MXPA96002984A

MXPA96002984A - Pharmaceutical compositions containing protease inhibitors

Info

Publication number: MXPA96002984A
Application number: MXPA/A/1996/002984A
Authority: MX
Inventors: Alrazzak Laman; Kaul Dilip; C Marsh Kennan; P Manning Lourdes
Original assignee: Abbott Laboratories
Priority date: 1994-01-28
Filing date: 1995-01-03
Publication date: 1998-01-01

Abstract

The present invention relates to a pharmaceutical composition comprising a solution of an HIV protease inhibitor compound in a pharmaceutically acceptable organic solvent comprising a mixture of (1) (a) a solvent selected from propylene glycol and polyethylene glycol or (b) a solvent selected from polyoxyethylene glycerol tri-ricinoleate, polyethylene glycol hydrogenated castor oil 40, fractionated coconut oil, polyoxyethylene sorbitan mono-oleate (20) and 2- (2-ethoxyethoxy) ethanol or (c) a mixture of the same and (2) ethanol or propylene glycol, wherein the HIV protease inhibitor compound is selected from the group consisting of: N- (2 (R) -hydroxy-1 (S) -indanyl) -2- (R ) -phenylmethyl-4 (S) -hydroxy-5- (1- (4- (3-pyridylmethyl) -2 (S) N '- (t-butyl carboxamido) -piperazinyl)) - pentanamide; N-terbutyl-decahydrate -2- (2 (R) -hydroxy-4-phenyl-3- (S) - ((N- (2-quinolylcarbonyl) -L-asparaginyl) amino) butyl) -4aS, 8aS) -isoquinoline-3- (S) -carboxamide; (1S- (1R * (R *) , 2S *)) - N- (3 - (((((1,1-dimethylethyl) amino) carbonyl) (2-methylpropyl) amino) -2-hydroxy-1- (phenylmethylpropyl) -2 - ((2- quinolinylcarbonyl) amino) -butand iamide;

Description

PHARMACEUTICAL COMPOSITIONS CONTAINING HIV PROTEASE INHIBITORS Technical Field A liquid pharmaceutical composition is described that provides improved oral bioavailability, for compounds that are inhibitors of VI H protease (in particular protease of HIV-1 and HIV-2). In particular, the composition comprises the HIV protease inhibitor and one or more pharmaceutically acceptable organic solvents. BACKGROUND OF THE INVENTION A measurement of the potential utility of an oral dosage form of a new pharmaceutical agent is the broavailability observed after oral administration of the dosage form. Several factors can affect the bioavailability of a drug when administered orally. These factors include aqueous solubility, absorption of drug through the tract -P- gastrointestinal, dose resistance and effect of the first step. Aqueous solubility is one of the most important of these factors. When a drug has poor aqueous solubility, frequently attempts are made to identify salts or other derivatives of the drug having improved aqueous solubility. When a salt or other derivative of the drug is identified, which has good aqueous solubility, it is generally accepted that an aqueous solution formulation of this salt or derivative provides bioavailability optimal oral. The bioavailability of the aqueous oral solution formulation of a drug is generally used afterwards as the normal or ideal bioavailability, against which other forms of oral doses are measured. Recently it has been determined that HIV protease inhibitor compounds are useful for inhibiting HIV protease in vitro and in vivo and are useful for inhibiting HIV infection (human immunodeficiency virus), and are useful for treating AIDS (syndrome of acquired immunodeficiency). Compounds that inhibit VI H protease are typically characterized by poor oral bioavailability. Examples of HIV protease inhibitor compounds include N- (2 (R) -hydroxy-1 (S) -indenyl) -2 (R) -phenylmethyl * 4 (S) -hydroxy-5- (1 - (4- ( 3-pyridylmethyl) -2 (S) -N '- (tertiary butylcarboxyamido) -piperazinyl)) -pentanoamide and related compounds, described in European Patent Application No. EP541 168, published May 12, 1993; N-butyl tertiary-decahydro-2- [2 (R) -hydroxy-4-phenyl-3 (S) - [[N- (2-quinolylcarbonyl) -L-asparaginyl] amino] butyl] - (4aS, 8aS) -isoquinolin-3 (S) carboxyamide and related compounds, described in the patent of E. U.A. No. 5, 196,438, issued March 23, 1993; [1 S- [1 R * (R *), 2S *]] - N 1 [3 - [[[(1,1-dimethylethyl) amino] carbonyl] (2-methyl-propyl) amino] -2-hydroxy -1- (phenylmethyl) propyl] -2 - [(2-quinolinylcarbonyl) -aminoj-butanediimide and related compounds, described in the patent application of! TCP No. WO92 / 08701, published May 29, 1992; Y and related compounds, described in PCT Patent Application No. WO93 / 07128, published April 15, 1993. Recently it has been determined that the compounds of formula I: wherein R is lower alkyl and R and R3 are phenyl, are inhibitors of HIV-1 and HIV-2 protease, and are useful for inhibiting HIV protease in vitro and in vivo, and are useful for inhibiting HIV infections (viruses of human immunodeficiency) and, therefore, are useful for the treatment of AIDS (acquired immunodeficiency syndrome).

In particular, it has been found that the compound of formula II is especially effective as a protease inhibitor of HIV-1 and HIV-2.

II The most preferred compound of formula II is (2S, 3S, 5S) -5- (N- (N - ((N-methyl-N - ((2-isopropyl-4-thiazolyl) methyl) -amino) sarbonyl ) valinyl) -amino) -2- (N - ((5-thiazolyl) methoxycarbonyl) amino) -1,6-diphenyl-3-hydroxy-hexane (compound III). Compound III has an aqueous solubility of about 6 micrograms per milliliter at pH > 2. It is considered to have extremely poor aqueous solubility and, therefore, it could be expected that compound III in the free base form, provides very low oral bioavailability. In fact, the free base form of compound III, administered as a solid not formulated in a capsule dosage form, is characterized by a bioavailability of less than 2%, following an oral dose of 5 mg / kg in dogs. The acid addition salts of! Compound III (for example, bis-hydrochloride, bis-tcsüsic, Bis-Methate, Synthacrylate) have aqueous solubilities of >0.1 milligrams / milliliter This is only a slight improvement over the solubility of the free base. This low aqueous solubility could render impractical the administration of therapeutic amounts of compound III as an aqueous solution. Furthermore, in view of this low aqueous solubility, it is not surprising that the bis-tosylate of compound III, administered as an unformulated solid in a capsule dosage form, is characterized by a bioavailability of less than 2%, following an oral dose. of 5 mg / kg in dogs. In order to have a suitable oral dosage form of compound III, the oral bioavailability of compound III could be at least 20%. Preferably, the oral bioavailability of compound III of the dosage form would be greater than about 40% and, more preferably, greater than about 50%. Although one might expect that some drugs have good solubility in organic solvents, not necessarily oral administration of said organic solution, would give good bioavailability for the drug. It has been found that the compound III has good solubility in pharmaceutically acceptable organic solvents. In addition, the solubility of the compound III in some organic solvents is improved in the presence of a pharmaceutically acceptable acid. Unexpectedly, the solutions of the compound III in pharmaceutically acceptable organic solvents provide a oral bioavailability of approximately 40% to around 100% in dogs. Description of the Invention According to the present invention, there is a pharmaceutical composition comprising a solution of a compound that inhibits the VI H protease (preferably, a compound of the formula II) in a pharmaceutically acceptable solvent, comprising a mixture of (1) (a) a solvent selected from propylene glycol and polyethylene glycol or (b) a solvent selected from polyoxyethylene glycerol tri-ricinoleate, castor oil hydrogenated with polyethylene glycol 40, fractionated coconut oil, polyoxyethylene sorbitan mono-oleate (20) and 2- (2-ethoxyethoxy) ethanol or (c) a mixture thereof and (2) ethanol or propylene glycol. A preferred composition of the invention comprises a solution of a VI H protease inhibitor compound (preferably a compound of formula II) in a pharmaceutically acceptable organic solvent, comprising a mixture of (1) propylene glycol or tri-ricinoleate of polyoxyethylenic glycol or a mixture thereof and (2) ethanol. The composition of the solution of the invention may also comprise other pharmaceutically acceptable organic solvents.

The composition of the solution of the invention can also comprise from about 0% to about 20% (preferably from about 0.2% to about 16% and more preferably from about 0.2% to about 6% by weight of the total solution) of a pharmaceutically acceptable acid or a mixture of pharmaceutically acceptable acids. The solution composition of the invention may also comprise from about 0% to about 25% (preferably, from about 0% to about 19% by weight of the total solution) of water. The composition of the solution of the invention may also comprise one or more pharmaceutically acceptable oils. The solution of the invention may also comprise pharmaceutically acceptable sweetening agents and / or pharmaceutically acceptable flavoring agents (eg, sucrose, aspartame, sorbitol, saccharin sodium and the like and / or cherry flavor, artificial banana flavor, caramel, chocolate-mint flavor, grape flavor, wild cherry flavor, raspberry flavor, strawberry flavor, citrus flavor, orange flavor, pineapple flavor, acid lime flavor, acidic cream flavor, cherry-vanilla flavor , mint flavor cream and the like). In addition, the composition of the solution of the invention may comprise antioxidants (eg, ascorbic acid, HAB (butylated hydroxyanisole), HTB (butylated hydroxytoluene), vitamin E, vitamin E PEG succinate 1000 and the like) for chemical stability. The compositions of this invention provide improved oral bioavailability for compound II when compared to non-formulated compound (II) (base) or non-formulated compound II (acid addition salt), or even when compared to a mixed aqueous / organic solution. (50% water, 20% ethanol, 30% propylene glycol) of compound II (acid addition salt of methanesulfonate). The term "pharmaceutically acceptable organic solvent" as used herein, refers to propylene glycol; polypropylene glycol; polyethylene glycol (e.g., polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 600, polyethylene glycol 900, polyethylene glycol 540 (all available from "Union Carbide") and the like); pharmaceutically acceptable alcohols (e.g., ethanol or 2- (2-ethoxyethoxy) ethanol ("Transcutol®, Gattefosse, Westwood, NJ 07675") and the like); polyoxyethylene castor oil derivatives (eg, polyoxyethylene glycerol tri-ricinoleate or polyoxyl castor oil 35 ("Cremophor®EL, BASF Corp."), polyoxyethylene glycerol oxa stearate ("Cremophor®RH 40" hydrogenated polyethylene glycol castor) or "Cremophor® RH 60 (polyethylene glycol hydrogenated castor oil 60)," BASF Corp. ") and the like), fractionated coconut oil (for example, triglycerides mixed with caprylic acid and capric acid ( "Miglyol®812", available from "Huis AG", Witten, Germany) and the like), "Tween® 80", isopropyl palmitate, isopropyl myristate, pharmaceutically acceptable silicon fluids, and the like The term "pharmaceutically acceptable acid" "as used herein, refers to (i) an inorganic acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid and the like, (ii) an organic mono-, di- or tricarboxylic acid (eg, formic acid, ac ethical, adipic acid, alginic acid, citric acid, ascorbic acid, aspartic acid, benzoic acid, butyric acid, camphoric acid, gluconic acid, glucuronic acid, galactonic acid, glutamic acid, heptanic acid, haxanoic acid, fumaric acid, lactic acid, lactobionic acid, malonic acid, maleic acid, nicotinic acid, oxalic acid, pamoic acid, pectinic acid, 3-phenylpropionic acid, picric acid, pivalic acid, propionic acid, succinic acid, tartaric acid, undecanic acid, and the like) or (iii ) a sulfonic acid (eg, benzenesulfonic acid, sodium bisulfate), sulfuric acid, camphorsulfonic acid, dodecyl sulfonic acid, ethanesulfonic acid, methanesulfonic acid, isothionic acid, naphthalenesulfonic acid, paratoluenesulfonic acid and the like). The term "pharmaceutically acceptable oil" as used herein, refers to mineral oil or a vegetable oil (e.g., safflower oil, peanut oil, olive oil, fractionated coconut oil (e.g., mixed triglycerides, with caprylic acid and capric acid ("Miglyol® 812", available from "Huis AG", Witten Germany) and the like.) The term "pharmaceutically acceptable surface active agent", as used herein, refers to a pharmaceutically active surfactant. acceptable (e.g., polyethylene-polypropylene glycol, such as "Ploxamer® 68" ("BASF Wyandotte Corp.") or a polyoxyethylene sorbitan fatty acid monoester (20) (e.g., polyoxyethylene sorbitan mono-oleate ( 20) (Tween® 80), plioxyethylene sorbitan monostearate (20) (Tween® 60), polyoxyethylene sorbitan monopalmitate (20) (Tween® 40), polyoxyethylene sorbitan monolaurate (20) (Tween® 20) and similar) and similar) or a pharmaceutically acceptable surfactant (for example, sodium lauryl sulfate and the like). A preferred composition of the invention comprises an HIV protease inhibitor compound (preferably, a compound of formula II) in the amount of about 1% to about 15% by weight of the total solution (more preferably, about 2.5%). to about 10% by weight of the total solution) in a pharmaceutically acceptable organic solvent, comprising a mixture of (1) (a) a solvent selected from propylene glycol and polyethylene glycol in the amount of about 10% to about 50 % by weight of the total solution or (b) a solvent selected from glycerol polyoxyethylene tri-ricinoleate, hydrogenated castor oil from polyethylene glycol 40, fractionated coconut oil, polyoxyethylene sorbitan mono-oleate (20) and 2- ( 2-ethoxyethoxy) ethane in the amount of about 5% to about 35% by weight of the total solution or (c) a mixture thereof and (2) ethanol or propylene glycol in the amount of about 5% to about 45% by weight of the total solution (more preferably, from about 20% to about 35% by weight of the total solution). Preferably, in the composition of the invention, the mixture of pharmaceutically acceptable organic solvents (including ethanol) comprises from about 50% to about 95% by weight of the total solution. More preferably, the mixture of pharmaceutically acceptable organic solvents comprises from about 70% to about 95% by weight of the total solution. In the composition of the invention, another preferred mixture of pharmaceutically acceptable solvents is a mixture of propylene glycol (approximately 42% by weight of the total solution), ethanol (approximately 32% by weight of the total solution) and water (approximately 16% to about 17% by weight of the total solution). In the composition of the invention, a preferred mixture of pharmaceutically acceptable solvents is a mixture of propylene glycol (approximately 32% by weight of the total solution), ethanol (approximately 37% by weight of the total solution) and water (approximately 15% by weight). % by weight of the total solution). In the composition of the invention, another preferred mixture of pharmaceutically acceptable solvents is a mixture of propylene glycol (from about 44% to about 45% by weight of the total solution), polyoxyethylene glycerol tri-ricinoleate (about 20% by weight) of the total solution) and ethanol (from about 24% to about 25% by weight of the total solution). In the composition of the invention, another preferred mixture of pharmaceutically acceptable solvents is a mixture of propylene glycol (from about 39% to about 40% by weight of the total solution)polyoxyethylene glycerol tri-ricinoleate (approximately 20% by weight of the total solution) and ethanol (approximately 24% by weight of the total solution). In the composition of the invention, another preferred mixture of pharmaceutically acceptable solvents is a mixture of propylene glycol (approximately 43% by weight of the total solution), ethanol (approximately 33% by weight of the total solution) and water (approximately 17%). % by weight of the total solution). In the composition of the invention, another preferred mixture of pharmaceutically acceptable solvents is a mixture of propylene glycol (approximately 36% by weight of the total solution), ethanol (approximately 36% by weight of the total solution) and water (approximately 19%). % by weight of the total solution). In the composition of the invention, another preferred mixture of pharmaceutically acceptable solvents is a mixture of propylene glycol (about 35% by weight of the total solution), ethanol (about 35% by weight of the total solution) and water (about 18%). in weight of the total solution). In the composition of the invention, another preferred mixture of pharmaceutically acceptable solvents is a mixture of propylene glycol (approximately 31% by weight of the total solution), polyoxyethylene glycerol tri-ricinoleate (approximately 10% by weight of the total solution) , ethanol (approximately 32% by weight of the total solution) and water (approximately 14% by weight of the total solution). In the composition of the invention, another preferred mixture of pharmaceutically acceptable solvents is a mixture of propylene glycol (approximately 46% by weight of the total solution), ethanol (approximately 21% by weight of the total solution) and tri-vicinoleate of polyoxyethylene glycerol (approximately 24% by weight of the total solution). A preferred pharmaceutically acceptable acid is citric acid. A more preferred composition of the invention comprises a solution of a compound of the formula III in the amount of from about 1% to about 15% by weight of the total solution (more preferably, from about 2.5% to about 12% by weight of the total solution) in a pharmaceutically acceptable organic solvent, comprising a mixture of (1) propylene glycol or polyoxyethylene glycerol tri-ricinoleate or a mixture thereof and (2) ethanol. In the most preferred composition of the invention, preferred pharmaceutically acceptable solvents and acids are as described above for the preferred composition of the invention.

