WO1993023373A1

WO1993023373A1 - N-[N'-(5-AMINO-4-HYDROXY-ACYLOYL)-α-AMINOACYLOYL] SUBSTITUTED HETEROCYCLES AND THEIR USE AS ANTIVIRAL AGENTS

Info

Publication number: WO1993023373A1
Application number: PCT/EP1993/000592
Authority: WO
Inventors: Colin William Greengrass; Geoffrey William Gymer; David William Thomas Hoople; Stephen Derek Albert Street; Peter John Whittle
Original assignee: Pfizer Limited; Pfizer Inc.
Priority date: 1992-05-20
Filing date: 1993-03-13
Publication date: 1993-11-25
Also published as: GB9210744D0; FI945438A; EP0641319A1; FI945438A0; CA2133583A1; AU3748293A; JPH07503482A

Abstract

Compounds of formula (I) wherein R1 is C1-C6 alkyl, C3-C8 cycloalkyl, aryl, heterocyclyl, or R?7R8NCO; R2 is C¿1-C6 alkyl, C3-C8 cycloalkyl(C1-C4)alkyl, aryl(C1-C4)alkyl, or heterocyclyl(C1-C4)alkyl; R3 is C1-C6 alkyl, 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 C1-C6 alkyl, C3-C8 cycloalkyl, aryl or heterocyclyl; R?5 and R6¿ are each independently H, C¿1?-C6 alkyl, C3-C7 cycloalkyl, or C1-C6 alkyl substituted by C1-C4 alkoxy, hydroxy or NR?7R8; or R5 and R6¿ are linked to form, together with the nitrogen atom to which they are attached, a pyrrolidine, piperidine, morpholine, piperazine or N-(C¿1?-C4 alkyl) piperazine group; each of R?7 and R8¿ is independently H, C¿1?-C6 alkyl or C3-C8 cycloalkyl or R?7 and R8¿ may be joined together to form, with the nitrogen to which they are attached, a 4 to 8 membered nitrogen-containing heterocyclic group; each of R?9, R10, R11 and R12¿ is independently H, C¿1?-C6 alkyl or C3-C8 cycloalkyl; or R?9 and R10, or R11 and R12¿ may be joined together to form a 3 to 8 membered carbocyclic ring; X is a 4-10 membered mono- or bicyclic heterocyclic group containing carbon ring atoms and one 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 -(CR11R12)m -NR5R6 substituent, it may be substituted by up to 4 further substituents each independently chosen from F, C¿1?-C6 alkyl, C3-C8 cycloalkyl, OH, C1-C6 alkoxy or NR?7R8¿; and n and m are each independently 0, 1 or 2; and wherein any alkyl or cycloalkyl group included in the aforementioned definitions may optionally be fully or partially substituted by fluorine; are inhibitors of retroviral proteases of utility in the treatment and prophylaxis of human retroviral infections.

Description

N-[N ' - ( 5-AMINO-4-HYDROXY-ACYLOYL)- α -AMINOACYLOYL] SUBSTITUTED HETEROCYCLES AND THEIR USE AS ANTIVIRAL AGENTS

The present invention relates to certain peptide derivatives containing a heterocyclic group which are useful in the treatment or prophylaxis of human retroviral infections.

The human immunodeficiency virus (HIV), a retrovirus, is the causative agent of a variety of clinical conditions, the most serious of which are commonly termed AIDS (Acquired

Immunodeficiency Syndrome), and ARC (AIDS-Related Complex).

Infection with HIV is characterised by progressive breakdown of the immune system and CNS dysfunction. Severely immune deficient patients suffer from a wide range of opportunistic infections (e.g. pneuroocvstis carinii, human cyteimegalovirus, or Candida), and cancers such as Kaposi's sarcoma. Loss of cells, particularly

CD4⁺ lymphocytes, following infection with HIV is an important factor in the progressive impairment of immune function. The infection of cells of raorκx-yte/macrophage lineage with HIV also contributes to the observed pathology. Unas, successful infection of CD4 cells by HIV is a key step in the disease process.

HIV is a retrovirus; it encodes its genetic information in RNA, which is converted into DNA after the virus enters the host cell. An essential step in the retroviral replication cycle is the processing of an initial polypeptide precursor into mature structural and replicative proteins. This processing is carried out by a virus-coded protease and, in the absence of this enzyme activity, viral replication is blocked.

We have discovered that certain peptide derivatives linked to a heterocyclic group are potent inhibitors of retroviral

proteases, both in a cell-free assay and in infected cells and, in addition, show antiviral activity in tissue culture assays. This activity renders such compounds useful for the treatment and prophylaxis of retroviral infections, in particular, those caused by HIV. Thus, the invention provides cxfmpσunds of the formula:-

and pharmaceutically acceptable salts thereof and bicprecursors therefor,

wherein R¹ is C₁-C₆ alkyl C₃-C₈ cycloalkyl, aryl, heterocyclyl or R⁷R⁸NCO;

R² is C₁-C₆ alkyl, C₃-C₈ cycloalkyl (C₁-C₄)alkyl, aryl (C₁-C₄) alkyl, or heterocyclyl (C₁-C₄) alkyl;

R³ is C₁-C₆ alkyl, 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 C₁-C₆ alkyl, C₃-C₈ cycloalkyl, aryl or heterocyclyl;

R ⁵ and R⁶ are each independently H, C₁-C₆ alkyl, C₃-C₇ cycloalkyl, or C₁-C₆ alkyl substituted by C₁-C₄ alkoxy, hydroxy or NR⁷R⁸; or R⁵ and R⁶ are linked to form, together with the nitrogen atom to which they are attached, a pyrrolidine, piperidine, morpholine, piperazine or N-(C₁-C₄ alkyl)piperazine group;

each of R⁷ and R⁸ is independently H, C₁-C₆ alkyl or C₃-C₈ cycloalkyl or R ⁷ and R⁸ may be joined together to form, with the nitrogen to which they are attached, a 4 to 8 membered nitrogen-containing heterocyclic group; each of R⁹, R¹⁰, R¹¹ and R¹² is independently H, C₁-C₆ alkyl or C₃-C₈ cycloalkyl, or R⁶ and R¹⁰, or R¹¹ and R¹² may be joined together to form a 3 to 8 membered carbocyclic ring;

X is a 4-10 membered mono- or bicyclic heterocyclic group containing carbon ring atoms and one 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 -(CR¹¹R¹²) -NR⁵R⁶ substituent, it may be substituted by up to 4 further substituents each independently chosen from F, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, OH, C₁-C₆ alkoxy or NR⁷R⁸;

and n and m are each independently 0, 1 or 2; and wherein any alkyl or cycloalkyl group included in the aforementioned definitions may optionally be fully or partially substituted by fluorine. In the above definition of R¹, R², R³ and R⁴, heterocyclyl means a 4 to 6 membered heterocyclic group containing as

heteroatoms up to four nitrogen atoms, or an oxygen or sulphur atom optionally with one or two nitrogen atoms. The ring may be aromatic, or fully or partially saturated and may optionally be benzo-fused or substituted by C₁-C₆ alkyl, C₁-C₈ cycloalkyl, C₂-C₅ alkanoyl, C₁-C₄ alkoxy, halo, hydroxy, oxo or aryl. Preferred heterocyclyl groups are pyridyl, pyrimidinyl, thienyl, isoquinolyl and tetrazolyl.

In the above definitions of R¹, R², R³ and R⁴, aryl means phenyl optionally substituted with from 1 to 3 substituents each independently selected from C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₁-C₄ alkoxy, C₂-C₅ alkanoyl, hydroxy, halo, C₁-C₄ alkyl fully or partially substituted by fluorine, C₁-C₄ alkoxy fully or partially substituted by fluorine, phenyl, phenoxy, benzyl, benzoyl, phenylSO₂-, pyridyl, tetrazolyl, phenyltetrazolyl, NR⁷R⁸ or

CONR⁷R⁸; wherein R⁷ and R⁸ are as previously defined.

Halo means fluoro, chloro, bromo or iodo. Alkyl and alkoxy groups containing 3 or more carbon atoms may be branched or straight-chain. Any alkyl, alkoxy or cycloalkyl group included in the above definitions may optionally be fully or partially substituted by fluorine.

The term bioprecursor in the above definition means a pharmaceutically acceptable biologically degradable derivative of the compound of formula (I) which, upon administration to an animal or human being, is converted in the body to produce a corpound of the formula (I). Examples include ester derivatives formed between the free hydroxy group in the compound of formula (I) and, for example, an amino acid (such as L-valine).

It will be appreciated that the compounds of formula (I) have a number of asymmetric carbon atoms and the invention includes all possible stereoisomers whether separated or not.

In one particular and preferred aspect of the invention there are provided compounds having the stereochemistry-:

In the above formula heavy bonds are used to indicate that the group lies above the plane of the molecule while a broken bond is used to indicate that the group lies below.

In the definition of R¹, aryl is preferably phenyl and heterocyclyl is preferably oxetan-3-yl or 1,1-dioxothietan-3-yl. R¹ is preferably t-butyl, isopropyl, oxetan-3-yl or 1,1-dioxothietan-3-yl and (CR⁹R¹⁰) is absent; or R¹ is phenyl and

(CR⁹R¹⁰)_n is CH₂; or R¹ is H₂NCO-, CH₃NHCO- or (CH₃)₂NCO- and

(CR⁹R¹⁰)_n is CH₂ or CH(CH₃) . Particularly preferred are compounds wherein R¹ is t-butyl, isopropyl or oxetan-3-yl and n is 0, most particularly where R¹(CR⁹R¹⁰) - is t-butyl.

In the definition of R², aryl is preferably phenyl and heterocyclyl is for example pyridyl, pyrimidinyl or thienyl. R² is preferably aryl(C₁-C₄) alkyl; benzyl is particularly preferred.

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

The heterocyclic group X is preferably a 4-6 membered saturated or mor-ounsaturated group and is most preferably an azetidine, pyrrolidine, tetrahydropyridine or piperidine group; piperidine being particularly preferred.

R⁷ and R⁸ are preferably H and m is preferably 0 or 1.

In the definition of R³, aryl is phenyl, unsubstituted or substituted as defined in the term aryl above, and heterocyclyl is for example pyridyl, pyrimidinyl, lsoquinolyl or thienyl. R³ is preferably aryl(C₁-C₄)alkyl or aryl(C₂-C₄)alkenyl; R³ is most preferably benzyl optionally substituted in the phenyl ring by methyl, chloro, trifluoromethyl, trifluoromethoxy, pivaloyl, OH,

CONMe₂ , phenoxy, phenylsulphonyl or pyridyl or is 3-phenylpropyl or 3-phenyl-prop-2-enyl.

Particular and preferred individual compounds include:

1-[N-((S)-5-t-butoxycarbonylamino-(S)-4-hydroxy-6-phenyl-(R)-2-(4-trifluoromethoxybenzyl)hexanoyl)-(S)-valyl]-4-methylaminopiperidine;

1-[N-((S)-5-t-butoxycarbonylamino-(S)-4-hydroxy-6-phenyl-(R)-2-(3-phenylprop-2-en-1-yl)hexanoyl-(S)-isoleucyl]-4-ethylaminopiperidine; and

1-[N-((R)-2-benzyl-(S)-5-t-butojtycarbonylamino-(S)-4-hydroxy-6-phenylhexanoyl)-(S)-α-cyclohexylglycyl]-4-(2-methoxyethylamino)piperidine.

In a second aspect of the present invention, there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use as a medicament, especially for use in the treatment or prophylaxis of human retroviral

infections, in particular HIV infections. The invention also includes the use of a compound of the formula (I), or of a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for use in the prophylaxis or treatment of retroviral infections.

The invention further includes a pharmaceutical composition comprising a compound of the formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.

The antiviral activity of the compounds of general formula (I) is established using in vitro assay systems. For example, the coπrpounds of formula (I) are able to completely protect human T-cell line H9 for 7 days from the progressive effects of HIV infection. Untreated virus-infected cells display typical cytopathic effects such as formation of syncytia and cell death, m addition, virus particles produced from virus-infected cells treated with a compound of formula (I) are non-infectious.

Examples of infections which may be treated or prevented fcy the compounds of formula (I) include those caused by human or animal refcroviruses, especially EHV-1. Clinical conditions which may therefore be treated or prevented include AIDS, ARC, and HEV related dementia. The compounds may also be used to block disease progression in symptomless infected individuals.

The compounds of formula (I) can be prepared using the 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 routes shown below for the preparation of compounds of formula (Ia):

The procedure outlined in Scheme A, starts with a protected lactone (II). This is alkylated, using for example n-butyllithium and hexamethyldisilazane followed by addition of a compound of formula R³Br and separation of the desired lsomer to give the product (III). The lactone ring is then opened by treatment with dilute alkali to give the corresponding hydroxy-acid and the hydroxy group is subsequently protected, for example as the t-butyldimetoylsilyl derivative by reaction with t-butyldimethylsilyl chloride in N,N-dimethylformamide, followed by hydrolysis of the protected ester to give the intermediate (IV).

Synthesis of the other fragment required and the final coupling and deprotection step is illustrated in Scheme B, for the case where X is piperidine, m is 0, and neither R⁵ nor R⁶ is H.

In this process the N-protected amino-acid (V) is coupled to

4-ketopiperidine and the coupled product (VI) is then subjected to reductive amination using, for example, sodium cγarκ3borohydride and an amine of formula NHR⁵R⁶ (wherein R⁵ and R⁶ are as

previously defined other than H). The N-protecting group is then removed and the amine product (VIII) is coupled to the

intermediate (IV) and the hydros-protecting group X removed from the coupled product (IX) to give the final product of formula

I(a).

In the case where one or both of R and R is H, the resulting amine corresponding to (VII) will require protection and thus is illustrated in Scheme C; the N and 0 protecting groups X and Y being removed in the final step of the process.

In an alternative synthesis shown in scheme D the

4-ketopiperidine group is carried through to the coupling stage and the reductive animation conducted on the coupled, protected product (XII) to give the product (IX) which is then deprotected to give the final product as before.

For compounds wherein R¹-(CR⁹R¹⁰) - is other than t-butyl, the process can be performed with the appropriate group present in the starting material of formula (II), or it can be performed using a coitpound of formula (IV) wherein R¹ is t-butyl (BOC derivative), and this is then removed after coupling to the intermediate (VIII) for exairple by treatment with trifluoroacetic acid. The free amine is then reacylated, for exairple, in the case where R¹ is oxetanyl and n is O, by reaction with 3-oxetanyloxycarbonyloxysuccinimide, before final removal of the protecting groups.

The above sequences can be adapted as appropriate to be performed with any of the variants claimed for R ¹ to R¹² by appropriate selection of starting materials.

Thus for example for compounds where X is other than

piperidine and n is 1 or 2, the synthesis is performed using the appropriate amine fragment of formula

in place of (VIII) or (X). Again, if one of R⁵ and R⁶ is H appropriate N-protection will be required.

In the above routes and specific Examples presented herein, certain hydroxy and amino-protecting and

carboxy-activating groups are required. It will be apparent to those skilled in the art that the coupling and protection

procedures described could be carried out by any standard method for peptide synthesis and these procedures are therefore included in the scope of the invention. The choice of a particular protecting group is dependent to a great extent upon the

availability of the necessary reagent, its effect upon solubility of the protected compound, its ease of removal and the presence of other groups which might be affected by its use. For exairple, it is necessary in the above process to protect and deprotect particular amino groups in order to permit further reaction at the regenerated amino group and the choice of protecting group for a given amino group will depend upon the role of said amino group in the overall reaction scheme, Amino protecting groups having varying levels of lability can be used. Such groups are known in the art and attention is directed to the reviews by Bodansky et al., "Peptide Synthesis", 2nd Ed., John Wiley & Sons, N.Y. (1976); Greene, "Protective Groups in Organic Synthesis", John Wiley & Sons, N.Y. (1981) ; McQmie, "Protective Groups in Organic Chemistry", Plenum Press, N.Y. (1973); and to Sheppard in

"Comprehensive Organic Chemistry, The Synthesis and Reactions of Organic Compounds", Pergamon Press, N.Y. (1979), edited by

E. Haslam, Part 23.6, pages 321-339.

A variety of conventional amino-protecting groups are known to those skilled in the art. Representative amino-protecting groups include but are not limited to aryloxycarbonyl such as benzyloxycarbonyl; substituted or unsubstituted aralkyl such as benzyl, trityl, benzhydryl and 4-nitrobenzyl; benzylidene;

arylthio such as phenylthio, nitrqphenylthio and trichlorophenylthio; phosphoryl derivatives such as dimethylphosphoryl and O,O-dibenzylphosphoryl; trialkylsilyl derivatives such as trimethylsilyl; and others as are described in U.S. Pat. No.

4,322,341. The preferred amino protecting group for use in the above sequence is t-butoxycarbonyl. Procedures for substituting said group on a given amino group are well known. In general they comprise acylating the appropriate amino compound with the corresponding carbonyl chloride or anhydride in a reaction inert solvent, e.g. water, methylene chloride or tetrahydrofuran, in the presence of a base (acid acceptor) e.g., sodium or potassium hydroxide when water is solvent; and, when an organic solvent is used, in the presence of a tertiary amine such as a triethylamine or pyridine. When an aqueous solvent system is used the pH of the reaction is typically held at about pH 8-10, and preferably at pH 9.

The protected amino groups are converted to the unprotected amino groups by procedures known to those skilled in the art as appropriate to the particular group employed. The t-butoxycarbonyl group is, for exairple, readily removed by treatment with dichloromethane saturated with hydrogen chloride gas.

Various hydroxy-protecting groups are also known and are described in the literative sources already cited above. A preferred hydroxy protecting group is t-butyldimethylsilyl. This is introduced as previously described and is readily removed by treatment with tetra-n-butylammonium fluoride in tetrahydrofuran at room temperature.

Activation of carboxy groups as a means of expediting a given acylation reaction is also methodology known to those skilled in the art. Especially useful in the herein described reaction sequence are the use of anhydrides and activated esters,

particularly those esters derived from N-hydroxyphtoalimide, N-hydroxysuccinimide or 1-hydroxybenzotriazole, all of which are used in peptide syntheses.

A dehydrative coupling agent is used to form the activated ester. Representative of such coupling agents are 1-cyclohexyl-3-(2-morpholincethyl)carbodiimide, N,N'dicyclohejylcarbodiimide, N,N'-carbonyldiimidazole, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, ethoxyacetylene, diphenylketene and N-ethyl-5-phenyl-isoxazoliner-3'-sulfonate. The reaction conditions for using such coupling agents are well described in the literature. In general they comprise the use of a reaction inert solvent and te-riperatures ranging from ambient to 100°. The above-mentioned carbodiimide reagents are favoured since they permit use of ambient reaction temperature and afford satisfactory yields of the desired esters.

Upon completion of the coupling reactions leading to the final products, the various protecting groups can be removed by the appropriate techniques previously discussed, and the compounds of the formula (I) isolated and purified using conventional procedures such as recrystallisation or column dircimatography.

The N-t-butoxycarbonyl (BOC-) derivatives of the naturally occurring amino acids used in the synthesis of the compounds of the formula (V) are commercially available as are their

hvdroxysuccinimido esters. The corresponding intermediates derived from unnatural amino acids can be prepared by standard procedures (see, for exairple, M. J. O'Donnell et. al., J. Amer. Chem. Soc., 1989, 111, 2353). The coπpσunds of formula (II) can be prepared from the corresponding t-butyloxycarbonyl-protected amino-aldehydes (see D. H. Rich et. al., J. Org. Chem., 1978, 43, 3624 and Y. Hamada et. al., Chem. Pharm. Bull.. 1982, 30(5), 1921) by reaction with ethyl propiolate (see A. H. Fray et. al., J. Org. Chem., 1986, 51, 4828), followed by reduction to give the

5-t-butyloxycarbonylamino-4-hydroxy-6-phenylhexanoate.

