R 'is hydrogen or an alkyl group of C? .6 are prepared using standard chemical reactions analogously known in the art. The process for preparing the substituted amino acids K-P4 where K is - where B is a -C (= O) - is described in scheme C where P4 and Z are as previously defined or are the functional equivalents of these groups.

Scheme C OR or G? Z - C - Cl (4) \ / I / ~ \ i or z - c (5) Specifically the amino acids K-P4 where K is - B - Z O where \ / B is a -C (= O) - are prepared by coupling the amino acid K-P4 wherein K is hydrogen with an acid chloride of structure (4) in the presence of one to four molar equivalents of a suitable amine which can act as a hydrogen halide acceptor. Amines suitable for use as hydrogen halide acceptors are tertiary organic amines such as tri-amines (lower alkyl) for example, triethylamine, or aromatic amines such as picolines, collidines, and pyridine. When pyridines, picolines, or collidines are used, they can be used in high excesses and therefore also act as the reaction solvent. The N-methylmorpholine ("MM") is particularly suitable for the reaction. The coupling reaction can be carried out by adding an excess, such as from 1-5, preferably about 4 times a molar excess, of the amine and then the acid chloride of 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 tetraeloride, 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. The preferred solvent is methylene chloride for this coupling reaction. The reaction is allowed to proceed for about 15 minutes to about 6 hours, depending on the reagents, the solvent, the concentrations, and other factors such as the temperature which may be from about 0 ° C to about 60 ° C, conveniently at approximately room temperature, that is, 25 ° C. The N-amino-protected amino acids, K-P, where K is wherein B is a -C (= O) - can be isolated from the reaction mixture by appropriate techniques such as by chromatography on silica gel. The substituted amino acids K-P4 where K is ~ B- where B is different from -C (= O) -, it can be prepared analogously, merely substituting the appropriate intermediary n where B is different from -C (= O) - and A is Cl or OH (the corresponding acid, acid chloride or sulfonyl chloride) for the compound of structure (5) in Scheme C. The acid chloride of the structure (4) and the appropriate intermediary of the formula A ~ B ~ Z O where \ B is different from -C (= O) - and A is Cl or OH (the corresponding acid, acid chloride or sulfonyl chloride) are commercially available or can be easily prepared by techniques and procedures well known and appreciated by someone of experience ordinary in the art. For example, the appropriate intermediaries of the formula they can be prepared as described in Scheme D where all the substituents are as previously defined. Scheme D or acid (6) Amidation (7) hydrolysis step c (9) OR Scheme D provides a general synthetic procedure for preparing the appropriate intermediaries of the formula where Z is as previously defined. In step a, the carboxylic acid functionality of the appropriate 2,5-pyridinedicarboxylic acid, 2-methyl ester (6) (Nippon Kagku Zasshi, 1967, 88, 563) is converted to its acid chloride using well-known techniques and procedures. 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- (morfoiino-4-carbonyl) acid ) -2-pyridinecarboxylic, (9).

In step C, the methyl ester functionality of (9) is hydrolyzed by techniques and procedures well known and appreciated by one of ordinary skill in the art, with, for example, lithium hydroxide in methanol, to give acid 5- (morpholine-4-carbonyl) -2-pyridinecarboxylic (10). In addition, the appropriate intermediary of the formula it can be prepared as described in Scheme E where all substituents are as previously defined. Scheme E (6) (11) hydrolysis step C (13) Scheme E provides a general synthetic procedure to prepare the appropriate intermediaries of the formula where Z is as previously defined. In step a, the functionality of free carboxylic acid of 2-methyl ester of 2,5-pyridinedicarboxylic acid, (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 approximate amount of tertiary butyl alcohol of dicyclohexylcarbodiimide (Synthesis, 1979, 579), to give the corresponding 2-methyl ester of corresponding 2,5-pyridinedicarboxylic acid , 5-t-butyl ester (11).

For example, the 2-methyl ester of 2,5-pipdinodicarboxylic acid (6) is combined with a molar excess the approximate amount of tertiary butyl alcohol in an appropriate organic solvent, such as methylene chloride. The reaction is usually carried out on a temperature scale of 0 ° C at room temperature and for a time ranging from 2-24 hours. The 2-methyl ester of 2,5-pyridinedicarboxylic acid, (11), is isolated from the reaction mixture by normal 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 morpholino (8) to give the corresponding tertiary butyl ester of 6- (morpholino-4-carbonyl) nicotinic acid (12). For example, the 2-methyl ester of 2,5-pyridinedicarboxylic acid, (11), is contacted with a molar excess of morpholine in an appropriate organic solvent, such as tetrahydrofuran. The reaction is usually carried out at a temperature scale from room temperature to reflux and for a time ranging from 5 hours to 3 days. The tertiary butyl ester of 6- (morpholino-4-carbonyl) nicotinic acid, (12) is isolated from the reaction mixture by normal 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 hydrolyzed, with for example, HCl in nitromethane, to give the corresponding 6- (morpholino-4-carbonyl) nicotinic acid (13).

The amino compounds of structure (1) wherein X is -C (= 0) -C (= O) -Y, can be prepared by techniques and procedures well known to one of ordinary skill in the art. For example, the amino compounds of structure (1) wherein X is -C (= O) -C (= O) -Y can be prepared as described in Scheme F where all substituents are as previously defined .

Esq uema F I 1) Ph3P (14) 2) Base Boc Ox [simple gen or 03 / (CH3) 2S or Oxone * ~ (twenty) i ° 1 { AcicWg) i) Base Specifically, the amino compounds of structure 81) wherein X is -C (= O) -C (= O) -Y can be prepared, as illustrated in Scheme F, by treatment of the protected tricarbonyl compound N-Boc ( 29) with a suitable acid, such as hydrogen chloride in ethyl acetate or nitromethane or pure trifluoroacetic acid as a solution in methylene chloride, followed by the generation of the free base (21) using an appropriate base. The intermediate (20) is generated from the ilido (19) by treatment with (a) ozone and dimethyl sulfide or (b) single oxygen or (c) OxoneR. The ozonolysis reaction can be conveniently carried out by, for example, bubbling an excess of ozone through a cooled solution of the appropriate iodide of structure 829). Suitable solvents include any non-reactive solvent in which the ylid of structure 829) is soluble, for example, alkyl esters of simple alkanoic acids such as ethyl acetate; chlorinated hydrocarbons such as carbon tetrachloride, chloroform, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane, and methylene chloride; aromatic hydrocarbons such as benzene, toluene, and xylene; a chlorinated aromatic such as 1,4-trichlorobenzene and o-dichlorobenzene; or an ether solvent such as diethyl ether, tetrahydrofuran (THF), and 1,4-dioxane. Methylene chloride is preferred. The temperature of the ozonolysis reaction mixture can be any temperature that conducts the reaction, usually about -35 ° C, and more preferably about -70 ° C. the time of the reaction will vary depending on the ilide, the concentration of the reactants, the temperature and other factors. Conveniently, ozone is bubbled into the reaction mixture until the solution turns blue indicating an excess of ozone. The ozonide is treated. then with an excess of a reducing agent such as zinc metal or preferably dimethyl sulfide. The compound (20) is isolated as the hydrate from the reaction mixture in any convenient manner, usually by solvent removal (via evaporation). Purification can be achieved by, for example, flash chromatography (Still, W.C., Kahn, M .; Mitra, A., J. Or. Chem. 1978, 43, 2923). OzoneR can be used in place of ozone when a softer and more selective reagent is desired. Typically, the ylido (19) is treated with 1.5 equivalents of Oxone® in THF-H2O and the resulting hydrolyzed tricarbonyl is isolated from the reaction mixture. Oxidations that use simple oxygen are well known. More specifically, the simple oxygen oxidation of an ilide to produce a tricarbonyl ester has been reported by h. Wasserman et al., J. Amer. Chem. Soc, 11, 371 (1989). simple oxygen can be generated by excitation of dyes-oxygen sensitizers, suitable dyes include Rose Bengal, Eosin Y and methylene blue. Other sensitizers include naftalentiofen. Normally Rose Bengal and Eosin Y are bound to a basic anion exchange resin and methylene blue is bound to an acid cation exchange resin. Excitation is achieved with a UV lamp such as a tungsten-iodine lamp. Suitable solvents are any solvents that promote and do not interfere with the desired reaction. Such solvents include aromatic hydrocarbons such as benzene and toluene; hydrocarbons such as hexane; ethereal solvents such as diethyl ether, tetrahydrofuran (THF), 1,4-dioxane; chlorinated hydrocarbons such as dichloromethane and chloroform; and carbon disulfide. The mixtures are operable. The temperature of the reaction mixture can be any suitable temperature from about -78 ° C to about 30 ° C, usually from about -78 ° C to -50 ° C. The reaction time will vary depending on the reagent, the solvent, concentrations and temperature, and may be from about 1 minute to about 2 hours. The purification and isolation can be by the methods described above for the specification and isolation of the ozonolysis reaction mixture product. The N-Boc protected ilido of structure (19) is prepared by coupling the protected N-Boc amino acid of structure 814) with the phosphonium ylide of structure (16) using a water soluble carbodiimide (WSDCi) such as 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (17) or 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide methiodide (18) in the presence of 4-dimethylaminoiridine (DMAP) in a suitable solvent such as THF or dichloromethane. The reaction will require from about 30 minutes to about 12 hours, usually from about 2 to 3 hours, depending on the acid, the substance, the solution (s), and the temperature which can be from about -15 ° C to about 60 ° C, but usually at 0 ° C. Isolation and purification are achieved by filtering the reaction mixture to remove solid products and subsequently chromatographing the filtrate, for example, on silica gel. The phosphorous ylido, Wittig's reagent, of structure (16) is prepared from the corresponding α-halocarboxylic acid derivative of structure (15) in the usual manner, ie, by reacting the α-halo ester with a tertiary phosphine such as triphenylphosphine to give a phosphonium salt. When treated with a base such as an organolithium compound, for example, lithium diisopropylamide (LDA), sodium hydride or sodium amide, the acidic proton is removed and the desired ylide is formed. Suitable solvents used to form the Wittig reagent, include any non-reactive solvent, for example, aromatic hydrocarbons such as benzene or toluene, chlorinated hydrocarbons such as carbon tetraeloride, chloroform, or methylene chloride, or ethereal solvents such as diethyl ether or THF. The reaction can be conveniently carried out from about 0 ° C to about 60 ° C, usually at room temperature, i.e., about 25 ° C. The halo group of the a-haloester is preferably a bromine group, but may be a chloro or iodo group or may be any leaving group that forms a stable phosphonium salt, such as a mesylate or tosylate group. In addition, amino compounds of structure (1) wherein X is -CHF (CH2) tCH3 can be prepared as described in Scheme G wherein all substituents are as previously defined.