An even more preferred composition of the invention comprises a solution of a compound of the formula III in the amount of about 5% to about 8% by weight of the total solution in a pharmaceutically acceptable organic solvent comprising a mixture of (1 propylene glycol in the amount of about 34% to about 36% by weight of the total solution, (2) ethanol in the amount of about 34% to about 36% by weight of the total solution and (3) water in the amount from about 18% to about 19% by weight of the total solution. The still more preferred composition also comprises citric acid in the amount of from about 0.3% to about 0.4% by weight of the total solution. - Another still more preferred composition of the invention comprises a solution of a compound of the formula III in the amount of about 7% to about 8% by weight of the total solution in a pharmaceutically acceptable organic solvent, comprising a mixture of (1) ) propylene glycol in the amount of about 45% to about 46% by weight of the total solution, (2) ethanol in the amount of about 21% by weight of the total solution, and (3) polyoxyethylene glycerol tri-ricinoleate in the amount of about 24% to about 25% by weight of the total solution. The still more preferred composition also comprises citric acid in the amount of about 0.5% by weight of the total solution.

A more highly preferred composition of the invention, comprises a solution of a compound of the formula III in the amount of about 7% to about 8% by weight of the total solution, in a pharmaceutically acceptable organic solvent, comprising a mixture of ( 1) propylene glycol in the amount of about 31% to about 32% by weight of the total solution (3) polyoxyethylene glycerol tri-ricinoleate in the amount of about 10% to about 11% by weight of the total solution, and (4) water in the amount of about 14% to about 15% by weight of the total solution. The still more preferred composition also comprises citric acid in the amount of from about 0.2% to about 0.3% by weight of the total solution. The compounds of formula I and II contain two or more asymmetric carbon atoms and therefore there may exist as pure diastereomers, mixtures of diastereomers, diastereomeric racemates or mixtures of diastereomeric racemates. It is intended that the present invention includes, within its scope, all isomeric forms. The configuration terms "R" and "S", as used herein, are defined by the Recommendations of the 1974 PIC IU, for "Fundamental Stereochemistry, Puré Appl. Chem.", Section E, (1976) 45 , 13-30. The preferred isomer of the compound of formula II is (2S, 3S, 5S) -5- (N- (N - ((N-methyl-N - ((2-Psopropyl-4-thiazole) methyl) amino) carbonyl) - valinyl) amino) -2- (N - ((5-thiazolyl) methoxycarbonyl) amino) -1,6-diflu enyl-3-hydroxyhexane (compound 11 l). The term "lower alkyl" as used herein, refers to straight or branched chain alkyl radicals containing from 1 to 6 carbon atoms including, but not limited to, methyl, ethyl, normal propyl, iso-propyl, normal butyl, iso-butyl, secondary butyl, normal pentyl, 1-methylbutyl, 2,2-dimethylbutyl, 2-methylpentyl, 2,2-dimethylpropyl, normal hexyl and the like. In general, the compositions of this invention can be prepared in the following manner. Ethanol and pharmaceutically acceptable acid (if present) and water (if present) and sweetener (if present) are mixed. To this solution is added the propylene glycol or polyethylene glycol and / or polyoxyethylene glycerol tri-ricinoleate, hydrogenated polyethylene glycol castor oil 40, fractionated coconut oil, polyoxyethylene sorbitan mono-oleate (20) or 2- (2-ethoxyethoxy) ethanol until the resulting solution is clear. Compound III (together with any other solvents, oils or other additives) are added to the solution and mixed until the solution clears. The resulting solution is brought to the desired final volume, with the addition of propylene glycol or polyethylene glycol and / or polyoxyethylene glycerol tri-ricinoleate, glyco-hydrogenated castor oil! polyethylene 40, fractionated coconut oil, polyoxyethylene sorbitan mono-oleate (20) or 2- (2-ethoxyethoxy) ethanol Alternatively, the ethanol and pharmaceutically acceptable acid (if present) are mixed, followed by the addition of the compound III. . To this mixture is added propylene glycol or polyethylene glycol and / or polyoxyethylene glycerol tri-ricinoleate, hydrogenated polyethylene glycol castor oil 40, fractionated coconut oil, polyoxyethylene sorbitan mono-oleate (20) or 2- (2 -ethoxyethoxy) ethanol, until the resulting solution is rinsed.

The water (if present) and the sweetener (if present), together with any other solvent, oils or other additives, are added with mixing until the solution is rinsed. The resulting solution is brought to the desired final volume with the addition of propylene glycol or polyethylene glycol and / or polyoxyethylene glycerol tri-ricinoleate, hydrogenated polyethylene glycol castor oil 40, fractionated coconut oil, polyoxyethylene sorbitan mono-oleate (20) or 2- (2-ethoxyethoxy) ethanol. The following examples will serve to further illustrate the invention. In particular, Examples 5-1 9 specifically refer to this invention. Example 1 (non-formulated capsule) An amount of compound 11 (free base) equivalent to a dose of 5 mg / kg was placed in hard gelatin capsules (gray, size 0). These capsules were administered to dogs on an empty stomach with 10 ml of water. Example 2 (Capsule) An amount of compound 11 (free base) equivalent to a dose of 5 mg / kg was placed in hard gelatin capsules (gray, size 0). These capsules were administered to dogs that were not fasting with ten milliliters of water. Example 3 (Capsule) An amount of the bis-tosylate salt of compound 11 was equivalent to a dose of 5 mg / kg of compound 11 (base equivalent) was filled into hard gelatin capsules (gray, size 0).

These capsules were administered to dogs that were not fasting with ten milliliters of water. Example 4 (Solution) A solution of 5 mg (equivalent of free base) / ml of the base compound III in 20% ethanol: 30% propylene glycol: dextrose containing 2 molar equivalents of methanesulfonic acid. Component% by weight Compound ll l (free base) 0.5 Propylene glycol (Aldrich reagent) 31 .9 Ethanol (USP, 200 test) 16.2 Methanesulfonic acid (Aldrich reagent) 0.14 Dextrose 3.6 Water for injection (USP) 47.6 Example 5 A 50 mg / ml solution of base compound III.

Compound% by weight Compound III (free base) 5. 1 Propylene glycol (USP) 42.22 Ethanol (USP, 200 test, dehydrated) 32.21 Critical acid (USP, anhydride powder) 3.93 Water for injection (USP) 16.54 Citric acid (77.0 g) was mixed with water (300 ml) and stirred until the solution was clear. Water was added to reach a volume of 400 ml solution. Propylene glycol (300 g) and ethanol (800 g) were mixed in a stainless steel beaker until the solution was rinsed. To the propylene glycol / ethanol solution, compound III (100.4 g) was added with stirring and mixing was continued until the solution cleared. To this solution was added the citric acid solution until the final volume was 2000 ml. If a flavoring agent is included, it could be added to the solution of the compound 11 before the addition of the citric acid solution. Example 6 A 25 mg / ml solution of the base compound Compound% by weight Compound III (free base) 2 6 Propylene glycol (USP) 43. 4 Ethanol (USP, 200 test, dehydrated) 33. 04 Critical acid (USP, anhydrous powder) 4 0 Water for injection (USP) 16.95 Example 7 A 50 mg / ml solution of base compound III.

Compound% by weight Compound III (free base) 5.37 Propylene glycol (USP) 28.85 Ethanol (USP, 200 test, dehydrated) 43.35 Critical acid (USP, anhydride powder) 4.3 Water for injection (USP) 18.14 Example 8 A 50 mg / ml solution of base compound III.

Composite% by weight Compound l l l (free base) 5. 3 Propylene glycol (USP) 31 Ethanol (USP, 200 test, dehydrated) 42. 1 Critical acid (USP, anhydride powder) 3. 8 Water for injection (USP) 16.05 Aspartame 1 .60 Wild cherry flavor 0 .14 Example 9 A 50 mg / ml solution of base compound 1 l.

Composite% by weight Compound l l l (free base) 5.3 Cremophor® EL (polyoxyl castor oil 35, N F) 32.18 Ethanol (USP, 200 test, dehydrated) 32.3 Miglyol® 812 30.13 Example 10 A 50 mg / ml solution of base compound 1 II. Compound% by weight Compound 11 (free base) 5.01 Propylene glycol (USP) 44.6 Ethanol (USP, 200 test, dehydrated) 24.53 Critical acid (USP, anhydride powder) 5.76 Cremophor® EL (polyoxyl castor oil 35, NF) 20.1 Example 11 A 50 mg / ml solution of base compound III. Compound% by weight Compound III (free base) 5.04 Propylene glycol (USP) 44.39 Ethanol (USP, 200 test, dehydrated) 24.42 Critical acid (USP, anhydride powder) 5.82 Cremophor® EL (polyoxyl castor oil 35, NF) 20.33 Citric acid (153.6 g) and ethanol (800 ml) were mixed until the solution cleared. To this solution was added with mixing, castor oil 35 (400 g) and sufficient propylene glycol until the solution was rinsed. Compound III (100 g) was added with mixing until the solution cleared. Propylene glycol was added to bring the final volume of the solution to 2000 ml.