Cyclization by refluxing in toluene then affords the lactones of formula (II), as mixtures of diastereomers which can be separated by standard procedures.

Compounds of formula (XIII) can be prepared by conventional synthetic methods, for example by coupling a N-protected amino acid with a N-substituted or N-protected 4-aminomethyl piperidine derivative.

Thus, according to a further aspect, the invention includes a process for preparing a compound of the formula (I) which comprises removing the protecting groups from a compound of the formula:

wherein X¹ is either H or a selectively removable hydroxy- protecting group and Y¹ is either R⁶, or a selectively removable nitrogen-protecting group and R¹ to R⁶ are as previously defined with the proviso that at least one of X¹ and Y¹ is a protecting group, and isolating the compound of formula (I) and optionally forming a pharmaceutically acceptable salt thereof.

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

The preferred protecting group for Y is benzyloxycarbonyl; this is removed by catalytic hydrogenation. The novel intermediates of formulae (IX) , (XI) , (XII) and (XIV) also form part of this invention.

Examples of pharmaceutically acceptable salts of the ccarpounds (I) are acid-addition salts, e.g. sulfates, bisulfates, phosphates, acetates, lactates, maleates, mesylates, fumarates, citrates, succinates and gluconates.

In the treatment of patients having a retrovirus infection, especially HIV, the compounds (I) will be administered by any suitable route, e.g. by the oral, parenteral (e.g. subcutaneous, intravenous, int ramuscular, or intradermal) , rectal, nasal, topical (including buccal and sublingual) or vaginal routes. The formulations, which will contain an antiviral agent of the invention together with one or more pharmaceutically acceptable carriers and optionally other therapeutic agents, can be prepared according to conventional techniques well known in pharmacy. Oral dosage forms include in particular syrups, tablets and capsules which may contain flavouring agents in addition to an inert carrier. Tablets can be made by conventional compression or moulding techniques by compressing a powder of the appropriate ingredients, e.g. the antiviral agent in conjunction with a binder, diluent, lubricant and surface-active agent. Rectal formulations will be in suppository form, and vaginal formulations as, for example, tampons, creams or foams. Parenteral

formulations will be in sterile form, e.g. as vials for injection containing aqueous or non-aqueous diluents, buffers and

antioxidants so that the formulation will be isotonic with blood. In general, the appropriate dose of the anti-retroviral agents of the formula (I) will be from 1-50 mg/kg/day, preferably 1-25 mg/kg/day given in up to six divided doses per day. There may be of course instances where higher or lower dosages are merited according to the age, weight, degree of illness and response of the patient, and appropriate therapy will be as determined by the medical practitioner.

The c ompounds of formula (I) may be used in combination with other drugs, same of which may potentiate their activity. Such drugs include the following:- (a) Reverse transcriptase inhibitors such as AZT, ddI, ddC, foscarnet, TIBO compounds, dipyridodiazepinones or

6-substituted acyclopyrimidine (HEPT) derivatives.

(b) gp120-CD4 blockers such as dextran sulphate and soluble CD4, including its combination with toxic agents such as

pseudomonas toxin.

(c) tat antagonists, such as D-penicillamine; and

(d) biological response modifiers including interferons,

interleukins or colony sti-mulating factors, e.g. GM-CSF.

The compounds of the invention were evaluated for antiviral activity by dissolving the test compound in 50 μl of DMSO and diluting in REMI 1640, a complex salts solution with a pH of 7.2, to 1 mg/ml. Testing was performed at 0.001, 0.01, 0.1, 1 and 10 as μg/ml against HIV 1 (strain IIIB) in a human T-cell line (H9) . Untreated control infections were initiated at the same time.

Seven days post infection, tissue culture supernatants were titrated for the presence of infectious virus on C8166 cells (human T-cell line). On days 3, 5, and 7 cultures were examined for appearance of syncytia. Control infections, untreated with drug, show typical viral cytopathic effects, including formation of syncytia and cell death. The IC₁₀₀ quoted is the lowest test concentration affording coirplete protection to the culture. Using this test method, the compounds had an IC₁₀₀ values in the range 0.1 to 10.0 μg/ml.

The preparation of certain starting materials and of the compounds of formula (I) will now be more particularly illustrated by reference to the following experimental Examples. The purity of compounds was routinely monitored by thin layer chσmatography using Merck Kieselgel 60 F₂₅₄ plates. ¹Η-Nuclear magnetic reasonance spectra were recorded using either a Nicolet QE-300 or a Bruker AC-300 spectrometer and were all in cases consistent with the proposed structures. Chemical shifts are given in

parts-per-million downfield from tetramethylsilane using

conventional abbreviations for designation of major peaks: s, singlet; d, doublet; t, triplet; m, multiplet and b, broad.

All temperatures are in degrees celsius. PREPARATION OF STARTING MATERIALS

INTERMEDIATE PREPARATION 1

(S) -5-[ (S)-1-t-Butoxyc arbonylamino-2-phenylet hyl]-gamma-butyrolactone

a) Ethyl (4S ,5S) - and (4R,5S) -5-t-butoxycarbonylamino-4-hydroxy-6-phenylhex-2-ynoate

A solution of diisopropylamine (6.4 ml) in dry

tetxahydrofuran (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 over 5 minutes, keeping the temperature below -20°. After a further 15 minutes at -20° the solution was cooled to -70° and ethyl propiolate (3.8 g) was added dropwise over 10 minutes, keeping the temperature below -65°. The resulting yellow suspension was stirred at -70° for a further 20 minutes and then treated dropwise, over 10 minutes, with a solution of N-t-butoxycarbonyl-L-phenylalaninal (6.5 g, see J. R. Luly et al, J. Org. Chem., 1987, 52, 1487) in dry tetrahydrofuran (15 ml), again keeping the temperature below -65° . The clear yellow solution was stirred at -70° for 2 hours then treated with acetic acid (4 ml). The cooling bath was removed and the mixture was allowed to warm to -30° at which point water (100 ml) and ethyl acetate (100 ml) were added with vigorous stirring. Separation of the organic layer, followed by successive washing with 1 molar hydrochloric acid (50 ml), saturated aqueous sodium bicarbonate (50 ml) and saturated brine (50 ml), gave the crude product as an oil after drying (Na₂SO₄) and evaporation of the solvent. The oil was purified by silica gel chroiratography using ethyl acetate-hexane (1:4) as the eluent. Evaporation of the product-ccnteining fractions gave an oil which solidified on standing overnight. Recrystallisation from ether-hexane afforded the title compounds as an approximately 2:1 mixture (4S,5S:4R,5S) of diastereomers, (4.3 g), m.p. 98-99°. Found: C,65.62; H,7.42; N,4.33. C₁₉H₂₅NO₅ requires C,65.70; H,7.20; N,4.03%.

N.M.R. (CDCl₃) 5 = 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 (2x brm, 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 × brm, 1H); 7.24-7.35 (m, 5H). b) Ethyl (4S,5S)- and (4R,5S) -5-t-butoxycarbonylamino-4-hydroxy-6-phenylhexanoate

The above product (1.17 g) was dissolved in ethanol (50 mg) and 5% Pd-BaSO₄ catalyst was added. The mixture was then hydrogenated at 50 psi (344.7 kPa) for 2 hours. Filtration, followed by evaporation of the solvent under vacuum, gave the title compounds (approximately 2:1 mixture of diastereo-mers) as a white solid, (1.18 g), m.p. 125-126°. Found: C,64.91; H,8.40; N,3.98, C₁₉H₂₉NO₅ requires C,64.95; H,8.26; N,3.98%.

N.M.R. (COCl₃) δ = 1.24-1.33 (m, 3H); 1.39 and 1.42 (2 × s, 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 × m, 1H exch. D₂O); 3.59-3.91 (m, 2H); 4.08-4.21 (m, 2H); 4.58-4.61 and 4.86-4.89 (2 × m, 1H); 7.22-7.37 (m, 5H). c) (S)-5-[(S)-1-t-Butoxycarbonylamino-2-phenylethyl]-crammabutyrolactone

The gamma-hydroxyester from (b) above was dissolved in 2.5% acetic acid-toluene (35 ml) and the solution was heated at reflux for 2 hours. After cooling and evaporation to dryness under vacuum, the residue was purified by silica gel

chromatography, eluting with diethyl ether-hexane (40:60), to afford the title compound (0.4 g), m.p. 98-99°. Found: C,66.77;

H,7.78; N,4.38. C₁₇H₂₃NO₄ requires: C,66.88; H,7.54; N,4.59%. m/e

= 306 (MH⁺) .

N.M.R. (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) . [α]²⁵ _D-22.6° (c = 1, MeOH).

I. R. (KBr) 1775, 1690, 1525 cm^-1. INTERMEDIATE PREPARATION 2

(S) -5-t-Butoxycarbonylamino-(S)4-(t-butyldimethylsilyloxy)-(R)-2-benzyl-6-phenylhexanoic acid

a) (S)-5-[ (S)-1-t-Butoxycarbonylamino-2-phenylethyl]-(R)-3-benzyl-gamma-butyrolactone.

A cold (-10°) solution of hexamethyldisilazane (7.9 ml) in tetrahydrofuran (15 ml) was treated over 3 minutes with 1.6M n-butyllithium in hexane (23 ml) , keeping the teirrperature below 0°. After a further 5 minutes at 0° the solution was cooled to -70° and a solution of (S)-5-[ (S)-1-t-butoxycarborylamino-2-phenylethyl]-gamma-butyrolactone

(5 g) in tetrahydrofuran (38 ml) was added, keeping the

te-rperature below -65°. The solution was stirred at -70° for 15 minutes before benzyl bromide (1.95 ml) in tetrahydrofuran (12.5 ml) was added over 1 minute and the solution stirred at -70° for an additional 10 minutes before being treated with acetic acid (6.5 ml) and the cooling bath removed. Water (50 ml) and ethyl acetate (50 ml) was added and the mixture allowed to warm to room temperature. Separation of the organic layer, followed by drying (MgSO₄ ) and evaporation of the solvent under vacuum gave the crude product as an oil. Chromatography on silica-gel, eluting with diethyl ether-hexane (50:50) , gave the title compound as a clear 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%.

[α]²⁵ _D -14° (c = 0.1%, MeOH)

N.M.R. (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) ; 7.21-7.36(m, 10H) . b) ( S)-5-t-Butoxycarbonylamino-(S)-4-(t- butyldimethylsilyloxy)-(R)-2-benzyl-6-phenylhexanoic acid.

A suspension of the product from (a) (17.63 g) in dioxan (120 ml) and water (60 ml) was treated with sodium hydroxide (1N, 53.5 ml) at room temperature. The reaction was stirred for 3 hours before being acidified to pH 5 by the addition of acetic acid. After standing for a further 30 minutes the precipitate was filtered off and washed with water. This solid was dissolved in ethyl acetate, dried (MgSO₄) and evaporated under vacuum to a white solid which was triturated with hexane, filtered and dried to give the intermediate hydroxy acid (17.85 g) . A solution of this hydroxy acid in N,N-dimethylformamide 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 under vacuum, the residue treated with ice/water, 10% citric acid to pH 4, and extracted using 2 × 400 ml portions of ethyl acetate. The combined extracts were dried (MgSO₄) and evaporated under vacuum to a pale oil (29.2 g). A solution of this oil in tetxahydrofuran (240 ml) was treated with acetic acid (240 ml) and water (80 ml) at room temperature. After stirring for 2 hours at room teirperature and 18 hours at 4°C the solution was evaporated under vacuum and the residue partitioned between water (400 ml) and ethyl acetate (400 ml). The separated organic layer was washed with water (2 × 400 ml), saturated brine (100 ml), dried (MgSO₄) and evaporated under vacuum to a pale oil.

Chromatography on silica-gel, eluting with diethyl ether-hexane (70:30) gave the title cσirpound as a white glass (22.4 g).

m/e 528 (MH)⁺

N.M.R. (DMSO-d₆) δ = 0.10(s,6H); 0.95(s,9H); 1.30(m,10H);

1.35(m,1H); 1.95(m,1H); 2.40(m,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).

INTERMEDIATΕ PREPARATION 3 a) 1-(N-t-Butoxycarbonyl-(S) -valyl)-4-ketopiperidine.

A solution of N-t-butoxycarbonyl-(S)-valine (3.64 g) , 1-(3-dimethylaιrιincpropyl)-3-etoylcarbodiimide hydrochloride (3.86 g) , 1-hydroxybenzotriazole hydrate (3.40 g) and N,N-diisopropylethylamine (4.39 ml) in N,N-dimethylformamide (20 ml) was treated with a solution of 4-ketopiperidine hydrochloride hydrate (3.87 g) and N,N-diisopropylethylamine (5.00 ml) in N,N-cUmethylfo-αr-amide (15 ml) at room temperature. After stirring for 18 hours the solvent was evaporated under vacuum and the residual oil was dissolved in water (50 ml) and ethyl acetate

(50 ml) . The separated organic layer was washed with saturated aqueous sodium bicarbonate (2 × 100 ml) , dried (MgSO₄) and evaporated under vacuum to an oil. Purification by silica-gel chrcmatography, eluting with ethyl acetate-hexane (60:40) , gave the title compound as a pale yellow oil (3.72 g) .

m/e = 299 (MH)⁺

N.M.R. (DMSO-d₆) δ = 0.75(d,6H) ; 1.3 (s,9H) ; 1.85(m,1H) ;

2.25(m, 3H) ; 3.5 (m,1H) ; 3.7(m,1H) ; 3.85(m, 3H) ; 4.2 (t,1H) ;

6.9(d,1H) . b) 1-(N-t-Butoxycarbonyl-(S)-valyl)-4-dimethylaminopiperidine

A solution of the product from (a) (1.5 g) in methanol (5 ml) was cooled in ice-water and treated with a solution of

dimethylamini (1.08 g) in methanol (10 ml). The pH of the solution was lowered to 6 by the careful addition of acetic acid before sodium cyanoborohydride (0.30 g) was added

portioπwise and the solution stirred for 18 hours. The solvent was evaporated under vacuum and the residual oil dissolved in ethyl acetate (50 ml), washed with aqueous sodium hydroxide

(1N, 2 × 50 ml) and saturated brine (50 ml), dried (MgSO₄) and evaporated under vacuum to a solid. Recrystallisation from hexane afforded the title compound (0.70 g). Found: C,62.35;

H,10.26; N,12.56. C₁₇H₃₃N₃O₃ requires C, 62.35; H,10.16;

N,12.83%.

m/e = 322 (MH)⁺.

N.M.R. (DMSO-d₆) δ = 0.89(2x s,6H); 1.0-1.3(m,2H); 1.3(s,9H);

1.6-1.8(m,2H); 1.8-1.9(m,1H); 2.1(s,6H); 2.2(m,1H); 2.5-2.6(m,1H); 3.0(m,1H); 4.0(m,1H); 4.15(m,1H); 4.3(m,1H); 6.7(dd,1H). INTERMEDIATE PREPARATION 4

a) 1-(N-t-Butoxycarbonyl-(S)-valyl)-4-methylaminopiperidine

The title compound was prepared by the same procedure as

described for intermediate (3b) by reductive amination of intermediate (3a) with metiiylamine. Purification by chromatography on silica-gel, eluting with methylene chloride-methanol-concentrated aqueous ammonia (90:10:1) gave the title c ompound as a colourless oil.

N.M.R. (DMSO-d₆) δ = 0.7 (m,6H) ; 0.8-1.2 (m,2H) ; 1.3 (s,9H) ; 1.6- 1.7(m,2H); 1.8(m,3H); 2.2(s,3H); 2.6-3.0(m,3H); 3.8(m,1H);

4.0(m,1H); 4.1(m,1H); 6.6(dd,2H).

b) 1-(N-t-Butoxycarbonyl-(S)-valyl)-4-(N-benzyloxycarbonyl-N-methylamino)piperidine

A solution of the product from a) (4.0 g) in methylene

chloride (300 ml) was treated with N-(benzyloxycarbonyloxy) succi-nimide (3.83 g) at room temperature and the solution stirred for 72 hours. The reaction mixture was washed with saturated aqueous sodium bicarbonate (150 ml), water (150 ml), dried (MgSO₄) and evaporated under vacuum to give an oil.

Purification by chromatography on silica-gel, eluting with diethyl ether-hexane (80:20) gave the title coπpound as a colourless foam (5.4 g) .

N.M.R. (DMSO-d₆) δ = 0.7(m,6H); 1.3(s,9H); 1.3-1.7 (m,4H);

1.8(m,1H); 2.4-3.0(m,4H); 3.1 (m,3H); 4.1(m,1H); 4.4 (m,1H);

5.0(s,2H); 6.7(dd,1H); 7.3(m,5H).

INTERMEDIATE PREPARATION 5

a) 1-(N-t-Butoxycarbonyl-(S)-isoleucyl)-4-ketopiperidine

The title corrpound was prepared as a colourless oil by the same procedure as described for intermediate (3a) reacting 4-ketopiperidine hydrochloride hydrate with N-t-butoxycarbonyl-(S)-isoleucine. m/e 313 (MH) ⁺

[α]_D ²⁵ -16° (c = 0.34%,MeOH)

N.M.R. (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,2H); 4.55(m,1H);

5.2(d,1H). b) 1-[N-((R)-2-Benzyl-(S)-5-butoxycartonylamino-(S)-4-t-butyldimethylsilyloxy-6-phenylhexanoyl)-(S)-isoleucyl]-4-ketopiperidine

A solution of the product from (a) (3 g) in methylene chloride (100 ml) was saturated with hydrogen chloride at 0° and kept at this temperature for a further 1 hour. Evaporation to dryness under vacuum gave the amine hydrochloride as a white foam. This was added to an active ester solution previously prepared by stirring together tiie product from Intermediate Preparation (2b) (2.92 g), 1-hydrαxybenzotriazole hydrate (1.12 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.33 g) and N,N-diisopropylethylamine (2.40 ml) in methylene chloride (500 ml) for 10 minutes. After stirring for a further 24 hours the solvent was evaporated under vacuum, the residue dissolved in ethyl acetate (250 ml), washed with water (2 × 200 ml), dried (MgSO₄) and evaporated under vacuum to give a white foam.

Purification by chrotmatography on silica-gel, eluting with ethyl acetate-hexane (50:50) gave the title compound as a white foam (3.39 g). Found: C, 67.28; H, 8.58; N, 5.62. C₄₁H₆₃N₃O₆Si. 0.5 EtOAc requires C, 67.58; H, 8.87; N, 5.43%.

m/e 722 (MH) ⁺

[α]_D ²⁵ -14° (c = 0.1%, MeOH)

N.M.R. (DMSO-d₆) δ = 0.05(d,6H); 0.78(t,6H); 0.85(s,9H);

1.15(m,4H); 1.26(s,9H); 1.5(m,1H); 1.77 (m,1H); 1.9(m,1H);

2.3(m,4H); 2.5(m,1H); 2.65(d,1H); 2.8(m,2H); 3.5(m,2H);

3.65(m,2H); 3.8(m,2H); 4.5(t,1H); 6.8(d,1H); 7.1(m,10H);

8.2(dd,1H). INTERMEDIATE PREPARATIONS 6-12

Cyclobutoxycarbonyloxysuccinimide

Bis-(trichloromethyl)carbonate (3.5 mmole, 1.04 g) was dissolved in dichloromethane (25 ml) under an atmosphere of nitrogen. The solution was cooled to -20°C using a solid carbon dioxide/acetone bath. Cyclobutanol (10 mmole, 0.72 g) and diisopropylethylamine (21 mmole, 2.71 g) were dissolved in dichloromethane (20 ml) and this solution was added dropwise to the above solution over 10 minutes. The mixture was then stirred at -20°C for 15 minutes and N-hydroxysuccinimide (10 mmole, 1.15 g) added in one lot. The solution was allowed to warm to room teπperature over 1.5 hours then poured into saturated aqueous sodium hydrogen carbonate solution and extracted with

dichloromethane (2 × 50 ml). The combined organic extracts were dried over MgSO₄, filtered and evaporated under vacuum. The residue was further purified by column chromatography on silica eluting with hexane:ethyl acetate 7:3. Evaporation of the product conteining fractions and recrystallisation from hexane gave the title σcarpound (515 mg), m.p. 88-90°C. Found: C,50.94; H,5.17; N,6.54%. C₉H₁₁NO₅ requires C,50.71; H,5.20; N,6.57%.