Scheme G Amidation Ri O I 11 BOCNH- VCH-CO2H BOCNH-CH-C-N-OCH3 I step to CH3 (22) (23) RENT OR RENT CH3 (CH2) tCH2 (24) I ?? BocNH-CH-C-CH2 (CH2) tCH3 ^ (25) step b FLUORATION RSO2-N (F) -SO R (26) Rl O or (27), (28) or (29) I ?? BocNH-CH-C-CHF (CH2) tCH3 (30) step c DESPROTECTION Rl O HCl gas / EtOAc i II HCl • H2NH-CH-C-CHF (CH2) tCH3 (30a) step d R = CF3, Phenyl Scheme G provides a general synthetic procedure for preparing amino compounds of structure (1) wherein X is -CHF (CH2) tCH3. In Scheme G, all substituents are as previously defined unless otherwise indicated. In step a, the appropriate acid of structure (22) is amidated with N-methyl-N-methoxyamine by techniques and procedures well known and appreciated by one of ordinary skill in the art, such as a coupling reaction using 1, 3-dicyclohexylcarbodi-imide (DCC) and 1-hydroxybenzotriazole (HOBT) to give the corresponding amide of structure (23). In step b, the appropriate amide of structure (23) is alkylated with the appropriate alkyl metal compound of structure (24) to give the corresponding keto compound of structure (25). For example, the appropriate amide of structure (23) is treated with the alkyl metal compound of structure (24) in a suitable aprotic anhydride organic solvent, such as tetrahydrofuran or diethyl ether. The reaction is usually carried out at a temperature scale of -78 ° C to -40 ° C and for a time ranging from 30 minutes to 5 hours. The corresponding keto compound of structure (25) is recovered from the reaction zone by extraction methods as is known in the art and can be purified by chromatography. In step c, the appropriate keto compound of structure (25) is fluorinated with the N-fluorosulfonimide compound of structure (26), or the alternative fluorination reagents (27), (28) or (29), for give the protected amino compounds of structure (30) which is the amino compound of structure (1) in which the amino terminal group is substituted with a Boc group and X is -CHF (CH2) tCH3. For example, the appropriate keto compound of structure (25) is treated with an appropriate non-nucleophilic base, such as lithium di-isopropylamide in a suitable aprotic organic anhydride solvent, such as tetrahydrofuran at a temperature scale of -78 ° C. at -40 ° C and for a time that varies from 5 minutes to 2 hours. The reaction mixture is then treated with the N-fluorosulfonimide compound of structure (25) and the reaction carried out on a temperature scale of -78 ° C to -40 ° C and for a time ranging from 30 minutes to 10 hours. The N-t-Boc protected amino compounds of structure (1) wherein X is -CHF (CH2) tCH3, is recovered from the reaction zone by extraction methods as is known in the art and can be purified by chromatography. Alternative routes for the preparation of compounds of structure (1), wherein X = -CF2CF3, is shown in scheme H. The required starting material defined by compound (31) is readily available either commercially or by applying principles and known prior art techniques. The term "Pg" refers to a suitable protecting group as defined above completely. In Scheme H, step A, the protected amino acid (31) is transformed into the hydroxamate (32). This amidation can be carried out using a coupling reaction between the two amino acids using the protected amino acid (31) and the N-alkyl-O-aiquiihydroxylamine. The collection reaction can be carried out using standard coupling procedures as previously described for coupling between two amino acids to provide the hydroxamate (32). In step b, the protected hydroxamate (32) is transformed into the protected pentafluoroketone (34) [or (35)]. 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, Tetrahedorn Letters, 33 (1992) 3265-3268.