Alternatively, citric acid (153.6 g) and ethanol (800 ml) were mixed until the solution was rinsed. Compound III (100 g) was added with mixing until the solution cleared. To this solution was added with mixing, polyoxyl castor oil 35 (400 g) and sufficient propylene glycol until the solution was rinsed. Propylene glycol was added to obtain a final volume of the solution at 2000 ml. Example 12 A 50 mg / ml solution of the base compound III. Component% in Weight Compound III (free base) 5.1 1 Propylene glycol (USP) - 24.05 Ethanol (USP, 200 test, dehydrated) 20.29 Cremophor® EL (polyoxyl castor oil 35, NF) 35.59 Miglyol® 812 5.0 Tween® 80 9.97 Example 13 A 100 mg / ml solution of the base compound III. Compound% by weight Compound III (free base) 10.05 Propylene glycol (USP) 39.64 Ethanol (USP, 200 test, dehydrated) 24.3 Cremophor® EL (polyoxyl castor oil 35, NF) 20.23 Critical acid (USP, anhydride powder) 5.76 Example 14 A 100 mg / ml solution of the base compound III. Composite% by weight Compound III (free base) 4.99 Propylene glycol (USP) 43.52 Ethanol (USP, 200 test, dehydrated) 24.2 Cremophor® EL (polyoxyl castor oil 35, NF) 19.96 Critical acid (USP, anhydride powder) 5.76 Banana flavor 0.5 Strawberry flavor 0.59 Sodium saccharine 0.5 Example 15 A solution of 130 mg / ml of base compound III. Compound% by weight Compound lll (free base) 12.0 Propylene glycol (USP) 32.4 Ethanol (USP, 200 test, dehydrated) 37.0 Cremophor® EL (polyoxyl castor oil 35, NF) 3.6 Water for injection (USP) 15.0 Example 16 A 50 mg / ml solution of base compound III. Composite% by weight Compound III (free base) 5.125 Propylene glycol (USP) 35.8 Ethanol (USP, 200 test, dehydrated) 35.75 Critical acid (USP, anhydride powder) 0.362 Water for injection (USP) 18.86 Sodium saccharin (USP, powder, dihydrate) 1.02 Wild cherry artificial flavor 3.0 Flavor enhancer (Prosweet® Liquid "K") 0.08 (Prosweet® "K" liquid available from Virginia Daré, 882 Third Ave., Brooklyn, NY) Dye, Red D &C No. 33 0.01 Example 17 A solution of 80 mg / mi of the compound lll of base.

Composite% by weight Compound III (free base) 7.96 Propylene glycol (USP) 34.72 Ethanol (USP, 200 test, dehydrated) 34.7 Critical acid (USP, anhydrous powder) 0.35 Water for injection (USP) 18.3 Sodium saccharine (USP, powder, dihydrate) 0.99 Artificial flavor of wild cherry 2.9 Flavor enhancer (Liquid Prosweet® "K") 0.08 Dye, Red D &C No. 33 0.01 Example 18 A solution of 80 mg / ml of base compound III.

Compound% by weight Compound III (free base) 7.88 Propylene glycol (USP) 31.31 Ethanol (USP, 200 test, dehydrated) 32.0 Critical acid (USP, anhydride powder) 0.27 Water for injection (USP) 14.18 Cremophor® EL 10.4 Saccharin of sodium (USP, powder, dihydrate) 0.98 Artificial flavor of wild cherry. 2.875 Flavor Enhancer (Prosweet® Liquid "K") 0.08 Dye, Red D &C No. 33 0.01 Water (14.4 ml) and ethanol (41.2 ml) were mixed and citric acid (276 mf) was added with stirring. Sodium saccharin (1.0 g), flavor enhancer (0.1 ml), propylene glycol (30.7 ml), compound III (8.0 g), red dye (10.0 mg) and cherry flavor (3.7 ml) were added sequentially with agitation. The resulting solution was brought to a final volume of 100 ml by the addition of Cremophor® EL. The final solution was stored at 2-8 ° C until it was filled into 15 ml reaction flasks. Example 19 A solution of 80 mg / ml of base compound III. Composite% by weight * Compound III (free base) 7.57 Propylene glycol (USP) 45.7 Ethanol (USP, 200 test, dehydrated) 21 .0 Critical acid (USP, anhydride powder) 0.51 Cremophor® EL 24.29 Sodium saccharin (USP, powder, dihydrate) 0.47 Incrementor of flavor (Prosweet® Liquid "K") 0.148 Chocolate-mint flavor 0.37 Ethanol (28.4 ml) was mixed and citric acid (545 mg) was added with stirring. Sufficient propylene glycol was added with stirring to rinse the resulting solution. Sodium saccharin (500 mg), flavor enhancer (0.2 ml), compound III (8.0 g), Cremophor® EL (24.5 ml), and chocolate-mint flavor (0.5 ml) were added sequentially with stirring. The resulting solution was brought to a final volume of 100 ml by the addition of propylene glycol. The final solution was stored at 2-8 ° C until it was filled in 15 ml flasks. The remaining examples provide the preparation of compound ll 1. Example 20 (2S.3S.5S) - (N- (N - ((N-methyl-N - ((2-isopropyl-4-thiazolyl) methyl) amino) carbonyl) valinyl) amino) -2- (N- ((5- triazolyl) methoxycarbonyl) amino) -1 .6-dif in il-3-h id roxy hexane A. N - (((N-benzyl) oxy) carbonyl) -L-phenylalaninal A solution of 24.5 ml of dimethyl sulfoxide anhydride in 870 ml of dichloromethane anhydride was cooled under N2 at -60 ° C and treated during a period of 15 min. with 131 ml of a 2M oxalyl chloride solution in dichloromethane, so that the internal temperature remained below -50 ° C. After the addition, the solution was stirred at -60 ° C for 1 5 min and was treated for a period of 20 min with a solution of 50 g (0.155 mol) of N - (((benzyl) oxy) -carbonyl) -L-phenylalaninol in 200 ml of dichloromethane. The resulting solution was stirred at -60 ° C for 1 h, then treated for a period of 1 5 min with 97 ml of triethylamine, in order that the internal temperature remained below -50 ° C. After the addition, the solution was stirred at -60 ° C for 1 5 min, then, with the cooling bath in place, treated rapidly (over a period of 1 min) with a solution of 163 g of citric acid in 550 ml of water. The resulting slurry was stirred vigorously for 10 min, allowed to warm, diluted to 1 L with water, and separated. The organic layer was washed with 700 ml of water followed by a mixture of 550 ml of water and 150 ml of saturated aqueous NaHCO3, dried over MgSO4, and concentrated in vacuo at 20 ° C to give the desired crude compound as a light yellow solid. B. (2S.3R .4R .5S.-2.5-Bis- (N- .... (Benzyloxycarbonyl) amino-3,4-dihydroxy-1,6-diphenylhexane v (2S.3S.4S.5S) -2.5-Bis - (N- (((benzyl) oxy) carbonyl) amino) -3,4-dihydroxy-1,6-diphenylhexane A suspension of 78.5 g of VCI3 (tetrahydrofuran) 3 and 16 g of zinc powder in 400 ml of dry dichloromethane was stirred under N2 atmosphere for 1 h at 25 ° C. A solution of 0.175 moles of N - (((benzyl) oxy) carbonyl) -L-phenylalaninal in 200 ml of dichloromethane was then added at one portion, and the resulting mixture was stirred at room temperature under N2 atmosphere for 16 h.The resulting mixture was added to 500 ml of 1 M aqueous HCl, diluted with 500 ml of hot chloroform, and stirred vigorously for 2 min. The layers were separated, and the organic layer was washed with 1 M aqueous HCl and separated The filtration of the organic phase provided the desired crude product as a solid residue The residue was 1.25 liters of acetone. ml of H2SO4 concentrated, was stirred for 16 h at room temperature. The resulting mixture was filtered, and the residue (residue A) was washed with 50 ml of acetone. The combined filtrate was concentrated to a volume of 250 ml, diluted with 1000 ml of dichloromethane, washed three times with water and once with saturated brine, dried over MgSO4, and concentrated to give a viscous oil. The oil was taken up in 1000 ml of 1 M HCl in methanol (prepared from 71 ml of acetyl chloride and 1000 ml of methanol) and stirred at room temperature for 2 h. The resulting precipitate was filtered, washed with methanol, and air dried on the filter to provide 26.7 g of the desired compound as a white solid. The filtrate was concentrated and filtered to give a second fraction (8.3 g) of (2S). , 3R, 4R, 5S) -2, 5-bis- (N- (((benzyl) oxy) carbonyl) amino) -3,4-dihydroxy-1,6-diphenylhexane. 1 H NMR (d6-DMSO) d 2.59 (dd, J = 13, 5 Hz, 2 H), 2.74 (dd, J = 13, 9 Hz, 2H), 3.26 (br, 2H), 4.19 (m, 2H ), 4.54 (m, 2H), 4.92 (m, 4H), 6.82 (d, J = 9 Hz, 2H), 7.0-7.35 (m, 20 H). Mass spectrum: (M + H) * = 569.

Residue A (above, 2.65 g) was suspended in 75 ml of tetrahydrofuran (THF) and 75 ml of 1 M aqueous HCl under reflux for 24 h. After concentration of the resulting solution in vacuo, the residue was taken up in 10% methanol in chloroform, washed twice with water, dried over Na2SO4, and concentrated in vacuo to provide (2S, 3S, 4S, 5S -2, 5-bis- (N - (((benzyl) oxy) carbonyl) amino) -3,4-dihydroxy-1,6-diphenylhexane, as a white solid. 1 H NMR (D6-DMSO) d 2.64 (m, 2H), 3.04 (m, 2H), 3.49 (m, 2H), 3.78 (m, 2H), 4.70 (d, J = 7 Hz, 2H), 4.93 (AA'- 4H), 7.1 -7.4 (m, 20 H). Mass spectrum: (M + H) * = 569. C. (2S.3R.4S.5S) -3-acetoxy-2.5-bis-. N - (((benzyl oxocarbonyl) amino) -3-bromo-1,6-diphenylhexane A suspension of 25 g (44 mmol) of (2S, 3R, 4R, 5S) -2,5-bis- (N - (( (benzyl) oxy) carbonyl) amino) -3,4-dihydroxy-1,6-diphenylhexane in 500 ml of 2: 1 dichloromethane / hexane was treated with 23 g of a-acetoxy-isobutyryl bromide. The resulting mixture was stirred at room temperature until the reaction was rinsed, washed with two 200 ml portions of saturated aqueous NaHCO3, dried over MgSO4, and concentrated in vacuo to give 30.8 g of the desired crude compound. chromatography on silica gel using dichloromethane: etacetate at 9: 1 to provide the desired pure compound, as a white solid: RM N 1 H (CDCl 3) d 2.21 (s, 3H), 2.62 (dd, J = 13, 11 Hz, 1 H), 2.75 (d, J = 7 Hz, 2 H), 2.95 (br d, J = 15 Hz, 1 H), 4.03 (br t, J = 10 Hz, 1 h), 4.40 (br d, J = 10 Hz, 1 H), 4.6-5.0 (m, 6H), 5.12 (br d, J = 13 Hz, 1 H), 5.33 (br d, J = 1 1 Hz, 1 H), 7.0 -7.4 (m, 10H) Mass spectrum s: (M + NH4) + = 690, 692. D. (2S.3R.4R.5S) -2.5-Bis- (N - ((.benzyl) oxocarbonyl) amino.-3,4-epoxy-1,6-diphenylhexane. A solution of 35.56 g (52.8 mmol) of (2S, 3R, 4S, 5S) -3-acetoxy-2,5-bis- (N - (((benzyl) oxy) carbonyl) amino) -3-bromo-1 , 6-diphenylhexane in 375 ml of dioxane, treated with 255 ml of 1 N aqueous sodium hydroxide and stirred at room temperature for 16 h, during which time the desired compound was precipitated. The resulting mixture was filtered, and the residue was washed with water and dried to provide 22.23 g (76%) of the desired compound as a white solid. 1 H NMR (CDCl 3) d 2.7-2.9 (m, 6 H), 3.9-4.0 (m, 2 H), 4.6-4.7 (m, 2 H), 5.03 (m, 4 H), 7.1 -7.4 (m, 10 H). E. (2S.3S.5S) .2.5-Bis-. N - (. (Benzyloxycarbonyl amine) - 1.6-dif eni-3-hydroxyhexane A mixture of 39.2 g 71.2 mmoles) of (2S, 3R, 4R, 5S) -2,5-bis- (N - (((benzyl) oxy) carbonyl) amino) -3,4-epoxy-1,6-diphenylhexane in 600 ml of THF was treated under N2 with 13 g (0.36 mole) of sodium borohydride. The resulting mixture was treated dropwise with 27.7 ml (0.36 moles) of trifluoroacetic acid. After being stirred for 3.5 h, at room temperature, the resulting mixture was cooled with 1N aqueous HCl, diluted with water, and stirred for 16 h. The resulting mixture was filtered, washed with water, and dried to provide 22.85 g (58%) of the desired compound as a white solid.

