OA10054A - Peptide compound its preparation pharmaceutical composition containing it and its application in medicine for the treatment of retrovirus infections - Google Patents

Description

0054 1

The present invention relates to certain heterocyclic group-containingpeptide derivatives, which are useful for the curative or preventive treatment of retrovirus infections in humans.

The human immunodeficiency virus (HIV), which is a retrovirus, is the causative agent of a variety of clinical conditions, the most serious of which are commonly referred to as AIDS (Acquired Immunodeficiency Syndrome) and CRS (Complex in relation to AIDS). HIV infection is characterized by progressive degradation of the immune system and dysfunction of the central nervous system. Patients with severe immunodeficiencies are suffering from a wide range of opportunistic infections (eg Pneumocystis carinii, cytomegalovirushumain or Candida) and cancers such as Kaposi's sarcoma. The loss of cells, particularly CD4 + lymphocytes, as a result of HIV infection is a major factor in the progressive impairment of immune function. Infection of cells of the monocyte / macrophage lineage with HIV also contributes to the observed pathology. Thus, the success of HIV VCD4 + cell infection is a key step in the evolution of the disease.

The HIV virus is a retrovirus; it encodes its genetic information in RNA that is converted to DNA after virus penetration into the host cell. An essential step in the retrovirus replication cycle is the transformation of an initial polypeptide precursor into mature structure and replication proteins. This transformation is accomplished by a protease encoded by levirus and, in the absence of this enzyme activity, viral replication is inhibited.

The Applicant has just demonstrated the fact that certain peptide derivatives attached to a heterocyclic group were potent inhibitors oftraviral proteases, both in a cell-free assay and in infected cells and, in addition, that they displayed antiviral activity in assays. of tissue cultures. This activity makes these compounds useful for the treatment and prophylaxis of retroviral infections, particularly those caused by HIV.

The present invention therefore provides compounds corresponding to the formula

and their pharmaceutically acceptable salts as well as their prodrugs, wherein R 1 is C 8 -C 8 alkyl, C 3 -C 8 cycloalkyl, aryl, heterocyclyl or CONR 1 R 10; R2 is (C1-C8) alkyl, (C1-C8) cycloalkyl (C1-C4) alkyl, aryl (C1-C4) alkyl or heterocyclyl (C1-C4) alkyl; R3 is (C1-C8) alkyl, (C1-C8) cycloalkyl, (C1-C8) cycloalkyl (C1-C4) alkyl, aryl (C1-C4) alkyl, aryl (C1-C4) alkenyl; ), hetero-cyclyl- (Cg-C alkyle) alkyl or heterocyclyl- (C₂-C alc) alkenyl R R is C groupe-Cg alkyl, cycloalkyl, Cg-Cg, aryl or heterocyclyl, each of R groupes, R6, R7 and R8 are, independently, H, C8-C8 alkyl or C8-C8 cycloalkyl, or R5 and R6, or R7 and R8, may associate to form a ring; carbocyclic ring of 3 to 8 members; X is a 4- to 10-membered cyclic or cyclic heterocyclic ring containing cyclic carbon atoms and a ring nitrogen atom through which the group is attached to the adjacent carbonyl group, the group may be saturated or partially unsaturated, and in addition to the substituent - (CR7R8) m - Het, it may carry up to four further substituents independently selected from F, C 1 -C 5 alkyl, C 3 -C 8 cycloalkyl, OR 11 and NR 9 R 10.

Het is an imidazolyl or triazolyl group, each of which may be optionally substituted with C8-C8cycloalkyl, NR9R10 orCONR9R10, each of R9 and R4 independently represents H, C1-C6 alkyl or C3-C8 cycloalkyl or R9 and R10 may combine to form, together with the nitrogen atom to which they are attached, a 4- to 8-membered nitrogen-containing heterocyclic group, R11 represents H, a C1-C8 alkyl group; at C8 or C3 to C8 cycloalkyl; and n and m each independently are 0, 1 or 2; any alkyl or cycloalkyl group included in the above-mentioned definitions may, optionally, be wholly or partially substituted by fluorine.

In the definition given above for R 1, F 2, R 3 and R 4, the term "heterocyclyl" refers to a 4- to 6-membered hetero-cyclic group containing as hetero-atones up to 4 nitrogen atoms or 1 oxygen atom or suffering with, optionally, 1 or 2 nitrogen atoms. The core may be aromatic, or it may be fully or partially saturated or may optionally be condensed with benzene or substituted with C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 2 -C 5 alkanoyl, C 4 -C 4 alkoxy , halo, hydroxy, oxo or aryl. Heterocyclyl substituted groups are pyridyl, pyrimidinyl, thienyl, isoquinolyl and tetrazolyl.

In the definitions given above for F.1, R2, R3 and R4, the term "aryl" refers to a phenyl group optionally having 1 to 3 substituents independently selected from C1 to C6 alkyl, C3 cycloalkyl substituents. C1 to C4 alkoxy, C2 to C4 alkanoyl, hydroxy, halogen, C1 to C4 alkyl fully or partially fluorinated, C1 to C4 alkoxy fully or partially fluorinated, phenyl, phenoxy, benzyl, benzoyl, phenylSO2-, pyridyl , tetrazolyl, phenyl-tetrazolyl, NR9R10 or CONR9R10, wherein R9 and R · 1 · O have the definitions given above.The term "halo" refers to fluoro, chloro, bromo or iodo radicals.

The imidazolyl or triazolyl group Het may be unsaturated with a cyclic carbon atom or an azotecyclic atom and may be unsubstituted or mono- di-uteri-substituted. The. term "triazolyl" refers to 1,2,3- and 1,2,4-triazolyl groups.

Alkyl and alkoxy groups containing 3 or more carbon atoms may be branched or straight chained. Any alkyl, alkoxy or cycloalkylenating group within the scope of the definitions given above may be optionally wholly or partly substituted with fluorine.

The term "bioprecursor" as used in the definition given above denotes a pharmaceutically acceptable biologicallydegradable derivative of the compound of formula (I) which, when administered to a person or to a human being, is converted into the body by producing a compound of formula (I). Examples include ester type derivatives formed between the free hydroxy group in the compound of formula (I) and, for example, an amino acid (such as L-valine).

It should be noted that the compounds of formula (I) have a certain number of asymmetric carbon atoms, and the invention covers all possible stereoisomers, whether they are separated or not,

According to a particular and preferred aspect of the invention, it is proposed compounds having lastéréochimie: 1 0054 R1- (CR5R6) nx 5 Ο Λ

X- (CR7R8) m-Het (la)

In the above formula, high-bound bonds are used to indicate that the group is above the plane of the molecule while an interrupted intricate link is used to indicate that the group is below.

In the definition of R 1, the aryl group is advantageously a phenyl group and the heterocyclyl group is preferably an oxetan-3-yl or 1,1-dioxo-thietan-3-yl group. R1 is advantageously tert-butyl, isopropyl, oxetan-3-yl or 1,1-dioxothietan-3-yl and (CR5R1) n is absent; or R 1 is phenyl and (CR 5 R 6) n is CH 2; or R1 is H2NCO-, CH3NHCO- or (CH3) 2NCO- and (CR5R6) n is CH2 or CH (CH3). Compounds in which R 1 is tert-butyl, isopropyl or oxetan-3-yl and n is 0, especially those in which R 1 (CR 5 R 6) n- is tert-butyl, are particularly preferred.

In the definition of R2, the aryl group is advantageously a phenyl group and the heterocyclyl group is for example a pyridyl, pyrimidinyl or thienyl group.

O R is preferably an aryl (C 1 -C 4) alkyl group, the benzyl group is particularly preferred.

In the definition of R4, the aryl group is advantageously a phenyl group and the heterocyclyl group is advantageously a pyridyl, pyrimidinyl outhenyl group. R4 is preferably a C1-C6 alkyl group; the isopropyl group and the sec-butyl group (valine or isoleucine derivatives) are particularly preferred. 10054 6

The heterocyclic group X is advantageously 4 to 6-membered saturated or non-unsaturated virigroup and is most preferably an azetidine, pyrrolidine, tetrahydropyridine or piperidine group; a piperidine group is particularly preferred. R 'and R8 are preferably H, and preferably m is 0 or 1.

In the definition of R3, aryl is phenyl, unsubstituted or substituted as defined for the above aryl, and heterocyclyl is, for example, pyridyl, pyrimidinyl, isoquinolyl or thienyl. R ~ is advantageously an aryl-C 1 -C 4 alkyl or C 1 -C 4 alkenyl group; R3 is most preferably a benzyl group optionally substituted in the phenyl with a fluoro, chloro, iodo, methyl, trifluoromethyl or trifluoromethoxy radical, or R3 is a 3-phenyl-prop-2-enyl or 3-phenylpropyl group.

Particular and particular individual compounds include the following: 1- [N - ((R) -2-Benzyl- (S) -5- (tert-butoxycarbonylamino) - (5) -4-hydroxy-6- phenylhexanoyl) - (S) -valyl] -3- (imidazol-1-yl) azetidine, 1- [N - ((R) -2-benzyl- (S) -5- (tert-butoxycarbonyl-amino); - (S) -4-Hydroxy-6-phenylhexanoyl) - (S) -valyl] -4- (imidazol-1-yl) piperidine, 1- [N- ((S) -5- (tert-butoxycarbonylamino) ) - (S) -4-hydroxy-6-phenyl- (R) -2- (3-phenylprop-2-en-1-yl) hexanoyl) - (S) -valyl] -4- (imidazole); 1-yl) piperidine, 1- [N - ((S) -5- (tert-butoxycarbonylamino) - (S) -4-hydroxy-6-phenyl- (R) -2- (4-trifluoromethoxybenzyl) hexanoyl) - (S) -valyl] -4- (imidazol-1-yl) piperidine, 1- [N - ((S) -5- (tert-butoxycarbonylamino) - (R) -2- (4-chlorobenzyl) - ( S) -4-hydroxy-6-phenylhexanoyl) - (S) -valyl] -3- (imidazol-1-yl) azetidine and 1- [N - ((S) -5- (tert-butoxycarbonylamino) - (S) 4-hydroxy-6-phenyl - (R) -2- (4-trifluoromethoxybenzyl) hexanoyl) - (S) -isoleucyl-4- (imidazol-1-yl) piperidine.

In a second aspect of the present invention, there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof or a compound thereof, for use as a medicament, particularly in the treatment of curative or preventative of human retroviral infections, especially HIV infections. The invention also comprises the use of a compound of formula (I), or a pharmaceutically acceptable salt or a prodrug thereof, for the preparation of a medicament for use in preventive treatment or curative of retrovirus infections. The invention furthermore relates to a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable unsel or bioprecursor thereof, and a pharmaceutically acceptable diluent or carrier.

The antiviral activity of the compounds of the general formula (I) is established using in vitro assays. For example, the compounds of formula (I) are capable of completely deprotecting the H9 cell line of human T cells for 7 days against the progressive effects of HIV infection. Unprocessed cells infected with the virus have typical cytopathic effects such as syncytium formation and cell death. In addition, virus particles produced from virally infected cells treated with a compound of formula (I) are noninfectious.

Examples of infections for which the compounds of Formula (I) enable curative or preventive treatment include infections that are caused by human or animal retroviruses, including HIV-1. Clinical conditions that can be treated or prevented include AIDS, CRS and dementia in relation to HIV. The compounds can also be used to stop the progression of the disease in infected individuals with no symptoms.

Compounds of formula (I) may be prepared by use of coupling and protection techniques which are familiar to those skilled in the art of peptide chemistry.

The process is illustrated by way of example by the diagrams shown below for the decomposed preparation of formula (Ia):

The procedure illustrated in the diagram A of a protected lactone (II). This lactone is alkylated, for example by the use of n-butyllithium or lithium-hexamethyldisilazide, followed by the addition of a compound of formula R3Br and the separation of the desired isomer, which is the product (III). The core of the lactone is then opened by treatment with a dilute alkali to give the corresponding hydroxyl-acid, and the hydroxy group is subsequently protected, for example, as the tert-butyldimethylsilyl derivative, by reaction with tert-butyldimethylsilyl chloride. in Ν, Ν-dimethylformamide, followed by hydrolysis of the protected ester to form the intermediate compound (IV).