Scheme H ' (35) (SEQ ID NO.4) In step c, hydroxamate (32) 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 deprotected hydroxamate. The deprotected hydroxamate is lengthened by coupling the next protected amino acid suitably, through a ligation of peptides using the methods previously described, or by condensation of fragments, or combination of both processes to provide the elongated peptide (33). In step d, the ketone (34) is deprotected under conditions previously described. The deprotected ketone (34) is lengthened by coupling the next appropriately protected amino acid, through a peptide ligation using the previously described methods, or by fragment condensation, or combination of both processes to provide the elongated ketone (35). Alternatively, the corresponding protected amino acid ester of (31) [ie, Pg N H -CH (R1) C (= O) OR4 ', (32a), wherein R' is defined as above] can be replaced by the hydroxamate (32). The corresponding esters of protected amino acids of (31) are commercially available or are readily synthesized from (31) by methods well known to one of ordinary skill in the art. In step b, it is amino acid ester (32a), it is transformed into the protected pentafluoroketone (34) [or (35)] in a form directly analogous to that used for the corresponding hydroxamate. Steps c and d, could be the same as those used when using hydroxamate (32). For example, the amino acid ester (26a) can be reacted with a suitable perfluorinating agent, such as, with 4 to 8 equivalents of perfluoroethyl iodide or perfluoroethyl bromide. Said reaction is carried out in the presence of a suitable alkali metal base, for example 4-8 equivalents of MeLi / LBr in a suitable anhydride solvent, such as ester, THF or toluene; the reaction being carried out at reduced temperature from -100 ° C to 0 ° C, preferably from -30 ° C to -80 ° C, to provide the protected perfluoropropyl amino ketone and the perfluorobutyl amino ketone, respectively, Steps c and d could be the same than employees when used in hydroxamate (32). Alternatively, the N-protected amino acid ester (32a) can be first deprotected and coupled with an appropriately N-protected peptide, in the presence of an appropriate coupling solvent. The N-protected peptide ester formed after, [KP4P3P2NH-CH (R1) C (= O) OR2, (33a)], could then be perfluorinated in a manner directly analogous to that used for the corresponding hydroxamate. Steps c and d, could be the same as those used when using hydroxamate (33). All the amino acids used in the synthesis of Formula 1 are either commercially available or are easily synthesized by someone of relevant experience in the art. For example, the amino acid derivative Pro (4-Ac) defined in P2 can be made by esterifying a Pro residue using techniques well known to one of ordinary skill in the art. The following examples present normal syntheses. 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; "mmoles" refers to millimoles; "mL" refers to milliliters; "pb" refers to boiling point; "pf" refers to melting 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 dicyclohexylcarbodiimide; "h" refers to hour; "DMF" refers to N, N'-dimethylformamide; "conc." refers to concentrate; "NMM" refers to N-methylmorpholine, "under vacuum" refers to removal of a solvent under reduced pressure. EXAMPLE 1 Preparation of N-f4- (4-morpholinylcarbonyl) benzoyl] -L-valyl-N'-f3,3,4,4,4-pentafluoro-1- (1-methylethyl) -2-oxobutyl-L-2 -azetamide a) Preparation of N-α (1,1-dimethylethoxy) carbonill-L-valyl-succinimide To a stirred solution (ice bath), of BOC-L-valine (4.56 g, 0.021 mole), and N-hydroxysuccinimide (2.41 g, 0.021 mole) in DME (50 ml) was added DCC (4.75 g, 0.023 moles). The reaction was stirred for 6 h at 5 ° C and then allowed to stand in the refrigerator overnight. The reaction was filtered cold, washed with Et2O, and concentrated to give a solid which was crystallized with EtOAc / hexane to give the desired product as a white crystalline solid (4.59 g, 69.5%): mp 123-124 ° C; 1 H NMR (300 MHz, CDCl 3) d 5.00-4.95 (d, 1 H, J = 9.3 Hz), 4.62 (dd, 1 H, J = 4.97 Hz), 2.85 (s, 4 H), 2.75-2.44 (m, 1 H) , 1.45 (s, 9H), 1.25.-0.90 (m, 6H); 13C NMR (CDCI3) d 1.68.6, 167.9, 155.1, 155.0, 80.4, 77.4, 77.2, 77.0, 76.6, 76.5, 57.0, 31.6, 31.1, 28.2, 28.1, 28.0, 27.99, 27.93, 25.5, 18.6, 17.3; MS (CI / CH4) m / z 315 (MH +), 299, 287, 259, 241, 215 (base peak), 173, 172, 145, 144, 116, 100, 72. Cale. Anal, for C? 4H22H2O6: C, 53.49; H, 7.05; N, 8.91. Found: C, 53.67; H, 7.06; N, 8.81. b) Nf (1,1-dimethylethoxy) carbonyl-L-valyl-L-2-azetidine carboxylic acid To a stirred solution of (S) - (-) - 2-acetidine-carboxylic acid, (1.0 g, 10 mmol ) and Et3N (1.5 mL, 11 mmol) in DMF (30 mL) was added the product of part (a) (2.8 g, 9.0 mmol) and the reaction was heated at 120 ° C for 2.5 h. Upon cooling, the reaction was concentrated in vacuo and the oily residue was dissolved in EtOAc and washed with 1N HCl (2 x 30 ml), dried (MgSO) and concentrated to give the desired product as a white foam (1.88 g). , 65%); 1 H NMR (300 MHz, CDCl 3) d 9.15 (br s, 1 H), 5.09 (d, 1 H, J = 8.8 Hz, NH), 5.00 (dd, 1 H, J = 9.2, 7.2 Hz, a-CH from Val ), 4.43 (dd, 1H, J = 7.0, 1.49 Hz), 4.17 (m, 1H), 3.94 (ap t, 1H, J = 8 Hz), 2.62 (m, 3H), 1.44 (s, 9H, tBu ), 0.97 (d, 6H, J = 6.7 Hz, 2 x CH3). c) NK 1,1-di methylethoxy) carbonill-L-valyl-N'-f 3.3,4.4, 4-pentaf luoro-1- (1-methylethyl) -2-oxobutyl-1-L-2-azetamide To a stirred solution of the product from part (b) (1.80 g, 6.0 mmol) and NMM (0.66 mL, 6.0 mmol) in dry CH2Cl2 (50 mL) at -20 ° C under nitrogen, isobutyl chloroformate (0.79 mL, 6.0 mL) was added dropwise. mmoles). After 20 minutes, 4-amino-1,1,1, 2,2-pentafluoro-5-methyl-3-hexanone hydrochloride (1.54 g, 6.0 mmol) was added (from European Patent Application OPI No. 0410411 , published on January 30, 1991), was followed immediately by another equivalent of NMM (0.66 ml, 6.0 mmol). The reaction mixture was stirred at -20 ° C for 1 h, then poured into cold diluted HCl and extracted with CH2Cl2. The organic extract was washed with water, dilute aqueous NaHCO3, brine, and dried (MgSO4). Concentration in vacuo gave the desired compound as a colorless oil (2.20 g, 73%); 1 H NMR (300 MHz, CDCl 3) d 8.4 (m, 1 H, NH), 5.12-4.90 (m, 2 H), 4.38 (m, 1 H), 4.11 (m, 1 H), 4.00 (m, 1 H), 2.73 ( m, 1H), 2.42 (2m, 2H), 1.92 (m, 2H), 1.45 (s, 9H, t-Bu), 1.11-0.85 (m, 12H, 4xCH3); 19F NMR d -82.4 (s, CF3), -120.99 and -123-09, -121.23 and -122.84 (2AB quatrains J = 296 Hz, CF2). d) L-valyl-N-f3,3,4.4.4-pentafluoro-1-M-methylethyl) -2-oxobutyl] -L-2-azetamide hydrochloride salt HCl gas was bubbled into a stirred solution of the product from part (c) (2.0 g, 3.98 mmol) in EtOAc (40 mL) at ice bath temperature for 4 minutes. The reaction was then stirred at room temperature for 2 h, concentrated in vacuo and azeotroped with EtOAc to give the desired product (1.63 g, 96%) as a white foam; IR (film) 3196, 2972, 2937, 2883.2636, 1755, 1655, 1523, 1471, 1398, 1373, 1350, 1222, 1201, 1159, 1116, 1093, 1066, 1014, 979, 922, 835, 815, 734, 646, 588; 1 H NMR (300 MHz, CDCl 3) d 8.0'9 (d, 1H, J = 8.2 Hz, NH), 8.02 (d, 1H, J = 8.5 Hz, HN), 5.15 (m, 1H), 5.00 (m, 1H), 4.55 (m 1H), 4.13 (m, 1H), 3.90 (m, 1H), 2.56 (m, 2H), 2.30 (m, 3H), 1.12-0.84 (m, 12H, 4xCH3); 13C NMR (CDCI3) d 193.2, 170.7, 170.4, 170.3, 169.9, 62.2, 61.5, 59.7, 59.5, 55.1, 55.0, 50.1, 30.0, 29.9, 28.9, 28.7, 19.8, 19.7, 18.8, 18.5, 18.2, 18.1, 17.8, 16.6, 16.3; 19F NMR d-82.06 and -82.14 (2s, CF3), -121.16 and -122.76, -121-33 and -122.88 (2AB quatrains J = 296 Hz, CF2); MS CI / CH4) m / z (intensity r.) 442 (6), 430 (18), 402 (MH +, 100), 303 (9), 72 (42). Anal. Cale, for C? 6H24F5N3? 3.HCI; C, 43.89; H, 5.53; N, 9.59. Found: C, 43.43; H, 6.07; N, 9.23. e) N-f4-) 4-morpholinylcarbonyl) benzoyH-L-valyl-N'-f3.3,4,4.4-pentafluoro-1- (1-methylethyl) -2-oxobutyl-L-2-acetamide (MDL 104.238 ) To a stirred suspension of 4- (4-morpholinylcarbonyl) benzoic acid (975 mg, 4.14 mmol) and benzyltriethylammonium chloride (4 mg, 0.008 mmol) in 1,2-dichloroethane (30 I) was added thionyl chloride ( 0.30 ml, 4.14 mmol) and the reaction was heated to reflux. After 2.5 h, the reaction was allowed to cool to room temperature and concentrated in vacuo. The residue was azeotroped with CCI4 and placed under vacuum to give morpholinoterephthalic acid chloride (quantitative) as a light orange oil which was used without further purification. In a separate RB flask, a stirred solution of the product from part (d) (1.5 g, 3.43 mmol) in CH2Cl2 (20 mL) was added at -20 ° C. NMM (1.35 mL, 12.3 mmol) and was immediately followed by the trickle addition of the morpholinoterephthalic acid chloride in CH 2 Cl 2 (5 mL) at said rate to maintain the internal reaction temperature at -10 ° C or less. After the addition was complete, the reaction mixture was allowed to warm to room temperature. After 1.5 h at room temperature, the reaction mixture was diluted with CH2Cl2 (20 ml), washed with 1N HCl (2x20 ml), saturated NaHCO3 (2x20 ml), brine (1x20 ml) dried (MgSO4) and concentrated under vacuum to give a white foam that was flash chromatographed (eluted with 1:27 MeOH-CH2Cl2) to give the desired product (MDL 104.238) (335 mg, 16%) as a white foam; IR (KBr) 3690, 3678, 3429, 3271, 3011, 2972, 2931, 2899, 2876, 2862, 1755, 1680, 1631, 1520, 1494, 1458, 1437, 1398, 1373, 1361, 1330, 1302, 1280, 1259, 1234, 1199, 1159, 1114, 1068, 1024, 1012, 896, 860, 842, 787, 773, 763, 669, 597, 563, 540; 1 H NMR (300 MHz, CDCl 3) d 8.32 (m, 1 H, NH), 7.86 (d, 2 H, J = 8.5 Hz, aryl), 7.49 (d, 2 H, J = 7.9 Hz, aryl), 6.70 (m, 1H, NH), 5.00 (m, 2H), 4.50 (m, 2H), 4.19 (m, 1h), 4.86-3.30 (series of m, 8H), 2.82-1.95 (series of m, 4H), 1.05 ( m, H, 3xCH3), 0.88 (d, 3H, J = 6.9 Hz, CH3), 0.88 (d, 3H, J = 6.9 Hz, CH3); 13C NMR 174.07, 174.05, 170.6, 169.2, 166.4, 138.66, 138.62, 135.0, 134.9, 127.4, 127.3, 66.8, 66.7, 62.0, 61.7, 59.7, 59.6, 54.1, 54.0, 49.3, 31.5, 31.4, 28.7, 28.5 , 20.0, 19.0, 18.8, 18.2, 18.1, 18.09, 18.005, 16.1, 16.0; 19F NMR d-82.12 (s, CF3), -120.98 and -123.12, -121.20 and -122.86 (2AB quatrains, J = 296 Hz, CF2); MS (CI / CH4) m / z (intensity re.) 647, 619 (MH +), 303 (100), 289, 218. Anal. Cale, for C28H35F5N4O6.0.3 H2O: C, 53.90; H, 5.75; N, 8.98. Found: C, 53.75; H, 5.86; N, 8.86. EXAMPLE 2 Preparation of N-f4- (4-morpholinylcarbonyl) benzoyl) -L-valyl-N '- [3,3,4,4,4-pentafluoro-1- (1-methylethyl) -2-oxobutin-D, L-2-pipecolinamide a) N - [(1,1-dimethyletoxy) carbonill-L-vali I-DL-2-pipecolinic acid To a stirred solution of D, L-pipecolinic acid (1.30 g, 10 moles) and Et3N (1.5 ml, mmoles) in DMF (30 ml) was added the product of example 1, part (a) (2.0 