F. (2S.3S.5S) -2.5-diamino-1,6-dif enyl-3-hydroxyhexane A suspension of 32 g of the crude resultant compound of Example 20E and 55.5 g (176 mmol) of barium hydroxide octahydrate in 400 ml of 1,4-dioxane and 400 ml of water, was heated to reflux for 4 h. The resulting mixture was filtered, and the residue was rinsed with dioxane. The combined filtrates were concentrated to a volume of approximately 200 ml and extracted with four 400 ml portions of chloroform. The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography using first 2% isopropylamine in chloroform and then 2% isopropylamine / 2% methanol in chloroform to provide 10.1 g (81%) of the desired pure compound as a white solid. 1 H NMR (CDCl 3) d 1.54 (dt, J = 14, 10Hz, 1H), 1.67 (dt, J = 14, 3 Hz, 1H), 2.50 (dd, J = 13, 8 Hz, 1H), 2.58 (dd, J = 13, 8 Hz, 1H), 2.8 (m, 2H), 2.91 (dd, J = 13, 5 Hz, 1H), 3.10 (m, 1H), 3.72 (ddd, J = 11, 3 , 2 Hz, 1H), 7.1-7.4 (m, 10 H). Mass spectrum: (M + H) + = 285. G. (4S.6S.1'S) -6- (1-amino-2-phenylethyl) -4-benzyl-2-phenyl-3-aza-2-bora-1-oxacyclohexane. A solution of 11.28 g (40 mmol) of (2S, 3S, 5S) -2,5-diamino-1,6-diphenyl-3-hydroxyhexane and 4.88 g (40 mmol) of phenylboronic acid in 1 liter of toluene was added. heated to reflux and the water was removed azeotropically with the aid of a "Dean Stark" trap until the distillate was clarified. The solvent was then removed by vacuum to provide the desired crude compound, which was used immediately without further purification. H. Tioformamide. To a 2-neck, 3-neck round bottom flask, cooled (0 ° C), equipped with an overhead stirrer loaded with a solution of formamide (30.5 ml, 0.76 moles) in 1 liter of diethyl ether, was added 89 g (0.19 moles) of phosphorous pentasul in small portions. The reaction mixture was allowed to warm to room temperature, stirred for 2 h, filtered, and concentrated in vacuo to give thioformamide as an odorous, irritating yellow oil, which was used without purification. L. ethyl 2-chloro-2-formylacetate - To a 2-necked, three-necked round bottom flask, it was charged with tertiary potassium butoxide (0.5 mole, 500 ml of a 1M solution in THF) and 500 ml of dry THF cooled to 0 ° C, a solution of ethyl chloroacetate (0.5 mole, 53.5 ml) and ethyl formate (0.5 mole, 40.4 ml) was added dropwise from an addition funnel into 200 ml of TH F for 3 hours. After the addition was complete, the reaction mixture was stirred for 1 hour and allowed to stand overnight. The resulting solid was diluted with diethyl ether and cooled in an ice bath. Then, the pH was decreased to about 3 using 6N HCl. The organic phase was separated, and the aqueous layer was washed 3 times with diethyl ether. The combined ether portions were dried over NaSO 4, and concentrated in vacuo. The desired crude compound was stored at -30 ° C and used without further purification. J. Ethyl thiazole-5-carboxylate To a round bottom flask was added 250 ml of dry acetone, 7.5 g (0.123 mole) of thioformamide, and 18.54 g (0.123 mole) of ethyl 2-chloro-2-formylacetate. The reaction was heated to reflux for 2 hours. The solvent was removed in vacuo, and the residue was purified by chromatography (SiO2, 6 cm column "od", 100% CHCl3, Rf = 0.25) to provide 1.1 g (60%) of the desired compound as a yellow oil pale. NMR (CDCl 3) d 1.39 (t, J = 7 Hz, 3 H), 4.38 (q, J = 7 Hz, 2 H), 8.50 (s, 1 H), 8.95 (s, 1 H). K. 5- (hydroxymethyl) thiazole. To a 500 ml three-necked flask, pre-cooled (ice bath), containing lithium aluminum hydride (76 mmol) in 250 ml of THF, was added thiazole-5-carboxylic acid ethyl ester (11.18 g). , 75.68 mmoles) in 100 ml of TH F per drop for 1.5 hours to avoid excess foam formation. The reaction was stirred for an additional hour, and carefully treated with 2.9 ml of water, 2.9 ml of 15% NaOH, and 8.7 ml of water. The solid salts were filtered, and the filtrate was discarded. The crude salts were heated to reflux in 100 ml of ethyl acetate for 30 min. The resulting mixture was filtered, and the two filtrates were combined, dried over Na2SO4, and concentrated in vacuo. The product was purified by silica gel cormatography eluting sequentially with methanol in 0% chloroform, 2%, 4%, to provide the desired compound, Rf = 0.3 (methanol in 4% chloroform), which solidified on being at rest with a yield of 75%. NMR (CDCl 3) d 4.92 (s, 2H), 7.78 (s, 1H), 8.77 (s, 1H). Mass spectrum: (M + H) + = 116. L. (((5-thiazolyl) methyl 4-nitrophenylcarbonate) A solution of 3.11 g (27 mmol) of 5- (hydroxymethyl) thiazole and excess N-methyl morpholine in 100 ml of methylene chloride was cooled to 0 ° C and treated with 8.2 g (41 mmoles) of 4-nitrophenyl chloroformate After being stirred for 1 h, the reaction mixture was diluted with CHCl 3, washed successively with 1 N HCl, saturated aqueous NaHCO 3, and Saturated brine, dried over NaSO4, and concentrated in vacuo The residue was purified by silica gel chromatography (SiO2, MeOH / -2% CHCl3, Rf = 0.5 in MeOH / 4% CHCl3) to yield 5.9 g (78%) of the desired compound as a yellow solid: NMR (CDCl 3) d 5.53 (s, 2H), 7.39 (dt, J = 9, 3 Hz, 2), 8.01 (s, 1H), 8.29 (dt, J = 9, 3 Hz, 2H), 8.90 (s, 1H) Mass spectrum: (M + H) + = 281.M (2S.3S.5S) -5-amino-2- (N - (( 5-thiazolyl) methoxycarbonyl) amino) -1,6-diphenyl-3-hydroxyhexane v (2S.3S.5S) -2-amino-5- (N - ((5-thiazolyl) -methoxycarbonyl) amino) -1,6-diphenyl- 3-hydroxyhexane. solution of 500 mg (1.76 mmol) of (2S, 3S, 5S) -2,5-diamino-1,6-diphenyl-3-hydroxyhexane and 480 mg (1.71 mmol) of (4-nitrophenyl) carbonate of ((5 -thiazolyl) methyl) in 20 ml of THF, was stirred at room temperature for 4 h. After removing the solvent in vacuo, the residue was purified by silica gel chromatography using first 2% and then 5% methanol in chloroform to provide a mixture of the two desired compounds. Silica gel chromatography of the mixture using a gradient of 0-1-2% methanol in isopropylamine loroform at 93: 2 provided 110 mg (16%) of (2S, 3S, 5S) -5-amino-2 - (N - ((5-thiazolyl) -methoxy-carbonyl) amino) -1,6-diphenyl-3-hydroxyhexane (Rf = 0.48, chloroform: methanol: isopropylamine 96: 2: 2) and 185 mg (28% ) of (2S, 3S, 5S) -2-amino-5- (N - ((5-triazolyl) methoxycarbonyl) amino) -1,6-difyl enyl-3-hydroxy-hexane (Rf = 0.44, chloroform: methanol : 96: 2: 2 isopropylamine). (2S, 3S, 5S) -5-amino-2- (N - ((5-thiazolyl) methoxycarbonyl) amino) -1,6-diphenyl-3-hydroxyhexane: NMR (CDCl 3) d 1.3-1.6 (m, 2H ) (dd, J = 14, 8 Hz, 1H), 2.78 (dd, J = 5 Hz, 1H), 2.88 (d, = 7 Hz, 2H) 3.01 (m, 1H), 3.72 (br q, 1H) , 3.81 (br d, J = 10Hz, 1H), 5.28 (s, 2), 5.34 (br d, J = 9 Hz, 1H), 7.07 (br d, J = 7 Hz, 2H), 7.15-7.35 ( m, 8H), 7.87 (s, 1H), 8.80 (s, 1H). Mass spectrum: (M + H) + = 426. (2S, 3S, 5S) -2-amino-5- (N - ((5-thiazolyl) methoxycarbonyl) amino) -1,6-diphenyl-3-hydroxyhexane: NMR (CDCl 3) d 1.55 (dt, J = 14 , 8 Hz, 1H), 1.74 (m, 1H), 2.44 (dd, J = 15, 1 Hz, 1H), 2.75-3.0 (m, 4H), 3.44 (m, 1H), 4.00 (br t, 1H) ), 5.28 (m, 3H), 7.1-7.4 (m, 10 H), 7.86 (s, 1H), 8.80 (s, 1H). Mass spectrum: (M + H) + = 426. N. (2S.3S.5S) -5-amino-2- (N - ((5-thiazolyl) methoxycarbonyl) amino) -1,6-diphenyl-3-idroxyhexane. A solution of 40 mmoles of crude (4S, 6S, 1'S) -6- (1-amino-2-phenylethyl) -4-benzyl-2-phenyl-3-aza-2-bora-1-oxacyclohexane in 700 ml of THF anhydride, cooled to -40 ° C, and treated by dripping over a period of 1 h with a solution of 7.83 g (27.9 mmoles) of ((5-thiazolyl) methyl (4-nitrophenyl) carbonate) in 300 ml of dry THF. The resulting solution was allowed to warm to 0 ° C for 3 h, then at room temperature for 16 h. The solvent was removed in vacuo, and the residue was taken up in 700 ml of ethyl acetate, washed with three portions of 150 ml of 1 N aqueous NaOH and a 150 ml portion of brine. The organic phase was dried over Na2SO and concentrated in vacuo. The purification of the residue of silica gel chromatography, using mixtures of methanol / chloroform, provided the desired compound mixed with its regioisomer. A second chromatography using 1 -3% isopropylamine in chloroform provided 5.21 g of the desired compound, which solidified upon standing. O. 2-methylpropane thioamide. A suspension of 100 g (1.15 mol) of isobutyramide in 4 l of diethyl ether was stirred vigorously and treated in portions with 51 g (0.1 15 mmol) of P4S? 0- The resulting mixture was stirred at room temperature for 2 h , filtered, and concentrated in vacuo to provide 94.2 g (80%) of the desired crude compound. 1 H NMR (CMSO-d6) d 1 .08 (d, J = 7 Hz, 6H), 2.78 (heptet.J = 7 Hz, 1 H), 9.06 (br, 1 H), 9.30 (br, 1 H ). Mass spectrum: (M + H) + = 104. P. 4- (Chloromethyl-2-isopropylthiazole) hydrochloride A mixture of 94.0 g (0.91 mole) of 2-methylpropane thioamide, 15.7 g (0.91 mole) of 1,3-dichloroacetone, and 109.7 g (0.91 moles) of MgSO 4 in 16 liters of acetone was heated to reflux for 3.5 hrs. The resulting mixture was allowed to cool, filtered, and the solvent was removed in vacuo to provide the crude compound desired as a yellow oil.1 H NMR (DMSO-d6) d 1.32 (d, J = 7 Hz, 6 H), 3.27 (heptet, J = 7 Hz, 1 H), 4.78 (s, 2H), 7.61 (s, 1 H) Mass spectrum: (M + H) + = 176. Q. 2-isopropyl-4 - (((N-methyl) amino) methyl) thiazo !. A solution of 40 g of hydrochloride 4- (Chloromethyl) -2-isopropylthiazole in 100 ml of water was added dropwise with stirring to 400 ml of 40% aqueous methylamine, the resulting solution was stirred for 1 h, then concentrated in vacuo. The residue was taken up in chloroform, dried over Na2SO4, and concentrated in vacuo. Silica gel omatography, using 10% methanol in chloroform, gave 21.35 g (55%) of the desired compound. 1H-NMR (DMSO-d6) d 1.34 (d, J = 7 Hz, 6H), 2.56 (s, 3H), 3.30 (heptet, J = 7 Hz, 1 H), 4.16 (s, 2H), 7.63 (s) , 1 HOUR). Mass spectrum: (M + H) + = 171. R. N - (((4-Nitrophenyl) oxy) carbonyl) -L-valine methyl ester. A solution of 66.1 g (0.328 mol) of 4-nitrophenyl chloroformate in 1.2 liters of CH2Cl2 was cooled to 0 ° C and treated with L-valine methyl ester hydrochloride. The resulting mixture was treated slowly, with stirring, with 68.9 ml (0.626 moles) of 4-methylmorpholine. The resulting solution was allowed to slowly warm to room temperature and was stirred overnight. After washing with 3 portions of 10% aqueous NaHCO3, the solution was dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with chloroform to provide the desired compound. 1 H NMR (DMSO-dβ) d 0.94 (d, J = 7 Hz, 3 H), 0.95 (d, J = 7 Hz, 3 H), 2.12 (octet, J = 7 Hz, 1 H), 3.69 (s, 3H), 4.01 (dd, J = 8, 6 Hz, 1 H), 7.41 (dt, J = 9, 3 Hz, 2H), 8.27 (dt, J = 9, 3 Hz, 2H), 8.53 (d, J = 8 Hz, 1 H). Mass spectrum: (M + NH4) + = 314. S. Methyl ester of N - ((N-methyl-N - ((2-isopropyl) -4- thiazolyl) methyl) amino) carbonyl) -L-va A solution of 15.7 g (92 mmol) of 2-isopropyl-4 - (((N-methyl) amino) methyl) thiazole in 200 ml of TH F was combined with a solution of 20.5 g (69 mmol) of N - (((4-nitrophenyl) oxy) carbonyl) -L-valine methyl ester. The resulting solution was treated with 1.6 g of 4-dimethylaminopyridine and 12.9 ml (92 mmol) of triethylamine, heated to reflux for 2 h, allowed to cool, and concentrated in vacuo. The residue was taken up in CH2Cl2, washed extensively with K2CO3, dried over Na2SO4, and concentrated in vacuo. The mixture of the resulting product was purified by silica gel chromatography using chloroform as an eluent to provide 16.3 g (54%) of the desired compound. 1 H NMR (DMSO-d6) d 0.88 (d, J = 7 Hz, 3H), 0.92 (d, J = 7 Hz, 3 H), 1.32 (d, J = 7 Hz, 3H), 2.05 ( octet, J = 7 Hz, 1 H), 2.86 (s, 3H), 3.25 (heptet, J = 7 Hz, 1 H) 3.61 (s, 3H), 3.96 (dd, J = 8, 7 Hz, 1 H ), 4.44 (AA ', 2H), 6.58 (d, J = 8 Hz, 1 H), 7.24 (s, 1 H). Mass spectrum: (M + H) + = 328.