The following sucoinimide esters were prepared from the appropriate alcohol using the method described above.

EXAMPLE 1

1-[N-( (R) -2-Benzyl-(S) -5-t-butoxycarbonylamino-(S) -4-t-butyldimethylsiloxy-6-phenylhexanoyl) -(S)-valyl]-4- dimethylaminopiperidine

A solution of 1-(N-t-butoxycarbonyl-(S)-valyl)-4-dimethylaminopiperidine (0.46 g) in methylene chloride (20 ml) was saturated with hydrogen chloride at 0° and kept at this temperature for a further 1 hour. Evaporation to dryness under vacuum gave the bis-amine di-hydrochloride as a white solid. A solution of this product and N,N-diisopropylethylamine (0.3 ml) in

N,N- dimethylformamide (5 ml) was added to an active ester solution previously prepared by stirring together the product from

intermediate preparation (2b) (0.5 g) , 1-hydroxybenzotriazole (0.19 g) , 1-(3- dimet hylaminopropyl) -3-ethylcarbodiimide

hydrochloride (0.22 g) and N,N-diisopropylethylamine (0.25 ml) in N,N-dimethylformamide (10 ml) for 10 minutes. After stirring for a further 24 hours, water was added and the product extracted into ethyl acetate (2 × 100 ml) . The combined organic layers were washed with saturated aqueous sodium bicarbonate (2 × 100 ml) , dried (MgSO₄) and evaporated under vacuum to give a yellow oil. Purification by chromatography on silica-gel, eluting with methylene chloride-methanol (90:10) , gave the title compound as a white glass (0.51 g) .

N.M.R. (DMSO-d₆) δ = 0.05 (s,6H) ; 0.8 (s,9H) ; 1.1-1.9 (m,6H) ;

1.2 (S,9H) ; 2.05(S,6H) ; 2.4-2.8 (m,8H) ; 3.0-4.0 (m, 4H) ;

4.2 (m,1H) ; 6.7 (m,1H) ; 7.1 (m, 10H) ; 7.8 (d,1H) .

EXAMPLE 2

1-[N-((R)-2-Benzyl-(S)-5-t-butoxycarbonylamino-(S)-4-hydroxy-6-phenylhexanoyl)-(S)-valyl]-4-dimethylaminopiperidine

The product from Exairple 1 (0.51 g) in tetrahydrofuran (15 ml) was treated with 1M tetra-n-butylammonium fluoride in tetrahydrofuran (2.03 ml) at room teπperature. After stirring for a further 48 hours the solvent was evaporated under vacuum and the residue dissolved in ethyl acetate (100 ml), washed with saturated aqueous sodium bicarbonate (2 × 100 ml), water (2 × 100 ml), dried (MgSO₄) and evaporated under vacuum. The crude product thus obtained was purified by chromatography on silica-gel eluting with methylene chloride-methanol (85:15) . After evaporation of the product fractions, the residue was crystallised from diethyl ether/hexane to afford the title compound (0.08 g) m.p. 176-178°. Found: C,

69.41; H, 8.47; N, 8.93. C₃₆H₅₄N₄O₅ requires C, 69.42; H, 8.74; N,

9.00%.

m/e 623 (MH)⁺

[α]_D ²⁵ -9° (c = 0.1%, MeOH)

N.M.R. (DMSO-d₆) δ = 0.7(d,6H) ; 1.1-1.4(m,3H) ; 1.3 (s,9H) ; 1.6- 1.8(m,3H) ; 2.15(S,6H) ; 2.25(m,1H) ; 2.5(m,4H) ; 2.8 (m,4H) ;

3.0(m,1H) ; 3.4(m,1H) ; 3.6(m,1H) ; 4.0(m,1H) ; 4.3 (m,1H) ;

4.5(m,1H) ; 6.4(d,1H) ; 7.2(m,10H) ; 7.8 (d,1H) .

EXAMPLE 3

1-[N-((R)-2-Benzyl-(S)-5-t-butoxycarbonylamino-(S)-4-t-butyldimethylsilyloxy-6-phenylhexanoyl)-(S)-valyl]-4-(N-benzyloxy¬carbonyl-N-methylamino)piperidine

A solution of 4-(N-berιzyoxycarbαnyl-N-methylam

carbonyl-(S)-valy)piperidine (5.4 g) in methylene chloride (200 ml) was saturated with hydrogen chloride at 0° and kept at this temperature for a further 1 hour. The solvent was evaporated under vacuum and the residue dissolved in methylene chloride (400 ml) and extracted with saturated aqueous sodium bicarbonate (300 ml) . The organic phase was washed with saturated brine (100 ml) , dried (MgSO₄) and evaporated under vacuum to give the amine free-base (3.1 g) . A solution of this product (1.18 g) in methylene chloride (70 ml) was added to an active ester solution previously prepared by stirring together the product from intermediate preparation (2b) (1.5 g) , 1-hydroxy-benzotriazole (0.575 g) , 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (0.65 g) and N,N-diisopropylethylamine (0.59 ml) in methylene chloride (150 ml) for 20 minutes. After stirring for a further 24 hours, the solution was washed with 1N hydrochloric acid (200 ml) , saturated aqueous sodium bicarbonate (200 ml) , saturated brine (100 ml) , dried (MgSO₄) and evaporated under vacuum. The residue was purified by chromatography on silica-gel, eluting with diethyl ether-hexane (20:80) , to give the title compound as a white foam (1.8 g).

N.M.R. (DMSO-d₆) δ = 0.05(S,6H); 0.8(m,6H); 0.9(s,9H); 1.25(s,9H);

1.2-1.6(m,6H); 1.9(m,2H); 2.4-3.1(m, 9H) ; 3.6(m,1H); 3.7(m,3H); 4.0(m,2H); 4.45(m,2H); 5.05(s,2H); 6.85(d,1H); 7.2(m,10H);

7.3(m,5H); 7.85 & 7.95(2x d,1H).

EXAMPLE 4

1-[N-((R)-2-Benzyl-(S)-5-t-butoxycarbonylamino-(S)-4-hydroxy-6-phenylhexanoyl)-(S)-valyl]-4-(N-benzyloxycarbonyl-N-methylamino)piperidine

The product from Example 3 (1.75 g) in tetrahydrofuran (150 ml) was treated with 1M tetra-n-butylammonium fluoride in

tetrahydrafrjran (6.12 ml) at room temperature. After stirring for a further 24 hours the solvent was evaporated under vacuum and the residue dissolved in ethyl acetate (300 ml) and washed with saturated aqueous sodium bicarbonate (200 ml) , 1N

hydrochloric acid (200 ml) , water (to pH 7) , dried (MgSO₄) and evaporated under vacuum to give the title coirpound as a white foam

(1.61 g) .

m/e 742 (MH)⁺

N.M.R. (DMSO-d₆) δ = 0.0 & 0.05(silyl residues); 0.75(m 6H) ;

0.8 (silyl residue); 1.2-1.7 (m,6H); 1.25(s,9H); 1.85(m,1H);

2.4-3.0(m,10H); 3.4(m,1H); 3.55(m,1H); 4.0(m,2H); 4.45(m,3H);

5.05(m,2H); 6.35(d,1H); 7.2(m,10H); 7.3(m,5H); 7.3 &

7.4(2x d,1H).

EXAMPLE 5

1-[N-((R)-2-Benzyl-(S)-5-t-butoxycarbonylamino-(S)-4-hydroxy-6-phenylhexanoyl)-(S)-valyl]-4-methylaminopiperidine

A solution of the product from Example 4 (1.5 g) in absolute ethanol (60 ml) was treated with 10% palladium on charcoal (200 mg). The mixture was stirred at room teirperature under hydrogen at a pressure of 30 psi for 3 hours. The catalyst was filtered and the solvent evaporated under vacuum to give a colourless oil which was purified by chromatography on silica-gel, eluting with methylene chloride-methanol-concentrated aqueous ammonia. After evaporation of the product fractions, the residue was crystallised from ethyl acetate/hexane to afford the title compound (0.765 g) m.p. 170-171°. Found: C, 69.10; H, 8.47; N, 9.14. C₃₅H₅₂N₄O₅ requires C, 69.04; H, 8.60; N, 9.20%.

m/e 609 (MH)⁺

[α]_D ²⁵ -19° (c = 0.1%, MeOH)

N.M.R. (DMSO-d₆) δ = 0.7(d,6H); 1.0(m,2H); 1.25(s,9H);

1.25(m,1H); 1.5-2.0(m,4H); 2.25(S,3H); 2.4-3.1(m,8H);

3.4(m,1H); 3.5(m,1H); 3.8(t,1H); 4.05(m,1H); 4.45(m,1H);

4.5(t,1H); 6.4(m,1H); 7.1-7.3(m,10H), 7.75(d,1H).

EXAMPLE 6

1-[N-((R)-2-Benzyl-(S)-5-butoxycarbonylamino-(S)-4-hydroxy-6-phenylhexanoyl)-(S)-isoleucyl]-4-ketopiperidine

A solution of the product from intermediate preparation (5b) (3.35 g) was treated with 1M tetra-n-butylammonium fluoride in

tetrtahydrofuran (13.9 ml) at room temperature. After stirring for a further 48 hours the solvent was evaporated under

vacuum, the residue dissolved in ethyl acetate (300 ml) and washed with saturated aqueous sodium bicarbonate (200 ml), 1N hydrochloric acid (200 ml), water (to pH 7) , dried (MgSO₄) and evaporated under vacuum to give a yellow foam. Purification by chromatography on silica-gel, eluting with ethyl acetate-hexane (50:50) gave the title compound as a white foam (0.848 g).

m/e 508 (M-100)H⁺

N.M.R. (DMSO-d₆) δ = 0.75(m,6H); 1.0-1.8(m,8H); 1.3(s,9H);

2.3(m,2H); 2.6(m,2H); 2.8(m,3H); 3.4-3.7(m,3H); 3.8(m,2H);

4.55(m,2H); 6.4(m,1H); 7.1-7.3 (m,10H); 7.85 & 8.0(2x d,1H).

EXAMPLE 7

1-[N-((R-2-Benzyl-(S) -5-t-butoxycarbonylamino-(S)-4-hydroxy-6-phenylhexanoyl)-(S)-isoleucyl]-4-methylaminopiperidine

A solution of the product from Example 6 (0.385 g) in methanol (20 ml) was added to a 33% solution of metoylamine in ethanol (0.5 ml) diluted with methanol (15 ml) and acidified to pH 5-6 with acetic acid. Sodium cyanoborohydride (28 mg) was added and the reaction stirred for a further 18 hours. The solution was diluted with ethyl acetate (100 ml) and washed with aqueous sodium hydroxide (1N, 2 × 50 ml), dried (MgSO₄) and evaporated under vacuum.

Purification by chromatography on silica-gel, eluting with methylene chloride-methanol-concentrated aqueous ammonia followed by recrystallisation from ethyl acetate/hexane afforded the title compound (0.195 g) m.p. 159-161°. Found: C, 68.93; H, 8.80; N, 8.89. C₃₆H₅₄N₄O₅.¼H₂O requires C,68.93; H, 8.76; N, 8.93%.

m/e 623 (MH)⁺

[α]_D ²⁵ -15° (c = 0.1%, MeOH)

N.M.R (DMSO-d₆) δ = 0.7(m,6H); 0.9-1.4(m,5H); 1.2(S,9H); 1.5-1.8(m,4H); 2.25(s,3H); 2.4-3.0(m,8H); 3.4(m,1H); 3.5(m,1H);

3.85(m,1H); 4.1(m,1H); 4.5(m,2H); 6.4(m,1H); 7.1(m,10H);

7.8(m,1H).

EXAMPLE 8

1-[N-( (R)-2-Benzyl-(S)-5-t-butoxycarbonylamino-(S)-4-hydroxy-6-phenylhexanoyl)-(S)-isoleucyl]-4-aminopiperidine

The title compound was prepared by the same procedure as described for Example 7 by reacting the product from Example 6 with ammonium acetate, m.p.161°. Found: C,68.32; N,8.59; N,9.03.

C₃₅H₅₂N₄O₅.¼H₂O requires C, 68.55; H,8.55: N,9.14%.

m/e 609 (MH)⁺

[α]_D ²⁵ -1° (c = 0.1%, MeOH)

N.M.R. (DMSO-d₆) δ = 0.7 (m, 6H) ; 0.9-1.4 (m,5H) ; 1.25(s,9H) ; 1.5-1.85(m,4H) ; 2.7-2.9 (m,8H) ; 3.0(t,1H) ; 3.5(m,1H) ; 3.8 (t,1H) ;

4.1(m,1H) ; 4.5(m,2H) ; 6.4 (d,1H) ; 7.1(m,10H) ; 7.8(m,1H) .

EXAMPLE 9

1-[N-((R)-2-Benzyl-(S)-5-t-butoxycarbonylamino-(S)-4-t-butyldimethylsilyloxy-6-phenylhexanoyl)-(S)-valyl]-4-(pyrrolidin-1-yl)piperidine

The title compound was prepared by the same procedure as

described for Example 1 by reacting the amine derived from 1-(N-t-butoxycarbonyl)-(S)-valyl-4-(pyrrolidin-1-yl)piperidine with an active ester derived from the product from intermediate

preparation (2b).

m/e 763 (MH)⁺

N.M.R. (DMSO-d₆) δ = 0.1(s,6H); 0.8(m,6H); 0.9(s,9H); 1.15(m,5H); 1.25(s,9H); 1.65(m,3H); 1.8(m,1H); 1.9(m,1H);

2.2(m,1H); 2.3-3.1(m,12H); 3.55 (m, 1H); 3.65(m,1H); 3.8(m,1H); 4.15(m,1H); 4.5(m,1H); 6.8(d,1H); 7.2(m,10H); 7.8 &

7.9(2x d,1H).

EXAMPLE 10

1-[N-((R)-2-Benzyl-(S)-5-t-butoxycarbonylamino-(S)-4-hydroxy-6-phenylhexanoyl)-(S)-valyl]-4-(pyrrolidin-1-yl)piperidine

The title compound was prepared from the product of Example 9 by the same procedure as described for Example 2, m.p. 187-188°. Found: C,69.31; H,8.76; N,8.64. C₃₈H₅₆N₄O₅.½H₂O requires

C,69.37; H,8.73; N,8.51%.

m/e 649 (MH)⁺

[α]_D ²⁵ -17° (c = 0.1%, MeOH).

N.M.R. (DMSO-d₆) δ = 0.65(d,6H); 1.1-1.3 (m,4H); 1.2(s,9H);

1.5-1.8(m,6H); 2.1(m,1H); 2.2-3.0(m,12H); 3.3(m,1H);

3.45(m,1H); 3.8(m,1H); 4.0(m,1H); 4.4(m,1H); 4.5(m,1H);

6.35(m,1H); 7.0-7.2 (m,10H); 7.7(m,1H).

EXAMPLE 11

4-Amino-1-(N-t-butoxycarbonyl)-(S)-valylpiperidine

The title compound was prepared by the same procedure as described for intermediate 3b) by reductive amination of intermediate 3a) with ammonium acetate,

m/e 300 (MH)⁺

N.M.R (DMSO-d₆) δ = 0.8(m,6H); 1.1(m,2H); 1.3(s,9H);

1.7(m,2H); 1.9(m,1H); 2.7-2.9(m,2H); 3.1(m,1H); 3.9(m,1H);

4.2(m,2H); 6.7(m,1H).

EXAMPLE 12

1-[(N-t-Butoxycarbonyl-(S)-valyl]-4-(N-benzyloxycarbonylamino)piperidine

The title compound was prepared from the product of Example 11 by the same procedure as described for intermediate (4b).

m/e 434 (MH)⁺

N.M.R (DMSO-d₆) δ = 0.8(m,6H); 1.15(m,1H); 1.3(m,1H);

1.35(s,9H); 1.7(m,2H); 1.9(m,1H); 2.7(m,1H); 3.1(m,1H);

3.55(S,1H); 3.9(m,1H); 4.2(m,2H); 5.0(s,2H); 6.7(m,1H); 7.35 (m, 6H) .

EXAMPLE 13

1-[N-((R)-2-Benzyl-(S)-5-t-butoxycarbonylamino-(S)-4-t-butyldimethylsilyloxy-6-phenylhexanoyl)-(S)-valyl]-4-benzyloxycarbonylaminopiperidine

The title compound was prepared by the same procedure as described for Example 3 by reacting the amine derived from the product of Example 12 with an active ester derived from the product from intermediate preparation (2b).

m/e 843 (MH)⁺

N.M.R (DMSO-d₆) δ = 0.1(s,6H); 0.8(m,6H); 0.9(s,9H); 1.1-2.0(m,7H); 1.3(s,9H); 2.4-2.9(m,6H); 3.1(m,1H); 3.5(m,1H);

3.7(m,1H); 4.0(m,1H); 4.2(m,1H); 4.5(m,1H); 5.0(s,2H);

6.75(m,1H); 7.1-7.5(m,16H); 7.85(d,1H).

EXftMPLE 14

1-[N-((R)-2-Benzyl-(S)-5-t-butoxycarbonylamino-(S)-4-hydroxy-6-phenylhexanoyl)-(S)-valyl]-4-benzyloxycarbonylaminopiperidine

The title compound was prepared from the product of Example 13 by the same procedure as described for Example 4, m.p. 185-187°.

Found: C, 69.51; H,7.72; N,7.67. C₄₂H₅₆N₄O₇ requires C,69.2;

H,7.74; N,7.69%.

m/e 729 (MH)⁺

N.M.R (DMSO-d₆) δ = 0.75(m,6H); 1.3(s,12H); 1.6(m,2H);

1.7(m,1H); 1.85(m,1H); 2.5(m,2H); 2.7-2.9 (m,4H); 3.1(m,1H);

3.4(m,1H); 3.5(m,2H); 3.85(m,1H); 4.15 (m, 1H); 4.5(m,1H);

4.55(m,1H); 5.0(s,2H); 6.4(t,1H); 7.0-7.5 (m, 16H); 7.75(d,1H).

EXAMPLE 15

4-Amino-1-[N-((R)-2-benzyl-(S)-5-t-butoxycarbonylamino-(S)-4-hydroxy-6-phenylhexanoyl)-(S)-valyl]piperidine

The title compound was prepared from the product of Example 14 by the same procedure as described for Example 5. Found: C,68.42; H,8.37; N,9.29. C₃₄H₅₀N₄O₅ requires C,68.60; H,8.47; N,9.42%. m/e 595 (MH)⁺

N.M.R. (DMSO-d₆) δ = 0.7(m,6H); 1.0(m,2H); 1.3(s,10H);

1.6(m,1H); 1.7(m,2H); 1.85(m,1H); 2.5-3.05(m,8H); 3.4(m,1H); 3.55(m,1H); 3.8(m,1H); 4.1(m,1H); 4.45(m,1H); 4.5(m,1H);

6.4(d,1H); 7.2(m,12H); 7.75(d,1H).

EXAMPLE 16

1-(N-t-Butoxycarbonyl)-(S)-valyl-4-ethylaminopiperidine

The title compound was prepared by the same procedure as described for intermediate 3b) by reductive amination of intermediate 3a) with ethylamine.