g, 6.0 mmol) and the reaction was heated at 120 ° C for 2.5 h. Upon cooling, the reaction was concentrated in vacuo and the oily residue was dissolved in EtOAc and washed with 3N HCl (2x30 ml), dried (Na2SO) and concentrated to a yellow foam which was flash chromatographed to give the desired compound (579). mg, 29%), a mixture of two compounds, such as a white foam; 1 H NMR (300 MHz, CDCl 3) d 8.94 (br s, 1 H), 5.62 (d, 1 H, J = 9.8 Hz, NH), 5.45 (d, 5 H, J = 3.98 Hz, L-Pec), 5.07 (d , .5H, J = 9.25, D-Pec), 4.60 (dd, 5H, J = 8.83, 5.06 Hz, a-CH of Val), 4.25 (dd, .5H, J = 8.69, 4.66 Hz, Val of the compound D), 3.93 (app d, 1H, J = 12.47 Hz, Pee), 3.25 (m, 1H, Pee), 2.31 (m, 1H, Pee) 2.20 (m, .5H, Val of compound D), 2.01 ( m, 5H, Val), 1.78-1.33 (m, 5H, Pee), 1.44 (s, 9H, tBu), 1.01-0.86 (m, 6H, 2xCH3). b) N -f 1,1 -di methylethoxy) carboni ll-L-val i I- N'-r3, 3.4.4.4- pentaf luoro- 1 - (1-methylethyl) -2-oxobutyH-D, L- 2-pipecolinamide To a stirred solution of the product from example 2, part (a) (450 mg, 1.37 mmol) and NMM (0.15 ml, 1.37 mmol) in dry CHSCIS (20 ml) at -20 ° C under nitrogen was added chloroformate of isobutyl by dripping (0.18 ml, 1.37 mmol). After 20 minutes, 4-amino-1,1,1,2-pentafluoro-5-methyl-3-hexanone hydrochloride (351 mg, 1.37 mmol). The reaction mixture was stirred at -20 ° C for 1 h, then poured into cold diluted HCl and extracted with CH2Cl2. The organic extract was washed with water, dilute aqueous NaHCO3, brine, and dried (MgSO4). Concentration in vacuo gave the desired compound (580 mg, 80%) as a colorless foam; 1 H NMR (300 MHz, CDCl 3) d 6.98 (m, 1 H, HN), 5.36-4.88 (m, 3 H), 4.60 (m, 1 H), 4.43 m, 1 H), 3.92 (m, 1 H), 3.10 (m , 1H, CH of Pee), 2.36-1.92 (series of m, 3H, Pee and CH or Val), 1.79-1.24 (m, 4H), 1.45 (s, 9H, tBu), 1.05-0.83 (m, 12H , 4xCH3); 19 F NMR d-82.10 (s, CF 3), -120.74 - -123.40 (m, CF 2). c) N-L-Valyl-N'-f3,3,4,4,4-pentafluoro-1- (1-methylethyl) -2-oxobutyl-D, L-2-pipecolinamide hydrochloride salt. HCl gas was bubbled into a stirred solution of the product of example 2 (b) (530 mg, 1.0 mmol) in 10 ml EtOAc) at ice bath temperature for 4 minutes. The reaction was then stirred at room temperature for 2 hours, concentrated in vacuo and azeotroped with EtOAc to give the desired compound (460 mg, 99%) as a white foam. d) N-r4- (4-morpholinylcarbonyl) benzoyl-N-valyl-N, -f3.3.4.4.4-pentafl uoro- 1- (1-methyl-diol) -2-oxobutyl-D, L-2-pipecolinamide (MDL 105,759) To a stirred suspension of 4- (4-morpholinylcarbonyl) benzoic acid (0.28 g, 120 mmol) and benzyltriethylammonium chloride (2 mg, 0.004 mmol) in 1,2-dichloroethane (25 mL) was added chloride of thionyl (0.09 ml, 1.20 mmol) and the reaction was heated to reflux. After 2.5 h, the reaction was allowed to cool to room temperature and concentrated in vacuo. The residue was then azeotroped with CCI4 and placed under vacuum to give morpholineroterephthalic acid chloride (quantitative) as a light orange oil which was used without further purification, in a separate RB flask, a stirred solution was cooled to -20 ° C. of the product of example 2 (c) (450 mg, 10.0 mmol) in CH2Cl2 (10 ml). NMM (0.5 ml, 4.0 mmol) was added and followed immediately by the dropwise addition of the morpholoterephthalic acid chloride in CH 2 Cl 2 (5 ml) at said rate to maintain the internal reaction temperature at -10 ° C or less. After the addition was complete, the reaction mixture was allowed to warm to room temperature. After 1.5 h, at room temperature, the reaction mixture was diluted with CH2Cl2 (20 ml), washed with 1N HCl (2x20 ml), saturated NaHCO3 (2x20 ml), brine (1x20 ml), dried (MgSO4) and concentrated in vacuo to give a crude foam (410 mg). The crude white foam was flash chromatographed (eluting with 1:27 MeOH-CH 2 Cl 2) to give the desired product (MDL 105,759) (270 mg, 42%) as a white foam.; 1 H NMR (300 MHz, CDCl 3) d 7.95-7.76 (m, 2H, aryl), 7.58-7.39 (m, 2H) 7.20-6.86 (m, 2H, aryl), 5.40-4.30 (m, 4H), 4.20- 3.20 (m, 10H, 2xNCH2CH2O and NCH2 from Pro), 2.60-1.95 (m, 3H), 1.90-1.82 (m, 4H), 1.25-0.75 (m, 12H); 19 F NMR (CDCl 3) d -81.97 (m, CF 3), -121.82 and -119.87 (m, CF 2); MS (CI / CH4) m / z (rel. Intensity) 647 (MH +), 564, 536, 474, 428, 363, 331 (100), 317, 289, 246, 218, 186, 158, 104, 84 72 EXAMPLE 3 Preparation of N-f4- (4-morpholinylcarbonyl) benzoyl-L-valyl-N'-f3,3,4,4,4-pentafluoro-1- (1-methylethyl) -2-oxobutyl-trans-4- hydroxyprolinamide a) N-K1, 1-dimethylethoxy) carbonin-L-valyl-trans-4-hydroxyproline To a stirred solution of trans-4-hydroxy-L-proline (1.31 g, 10 mmol) and Et3N (1.4 ml, 10 mmol) in DMF (40 ml) was added the product of example 1 (a) (3.14 g, 10 mmol) and the reaction was heated at 110 ° C for 3 h. Upon cooling, the reaction was concentrated in vacuo and the oily residue was dissolved in EtOAc and washed with 3N HCl (2x30 ml), H2O (2x10 ml), dried (Na2SO) and concentrated to give the desired compound (1.85 g). , 56%) as a white foam; 1 H NMR (300 MHz, CDCl 3) d 5.70-5.25 (m, 1H, NH), 5.05 (m, 1H), 4.80-3.95 (m, 4H), 3.85-2.80 (series of m, 3H), 2.35-1.80 (m, 2H), 1.44 (s, 9H, tBu), 1.01-0-95 (m, 6H, 2xCH3); MS (CI / CH4) m / z (laughing intensity), 331 (MH +), 303, 275 (100), 259, 231, 217, 172, 162, 144, 132, 116, 86, 72. b) N- f (1,1-di methylethoxy) carbonin-L- va lyl-N'-f 3, 3.4.4.4-pentaf luoro- 1 - (1-methylethii) -2-oxobutip-trans-4-hydroxyproline. a stirred solution of the product of Example 3 (a) (180 g, 5.60 mmol) and NMM (0.60 mL, 5.60 mmol) in CH2Cl2 (30 mL) at -20 ° C under nitrogen, was added dropwise isobutyl chloroformate ( 0.70 ml, 5.60 mmol), After 20 min, 4-amino-1,1,1,2-pentafluoro-5-methyl-3-hexanone hydrochloride (1.40 g, 5.60 mmol) was added, followed immediately by another equivalent of NMM (0.60 ml, 5.60 mmol). The reaction mixture was stirred at -20 ° C for 1 h, then allowed to warm to room temperature and poured into cold diluted HCl, and extracted with CH2Cl2. The organic extract was washed with water, dilute aqueous NaHCO3, brine, dried (MgSO) and concentrated in vacuo to give a crude oil which was flash chromatographed (5% MeOH / CH2Cl2) to give the desired compound (1.44 g, 48 g). %) as a white foam; 1 H NMR (300 MHz, CDCl 3) d 7.98 (br d, .5H, J = 7.6 Hz, NH), 7.73 (br d, .5H, J = 7.6 Hz, NH), 5.47 (br, d, 1H, J = 8.6 Hz, NH), 5.04-4.95 (m, 1H), 4.76-4.67 (m, 1H), 4.49 (br s, 1H), 4.23 (m 1H), 3.94 (br d, 1H, J = 10.8 Hz ), 3.66-3.59 (m, 1H), 2.50.1.98 (series of m, 4H), 1.42 (s, 9H, t.Bu), 1.09-0.88 (m, 12H, 4 X CH3); 13C NMR d 173.9, 173.2, 170.6, 170.4, 156.3, 156.2, 80.5, 80.4, 77.4, 77.2, 77.0, 76.5, 70.0, 69.8, 59.7, 59.5, 58.2, 57.7, 57.6, 55.7, 55.5, 35.7, 34.7, 31.0 , 30.9, 29.0, 28.6, 28.3, 28.2, 20.2, 19.9, 19.3, 19.7, 18.3, 18.2, 16.4, 16.1; 19 R NMR d-82.17 (s, CF3), -82.18 (s, CF3), -121.6 and -122.8 (AB quartet, J = 296 Hz, CF2); MX (CI / CH4) m / z (intensity reí.) 549 (MNH4 +, 12), 532 (MH *, 54), 482 (11), 330 (15), 245 (100), 189 (15). c) NL-Valyl-N'-f hydrochloride salt 3.3.4.4.4-pentafluoro-1- (1-methylethyl) -2-oxobutip-trans-4-hydroxyprolinemide, NL-valil-N 'hydrochloride salt -f3.3,4,4,4-pnetafluoro-1- (1-methylethyl) -2-oxobutyl-trans-4-acetoxiprolinamide. HCl gas was bubbled into a stirred solution of the product from example 3 (b) (1.44 g, 2.70 mmol) in EtOAc (20 ml) at ice bath temperature for 2 h, concentrated in vacuo and azeotroped with EtOAc to give the desired combination of derivatives (1.27 g, 100%), the acetoxy derivative being the minor derivative, as a white foam. d) N-f4- (4-morpholinylcarbonyl) benzoin-L-valyl-N'-f3.3.4.4.4-pentafluoro-1- (1-methylethyl) -2-oxobutyn-trans-4-hydroxyprolinemide (MDL 105.160) v NL-valyl-N'-r3.3.4.4,4-pentaf luoro-1- (1-methylethyl) -2-oxobutyn-trans-4-acetoxyprrolinamide (MDL 105,683) To a stirred suspension of 4- (4-) acid morpholinicarbonyl) benzoic acid (2 mg, 0.004 mmol) in 1,2-dichloroethane (20 ml) was added thionyl chloride (0.15 ml, 1.90 mmol) and the reaction was heated to reflux. After 2 h, the reaction was allowed to cool to room temperature and concentrated in vacuo. The residue was then azeotroped with CCI4 and placed under vacuum to give morpholinoterephthalic acid chloride (quantitative) as a light orange oil which was used without further purification. In a separate RB flask, a stirred solution of the product of example 3 (c) (800 mg, 1.71 mmol) in CH2Cl2 (15 ml) was cooled to -20 ° C. NMM (0.42 ml) was added; 3.80 mmoles) and the dropping addition of the morpholinoterephthalic acid chloride in CH 2 Cl 2 (5 ml) followed immediately afterwards to maintain the internal reaction temperature at -10 ° C or less. After the addition was completed, the reaction mixture was allowed to warm to room temperature. After 2 h at room temperature, the reaction mixture was diluted with CH2Cl2 (20 ml), washed with 1N HCl (2 x 20 ml), saturated NaHCO3 (2x20 ml), brine (1x20 ml), dried (Na2SO) and concentrated in vacuo to give a mixture of two compounds (MDL 105.160 as the main product and MDL 105.683 as the secondary product) as a crude foam, e) N-f4- (4-morpholinylcarbonyl) benzoin-L-valyl-N '-f3,3,4,4,4-pentafl uoro-1- (1-methyl-ethyl) -2-oxobutyn-trans-4-hydroxyprolinemine (MDL 105,160). The mixture of the two compounds defined in Example 3 (d) was flash chromatographed on SiO2, eluting with 1:27 MeOH-CH2Cl2 to yield the desired compound (MDL 105.160) (160 mg, 14.5%) as the upper Rf material (Rf approximately 0.3-0.4) as a white foam; 1 H NMR (300 MHz, CDCl 3) d 7.82 (m, 2 H, aryl), 7.45 (d, 2 H, J = 8.3 Hz, aryl), 7.35 (d, .5 H, J = 8.4 Hz, NH), 6.91 (d , 1H, J = 8.7 Hz, NH), 4.99 (m, 1H), 4.84 Hz, NH), 6.91 (d, 1H, J = 8.7 Hz, NH), 4.55 (br s, 1H), 4.18 (m, 1h), 3.8-3.4 (br s overlapping m, 9H), 2.86-2.03 (series of m, 4H), 1.26 (m, 9H, 3x CH3), 0.96 (m, 3H, CH3); 13C NMR 173.2, 172.5, 170., 170.4, 160.2, 167.1, 138.8, 134.9, 127.52, 127.50, 127, .4, 127.3, 77.55, 77.52, 77.51, 77.46, 77.44, 77.3, 77.2, 77.1, 77.0 , 76.88, 76.85, 76.6, 76.56, 76.54, 70.1, 69.9, 66.8, 59.6, 59.5, 58.5, 57.9, 57.0, 56.0, 56.0, 55.7, 36.0, 34.9, 31.42, 31.40, 31.3, 29.2, 28.8, 20.0, 19.85 , 19.83, 19.4, 19.2, 18.4, 16.5, 16.4, 16.3, 16.2, 19F NMR (CDCI3) d -82.1, -82.15 (s, CF3), -121.31, -123.02 (AB quartet J = 293 Hz, CF2) and -121.35, -122.82 (AB quartet, J = 298 Hz, CF2); MS (Ci / CH4) m / z (intensity r.) 649 (MH +), 361, 334, 333 (100), 317, 289, 218, 200, 111, 86. Anal. Cale, for C, 53.70; H, 5.75; N, 8.64. Found: C, 53.44; H, 5.77; N, 8.38. EXAMPLE 4 Preparation of Nf4- (4-morpholinylcarbonyl) benzoyl-1-L-valyl-N'-f3.3.4,4.4-pentafluoro-1- (1-methylethyl) -2-oxobutyl-H-trans-4-acetoxiprolinamide a) NL-valyl-N'-f3,3,4,4,4-pentafluoro-1- (1-methylethyl) -2-oxobutyM-trans-4-acetoxyprrolinamide (MDL 105,683). MDL 105,683 was obtained as the material of Lower Rf (Rf of about 0.05-0.1) of the mixture of the two compounds that were flash chromatographed as described in example 3 (e). This process produced MDL 105,683 (90 mg, 7.6%) as a white foam; 1 H NMR NMR (300 MHz, CDCl 3) d 7.84 (d, 2H, J = 8.4 Hz, aryl), 7.72 (.5H, J = 8.4 Hz, NH), 7.47 (d, 2H, J = 8.3 Hz, aryl) , 6.74 (d, 1H, J = 8.6 Hz, NH), 5.36 (m, 1H), 5.00 (m, 1H), 4.83 (dd, 5H, J = 8.6, 7.2 Hz), 4.69 (t, 5H), 4.08 (br d, 1H), 3.9-3.3 (br s overlapping m, 9H), 2.81 (m, .5H, OCH3), 1.02 (m, 9H, 3xCH3), 0.94 (m, 3H, CH3); 13C NMR d 173.0. 