Coupling of this intermediate with the other moiety (VIII) to produce the compounds of formula (Ia) is illustrated in Scheme B. In this process, the protecting group carried by the intermediate compound (V) is removed ( in the case of the tert-butoxycarbonyl group, by treatment with HCl) and the resulting compound. (VI) is reacted with 1-amino acid Boc-NHCH (R4) CCn.Protected on nitrogen, using an amide as a coupling reagent to give the intermediate compound (VII). The nitrogen protecting group is then removed from (VII) and the amine product (VIII) is coupled to the intermediate product (IV) to give the intermediate compound (IX). Group X protecting the hydroxy function is then removed from (IX) endonating the final product of formula (Ia). Alternatively, the intermediate compound (IX) can be produced by coupling the intermediate compound (X) with the intermediate compound (VI). The intermediate compound (X) can be prepared from the intermediate compound (IV) by reaction with an amino -H 2 NCH (R 4) CO 2 -R, protected carboxyl group, followed by basic hydrolysis. 10

SCHEME A

(H) 1 0054

1. IJIIMDS 2. R3-Br

R ^ -O ^ CRSR

X1 protecting group: tert-butyldimethylsilyl is preferred. the preference is given to 2-tert-butyl or benzyl group 5

BRIEF DESCRIPTION OF THE DRAWING FIGS. BRIEF DESCRIPTION OF THE DRAWING FIGS. BRIEF DESCRIPTION OF THE DRAWING FIGS. 1B-1C-10- (CR, Kf ') n-1; and (V) I Elimination [Protecting Group II-X- (CRTR *) m-1Cl (VI)

Boc-NllCH (ir> C () 2H Coupling friendly reagent Ο Π <, B ^ o ^ NH \ rx '(Cp7RVHet (VII) «

"I1-X- (CR7R") - IIcI (VI) amidic reagent decoupling on

ο η2 o n4nqcnw) n.oAN, OH

1. Amide, amidic reactive 2. Base (IV) Amide coupling reagent: for example 1- (3-dimethyl-apropyl) -3-ethylcarbodiimide, m.p.

Protective groups: P; tert-butoxycarbonyl or benzyloxycarbonyl X 'are preferred; tert-butyldimethylsilyl group is preferred; preference is given to the methyl or ethyl group

In another alternative embodiment illustrated in Scheme C, removal of the tert-butoxycarbonyl group from the intermediate compound (XI) by treatment with an acid, for example trifluoroacetic acid, followed by the reaction with a carbonate derivative. of formula (XII), gives products of formula (XIII) in which the group R! (O 5 R 6) is other than a tertiary butyl group. For example, reaction of the products of formula (XI) with 3-oxetanyloxycarbonyloxy succinimide gives products (XIII) wherein R 1 is a 3-oxetanyl group and n is 0.

SCHEME C

X- (CR7R8) m -Het R1- (CR5R6) n

## STR2 ## represents H or a protecting group, for example tert-butyldimethylsilyl Y is a group which is susceptible to nucleophilic displacement - preference is given to the succinimidoxy group.

The starting materials of formula (V) required for the procedure described above are in some cases compounds of the literature, or they may be prepared by conventional methods of synthesis from readily available materials. Thus, for example, reaction of 1- (N-tert-butoxycarbonyl) -3-hydroxyazetidine with methanesulfonyl chloride, followed by reaction with a compound of formula Het-H in the presence of a base, gives the desired compounds of Formula (V) wherein X is azetidine ring. Alternatively, for example, 1- (N-benzyloxycarbonyl) -4-ketopiperidine is converted to the 4-aminopar derivative reaction with sodium cyanoborohydride in the presence of ammonium acetate. The subsequent reaction with azine of dimethylformamide gives the derivative bearing the 4- (1,2,4-triazol-4-yl) group.

The reaction of 1- (N-tert-butoxycarbonyl) -4-ketopiperidine with the anion obtained by reacting 1- (diethoxymethyl) imidazole with n-butyllithium and then introducing the product with methanesulfonyl chloride in the presence of As an intermediate, a base gives 4-imidazol-2-yl (1,2,5,6-tetrahydropyridine) protected on the nitrogen atom. Catalytic hydrogenation gives the protected 4- (imidazol-2-yl) -piperidine on the corresponding nitrogen. Reaction of the above ketone compound directly with a heterocyclic compound, for example imidazole, in the presence of thionyl chloride gives compounds of the formula (V) wherein X is tetrahydropyridine, the reduction giving back the piperidine derivative.

Intermediate compounds of formula (V) in Scheme B, wherein m is not 0, may be prepared by standard transformations from appropriate precursors using, for example, the epoxide group-based nucleophenolide to introduce the group Het . Thus, for example, the reaction of 1- (N-tert-butoxycarbonyl) -4-ketopiperidine with trimethylsulfonium iodide in the presence of a base gives 4-spiro-2'-oxirane. this product with imidazole followed by removal of the 4-hydroxy group gives 1- (N-tert-butoxycarbonyl) -4- (imidazol-1-yl) -methyl-1,2, 5,6-tetrahydrocyridine; the reduction gives the corresponding piperidine derivative.

The N-tert-butoxycarbonyl derivatives (BOC-) of the natural amino acids used in the synthesis of the compounds of formula (VII) are commercially available, as are their hydroxysuccinimido esters. The corresponding intermediate compounds derived from unnatural amino acids can be prepared by standard procedures (see, for example, M.J. O'Donnell et al., J. Amer Chem Soc., 1989, 111, 2353). The compounds of formula (II) can be prepared from the corresponding tert-butyloxycarbonyl-protected amino-aldehydes (see DH Rich et al., J. Orq.Chem 1978, 43, 3624 and Y. Hamada et al. Chem.

Pharm___Bull. 1982, 30 (5). 1921) by reaction with ethyl propiolate (see AH Fray et al., J.Org Chem., 1986, 51, 4828), followed by a reduction to give 5-tert-butyloxycarbonylamino-4-hydroxy- € i-ptényl hexanoate. Cyclization by reflux in toluene then gives the lactones of formula (II) in the form of mixtures of diastereoisomers which can be separated by conventional operations.

In the foregoing pathways and in the particular examples set forth herein, certain groups protecting the hydroxy and amino functions activating the carboxy function are required. It is obvious to those skilled in the art that the coupling and protection procedures described could be carried out by any conventional method for the synthesis of peptides, and these processes are therefore: within the scope of the invention, the choice of a protecting group In particular, the extent to which the reagent required depends on the solubility of the protected compound, the safacility of elimination and the presence of other groups which may be affected by its use. For example, it is necessary in the above process to protect and remove protective amino groups so as to allow subsequent reaction at the regenerated amino group, and selection of the protecting group for an amino group. given depends on the role of this amino group in the overall reaction scheme. Groups protecting the amino function having varying degrees of lability can be used. These groups are known in the art and draw attention to Bodansky and coworkers' comprehensive studies, "Peptide Synthesis," Second Edition, John Wiley &amp; Sounds, N.Y., (197 6); Greene, "Protective Groups in Organic Synthesis," John Wiley &amp; Sounds, N. Y. (1981); McOmie, "Protective Groups in Organic Chemistry", Plenum Press, N.Y. (1973); and Sheppard in "Comprehensive Organic Chemistry, The Synthesis and Reactions of Organic Compounds", PergamonPress, N.Y. (1979), edited by E. Haslam, Part 2 3.6, pages 321-339.

Representative examples of amino protecting groups include, but are not limited to, aryloxycarbonyl groups such as benzyloxycarbonyl; substituted or unsubstituted aralkyl groups such as benzyl, rrityl, benzhydryl and 4-nitrobenzyl; the benzine group Jenene? arylthio groups such as phenylthio, nitrophenylthio and trichlorophenylthio; phosphicrylic derivatives such as dimethylphosphoryl and 0.0-dibenzyl-phosphoryl derivatives; trialkylsilyl derivatives such as a trimethylsilyl derivative; as well as others, as described in US Pat. No. 4,322,341. The amino protecting group whose use is appreciated in the above sequence is tert-butoxycarbonyl. Procedures allowing the substitution of this group on a given amino group are well known. In general, they include the acylation of the appropriate amine compound with carbonyl chloride or the corresponding anhydride in a solvent inert to the reaction, for example, water, methylene chloride or 10054 tetrahydrofuran, in the presence of a base (acid acceptor), for example sodium or potassium hydroxide when water is the solvent; and when using an organic solvent, in the presence of a tertiary amine such as triethylamine or pyridine. When an aqueous solvent system is used, the pH of the reaction is normally maintained at a value of about 8-10 and preferably 9.

Protected amino groups are converted to unprotected amino groups by operations known to those skilled in the art as being appropriate to the particular group used. The tert-butoxycarbonyl group is, for example, easily removed by treatment with dichloromethane saturated with gaseous hydrogen chloride.

Various groups protecting the hydroxys function are also known and are described in the bibliographic references mentioned above. A preferred hydroxy-protecting group is the tert-butyldimethylsilyl group. This group is introduced as previously described and is easily removed by treatment with tetrahydrofuran de-tert-butylammonium fluoride at room temperature. Activation of carboxy groups as a means of accomplishing a given acylation reaction is also a methodology known to those skilled in the art. In the reaction sequence described herein, it is of particular interest to use anhydrides and activated esters, especially the esters which are derived from N-hydroxyphthalimide, N-hydroxysuccinimide or 1-hydroxybenzotriazole, all of which are used in syn-theses of peptides.

A desiccant coupling agent is used to form the activated ester. Representative examples of such coupling agents are 1-cyclohexyl-3- (2-roorphol-noethyl) -carbodiimide, N, N-1-dicyclohexyl-carbodiimide, N, N'-carbonyldiimidazole, 1- (3-dimethylaminopropyl) 1004 ethylcarbodiimide, 11 ethoxyacetylene, diphenylketene and N-ethyl-5-phenylisoxazolin-3'-sulfonate. The reaction conditions for the use of these coupling agents are well described in the literature. In general, they include the use of an inert reaction solvent and temperatures ranging from room temperature to 100 ° C. The carbodiimidic reagents mentioned above are preferred because they allow the use of the ambient reaction temperature and give the desired esters in satisfactory yields.

When the coupling reactions which lead to the final products are terminated, the various protecting groups can be removed by the appropriate techniques as previously discussed, and the compounds of formula (I) are isolated and purified by conventional operations such as recrystallization or chromatography. column.

The above sequences may be adapted as appropriate to be implemented with any of the claimed variants for R1 to R8, X and Het by the appropriate choice of starting materials.

Thus, in accordance with another aspect, the invention relates to a process for producing a compound of Formula (I), which comprises removing the protecting group from a compound of the formula:

X- (CR7R ") m -Het (ix) wherein R4 is a selectively selectively removable hydroxy-protecting group, and isolating the compound of formula (I) and optionally forming a pharmaceutically acceptable salt; pharmaceutical composition of this compound. 18

The preferred protecting group for X 1 is tert-butyldimethylsilyl; this group is removed by treatment with tetra-n-butylammonium fluoride in an organic solvent, preferably tetrahydrofuran.

Novel intermediates of formulas (VIII), (IX) and (X) are also part of the present invention.

Examples of pharmaceutically acceptable salts of the compounds (I) are acid addition salts, for example, sulfates, bisulfates, phosphates, lactates, mesylates, fumarates, citrates, succinates and gluconates.

In the treatment of patients with retrovirus infection, including an HIV virus, the compounds (I) are administered by any suitable route, for example orally, parenterally (for example subcutaneously, intramuscularly, intramuscularly or intradermally), rectally nasal, topical (including the oral and the vaginal route) or vaginal. The formulations, which contain an antiviral agent of the invention together with one or morepharmaceutically acceptable carriers and, optionally, other therapeutic agents, may be prepared according to conventional techniques well known in the art. Oral dosage forms include, in particular, syrups, tablets and capsules which may contain aromatic agents in addition to an inert carrier. Tablets can be prepared by conventional compression or molding techniques, parmpressing a powder of the appropriate ingredients, for example the antiviral agent together with a binder, diluent, lubricant and surfactant. Rectal formulations are in the form of suppositories and vaginal formulations are for example in the form of pads, creams or foams. Parenteral formulations are in sterile form, for example, injectable ampoules containing aqueous or nonaqueous diluents, buffers and antioxidants so that the formulation is isotonic with the blood. In general, the appropriate dose of antiretroviral agents of formula (I) is 1 to 50 mg / kg / day, preferably 1-25 mg / kg / day, which is administered up to 6 divided doses. per day. There may be cases where higher or lower doses are required depending on age, weight, degree of disease and patient response, and appropriate treatment will be determined by the attending physician.

The compounds of formula (I) may be used in combination with other medicaments, some of which may exalt their activity. These drugs include: (a) reverse transcriptase inhibitors such as AZT, ddI, ddC, foscarnet, TBO compounds, dipyrido-diazepinones, and 6-substituted acyclo-pyrimidine derivatives (HEPT); (b) gpl20-CD4 inhibitors such as dextran sulfate and soluble CD4, including its combination with toxic agents such as Pseudomonasin toxin; (c) TAT antagonists, such as D-penicillamine; (d) other protease inhibitors of; retro-viruses, such as Ro 31-8959; and (e) biologic response modifiers comprising interferons, interleukins or colony-stimulating factors, for example GM-CSF. The antiviral activity of the compounds of the invention was evaluated by dissolving the test compound in 50 μl of DMSO and diluting to 1 mg / ml in RPMI 1640 which is a solution of complex salts having a pH of 7.2. The tests were performed at concentrations of 0.001, 0.01, 0.1, 1 and 10 μg / ml against the HIV 1 virus (strain IIIB) in; the line (H9) of human T cells. Untreated control infections were initiated at the same time.