N.M.R. (DMSO-d₆) δ = 0.8(m,6H); 1.0(t,3H); 1.2(m,2H); 1.4(s,9H); 1.8(m,2H); 1.9(m,1H); 2.5(q,2H); 2.6-2.8(m,2H); 3.0(m,1H);

3.9(m,1H); 4.2(m,2H); 6.7(dd,1H).

EXAMPLE 17

4-(N-Benzyloxycarbonyl-N-ethylamino)-1-(N-t-butoxycarbonyl)-(S)-valylpiperidine

The title compound was prepared from the product of Example 16 by the same procedure as described for intermediate (4b).

N.M.R. (DMSO-d₆) δ = 0.8(m,6H); 1.0(t,3H); 1.35(s,9H); 1.4-1.8(m,4H); 1.9(m,1H); 2.5(m,2H); 3.0-3.2 (m,2H); 3.9-4.3 (m,3H); 4.5(m,1H); 5.1(s,2H); 6.7 & 6.9(2x d,1H); 7.4(m,5H).

EXAMPLE 18

1-[N-((R)-2-Benzyl-(S)-5-t-butoxycarbonylamino-(S)-4-t-butyldimethylsilyloxy-6-phenylhexanoyl)-(S)-valyl]-4-(N-benzyloxycarbonyl-N-ethylamino) piperidine

The title compound was prepared by the same procedure as described for Example 3 by reacting the amine derived from the product of Example 17 with an active ester derived from the product from intermediate preparation (2b).

Found: C,68.34; H,8.38; N,6.43. C₅₀H₇₄N₄O₇Si.½H₂O requires C,68.16; H,8.52; N,6.36%.

m/e 871 (MH) ⁺

[α] ²⁵ -13° (C = 0.12%, MeOH)

N.M.R. (DMSO-d₆) δ = 0.1(s,6H); 0.8(m,6H); 0.9(s,9H);

1.0(m,3H); 1.2(s,9H); 1.2-1.7 (m,6H); 2.0(m,2H): 2.4-3.0 (m, 6H); 3.0-3.2(m,2H); 3.6(m,1H); 3.7(m,1H); 3.8-4.1(m,2H);

4.45(m,2H); 5.1(s,2H); 6.75(d,1H); 7.2(m,10H); 7.4(m,5H); 7.8 & 7.9 (2x d,1H) .

EXAMPLE 19

1-[N-((R)-2-Benzyl-(S)-5-t-butoxycarbonylamino-(S)-4-hydroxy-6-phenylhexanoyl)-(S)-valyl]-4-(N-benzyloxycarbonyl-N-ethylamino)piperidine

The title corrpound was prepared from the product of Example 18 by the same procedure as described for Example 4. Found: C,69.59; H,7.85; N,7.43. C₄₄H₆₀N₄O₇ requires C,69.81; H,7.99; N,7.43%.

m/e 757 (MH)⁺

[α]_D ²⁵ -10° (c = 0.1%, MeOH)

N.M.R. (DMSO-d₆) δ = 0.75(m,6H); 1.0(m,3H); 1.25(s,9H); 1.2-1.7(m,6H); 1.9(m,1H); 2.4-2.6(m,4H); 2.6-2.9(m,3H); 3.0-3.2(m,2H); 3.4(m,1H); 3.55(m,1H); 3.8-4.1(m,2H); 4.4-4.6(m,3H); 5.1(m,2H); 6.4(m,1H); 7.1-7.3 (m, 10H); 7.4(m,5H); 7.8 &

7.9(2x d,1H).

EXAMPLE 20

1-[N-((R)-2-Benzyl-(S)-5-t-butoxycarbonylamino-(S)-4-hydroxy-6-phenylhexanoyl)-(S)-valyl]-4-ethylaminopiperidine

The title compound was prepared from the product of Example 19 by the same procedure as described for Example 5. Found:

C,69.34; H,9.06; N,9.27. C₃₆H₅₄N₄O₅ requires C,69.42; H,8.74;

N,9.00%.

m/e 623 (MH)⁺

[α] ²⁵ -10° (c = 0.11%, MeOH)

N.M.R. (DMSO-d₆) δ = 0.7(d,6H); 0.95(t,3H); 1.0-1.1(m,2H);

1.2(s,9H); 1.4-1.9(m,5H); 2.4-3.0(m,10H); 3.4(m,1H);

3.55(m,1H); 3.8(m,1H); 4.1(m,1H); 4.45(t,1H); 4.5(t,1H);

6.4(m,1H); 7.1-7.3(m,10H); 7.8(m,1H).

EXAMPLE 21

(S)-5-((S)-1-t-Butoxycarbonylamino-2-phenethyl)-(R)-3-(3-phenylprop-2-enyl)-gamma-butyrolactone.

The title compound was prepared by the same procedure as described for Intermediate Preparation (2a) by alkylation of the lactone with 1-bromo-3-phenylprop-2-ene. Found: C,73.95; H,7.22; N,3.29. C₂₆H₃₁NO₄ requires C,74.08; H,7.41; N, 3.32%.

m/e 421 (MH⁺)

[α]²⁵ _D +1° (c = 0.1%, MeOH)

N.M.R. (DMSO-d₆) δ = 1.24(s,9H) ; 2.05(m,1H) ; 2.31(m,2H) ;

2.6(m,1H) ; 2.76 (m,3H) ; 3.81(m,1H) ; 4.5 (m,1H) ; 6.23 (m,1H) ;

6.45(d,1H) ; 7.07 (d,1H) ; 7.32 (m,10H) .

EXAMPLE 22

(S)-5-t-Butoxycarbαnylamino-(S)-4-(t-butyldimethylsilyloxy)- (R)-2-(3-phenylprop-2-enyl)-6-phenylhexanoic acid.

The title compound was prepared from the product from Example 21 by the same procedure as described for Intermediate Preparation

(2b). Found: C,69.53; H,8.59; N,2.52. C₃₂H₄₇NO₅Si

requires C,69.40; H,8.55; N,2.53%.

m/e 452 (M⁺-101)

[α]²⁵ _D -28° (c = 0.1%, MeOH)

N.M.R. (DMSO-d₆) δ = 0.1(d,6H); 0.9l(s,9H); 1.27 (s,9H);

1.38(m,1H); 1.94(m,1H); 2.41(m,3H); 2.58(m,1H); 2.72(d,1H);

3.62(b,1H); 3.75(b,1H); 6.2(m,1H); 6.43(d,1H); 6.86(d,1H);

7.25(m,10H); 12.13 (b,1H).

EXAMPLE 23

1-[N-((S)-5-t-Butoxyoarbonylamino-(S)-4-t-butyldimethylsilyloxy-6-phenyl-(S)-2-(3-phenylprop-2-en-1-yl))hexanoyl-(S)-valyl]-4-ketopiperidine

The title cxmpαund was prepared from the product from Example 22 and the product from Intermediate Preparation (3a) by the same procedure as described for Intermediate Preparation (5b). Found: C,68.63; H,8.80; N,5.71. C₄₂H₆₃N₃O₆Si requires C,68.72; H,8.65; N,5.72%.

m/e 734 (MH⁺)

[α]²⁵ _D +5° (c = 0.1%, MeOH)

N.M.R. (CDCl₃) δ = 0.13(d,6H); 0.92(m,6H); 1.0(s,9H); 1.37(s,9H);

1.72(m,1H); 1.85(m,1H); 2.0-2.45(m,7H); 2.52(m,1H); 2.72(m,2H);

3.52(m,1H); 3.77(m,4H); 4.0(m,1H); 4.72(m,2H); 6.1(m,1H);

6.25(d,1H); 6.33(d,1H); 7.3(m,10H). EXAMPLE 24

1-[N-((S)-5-t-Butoxycarbonylamino-(S)-4-t-butyldimethylsilyloxy-6-phenyl-(S)-2-(3-phenylprop-2-en-1-yl)hexanoyl)-(S)-valyl]-4-methylaminopiperidine

The title compound was prepared by the same procedure as

described for Example 7 by reacting the product from Example 23 with methylamine.

N.M.R. (DMSO-d₆) δ = 0.13(s,6H); 0.71(m,6H); 0.9(s,9H);

1.15(b,2H); 1.27(s,10H); 1.72(m,2H); 1.98(m,2H); 2.21(s,3H);

2.32(b,2H); 2.5(b,2H); 2.67(m,1H); 2.73-3.95 (m, 2H) ; 4.14(m,1H); 3.58(b,1H); 3.7(b,1H); 3.92(m,1H); 4.10(m,1H); 4.53(m,1H);

6.13(m,1H); 6.35(m,1H); 6.79(m,1H); 7.22(m,10H); 7.93(m,1H).

EXAMPLE 25

1-[N-((S)-5-t-Butoxycarbonylamino-(S)-4-hydroxy-6-phenyl-(S)-2- (3-phenylprop-2-en-1-yl)hexanoyl)-(S)-valyl]-4-methylaminopiperidine

The title compound was prepared from the product from Example 24 by the same procedure as described for Example 2, m.p. 149-151°.

Found: C, 69.98; H,8.53; N,8.66. C₃₇H₅₄N₄O₅ requires C, 70.00;

H,8.57; N,8.82%.

[α]²⁵ _D + 16° (c = 0.1%, MeOH)

N.M.R. (DMSO-d₆) δ = 0.76(d,6H); 0.92(m,1H); 1.07(m,1H);

1.27(s,9H); 1.33(m,1H); 1.65(m,3H); 1.9(m,1H); 2.18(s,3H);

2.3(m,2H); 2.43(m,2H); 2.58(m,1H); 2.76(m,2.5H); 3.08(t,0.5H);

3.41(m,1H); 3.55(m,1H); 3.73(m,1H); 4.04(m,1H); 4.52(m,1H);

4.6(d,1H); 6.08(m,1H); 6.31(m,1H); 6.42(d,1H); 7.24(m,10H);

7.85(m,1H).

EXAMPLE 26

4-Amino-1-[N-((S)-5-t-butoxycarbonylamino-(S)-4-t-butyldimethylsilyloxy-6-phenyl-(S)-2-(3-phenylprop-2-en-1-yl)hexanoyl-(S)-valyl]piperidine

The title compound was prepared by the same procedure as described for Example 7 by reacting the product from Example 23 with ammonium acetate. m/e 735 (MH⁺)

N.M.R. (DMSO-d₆) δ = 0.17(s,6H); 0.85(m,6H); 0.93 (s,9H);

1.22(b,2H); 1.31(s,10H); 1.68(b,2H); 2.0(b,2H); 2.34(m,2H);

2.46(b,1H); 2.54(1H); 2.65-2.95(m,3.5H); 3.13(m,0.5H); 3.62(b,1H); 3.71(b,1H); 3.93(b,1H); 4.17(b,1H); 4.58(m,1H); 6.l9(m,1H);

6.38(1H); 6.81(m,1H); 7.3(m,10H); 7.93(t,1H).

EXAMPLE 27

4-Amino-1-[N-((S)-5-t-buto-xycarbonylamino-(S)-4-hydroxy-6-phenyl- (S)-2-(3-phenylprop-2-en-1-yl)hexanoyl)-(S)-valyl]piperidine

The title compound was prepared by the same procedure as

described for Example 26, m.p. 111-112°. Found: C,69.44; H,8.53;

N,8.89. C₃₆H₅₂N₄O₅ requires C,69.64; H,8.44; N,9.02%.

m/e 621 (MH )

[α]²⁵ _D + 18° (c = 0.1% MeOH)

N.M.R. (DMSO-d₆) δ = 1.27(d,6H); 1.05(m,2H); 1.23(s,9H);

1.33(m,1H); 1.64 (b,3H); 1.9(m,1H); 2.l8(m,1H); 2.35(m,2H);

2.58(m,1H); 2.72(m,3.5); 3.05(m,0.5); 3.41(b,1H); 3.55(b,1H);

3.85(m,1H); 4.1(m,1H); 4.52(m,1H); 4.6(d,1H); 6.09(m,1H);

6.32(m,1H); 6.42(d,1H); 7.26(m,10H); 7.85(d,1H).

EXAMPLE 28

1-[N-((S)-5-t-Butoxycarbonylamino-(S)-4-hydroxy-6-phenyl-(S)-2-(3-phenylprop-1-yl)hexanoyl)-(S)-valyl]-4-methylaminopiperidine

A solution of the product from Example 25 (0.25 g) in absolute ethanol was treated with 10% palladium on charcoal (25 mg). The mixture was stirred at room temperature under hydrogen at a pressure of 30 psi (2 bar) for 4 hours. The catalyst was filtered and the solvent evaporated under vacuum to give a foam which was purified by chrϋmatography on silica-gel, eluting with methylene chloride-methanol-c»ncentrated aqueous ammonia. After evaporation of the product fractions the residue was recrystallised from ethyl acetate/hexane to afford the title compσund m.p. 101-105°. Found: C,68.89; H,8.79; N,8.68. C₃₇H₅₆N₄O₅. 0.4 EtoAC requires C,68.97; N,8.87; N,8.33%.

m/e 637 (MH⁺)

[α]²⁵ _D - 5° (c = 0.1%, MeOH) N.M.R. (DMSO-d₆) 0.75(d,6H); 1.04(m,2H); 1.26(s,l1H); 1.4(m,3H);

1.59(m,1H); 1.74(m,2H); 1.92(m,1H); 2.24(d,3H); 2.5(b,6H);

2.75(m,2H); 3.05(m,1H); 3.37(m,1H); 3.55(m,11); 3.91(m,1H);

4.12(m,1H); 4.56(m,2H); 6.42(d,1H); 7.17(m,10H); 7.83(d,1H).

EXAMPLE 29

(S)-5-((S)-1-t-Butoxycarbonylamino-2-phenylethyl)-(R)-3-(4-methylbenzyl)-gamma-butyrolactone.

The title compound was prepared by the same procedure as described for Intermediate Preparation (2a) by alkylation of the lactone with 4-methylbenzyl bromide. Found: C,73.28; H,7.65; N,3.40.

C₂₅H₃₁NO₄ requires C,73.32; H,7.63; N,3.42%.

[α]²⁵ _D - 20° (c = 0.1% MeOH).

N.M.R. (CDCl₃) δ = 1.36(s,9H); 1.97(m,1H); 2.22 (m,1H);

2.32(s,3H); 2.76(m,1H); 2.75(m,2H); 2.94(m,1H); 3.07(d,d,1H);

3.95(m,1H); 4.24(t,1H); 4.53(d,1H); 7.l3(d,d,1H); 7.26(m,5H).

EXAMPLE 30

(S)-5-t-Butoxycarbonylamino-(S)-4-(t-butyldimethylsilyloxy) -(R)-2-(4-methylbenzyl)-6-phenylhexanoic acid.

The title compound was prepared from the product from Example 29 by the same procedure as described for Intermediate Preparation (2b) . Found: C,68.94; H,8.69; N,2.55. C₃₁H₄₇NO₅Si requires C,68.72; H,8.74; N,2.58%.

m/e 542 (MH⁺)

N.M.R. (DMSO-d₆) , δ = 0.11(m, 6H) ; 0.95(s,9H) ; 1.31(d,9H) ;

1.62 (m,1H) ; 2.0(m,1H) ; 2.33 (d,3H) ; 2.45-3.13 (m, 5H) ;

3.68-4.02 (m,2H) ; 4.75(m, 0.5H) ; 6.3 (m,0.5H) ; 7.0-7.4 (m, 9H) ;

9.4-10.0 (broad, 1H) .

EXAMPLE 31

1-[N-((S)-5-t-Butoxycarbonylamino-(S)-4-t-butyldimethylsilyloxy- (R)-2-(4-methylbenzyl)-6-phenylhexanoyl)-(S)-valyl]-4-ketopiperidine

The title compound was prepared from the product from Example 30 and the product from Intermediate Preparation (3a) by the same procedure as described for Intermediate Preparation (5b). m/e 722 (MH⁺)

N.M.R. (DMSO-d₆) δ = 0.13(s,6H); 0.83(d,6H); 0.9(s,9H);

1.25(s,11H); 1.95(m,2H); 2.2(s,3H,); 2.25(m,3H); 2.44(m,2H);

2.55(m,1H); 2.79(m,2H); 3.55(m,2H); 3.71(m,2H); 3.84(m,2H);

4.51(t,1H); 6.77 (d,1H); 7.03(dd,4H); 7.2(m,5H); 8.0(d,1H).

EXAMPLE 32

1-[N-((S)-5-t-Butoxytarbonylamino-(S)-4-hydroxy-(R)-2-(4-methylbenzyl)-6-phenylhexanoyl)-(S)-valyl]-4-ketopiperidine

The title compound was prepared from the product from Example 31 by the same procedure as described for Example 6.

m/e 608 (MH⁺)

N.M.R. (CDCl₃) δ = 0.87(d,d,6H); 1.41(s,9H); 1.73(b,2H);

1.98(m,1H); 2.26(s,3H); 2.4(m,4H); 2.64(m,1H); 2.87(m,4H);

3.65(m,4H); 3.88(m,1H); 4.00(m,1H); 4.72(t,1H); 4.88(d,1H);

6.38(d,1H); 6.93(q,4H); 7.27(m,5H).

EXAMPLE 33

1-[N-((S)-5-t-Butoxycarbonylamino-(S)-4-hydroxy-(R)-2-(4-methylbenzyl)-6-phenylhexanoyl)-(S)-valyl]-4-methylaminσpiperidine

The title compound was prepared from the product from Example

32 by the same procedure as described for Example 7, m.p.

182-184°. Found: C,69.40; H,8.66; N,9.01. C₃₆H₅₄N₄O₅ requires

C,69.42; H,8.74; N,8.99%.

m/e 623 (MH⁺)

[α]_D ²⁵ - 20° (c = 0.1%, MeOH)

N.M.R. (DMSO-d₆) δ = 0.72(d,6H); 1.06(m,2H); 1.29(s,10H);

1.01(m,1H); 1.73(m,2H); 1.88(m,1H); 2.24(d,6H); 2.45(m,1H);

2.52(m,1H); 2.72(m,5H); 3.04(m,1H); 3.42(m,1H); 3.53(b,1H);

3.8(m,1H); 4.08(m,1H); 4.5(m,2H); 6.37(m,1H); 6.98(s,4H);

7.2(m,5H); 7.74(d,1H).

EXAMPLE 34

4-Amino-1-[N-((S)-5-t-butoxycarbonylamino-(S)-4-hydroxy-(R)-2-(4-methylbenzyl)-6-phenylhexanoyl)-(S)-valyl]piperidine

The title compound was prepared from the product from Example 32 by the same procedure as described for Example 8, m.p.167-168 Found: C,68.87; H,8.37; N,8.96. C₃₅H₅₂ N₄ O₅ requires C, 69.04;

H,8.61; N,9.20%.

m/e 609 (MH⁺)

[α]_D ²⁵ -2° (c = 0.1%, MeOH)

N.M.R. (DMSO - d₆) δ = 0.72(d,6H); 1.02(m,2H); 1.25 (b,10H);

1.63(b,5H); 1.86(m,1H); 2.23(s,3H); 2.56(m,1.5H); 2.73(b,4.5H);

3.02(m,0.5); 3.4(b,1H); 3.52(b,1H); 3.89(m,0.5H); 4.1(d,1H);

4.47(m,2H); 6.4(m,1H); 6.97(m,5H); 7.17(m,6H); 7.74(d,1H).

EXAMPLE 35

(S)-5-((S)-1-t-Butoxycarbonylamino-2-phenylethyl)-(R)-3-(3-methylbenzyl)-gamma-butyrolactone.

The title compound was prepared by the same procedure as described for Intermediate Preparation (2a) by alkylation of the lactone with 3-methylbenzyl bromide.

N.M.R. (CDCl₃) δ = 1.36(S,9H); 1.96(m,1H); 2.23(m,1H); 2.30(s,3H); 2.73(dd,1H); 2.88(m,2H); 2.96(m,1H); 3.10(dd,1H); 3.95(q,1H);

4.26(m,1H); 4.53(d,1H); 7.0(m,3H); 7.26(m,6H).