172.3, 170.4, 170.1, 169.9, 169.2, 166.3, 138.7, 127.4, 127.3, 72.5, 72.4, 66.8, 59.6, 59.5, 58.5, 57.8, 56.3, 56.2, 53.2, 52.9, 34.0, 32.8, 31.8, 31.8, 31.7, 31.6, 29.3, 29.2, 28.8, 24.9, 20.9, 20.0, 10.8, 10.5, 19.3, 17.95, 17.92, 17.7, 16.4, 16.2; 19F NMR (CDCl3) d -82.1, -82.13 (s, CF3), -121.22, -123.06 (AB quartet J = 296 Hz, CF2) and -121.28, -122.86 (AB quartet, J = 301 Hz, CF2); MS (CI / CH4) m / z (inverse intensity) 691 (MH +), 631, 472, 444, 389, 375 (100), 349, 318, 317, 289, 264, 225, 218, 128, 100 Anal Cale, for C3? H39F5N4O8: C, 53.91; H, 5.69; N, 8.11. Found: C, 54.40; H, 5.79; N, 8.15. EXAMPLE 5 DD Preparation of N-'4- (4-morpholylcarbonyl) benzoyl-L-valyl-N '- [3.3.4.4.4-pentafluoro-1- (1-methylethyl) -2-oxobutin-trans-4 - benzyloxyprolinemide a) Trans-4-benzyloxyproline hydrochloride salt HCl gas was bubbled for 2 min in an ice-cooled solution of t-butyloxycarbonyl-O-benzyl-L-hydroxyproline (5.0 g, 15.6 mmol) in EtOAc (30 mL). The reaction was then stopped, stirred at room temperature for 1 hour and concentrated in vacuo to provide a white solid which was triturated with ether and dried under vacuum to give the desired compound (3.92 g, 98%), mp 188- 190 ° C; 1 H NMR (300 MHz, CDCl 3) d 9.1 (br s, 1 H), 7.3 (m, 5 H), 4.56 (s, 2 H), 4.4-4.2 (m, 2 H), 3.6-3.38 (m, 3 H), 2.6 -2.58 (m, 1H), 2.26- 2.1 (m, 1H); m / z) (intensity reí.) 262 (M + + C3H5), 250 (M + + C2H5), 222 (MH +, 100), 176, 130, 107, 91, 85, 69. b) Nf (1, 1-dimethylethoxy) carbonyl] -L-valyl-trans-4-hydroxy proline mine To a stirred solution of trans-4-benzyloxy-L-proline hydrochloride salt, (2.57 g, 10 mmol) and Et3N (3.0 ml, 22 mmol) in DMF (25 ml) was added the product of example 1 (a) (3.14 g, 10 mmol) and the reaction was heated to 80 C for 1.5 h. Upon cooling, the reaction was concentrated in vacuo and the oily residue was dissolved in EtOAc and washed with 3N HCl (2x30 ml), H2O (2x10 ml), dried (Na2SO4) and concentrated to give the desired compound (1.8 g , 42%). Crystallization (EtOAc / hexane) gave a white solid; mp 125-128 ° C; 1 H NMR (300 MHz, CDCl 3) d 8.0 (br, s, 1H), 7.4-7.2 (m, 5H), 5.35 (d, 1H), J = 9.2 Hz, NH), 4.65 (m, 1H), 4.52 (m, 2H), 3.70 (m, 1H), 2.5-1.8 (m series, 3H), 1.44 (s, 9H, tBu), 0.98 (d, 3H, J = 6.8 Hz, CH3), 0.92 (d , 3H, J = 6.8 J = 6.8 Hz, CH3). c) Nf (1,1-dimethylethoxycarbonyl) -1-L-valyl-N'-f 3.3.4.4.4-pentaf luoro-1- (1-methylethyl) -2-oxobutyl-trans-4-benzyloxyprrolinamide To a stirred solution of the Example product 5 (b) (1.40 g, 3.30 mmol) and NMM (0.36 ml, 3.30 mmol) in CH2Cl2 (20 ml) at -20 ° C under nitrogen was added dropwise isobutyl chloroformate (0.43 ml, 3.30 mmol) After 20 min, 4-amino-1,1,1,2-pentafluoro-5-methyl-3-hexanone hydrochloride (840 mg, 3.30 mmol) was added, followed immediately by another equivalent of NMM ( 0.36 ml, 3.30 mmol) The reaction mixture was stirred at -20 ° C for 1 h, then allowed to warm to room temperature and poured into cold diluted HCl and extracted with CH CI2.The organic extract was washed with water NaHCO3, dilute aqueous NaHCO3, brine and dried (Na2SO) and concentrated in vacuo to give the desired compound (2.0 g, 95%), as a white solid, mp 91-93 ° C; 1 H NMR (300 MHz, CDCl3) d 7.96 (5H NH), 7.33 (m, 5H), 5.28 (m, 1H, NH), 4.95 (m, 1H), 4.83 (m, 1H), 4.70 (t, .5H), 4.54 (q, 2H, CH2Ph), 4.30 (m, 2H), 4.07-3.9 (m, 1H), 3.60 (m, 1H), 2.68 (dt, .5H), 2.49 (dt, .5H9, 2.33 (m, 1H), 2.2-1.88 m, 3H), 1.44 (s, 9H, tBu), 1.09 -0.86 (m, 12H, 4xCH3). d) NL-Valyl-N'-f3.3.4.4.4-pentafluoro-1- (1-methylethio-2-oxobuty-M-trans-4-benzyloxyprolinamide hydrochloride salt HCl gas was bubbled into a stirred solution of the example product 5 (c) (330 mg, 0.53 mmol) in EtOAc (10 mL) at ice bath temperature for 2 minutes The reaction was then stirred at room temperature for 1 h, concentrated in vacuo and azeotroped with EtOAc to give the desired compound (240 mg, 81%), as a white foam, * H NMR (300 MHz, CDCl 3) d 8.22 (m, 2 H, NH 2), 7.33 (m, 5 H), 5.04 (app q, 1 H), 4.88 (dq, 1H), 4.52 (q, 2H, CH2Ph), 4.33 (m, 1H), 4.0-3.8 (series of m, 4H), 2.42-2.1 (m, 4H), 1.09-0.86 (m, 12H, 4xCH3) e) N-r4- (4-morpholinylcarbonyl) benzoin-L-valyl-N'-f3.3.4.4,4-pentafl uoro-1- (1-methyl-ethyl) -2-oxobutyl-trans -4-benzyloxyprrolinamide (MDL 104.865) To a stirred suspension of 4- (4-morpholinylcarbonyl) benzoic acid (280 mg, 1.90 mmol) and benzyltriethylammonium chloride (2 mg, 0.004 mmol) in 1,2-dichloroethane (20 ml) it will be Thionyl chloride (0.15 ml, 1.90 mmol) was added and the reaction was refluxed. After 2 h, the reaction was allowed to cool to room temperature and concentrated in vacuo. The residue is azeotrop? with CCI4 and placed under vacuum to give morpholinoterephthalic acid chloride (quantitative) as a light orange oil that was used without further purification. In a separate RB flask, a solution of the product of Example 5 (d) (558 mg, 1.0 mmol) in CH2Cl2 (15 mL) was cooled to -20 ° C. NMM (0.40 ml, 4.0 mmol) was added and was immediately followed by the trickle addition of the morpholinoterephthalic acid chloride in CH 2 Cl 2 (5 ml) at such a rate to maintain the internal reaction temperature at -10 ° C or less. After the addition was complete, the reaction mixture was allowed to warm to room temperature. After 2 h at room temperature, the reaction mixture was diluted with CH2Cl2 (20 ml), washed with 1N HCl (2 x 20 ml), saturated NaHCO3 (2x20 ml), brine (1x20 ml), dried (Na2SO4) and concentrated in vacuo to give a foam that was flash chromatographed (eluting with MeOH-CH2Cl2 1:27) to give the desired product (520 mg, 70%) as a white foam; 1 H NMR NMR (300 MHz, CDCl 3) d 7.84 (dd, 2 H, aryl), 7.78 (d, 5 H, NH), 7.45 (dd, 2 H, aryl), 7.29 (m, 5 H), 7.21 (d,. 5H, NH), 6.87 (d, 1H, NH), 4.98 (m, 1H), 4.82 (m, 1H), 4.69 (t, .5H), 4.54 (dq, 2H, CH2Ph), 4.31 (br s, 1H), 4.08 (dq, 1H), 3.9-3.25 (series of m, 9H), 2.69 (dt, 5H), 2.46 (dt, 5H), 2.34 (m, 1H) 2.17 (m, 1H), 1.02 ( m, 9H, 3xCH3), 0.89 (m, 3H, CH3); 13C NMR (CDCI3) d 193.1, 172.9, 172.2, 170.7, 170.4, 170.4 169.3, 166.2, 138.4, 137.5, 137.4, 135.2, 128.5, 128.4, 128.2, 127.9, 127.8, 127.78, 127.73, 127.71, 127.5, 127.4, 127.3 , 119.5, 115.76, 107.1, 106.6, 71.4, 71.2, 66.7, 59.6, 59.4, 58.7, 58.0, 56.0, 52.6, 52.3, 48.14, 48.11, 48.10, 48.0, 42.6, 42.57, 42.52, 42.4, 33.5, 32.4, 31.8, 29.1, 28.6, 20.0, 19.8, 19.4, 19.3, 17.8, 17.6, 16.3, 16.1; 19F NMR (CDCI3) d -82.10, -82.13 (s, CF3), -121.3, -122.9 and -121.4, -122.8 (AB quartet J = 296 Hz, CF2) and -121.4, -122.8 (AB quartet, J = 296 Hz, CF2); MS (CI / CH4) m / z (inverse intensity) 767 (MH + +29), 740 (10), 739 (MH +, 27), 632 (11), 520 (7), 492 (5), 424 (18), 423 (100), 403 (3), 345 (5), 317 (30), 389 (4), 218 (3), 176 (11), 91 (2). Anal. Cale. for C36H43F5N4O7.0.4H2O: C, 57.95; H, 5.92; N, 7.54. Found: C, 58.10; H, 5.84; N, 7.49. EXAMPLE 6 Alternative preparation of Boc-Val-CF? CF3 A mixture of 288.0 g (1.11 moles) of Boc-Val N-methyl-O-methyl hydroxamic acid, and 4.7 L of anhydrous Et 2 O, was charged to a 3-neck, 12-liter flask, adapted with a stirrer, thermometer, dry ice condenser, gas dispersion tube and continuous N2 purge. The resulting solution was cooled from -60 ° C to -65 ° C. A total of 885.2 g (3.60 moles) of C2Fsl was added via a gas dispersion tube for approximately 30 minutes to the solution of Boc-Val N-methyl-O-methyl hydroxamic acid while maintaining a temperature of about -65 ° C. Immediately upon completion of the gas addition, a total of 2.39 I of CH3Li.LiBr 1.5M in Et2O (3.59 moles) was added over 1 hour maintaining a reaction temperature of -52 ° C to -58 ° C. A precipitate formed after about 1/3 of the CH3Li.LiBr was 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 GC (Rt of MDL 101.286 = 1.3 min, Rt of Boc-Val N-methyl-O-methyl hydroxamic acid = 5.1 minutes) was found to contain 7.2% of Boc-Val N-methyl hydroxamic acid -O-methyl. A total of 255 ml (3.47 moles) of acetone was added for about 15 minutes maintaining a reaction temperature of -51 ° C to -58 ° C and the resulting mixture was stirred for 10 minutes. The mixture was cooled in a 22 L flask containing 4.7 I of 0.75M KHSO which has been cooled to about 0 ° C. The organic layer was separated and washed with 3 I of H2O. The organic layer was dried using 500 g of MgSO 4 and filtered to remove the drying agent. The filtrate was concentrated at 40 ° C / 100 torr. To a semi-solid that weighs 408g. The crude material was dissolved in 1.2 I of hexane at 45 ° C and cooled slowly for about 30 minutes at -25 ° C to -30 ° C. The solid that crystallized, was filtered and washed with 250 ml of hexane at -30 ° C. The obtained MDL 101.286 was vacuum dried (25 ° C / 100 torr) to give 176.7 g. The filtrate was concentrated at 35 ° C / 100 torr to a residue weighing 153.5 g. the material was placed in a Kugelrohr distillation apparatus and an anterior part was collected at 40 ° C / 0.6 torr. The receptor was changed and a total of 100.5 g of crude MDL 101,286 was collected at 40 ° C-60 ° C / 0.6 torr. the crude product was dissolved in 500 ml of hexane at about 50 ° C. The resulting solution was cooled to -30 ° C. The solid that crystallized was filtered and washed with 100 ml of cold hexane (-30 ° C). The product was dried under vacuum at 25 ° C / 100 torr to give another 68.0 g of MDL 101.286 for a total yield of 244.7 g (70% yield) which was 99.9% pure by GC. Analysis Calculated for C? 2 H 18 F5 NO 3 (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. In a further embodiment, the present invention provides a method for the treatment of a patient suffering from an inflammatory disease associated with neutrophils comprising the administration thereto of a therapeutically effective amount of a compound of formula I. 