Seven days after infection, the tissue culture light liquors were titrated to detect the presence of infectious virus on C8166 cells (human T cell line). On the third, fifth, and seventh days, cultures were examined for the appearance of syncytia. Control infections, untreated with the drug, show characteristic viral cytopathic effects, including formation of syncytia and death of cells. The CI ^ q value noted and the minimum test concentration providing total protection to the crop. In practicing this test method, the compounds exhibited IC100 values in the range of 0.1 to 10.0 μg / ml.

The preparation of certain starting materials and compounds of formula (I) is illustrated more particularly hereinafter from the following experimental examples. Lapurity of the compounds was conventionally controlled by thin layer chromatography using silica gel Kieselgel 60 F254 plates from Merck. The proton magnetic resonance spectra were recorded using a Nicolet QE-300 or Brucker AC-300 spectrometer and in any case they were in agreement with the proposed structures. The chemical shifts are expressed in parts; million with respect to tetramethylsilane, using conventional abbreviations for the designation of main peaks: s, singlet; d, doublet; t, triplet; m, multiplet and 1, broad. The readings of optical rotations were made at a concentration of 0.1% in methanol at 25 ° C unless otherwise specified. All temperatures are in degrees Celsius. 10054 21

PREPARATION OF STARTING MATERIALS

AND INTERMEDIATE PRODUCTS PREPARATION 1 (S) -5-Γ (S) -1-tert-butoxycarbonylamino-2-phenylethyl-n-gamma-butylactone) a) (4S.5S) - and (4R, 5S) -5 Ethyl-tert-butoxycarbonyl-amino-4-hydroxyl-6-phenylhex-2-ethylate

A. diisopropylamine solution. (6.4 ml) in anhydrous tetrahydrofuran (25 ml) was stirred under nitrogen at -25 ° C and a 1.6-molar solution of n-butyllithium in hexane (24.4 ml) was added in vacuo. minutes, the temperature being kept below -20 °. After another 15 minutes at -2 ° C., the solution was cooled to -70 ° and ethyl propiolate (3.8 g) was added dropwise at 10 minutes, the temperature being kept below 65 °. The resulting hot suspension was stirred at -70 ° for a further 20 minutes and then treated by dropwise addition, in 10 minutes, of a solution of N-tert-butoxycarbonyl-L-phenylalaninal (6.5 g, see JR Luly et al., J. Org. Chem., 1987, 52, 1487) in anhydrous tetrahydrofuran (15 ml) again maintaining the temperature below -65 °. The clear yellow solution was stirred at -70 ° for 2 hours and then treated with acetic acid (4 ml). The cooling bath was removed and the mixture was allowed to warm to -30 °, and at this point water (100 ml) and ethyl acetate (100 ml) were added with vigorous stirring. Separating the organic phase and then washing successively with 1M hydrochloric acid (50 ml), aqueous saturated sodium bicarbonate (50 ml) and saturated brine (50 ml), the crude product was obtained as a oil after dehydration (Na2SO4) and evaporation of the solvent. The oil was purified by silica gel chromatography using ethyl acetate-hexane (1: 4) as eluent. Evaporation of the fractions containing the product gave an oil which solidified on rest for one night. Recrystallization from ether-hexane gave the title compounds as a mixture of about 2: 1 (4S, 5S: 4R, 5S) diastereoisomers (4.3 g) having one dot. melting point of 98-99 °. Found: C, 65.62; ! K, 7.42 N, 4.33. C19H25NO5 requires C, 65.70; H, 7.20; N, 4.03%. NMR (CDCl3) δ = 1.30-1.39 (m, 3H); 1.43 (s, 9H); 2.90-3.11 (m, 2H); 3.37-3.38 and 4.16-4.19 (2 'x 11a, 1H); 3.93-4.04 (m, 1H); 4.22-4.33 (m, 2H); 4.51 -4.56 (m, 1H); 4.77-4.79 and 4.87-4.90 (2 x lm, 1H); 7.24-7.75 (1α, 5H). b) (4S.5S) - and (4R, 5S) -5-tert-butoxycarbonylamino-4-hydroxy-6-phenylhexanoate d1 ethyl

The above product (1.17 g) was dissolved in ethanol (50 mg) and a 5% Pd catalyst over 3%. BaSO4 has been added. The mixture was then hydrogenated at 50 psi (344.7 kPa) for 2 hours. Filtration followed by evaporation of the solvent in vacuo afforded title compounds (mixture of about 2: 1 diastereoisomers) as a white solid (1.18 g), m.p. 125-126 °. Found: C, 64.91; H, 8.1C; N, 3.98; C 1 H 2 GNO 5 requires C, 64.95; H, 8.26; N, 3.98%. NMR (CDCl3) δ = 1.24-1.33 (m, 3H); 1.39 and 1.42 (2xs, 9H); 1.72-1.95 (m, 2H); 2.38-2.62 (m, 2H); 2.77-2.98 (m, 2H); 3.02-3,, 04 and 3.40-3.42 (2 x m, 1H D2O); 3.59-3.91 (m, 2H); 4.08-4.22 (m, 2H); 4.58-4.61 and 4.85-4.89 (2 x m, 1H) · 7.22-7.37 (m, 5H). c; (5) -5 - ((S) -1-tert-butoxycarbonylaryl-2-phenylethyl-gamma-butyrolactone

The gamma-hydroxyester obtained in (b) above was dissolved in a mixture of 2.5% acetic acid and toluene (35 ml) and the solution heated at reflux for 2 hours. After cooling and evaporation to dryness, the residue was purified by flash chromatography of silica eluting with ether diethyl hexane (40:60) to give the title compound (0.4 g), Mp 98-99 °. Found: C, 66.77; H, 7.78; N, 4.38. C requires a C, <56.88; H, 7.54; N, 4.59%. m / e = 306 (MH +). NMR (CDCl3) δ = 1.42 (s, 9H); 2.11-2.19 (m, 2H); 2.51-2.58 (m, 2H)? 2.87-3.02 (m, 2H); 4.00-4.07 (m, 1H); 4.47-4.52 (m, 1H); 4.63 (d, J = 10, NH); 7.26-7.36 (m, 5H).

[? 22] - 22.6 ° (c = 1, MeOH). I.R. (KBr) 1775, 1690, 1525 cm-1. PREPARATION 2

(R) -2-Benzyl- (S) -5-tert-butoxycarbonylamino- (S) -4- (tert-butyl-dimethylsilyloxy) -6-phenylhexanoic acid a) (R) -3-henzyl (S) -5 -3 (S) -1-tert-butoxycarbonyl-amino-2-phenylethyl-1-butamrolactone

A cold solution (-10 ° C) of hexamethyldisilazane (7.9 ml) in tetrahydrofuran (15 ml) was treated for 3 minutes with 1.6M n-butyllithium in hexane (23 ml), maintaining the temperature below 0 °. After another period of 5 minutes at 0 °, the solution was cooled to -70 ° and a solution of (S) -5 ~ [(S) -1-tert-butoxycarbonylamino-2 phenylethyl) -gamma-butyrolactone (5 g in tetrahydrofuran (38 ml) was added, keeping the temperature below -65 ° C. The solution was stirred at -70 ° for 15 minutes before addition in 1 minute. benzyl bromide (1.95 ml) in tetrahydrofuran (12.5 ml) and the solution was stirred at -70 ° for a further 10 minutes before being treated with acetic acid (6.5 ml) Before the cooling bath was removed, water (50 ml) and ethyl acetate (50 ml) were added and the mixture was allowed to warm to room temperature. The addition of the organic phase followed by dehydration (MgSO 4) and evaporation of the solvent in vacuo gave the crude product as an oil. Chromatography on silica gel eluting with diethyl ether-hexane (50:50) gave the title compound as an oil (3.52 g). Found: C, 73.22; H, 7.50; N, 3.50. C24H29NO4 requires C, 72.91; H, 7.34; N, 3.54%.

[?] 14 ° (c = 0.1, MeOH). NMR (CDCl3) δ = 1.37 (s, 9H); 1.95-2.30 (m, 2H); 2.79-3.20 (m, 5H); 3.92-4.01 (m, 1H); 4.21-4.25 (m, 1H); 4.52-4.56 (m, 1H); 7.36 (m, 10H). b) (R) -2-Benzyl- (S) -5-tert-butoxycarbonyl-amino- (S) -4-tert-butyl dimethylsilyloxy) -6-phenylhexanoic acid

A suspension of the product from (a) (17.63g) in dioxane (120ml) and water (60ml) was treated with sodium hydroxide (1N, 53.5ml) at room temperature. ambient temperature. The reaction mixture was stirred for 3 hours before being acidified to pH 5 by addition of acetic acid. After standing for another 30 minutes, the precipitate was filtered off and washed with water. This solid material was dissolved in ethyl acetate, the solution was dried (MgSO 4) and evaporated in vacuo to give a white solid, which was triturated with hexane, filtered and dried to give the hydroxide. intermediate acid (17.85 g). A solution of this hydroxy acid in N, N-dimethylformaldehyde was treated with imidazole (29.38 g) and t-butyldimethylsilyl chloride (32.53 g) at room temperature. After stirring for 18 hours, the solvent was evaporated in vacuo, the residue was treated with a mixture of ice and water, 10% citric acid added to pH 4 and extracted with 400 ml portions of sodium acetate. 'ethyl. The combined extracts were dried (MgSO 4) and evaporated under vacuum to a pale oil (29.2 g). A solution of this oil in tetrahydrofuran (240 ml) was treated with acetic acid (240 ml) and water (80 ml) at room temperature. After stirring for 2 hours at room temperature and 18 hours at 4 ° C, the solution was evaporated in vacuo and the residue was partitioned between water (400 ml) and ethyl acetate ( 400 ml). The separated organic phase was washed with water (2 x 400 ml), saturated brine (100 ml), dried (MgSO 4) and evaporated to give a pale oil. By chromatography on silica gel eluting with a mixture of diethyl ether and hexane (70:30), the title compound was obtained as a white glassy substance (22.4m / e 528 (MH)). + g) - 1.30 NMR (DMSO-d6) δ = (m, 10H); 1.35 (m, 1H); 0.10 1.95 (s, (m, 6H) 1H); 0.95; 2.40 (s, (m, 9H) 1H) 2.72 (m, 2H); 2.85 (m, 1H); 3.60 (m, 1H); 3.75 (m, 1H) 6.88 (d, 1H); 7.22 (m, 10H). PREPARATION 3 5-bromomethylisoquinoline

A solution of an isomeric mixture of 5 "and 7-bromisoquinoline (5: 7, 40:60, 1.0 g, see Glyde and

Taylor, J. Chem. Perkin Trans 2. 1975, 1783) in dry tetrahydrofuran (15 mL) was treated with 1.6M n-butyllithium in hexane (3.3 mL) at -70 ° C. The reaction mixture was maintained at this temperature for 3 minutes and then a solution of anhydrous dimethylformamide (0.74 mL) in dry tetrahydrofuran (5 mL) was added. After another 15 minutes, the reaction mixture was quenched with ethanol (5 mL) and allowed to warm to room temperature. A saturated solution of ammonium chloride (10 ml) and diethyl ether (15 ml) were then added successively and the organic phase was separated, washed with brine, dried (MgSO 4) and evaporated in vacuo. Lapuration by silica gel chromatography eluting with hexane-ethyl acetate (50:50) and isolation of the larger aldehyde gave 5-formylisoquinoline as an unstable yellow solid (0.degree. , 05 g). Rf 0.3 (hexane-ethyl acetate 50:50).

A solution of this product (0.88 g) in anhydrous ethanol (20 ml) was treated with sodium borohydride (0.53 g) at 5 ° C and the resulting mixture was allowed to warm to room temperature and the mixture was stirred at room temperature. held for 1 hour at this temperature. The solution was diluted with diethyl ether (20 ml) and water (10 ml) was then added. The two phases were separated and the aqueous phases were extracted with diethyl ether (20 ml). The two organic phases were collected, washed with saturated sodium chloride solution (20 ml), dried (MgSO 4) and evaporated in vacuo to 5-hydroxymethyl isoquinoline as a pale yellow powder (0.37 g). Mp 71-72 ° C. Found: C, 75.06; H, 5.72; N, 8.66. <? 1θΗ9ΝΟ requires C, 75.45; H, 5.70; N, 8.80%.