T. N - ((N-methyl-N - ((2-isopropyl-4-thiazolyl) methyl)) amino) carbonyl) -L-valine. A solution of 1.42 g (4.3 mmol) of the compound resulting from Example 20S in 17 ml of dioxane was treated with 17.3 ml of 0.50 M aqueous LiOH. The resulting solution was stirred at room temperature for 30 min, treated with 8.7 ml of HCl 1 M, and concentrated in vacuo. The residue was taken up in dichloromethane, washed with water, dried over Na2SO, and concentrated in vacuo to provide 1.1 g (81%) of the desired compound. Mass spectrum: (M + H) + = 314. U. (2S.3S.5S) -5- (N- (N - ((N-methyl-N - ((2-isopropyl-4-thiazolyl) methyl) amino) carbonyl) valinyl) amino) -2- ( N - ((5- thiazolyl) methoxycarbonyl) amino) -1,6-diphenyl-3-hydroxy hexane. A solution of 70 mg (0.223 mmol) of N - ((N-methyl-N - ((2-isopropyl-4-thiazolyl) methyl) amino) carbonyl) -L-valine, 79 mg (0.186 mmol) of (2S , 3S, 5S) -5-amino-2- (N - ((5-thiazolyl) methoxycarbonyl) -amino) -1,6-diphenyl-3-hydroxyhexane, 30 mg (0.223 mmol) of 1-hydroxybenzotriazole hydrate, and 51 mg (0.266 mmoles) of N-ethyl-N'-dimethylaminopropyl carbodiimide in 2 ml of THF was stirred at room temperature for 16 hr. The resulting solution was concentrated in vacuo, and the residue was purified by silica gel chromatography using CH 2 Cl 2: CH 3 OH 97: 3, to provide 100 mg (74%) of the desired compound (Rf 0.4, CH 2 Cl 2: CH 3 OH 95: 5) as a solid, mp 61 -63 ° C. Mass spectrum: (M + H) + = 721. Anal. Cale, for C37H49N6O5S20.5 H2O: C, 60.88; H, 6.77; N 11.51. Found: C, 60.68; H, 6.53: N, 11.36. Example 21 (2S.3S.5S) -2- (N.N.-dibenzylamino) -3-hydroxy-5- (butylaxy-tertiary-carbonylamino) -1,6-diphenylhexane. To a stirred solution of (2S, 3S, 5S) -2- (N, N-dibenzylamino) -3-hydroxy-5-amino-1,6-diphenylhexane (10.0 g, 21.6 mmol) in tetrahydrofuran (200 ml), potassium carbonate (6.0 g, 43.2 mmol) in H20 (200 mL) was added. To this solution was added tertiary di-butyl dicarbonate (5.64 g, 25.9 mmol) in tetrahydrofuran (10 ml). The resulting solution was stirred at room temperature for 3 hours. N, N-dimethylethylenediamine (1 ml, 8.6 mmofes) was added and the reaction mixture was stirred at room temperature for an additional hour. Ethyl acetate (400 ml) was added and the organic layer was separated and washed with KH2PO4 (2x200 ml) water (1x200 ml), saturated NaHCO3 (2x200 ml) and water (1x200 ml). The organic solution was dried over sodium sulfate and concentrated under reduced pressure to provide the desired product as a pale yellow oil. 300 MHz 1 H NMR (CDCl 3) d 1.40 (s, 9 H), 1.58 (s, 2 H), 2.45-2.85 (m, 4 H), 3.05 (m, 1 H), 3.38 (d, 2 H), 3.6 (m, 1 H) ), 3.79 (m, 1H), 3.87 (d, 2H), 4.35 (s, 1H), 4.85 (s, broad, 1H), 7.- 7.38 (m, 20 H). Example 21B (2S.3S, 5S) -2-amino-3-idroxy-5- (tertiary butyloxycarbonylamino) -1,6-diphenylhexane.

To a stirred solution of (2S, 3S, 5S) -2- (N, N-dibenzylamino) -3-hydroxy-5- (tertiary butyloxy-carbonylamino) -1,6-diphenylhexane (12 g, 21.3 mmoles) in methanol (350 ml) was charged ammonium formate (8.05 g, 128 mmol, 6.0 eq) and palladium on carbon at 10% (2.4 g). The solution was stirred under nitrogen at 60 ° C for three hours and then at 75 ° C for 12 hours. An additional amount of ammonium formate (6 g) and 10% palladium on carbon (1.5 g) was added, as well as 1 ml of glacial acetic acid. The reaction was induced to complete within 2 hours at a reflux temperature. The reaction mixture was then cooled to room temperature and then filtered through a pad of celite. The filter cake was washed with methanol (75 ml) and the combined filtrates were concentrated under reduced pressure. The residue was taken up in 1 N NaOH (300 ml) and extracted into methylene chloride (2 × 200 ml). The combined organic layers were washed with brine (250 ml) and dried over sodium sulfate. Concentration of the solution under reduced pressure provided the desired product as a light colored oil which crystallized slowly on standing (5 g). Further purification of the product could be achieved by flash chromatography (silica gel, 5% methanol in methylene chloride). 300 Mhz 1 H NMR (CDCl 3) d 1 .42 (s, 9 H), 1.58 (m, 1 H), 1.70 (m, 1 H), 2.20 (s, broad, 2 H), 2.52 (m , 1 H), 2.76-2.95 (m, 4 H), 3.50 (m, 1 H), 3.95 (m, 1 H), 4.80 (d, broad, 1 H), 7.15-7.30 (m, 10H). Example 22 Alternative Preparation of (2S.3S.5S) -2-amino-3-hydroxy-5- (tertiary butyloxycarbonylamino) -1,6-diphenylhexane. Example 22A (5S) -2- (tertiary butyloxy-carbonylamino) -5- (N, N-dibenzylamino) -1,6-diphenyl-4-oxo-2-hexene A 9.21 gram (30 mmoles) of (S) -2 -amino-5- (N, N-dibenzylamino) -1,6-diphenyl-4-oxo-2-hexene and 0.37 g (3 mmoles) 4-N, N-dimethylaminopyridine in 100 ml methyl tertiary butyl ether, a solution containing 4.80 grams (22 mmoles) of tertiary dibutyl dicarbonate in the same solvent (25 ml) was added via a syringe pump over a period of 6 hours. An additional amount (3 ml) of methyl tertiary butyl ether was then added to complete the addition. After stirring at room temperature for 18 hours, the reaction mixture was cooled with the aid of an ice water bath. The resulting solid was collected by suction filtration and washed with methyl tertiary butyl ether (0 ° C) and hexane and dried under vacuum to give 9.9 grams of crude material as a white solid. The material thus isolated was dissolved in a minimum amount of dichloromethane and purified by flash chromatography on silica gel. Elution of the column with a mixture of hexane-ethyl acetate-dichloromethane (8: 1: 1) gave, after concentration of the appropriate fractions, 8.1 gram (72%) of the desired compound. Mp. 191 -193 ° C. [a] D -183.7 ° (c = 1 .05, CHCI3). 1 H NMR (CDCl 3, d): 1 1 .68 (bs, 1 H), 7.05 - 7.47 (m, 20H), 5.28 (s, 1 H), 4.27 (d, J = 16 Hz, 1 H), 4.02 (d, J = 16Hz, 1H), 3.58 (m, 4H), 3.40 (m, 1H), 3.11 (m, 1H), 2.90 (m, 1H), 1. 48 (s, 9H). Example 22B Alternating preparation of (5S) -2- (tertiary butyloxy-carbonylamino) -5- (N-dibenzylamine) - 1,6-difnyl-4-oxo-2-hexene A suspension of (S) -2- amino-5- (N, N-dibenzylamino) -1,6-diphenyl-4-oxo-2-hexene (100.0 g, 0.217 mol) in 15% ethyl acetate / hexanes (2 liters) under N2 was heated to approximately 40 ° C. The resulting solution was cooled to room temperature before adding 4.0 g (33 mmol) of N, N-dimethyl-4-aminopyridine and 49.7 g. (0.228 moles) of tertiary dibutyl dicarbonate. The reaction mixture was allowed to stir overnight at room temperature.

(After about an hour, a white precipitate began to form). The suspension was filtered and the precipitate was washed with hexanes to give the desired product as colorless crystals. CLF: 25% ethyl acetate / hexanes R, 0.38. Example 22C (2S.3S, 5S) -2- (N, N-dibenzylamino) -5- (tertiary butyloxycarbonylamino) -3-hydroxy-1, 6-dif eni I hexane. A solution of the product from Example 22A (5 g, 8.9 mmol) in dichloromethane (100 ml) and 1,4-dioxane (100 ml) was cooled between -10 ° and -15 ° C and treated by dripping with 1M BH3THF ( 26.7 ml, 26.7 mmoles).

The solution was stirred at this temperature for 3 hours. The clear solution was quenched with excess methanol (20 ml) and stirred at room temperature for 30 min. The solvent was removed in vacuo. The resulting white foam was dissolved in TH F (75 ml) and cooled to -40 ° C. A solution of LAH (9 mL, 1 M in THF, 9 mmol) was added dropwise. After 10 minutes, the solution was quenched with water followed by dilute aqueous HCl. The organics were removed and the aqueous layer was extracted with ethyl acetate (3x20 ml). The combined organics were washed (saturated aqueous bicarbonate followed by brine), dried (Na 2 SO 4), filtered and evaporated to give 4.9 g (99%) of the desired product as a white foam. Alternatively, the white foam resulting from the reaction step of BH3THF, was dissolved in MeOH (845 ml), cooled to + 3 ° C and treated in portions with KBH4 (1.44 g, 26.7 mmol). After the addition of the last portion of KBH4, the reaction was stirred for an additional 4 hours at +4 to +5 ° C. The solution was concentrated to half the volume in vacuo, diluted with hexane-EtOAc 1/1 (70 ml) and quenched (with cooling, maintaining the temperature at <30 ° C) by adding a 10% solution of KHSO4 at pH = 5 approximately. NaOH (15% aqueous) was added at pH = 12-13. The insoluble salts were removed by filtration, and the filter cake was washed 3 times with 7 ml of hexane / EtOAc 1/1. The filtrate and the washings were transferred to a separatory funnel, diluted with 15 ml of hexane and 15 ml of H2O. The organics were removed and the aqueous layer was extracted once with 20 ml (1/1) hexane-EtOAc. The combined organics were washed (saturated brine), dried (Na 2 SO 4), filtered, and evaporated to give 5.2 g of the desired product, which was used without further purification in subsequent reactions. Rf 0.5 (25% EtOAc / hexane) 1 H NMR (CDCl 3) d 7.37-7.10 (m, 20H); 6.78 (br, s, 1 H); 4.62 (d, 1 H); 4.50 (s, 1 H); 4.18 (dd, 1 H); 3.9 (d, 2H); 3.65 (dd, 2H); 3.40 (d, 2H); 3.00 (m, 2H); 2.77 (m, 1 H); 1 .39 (s, 9H). MS (El) m / e 565 (M + H). Example 22D (2S.3S.5S) -2-amino-3-hydroxy-5- (tertiary butyloxycarbonyl) -1,6-diphenylhexane. A solution of the product of Example 22C (150 grams, 250 mmol) was dissolved in absolute EtOH (2 liters), treated with Pd / C at % (18 grams, pre-moistened), followed by the addition of ammonium formate (78.6 grams, 1.25 moles), dissolved in H O (200 ml). The resulting mixture was stirred at reflux for 2.5 hours.