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 proteolytic degradation of biological matrices. Inflammatory diseases associated with neutrophils for which treatment with a compound of formula I will be particularly useful, include: emphysema, cystic fibrosis, respiratory distress syndrome in adults, septicemia, disseminated intravascular coagulation, gout, rheumatoid arthritis, chronic bronchitis and Inflammatory bowel disease. The compounds of the formula I 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, 4-pentaf luoro-1- (1-methylethyl) -2-oxobutyl] -L-2-azetamide; N- [4- (4-morpholinylcarbonyl) benzoyl] -L-valyl-N '- [3,3,4,4,4-pentafluoro-1- (1-methylethyl) -2-oxobutyl] -D, L- 2-pipecolinamide; N- [4- (4-morpholinylcarbonyl) benzoyl] -L-valyl-N '- [3,3,4,4,4-pentaf luoro- 1- (1-methyl-ethyl) -2-oxobu ti I] - frans-4- hydroxy prol i nam ida; N- [4- (4-morpholinylcarbonyl) benzoyl] -L-valyl-N '- [3,3,4,4,4-pentafluoro-1- (1-methylethyl) -2-oxobutyl] - / rans-4 -acetoxiprolinamide; N- [4- (4-morpholinylcarbonyl) benzoyl] -L-valyl-N '- [3,3,4,4,4-pentafluoro-1- (1-methylethyl) -2-oxobutyl] -frar? S- 4-benzyloxyprolinemide. As used herein, the term "patient" refers to a warm-blooded animal such as a mammal suffering from a particular state of inflammatory disease. It is understood that the guinea pigs of India, 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 effective, under the administration of single or multiple doses, to the patient, providing relief of symptoms associated with inflammatory diseases associated with neutrophils. As used herein, "symptom relief" of a respiratory disease refers to a decrease in severity over that expected in the absence of treatment and does not necessarily indicate a complete elimination or cure of the disease, to determine the amount or dose therapeutically Effective, a number of factors are considered by the person diagnosing, including, but not limited to: mammalian species; its size, age, and general health; the specific disease involved, the degree or implication or severity of the disease; the response of the individual patient; the particular compound administered; the mode of administration; the bioavailability characteristics of the preparation administered; the selected dose regimen; the use of concomitant medication; and other relevant circumstances. A therapeutically effective amount of a compound of the formula I is expected to range from about 0.1 milligrams per kilogram of body weight per day (mg / kg / day) to about 100 mg / kg / day. The preferred amounts are expected to vary from about 0.5 to about 10 mg / kg / day. The compounds of this invention are prodrugs of highly potent elastase inhibitors, particularly human neutrophil elastase, or are elastase inhibitors in their own way. It is thought that the compounds of this invention exert their inhibitory effect through the inhibition of the enzyme elastase and thereby provide relief for elastase-mediated diseases including, but not limited to emphysema, cystic fibrosis, respiratory distress syndrome in adults, septicemia, disseminated intravascular coagulation, gout, rheumatoid arthritis, chronic bronchitis and inflammatory bowel disease. However, it is understood that the present invention is not limited by any particular theory or proposed mechanism to explain its effectiveness in an end-use application. To effect the treatment of a patient suffering from a disease state described above, a compound of the formula I can be administered in some form or mode that makes the compound available in effective amounts, including oral, aerosol, and parenteral routes. For example, the compounds of formula I can be administered orally, by aerosol, subcutaneously, intramuscularly, intravenously, transdermally, intranasally, rectally, topically, and the like. Generally, oral or aerosol administration is preferred. One skilled in the art to prepare formulations can easily select the appropriate form and manner of administration depending on the particular characteristics of the selected compound, the condition of the disease to be treated, the stage of the disease, and other important circumstances. Remington's Pharmaceutical Sciences, 18th edition, Mack Publish Co. (1990). The compounds may be administered alone or in the form of a pharmaceutical composition in combination with pharmaceutically acceptable carriers or excipients., the proportion and nature of which, is determined by the solubility and chemical properties of the selected compound, the chosen route of administration, and normal pharmaceutical practice. The compounds of the invention, given that they are effective themselves, can be formulated and administered in the form of their pharmaceutically acceptable salts, such as, for example, acid addition salts, for purposes of stability, convenience of crystallization, increased solubility and the like. . In another embodiment, the present invention provides compositions comprising a compound of formula Y in admixture or otherwise, in association with one or more inert carriers. These compositions are useful, for example, as normal for analysis, as convenient means for carrying bulk shipments, or as pharmaceutical compositions. An analyzable amount of a compound of formula I is an amount that can be easily read by standard methods and techniques of analysis, since they are well known and appreciated by those skilled in the art. The analyzable amounts of a compound of the formula I will generally vary from about 0.001% to about 75% of the composition by weight. Inert carriers can be of any material, which is not degraded or reacted covalently in any way with a compound of formula I. Examples of suitable inert carriers with water; aqueous buffer solutions, such as those which are generally useful in High Performance Liquid Chromatography (HPLC) analysis: organic solvents, such as acetonitrile, ethyl acetate, hexane and the like; and pharmaceutically acceptable excipients. More particularly, the present invention provides pharmaceutical compositions comprising a therapeutically effective amount of a compound of formula I in admixture or in some other manner in association with one or more pharmaceutically acceptable carriers or excipients. The pharmaceutical compositions are prepared in a manner well known in the pharmaceutical art. The vehicle or excipient can be a solid, semi-solid, or liquid material that can serve as a vehicle or medium for the active ingredient. Suitable carriers or excipients are well known in the art. The pharmaceutical composition can be adapted for oral, parenteral or topical use and can be administered to the patient in the form of tablets, capsules, suppositories, solution, suspensions, or the like. The compounds of the present invention can be administered orally, for example, with an inert diluent or with an edible carrier. They can be enclosed in gelatin capsules compressed into tablets. For the purpose of therapeutic oral administration, the compounds may be incorporated with excipients and used in the form of tablets, troches, capsules, elixirs, suspensions, syrups, obieas, chewing gums, and the like. These preparations must contain at least 4% of the compound of the invention, the active ingredient, but may vary depending on the particular form, and conveniently may be between 4% and 70% of the weight of the unit. The amount of the compound present in compositions is such that a suitable dose will be obtained, the preferred compositions and preparations according to the present invention are prepared in such a way that the unit dose form contains between 5.0-300 milligrams of a compound of the invention. The tablets, pills, capsules, troches and the like may also contain one or more of the following auxiliaries: binders such as microcrystalline cellulose, gum tragacanth or gelatin; excipients such as starch or lactose, disintegrating agents such as alginic acid, Primogel, corn starch and the like; lubricants such as magnesium stearate or Sterotex; sliders such as colloidal silicon dioxide; and sweetening agents such as sucrose or saccharin can be added, or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring. When the dosage unit 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 oil. Other dosage unit forms may contain other different materials that modify the physical form of the dosage unit, for example, coatings. Therefore, tablets or pills can be coated with sugar, shellac or other enteric coating agents. A syrup may contain, in addition to the compounds herein, sucrose as a drying agent, and certain preservatives, dyes and dyes, and flavors. The materials used to prepare various compositions can be pharmaceutically pure and non-toxic in the amounts used. For the purposes of parenteral therapeutic administration, the compounds of the present invention can be incorporated into a solution or suspension. These preparations must contain at least 0.1% of a compound of the invention, but may vary to be between 0.1 and about 50% of the weight thereof, the amount of the inventive compound present, in said compositions, it is thus that a adequate dose. Preferred compositions and preparations according to the present invention are prepared in such a way that a unit parenteral dose contains between 5.0 to 100 milligrams of the compound of the invention. The compounds of the formula I of the present invention, can also be administered by aerosol. The term aerosol is used to denote a variety of systems ranging from colloidal to systems consisting of pressurized packages. The distribution can be done by means of a liquefied or compressed gas or by means of a suitable pumping system that administers the active ingredients. The aerosols of compounds of the formula I can be distributed in a single-phase, two-phase or three-phase system, in order to distribute the active ingredient. The aerosol distribution includes the necessary recipient, activators, valves, subcontainers, and the like. The preferred aerosol can be determined by someone skilled in the art. The compounds of formula I of this invention may also be administered topically, and when made, the vehicle * may 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 alcohol, and emulsifiers and stabilizers. Topical formulations may contain a concentration of formula 1 or its pharmaceutical salt of from about 0.1 to about 10% w / v (weight per unit volume). The solutions or suspensions may also include one or more of the following auxiliaries, sterile diluents such as water for injection, saline, fixed oils, polyethylene glycols, glycerin, propylene glycol or other synthetic solvents.; antibacterial agents such as benzyl alcohol or methylparaben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; pH regulating solutions such as acetates, citrates or phosphates and tonicity adjusting agents such as sodium chloride or dextrose. The parenteral preparation can be packaged in ampoules, disposable syringes or multiple dose vials made of glass or plastic.