A solution of the above product (1.11 g) in glacial acetic acid (15 ml) was treated with 49% aqueous hydrobromic acid (30 ml) and the resulting mixture was refluxed for 2 hours. . The reaction mixture was then concentrated in vacuo and the residue was suspended in methylene chloride and basified with saturated aqueous sodium bicarbonate solution. The two phases were separated and the phasicose was extracted with methylene chloride. The combined organic phases were washed with saturated aqueous sodium bicarbonate solution, dried (MgSO 4) for 0.5 h and evaporated in vacuo at room temperature to give the title product as a colorless solid substance. The solid formed a toluene azeotope and was used directly (1.28 g). NMR (CDCl3) δ = 4.90 (s, 2H); 7.50 (t, 1H); 7.70 (d, 1H); 7.90 (m, 2H); 8.65 (d, 1H); 9.25 (s, 1H). PREPARATION 4 7-bromomethylisoquinoline

7-Formylisoquinoline was obtained in the initial step of Preparation 3 as a product of lower flow distance and was isolated as a yellow solid (0.08 g). Rf 0.25 (50:50 ethyl hexane-ethyl acetate). By reaction with sodium borohydride as described above, 7-hydroxy-methyl-isoquinoline was obtained, m.p. 129-130 ° C.

A solution of the hydrochloride salt of the above product (0.05 g) in thionyl bromide (0.5 ml) was heated to 60 ° C and held at that temperature for 45 minutes. The reaction mixture was then cooled to room temperature. ice and excess water was added cautiously, followed by diethyl ether (15 ml). A concentrated aqueous solution of ammonia was then added to pH 9 and the ether phase was separated, washed with water and dried (MgSO 4). A solution of hydrogen chloride in isopropyl alcohol ( 0.06 ml, 5.9 N) was then added and the resulting suspension was evaporated in vacuo at room temperature. The residue azeotroped with toluene exodising the product hydrochloride as a colorless solid (0.04 g). m / e (MH) + 222 NMR (DMSO-d6) δ = 5.05 (s, 2H); 8.10 (d, 1H); 8.25 (d, 1H); 8.30 (d, 1H); 8.45 (s, 1H)? 8.65 (d, 1H); 9.70 (s, 1H). PREPARATIONS 5-13

The following compounds of formula (IV) were prepared by the procedure described in Preparation 2, but using the appropriate substituted benzyl bromide or bromomethylisoquinoline to alkylate gamma-butyrolactone in step (a), the operation being followed by ring opening and reaction with the tert-butyldimethylsilyl chloride as described in step (b).

## STR2 ## 31 2.56) 6 ^ -Q-CI 562.2 7 F ch2- ^ ~ ^ -f 564.6 8 οη2 ^ ~ ^ -ι 654.1 54.9 6.75 2.07 (55.1 6 , 78? -, 14) 9 CH? N? CF? 596 62.2 7.71 2.26 (62.5, 7.44, 2.35) CH 2 O 2? OCF 3 612.4 61.20 7, 30 2.30 (60.90 7.30 2.30) 11 12 XCH2CH = CH ^ 452 69.53 8.59 2.52 (69.40 8.55 2.53) ch2 ΓγΊι 579 67.92 7 92.72 (68.26, 8.02, 4.82) 13 17 57 67.77 7.85 4.64 (67.78 8.04 4.79) 7

1. 0.1 mm H 2 O

2. 0.33 mole of H 2 O 5 PREPARATION 1- (N-tert-butoxycarbonyl) -3-methanesulfonyloxy azetidine a) Azetidine-3-ol hydrochloride (2.10 g) was stirred in of. methylene chloride (40 ml), and diisopropylethylamine (2.59 g) was added followed by di-tert-butyl dicarbonate (4.36 g). The mixture was stirred at room temperature for 4 hours and the solvent was evaporated in vacuo. The residue was dissolved in ethyl acetate (200 ml) and washed with 1.5M hydrochloric acid (50 ml), saturated sodium bicarbonate solution (25 ml) and brine ( 25 ml). Organic Laphase was dehydrated (MgSO4), filtered and evaporated in vacuo. By chromatography on silica gel eluting with a mixture of ethyl acetate and hexane (50:50), 1- (N-tert-butoxycarbonyl) -3-hydroxyazetidine was obtained as a white solid (2.57 g), mp 51-53 ° C. Found: C, 55.29; H, 8.70; N, 7.98. CgH15NO3 requires C, 55.47; H, 8.73; N, 8.09%. b) A solution of the above product (1.0 g) in methylene chloride (35 ml) was treated with methanesulfonyl chloride (0.75 ml) and pyridine (1.5 ml) and the mixture was stirred. It was stirred for 3 days at room temperature. The solution was diluted with methylene chloride (75 ml), washed with a citric acid (5%, 100 ml) solution, 1 ml. aqueous sodium bicarbonate solution (100 ml), dried (MgSO4) and evaporated in vacuo to give the title product as a colorless oil (1.4 g). Found: C, 43.00; H, 6.80; N, 5.50. CgH17NO5S requires C, 43.03; H, 6.77; N, 5.58%. m / e 266 (MNH4) +. NMR (DMSO-d6) δ = 1.37 (s, 1H); 3.24 (s, 3H); 3.88-3.96 (m, 2H); 4.17-4.28 (m, 2H); 5.25 (m, 1H). PREPARATION 1- (N-benzyloxycarbonyl) - (R) -3-methanesulfonyloxypropylrolidineThe title compound was prepared from 1- (N-benzyloxycarbonyl) - (R) -3-hydroxypyrrolidine (J. Med.

Chem., 1992, 35, 1764) using the procedure described in Preparation 14 above, except that the triethylamine was used as a base instead of pyridine as the product as an oil. Found: C, 51.60; H, 5.80; N, 4.30. ## STR2 ## H 6 requires C, 51.63; H, 5.78? N, 4.63%. m / e MH + 300. NMR (CDCl3) δ = 2.15 (m, 1H); 2.55 (m, 1H); 3.0 (s, 3H); 3.45-3.80 (m, 4H); 5.10 (s, 2H); 5.25 (m, 1H), 7.30 (m, 5H). PREPARATION 16 1- (N-Benzyloxycarbonyl) - (S) -3- (paratoluene) -sulfonyloxy-pyrrolidine

Triphenylphosphine (13.58 g) was added to a solution of 1- (N-benzyloxycarbonyl) - (R) -3-hydroxypyrrolidine (7.90 g) in anhydrous tetrahydrofuran (100 ml) under nitrogen. The resulting solution was cooled to -30 ° C and addition of methyl tosylate (10.06 g), followed by diethylazodicarboxylate (10.41 g) over a period of 0.5 hour. After another one hour period, the reaction mixture was allowed to warm to room temperature and held there for 65 hours. The reaction mixture was evaporated in vacuo, the residue was dissolved in dichloromethane, washed with water, dried (MgSO4) and evaporated under vacuum to give an oil. Purification by chromatography on silica gel eluting with methylene chloride-methanol (98: 2 to 96: 4), followed by a second chromatography eluting with a mixture of hexane-ethyl acetate (80: 1). 20 to 50:50) gave the product as an oil: golden (10.22 g). Found: C, 60.59; H, 5.68; N, 3.67. C 39 H 21 NO 5 S requires C, 60.78; H, 5.64; N, 3.73%.

[?] 25 + 9 ° (c = 0.1%, MeOH)

D NMR (CDCl3) δ = 1.85-2.25 (m, 2H); 2.45 (s, 3H); 3.40-3.65 (m, 4H); 4.95-5.15 (m, 3H); 7.20-7.35 (m, 7H); 7.75 (d, 2H). 10054 31 PREPARATION 17 1- (N-tert-butoxycarbonyl) -4-methanesulfonyloxypiperidine

The title compound was prepared from 1- (N-tert-butoxycarbonyl) -4-hydroxypiperidine, following the procedure described in Preparation 14, m.p. 85-86 ° C. Found: C, 47.2; H, 7.66; N, 4.91. C n H 21 O 5 requires C, 47.3; H, 7.58; N, 5.02%. NMR (CDCl3) δ = 1.5 (s, 9H); 1.85 (m, 2H); 2.0 (m, 2H); 3.08 (s, 3H); 3.35 (m, 2H); 3.75 (m, 2H); 4.9 (m, 1H). PREPARATION 18 1- (N-tert-butoxycarbonyl) -3- (imidazol-1-yl) azetidine

A solution of imidazole (0.41 g) in N, N-dimethylformamide (30 ml) was treated with sodium hydride (60%, 0.24 g) and the mixture was stirred at room temperature. for 1 hour. 1- (N-tert-butoxycarbonyl) -3-methanesulfonyloxyazetidine (Preparation 14) (1.4 g) was added and the mixture was heated at 75 ° C for 3 days. vacuum-stripped and the residue was dissolved in ethyl acetate (50 ml), the solution was washed with water (2 x 50 ml), dried (MgSO 4) and evaporated in vacuo to give a colorless oil Purification by silica gel chromatography eluting with methylene chloride-methanol-concentrated aqueous ammonia solution (93: 7: 1) gave the title compound as an oil (0.72 g). ), m / e 224 (MH) + NMR (DMSO-d6) δ = 1.40 (s, 9H), 3.95-4.06 (m, 2H), 4.26-4.35 (m, 2H), 5.12 (m, 1H), 6.96 (s, 1H), 7.43 (s, 1H), 7.79 (s, 1H) PREPARATIONS 19-25

The following compounds of formula (V) were prepared according to the procedure described in Preparation 18 above but using the appropriate preparation material from Preparations 14-17 and conducting the reaction with imidazole and substituted or unsubstituted substituted triazole. ## EQU1 ## TiN PX- (CR7Ke) ", - let (MH)" Analy.% CHN Theoretical values in parenthesis;) 19 NH, i BocN ^ t-hT SN L-7 239, 55.1 7.50 22.9 (55.4, 7.67, 23.5) Boc-N "NZNC 3 NMR: 1.33 (s, 911) 4.05 (m, 2H) ; 4.24 (m, 2H); 5, l (m, III); 7.99 (s, lH); 8, l5 (s, lH). 21 Cbz-N ^^ N ^ N V_7 \ = / 272 65,57 6,37 15,04 (65,60 6,25 15,25) '22 Cbz-Nr ~ N ^ N V_ / V- ^ 7,272 65.69 6.33 15.25 (65.60 6.25 15.25) 23 Boc-N> -NN 252 24 BcrZ YN "^ NKV M- / 253 25 CIL / ___ 1 J Boc-N / - NN ^ -7 265.9 61.0 8.92 15.6 (61.3 8.82 15.3) '1. 0.05 mole CF 2 C ^ 2. Hemihydrate 1005 4 34 PREPARATION 26 (a) 1- (N-tert-Butoxycarbonyl) -4- (4-methylmidazol-1-yl) piperidine

The reaction of 4-methylimidazole with 1- (N-tert-butoxycarbonyl) -4-methanesulfonyloxypiperidine yielded regioisomeric products which were chromatographically separated on silica gel eluticated by a mixture of dichloromethane, methanol and aqueous ammonia solution. (96: 3: 0.5). Principal isomer, Rf 0.47, m / e 265.9 (MH) + NMR (DMSO-d6) S = 1.43 (s, 9H); 1.7 (dq, 2H); 1.93 (1, 2H); 2.07 (s, 3H); 2.83 (m, 2H); 4.05 (ra, 3H) 6.95 (s, 1H); 7.55 (s, 1H). () 1- (N-tert-butoxycarbonyl) -4- (5-methylimidazol-1-yl) -piperidine

Secondary isomer, Rf 0.52. m / e 265.9 (MH) + NMR (DMSO-d6) δ = 1.43 (s, 9H); 1.7 (dq, 2H); 1.9 (1, 2H); 2.05 (s, 3H); 2.88 (m, 2H); 4.05 (m, 3H); 6.6 (s, 1H)? 7.65 (s, 1H). PREPARATION 27 1- (N-tert-butoxycarbonyl) -4- (imidazol-2-yl) - (1,2,5,6-tetrahydropyridine) (a) 1- (Diethoxymethyl) imidazole (6.8 g) in anhydrous tetrahydrofuran (50 ml) under nitrogen at -40 ° C. n-Butyllithium (25 ml, 1.6N in hexane) was added at a rate selected so that the temperature was below 35 ° C. 1- (N-tert-butoxycarbonyl) -4-ketopiperidine (2.65 g) in anhydrous tetrahydrofuran (10 ml) was added dropwise over 10 minutes keeping the temperature below -40 ° C. The reaction mixture was stirred at -40 ° C. for 2 hours and the reaction mixture was stirred with hydrochloric acid (50 ml, 0.1 mmol) for 15 minutes, ethyl acetate (50 ml, 50 ml. ml) was then added and the resulting mixture was stirred for 5 minutes The organic layer was separated and the aqueous layer was extracted with ethyl acetate (1 x 50 ml).