The mixture was cooled to room temperature and filtered through an infusorial earth pad (20 g). The filter cake was washed 3 times with EtOH (70 ml each). The filtrate was concentrated in vacuo. The residue was dissolved in EtOAc (1 L) and washed (1 N NaOH, followed by H2O)., followed by brine), dried (Na2SO4), filtered and concentrated in vacuo, to a constant weight of 95 grams, (99.2% of theory). The light yellow solid (91.5 grams of 95 grams) was letred in hot heptane (600 ml) (steam bath) and treated with isopropanol (45 ml), and swirled to effect the solution. The solution was allowed to cool slowly to room temperature for 3 hours, maintained at room temperature for 2 more hours, and filtered. The filter cake was washed 10 times with hexane-isopropanol 9/1 (30 ml each) to give the desired product as a finely crystalline off-white solid, which was dried at a constant weight of 57.5 grams. The crude product (20 grams) was recrystallized from 140 ml of heptane / 1 7 ml of isopropanol. After allowing the solution to cool slowly to room temperature, the mixture was allowed to stand at room temperature for 2 hours and was then filtered. The filter cake was rinsed (5x15 ml (8/1) heptane / isopropanol) and dried at a constant weight of 18.5 grams. EXAMPLE 23 Alternative preparation of (2S.3S.5S) -5- (N - ((N-methyl-N - ((2-isopropyl-4-thiazolyl) methyl) amino) carbonyl) valinyl) amino) -2 - (N - ((5-triazolyl) methoxycarbonyl) amino) -1,6-dif in il-3-hydroxy hexane Example 23A (2S.3S.5S) -5- (tertiary butyloxy, ilamino carbon) -2- ( N - ((5- thiazolyl) methoxycarbonyl) amino) -1,6-diphenyl-3-hydroxyhexane The product of Example 22D (6.0 g, 15.6 mmol) was dissolved in 60 ml of DMF under nitrogen atmosphere. To this solution stirred at room temperature, 5- (para-nitropheni! Oxycarbonyl! Oxymethyl!) Thiazole (4.67 g, 1 5.6 mmol) was added and the resulting solution was stirred for 4 hours. The solvent was removed under reduced pressure by rotary evaporation and the residue was dissolved in 150 ml EtOAc. This solution was washed with 5 x 75 ml of 1 N NaOH solution, 10 ml of brine, dried over Na2SO. The solvent was removed to give 8.02 g of a slightly yellow oil. This material was crystallized from 30 mL of EtOAc and 40 mL of hexane to give 6.53 g (80%) of the desired product as a white solid. pH 118-120 ° C H 1 NMR (CDCl 3) d 8.79 (s, 1 H), 7.83 (s, 1 H), 7.30-7.15 (m, 8H), 7.08 (m, 2H), 5.23 (s, 2H) , 5.14 (d, 1 H, J = 9 Hz), 4.52 (m, 1 H), 3.92-3.72 (m, 3H), 3.65 (m 1 H), 2.85 (d-evident, 2H, J = 7.5 Hz ), 2.72 (d, evident, 2H, J = 7 Hz), 1.61 (m, 2H), 1.38 (s, 9H). CIMS m / z (526) (M + H) + 543 (M + 18) +. Example 23B (2S.3S, 5S) -5-amino-2- (N - ((5-thiazolyl) methoxycarboni amino) -1,6-diphenyl-3-hydroxyhexane The product of Example 23A (6.43 g, 12.23 mmole) was dissolved In 25 ml of dioxane at room temperature under nitrogen, 20.25 ml of 4N HCl in dioxane were added to this stirred solution, and after about 10 minutes, a thick precipitate formed, an additional 10 ml of dioxane was added to give the dioxane. The mixture was stirred for 1 hour and then filtered.The filter cake of the bis-HCl salt product was washed with 20 ml of dioxane, dried in the air, and then dissolved in 175 ml of water. 175 ml of ethyl acetate were added to this solution and the two-phase mixture was stirred rapidly.The pH of this mixture was adjusted to pH = 10 by the dropwise addition of 3N NaOH to the stirred mixture rapidly. isolated, washed with brine (150 ml) and dried over Na 2 SO 4, The solvent was removed to give 5.18. g (99%) of the desired product as a clear oil. 1 H-NMR (CDCl 3) d 8.81 (s, 1 H), 7.87 (s, 1 H), 7.35-7.05 (m, 10 H), 5.33 (d, 1 H, J = 9.3 Hz), 5.28 (m, 2H) ), 3.81 (m, 1 H), 3.72 (m, 1 H), 3.01 (m, 1 H), 2.88 (m, 2H), 2.78 (dd, 1 H, J = 13.5, 5.1 Hz), 2.39 ( dd, 1 H, J = 9.0, 4.5 Hz), 1.57-1.30 (m, 2H), CIMS m / z 426 (M + H) +. Example 23C (2S.3S.5S) -5- (N- (N - ((N-methyl-N - ((2-isopropyl-4-thiazolyl) methyl) amino) carbonyl) valinyl) amino) -2- ( N - ((5- thiazolyl) methoxycarbonyl) ami no) - 1,6-dif in il-3-hydroxy hexane N - ((N-methyl-N - ((2-isopropyl-4-thiazolyl) methyl) amino) carbonyl) -L-valine (4.13 g, 13.18 mmol) and hydroxybenzotriazole "(2.23 g), 16.48 mmoles) were dissolved in 70 ml of THF and then dicyclohexyl carbodiimide (2.71 g, 13.18 mmoles) were added in one portion a to the stirred solution under nitrogen atmosphere. This mixture was stirred for 4 hours at room temperature and then filtered to remove the precipitate of dicyclohexylurea. (2S, 3S, 5S) -5-amino-2- (N - ((5-thiazolyl) -methoxycarbonyl) amino) -1,6-diphenyl-3-hydroxyhexane (5.1 g, 1.99 mmoles) was dissolved in 100 g. ml of THF under nitrogen atmosphere. To this stirred solution was added the HOBT-active ester filtrate and the resulting solution was stirred at room temperature for 4 hours, and the solvent was removed via rotary evaporation. The residue was dissolved in 150 ml of ethyl acetate and washed with 2 x 100 ml of 1 N NaOH, 100 ml of brine, 100 ml of 1% aqueous KHSO 4 w / w and the solvent was removed by rotary evaporation to give a residue. The residue was dissolved in 175 ml of 1 N HCl, and the solution was filtered to remove the small amount of d-cyclohexylurea. The filtrate solution was added to 175 ml of ethyl acetate and the two-phase mixture was mixed rapidly. The pH of this rapidly stirred mixture was adjusted to pH = 7 by dropwise addition of cold 3N NaOH. The organic layer was isolated, washed with 100 ml of brine, dried over Na2SO4, filtered, and the solvent was removed to give 8.6 g of a colorless foam. This material was crystallized from 42 ml of EtOAc and 21 ml of hexane to give 7.85 grams of the desired product as a white solid. mp = 122-123 ° C CIMS m / z 721 (M + H) +. Example 24 Alternative Preparation of (2S.3S.5S) -5-amino-2- (N - ((5-tiazolymethylcarbonyloam) -1,6-difyl en-l-3-hydroxyhexane Alternative A The product of Example 17F ( 9.5 g, 33.4 mmoles) and phenylboronic acid (4.1 g, 33.6 mmoles) were combined in toluene (150 ml) and refluxed for 2.5 hours with azeotropic water removal ("Dean-Stark" trap). (100 ml) at atmospheric pressure, then the remaining toluene was removed under vacuum to provide a yellow syrup which was dissolved in DMF (50 ml) and cooled to -60 ° C. A solution of 5- (para-nitrophenyloxycarbonyloxy) methyl) thiazole (9.5 g, 33.5 mmol) in DMF (50 ml) was added over 45 minutes.The resulting mixture was stirred for 8 hours at -55 + 5 ° C, then 14 hours at -25 ° C, after allowed to warm to room temperature The reaction mixture was diluted with 1 N HCl (250 ml) and washed with CH 2 Cl 2 (2x80 ml) The combined organic layers were extracted again on 1 N HCl (60 ml) The combined aqueous HCl layers were cooled in an ice bath at 2 ° C, and concentrated HCl (37%) (30 ml) was added for 5 minutes. The desired product (bis HCl salt) was started to precipitate within 30 minutes. The slurry was stirred for 3 hours at 2-5 ° C, then the product (bis HCl salt) was collected by filtration and dried in a vacuum oven at 55-60 ° C. Yield 1 1.4 g (68%). Recovery of second batch: HCl mother liquors were shaken with ethyl acetate (190 ml) and neutralized to pH 9-10 with K2CO3 (200-300 g of 25% w / w K2CO3 were required). The ethyl acetate layer was concentrated under vacuum to an oil which was redissolved in 1 N HCl (90 ml) and washed with methylene chloride (45 ml). The aqueous layer was cooled to 2 ° C. Concentrated HCl (37%) (9.0 ml) was added to precipitate a second fraction. After stirring for 1 -3 hours at 2-5 ° C, the solid was collected by filtration and dried in a vacuum oven at 55-60 ° C, Yield 2.1 g (12.6%). Bis HCl salt neutralization: The bis HCl salt (10.66 g, 21 .4 mmol, mixture of first and second fractions) was stirred with CH 2 Cl 2 (10 mL) and 5% aqueous NaHCO 3 (10 mL) until all solids dissolved (2 hours). The aqueous layer was separated and extracted with another 50 ml CH2Cl2. The combined organic extracts were dried with H2SO4 (10 g), filtered and concentrated under vacuum to <40 ° C to an oil. The oil was dried over a vacuum pump to give the title compound as a yellow foam, 9.1 g (100%). Alternative B The product of Example 17F (15.0 g, 0.053 mol) was dissolved in DMF (75 ml). Tri isopropyl borate (24.4 ml, 0.105 moles) was added and stirred at room temperature for about 1.5 hours. The solution was cooled to -10 ° C and a solution of 5- (para-10-nitrophenyloxycarbonyloxymethyl) thiazole (15.0 g, 0.054 mol) in DMF (75 ml) was added over 80 minutes. The reaction was stirred for about 1 hour at -10 ° C, then diluted-with methylene chloride (250 ml) and quenched with a mixture of triethanolamine (24.8 g) and 5% aqueous sodium bicarbonate (300 ml). . Mix The biphasic mixture was stirred for 1 hour, then the layers were separated and the aqueous phase was extracted with another portion of methylene chloride (50 g. ** "ml." The combined organic layers were extracted with 1 N HCl. (1 x390 ml, then 1 x 95 ml). The acid layers were combined, cooled in an ice bath, and further acidified with HCl concentrate (50 ml) which produced a white slurry of the product. The slurry was stirred for about 1 hour at 2 ° C. The desired product (bis HCl salt) was collected by filtration and dried at 55 ° C in a vacuum oven. Yield of 18.5 g (70%).

Example 25 Alternative preparation of (2S.3S.5S) -5- (N - ((N-methyl-N - ((2-isopropyl-4-triazolyl) methyl) amino) carbonyl) valinyl) amino) -2- (N - ((5-thiazolyl) methoxycarbonyl) amino) -1,6-difyl enyl-3-hydroxyhexane To a solution of the product of Example 24 (9.1 g, 21.4 mmol), HOBT (3.6 g, 23.5 mmol) and N - ((N-Methyl-N - ((2-isopropyl-4-triazolyl) methyl) amino) -carbonyl) -L-valine (7.37 g, 23.5 mmol) in THF (170 mL) was added DCC (4.85 g, 23.5 mmoles). The solution was stirred at room temperature for 16 hours (precipitates of DCU). THF was removed under vacuum and the resulting slurry was stirred with cold 1 N HCl (106 ml at 5 ° C) for 3 hours to dissolve the crude product. The DCU was removed by filtration and the filter cake was washed with 1 N HCl (106 ml at 5 ° C) for 3 hours to dissolve the crude product. The DCU was removed by filtration and the filter cake was washed with 1 N HCl (30 ml). KH2PO4 (3.2 g) was dissolved in the combined HCl filtrates. The solution was mixed with ethyl acetate (80 ml) and neutralized to pH 7 with aqueous NaOH (60.3 g of 10% w / w NaOH). The aqueous layer was extracted with another 25 ml of ethyl acetate and the combined ethyl acetate extracts were washed with aqueous NaHCO3 (2x37 ml of 5% NaHCO3 w / w). The organic layer was dried with Na2SO4 (13 g), filtered, and concentrated under vacuum at 45 ° C. The residue was dissolved in a 1: 1 ethyl acetate / heptane mixture (200 ml) at 70 ° C. The solution was allowed to cool slowly and was stirred overnight at room temperature to provide a thick slurry. The product was collected by filtration and washed with ethyl acetate / heptane 1: 1 (20 ml). The product was briefly dried at 55 ° C in a vacuum oven to obtain an approximate weight before the second crystallization (12.85 g, 83%). A second crystallization of 144 ml of ethyl acetate / heptane at 2: 1 (dissolved at -70 ° C, then stirred at room temperature for 12 hours) yielded a thick slurry of fine white solid. The product was collected by filtration and washed with 15 ml of ethyl acetate / heptane 2: 1, then dried in a vacuum oven at 55 ° C for 2 days to give the desired product. Yield 11.9 g (77%). EXAMPLE 26 Alternative Preparation of ((5-tiazolyOmethyl) (4-nitrophenyl) carbonate Example 26A 2-Amino-5- (ethoxycarbonyl) thiazole hydrochloride To a solution of -10 ° C of tertiary potassium butoxide (1 10 g, 0.98 moles) in THF (1.9 L) was added a solution of ethyl chloroacetate (100 ml, 0.934 moles) and ethyl formate (75 ml, 0.928 moles) in THF (400 ml) by dripping for 2 hours, with good mechanical stirring The thick solution was stirred for another 2 hours at about -1 ° C, then the reaction was quenched by the addition of a solution of NaCl (150 g) in 1 N HCl (750 ml). 20 ° C and the lower aqueous layer was separated (containing some precipitated salt) The organic layer was separated under vacuum on a rotary evaporator The oil was redissolved in 500 ml of ethyl acetate, dried with 75 g of Na 2 SO 4 for 1 hour, it was filtered and concentrated under vacuum (bath temperature 40-50 ° C) to an oil.Cl chloraldehyde The resulting crude (161 g) and thiourea (70 g, 0.92 mol) were dissolved in TH F (2 I) and heated to gentle reflux (60 ° C). Thiourea dissolved during heating, and within 20 minutes, the product was precipitated from the solution. After 100 minutes, the suspension was allowed to cool to room temperature, then cooled in an ice bath for 1 hour. The product was collected in a frit Buchner funnel and washed with 2 x 100 ml of cold THF, then dried overnight in a vacuum oven at 50 ° C. Yield: 122 g of the title compound as a tan solid, m.p. 182-185 ° C (dec). 1 H-NMR (DMSO-d 6) d 7.86 (s, 1 H), 4.19 (q, 2H), 1.21 (t, 3H). 13 C NMR (DMSO-dβ) d ~ 171.9, 160.4, 140.4, 1 14.4, 61.1, 14.2. Example 26B 2-amino-5- (ethoxycarbonyl) thiazole To a solution of -10 ° C of tertiary potassium butoxide (150 g, 1.3 mols) in THF (1.35 L) was added a solution of chloroacetate of ethyl (139 ml, 1.3 moles) and ethyl formate (103 ml, 1.227 moles) in TH F (150 ml) were dripped for 75 minutes, with good mechanical agitation. A rinse of THF (25 ml) was added for 5 minutes. The thick solution was stirred for another 3 hours at about -5 to 0 ° C, then the reaction was quenched by the addition of a solution of NaCl (240 g) and conc. HCl. (90 ml) in water (960 ml). The mixture was allowed to warm to 15 ° C and the lower aqueous layer was discharged. Thiourea (97 g, 1.27 mol) was dissolved in the crude THF solution of chloroaldehyde. The solution was heated to 65 ° C and refluxed for 1 hour, then cooled to 30 ° C. The addition of a solution of K2CO3 (88g, 0.64 moles) in 1500 ml of water yielded two layers (pH = 7 aqueous). The THF was removed under vacuum at < _ 45 ° C, causing the product to precipitate as a yellow solid. The slurry was cooled to 15 ° C, and the product was collected in a frit Buchner funnel and washed with 3 x 200 ml of water, then dried 24 hours in a vacuum oven at 55 ° C to provide 151 g. of the title compound as a yellow solid, mp 155-158 ° C. 1 H NMR (DMSO-de) d 7.8 (broad s, 2H, NH 2), 7.62 (s, 1 H), 4.13 (q, 2H), 1.18 (t, 3H). 13 C NMR (DMSO-dβ) d 173.4, 161.3, 147.9, 1 14.5, 60.1, 14.3. Example 26C 5- (Ethoxycarbon I) azol A solution of 2-amino-5- (ethoxycarbonyl) thiazole (50 g, 0.29 mmol) in a mixture of DMF (83 ml) and THF (317 ml) was added by trickling for 87 minutes to a stirred solution at 41 ° C of isoamyl nitrite (59 ml, 0.44 moles) in DMF (130 ml). During the exothermic addition a maximum temperature of 60 ° C was observed. After another 40 minutes, the THF was removed under vacuum at 45 ° C. The concentrated DMF solution was cooled to 25 ° C and diluted with toluene (420 ml) and water (440 ml). The toluene layer was extracted with 3 x 120 ml of water, then dried with Na2SO4 (50 g) for 1 hour. After filtration, the toluene layer was separated on a rotary evaporator at bath temperature at 50 ° C, then in a vacuum pump at 21 ° C. The crude residue containing the title compound weighed 65.6 g. This material was used directly in the next step. A sample of similarly prepared material was purified by column chromatography to give a yellow oil. 1 H NMR (CDCl 3) d 8.95 (s, 1 H), 8.51 (s, 1 H), 4.39 (q, 2H), 1.40 (t, 3H). 13 C NMR (CDCl 3) d 8.95 (s, 1 H), 8.51 (s, 1 H), 4.39 (q, 2 H), 1.40 (t, 3 H). 13 C NMR (CDCl 3) d 161.0, 157.9, 148.6, 129.8, 61.6, 14.1. Example 26D 5- (Hydroxymethyl) thiazole To a slurry of lithium aluminum hydride (9.0 g) in THF (633 ml) was added a solution of crude 5- (ethoxycarbonyl) thiazole (65.6 g) in THF (540 ml). for 95 minutes at 0-5 ° C. After an additional 25 minutes, the reaction was quenched at 5 ° C by the serial addition of water (8.1 ml), 15% NaOH (8.1 ml), and water (24.3 ml). After drying with Na2SO (44 g) for 2 hours, the slurry was filtered, and the filter cake was washed with 100 ml of TH F. The combined filtrates were concentrated under vacuum at 45 ° C to a brown oil (39 g). ). The oil was fractionally distilled through a short-path apparatus. The product fractions were distilled at a vapor temperature of 97-104 ° C to 3-5 mm, providing 20.5 g of the title compound as a cloudy orange oil. 1 H NMR (CDCl 3) d 8.74 (s 1 H), 7.72 (s, 1 H), 4.89 (s, 2 H), 3.4 (broad s, 1 H, OH). 13 C NMR (CDCl 3) d 153.4, 140.0, 139.5, 56.6.