EXAMPLE 36

(S)-5-t-Butoxycarbonylamino-(S)-4-(t-butyldimethylsilyloxy)- (R)-2-(3-methylbenzyl)-6-phenylhexanoic acid.

The title compound was prepared from the product from Example 35 by the same procedure as described for Intermediate preparation

(2b). Found: C,68.60; H,9.11; N,2.63. C₃₁H₄₇NO₅Si requires..

C,68.72; H,8.74; N,2.58%.

m/e 542 (MH⁺)

[α]_D ²⁵ -53° (c = 0.1%, MeOH)

N.M.R. (DMSO-d₆) δ = 0.1(d,6H); 0.9(s,9H); 1.3(s,9H); 1.3(m,1H);

1.91(m,1H); 2.24(s,3H); 2.55-2.91(complex 5H,) ; 3.56(b,1H);

3.72(b,1H); 6.85(d,1H); 6.98(m,3H); 7.2(6H,m).

EXAMPLE 37

1-[N-((S)-5-t-Butoxycarbonylamino-(S)-4-t-butyldimethylsilyloxy- (R)-2-(3-methylbenzyl)-6-phenylhexanoyl)-(S)-valyl]-4-ketopiperidine

The title compound was prepared from the product from Example 36 and the product from Intermediate Preparation (3a) by the same procedure as described for Intermediate Preparation (5b) .

Found: C, 67.86; H,8.97; N,5.70. C₄₁Hg₃N₃0gSi requires C,68.19;

H,8.79; N,5.82%.

m/e 722 (MH⁺)

[α]_D ²⁵ - 16° (c =0.1%, MeOH)

N.M.R. (DMSO-d₆) δ = 0.08(d,6H); 0.83 (broad based singlet 17H);

1.21(s,10H); 1.93(m,2H); 2.17(s,3H); 2.25(b,2H); 2.42(m,2H);

2.63(d,1H,); 2.82(m,2H); 3.53(b,2H); 3.65(b,2H); 3.81(b,2H);

4.47(t,1H); 6.73(d,1H); 6.9-7.26(m,9H); 8.04(d,1H).

EXAMPLE 38

1-[N-((S)-5-Butoxycarbonylamino-(S)-4-t-butyldimethylsilyloxy-(R)- 2-(3-methylbenzyl)-6-phenylhexanoyl)-(S)-valyl]-4-methylaminopiperidine

The title compound was prepared from the product from Example 37 by the same procedure as described for Example 24. Found:

C,67.70; H,9.37; N,7.49 C₄₂H₆₈N₄O₅Si 0.5 H₂O requires C,67.60;

H,9.32; N,7.50%.

m/e 737 (MH⁺)

[α]_D ²⁵ - 10° (c = 0.1% MeOH)

N.M.R. (DMSO-d₆) δ = 0.05(m,6H); 0.78(m,6H); 0.83 (s,9H);

1.05(m,2H); 1.2(s,10H,); 1.7(m,2H); 1.91(m,2H); 2.22(d,6H);

2.38(b,2H); 2.48(m,1H); 2.6-2.85 (complex 4.5H); 3.05(m,0.5H); 3.5(b,1H); 3.62(m,1H); 3.81(m,1H); 4.05(m,1H); 4.43(m,1H);

6.67(d,1H); 7.06(m,10H); 7.85(dd,1H).

EXAMPLE 39

1-[N-((S)-5-t-Butoχycarbonylamino-(S)-4-hydroxy-(R)-2-(3-methylbenzyl)-6-phenylhexanoyl)-(S)-valyl]-4-methylaminopiperidine

The title ccmpound was prepared from the product from Example 38 by the same procedure as described for Example 2, m.p. 174-176°. Found: C,69.73; H,8.73; N,8.93. C₃₆H₅₄N₄O₅ requires C,69.42; H,8.74; N,8.99%.

m/e 622 (MH⁺)

[α]_D ²⁵ +1.0 (c = 0.1% MeOH) N.M.R. (DMSO-d₆) δ = 0.73 (d,6H) ; 1.05(m,2H) ; 1.29 (s, 10H) ;

1.61(b,1H) ; 1.71(m,2H) ; 1.85(m,1H) ; 2.24 (s,6H) ; 2.43 (m,2H) ;

2.62 (m,2H) ; 2.76(m,3.5) ; 3.05(m,0.5H) ; 3.42 (b,1H) ; 3.53 (b,1H) ; 3.78 (m,1H) ; 4.07 (m,1H) ; 4.5(m,2H) ; 6.48 (m,1H) ; 6.9 (m,3H) ;

7.15(m,6H) ; 7.77(m,1H) .

EXAMPLE 40

1-[N-( (S)-5-t-Butoxycarbonylamino-(S)-4-t-butyldimethylsilyloxy-6-phenyl-(R)-2-(3-phenylprop-2-en-1-yl)hexanoyl)-(S)-valyl]-4-ethylaminopiperidine

The title compound was prepared by the same procedure as described for Example 7 by reacting the product from Example 23 with ethylamine. Found: C,68.01; H,9.23; N,7.34. C₄₄H₇₀N₄O₅Si. 0.2 CH₂Cl₂ requires C,68.04; H,9.09; N,7.18%.

m/e 763 (MH⁺)

[α]_D ²⁵ + 12° (c = 0.1 MeOH)

N.M.R. (DMSO-d₆) δ=0.1(s,6H); 0.72(m,6H); 0.9(s,9H); l.θ(m,5H);

1.27(s,10H); 1.7(m,2H); 1.98(m,2H); 2.31(m,2H); 2.5(m,5H);

2.64(m,1H); 2.8-3.05(complex, 1H) ; 3.57(m,1H); 3.68(m,1H);

3.92(m,1H); 4.10(m,1H); 4.62(m,1H); 6.14(m,1H); 6.34(m,1H);

6.79(m,1H); 7.25(complex; 10H) ; 7.92(m,1H).

EXAMPLE 41

1-[N-((S)-5-t-Butoxycarbonylamino-(S)-4-hydroxy-6-phenyl-(R)-2-(3-phenylprop-2-en-1-yl)hexanoyl)-(S)-valyl)-4-ethylaminopjperidine The title compound was prepared from the product from Example 40 by the same procedure as described for Example 2, m.p. 152-154°. Found: C,70.60; H,8.91; N,8.60. C₃₈H₅₆N₄O₅ requires C,70.33; H,8.69; N,8.63%.

m/e 649 (MH⁺)

[α] + 19° (c = 0.1% MeOH)

N.M.R. (DMSO-d₆) δ = 0.73(d,6H); 0.96(m,3H); 1.09(m,2H);

1.26(s,9H); 1.47(m,1H); 1.66(m,3H); 1.92(m,1H); 2.19(m,1H);

2.38(m,2H); 2.55-3.15(complex 7H); 3.42(m,1H); 3.57 (m, 1H);

3.87(m,1H); 4.10(m,1H); 4.5(m,1H); 4.62(d,1H); 6.1(m,1H);

6.37(m,2H); 7.24(m,10H); 7.88(d,1H). EXAMPLE 42

1-[N-((S)-5-t-Butoxycarbonylamino-(S)-4-t-butyldimethylsilyloxy- 6-phenyl-(R)-2-(3-phenylprop-2-en-1-yl)hexanoyl)-(S)-isoleucyl]- 4-ketopiperidine

The title compound was prepared from the product from Example

22 and the product from Intermediate Preparation (5a) by the same procedure as described for Intermediate Preparation (5b) . Found:

C,68.70; H,9.00; N,5.62. C₄₃H₆₅N₃O₆Si requires C,69.03; H,8.76;

N,5.62%.

m/e 748 (MH⁺)

[α]_D ²⁵ = +22° (c = 0.1% MeOH)

N.M.R. 0.13(s,6H); 0.81(m,6H); 0.92(s,9H); 1.2(m,3H); 1.29(s,9H);

1.55(m,1H); 1.72(m,1H); 2.05(m,2H); 2.3(m,3H); 2.45(m,2H);

2.67(b,1H); 2.8(m,1H); 3.5-3.8(m,5H); 3.9(m,1H); 4.6(m,1H);

6.17(m,1H); 6.33(m,1H); 6.78(d,1H); 7.23(m,10H); 8.l2(d,1H).

EXAMPLE 43

1-[N-((S)-5-t-Butoxycarbonylamino-(S)-4-t-butyldimethylsilyloxy-6-phenyl-(R)-2-(3-phenylprop-2-en-1-yl)hexanoyl)-(S)-isoleucyl]-4-methylaminopiperidine

The title ccmpound was prepared by the same procedure as described for Example 7 by reacting the product from Example 42 with methylamine. Found: C,68.04, H,9.09; N,7.18. C₄₄H₇₀N₄O₅Si. 1/5 CH₂Cl₂ requires C, 67.76; H,9.09; N,7.19%.

m/e 763 (MH⁺)

[o.]²⁵ + 4° (c = 0.1% MeOH)

N.M.R. (DMSO-d₆) δ = 0.12(s,6H); 0.78(m,6H); 0.9(s,9H);

0.95-1.15(m,4H); 1.29(s,9H); 1.49(b,1H); 1.73(m,3H); 2.01(b,1H); 2.22(s,3H); 2.31(m,3H); 2.5(m,2H); 2.65(b,1H); 2.82(m,1H); 2.93 + 3.12(m,1H); 3.63(m,2H); 3.85-4.2 (m,2H) ; 4.55(m,1H); 6.l3(m,1H); 6.33(dd,1H); 6.27(m,1H); 7.25(m,10H); 7.97(dd,1H). EXAMPLE 44

1-[N-( (S)-5-t-Butoxycarbonylamino-4-hydroxy-6-phenyl-(R)-2 (3-phenylprop-2-en-1-yl)hexanoyl) -(S)-isoleucyl]-4-methylaminopiperidine

The title compound was prepared from the product from Example 42 by the same procedure as described for Example 2, m.p. 145-147° .

Found: C,67.39; H,8.63; N,8.25. C₃₈ H₅₆N₄O₅ 3/2 H₂O requires

C,67.52; H,8.79; N,8.29.

m/e 649 (MH⁺)

[α]_D ²⁵ = +6° (c = 0.1% MeOH)

N.M.R. (DMSO-d₆) δ = 0.73(m,6H); 0.82-1.17 (m,3H) ; 1.26(s,10H);

1.38(b,1H); 1.7(m,4H); 2.2(s,4H); 2.3(m,1H); 2.43(m,3H);

2.52-2.82(m,3H); 2.86(m,0.5); 3.10(m,0.5); 3.4(b,1H); 3.57(m,1H); 3.8-4.l6(m,2H); 4.58(m,2H); 6.08(m,1H); 6.32(m,1H); 6.43(d,1H); 7.22 (m,10H); 7.88 (t,1H).

EXAMPLE 45

1-[N-((S)-5-t-Butoxycarbonylamino-(S)-4-t-butyldimethylsilyloxy- 6-phenyl-(R)-2-(3-phenylprop-2-en-1-yl)hexanoyl)-(S)-isoleucyl]¬

4-ethylaminopiperidine

The title compound was prepared by the same procedure as described for Example 7 by reacting the product from Example 42 with ethylamine. Found: C, 68.46; H,9.22; N,7.24. C₄₅H₇₂N₄O₅Si 0.2

CH₂Cl₂ requires C,68.36; H,9.18; N,7.05%.

m/e 777 (MH⁺)

[α]_D ²⁵ +6° (c = 0.1% MeOH)

N.M.R. (DMSO-d₆) δ = 0.11(s,6H); 0.78(m,6H); 0.91(s,9H);

0.97(m,5H); 1.12(m,1H); 1.24(s,10H); 1.46(b,1H); 1.71(m,3H);

2.02(m,1H); 2.3(m,2H); 2.50(m,5H); 2.62(b,1H); 2.78(m,1H);

2.85-3.15(m,1H); 3.64(m,2H); 3.85-4.2 (m,2H); 4.56(m,1H);

6.12(m,1H); 6.32(m,1H); 6.75(m,1H); 7.24(m,10H); 7.9(dd,1H).

EXAMPLE 46

1-[N-((S)-5-t-Butoxycarbonylamino-(S)-4-hydroxy-6-phenyl-(R)-2- (3-phenylprop-2-en-1-yl)hexanoyl-(S)-isoleucyl-4-ethylaminopiperidine The title compound was prepared from the product from Example 45 by the same procedure as described for Example 2, m.p. 150-151°.

Found: C,69.85; H,8.70; N,8.34. C₃₉H₅₈N₄O₅0.5 H₂O requires

C69.71; H,8.85; N,8.34%.

m/e 663 (MH⁺)

[α]_D ²⁵ + 14° (c = 0.1% MeOH)

N.M.R. (DMSO-d₆) δ = 0.75(m,6H); 0.97(m,5H); 1.03(m,1H);

1.25(s,9H); 1.35(m,2H); 1.69(m,4H); 2.18(m,1H); 2.33(m,1H);

2.4-2.84(m,7H); 2.85(m,0.5); 3.18(m,0.5); 3.4(m,1H); 3.55(m,1H);

3.8-4.15(m,2H); 4.59(m,2H); 6.09(m,1H); 6.32(m,1H); 6.42(d,1H);

7.23 (m,10H); 7.37(t,1H).

EXAMPLE 47

4-Acetamidomethylpyridine

An ice-cooled solution of 4-aπtincHretftylpyridine (25 g) and triethylamine (34.8 g) in methylene chloride (100 ml) was treated with a solution of acetic anhydride (30.5 g) in methylene chloride (50 ml) over 15 minutes. The reaction was allowed to warm to room temperature where it was stirred overnight before being washed with saturated brine (25 ml), dried (MgSO₄) and evaporated under vacuum to provide a dark brown semi-solid (45 g, still contains triethylamine) which was used directly for the next stage.

EXAMPLE 48

1-t-Butoxycarbonyl-4-acetamidomethylpiperidine

A solution of the product from Example 47 (45 g) in acetic acid (300 ml) was treated with platinum oxide (0.5 g) and was stirred under an atmosphere of hydrogen at 60 psi (4.1 bar) and 60°C for 24 hours before the solvent was removed by evaporation under vacuum. A solution of the residue in methylene chloride (300 ml) was treated at room teiiperature with di-tert-butyl dicarbonate (50.2 g) and stirred for a further 18 hours. The reaction was diluted with methylene chloride (150 ml) and washed with water (3 × 150 ml), dried (MgSO₄) and evaporated under vacuum to give a light brown solid which was triturated with hexane, filtered and dried under vacuum to provide the title compound, (24.1 g), m.p. 90-92°. Found: C,60.89; H,9.32; N,10.81. C₁₃H₂₄N₂O₃ requires C, 60.94; H,9.40; N, 10.94%.

m/e 256 M⁺

N.M.R (DMSO-d₆) δ = 0.95 (m,2H) ; 1.4 (s,9H) ; 1.45-1.6 (m, 3H) ;

1.8 (S, 3H) ; 2.65 (m,2H) ; 2.9 (t,2H) ; 3.9 (m,2H) ; 7.85 (t,1H) .

EXAMPLE 49

1-t-Butoxycarbonyl-4-aminomethylpiperidine

A solution of the product from Example 48 (21 g) and sodium hydroxide (9 g) in methanol (100 ml) and water (20 ml) was heated under reflux for 72 hours. The reaction was allowed to cool and the solution extracted with ethyl acetate (5 × 100 ml). The ccmbined organic layers were dried (MgSO₄) and evaporated under vacuum to provide the title compound as a colourless oil, (12.2 g).

m/e 214 M⁺

N.M.R. (DMSO-d₆) δ = 1.0(m,2H); 1.4(s,9H); 1.7(m,3H);

2.4(d,2H); 2.65(m,2H); 4.0(m,2H).

EXAMPLE 50

4-Benzyloxycarbonylaminoethyl-1-t-butoxycar

A solution of the product from Example 49 (12.2 g) in

methylene chloride (150 ml) at room temperature was treated with N-(benzyloxycarbonyloxy)succinimide (17.05 g) and the reaction stirred for an additional 4 hours. The solution was diluted with methylene chloride (150 ml), washed with water (3 × 100 ml), dried (MgSO₄) and evaporated under vacuum to give a solid residue. Recrystallisation from ethyl acetate/hexane provided the product as a white solid (13.6 g), m.p. 106-107°.

Found: C,64.02; H,8.03; N,7.93. C₁₉H₂₈N₂O₄· 0.5 H₂O requires

C,63.78; H,8.11; N,7.83%.

m/e 348.9 (MH)⁺

N.M.R. (DMSO-d₆) δ = 0.9(m,2H); 1.4(s,9H); 1.6(m,3H);

2.65(m,2H); 2.9(t,2H); 3.9(m,2H); 5.0(s,2H); 7.4(m,6H).

EXAMPLE 51

4-Benzyloxycarbonylaminomethylpiperidine

A solution of the product from Example 50 (5.0 g) in methylene chloride (40 ml) was saturated with hydrogen chloride at 0° and kept at this temperature for a further 1 hour. The solvent was evaporated under vacuum to give a colourless foam which was dissolved in distilled water (40 ml) and lyophilised to provide the title conpound, 3.77 g. Found: C,57.80; H,7.13; N,9.42.

C₁₄H₂₀N₂O₂.HCl.¹/₃H₂O requires C,57.77; H,7.10; N,9.65%.

m/e 249.03 (MH)⁺

N.M.R. (DMSO-d₆) δ = 1.2-1.4(m,2H); 1.6-1.8(m,3H); 2.8(m,2H);

2.9(t,2H); 3.25(d,2H); 5.0(s,2H); 7.3-7.5(m,6H); 8.8(brs,1H);

9.2(brs,1H).

EXAMPLE 52

4-Benzyloxycarbonylaminomethyl-1-(N-t-butoxycarbonyl)-(S)-valylpiperidine

A active ester solution previously prepared by stirring

together N-t-butoxycarbonyl valine (1.91 g) , 1-hydroxybenzotriazole hydrate (1.31 g) , 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.2 g) and N,N-diisopropylethylamine (7.7 ml) in methylene chloride (100 ml) for 30 minutes was treated with the product from

Example 51 (1.91 g) at room temperature and the reaction

stirred for 18 hours at this temperature. The solvent was evaporated under vacuum and the residue partitioned between ethyl acetate (100 ml) and water (100 ml) . The organic layer was separated, dried (MgSO₄) and evaporated under vacuum to give a foam. Purification by chraratography on silica-gel, eluting with ethyl acetate-hexane (80:20) , gave the title compound (3.3 g) . Found: C,63.44; H,8.15; N,9.71.

C₂₄H₃₇N₃O₅. 0.5 H₂O requires C,63.32; H,8.31; N,9.23%.

m/e 448.25 (MH) ⁺

N.M.R. (DMSO-d₆) 5 = 0.8(m,6H) ; 1.0(m,2H) ; 1.35(s,9H) ; 1.65(m,3H) ; 1.9 (m,1H) ; 2.5(m,1H) ; 2.85-3.05 (m, 3H) ; 4.0(m,1H) ; 4.2 (m,1H) ;

4.35(m,1H) ; 5.0(s,2H) ; 6.15 & 6.2 (2xd,1H) ; 7.3-7.4 (m,6H) .

EXAMPLE 53

1-[N-((R)-2-Benzyl-(S)-5-t-butoxycarbonylamino-(S)-4-t-butyldimethylsilyloxy-6-phenylhexanoyl)-(S)-valyl]-4-(N-benzyloxycarbonylaminomethyl)piperidine

The title compound was prepared as a colourless foam by reacting the amine derived from the product of Example 52 with the active ester derived from the product of Intermediate Preparation 2b, using the same procedure as described for Example 3. Found:

C,67.80; H,8.56; N,6.39. C₄₉H₇₂N₄O₇Si. 0.5 H₂O requires C,67.88;

H,8.42; N,6.46%.

m/e 856.93 (MH)⁺

N.M.R. (DMSO-d₆) δ = 0.05(2xs,6H); 0.75-0.9(m,8H); 0.85(S,9H);

1.15(m,1H); 1.2(s,9H); 1.55(m,3H); 1.9(m,2H); 2.4-3.0(m,9H);

3.55(m,1H); 3.65(m,1H); 3.85(m,1H); 4.8(m,1H); 4.95(m,1H);

5.0(s,2H); 6.75(t,1H); 7.1-7.4 (m,16H); 7.8(m,1H).