The combined organic extracts were washed with saturated solution of sodium bicarbonate (1 × 50 ml) and then with saturated sodium chloride solution. The organic phase was then dried (MgS 4) and evaporated to give a yellow oil. 0 g. Chromatography on silica gel eluting with ethyl acetate: methanol: concentrated aqueous ammonia (90: 10: 1) gave 1- (N-tert-butoxycarbonyl) -4-hydroxy. 4-Imidazol-2-yl) -piperidine as a cream solid (2.2 g), m / e 268.0 (MH) +. (b) The above product (267 mg) was stirred with diisopropylamine (350 mL) in dry dimethylformamide (2 mL) at 0 ° C. Methanesulfonyl chloride (155 ml) was added in one portion and the reaction mixture was stirred for 2 hours at 0 ° C. Further portions of diisopropylamine (350 ml) and methanesulfonyl chloride (155 ml) were then added and the reaction mixture was stirred for 16 hours at room temperature. The resulting mixture was diluted with water (4 mL), adjusted to pH 9 with 1M sodium hydroxide solution, and extracted with ethyl acetate (3 x 10 mL). The combined organic extracts were dehydrated (MgSO4) and evaporated to give a gum, 260 mg. Parchromatography, on silica gel eluting with a mixture of dichloromethane methanol: concentrated aqueous ammonia solution (95: 5: 1), gave the title product as a yellow gum, 144 mg. m / e 250.1 (MH) +. NMR (CDCl3) δ = 1.46 (s, 9H); 2.6 (1, 2H); 3.53 (t, 2H); 4.0 (1, 2H); 6.3 (m, 1H); 7.0 (s, 2H); 9.4 (1.1H). PREPARATION 28 1- (N-tert-butoxycarbonyl) -4-imidazol-2-ylpiperidine

The product from the intermediate preparation (27) (0.55 g) was dissolved in ethanol (30 ml) and the solution was hydrogenated under pressure of 30 psi (2.0 bar) in the presence of a palladium catalyst attached to carboxy (200 mg, 10%). Filtration of the catalyst and removal of the solvent gave a foam of 55 g. m / e 252.1 (MH) +. NMR (CDCl3) δ = 1.4 (s, 9H); 1.68 (qd, 2H)? 1.95 (1, 2H); 2.75 (1, 2H); 2.92 (1, 1H); 4.1 (1, 2H); 6.9 (s, 2H); 8.77 (1, 1H). PREPARATION 29 1- (N-tert-butoxycarbonyl) -4- (imidazol-1-yl) methyl-1,2,5,6-tetrahydropyridine (a) A 60% dispersion in sodium hydride oil ( 4 g) in anhydrous dimethylsulfoxide (100 ml) was freed from the oil by washing with hexane and heated to 70 ° C with stirring for one hour. Anhydrous tetrahydrofuran (100 ml) was added and the reaction mixture was cooled to -20 ° C. A solution of trimethylsulfonium iodide (20.4 g) in dimethylsulfoxide (80 ml) was then added, followed by 1- (N-tert-butoxycarbonyl) -4-ketopiperidine (19.9 g) in tetrahydrofuranhydride. (100 ml) and the reaction mixture was stirred for 0.5 hours at -10 ° C and then for one hour at room temperature. Water (500 ml) was then added and the reaction mixture was extracted with ethyl acetate (3 x 250 ml). The combined extracts were then washed with brine, dried (MgSO 4) and evaporated under reduced pressure. Purification by silica gel chromatography eluting with a cyclohexane-ether-isopropyl alcohol mixture (60: 40: 1) afforded 1- (N-tert-butoxycarbonyl) -piperidine-4-spiroanalysed 2'-oxirane as a colorless solid substance (19.6 g), mp 65-66 ° C. Found: C, 62.11; H, 9.06; N, 6.55. ## STR2 ## requires C, 61.97; H, 8.92; N, 6.57%. (b) A stirred solution of imidazole (1.91 g) in anhydrous acetonitrile (30 ml) under nitrogen was treated with 80% dispersion in sodium hydride oil (0.84 g) and the resulting mixture was heated at 90 ° to 60 ° C until dissolution occurred. After 15 minutes, the product from step (a) (2.0 g) was added and the reaction mixture was left for 5 hours. After allowing the reaction mixture to stand at room temperature overnight, the solvent was evaporated in vacuo and the oily residue was partitioned between methylene chloride (40 ml) and water (20 ml). The organic phase was separated and washed with water, dried (MgSO4) and evaporated in vacuo. Purification by silica gel chromatography eluting with a mixture of methylene chloride, methanol and concentrated aqueous ammonia solution 880 (95: 4: 1) afforded 1- (N-tert-butoxycarbonyl) - 4-Hydroxy-4- (imidazol-1-yl) methylpiperidine is a colorless powder (2.13 g). Found: C, 58.35; ΐ '., 8.30; N, 14.52. CL3H23N3O3 1/10 CH2Cl2 requires C, 58.43; H, 8.07; N, 14.50%. m / e 282 (MH) +. (c) A stirred solution of the product from step (b) (2.0 g) and triethylamine (5.44 ml) in anhydrous methylene chloride (80 ml) at 0-5 ° C was treated, with a solution of methanesulfonyl chloride (2.2 ml) in dry methylene chloride (10 ml), and the resulting mixture was allowed to warm to room temperature where it was held for 14 hours. The reaction mixture was then washed with water, dried (MgSO 4) and evaporated under vacuum. Purification of the residue by silica gel chromatography eluting with a mixture of methylene chloride-methanol-concentrated aqueous ammonia solution 880 (96: 4: 0 to 95: 4: 1) afforded the product as a reaction product. a golden colored oil (1.36 g). Found: C, 59.93, H, 7.60; N, 14.79. εΐ3Η2ιθ2 1 // 4 CH2Cl2 requires C, 60.14, H, 7.61; N, 14.77%. m / e (MH) + 264. NMR (CDCl3) δ = 1.45 (s, 9H); 1.97 (m, 2H), 3.50 (t, 2H); 3.90 (s, 2H); 4.50 (s, 2H); 5.50 (s, 1H); 6.90 (s, 1H); 7.10 (s, 1H); 7.55 (s, 1H). PREPARATION 1- (N-tert-butoxycarbonyl) -4- (imidazol-1-yl) -methyl-piperidine

A solution of the product from Preparation 29 (1.33 g) in absolute ethanol (25 ml) was hydrogenated or stirred on 10% palladium on carbon (0.3 g) at 50 psig ( 3.5 bar) at ambient temperature for 4 hours. The reaction mixture was then filtered and evaporated under vacuum, forming an azeotrope with methylene chloride. Purification by silica gel chromatography eluting with methylene chloride-methanol (96: 4) afforded the product as a colorless oil (1.09 g). Found: C, 63.08; H, 8.60, N, 15.50. ## STR2 ## requires C, 63.36, H, 8.74, n, 15, 84%, m / e (MH) + 266 NMR (CDCl 3) δ = 1.15. (m, 2H), 1.45 (s, 9H) 1.58 (m, 2H), 1.85 (m, 1H), 2.65 (t, 2H), 3.80 (c 1, 2H) 4 10 (m, 2H), 6.90 (s, 1H), 7.10 (s, 1H), 7.45 (s, 1H), PREPARATION 31 1- (N-tert-butoxycarbonyl) -4- (Imidazol-1-yl) -1,2,5,6-tetrahydropyridine

Imidazole (8.20 g) was stirred in dry methylene chloride (30 ml) at -10 ° C and thionyl chloride (4.8 ml) was added in methylenechloride chloride (30 ml). The resulting slurry was allowed to warm to room temperature, and after 2 hours a solution of 1- (N-tert-butoxycarbonyl) -4-ketopiperidine (6.0 g) in chloride was added dropwise. anhydrous demethylene (50 ml). The reaction mixture was stirred overnight and then evaporated in vacuo. Potassium carbonate (6.0 g) in water (30 ml) was added to the oily residue and the product was extracted with methylene chloride (2 x 60 ml). The combined extracts were washed with water (40 ml), dried (MgSO 4) and evaporated in vacuo. Purification by chromatography on silica gel eluting with ethyl acetate-methanol (100: 0 to 100 ° C. 90:10) gave the product as an oil (1.0 g). NMR (CDCl3) δ = 1.50 (s, 9H); 2.55 (s, 2H); 3.70 (t, 2H); 4.05 (s, 2H); 5.80 (s, 1H)? 7.10 (s, 2H); 7.65 (s, 1H) • PREPARATION 32 1- (N-Benzyloxycarbonyl) -4- (1,2,4-triazole-4-yl) -piperidine

Ammonium acetate (16.5 g) and sodium cyanoborohydride (0.94 g) were added to a solution of 1- (N-benzyloxycarbonyl) -4-ketopiperidine (5.0 g) in methanol ( 25 ml), and the mixture was stirred at room temperature for 24 hours. The solvent was then removed under reduced pressure and the residue was partitioned between ethyl acetate and 1K sodium hydroxide solution. The ethyl acetate phase was separated, dried over magnesium sulfate and evaporated. under reduced pressure as a yellow oil. Chromatography of this residue on silica gel eluting with methylene chloride-methanol-concentrated aqueous ammonia solution (95: 5: 1) gave 4-amino-1- (N-benzyloxycarbonyl) -piperidine. in the form of a yellow oil. A solution of this product (1.5 g) in toluene (1 ml) was treated with dimethylformamideazine (1.0 g) and p-toluenesulfonic acid (0.1 g) and the The mixture was refluxed for 24 hours. The solvent was then removed under reduced pressure and the residue was chromatographed on silica gel, eluting with a mixture of methylene chloride-methanol-concentrated aqueous ammonia solution (95: 5: 1) to give the title compound. as a colorless oil, m / e (MH +) 287 NMR (DMSO-d6) δ = 1.82 (m, 2H); 2.01 (nl, 2H); 2.83-3.09 (m, 2H); 4.12 (m, 2H); 4.40 (m, 1H); 5.11 (s, 2H); 7.28-7.45 (m, 5H); 8.65 (s, 2H). PREPARATION 33 1- (N-tert-butoxycarbonyl-(S) -valvl) -3- (imidazol-1-yl) azetidine 1 0054 40

A solution of 1- (N-tert-butoxycarbonyl) -3- (imidazol-1-yl) -azetidine (from Preparation 18) (0.72 g) in methylene chloride (30 ml) was saturated with chloride. hydrogen at 0 ° C and maintained at this temperature for another hour. The solvent was chased under vacuum to give the amine hydrochloride which was dissolved in N, N-dimethylformamide (25 ml) and the solution was treated at room temperature with the N-N-hydroxy-succinimide ester. -tertio-butoxycarbonyl (S) -valine (1.01 g) and N, N-diisopropylethylamine (1.7 ml). The reaction mixture was stirred for 18 hours at room temperature and the solvent was removed under vacuum. Purification of the residue by chromatography on silica gel eluting with methylene chloride-methanol-concentrated ammonia solution (97: 7: 1) afforded the title compound as a colorless foam (0.degree. 79NMR (DMSO-d6) δ = 0.89, 3.61-3.78 (m, 1H), g), m / e 323 (MH) + (m, 6H); 1.38 (s, 9H); 3.92-4.10 (m, 1H); 4.24-1.90 (m, 1H) 4.80 (m, 3H); 5.19 (m, 1H); 6.98 (s, 1H); 7.06 (dd, 1H)? 7.38 (s, 1H); 7.77 (s, 1H). PREPARATIONS 34-43

The following compounds of formula (VII) wherein R 4 is (S) -isopropyl and R 7 and R? Hydrogen were prepared according to the operating mode of Preparation 33 using the appropriate intermediate compound from Preparations 18 to 32 andby coupling to the N-t-butoxycarbonyl- (S) N-hydroxysuccinimide ester. -valine. Bu

CO-X- (CH 2) m -Het 10054 Preparation number -X- (CH 2) m Het MH * Analysis% Theoretical values in parentheses) CHN 3 4 NIL 1 338 35 -nQ ^ -n ^ h ν = (CF9 391 52.09 (52.32 6.73 6.46 14.03 14.36) 36 -'CFO 337 58.76 (59.11 8.51 8.46 16.6316.22) 337 59.46 (59.54 8,548.24 15,96 16,24) 38 -n Vn ^ n \ __ / / 351 39 ch3 l / \ -Ν ^ Ν V "/ 365 61.1 (61.1 9.23 8.91 14.9 15.0) 1 40 -Ο ~ ΝΓΝ 364.9 61.9 (61.9 9.15 8.9 14.9 15 ## EQU1 ## where: 365 59.29 (59.44 8.15 8.43 14.29 14.37) 43 ## EQU1 ## 0.5 mol of Cl 2 Cl 2 0.1 mol of CH 2 Cl 2 0 0.3 mol of CH 2 Cl 2 0054 PREPARATIONS 44-48

The following compounds of formula (VII) wherein R 4 is a sec-butyl group and m is equal. 0 were prepared following the production method of Preparation 33, using N-tert-butoxycarbonyl- (S) -isoleucine N-hydroxysuccinimide ester in the neck step. Bu