It is thought that the in vivo compounds of formula 1 are converted by esterases to compounds known to be active as inhibitors of human elastase. For example, the compounds of the formula I are converted to compounds described in the European Patent Application OPI No. 041041 1, published on January 30, 1991; European Patent application. OPI NO. 0195212, published on September 24, 1986; European Patent Application OPI No. 0529568, published March 3, 1993, said references are described herein by reference, as fully set forth. The following examples illustrate the degree of elastase inhibition by the selected compounds of Formula I. TABLE 2 * for the human neutrophysia test, using N-MeOsucAiaAia ProVa l-pNA as its substrate Table 2 (cont. for human neutrophil elastase, using N-MeOsucAlaAla ProVal-pNA as substrate SEQUENCE LIST (1) GENERAL INFORMATION: (i) APPLICANT: (A) NAME: MARION MERREL DOW INC. (B) STREET: 2110 E. GALBRAITH ROAD (C) CITY: CINCINNATI (D) STATE: OHIO (E) COUNTRY: UNITED STATES OF AMERICA (F) ZIP CODE: 45215 (G) TELEPHONE: 513-948- 7960 (H) TELEFAX: 513-948-7961 (I) TELEX: 214320 (ii) TITLE OF THE INVENTION: ELASTASA INNOVATIVE INHIBITORS (iii) NUMBER OF SEQUENCES: 4 (iv) METHOD OF READING IN COMPUTER: (A) ) TYPE OF MEDIUM: Soft disk (B) COMPUTER: IBM compatible PC (C) OPERATING SYSTEM: PC-DOS / MS-DOS (D) SOFTWARE: Patentin Relay # 1.0, Version # 1.30 (EPO) (2) INFORMATION FOR SEQ ID NO: 1: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 4 amino acids (B) TYPE: amino acid (D) TOPOLOGY, linear (ii) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF SEQUENCE: SEQ ID NO: 1: Xaa Xaa Xaa Xaa 1 (2) INFORMATION FOR SEQ ID NO: 2: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 4 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (ix) 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: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 3: Xaa Xaa Xaa Xaa 1 (2) INFORMATION FOR SEQ ID NO: 4: (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