EXAMPLE 54

1-[N-((R)-2-Benzyl-(S)-5-t-butoxycarbonylamino-4-hydroxy-6-phenylhexanoyl)-(S)-valyl-4-(N-benzyloxycarbonylaminomethyl)piperidine The title compound was prepared from the product of Example 53 using the procedure described for Example 4, m.p. 187-188°. Found: C,69.53; H,7.78; N,7.74. C₄₃H₅₈N₄O₇ requires C,69.52; H,7.87;

N,7.54%.

m/e 742.89 (MH)⁺

[α]_D ²⁵ -15° (c = 0.11%, MeOH)

N.M.R. (DMSO-d₆) δ = 0.75(d,6H); 0.7-1.0(m,2H); 1.3(s,9H);

1.3(m,1H); 1.6(m,4H); 1.85(m,1H); 2.4-3.0(m,9H); 3.4(m,1H);

3.55(m,1H); 3.9(m,1H); 4.3(m,1H); 4.45(m,1H); 4.6(m,1H);

5.0(d,2H); 6.4(d,1H); 7.1-7.35(m,16H); 7.75(m,1H).

EXAMPLE 55

1-[N-((R)-2-Benzyl-(S)-5-t-butoxycarbonylamino-(S)-4-hydroxy-6-phenylhexanoyl)-(S)-valyl-4-methylaminopiperidine

The title compound was prepared from the product of Example 54 using the procedure described for Example 5. Found: C,67.91;

H,8.51; N,9.12. C₃₅H₅₂N₄O₅ requires C,68.01; H,8.59; N,9.07%.

m/e 609.57 (MH)⁺

[α]_D +1-8° (c = 0.11%, MeOH)

N.M.R. (DMSO-d₆) δ = 0.75(d,6H); 0.87(m,4H); 1.25(s,9H);

1.4(m,1H); 1.5-1.8(m,4H); 1.85(m,1H); 2.4(t,2H); 2.45-3.0(m,7H); 3.12-3.50(m,2H); 3.6(m,1H); 4.35(m,1H); 4.4(m,1H); 4.55(m,1H); 6.4(d,1H); 7.1-7.3(m,10H); 7.8(d,1H). EXAMPLE 56

4-Methylaminomethylpyridine

A solution of 4-pyridinecarboxaldehyde (30 g) in absolute ethanol (180 ml) was treated with a 33% solution of methylamine in ethanol (180 ml) and 10% palladium on charcoal and was stirred under an atmosphere of hydrogen for 8 hours at room temperature. The catalyst was filtered and the solvent evaporated under vacuum to give a brown oil. Distillation under vacuum provided the title co-rpound as a colourless oil, (23 g) , b.p. 96-98°, 11mmHg.

N.M.R. (CDCl₃) δ = 1.3(brs,1H); 2.4(s,3H); 3.75(s,2H);

7.2(d,2H); 8.5(d,2H).

EXAMPLE 57

4-(N-Acetyl-N-methylaminomethyl)pyridine

An ice-cooled solution of the product from Example 56 (23 g) and triethylamine (29.3 g) in methylene chloride (150 ml) was treated with acetic anhydride (25.5 g) over 30 minutes. The reaction was allowed to warm to room temperature where it was stirred overnight before the solvent was evaporated under vacuum , the residue dissolved in methylene chloride (250 ml) and washed with aqueous sodium hydroxide solution (IN, 100 ml). The organic layer was dried (Na₂CO₃) and evaporated under vacuum to give the title compound as a brown oil which

solidified on standing.

N.M.R. (CDCl₃) δ = 2.1 & 2.15(2xs,3H); 2.9(2xs,3H); 4.5 &

4.55(2XS,2H) ; 7.1(m,2H); 8.5-8.6(m,2H).

EXAMPLE 58

4-(N-Acetyl(N-methylaminomethyl)-1-t-butoxycarbonylpiperidine

A solution of the product from Example 57 (17.5 g) in acetic acid (250 ml) was treated with platinum oxide (1.0 g) and was stirred under an atmosphere of hydrogen at 60 psi and 60°C for 48 hours before tiie catalyst was filtered and the solvent removed ty evaporation under vacuum. The residue was partitioned between methylene chloride (200 ml) and water (200 ml) which was treated with aqueous sodium hydroxide solution to pH 10 and then saturated with sodium chloride. The organic layer was separated and the aqueous extracted with methylene chloride (3 × 150 ml). The combined organic extracts were dried (MgSO₄) and evaporated under vacuum to provide the title conpound as a yellow oil which solidified on standing, (13.1 g). A suspension of this product (16.3 g) in dioxan (120 ml) was treated with di-tert-butyl dicarbonate (24 g) at room teirperature and the reaction stirred for 60 hours. The solvent was evaporated under vacuum and the residue partitioned between methylene chloride (150 ml) and water (150 ml). The organic layer was washed with aqueous citric acid solution (5%, 100 ml), dried (MgSO₄) and evaporated under vacuum to give a yellow oil. Purification by chrcmatography on

silica-gel, eluting with ethyl acetate-methanol (9:1) gave the title compound as a colourless oil which crystallised on standing to a low melting point solid, (19.6 g).

m/e 271.04 (MH)⁺

N.M.R (CDCl₃) δ = 1.2(m,2H); 1.4(s,9H); 1.6(m,2H); 1.8(m,1H); 2.1(s,3H); 2.65(t,2H); 2.9 & 3.0(2xs,3H); 3.1-3.3 (m,2H);

4.1(m,2H).

EXAMPLE 59

1-t-Butoxycarbonyl-4-(N-methylaminomethyl)piperidine

The title compound was prepared from the product of Example 58 by the same procedure as described for Example 49.

m/e 456.90 (MH)⁺

N.M.R. (CDCl₃) δ = 1.15(m,2H) ; 1.4 (s,9H) ; 1.5-1.75 (m,4H) ;

2.45(s,3H) ; 2.5(m,2H) ; 2.7 (t,2H) ; 4.1(m,2H) .

EXAMPLE 60

4-(N-Benzyloxycarbonyl-N-methylaminomethyl)-1-t-butoxycarbonylpjperidine

The title compound was prepared from the product of Example 59 by the same procedure as described for Example 50. Purification fcy chromatography on silica-gel, eluting with hexane-ethyl acetate (3:2) gave the title compound as a colourless oil.

m/e 352.91 (MH)⁺

N.M.R (CDCl₃) δ = 1.25(m,2H); 1.4(s,9H); 1.6(m,2H); 1.8(m,1H); 2.65(m,2H); 2.95(s,3H); 3.2(m,2H); 4.1(m,2H); 5.1(s,2H);

7.4(m,5H). EXAMPLE 61

4-(N-Benzyloxycarbonyl-N-methylaminomethyl)piperidine

The title ccatpound was prepared from the product of Example 60 by the same procedure as described for Example 51, m.p. 193-196°.

Found: C,59.54; H,7.60; N,9.41. C₁₅H₂₂N₂O₂.1.1HCl

requires C,59.57; H,7.64; N,9.27%.

m/e 262 M⁺

N.M.R. (DMSO-d₆) δ = 1.3-1.5(m,2H) , 1.7(m,2H) ; 1.9(m,1H) ; 2.7- 3.0(m,5H) ; 3.1-3.3 (m,4H) ; 5.05(s,2H) ; 7.35(m,5H) ; 8.8 (brs,1H) ; 9.2 (brs,1H) .

EXAMPLE 62

4-(N-Benzyloxycarbonyl-N-methylaminomethyl)-1-(N-t-butoxycarbonyl)-(S)-valylpiperidine

A solution of the product of exairple 61 (1.62 g) in N,N-dimethylformamide (35 ml) was treated at room temperature with N-t-butoxycarbonyl-(S)-valine N-hydroxysuccinimide ester (1.7 g) and N,N-diisopropylethylamine (4.7 ml) and the reaction stirred for 18 hours. The solvent was evaporated under vacuum and the residue partitioned between ethyl acetate (75 ml) and water (75 ml) . The organic layer was separated, washed with aqueous citric acid solution (5%, 50 ml) , saturated brine (50 ml) , dried (MgSO₄) and evaporated under vacuum to a colourless foam. Purification by c hromatography on silica-gel, eluting with hexane-ethyl acetate (2:1) gave the title cxmpound, (1.96 g) .

m/e 462.11 (MH) ⁺

N.M.R. (DMSO-d₆) δ = 0.8(m,6H) ; 0.8-1.2 (m,2H) ; 1.35(s,9H) ;

1.5-1.7(m,2H) ; 1.8-2.0(m,2H) ; 2.55(m,1H) ; 2.85-3.2(m,6H) ;

4.0(m,1H) ; 4.2 (m,1H) ; 4.3 (m,1H) ; 5.05(s,2H) ; 6.7 &

6.8(2xm,1H) ; 7.4(m,5H) .

EXAMPLE 63

1-[N-((R)-2-Benzyl-(S)-5-t-butoxycarbonylamino-(S)-4-butyldimethylsilyloxy-6-phenylhexanoyl)-(S)-valyl]-4-(N-benzyloxycarbonyl-N-methylaminomethyl)piperidine The title compound was prepared as a colourless foam by reacting the amine derived from the product of Example 62 with the active ester derived from the product of Intermediate Preparation 2b, using the same procedure as described for Example 3.

m/e 871.21 (MH)⁺

N.M.R. (DMSO-d₆) δ = 0.15(S,6H); 0.8-1.15(m,8H); 0.9(s,9H);

1.3(s,9H); 1.5(m,1H); 1.55(m,2H); 1.8-2.l(m,3H); 2.5-3.0(m,10H); 3.1(m,2H); 3.6(m,1H); 3.7(m,1H); 3.8-4.1(m,1H);

4.35(m,1H); 4.5(m,1H); 5.1(s,2H); 6.8-8.0(m,17H).

EXAMPLE 64

1-[N-((R)-2-Benzyl-(S)-5-t-butoxycarbonylamino-(S)-4-hydroxy-6-phenylhexanoyl)-(S)-valyl]-4-(N-benzyloxycarbonyl-N-methylaminomethyl)piperidine

The title compound was prepared as a colourless foam from the product of Example 63 using the procedure described for Example 4. Found: C,70.05; H,8.07; N,7.34. C₄₄H₆₀N₄ O₇ requires C,69.81;

H,7.99; N,7.40%.

m/e 757.06 (MH)⁺

[α]_D ²⁵ -8° (c = 0.1%, MeOH)

N.M.R. (DMSO-d₆) d = 0.75(m,6H); 0.8-1.0(m,2H); 1.3(s,9H);

1.3(m,1H); 1.5-1.7(m,3H); 1.85(m,2H); 2.4-2.6 (m, 4H) ; 2.7-2.9(m,6H); 3.1(m,2H); 3.45(m,1H); 3.55(m,1H); 3.9(m,1H);

4.8(m,1H); 4.4-4.6(m,2H); 5.1(m,2H); 6.4(d,1H); 7.1-7.4(m,15H); 7.75(m,1H).

EXAMPLE 65

1-[N-((R)-2-Benzyl-(S)-5-butoxycarbonylamino-4-hydroxy-6-phenyl¬hexanoyl)-(S)-valyl)-4-methylaminomethylpiperidine

The title compound was prepared as a colourless for from the product of Example 64 using the procedure describe for Example 5. Found: C,69.26; H,8.43; N,8.88. C₃₆H₅₄N₄O₅ requires C,69.45;

H,8.68; N,9.00%.

m/e 623.11 (MH)⁺

[α]_D ²⁵ -1° (c = 0.1%, MeOH)

N.M.R. (DMSO-d₆) δ = 0.8(d,6H); 0.8-1.0(m,2H); 1.3 (m, 1H);

1.3(S,9H); 1.6-1.8(m,4H); 1.85(m,1H); 2.25(S,3H); 2.8(t,2H);

2.4-3.1(m,7H); 3.45(m,1H); 3.55(m,1H); 3.9(m,1H); 4.3(m,1H); 4.5(m,1H) ; 4.6(m,1H) ; 6.4(d,1H) ; 7.05-7.29 (m,10H) ; 7.73 (d,1H) .

EXAMPLE 66

(S)-5-t-Butoxycarbonylamino-(S)-4-(t-butyldimethylsilyloxy)-(R)-2-[4-(2-phenyl-2H-tetrazol-5-yl)benzyl]-6-phenylhexanoic acid. The title compound was prepared by the same procedure as described for Intermediate Preparation 2 using 5-(4-bromobenzyl)-2-phenyl-2H-tetrazole.

N.M.R. (DMSO-d₆) δ = 0.12(d,6H); 0.91(s,9H); 1.30(s,9H);

1.42(t,1H); 1.97(t,1H); 2.50(m,2H); 2.72-3.04 (m,4H); 3.61(t,1H); 3.76(d,1H); 6.88(d,1H); 7.10-7.28 (m,5H); 7.42(d,2H);

7.61-7.73(m,3H); 8.11(d,2H); 8.17(d,2H).

EXAMPLE 67

4-(N-Benzyloxycarbonyl-N-methylamino)-1-[N-( (S)-5-t-butoχycarbonylamino-(S)-4-t-butyldimethylsilyloxy-6-phenyl-(R)-2-[4-(2- phenyl-2H-tetrazol-5-yl)benzyl]hexanoyl)-(S)-valyl ]piperidine The title compound was prepared from the product of Example 66 and the product from Intermediate Preparation (4b) by the same procedure as described for Example 3. m.p. 103-106° . Found:

C,67.35; H,7.75; N,11.09. C₅₆H₇₆N₈O₇Si requires C,67.11; H,8.06; N,11.18%.

m/e 108 (M + NH₄) ⁺

N.M.R. (DMSO-d₆) δ = 0.15(d,6H); 0.82-0.91(m,6H); 0.93(s,0H);

1.4(d,9H); 1.54(broads 3H); 1.90-2.10(broad 2H); 2.52(s,7H);

2.56-2.78 (m,6H); 2.85-3.10(m,2H); 3.58(broad s,1H);

3.73 (broad,1H); 3.80-4.14(m,2H); 4.35-4.58 (m,2H); 5.03(s,2H);

6.70(t,1H); 7.11-7.46(m,12H); 7.58-7.69 (m,3H); 7.94(dd,1H);

8.04(d,2H); 8.13(d,2H).

EXAMPLE 68

4-(N-Benzyloxycarbonyl-N-methylamino-1-(S)-5-t-butoxycarbonylamino-(S)-4-hydroxy-6-phenyl-(R)-2-[4-(2-phenyl-2H-tetrazol-5-yl)benzyl]hexanoyl]-(S)-valylpiperidine

The title compound was prepared from the product of Example 67 by the same procedure as described for Example 4. Found: C,67.80; H,6.84; N,12.70. C₅₀H₆₂N₈O₇ requires C,67.70; H,7.04; N,12.63%. m/e 887 (MH⁺) N.M.R. (DMSO-d₆) δ = 0.77 (d, 6H) ; 1.30 (S,9H) ; 1.38-1.55 (m,3H) ;

1.70 (t,1H) ; 1.88 (m,1H) ; 2.52 (s, 3H) ; 2.35-2.80 (m,2H) ; 2.61 (S,2H) ; 2.68(s,2H) ; 2.87-3.07(m,2H) ; 3.46 (broad,1H) ; 3.59 (broad, 1H) ;

3.90-4.11(m,2H) ; 4.31-4.57(m,3H) ; 4.60(d,1H) ; 5.03(s,2H) ;

6.44 (d,1H) ; 7.l2-7.39(m,l2H) ; 7.59-7.72 (m, 3H) ; 7.88 (dd,1H) ;

8.03 (d, 2H) ; 8.16 (dd, 2H) .

EXAMPLE 69

1-[N-((S)-5-t-Butoxycarbonylamino-4-hydroxy-6-phenyl-(R)-2-[4-(2-phenyl-2H-tetrazol-5-yl)benzyl]hexanoyl-(S)-valyl]-4-methylaminopiperidine

The title compound was prepared from the product of Example 68 by the same procedure as described for Example 5. Found: C,66.89; H,7.27; N,14.97. C₄₂H₅₆N₈O₅ requires C,67.00; H,7.50; N,14.88%. N.M.R. (DMSO-d₆) δ = 0.73(d,6H); 0.85-1.08(m,2H); 1.31(s,9H);

1.54-1.74(m,2H); 1.78-1.89(m,1H); 2.13(d,3H); 3.73(dd,1H);

3.98(t,1H); 4.47(dt,1H); 4.64(dd,1H); 6.47(dd,1H);

7.l2-7.26(m,5H); 7.37(d,2H); 7.61-7.74 (m,3H) ; 7.80(t,1H);

8.04(m,2H); 8.18(d,2H).

m/e 753 (MH)⁺

EXAMPLE 70

(S)-5-[(S)-1-t-Butoxycarbonylamino-2-phenylethyl]-(R)-3-(3-chlorobenzyl)-gamma-butyrolactone.

The title conpound was prepared ty the same procedure as described for Intermediate Preparation (2a) by alkylation of the lactone with 3-chlorobenzyl bromide.

Found: C,66.78; H,6.73; N,3.17. C₂₄H₂₈ClNO₄ requires C,67.05; H,6.56; N,3.17%.

[α]_D ²⁵ -7.4° (c = 0.1%, MeOH)

m/e 447.43, 449.50 (MNH₄)⁺

N.M.R. (CDCl₃) δ = 1.4(s,9H); 2.0(m,1H); 2.3(m,1H); 2.75(dd,1H); 2.9-3.1(m,3H); 3.15(dd, 1H) ; 4.0(q,1H); 4.3(t,1H); 4.55(d,1H); 7.0-7.4(m,9H).

EXAMPLE 71

(S)-5-t-Butoxycarbonylamino-(S) -4-t-butyldimethylsilyloxy-(R) -2-(3-chlorobenzyl) -6-phenylhexanoic acid. The title compound was prepared from the product from Example 70 by the same procedure as described for Intermediate Preparation

(2b), m.p. 65-67° (glass). Found: C,63.90; H,7.50; N,2.40.

C₃₍₎H₄₄ClNO₅Si requires C,64.00; H,7.90; N,2.50%.

m/e 562.09, 563.92

[α]_D ²⁵ -24° (C = 0.1%, MeOH)

N.M.R. (CDCl₃) δ = 0.05(d,3H); 0.15(d,3H); 0.95(s,9H);

1.4(s,9H); 1.6(m,2H); 2.4-3.1(m,5H), 3.85(d,1H); 4.0(dd,1H);

4.8 (d, 1H) ; 6.9-7.4 (m, 9H) .

EXAMPLE 72

1-[N-((S)-5-t-Butoxycarbonyla ino-(S)-4-t-butyldimethylsilyloxy-(R)-2-(3-chlorobenzyl)-6-phenylhexanoyl)-(S)-isoleucyl]-4-ketopiperidine.

The title compound was prepared from the product of Example 71 and the product from Intermediate Preparation (5a) by the procedure described for Intermediate (5b) . Found: C,65.00;

H,8.30; N,5.70. C₄₁H₆₂ClN₃O₆Si requires C,65.10; H,8.30; N,5.60%. m/e 756.21 (MH)⁺

[α]_D ²⁵ +4.4° (c = 0.1%, MeOH)

N.M.R. (DMSO-d₆) δ = 0.15(s,6H); 0.85(m,6H); 0.9(s,9H);

1.15(m,2H); 1.3(s,9H); 1.55(m,1H); 1.8(m,1H); 2.0(m,1H); 2.2-2.95(m,9H); 3.55(m,2H); 3.65(m,1H); 3.75(m,1H); 3.9(m,2H)

4.55(m,1H); 6.75(d,1H); 7.1-7.4(m,9H); 8.2(d,1H).