Preparatory No. -X-Het MIC "Snalÿse% (Theoretical values in parentheses) NCH 44 365 62.01 9.28 1.4.9 1 -N Vnan J lJ (61.99 8.87 15, 22) 451-N-N-N- / F-7 3 66.3 46 Cl-379 61.7 9.22 14.5 N-y-y (62.0 9.10 14.5) 2 4 7 Γ '379.9 62.2 8.98 14.3 3 -N V_) -NN ./ (62.0 9.10 14.5) 2 33 48 Γ NV \ -ΙΊ ^ Η / d. / 379.9 ch /

1. 0.2 mole of H 2 O 2 0.5 mole of 1 0054 43 PREPARATION 49 1- (N-tert-butoxycarbonyl) - (S) -isoleucyl) -4-ketopiperidine

The title compound was prepared using the same procedure as that described for

Preparation 33 but using ketopiperidine hydrochloride hydrate instead of 3- (imidazol-1-yl) azetidine hydrochloride, and (S) -isoleucine N-hydroxysuccinimide ester. m / e 313 (MH) + [α] 25 -16 ° (c = 0.34%, MeOH)

NMR (CDCl3) δ = 0.9 (m, 6H); 1.2 (m, 1H); 1.4 (s, 9H); 1.6 (m, 1H); 1.75 (m, 1H); 2.5 (m, 4H); 3.7 (m, 2H); 4.15 (m, 2K); 4.55 (m, 1H); 5.2 (d, 2H). PREPARATION 50 N- ((R) -2-Benzyl- (S) -5-tert-butoxycarbonylamino (S) -4- (tert-butyl dimethylsilyloxy) -6-phenylhexanovl) - (S) -valine

The title compound was prepared following the operating method described by S. J. de Solms et al. In J. Med. Chem. . 1991, 34, 2852. PREPARATION 51 1-Isocvano-3-methyl-1- (p-toluenesulfonyl) -but-1-ene

The title compound was prepared from p-toluenesulfonylmethylisocyanide and isobutyraldehyde by the procedure of Van Leusen, Schaart and Van Leusen, Rec. 98, No. 5, 258 (1979). I.R. (Nujol) 2100 cm -1 m / e 267 (M + NH 3) + NMR (CDCl 3) δ = 1.15 (d, 6H); 2.5 (s, 3H); 2.34 (m, 1H); 6.88 (d, 1H); 7.4 (d, 2H); 7.85 (d, 2H). PREPARATION 523-oxetanyloxycarbonyloxysuccinimide

Oxetan-3-ol (2.0 g) and N, N-diisopropylethylamine (7.76 g) were dissolved in methylene chloride (50 ml) and the solution was added dropwise to solution of bis-trichloromethyl carbonate (2.69 g) in methylene chloride (100 ml) maintained at -20 ° C for a period of 15 minutes under a nitrogen atmosphere. The solution was then stirred for a further 100 minutes at -20 ° C. and N-hydroxysuccinimide (3.45 g) was added in one portion and the solution was allowed to warm to room temperature. 2 hours, then washed with water (50 ml), saturated aqueous solution of sodium bicarbonate (50 ml) and a solution of salt (25 ml) The organic phase was then dried (MgSO 4), filtered and the solvent was chased off to give the title compound as a light brown oil (4.65 g) NMR (CDCl3) δ = 2.83 (s, 4H) 4.75 (m, 2H) 4.90 (m, 2H); 5.58 (m, 1H). EXAMPLE 1 1- [- ((R) -2-benzyl] -5- (tert-butoxycarbonylamino) - (S) - 4-hydroxy-6-phenylhexanovl) - (S) -valvl-1-3- (imidazol-1-yl) -azetidine a) 1- ΓΝ- ((R) -2-benzyl) (S) -5- ( tert-Butoxycarbonylamino) - (S) -4-tert-butyldimethylsilyloxy-6-phenylhexanovl) - (S) -valyll-3- (imidazol-1-yl) -azetidine

A solution of 1- (N-tert-butyloxycarbonyl- (S) -valyl] -3- (imidazol-1-yl) -azetidine (from Preparation 33, 0.79 g) in methylene chloride (50 ml) The solvent was evaporated in vacuo to give the amine as a colorless solid substance A solution of this product in dimethylformamide (20 ml) was saturated with methylene chloride at 0 ° C. and kept at this temperature for a further hour. was added to an active ester solution previously prepared by stirring together (R) -2-benzyl- (S) -2-tert-butoxycarbonylamino- (S) -4-tert-butyldimethylsilyloxy-6-phenylhexanoic acid (from of Preparation 2, 1.32 g), 1-hydroxybenzotriazole (0.36 g), 1- (3-dimethylaminopropyl) -3-ethylcarbodi-imide hydrochloride (0.58 g) and N, N- diisopropylethylamine (1.75 ml) in dimethylformamide (75 ml) for 20 minutes After stirring for another 24 hours, the solvent was removed in vacuo and the residue was partitioned between ethyl acetate and water. The ethyl acetate layer was separated, dried (MgSO4) and removed in vacuo to give a colorless oil. Purification by chromatography on silica gel eluting with ethyl acetate-methanol-concentrated ammonia solution (90: 10: 1) gave the title compound as a colorless foam: (1) , 1 g). Found: C, 66.04; H, 8.26; N, 9.61. C41H61N5O £ Si. 1/2 H 2 O requires C, 66.39; H, 8.36; N, 9.44%. m / e 733 (MH) + [α] 25 -6 ° (c = 0.29%, MeOH)

NMR (DMSO-d6) δ = 0.12 (m, 6H); 0.90 (m, 15H); 1.25-1.29 (2 x s, 9H); 1.96 (m, 1H); 2.32-2.77 (m, 4H); 2.89 (m, 1H); 3.48-3.74 (m, 2H)? 3.88-4.06 (m, 3H); 4.18- 4.66 (m, 4H)? 5.12 (m, 1H); 6.77 (t, 1H); 6.98 (s, 1H); 7.07-7.32 (m, 10H); 7.40-7.82 (2 x s, 1H); 7.76-7.96 (2xs, 1H); 3.0-8.20 (2 X d, 1H). b) 1-ΓΝ - ((R) -2-Benzyl- (S) -5- (tert-butoxycarbonylamino) - (S) -4-hydroxy-6-phenylhexanovl) - (S) -valvll-3- (imida-zole-1-yl) -azetidine

The product from step (a) (1.19 g) was dissolved in tetrahydrofuran and the solution was treated with 1 M tetra-n-butylammonium fluoride in tetrahydrofuran at room temperature.

After 48 hours, the solvent was removed in vacuo. The product was taken up in ethyl acetate, washed with saturated aqueous sodium bicarbonate solution and water, dried over MgSO 4, and dried. the solvent was evaporated under vacuum. Chromatographic purification on silica gel eluting with methylene chloride-methanol-ammonia in a concentrated aqueous solution (93: 7: 1), followed by recrystallization from ethyl acetate / hexane, afforded produced as a colorless solid (0.52 g), mp 124-126 °. Found: C, 67.99; H, 8.01; N, 11.06. C35H47N5O5 requires C ,. 68.05; H, 7.67; M, 11.34%. m / e 618 (MH) + [α] 25 -3 ° (c = 0.14% MeOH)

NMR (DMSO-d6) δ = 0.80 (m, 6H); 1.21-1.47 (ff, 1H); 1.27 (s, 9H); 1.58-1.71 (m, 1H); 1.81-1.93 (m, 1H)? 2.44-4.62 (m, 2H); 2.68-2.92 (m, 3H); 3.37 -3.62L (1H, 2H); 3.85-4.02 (m, 2H); 4.13-4.36 (m, 2H); 4.41-4.56 (m, 2H); 5.18 (m, 1H); 6.43 (d, 1H); 6.98 (s, 1H); 7.05-7.30 (m, 10H); 7.26-7.77 (2xs, 1H); 7.38-7.82 (2 X s, 1H); 7.88-7.98 (2 X d, 1H). EXAMPLES 2-10

The following compounds were prepared according to the general procedure described in Example 1 but using the appropriate protected carboxylic acid representative of the intermediate compound of formula (IV), and the appropriate amine of formula (VIII) in coupling step (a), the tert-butyldimethylsilyl protecting group being subsequently removed as described in step (b).

O 1 0054 47

10054 48

EXAMPLE 11 1- (S) -5- (tert-butoxycarbonylamino) - (S) -4-hydroxy-6-phenyl- (R) -2- (4- (trifluoromethoxy) benzyl) hexanoyl ) - (S) - valvl 1 - (S) -3- (irnidazol-1-yl) -pyrrolidine

The procedure of Example 1 was followed using 1- (N-tert-butoxycarbonyl- (S) -valyl) -3- (S) -imidazol-1-yl) -pyrrolidine (Preparation 36). step of: coupling followed by removal of the t-butyldimethylsilyl group as described in Example 1 (b) to give the title product. Mp 111-112 ° C Found: C, 61.90, H, 6.85, N, 9.61, C37H48F3N5O6 requires C, H, 6.76, N, 9.78% m / e (MH ) + 716 [a] 25 i 2 - (c = 0.1%, MeOH) D [a] 25 + 14 ° (c = 0.1%, MeOH) 365 NMR (DMSO-d6) δ = 0.65 0.90 (m, 6H); 3.7 (m, 1H); 4.40 (m, 1H); 4.40 (m, 1H); 4.40 (m, 1H); 1H), 6.90-6.95 (2 xs, 1H), 7.10-7.30 (m, 10H), 7.70-7.80 (2 X s, 1H), 7.90-8; EXAMPLE 12 1-ΓΝ - ((S) -5- (tert-butoxycarbonylamino) - (S) -4-hydroxyl-6-phenyl- (R) -2- (4- (2Xd, 1H)) (Trifluoromethoxy) -benzyl) -hexanoyl · - (S) - valyl1 - (R) -3- (imidazol-1-yl) -pyrrolidine

The procedure described above was followed, but starting from 1- (N-tert-butoxycarbonyl- (S) -vyl-3 - (R) imidazol-1-yl) -pyrrolidine, which resulted in given the product of the title, mp 109 ° C. Found: C, 61.44; H, 7.05; N, 9.71. C37H48F3N5 ° 6 2/5 H2 ° requires C, 61.47; H, 6.80; N, 9.69%. m / e (MH) + 716.

[?] 25 - 23 ° (c = 0.1%, MeOH)

NMR (DMSO-d6) δ = 0.70-0.85 (m, 6H); 1.15-1.40 (m, 10H); 1.60 (m, 1H)? 1.85 (m, 1H); 2.00-2.90 (m, 7H): 3.25-3.70 (m, 5H); 3.95 (m, 1H); 4.20 (m, 1H); 4.45-4.65 (m, 1H); 4.75-4.95 (2 x m, 1H); 6.40 (m, 1H); 6.90 (s, 1004 50 1H); 7.05-7.25 (m, 1OH); 7.70-7.75 (2 x s, 1H); 7.90-8.05 (2 x d, 1H). EXAMPLE 13 1 - ΓΝ - ((R) -2-Benzyl- (S) -5- (tert-butoxycarbonylamino) - (S) -4-hydroxy-6-phenylhexanoyl) - (S) -valyl-1- ( imidazol-1-yl 1-piperidine a) 1- [1- (R) -2-benzyl- (S) -5- (tert-butoxycarbonyl) amino) - (S) -4-tert-butyldimethylsilyloxy-6-phenylhexanoyl ) - (S) -valvl1-4- (imidazol-1-yl) -piperidine

The title compound was prepared from 1- (N-tert-butyloxycarbonyl- (S) -valyl] -4- (imidazol-1-yl) -piperidine and (S) -5-tert-butoxycarbonylamino acid. - (S) -4-tert-butyldimethylsilyloxy) - (R) -2-benzyl-6-phenylhexanoic using the same procedure as that which was written in step (a) of Example 1. By chromatographic purification on silica gel eluting with ethyl acetate-methanol-concentrated aqueous ammonia (90: 10: 1), the product was obtained as a colorless foam (0.71 g). Found: C, 67.32; H, 8.44; N, 9.22. C43H65N5O5 Si. 1/4 H20 requires C, 67.54; H, 8.56, N, 9.15%. m / e 760 (MK) + NMR (DMSO-d6) δ = 0.12 (m, 6H); 0.91 (m, 15H); 1.13-1.30 (m, 2H); 1.26 (s, 9H); 1.47-1.76 (m, 2H); 1.89-2.08 (m, 4H); 2.36-2.97 (m, 6H); 3.50-3.75 (m, 2H); 3.99-4.61 (m, 4H); 6.79 (m, 1H); 6.90 (d, 1H); 7.07-7.29 (m, 11H); 7.68-7.73 (2 X s, 1H); 7.93-7.99 (2 X s, 1H). b) 1- ΓΝ-f (R) -2-Benzyl- (S) -5- (tert-butoxycarbonylamino) - (S) -4-hydroxyl-6-phenylhexanoyl) - (S) -valyl-4-one (imida-zole-1-yl) -piperidine

The title compound was prepared from the product of step (a) above in the same operating mode as that described for step (b) of Example 1. By chromatographic purification on gel desilice with elution with a methylene chloride-methanol-concentrated aqueous ammonia solution, followed by recrystallization from ethyl acetate / hexane, the product was obtained as a solid colorless, P, .F. 121-123 ° (0.48 g). Found: C, 68.38; H, 7.96; N, 10.59. C 37 H 51 N 5 O 5 1/4 H 2 O requires C, 68.30; H, 7.92; N, 10.77%. m / e 646 (MH) + (a) 25-10 ° (c = 0.1% MeOH)

NMR (DMSO-d6) δ = 0.77 (m, 6H); 1.19-1.37 (m, 1H); 1.28 (s, 9H); 1.48-1.72 (m, 3H); 1.82-2.04 (m, 3H); 2.42-2.94 (m, 7H); 3.38-3.60 (m, 2H); 3.96-4.15 (m, 1H); 4.28 (m, 1H); 4.37-4.58 (m, 3H); 6.43 (d, 1H); 6.88 (s, 1H); 7.04-7.29 (m, 11H); 7.65-7.92 (2 x s, 1H); 7.84-7.88 (2 X d, 1H). EXAMPLES 14-37

The following compounds were prepared according to the general procedure described in Example 13 but using the appropriate intermediate protected carboxylic acid of formula (IV) and the appropriate valine or isoleucine derivative of formula (VIII) in the coupling step (a), the operation being followed by the removal of the tert-butyldimethylsilyl protecting group as described in step (b).