Claims (10)

1. A compound of the formula or a hydrate, isostero, or pharmaceutically acceptable salt thereof wherein P4 is Ala, bAla, Leu, Me, Val, Nva, bVal, NIe or a ligation; P3 is Ala, bAla, Leu, Me, Val, Nva, bVal, NIe, or Lys substituted in their amino group epsilon with a group B morpholino; P2 is Pro (4-Obzl); Ri is a side chain of Ala, Leu, II, Val, Nva or bVal; K is - ~ B O \ / where Z is N or CH, and B is a group of formulas o o O O c-h, CH - C ~ C - CH -l R * O o o or and wherein R 'is hydrogen or an alkyl group of C? -6.

2. A compound of claim 1 wherein: R- is CH (CH3) 2 or -CH2CH2CH3.

3. A compound of claim 2, wherein D is B - Z O \ / where Z is N and B is a group of the formulas or O - c-h CH - Cf C - CH R ' and wherein R 'is a hydrogen or an alkyl group of C? .6.

4. A compound of claim 3, wherein P3 is ile. VaJ, or Ala.

5. A compound of claim 4, wherein P4 is Ala or a ligature

6. A compound of claim 5, wherein Ri is

CH (CH3) 2. 7. A compound of claim 6, wherein K is \ fB- O and wherein Z is N and B is a group of the formulas O 0 0 or - c-f- CH C - CH C -f

R 'R' O 0 and wherein R 'is hydrogen or an alkyl group of C? .6, are particularly preferred. 8. A compound of claim 7, wherein P3 is Val.

9. A compound of claim 8, wherein P4 is a ligation.

10. A compound according to claim 1 wherein the compound is N- [4- (4-morfoiinylcarbonyl) benzoyl] -L-vaiylN- [3,3,4,4,4-pentafluoro-1] - (1-methylethyl) -2-oxobutyl] -trans-4-benzyloxyprrolinamide. eleven . A composition comprising a compound of claim 1 and a vehicle. 12. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier. The use of a compound as in one of claims 1-10, optionally in combination with a pharmaceutically acceptable carrier, for the preparation of a human neutrophil elatase inhibitor. 14. Use of a compound as in claims 1-10, optionally in combination with a pharmaceutically acceptable carrier, for the preparation of a pharmaceutical composition for the treatment of an inflammatory disease associated with neutrophils. 15. Use of a compound as in one of claims 1-10, optionally in combination with a pharmaceutically acceptable carrier, for the preparation of a pharmaceutical composition for the treatment of emphysema.