EXAMPLE 73

1-[N-((S)-5-t-Butoxycarbonylamino-(S)-4-t-butyldimethylsilyloxy-(R)-2-(3-chlorobenzyl)-6-phenylhexanoyl)-(S)-isoleucyl]-4-(2-methoxyethylamino)piperidine.

The title compound was prepared by the same procedure as described for Example 7 by reacting the product of Example 72 with

2-methoxyethylamine. Found: 0,64.60; H,8.90; N,6.70.

C₄₄H₇₁ClN₄O₆Si requires C,64.80; H,8.80; N,6.90%.

m/e 815.02 (MH)⁺

[α]_D ²⁵ -7.0° (c = 0.1%, MeOH)

N.M.R. (DMSO-d₆) δ = 0.1(s,6H); 0.8(m,6H); 0.9(s,9H); 0.95-1.25(m,3H); 1.3(s,9H); 1.6(m,2H); 1.75(m,3H); 1.95(m,1H); 2.4-2.95-3.1(m,10H); 3.2(s,3H); 3.35(t,2H); 3.45-3.7 (m,2H) ; 3.9 (m,1H) ; 4.15 (m, 1H) ; 4.55 (m,1H) ; 6.75 (m,1H) ; 7.05-7.35 (m, 9H) ; 7.95 & 8.05 (2xd,1H) .

EXftMPLE 74

1-[N-((S)-5-t-Butoxycarbonylamino-(R)-2-(3-chlorobenzyl)-(S)-4-hydroxy-6-phenylhexanoyl)-(S)-isoleucyl]-4-(2-methoxyethylamino)piperidine.

The title compound was prepared from the product of Example 73 by the same procedure as described for Example 2. Found: C,65.00; H,8.40; N,8.00. C₃₈H₅₇ClN₄O₆ requires C,65.10; H,8.20; N,8.00%. m/e 700.95 (MH)⁺

[α]_D ²⁵ +7.5° (c = 0.1%, MeOH)

N.M.R. (EMSO-d₆) δ = 0.75(m,6H); 1.0(m,4H); 1.3(s,9H); 1.2-1.8(m,5H); 2.5-3.05(m,10H); 3.2(s,3H); 3.35(t,2H); 3.45(m,1H); 3.55(m,1H); 3.8(m,1H); 4.1(m,1H); 4.55(m,2H); 6.4(m,1H); 7.0-7.25(m,9H); 7.85(m,1H).

EXAMPLE 75

1-[N-((S)-5-t-Butoxycarbonylamino-(S)-4-t-butyldimethylsilyloxy-(R)-2-(3-chlorobenzyl)-6-phenylhexanoyl)-(S)-valyl]-4-(N-benzyloxycarbonyl-N-methylamino)piperidine.

The title conpound was prepared from the product of Example 71 and the product from Intermediate Preparation (3b) by the same procedure as described for Example 3, m.p. 80-90° (glass). Found: C,66.00; H.7.80; N,6.20. C₄₉H₇₁ClN₄O₇Si requires C,66.00; H,8.00; N,6.30%.

m/e 891.07, 892.56

[α]_D ²⁵ -14° (c = 0.1%, MeOH)

N.M.R. (CDCl₃) δ = 0.15(d,6H); 0.85(dd,6H); 0.95(s,9H);

1.3(m,2H); 1.4(s,9H); 1.5-2.1(m,5H); 2.35-3.05 (m, 11H) ;

3.75(m,1H); 4.0(m,1H); 4.25(m,1H); 4.5-4.8(m,3H); 5.15(s,2H); 6.15 & 6.4(2xd,1H); 6.8-7.5(m,14H).

EXAMPLE 76

1-[N-((S)-5-t-Butoxycarbonylamino-(R)-2-(3-chlorobenzyl)-(S)-4-hydroxy-6-phenylhexanoyl)-(S)-valyl]-4-(N-benzyloxycarbonyl-N-methylamino)piperidine.

The title compound was prepared from the product of Example 75 by the same procedure as described for Example 4. m.p. 95- 100° (glass). Found: C,66.50; H,7.40; N,7.20. C₄₃H₅₇CIN₄O₇ requires C,66.40; H,7.40; N,7.20%.

m/e 676.9 (MH-^tBOC)⁺

[α]_D ²⁵0.0° (c = 0.1%, MeOH)

N.M.R. (CDCl₃) δ =0.8(d,3H); 0.9(d,3H); 1.4(s,9H); 1.55(m,2H); 1.65-1.85(m,4H); 1.9(m,1H); 2.5-3.2(m,11H); 3.6-3.9(m,3H);

4.05(d,1H); 4.5-4.8(m,2H); 4.95(m,1H); 5.15(S,2H); 6.4 &

6.6 (2xd,1H); 6.8-7.5 (m, 14H).

EXAMPLE 77

1-[N-((S)-5-t-Butoxycarbonylamino-(R)-2-(3-chlorobenzyl)-(S)-4-hydroxy-6-phenylhexanoyl)-(S)-valyl]-4-methylaminopiperidine. The title compound was prepared from the product of Example 76 by the same procedure as described for Example 5, m.p. 164-166°.

m/e 642.98, 644.00 (M⁺)

N.M.R. (CDCl₃) δ = 0.8(d,3H); 0.9(m,3H); 1.3(m,2H); 1.4(s,9H); 1.5-2.0(m,5H); 2.55-3.1(m,11H); 3.55-3.85(m,2H); 3.9(d,1H);

4.35(d,1H); 4.7(m,1H); 4.9(m,1H); 6.45 & 6.55(2xd,1H); 6.8-7.5(m,9H).

EXAMPLE 78

(S)-5-[(S)-1-t-Butoxycarbonylamino-2-phenylethyl]-(R)-3-(4-trifluoromethoxybenzyl)-gamma-butyrolactone.

The title compound was prepared by the same procedure as described for Intermediate Preparation (2a) by alkylation of the lactone with 4-trifluoromethoxybenzyl bromide,

m/e 479.9 (MH) ⁺

[α]_D ²⁵ -8° (c = 0.1%, MeOH)

N.M.R. (CDCl₃) δ = 1.4(s,9H); 1.95(m,1H); 2.3(m,1H); 2.75-3.05(m,4H); 3.15(dd,1H); 4.0(dd,1H); 4.3(dd,1H); 4.55(d,1H);

7.1-7.35(m,9H).

EXAMPLE 79

(S)-5-t-Butoxycarbonylamino-(S)-4-(t-butyldimethylsilyloxy)-6-phenyl-(R)-2-(4-trifluoromethoxybenzyl)hexanoic acid.

The title compound was prepared from the product from Example 78 by the same procedure as described for Intermediate Preparation (2b) , m.p. 65-75° (glass) . Found: C,61.20; H,7.30; N,2.30.

C₃₁H₄₄F₃NO₆Si requires C,60.90; H,7.30; N,2.30%.

m/e 612.41 (MH)⁺

[α]_D ²⁵ -25° (c = 0.1%, MeOH)

N.M.R. (CDCl₃) δ = 0.1(d,6H) ; 1.0(s,9H) ; 1.4 (s,9H) ; 1.6(m,2H) ;

2.6(dd,1H) ; 2.75(m,2H) ; 2.95(dd,1H) : 3.1(m,1H) ; 3.7(dd,1H) :

3.95(dd,1H) ; 4.8(d,1H) ; 7.0(m,9H) .

EXAMPLE 80

1-[N-( (S)-5-t-Butoxycarbonylamino-(S)-4-t-butyldimethylsilyloxy-6-phenyl-(R)-2-(4-trifluoromethoxybenzyl)hexanoyl) -(S)-valyl]-4-(N-benzyloxycarbonyl-N-methylamino)piperidine.

The title compound was prepared from the product of Example 79 and the product from Intermediate Preparation (4b) by the same procedure as described for Example 3, m.p. 80-90° (glass) .

Found: C,63.90; H,7.50; N,5.90. C₅₀H₇₁F₃N₄O₈Si requires

C,63.80; H,7.60; N,5.90%.

m/e 941.08 (MH)⁺

[α]_D ²⁵ -3° (c = 0.1%, MeOH)

N.M.R. (CDCl₃) δ = 0.05(d,6H) ; 0.85(m,6H) ; 0.95 (s,9H) ; 1.3-1.8 (m,7H) ; 1.4 (s,9H) ; 2.4-3.0 (m, 11H) ; 3.75(m,1H) ; 4.0(m,2H) ;

4.6(m,3H) ; 5.15(s,2H) ; 6.2 & 6.4 (2xd,1H) ; 7.0-7.4 (m, 14H) .

EXAMPLE 81

1-[N-((S)-5-t-Butoxycarbonylamino-(S)-4-hydroxy-6-phenyl-(R)- 2-(4-trifluoromethoxybenzyl)hexanoyl)-(S)-valyl]-4-(N-benzyloxycarbonyl-N-nethylamino)piperidine.

The title compound was prepared from the product of Example 80 by the same procedure as described for Example 4, m.p. 188-190°.

Found: C,64.20; H,7.00; N,6.80. C₄₄H₅₇F₃N₄O₈ requires C,63.90;

H,7.00; N,6.80%.

m/e 826.86 (MH)⁺

[α]_D ²⁵ -6.3° (c = 0.1%, MeOH)

N.M.R. (CDCl₃) δ = 0.8(t,3H); 0.9(m,3H); 1.4(s,9H); 1.4- 2.0(m,7H); 2.5-3.2(m,l1H); 3.5-3.85(m,3H); 4.0(d,1H); 4.7(m,2H);

4.9(m,1H); 5.15(s,2H); 6.4 & 6.55(2xd,1H); 7.0-7.4 (m, 14H). EXAMPLE 82

1-[N-( (S)-5-t-Butoxycarbonylamino-(S)-4-hydroxy-6-phenyl-(R)- 2-(4-trifluoromethoxybenzyl)hexanoyl)-(S)-valyl]-4-methylamtinopiperidine.

The title compound was prepared from the product of Example 81 by the same procedure as described for Example 5, m.p.186-188°.

Found: C,62.30; H,7.40; N,8.00. C₃₆H₅₁F₃N₄O₆ requires C,62.40;

H,7.40; N,8.10%.

m/e 692.9 (MH)⁺

[or]_D ²⁵ -2.9° (c = 0.1%, MeOH)

N.M.R. (CDCl₃) δ = 0.8(s,3H) ; 0.9(s,3H) ; 1.2-1.5 (m,1H) ;

1.4(s,9H) ; 1.6-2.1(m,6H) ; 2.5(s,3H) ; 2.6-3.1(m,8H) ; 3.5- 4.0(m,4H) ; 4.45(m,1H) ; 4.7(m,1H) ; 4.9(d,1H) ; 6.55(m,1H) ; 7.0- 7.4(m,9H)

EXAMPLE 83

1-[N-( (S)-5-t-Butoxycarbonylamino-(S)-4-t-butyldimethylsilyloxy-6-phenyl-(R)-2-(4-trifluoromethoxybenzyl)hexanoyl)-(S)-isoleucyl]-4-ketopiperidine.

The title compound was prepared from the product of Example 79 and the product from Intermediate Preparation (5a) by the procedure as described for Intermediate (5b) . Found: C,62.50; H,8.00; N,5.20.

C₄₂H₆₂F₃N₃O₇Si requires C,62.60; H,7.80; N,5.20%.

m/e 806.54 (MH) ⁺

[α]_D ²⁵ -5.3° (C = 0.1%, ϊfeOH)

N.M.R. (DMSO-d₆) δ = 0.1(s,6H) ; 0.85(m,6H) ; 0.9 (s,9H) ;

1.15(m,2H) ; 1.3 (s,9H) ; 1.55(m,1H) ; 1.8(m,1H) ; 2.0(m,1H) ; 2.2-2.95(m,9H) ; 3.6(m,3H) ; 3.85(m,3H) ; 4.55(m,1H) ; 6.75(d,1H) ;

7.1-7.3 (m,9H) ; 8.15(d,1H) .

EXAMPLE 84

1-[N-( (S)-5-t-Butoxycarbonylamino-(S) -4-t-butyldimethylsilyloxy-6-phenyl-(R)-2-(4-trifluoromethoxybenzyl)hexanoyl)-(S)-isoleucyl]-4-ethylaminopiperidine.

The title compound was prepared by the same procedure as described for Example 7 by reacting the product of Example 83 with

ethylamine. Found: C,63.50; H,8.45; N,6.70. C₄₄H₆₃F₃N₄O₆Si requires

C63.30; H,8.30; N,6.70%.

m/e 835.16 (MH)⁺

tα]_D ²⁵ -24° (c = 0.1%, MeOH)

N.M.R. (DMSO-d₆) δ = 0.1(S,6H); 0.8(m,6H); 0.9(s,9H);

1.0(m,3H); 1.05-1.25(m,4H); 1.3(s,9H); 1.45(m,1H); 1.75(m,3H); 1.95(m,1H); 2.4-3.1(m,10H); 3.5-3.7(m,2H); 3.9(m,1H); 4.15(m,1H); 4.55(m,1H); 6.75(m,1H); 7.1-7.3 (m,9H); 7.9 & 8.0(2xd,1H).

EXAMPLE 85

1-[N-((S)-5-t-Butoxycarbonylamino-(S)-4-hydroxy-6-phenyl-(R)- 2-(4-trifluoromethoxybenzyl)hexanoyl)-(S)-isoleucyl]-4-ethylaminopiperidine.

The title ccarpound was prepared from the product of Example 84 by the same procedure as described for Example 2, m.p. 172-174°.

Found: C,63.00; H,7.90; N,7.70. C₃₈H₅₅F₃N₄O₆ requires C,63.30;

H,7.70; N,7.80%.

[α]_D ²⁵ -4° (c = 0.1%, MeOH)

m/e 721.57 (MH⁺)

N.M.R. (DMSO-d₆) δ = 0.7(d,3H); 0.8(d,3H); 1.0(m,3H); 1.0- 1.45(m,5H); 1.25(s,9H); 1.7(m,4H); 2.4-3.05(m,10H); 3.4(m,1H);

3.55(m,1H); 3.9(m,1H); 4.l(d,1H); 4.55(m,2H); 6.4(d,1H); 7.1- 7.3(m,9H); 7.85(m,1H).

EXAMPLE 86

N-t-Butoxycarbonyl-α-cyclohexylglycine

A suspension of (S)-α-cyclohexylglycine (J. Chem. Soc., 1957, 2076) (5.6 g) and potassium carbonate (4.92 g) in dioxan (120 ml) and water (30 ml) was treated with a solution of di-t-butyl dicarbonate (8.56 g) in dioxan (40 ml) and water (10 ml). The reaction was stirred at room teirperature for 18 hours before the solvent was evaporated under vacuum, the residue dissolved in water (100 ml) and then washed with ether. The aqueous layer was treated with acetic acid to pH 3.5 and extracted with ethyl acetate (3 × 50 ml). The combined organic extracts were dried (MgSO4), and evaporated under vacuum to give the title compound (9.59 g).

m/e 257.99 (MH)⁺ [α]_D ²⁵ +8° (c = 0.1%, MeOH)

N.M.R. (DMSO-d₆) δ = 1.05(m,5H) ; 1.3 (s,9H) ; 1.6(m,6H) ;

3.73 (t,1H) ; 6.9(d,1H) . EXAMPLE 87

1-(N-t-Butoxycarbonyl-(S)-α-cyclohexylglycyl)-4-ketopiperidine.

The title compound was prepared from the product of Example 86 and 4-ketopiperidine hydrochloride hydrate by the same

procedure as described for Intermediate Preparation (3a) .

Found: C, 63.80; H,8.85; N,8.24. C₁₈H₃₀N₂O₄ inquires C,63.89;

H,8.94; N,8.28%

m/e 339.11 (MH) ⁺

[α]_D ²⁵ 0° (c = 0.1%, MeOH)

N.M.R. (DMSO-d₆) δ = 1.1(m,5H) ; 1.35(s,9H) ; 1.7(m,6H) ;

2.33(m,3H) ; 2.45(m,1H) ; 3.55(m,1H) ; 3.75(m,1H) ; 4.9(m,2H) ;

4.3 (t,1H) ; 6.95(d,1H).

EXAMPLE 88

1-[N-(-(R)-2-Benzyl-(S)-5-t-butoxycarbonylamino-(S)-4-t-butyldimethylsilyloxy-6-phenylhexanoyl)-(S)-α-cyclohexylglycyl]-4- ketopiperidine.

The title compound was prepared from the product of Example 87 and the product from Intermediate Preparation (2b) by the same procedure as described for Intermediate (5b) . Found: C, 69.04; H,8.76; N,5.62. C₄₃H₆₅N₃O₆Si requires C,69.24; H,8.23; N,5.71 m/e 748 (MH)⁺

[α]_D ²⁵ -9° (c = 0.1%, MeOH)

N.M.R. (DMSO-d₆) δ = 0.05(s,6H) ; 0.85(s,9H) ; 0.8-1.3(m,6H) ;

1.25(s,9H) ; 1.4-2.0(m, 7H) ; 2.1-2.9 (m, 9H) ; 3.5(m,2H) ;

3.65(m,2H) ; 3.85(m,2H) ; 4.5(m,1H) ; 6.75(d,1H) ; 7.0-7.25 (m, 10H) ; 8.0 (m, 1H) .

EXAMPLE 89

1-[N-( (R)-2-Benzyl-(S)-5-t-butoxycarbonylamino-(S)-4-t-butyldimethylsilyloxy-6-phenylhexanoyl)-(S)-α-cyclohexylglycyl]-4-methylaminopiperidine. The title conpound was prepared from the product of Example 88 by the same procedure as described for Example 7. Found: C, 68.47;

H,9.10; N,7.29. C₄₄H₇₀N₄O₅S_i·½H₂O requires C,68.45; H,9.27;

N,7.26

m/e 762.97 (MH)⁺

[α]_D ²⁵ -6° (c = 0.1%, MeOH)

N.M.R. (DMSO-d₆) δ = 0.1(s,6H); 0.85(s,9H); 0.9-1.3 (m,7H);

1.25(s,9H); 1.5-1.85(m,9H); 1.95(m,1H); 2.25(s,3H); 2.4-3.1(m,8H); 3.55(m,1H); 3.6(m,1H); 3.85(m,1H); 4.1(m,1H);

4.55(m,1H); 6.75(d,1H); 7.1-7.3(m,10H); 7.85(2xd,1H).

EXAMPLE 90

1-[N-(-(R)-2-Benzyl-(S)-5-t-butoxycarbonylamino-(S)-4-hydroxy-6-phenylhexanoyl)-(S)-α-cyclohexylqlycyl]-4-methylaminopiperidine. The title compound was prepared from the product of Example 89 by the procedure as described for Example 2, m.p. 132-136°. Found: C, 70.74; H,8.51; N,8.59. C₃₈H₅₆N₄O₅ requires 0,70.34; H,8.70; N,8.63 m/e 648.98 (MH)⁺

[α]_D ²⁵ -7° (c = 0.1%, MeOH)

N.M.R. (DMSO-d₆) δ = 0.8-1.4(m,7H); 1.3(s,9H); 1.4-1.8(m,10H); 2.25(s,3H); 2.4-3.1(m,8H); 3.5(m,1H); 3.6(m,1H); 3.85(m,1H);

4.1(m,1H); 4.55(m,2H); 6.4(d,1H); 7.1-7.3 (m,10H); 7.75(m,1H).