10054 52

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(NOT

fzT 54

Tartaric acid, hemihydrate 100 EXAMPLE 31 1-ΓΝ- (R) -2-Benzyl- (S) -5- (tert-butoxycarbonylamino) - (S) -4-hydroxy-6-phenylhexanoyl) - (S) ) -valyl1- (S) -4- (1,2,4-triazol-4-yl) -piperidine

The benzyloxycarbonyl protecting group was removed from 1- (H-benzyloxycarbonyl) -4- (1,2,4-triazol-4-yl) -piperidine (Preparation 32) by catalytic hydrogenation and the product amine was coupled to N - ((R) -2-Benzyl- (S) -5- (tert-butoxycarbonylamino) - (S) -4- (tert-butyldimethylsilyloxy) -6- (phenylhexanoyl) - (S) -valine by the method of operation described for step (a) of Example 1, exonating 1- (N - ((R) -2-benzyl- (S) -5- (tert-butoxycarbonyl-amino) - (S) -4- (tert-Butyldimethylsilyloxy) -6- (phenylhexanoyl) - (S) -valyl] -4- (1,2,4-triazol-4-yl) -piperidine, m / e761 (MH) +.

The above product was treated with tetra-n-butylammonium fluoride by the procedure of step (b) of Example 1 to give the title product. Found: C, 64.90; H, 7.93; N, 12.48. C36H50N6O • H2O requires C, 65.06, H, 7.83; N, 12.65%. m / e 647 (MH) + [α] 25 ° -9 ° (c = 0.12%, MeOH)

D (m, 10H) (m, 7H) (m, 4H) (m, 1H) NMR (DMSO-d6) δ = 0.70-0.92 (m, 6H); 1.46-1.76 (m, 3H); 1.81-2.16 (m, 3H); 3.38-3.64 (m, 2H); 3.95-4.15 (m, 1H); 6.36-6.44 (m, 1H); 7.01-7.12 (m, 10H); 8.54 (s, 1H); 8.60 (s, 1H). EXAMPLE 32 1.15-1.41 2.53-2.96 4.27-4.61 7.78-7.91

1 - ΓΝ - ((S) -5- (tert-butoxycarbonylamino) - (S) -4-hydroxy-6-phenyl- (R) -2- (4-trifluoromethoxybenzyl) hexanoyl) - (S) - tartrate valyl. 1- (Imidazol-1-yl) -1,2,5,6-tetrahydropyridine a) Reaction of (S) -5-tert-butoxycarbonylamino- (S) -4-tert-butyldimethyl-3-yloxy-acid ) - (R) -2- (4-trifluoromethoxybenzyl) -6-phenylacetic acid and amineprepared by removal of the protecting group for 1- (N-tert-butoxycarboriyl) -4-imidazol-2-yl- (1, 2,5,6-tetrahydro-pyridine) according to the same procedure of Example 1 (a) gave 1- [N - ((S) -5-tert-butyloxycarbonylamino) - ( S) -4-tert-butyldimethylsilyloxy) -6-phenyl- (R) -2- (4-trifluoro-methoxybenzyl) -hexanoyl- (S) -valyl] -4- (imidazol-1-yl) -l, 2,5,6-tetrahydropyridine. Found: C, 62.19; H, 7.39; N, 8.38. C33H62F3N5 ° 6i; 1/10 CH2Cl2 requires C, 62.27; H, 7.37; N, 8.23%. m / e 842 (M) + [α] 25 - 10 ° (c = 0.1%, MeOH)

D 7.30 (m, 11H) b) NMR (CDCl 3) δ = 0.10 (m, 6H); 0.80 (d, 6H); 0.90 (s, 9H); 1.35 (s, 9H); 1,, 20-1.95 (m, 5H); 2.35-2.55 (m, 3H)? 2.70 (m, 2H); 3.41-4.10 (m, 6H); 4.55 (m, 1H); 4.65 (d, 1H); 5.60-5.80 (2 X s, 1H); 6.25 (d, 1H); 6.90- 7.65 (s, 1H). Removal of the protecting group by reaction with tetra-n-butylammonium fluoride according to the procedure of Example 1 (b) gave the title product as the free base. The latter was dissolved in absolute ethanol and the solution was treated with a solution of 1-tartaric acid (0.14 g) in absolute ethanol. The addition of ether gave a precipitate which was filtered off. and dried to give the 1-tartaric salt as a colorless solid substance, m.p. 92-152 ° C (0.61 g). Find ::

ί16 ° 6 V3 H2O C, 57.40; H, 6, 4; N, 7.51. C38H38N5O65 requires C, 57.11; H, 6, 23; N, 7.93%. m / e (MH) + 728 [a] 25-6.7 ° (c = 0.1%, MeOH) D [a] 25 - 6.7 ° (c = 0.1%, MeOH) 365 NMR ( DMSO-d6) δ = 0.75 (m, 6H); 1.25 (s, 9H); 0.95-1.40 (m, 1H); 1.50 (m, 1H); 2.35-2.95 (m, 7H); 3.0-3.85 (m, 4H) 4.10 (m, 1H); 4.10 (m, 1H); 4.25 (s, 1H) 2H); 6.0 (m, 1H); 6.40 (d, 1H); 7.0 (s, (m, 9H), 7.50 (s, 1H), 7.95 (m, 2H), 1.2 (m, 6H), H); 1.90 (m, 4.0 (m, 1H); 4.40-4.50 (m); 7.10-7.30 10054 EXAMPLE 33 1- (S) -5- ( tert-Butoxycarbonylamino) - (S) -4-hydroxy-6-phenyl- (R) -2- (4-trifluoromethoxybenzyl) -hexanovl) - (S) -isoleucyl-4- (5-isopropylimidazol-1-yl) - piperidine a) Removal of the 1- (M-tert-butoxycarbonyl- (S) -isoleucyl) -4-ketopiperidine-protecting group (Preparation 49) followed by reaction with (S) -5-acid -butyloxycarbonylamino- (S) -4- (tert-butyldimethylsilyloxy) -6-phenyl- (R) -2- (4-trifluoromethoxybenzyl) hexanoic acid (Prep. 10) gave N - ((S) -5- (tert-butoxycarbonylamino- (S) -4- (tert-butyldimethylsilyloxy) -6-phenyl- (R) -2- (4-trifluoromethoxybenzyl) hexanoyl- (S) -isoleucyl] -4-ketopiperidine Found: C, 62.50, H, 8.00, N, 5.20, C 42 H 62, 33 ° C, requires C, 62.60, H, 7, 80, N, 5.20%, m / e 806.5 (M) -1, [α] 25 - 5.30 (c = 0.1%, MeOH).

B) The above product (2.0 g) and an aqueous ammonia solution (density 0.88) in ethanol (25 ml) were hydrogenated with palladium on carbon (100 mg) under pressure of 30 psi (2.0 bar) for 4 hours. Filtration of the catalyst and evaporation of the solvent gave 2.0 g of a colorless foam which was chromatographed on silica gel eluting with dichloromethane: methanol: concentrated aqueous ammonia solution (90:10: 1) to give, after concentration of the appropriate fractions, 1- [N - ((S) -5-tert-butoxycarbonyl-amino- (S) -4-tert-butyldimethylsilyloxy-6-phenyl- (R) 2 - (4-trifluoromethoxy) -benzyl) hexanoyl) - (S) -isoleucyl] -4-amino-piperidine as a colorless glassy substance in an amount of 1.53 g. c) The product from step b) above (404 mg) and 1-isocyano-3-methyl-1- (p-toluenesulfonyl) -but-1-ene (from preparation 51, 150 mg ) were stirred together in methanol (15 ml) with diisopropylethylamine (100 mg) for 16 hours. The solvent was stripped at 40 ° C and the residue was purified by chromatography on silica gel eluting with dichloromethane: methanol: concentrated aqueous ammonia solution (98: 2: 04). gave 1- (N - ((S) -5- (tert-butoxycarbonylamino) - (S) -4-tert-butyldimethylsilyloxy-6-phenyl- (R) -2- (4-trifluoromethoxybenzyl) hexanoyl) - (S) -isoleucyl] -4- (5-isopropylimidazolyl-1-yl) -piperidine as a colorless glassy substance (380 mg) m / e 900 (MH) + d) The product from step c) above was stripped of the protecting group by treatment with tetra-n-butylammonium fluoride according to the procedure of Example 1 (b) to give the title product.

Found: C, 63.5; H, 7.70; N, 8.70. C42H58F3N5O6. 1/2 H 2 O requires C, 63.5, H, 7.48; N, 8.81%. me. 785.9 (MH) + NMR (DMSO-d6) δ = 0.8 (m, 6H); 1.05 (m, 1H); 1.2 (m, 6H); 1.3 (s, 9H); 1.3-2.0 (m, 7H); 2.5-3.0 (m, 6.5H); 3.2 (1, 0.5H); 3.3 (m, 1H); 3.58 (m, 1H); 4.13 (m, 3H); 4.4-4.65 (m, 4H); 6.43 (m, 1H); 6.63 (s, 1H); 7.1-7.3 (m, 9H); 7.47, 7.6 (s, s, 1H); 7.95 (Lt, 1H). EXAMPLE 34 1- (N - ((S) -4-Hydroxy- (S) -5- (oxetane-3-yl) oxycarbonylamino-6-phenyl- (R) -2- (4-trifluoromethoxybenzyl) hexanoyl) - (S) ) -valyll-4- (imidazole-1-yl) -piperidine

The product from Example 16 (4.0 g) was dissolved in methylene chloride (40 ml) and the solution was cooled in an ice bath. Trifluoroacetic acid (10 ml) was added dropwise over a period of 5 minutes and the solution was stirred at 0 ° C for 1.5 hours. The solvent was evaporated in vacuo and the residue was taken up in ethyl acetate (250 ml) and washed with 1M sodium hydroxide (50 ml) and brine (50 ml). The organic solution has been dehydrated! (MgSO4), filtered and the solvent evaporated in vacuo. By chromatography on silica gel eluting with a mixture of ethyl acetate, methanol and aqueous ammonia solution (90: 10: 1), 1 - [N - ((S) - was obtained. Amino- (S) -4-hydroxy-6-phenyl- (R) -2- (4-trifluoromethoxy-benzyl) -hexanoyl) - (S) -valyl] -4- (imidazole-1) -yl) -piperidines in the form of a white solid (2.98 g), m / e 630 (MH) + NMR (DMSO-d6) δ = 0.78 (m, 6H); 1.34-1.75 m-4H); 1.81-2.07 (m, 3H); 2.37-2.93 (m, 8H); 3.05-3.29 (m, 3H); 4.05-4.56 (m, 5H); 6.88 (s, 1H); 7.10 -7.27 (m, 10H); 7.67 (d, 1H); 7.95 (m, 1H). b) The product from step a) (0.818 g) was dissolved in methylene chloride (30 ml). 3-Oxetan-N-carbonyloxysuccinimide (0.344 g) was added and the solution was stirred at room temperature for 1 hour. The solution was then washed with 0.5M desodium hydroxide (15 ml) and brine (15 ml), dried (MgSO4), filtered and evaporated in vacuo. The resulting solid was recrystallized from ethyl acetate to give the title compound as a white solid, m.p. 201-203 ° C. Found: C, 60.32; H, 6.22; N, 9.15. C37H46F3N5O7 1/2 "20 requires Cr60.15; H, 6.41; N, 9.48%. m / e 730 (MH) + [α] 25 + 3 ° (c = 0.1%, MeOH)

D

[?] 25 + 32 ° (c = 0.1, MeOH) NMR (DMSO-d6) δ = 0.77 (m, 6H); 1.22-2.05 (m, 7H)? 2.50-2.93 (m, 8H); 3.42-3.60 (m, 2H); 4.08 (d, 1H); 4.22-4.73 (m, 7H); 5.12 (m, 1H); 6.89 (s, 1H)? 7.11-7.28 (m, 11H); 7.67 (d, 1H); 7.86 (d, 1H). EXAMPLE 35 1-ΓΝ- (S) -4-Hydroxy- (S) -5- (oxetane-3-yloxycarbonylamino) -5-phenyl- (R) -2- (3-phenylprop-2-enyl) hexanoyl) - (SI-isoleucyl-4- (imidazol-1-yl) piperidine

A solution of the product from Example 13 (0.45 g) in methylene chloride (20 ml) was treated with anhydrous trifluoroacetic acid (4 ml) at 0-5 ° C. for 5 hours; The reaction mixture was then concentrated in vacuo and the residual gum azeotroped with toluene (x3) and dehydrated. A solution of the crude amine product and diisopropylethylamine (0.82 ml) in sodium chloride. Methylene (25 ml) was then cooled to 5 ° C and a solution of 3-oxetanyloxycarbonyloxysulfinimide (0.22 g) in methylene chloride (5 ml) was added dropwise. The reaction mixture was allowed to warm to room temperature, held there for 17 hours, then washed with water, dried (MgSO4) and evaporated under vacuum. Purification by chromatographic purification on silica gel eluting with methylene chloride-methanol-concentrated aqueous ammonia solution (95: 4: 1) afforded the product as a colorless foam, m.p. 157-160 ° C. (0.26 g).