Example 26E Hydrochloride 5- (para-nitrofeni loxycarbon i loxy methyl) thiazole 5- (hydroxymethyl) thiazole distilled (14.1 g, 123 mmol) and triethylamine (17.9 ml, 129 mmol) were dissolved in ethyl acetate (141 ml) and it was cooled to -1 ° C (ice / salt bath). A solution of 4-nitrophenyl chloroformate (26.0 g, 129 mmol) dissolved in ethyl acetate (106 ml) was added dropwise over 50 minutes at an internal temperature of 0-4 ° C. An ethyl acetate rinse (20 ml) in flask was also added. The salts were precipitated from the solution during the addition. The yellow mixture was stirred another hour with 45 minutes at 0-2 ° C., then a dilute HCl solution (3.1 g, 31 mmol concentrated HCl, in 103 ml of water) was added at once. The mixture was stirred for 0.5 hour while it was heated to 15 ° C, then the stirring was stopped. The organic layer was washed twice with 5% aqueous K2CO3 solution (2 x 70 ml), then dried with Na2SO (30 g). After the filtered solution was concentrated under vacuum on a rotary evaporator (bath temperature of 41 ° C) to a brown oil (38 g). The crude 5- (para-nitrophenyloxycarbonyloxymethyl) thiazole was dissolved in ethyl acetate (282 ml), then cooled in an ice bath at 2 ° C. HCl gas was slowly bubbled (7.1 g, 195 mmol) for 50 minutes (temperature 2-4 ° C). After stirring for another hour with 45 minutes at 2-4 ° C, the solid precipitate was collected in a glass funnel formed under a blanket of nitrogen and the flask was washed with 50 ml of cold ethyl acetate, which was used to rinse the filter cake. The cake was dried in a funnel under strong nitrogen purge for 15 minutes then dried in a vacuum oven at 50 ° C with a nitrogen purge to provide 29.05 g of the title compound as a tan powder, m.p. 131 -135 ° C (dec). 1 H-NMR (DMSO-dβ) d 9.21 (d, 1 H), 8.27 (m, 2 H), 8.06 (d, 1 H), 7.52 (m, 2 H), 5.54 (s, 2 H). 13 C NMR (DMSO-d6) d 157.3, 155.2, 151.2, 151.8, 145.3, 143.7, 131.9, 125.5, 122.7, 62.1. Example 26F 5- (Para-nitrophenoxycarbonyloxymethyl) thiazole 5- (Para-nitrophenoxycarbonyloxymethyl) thiazole hydrochloride (3.0 g) in ethyl acetate (30 ml) was added and cooled to 10-15 ° C. A solution of 5% aqueous potassium carbonate (30 ml) was added with rapid stirring. After 15 minutes, the stirring was stopped and the aqueous layer was separated. The organic layer was dried with Na2SO4 (3 g), filtered, and the solvent was distilled under vacuum to give 2.49 g of the title compound as a brown syrup which slowly solidified, m.p. 62-64 ° C. 1 H NMR (CDCl 3) d 8.90 (d, 1 H), 8.29 (m, 2 H), 8.01 (d, 1 H), 7.39 (m, 2 H), 5.52 (s, 2 H). 13 C NMR (CDCl 3) d 155.4, 155.2, 152.2, 145.4, 144.9, 130.6, 125.3, 121.6, 61.9. EXAMPLE 27 Alternative Preparation of N - ((N-methyl-N - ((2-isopropyl-4-thiazole I) methyl) amino) carbonyl) -L-valine Example 27A Thioisobutyramide To a 1-liter, three-necked round flask , equipped with mechanical stirrer, nitrogen atmosphere, condenser, thermocouple and water bath at 15 ° C, was charged isobutyramide (26.0 g, 0.298 mol) followed by phosphate pentasulfide (19.9 g, 0.045 mol) and 375 ml of THF. This solution was stirred at 20 + 5 ° C for 3 hours, then heated to 60 ° C and stirred an additional 3 hours. The THF was removed under vacuum with a bath temperature at 50 ° C to give a yellow oil. This oil was neutralized with a solution of 5 g of NaOH, 10 g of NaCl and 90 g of water. The product was then extracted into EtOAc (2x250 ml) and the combined organics were reduced under vacuum to an oil. The oil was dissolved in 50 ml of THF and again the solvent was removed under vacuum to give the desired product as a yellow oil, (yield 27 grams 88%). Example 27 B 2-isoporopyl-4 - (((N-methyl) amino) methyl) thiazole The thioisobutyramide resulting from Example 24A was dissolved in 70 ml of THF and added slowly to a solution of 1,3-dichloroacetone (34.1 g, 27 moles) in 40 ml of THF. A rinse of 10 ml of THF was used to completely transfer the thioamide. The reaction was carried out in a 250 ml flask with mechanical stirring under a nitrogen atmosphere. The reaction temperature was maintained below 25 ° C during the addition with a bath of 15 + 5 ° C. The bath was held in place for 1 hour, after which it was removed and the reaction was stirred for 18 hours. Then this stirred solution of chloromethyl thiazole was added to 376 ml (4.37 mol) of 40% aqueous methylamine solution at 15 ° C in a 1 liter flask. The temperature was kept below 25 ° C during the addition. After half an hour, the The bath was removed and the reaction was stirred for 3 hours at room temperature. The solvent was removed under vacuum with a bath of 50 ° C to a final volume of 310 ml. The residue was then basified with 50g of 10% NaOH to pH 12 and extracted into methylene chloride (2x160 ml). The combined organics were then washed with 1x150 g of 20% ammonium chloride followed by 1x90 g of 20% ammonium chloride. The combined aqueous washings were back-extracted with 150 ml of methylene chloride. The methylene chloride layers of the combined product, were then extracted with 100 g of a solution of 25 g of concentrated HCl and 75 g of water. The solution of the acid product was then washed with 135 ml of methylene chloride. After the acid product solution was cooled, it was neutralized with 100 g of 20% NaOH solution. The product was extracted from this mixture with methylene chloride (2 x 135 ml). The solvent was removed under vacuum to give the desired product as an amber oil (yield about 28 grams). EXAMPLE 27C N - ((N-Methyl-N ((2-isopropyl-4-thiazolyl) methyl) amino) carbonyl) -L-valine Methyl ester In a 500 ml 3-necked round bottom flask, equipped with mechanical stirrer, nitrogen atmosphere, thermocouple, heating mantle and condenser, the product of Example 27B (28. 1 g, 165 mol), phenoxycarbonyl- (L) -valin (41.5 g, 165 mol) was charged and 155 ml of toluene. This solution was heated to reflux (1110 ° C) and stirred for three hours, then cooled to 20 + 5 ° C and washed with 2x69 ml of 10% citric acid for 1 x 69 ml of water, 1 z 1 16 ml of 4% sodium hydroxide, 1 x58 ml of 4% sodium hydroxide and finally 1 x 58 ml of water. The organic product solution was then treated with 3 grams of activated charcoal at reflux for 15 minutes, filtered through infusorium soil to remove char, and the charcoal / infusorial cake was washed with 25 ml of hot toluene. the solvent was removed to give a brown oil which solidified upon cooling. This coffee solid was dissolved with heating in 31 ml of EtOAc and 257 ml of heptane at 60 + 5 ° C. This solution was slowly cooled to 25 ° C, stirred 12 hours, further cooled to 0 ° C, and stirred 3 hours. The crystals were collected by filtration and washed with 50 ml EtOAc / heptane at 1: 9. The solid was dried in a vacuum oven at 50 ° C for 12 hours to give 41.5 grams of the desired product as a tan solid (76.9%). Example 27D N - ((N-methyl-N - ((2-isopropyl-4-thiazolyl) methyl) amino) carbonyl) -L-valine To a 1-liter three neck flask, the product of Example 27C was charged. (60 g, 0. 153 mole), lithium hydroxide monohydrate (1.3 g, 0.31 mole), 200 ml of TH F and 190 ml of water. This cloudy solution was stirred for 2 hours. The reaction was quenched with a concentrated HCl solution (32.4 g, 0.329 mol) in 65 mL of water, TH F was removed under vacuum and the product was extracted into methylene chloride (3x210 mL). (NOTE: If necessary, the pH of the aqueous layer should be adjusted to maintain pH 1-4 during extractions). The combined organics were then dried with 50 grams of sodium sulfate, filtered with a rinse of 150 ml of methylene chloride, of sodium sulfate, and the solvent was removed under vacuum. The product was dissolved in 450 ml of THF and again the solvent was removed. The product was then dissolved in 475 ml of TH F containing 0.12 g of butylated hydroxytoluene (BHT) for storage. If desired, the solvent can be removed under vacuum and the residual syrup dried in a vacuum oven at 55 ° C to provide a crystalline solid. The above process for the preparation of compound I I I was described in PCT Patent Application No. WO94 / 14436, published July 7, 1994, which is incorporated herein by reference. Protocol for Oral Bioavailability Studies Protocol A (solid dose forms) Dogs were fasted ("Beagle" dogs, mixed sexes, weighing 7-14 kg), overnight before dosing, but were allowed to water to free will. Each dog received a subcutaneous dose of 0.5 mg / kg histamine, approximately 30 minutes before dosing. Each dog received a single form of two solid s corresponding to 5 mg / kg dose of the drug. The dose was followed by approximately 10 milliliters of water. Blood samples were obtained from each animal before dosing at 0.25, 0.5, 1.0, 1.5, 2, 3, 4, 6, 8, 10 and 12 hours after the administration of the drug. The plasma was separated from the red blood cells by centrifugation and was frozen (-30 ° C) until analysis. The concentrations of the parent drug were determined by reverse phase HPLC with low wavelength UV detection following the liquid-liquid extraction of the plasma samples. The area of the parent drug under the curve was calculated by the trapezoidal method during the course of the study time. The absolute bioavailability of each test composition was calculated by comparing the area under the curve - after oral dosing to that obtained from a single intravenous dose. Each capsule or capsule composition was evaluated in a group containing six dogs; the values reported are averages for each group of dogs. The average bioavailability data for the compositions of the Examples is shown in Table 1. Protocol B (liquid dosage forms) Dogs ("Beagle" dogs, of mixed sex, weighing 7-14 kg) were fasted before dosing, but were allowed free water. Each dog received a subcutaneous dose of 0.5 mg / kg of histamine, approximately 30 minutes before dosing. A dose of 5 mg / kg, measured in a disposable syringe, was placed in the back of each animal's throat. The dose was followed by approximately 10 milliliters of water. Blood samples were obtained from each animal before dosing at 0.25, 0.5, 1.0, 1.5, 2, 3, 4, 6, 8, 10 and 12 hours after drug administration. The plasma was separated from the red blood cells by centrifugation and frozen (-30 ° C) until analysis. The concentrations of the parent drug were determined by reverse phase HPLC with low wavelength UV detection following the liquid-liquid extraction of the plasma samples. The area of the parent drug under the curve was calculated by the trapezoidal method during the course of the study time. The absolute bioavailability of each test composition was calculated by comparing the area under the curve after oral dosing to that obtained from a single intravenous dose. Each liquid composition was evaluated in a group containing six dogs; the values reported are averages for each group of dogs. The average bioavailability data for the compositions of the Examples is shown in Table 1. Protocol C (liquid dose form, followed by milk) The animals were selected and pretreated with histamine as described in Protocol B above. The liquid dose form (dose of 5 mg / kg), measured in a plastic syringe, was poured into the back of each animal's throat. An aliquot of 10 ml of milk was also administered in the back of each dog's throat. The liquid / milk dosage form combination was passed with an additional 1% water as described in Protocol B above. The sample times, sample preparation and data analysis were as described in Protocol B. Protocol D (liquid dose form with milk) Animals were selected and pretreated with histamine as described in Protocol B above. The liquid dosage form (dose of 5 mg / kg) was diluted ten times with milk. The diluted dose was measured in a plastic syringe and poured into the back of each animal's throat. The liquid dose form was passed with an additional aliquot of water as described in Protocol B above. The sample times, sample preparation and data analysis were as described in Protocol B. TABLE 1 Medium Example No. Bioavailability Protocol Example 1 0.0 A Example 2 0.0 A Example 3 2.5 A Example 4 37.4 B Example 5 56.7 D Example 6 72.7 B Example 7 42.1 C Example 8 62.0 D Example 9 53.7 D Example 10 78.9 C Example 1 1 100.0 C Example 12 58.3 B Example 13 89.7 C Example 14 65.1 C Example 16 87.2 C Example 17 78.2 C Example 18 66.4 C Example 19 100.0 C These data indicate that the formulations of the solution gave significantly better bioavailability than the non-formulated compound III. Compounds I, II and III are protease inhibitors of HIV-1 and VI H-2. They are useful for inhibiting HIV infection and treating AIDS in humans. The total daily dose of compound I, II or ll administered to a human being in single or divided doses may be in amounts of, for example, 0.001 to 1000 mg / kg of body weight daily but more usually 0.1 to 50 mg / kg of body weight per day. Dosage unit compositions may contain said amounts of submultiples thereof to form the daily dose. However, it will be understood that the specific dose level for a particular patient will depend on a variety of factors including age, body weight, general health, sex, diet, time of administration, excretion regimen, drugs administered in combination, and the severity of the particular disease that is undergoing therapy. The foregoing is merely illustrative of the invention and is not intended to limit the invention to the compounds, methods and compositions described. It is intended that variations and changes that are obvious to one skilled in the art are within the scope and nature of the invention, which are defined in the appended claims.