Found: C, 66.45; H, 7.49; N, 10.22. C38H49N5 ° 6 3/4 H2 ° requires C, 66.60; H, 7.43; N, 10.22 [α] 25 + 32 ° (c = 0.1%, MeOH)

NMR (DMSO-d6) δ = 0.75 (m, 6H); 1.25-2.95 (m, 12H); 3.05-3.65 (m, 4H); 3.95-4.75 (m, 10H) 5.05 (m, 1H); 6.10 (m, 1H); 6.30 (d, 1H); 6.80-6.85 (2 x s, 1H); 6.95-7.35 (m, 11H); 7.55-7.65 (2 X s, 1H); 7.95 (d, 1H), EXAMPLE 36

1- (S) -4-Hydroxy (S) -5- (isopropyloxycarbonylamino) -6-phenyl- (R) -2- (3-phenylprop-2-enyl) hexanoyl tartarate ) - (S) --isoleucvll-4- (imidazol-1-yl) -piperidine

The title compound was prepared following the procedure described above for Example 35, except that isopropyl chloroformate was used for reaction with the intermediate amine. On chromatographic purification on silica gel eluting with a methylene chloride-methanol-aqueous concentrated ammonia solution (97: 2: 1 to 95: 4: 1), the product was obtained in the form of a colorless powder which was recrystallized from a mixture of ethyl acetate and hexane. The free base was dissolved in ethanol and the solution was treated with 1-tartaric acid solution. By addition of diethyl ether, the tartaric acid was obtained as a colorless powder, m.p. 156-157 ° C.

Found: C, 61.60; H, 6.87; N, 8.38 C 38 H 51 N 5 O 5 C 4 H 6 O 6 T 2 H 2 O requires C, 61.75; H, 7.16; N, 8.57%. m / e 658 (MH) + [α] 25 + 26 ° (c = 0.1%, MeOH)

NMR (DMSO-d6) δ = 0.75 (m, 6H); 1.0 (m, 6H); 1.25-3.65 (m, 14H); 3.95-4.70 (m, 10H); 6.10 (m, 1H); 6.30 (d, 1H); 6.65 (d, 1H); 6.85-6.90 (2 x s, 1H); 7.05-7.35 (m, 11H); 7.65-7.75 (2 X s, 1H); 7.90 (d, 1H). EXAMPLE 37

1-N- (S) -5- (tert-butoxycarbonylamino) -6-phenyl-L (R) -2- (4-trifluoromethoxybenzyl) -4- (S) -valyloxy) -hexanoyl) - (S) - tartrate valyl 1-4- (imidazol-1-yl) -piperidine a) N-Benzyloxycarbonyl-L-valine (1.03 cf) and dicyclohexylcarbodiimide (0.51 g) were dissolved in dichloromethane (25 ml) and the mixture was stirred for 3 hours. The precipitated dicyclohexylurea was collected by filtration and the filtrate was evaporated to give a white foam. This white foam was mixed with the product of Example 16 in N, N-dimethylformamide (20 mL), and dimethylaminopyridine (0.025 g) was added. After stirring at room temperature for 5 days, the mixture was partitioned between ethyl acetate and water. Dehydration of the organic extract (MgSO 4) and evaporation of the solvent followed by chromatography on silica gel, eluting with a mixture of ethyl acetate and methanol (0-10%), gave 1- [N- (S) -4- (Benzyloxycarbonyl- (5-valyloxy) - (S) -5- (tert-butoxycarbonylamino) -6-phenyl- (R) -2- (4- (trifluoromethoxy) -benzyl) hexanoyl- (S) -valyl] -4- (imida- 10054 62

zole-1-yl) -piperidine as a white foam. Found: C, 62.63; H, 6.73; N, 8.37. C 8 H 18 F 4 O 5. H2O requires C, 62.43; H, 6.88; N, 8.56%. m / e 963 (MH) + b) The product from step a) above (0.95 g) was dissolved in absolute ethanol (50 ml) and the solution was treated with palladium at 10% on duchabon (0.1 g) and hydrogenated under pressure. 60 lb / in2 (4.1 bar) at room temperature for 4 hours. After removal of the catalyst, the filtrate was evaporated to dryness. Chromatographic purification on silica gel eluting with dichloromethane-methanol-aqueous concentrated ammonia solution (97: 3: 0.5), the product was obtained as a white foam. This foam was dissolved in ethyl acetate (6 ml) and tartaric acid solution (0.089 g) in a mixture of 10% methanol and ethyl acetate (10 ml) was added . Evaporation of the solvent and trituration with diethyl ether afforded the product as a white glass (0.48 g) having a melting point of 122 ° C. Find: C, 56.74; H, 6.78; N, 8.56. c43H5gF3NgO7: H2O requires C, 56.61; H, 6.77; N, 8.43%. NMR (DMSO-d 6) 6 = 0.8-0.95 (m, 12H); 1.2 (s, 11H); 1.35-1.77 (m, 2H); 1.8-2.15 (m, 4H); 2.4-3.2 (m, 8H); 3.51 (m, 1H); 3.8 (m, 1H); 4.1 (m, 1H); 4.3 (m, 1H); 4.4-4.65 (m, 2H); 4.81 (m, 1H); 6.83 (s, 1H); 7.0-7.32 (m, 12H); 7.66 (d, 1H)? 7.73-8.0 (m, 1H).

Claims (13)

10054 63 CLAIMS 1. Compound characterized in that it corresponds to the formula ## STR5 ## OR pharmaceutically acceptable salts of this compound or suitable bioprecursors, wherein R 1 is C 1 -C 6 alkyl, C 1 -C 8 cycloalkyl, aryl, heterocyclyl or CONR 9 R 10; R2 is (C1-C6) alkyl, (C3-C8) cycloalkyl (C1-C4) alkyl, aryl (C1-C4) alkyl (C1-4) or heterocyclyl (C1-4) alkyl; R3 is a C1-C4 alkyl group. C6, C3-C8 cycloalkyl, (C3-C8) -cycloalkyl (C1-C4) alkyl, aryl (C1-C4) alkyl, aryl (C2-C4) alkenyl, heterocyclyl (C1-C4) alkyl ) or heterocyclyl (C2-C4 alkenyl); R4 is C3-C6alkyl, C3-C8cycloalkyl, aryl or heterocyclyl, each of R5, R6, R7 and R8 is, independently, H, C1-C6alkyl or C3-C6cycloalkyl; or R5 and R6, or R7 and R8, may associate to form a 3- to 8-membered carbocyclic ring; X is a 4- to 10-membered monocyclic orbicyclic heterocyclic group containing cyclic carbon atoms and a ring nitrogen atom through which the group is attached to the adjacent carbonyl group, the group may be saturated or partially unsaturated, and With the substituent - (CR7R8) m - Het, it may carry up to four further substituents independently selected from F, C₁ to C C alkyl, Cg to C8 cycloalkyl, OR11 and NR9R10; Het is an imidazolyl or triazolyl group. Each may optionally be substituted with C 6 -C 8 cycloalkyl, C 3 -C 8 cycloalkyl, NR 'R 10 or CONR 9 R 10, each of R 9 and R 10 independently represents H, C 1 -C 6 alkyl or C 3 -C cycloalkyl. Where R 'and R' may combine to form, together with the azo atom to which they are attached, a 4 to 8-membered nitrogen-containing heterocyclic group, R11 is H, C1-C6 alkyl or C8-cycloalkyl; Cg; n and ra are each independently 0, 1 or 2; any alkyl or cycloalkyl group included in the above-mentioned definitions may, optionally, be wholly or partially substituted by fluorine. 2. Compound according to claim 1, character-ized in that it has the stereochemistry: OR2 OR4 R '- (CR = R' =) ^ oANHk ^^ ANHkrX- (CR7R8) m -HetHÔ R3 O in which R1 to R8, n, m, X and Het are as previously defined in claim 1. 3. A compound according to claim 1 or claim 2 characterized in that R 1 is a tetra-butyl, isopropyl or oxetanyl group and n is 0. 4. Compound according to claim 3, character-ized in that R ^ is the benzyl group. 10054 65 5. A compound according to claim 3 or claim 4 characterized in that R4 is isopropyl or sec-butyl. 6. A compound according to any one of claims 3 to 5, characterized in that R 3 is a benzyl group, optionally substituted on the phenyl ring with a methyl, fluoro, chloro, iodo, CF 3 or OCF-j radical, or R3 is 3-phenylpropyl or 3-phenylprop-2-enyl. 7. A compound according to any one of claims 3 to 6, characterized in that each of R5, R6, R7 and R8 is hydrogen. 8. A compound according to any one of claims 3 to 7, characterized in that m has the value 0 or 1. 9. Compound according to claim 1, character-ized in that it is: 1- [N - ((R) -2-benzyl- (S) -5- (tert-butoxycarbonylamino) - {S) 4-hydroxy-6-phenylhexanoyl) - (S) -valyl] -3- (imidazol-1-yl) azetidine, 1- [N - ((R) -2-benzyl- (S) -5- ( tert-butoxycarbonylamino) - (S) - 4-hydroxy-6-phenylhexanoyl) - (S) -valyl] -4- (imidazol-1-yl) piepridine, 1- [N- ((S) - 5- (tert-Butoxycarbonylamino) - (S) -4-hydroxy-6-phenyl- (R) -2- (3-phenylprop-2-en-1-yl) hexanoyl) - (S) -valyl] - 4- (Imidazol-1-yl) piperidine, lal- [N - ((S) -5- (tert-butoxycarbonylamino) - (S) -4-hydoxy-6-phenyl- (R) -2- ( 4-trifluoromethoxybenzyl) hexanoyl) - (S) -valyl] -4- (imidazol-1-yl) piperidine, 1- [N- ((S) -5- (tert-butoxycarbonylamino) - (R) -2- (4-Chlorobenzyl) - (S) -4-hydroxy-6-phenylhexanoyl] - (S) -valyl] -3- (imidazol-1-yl) azetidine and 1 - [N - ((S) -5- (tert-Butoxycarbonylamino) - (S) - 4-hydroxy-6-phenyl- (R) -2- (4-trifluoromethoxybenzyl) hexanoyl) - (S) -isoleucyl] -4- (imidazol-1-yl) piperidine . 10. Process for the production of a compound of formula (I) according to claim 1, characterized in that it comprises the removal of the protective groups of a compound of formula: X- (CR7Rf1) m -Het wherein X * is a selectively removable hydroxy-protecting group, and R1-R8, X and Het are as defined in claim 1 and the compounded isolation of formula ( I) and optionally forming a pharmaceutically acceptable salt thereof. A pharmaceutical composition, characterized in that it comprises a compound of formula (I) or (Ia) or a pharmaceutically acceptable salt thereof, or a suitable prodrug as defined in any one of claims 1 to 9, together with a diluent or carrier acceptable from a pharmaceutical point of view. 12. A compound of formula (I) or (la) or its pharmaceutically acceptable salt or a suitable bioprecursor according to any one of claims 1 to 9 for use in medicine, especially in the treatmenturative or preventive treatment of human retroviral infections . 13. Use of a compound of formula (I) or (la) according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for use in clans the curative or preventive treatment of retroviral infections;