Claims

CLAIMS 1. A pharmaceutical composition comprising a solution of an HIV protease inhibitor compound in a pharmaceutically acceptable organic solvent comprising a mixture of (1) (a) a solvent selected from propylene glycol and polyethylene glycol or (b) a solvent selected from tri-ricinoieate of polyoxyethylene glycerol, hydrogenated polyethylene glycol castor oil 40, fractionated coconut oil, polyoxyethylene sorbitan mono-oleate (20) and 2- (2-ethoxyethoxy) ethanol or (as a mixture thereof and (2) ethanol or propylene glycol 2. The composition of claim 1, comprising a solution of an HIV protease inhibitor compound, in a pharmaceutically acceptable organic solvent comprising a mixture of (1) propylene glycol or polyoxyethylene glycerol tri-ricinoleate or a mixture thereof and (2) ethanol 3. The composition of claim 1, further comprising a pharmaceutically acceptable acid. 4. The composition of claim 1, further comprising water. The composition of claim 1, further comprising one or more additives independently selected from pharmaceutically acceptable organic solvents, pharmaceutically acceptable oils, pharmaceutically acceptable sweetening agents, pharmaceutically acceptable flavoring agents, pharmaceutically acceptable surface active agents, and antioxidants. 6. A pharmaceutical composition comprising a solution of a compound of the formula: in a pharmaceutically acceptable organic solvent comprising a mixture of (1) (a) a solvent selected from propylene glycol and polyethylene glycol or (b) a solvent selected from polyoxyethylene glycerol tri-ricinoleate, polyethylene glycol 40 hydrogenated castor oil, fractionated coconut oil, polyoxyethylene sorbitan mono-oleate (20) and 2- (2-ethoxyethoxy) ethanol or (c) a mixture thereof and (2) ethanol or propylene glycol. The composition of claim 6, comprising a solution of a compound of the formula: in a pharmaceutically acceptable organic solvent comprising a mixture of propylene glycol (1) or polyoxyethylene glycerol tri-ricinoleate or a mixture thereof and (2) ethanol. The composition of claim 6, further comprising a pharmaceutically acceptable acid or a mixture of pharmaceutically acceptable acids. 9. The composition of claim 6, further comprising water. The composition of claim 6, further comprising one or more additives independently selected from pharmaceutically acceptable organic solvents, pharmaceutically acceptable oils, pharmaceutically acceptable sweetening agents, pharmaceutically acceptable flavoring agents, pharmaceutically acceptable surface active agents and antioxidants. The composition of claim 6, comprising a solution of about 1% to about 15% by weight of the total solution of a compound of the formula: in a pharmaceutically acceptable organic solvent comprising a mixture of (1) propylene glycol in the amount of about 10% to about 50% by weight of the total solution of glycerol polyoxyethylene tri-ricinoleate in the amount of about 5% to about 35% by weight of the total solution or a mixture thereof and (2) ethanol in the amount of about 5% to about 45% by weight of the total solution. The composition of claim 1, further comprising a pharmaceutically acceptable acid in the amount of about 0.2% to about 16% by weight of the total solution. The composition of claim 1, comprising a solution of about 1% to about 15% by weight of the total solution of (2S, 3S, 5S) -5- (N- (N - ((N-methyl- N - ((2-isopropyl-4-thiazolyl) methyl) -amino) carbonyl) valinyl) amino) -2- (N - ((5-thiazolyl) methoxycarbonyl) amino) - 1, 6-difenin l-3-hydroxyhexane in a pharmaceutically acceptable organic solvent comprising a mixture of (1) propylene glycol in the amount of about 10% to about 50% by weight of the total solution or glycerol polyoxyethylene glycerol in the amount of about 5% to about 35% by weight of the total solution or a mixture thereof and (2) ethanol in the amount of about 5% to about 45% by weight of the total solution. 14. The composition of claim 13, further comprising a pharmaceutically acceptable acid in the amount of about 0.2% to about 16% by weight of the total solution. 15. The composition of claim 14, wherein the pharmaceutically acceptable acid is citric acid. 16. The composition of claim 6, comprising a solution of about 5% by weight of the total solution of (2S, 3S, 5S) -5- (N - ((N-methyl-N - ((2-isopropyl) -4-thiazolyl) methyl) -amino) -carbonyl) valinyl) amino) -2- (N - ((5-thiazolyl) methoxycarbonyl) amino) -1,6-diphenyl-3-hydroxyhexane and approximately 4% by weight of the total solution of citric acid in a pharmaceutically acceptable organic solvent comprising a mixture of (1) propylene glycol in the amount of about 42% by weight of the total solution, (2) ethanol in the amount of about 32% by weight of the total solution and (3) water in the amount of about 17% by weight of the total solution. The composition of claim 6, comprising a solution of about (12% by weight of the total solution of (2S, 3S, 5S) -5 - ((N- (N - ((N-methyl-N- ( (2-isopropyl-4-thiazolyl) methyl) -amino) carbonyl) valinyl) amino) -2- (N - ((5-thiazolyl) methoxycarbonyl) amino) -1,6-diphenyl-3-hydroxyhexane and about 3 % to about 4% by weight of the total citric acid solution in a pharmaceutically acceptable organic solvent comprising a mixture of (1) propylene glycol in the amount of about 32% by weight of the total solution, (2) ethanol in the amount about 37% by weight of the total solution and (3) water in the amount of about 15% by weight of the total solution 18. The composition of claim 6, comprising a solution of about 5% by weight of the total solution of (2S, 3S.5S) -5- (N- (N - ((N-methyl-N - ((2-isopropyl-4-thiazolyl) methyl) amino) -carbonyl) valinyl) amino) -2 - (N - ((5-thiazolyl) methoxycarbonyl) amino) -1,6-dif nyl-3-hydroxyhexane and from about 5% to about t6% by weight of the total citric acid solution in a pharmaceutically acceptable organic solvent comprising a mixture of (1) propylene glycol in the amount of about 44% to about 45% by weight of the total solution, (2) ethanol in the amount of about 24% by weight of the total solution and (3) polyoxyethylene glycerol tri-ricinoleate in the amount of about 20% by weight of the total solution. The composition of claim 6, comprising a solution of about 10% by weight of the total solution of (2S, 3S, 5S) -5- (N- (N - ((N-methyl-N- ((2 isopropyl-4-triazolyl) methyl) amino) -carbonyl) valinyl) amino) -2- (N - ((5-triazolyl) methoxycarbonyl) amino) -1,6-diphenyl-3-hydroxyhexane and of about 5 % to about 6% by weight of the total citric acid solution in a pharmaceutically acceptable organic solvent comprising a mixture of (1) licol propylene glycol in the range of about 39% to about 40% by weight of the total solution , (2) ethanol in the amount of about 24% by weight of the total solution and (3) polyoxyethylene glycerol tri-ricinoleate in the amount of about 20% by weight of the total solution. The composition of claim 6, comprising a solution of about 2% to about 3% by weight of the total solution of (2S, 3S, 5S) -5- (N- (N - ((N-methyl-N) - ((2-isopropyl-4-thiazolyl) methyl) amino) carbonyl) valinyl) amino) -2- (N - ((5-thiazolyl) methoxy-carbonyl) amino) -1,6-diphenyl-3-hydroxyhexane and about 4% by weight of the total citric acid solution in a pharmaceutically acceptable organic solvent comprising a mixture of (1) propylene glycol in the amount of about 43% by weight of the total solution, (2) ethanol in the amount of about 33% by weight of the total solution and (3) water in the amount of approximately 17% by weight of the total solution. twenty-one . The composition of claim 6, comprising a solution of about 5% by weight of the total solution of (2S, 3S, 5S) -5- (N - ((N-methyl-N - ((2-isopropyl-4-thiazolyl) methyl) amino) carbonyl) valino) amino) -2- (N - ((5-thiazolyl) methoxycarbonyl) amino) -1,6-diphenyl-3-hydroxyhexane and from about 0.3 to about 0.4% by weight of the total solution of citric acid in a pharmaceutically acceptable organic solvent comprising a mixture of (1) propylene glycol in the amount of about 36% by weight of the total solution, (2) ethanol in the amount of about 36% by weight of the total solution and ( 3) water in the amount of about 19% by weight of the total solution. 22. The composition of claim 6, comprising a solution of about 8% by weight of the total solution of (2S, 3S, 5S) -5- (N- (N - ((N-methyl-N - ((2-isopropyl-4-thiazolyl) methyl) amino) -carbonyl) valinyl) amino) -2- (N - ((5-thiazolyl) methoxycarbonyl) amino) -1,6-diphenyl-3-hydroxyhexane and from about 0.3 to about 0.4% by weight of the total citric acid solution in a pharmaceutically acceptable organic solvent comprising a mixture of ( 1) propylene glycol in the amount of about 35% by weight of the total solution, (2) ethanol in the amount of about 35% by weight of the total solution, and (3) water in the amount of about 18% by weight of the total solution. The composition of claim 6, comprising a solution of about 7% to about 8% by weight of the total solution of (2S, 3S, 5S) -5- (n- (N - ((N-methyl-N) - ((2-isopropyl-4-thiazolyl) methyl) amino) carbonyl) valinyl) amino) -2- (N - ((5-thiazolyl) methoxycarbonyl) amino) -1,6-diphenyl-3-diphenyl-3- hydroxyhexane and about 0.5% by weight of the total citric acid solution in a pharmaceutically acceptable organic solvent comprising a mixture of (1) propylene glycol in the amount of about 45% to about 46% by weight of the total solution (2) ethanol in the amount of about 21% by weight of the total solution and (3) polyoxyethylene glycerol tri-ricinoleate in the amount of about 24% to about 25% by weight of the total solution. 24. A pharmaceutical composition comprising a solution of about 7% to about 8% by weight of the total solution of (2S, 3S, 5S) -5- (N- (N - ((N-methyl-N- ((2 isopropyl-4-thiazolyl) methyl) -amino) carbonyl) valinyl) amino) -2- (N - ((5-thiazolyl) methoxy-carbonyl) amino) -1,6-diphenyl-3-hydroxyhexane and about 0.2 % to about 0.3% by weight of the total citric acid solution in a pharmaceutically acceptable organic solvent comprising a mixture of (1) propylene glycol in the amount of about 31% to about 32% by weight of the total solution, (2) ethanol in the amount of about 32% by weight of the total solution, (3) polyoxyethylene glycerol tri-ricinoleate in the amount of about 10% to about 11% by weight of the total solution and (4) water in the amount of about 14% to about 15% by weight of the total solution.