EXAMPLE 91

1-[N-( (R)-2-Benzyl-(S)-5-t-butoxycarbonylamino-(S)-4-t-butyldimethylsilyloxy-6-phenylhexanoyl)-(S) -α-cyclohexylqlycyl]-4-(2-methoxyethylamino)piperidine.

The title compound was prepared by the same procedure as described for Example 7 by reacting the product of Example 88 with

2-.metho-xyethylamine. Found: C, 68.11; H,9.31; N,6.89. C₄₆H₇₄N₄O₆Si requires 0,68.45; H,9.24; N,6.94

m/e 806.97 (MH)⁺

[α]_D ²⁵ -9° (C = 0.1%, MeOH)

N.M.R. (DMSO-d₆) δ = 0.1(s,6H) ; 0.9(s,9H) ; 0.9-1.3 (m,7H) ;

1.3 (s,9H) ; 1.45-1.9 (m,9H) ; 1.95(m,1H) ; 2.4-3.1 (m, 10H) ;

3.2(s,3H) ; 3.4(t,2H) ; 3.6(m,1H) ; 3.65(m,1H) ; 3.9(m,1H) ;

4.15(m,1H) ; 4.55(m,1H) ; 6.75(m,1H) ; 7.1-7.3 (m,10H) ;

7.82 (2xd,1H) . EXAMPLE 92

1-[N-( (R)-2-Benzyl-(S)-5-t-butoxycarbonylamιino-(S)-4-hydroxy-6-phenylhexanoyl)-(S)-α-cyclohexylglycyl]-4-(2-methoxyethylamino)piperidine.

The title compound was prepared from the product of Example 91 by the same procedure as described for Example 2, m.p. 118-122°. Found: C,68.73, H,8.56, N,7.93. C₄₀H₆₀N₄O₆. ½H₂O requires C,68.45; H,8.76; N/7.98

m/e 692.98 (MH) ⁺

[α]_D ²⁵ -1° (c = 0.1%, MeOH)

N.M.R. (DMSO-d₆) δ = 0.8-1.4 (m,8H) ; 1.3 (s,9H) ; 1.4-1.85 (m,9H) ; 2.4-3.1(m,10H) ; 3.2(s,3H) ; 3.35(t,2H) ; 3.45(m,1H) ; 3.55(m,1H) ; 3.85(m,1H) ; 4.1(m,1H) ; 4.55(m,2H) ; 6.4(d,1H) ; 7.2 (m,10H) ;

7.75(m,1H) .

EXAMPLE 93

(S)-5-[ (S)-1-t-Butoxycarbonylamino-2-phenylethyl]-(R)-3-(4-N,N-dimethylcarbamoylbenzyl)-gamma-butyrolactone.

A solution of the active ester prepared from (S)-5-[ (S)-1-t-butoxycartorιylamino-2-phenylethyl]-(R)-3-(4-carboxybenzyl)gamma-butyrolactone (2.5 g) in N,N-di-methylformamide (20 ml) was treated with 1-hydroxybenzotriazole hydrate (1.15 g) , 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.36 g) and N,N- diisopropylethylamine (2.47 ml) was treated with dimethylamine hydrochloride (0.55 g) and the reaction stirred for 3 hours at room temperature. The mixture was partitioned between water (150 ml) and ethyl acetate (2 × 100 ml) . The combined organics were washed with IN hydrochloric acid (100 ml) , saturated aqueous sodium bicarbonate (100 ml) , saturated brine (100 ml) , dried (MgSO₄) and evaporated under vacuum. The resulting white foam was purified by chrcamatography on silicagel, eluting with hexane-ethyl acetate (20:80) to give the title compound, (1.96 g) . Found: C,69.44; H,7.28; N,6.05.

C₂₇H₃₄ N₂O₅ requires C,69.50; H,7.34; N,6.00%.

m/e 467 (MH⁺) EXAMPLE 94

(S)-5-t-Butoxycarbonylamino-(S)-4-t-butyldimethylsilyloxy-(R)-2-(4-N-N-dimethylcarbamoylbenzyl)-6-phenylhexanoic acid.

The title compound was prepared from the product from Example 93 by the same procedure as described for Intermediate (2b).

m/e 599 (MH⁺)

N.M.R. (DMSO-d₆) δ = 0.09(d,6H); 0.87(s,9H); 1.26(s,9H);

1.35(m,1H); 1.92(m,1H); 2.4(m,1H); 2.64-3.00(m, 10H); 3.48(m,1H); 3.72(m,1H); 6.86(d,1H); 7.2(m,9H).

EXAMPLE 95

1-[N-((S)-5-t-Butoxycarbonylamino-(S)-4-t-butyldimethylsilyloxy- (R)-2-(4-N,N-dimethylcarbamoylbenzyl)-6-phenylhexanoyl)-(S)-isoleucyl]-4-ketopiperidine.

The title compound was prepared from the product from Example 94 and the product from Intermediate Preparation (5a) by the procedure as described for Intermediate Preparation (5b) . Found:

C,66.80; H,8.41; N,7.02. C₄₄H₆₈N₄O₇Si requires C,66.63; H,8.64;

N,7.06%.

(c = 0.1% MeOH)

N.M.R. (DMSO-d₆) δ=0.1(s,6H); 0.81(m,6H); 0.89(s,9H);

1.16(m,2H); 1.26(s,9H); 1.52(m,1H); 1.79(m,1H); 1.96(m,1H);

2.17-2.74 (complex 6H) ; 2.9 (broad,9H) ; 3.5-3.95(complex 6H) ;

4.55(m,1H); 6.77(d,1H); 7.2(m,9H); 8.l5(d,1H).

EXAMPLE 96

1-[N-((S)-5-t-Butoxycarbonylamino-(S)-4-t-butyldimethylsilyloxy- (R)-2-(4-N,N-dimethylcarbamoylbenzyl)-6-phenylhexanoyl)-(S)- isoleucyl]-4-(2-methoxyethylamino)piperidine.

The title compound was prepared from the product from Example 95 by the procedure as described for Example 73.

Found: C,64.86; H,9.03; N,8.18. C₄₇H₇₇N₅O₇Si, 0.25 CH₂Cl₂ requires C,64.97; H,8.94; N,8.01%

m/e 852 (MH⁺) (c = 0.1% MeOH)

N.M.R. (DMSO-d₆) δ = 0.1(s,6H); 0.28(m,6H); 0.35(s,9H);

0.95-1.33 (complex, 13H) ; 1.47(m,1H); 1.8(m,3H); 2.45(m,1H);

2.4-3.14 (complex, 16H) ; 3.23(s,3H); 3.37(m,2H); 3.55(b,1H);

3.67(m,1H); 3.95(m,1H); 4.17(m,1H); 4.54(m,1H); 6.74(d,1H);

7.2(m,9H); 7.95(m,1H).

EXAMPLE 97

1-[N-((S)-5-t-Butoxycarbonylaιnino-(R)-2-(4-N,N- dimethylcarbamoylbenzyl)-(S)-4-hydroxy-6-phenylhexanoyl)-(S)- isoleucyl]-4-(2-methoxyethylamino)piperidine.

The title compound was prepared from the product from Example 96 by the procedure as described for Example 2.

m/e 738 (MH⁺)

(c = 0.1% MeOH)

N.M.R. (DMSO-d₆) δ = 0.73(m,6H); 1.03(m,2H); 1.26(s,9H);

1.3-1.43 (m, 3H) ; 1.58-1.86 (m, 4H) ; 2.5-3.07 (complex, 16H) ;

3.23(s,3H); 3.4(m,3H); 3.57(m,1H); 3.9(m,1H); 4.1(m,1H);

4.55(m,2H); 6.4(d,1H); 7.17(m,9H); 7.80(m,1H).

EXAMPLE 98

( S)-5-[(S)-1-t-Butoxycarbonylamino-2-phenylethyl]-(R)-3-(4-N- isopropylcarbamoylbenzyl)-gamma-butyrolactone.

The title compound was prepared from (S)-5-[(S)-1-t- butoxycarbonylamino-2-phenylethyl]-(R)-3-(4-carboxybenzyl)- gamma-butyrolactone (Example 1, PLC 546) and isopropylamine by the procedure as described for Example 93. Found: C,68.91;

H,7.59; N,5.65. C₂₈H₃₆N₂O₅; 0.5 CH₃CO₂C₂H₅ requires C,69.29;

H,7.62; N,5.57%.

m/e 481 (MH⁺)

(c = 0.1% MeOH)

N.M.R. (DMSO-d₆) δ = 1.15(d,6H); 1.21(s,9H); 2.05(m,2H);

2.7(m,3H); 2.9l(m,1H); 3.05(dd,1H); 3.75(m,1H); 4.08(m,1H);

4.38(m,1H); 7.03(d,1H); 7.24(m,7H); 7.77(d,2H); 8.l3(d,1H). EXAMPLE 99

(S)-5-t-Butoxycarbonylamino-(S)-4-t-butyldimethylsilyloxy-(R)-2-(4-N-isopropylcarbamoyl)benzyl-6-phenylhexanoic acid.

The title compound was prepared from the product from Example 98 by the same procedure as described for Intermediate (2b).

Found: C,66.32; H,8.53; N,4.45. C₃₄H₅₂N₂O₆ requires C,66.63;

H,8.55; N,4.57%.

m/e 613 (MH⁺)

(C = 0.1% MeOH)

N.M.R. (DMSO-d₆) δ = 0.1(d,6H); 0.9(s,9H); 1.15(d,6H); 1.24(s,9H);

1.37 (m,1H); 1.93(m,1H); 2.4(m,1H); 2.75(m,3H); 2.9(m,1H);

3.6(m,1H); 3.72(m,1H); 4.07(m,1H); 6.86(d,1H); 7.2(m,7H);

7.74(d,2H); 8.11(d,1H); 12.15(S,1H).

EXAMPLE 100

1-[N-( (S)-5-t-Butoxycarbonylamino-(S)-4-t-butyldimethylsilyloxy- (R)-2-(4-N-isopropylcarbamoyl)benzyl-6-phenylhexanoyl)-(S)-isoleucyl]-4-ketopiperidine.

The title compound was prepared from the product from Example 99 and the product from Intermediate Preparation (5a) by the procedure as described for Intermediate Preparation (5b). Found: 0,67.22; H,8.90; N,6.81. C₄₅H₇₀N₄O₇Si requires C,66.96; H,8.74;

N,6.94%.

(c = 0.1% MeOH)

N.M.R. (DMSO-d₆) δ = 0.05(d,6H); 0.76(m,6H); 0.83(s,9H);

1.1(m,8H); 1.21(s,9H); 1.49(m,1H); 1.75(m,1H); 1.92(m,1H);

2.1-2.92 (complex, 9H) ; 3.5(m,2H); 3.6-3.9 (m,4H); 4.05(m,1H);

4.52(m,1H); 6.72(d,1H); 7.l4(m,7H); 7.68(d,2H); 8.03(m,2H).

EXAMPLE 101

1-[N-((S)-5-t-Butoxycarbonylamino-(S)-4-t-butyldimethylsilyloxy- (R)-2-(4-N-isopropylcarbamoyl)benzyl-6-phenylhexanoyl)-(S)-isoleucyl]-4-ethylaminopiperidine.

The title compound was prepared by the same procedure as described for Example 7 by reacting the product of Example 100 with ethylamine. Found: 0,66.70; H,9.14; N,8.30. C₄₇H₇₇N₅O₆Si; 0.2

CH₂Cl₂ requires C,66.96; H,9.21; N,8.29%.

m/e 836 (MH⁺)

(c = 0.1% MeOH)

N.M.R. (DMSO-d₆) δ = 0.1(s,6H); 0.76(m,6H); 0.87(s,9H);

0.95(m,3H); 1.03-1.22(m,10H); 1.28(s,9H); 1.46(m,1H); 1.7(m,3H); 1.95(m,1H); 2.4-3.1(complex, 10H); 3.48-4.2(m,5H); 4.5(m,1H);

6.78(d,1H); 7.19(m,7H); 7.72(d,2H); 7.8(d,0.5H); 7.8,7.95(2xd,1H); 8.1(d,1H).

EXAMPLE 102

1-[N-( (S)-5-t-Butoxycarbonylamino-(S)-4-hydroxy-(R)-2-(4-N- isopropylcarbamoyl)benzyl-6-phenylhexanoyl)-(S)-isoleucyl]-4- ethylaminopiperidine.

The title compound was prepared from the product from Example 101 by the procedure as described for Example 2. Found: C,68.08;

H,8.59; N,9.64. C₄₁H₆₃N₅O₆ requires C,68.20; H,8.79; N,9.70%. m/e 722 (MH⁺)

(c = 0.1% IfeOH)

N.M.R. (DMSO-d₆) δ = 0.73 (m,6H) ; 0.85-1.5(complex; 23H) ;

1.67(m,4H); 2.5-3.05(coπplex 10H) ; 3.41(m,1H); 3.56(m,1H);

3.67-3.91(complex, 1H); 4.05(m,2H); 4.55(m,2H); 6.4(t,1H);

7.19(m,7H); 7.72(d,2H); 7.8(m,1H); 8.08(d,1H).

EXAMPLE 103

(S)-5-[ (S)-1-t-Butoxycarbonylamino-2-phenylethyl]-(R)-3-(4- benzyloxybenzyl)-ga mma-butyrolactone.

The title conpound was prepared by the sane procedure as described for Intermediate Preparation (2a) by alkylation of the lactone with 4-benzyloxybenzyl bromide.

m/e 523.9 (MNa) ⁺

N.M.R. (DMSO-d₆) δ = 1.2(s,9H) ; 2.0(m,2H) ; 2.6(m,3H) ;

2.85(m,2H) ; 3.7(m,1H) ; 4.3 (m,1H) ; 5.0(s,2H) ; 7.2 (m,14H) . EXAMPLE 104

(R)-2-(4-Benzyloxybenzyl)-(S)-5-t-butoxycarbonylamino-(S)-4-t-butyldimethylsilyloxy-6-phenylhexanoic acid.

The title conpound was prepared from the product from Example 103 by the sane procedure as described for Intermediate (2b). Found: C,69.99; H,7.90; N,2.40. C₃₇H₅₁NO₆Si requires C,70.11; H,8.11; N,2.21%.

m/e 633.96 (MH)⁺

N.M.R. (DMSO-d₆) δ = 0.06(d,6H); 0.85(S,9H); 1.15(t,1H);

1.2(s,9H); 1.85(t,1H); 2.4(m,1H); 2.7(m,4H); 3.55 (m,1H) ;

3.7(m,1H); 5.0(S,2H)-; 6.85-7.4(m,15H).

EXAMPLE 105

1-[N-((R)-2-(4-Benzyloxybenzyl)-(S)-5-t-butoxycarbonylamino-(S)-4-t-butyldimethylsilyloxy-6-phenylhexanoyl)-(S)-isoleucyl]-4-ketopiperidine.

The title compound was prepared from the product from Example 104 and the product from Interπediate Preparation (5a) by the procedure as described for Intermediate Preparation (5b).

Found: 0,68.64; H,8.22; N,5.02. C₄₈H₆₉N₃O₇Si.½H₂O requires C,68.86; H,8.43; N,5.02%.

[α]_D ²⁵ -5° (c = 0.15, MeOH)

m/e 935.94 (M+thio)H⁺

N.M.R. (DMSO-d₆) δ = 0.03(s,6H); 0.8(m,6H); 0.85(s,9H)

1.15(m,3H); 1.25(s,9H); 1.5(m,1H); 1.65(m,1H); 1.9(m,1H);

2.25(m,4H); 2.7(m,4H); 3.5(m,2H); 3.65(m,2H); 3.9(m,2H);

4.5(m,1H); 5.0(s,2H); 7.2(m,15H); 8.05(d,1H).

EXAMPLE 106

1-[N-( (R)-2-(4-Benzyloxybenzyl) -(S)-5-t-butoxycarbonylamino-(S)-4-t-butyldimethylsilyloxy-6-phenylhexanoyl) -(S)-isoleucyl]-4-nethylaminopiperidine.

The title compound was prepared by the same procedure as described for Example 7 by reacting the product of Example 105 with methylamine.

m/e 842.88 (MH)⁺ N.M.R. (DMSO- d₆) δ = 0.1(S,6H) ; 0.8 (m,6H) ; 0.9 (s,9H) ;

1.1(m,6H) ; 1.25(s,8H) ; 1.5(m,1H) ; 1.75(m,3H) ; 1.95 (m, 1H) ;

2.3 (s,3H) ; 2.53(m,4H) ; 2.75(m,4H) ; 3.6(m,2H) ; 3.95(m,1H) ;

4.15(m,1H) ; 4.55(m,1H) ; 5.0(s,2H) ; 6.75(d,1H) ; 6.9-7.45(m,14H) ; 7.9(2xd,1H) .

EXAMPLE 107

1-[N-( (R)-2-(4-Benzyloxybenzyl)-(S)-5-t-butoxycarbonylamino- (S)-4-hydroxy-6-phenylhexanoyl)-(S)-isoleucyl]-4-methylaminopiperidine.

The title ccmpound was prepared from the product from Example 106 by the procedure as described for Example 2, m.p. 157-159°. Found:

C,70.46; H,8.25; N,7.59. C₄₃H₆₀N₄O₆ requires C,70.85; H,8.30;

N,7.69%.

[α]_D ²⁵ +33° (c = 0.1%, MeOH)

m/e 728.96 (MH)⁺

N.M.R. (DMSO- d₆) δ = 0.75(m,6H); 0.9-1.2(m,3H); 1.3(s,9H);

1.3-1.5(m,2H); 1.55-1.85(m,4H); 2.3(s,3H); 2.5-2.85(m,8H);

3.4(m,1H); 3.55(m,1H); 3.9(m,1H); 4.1(m,1H); 4.55(m,2H);

5.05(s,2H); 6.4(m,1H); 6.85(m,2H); 7.0(d,2H); 7.1-7.25(m,5H);

7.3-7.45(m,5H); 7.8(t,1H).

EXAMPLE 108

1-[N-((S)-5-t-Butoxycarbonylamino-(S)-4-hydroxy-(R)-2-(4-hydroxybenzyl)-6-phenylhexanoyl)-(S)-isoleucyl]-4-methylaminopiperidine.

A solution of the product from Example 107 (0.3 g) in methanol (60 ml) was treated with 10% palladium on charcoal (0.25 g) and was stirred under an atmosphere of hydrogen at 30 p.s.i. (2.0 bar) for one hour at room temperature. The catalyst was filtered off and the solvent evaporated under vacuum to give a white foam.

Purification by chromatography on silica-gel, eluting with methylene chloride-methanol-concentrated aqueous ammonia (90:10:1) gave the title conpound which was recrystallised from ethyl acetate/hexane to give a white powder, (0.117 g), m.p. 201-203°. Found: C,65.77; H,8.24; N,8.44. C₃₆H₅₄N₄O₆·H₂O requires C,65.83; H,8.59; N,8.53%.

[α]_D ²⁵ -12° (c = 0.1%, MeOH)

m/e 638.99 (MH)

N.M.R. (DMSO- d₆) δ = 0.75(m,6H); 0.9-1.15(m,2H); 1.2(s,1H);

1.3(s,8H); 1.3-1.45(m,2H); 1.55-1.8 (m,4H); 2.25(s,3H); 2.5-3.1(m,9H); 3.4(m,1H); 3.55(m,1H); 3.85(m,1H); 4.1(m,1H);

4.5(m,2H); 6.4(d,1H); 6.55(m,2H); 6.85(d,2H); 7.1-7.25(m,5H), 7.75(d,1H).

EXAMPLE 109

4-(2-t-Butyl-1,3-dioxolan-2-yl)benzyl bromide

A solution of 4-(2-t-butyl-1,3-dioxolan-2-yl) toluene [D.E.

3,235,589] (0.22 g) in carbon tetrachloride (8 ml) was treated with sodium hydrogen carbonate (84 mg) and N-bromosuccinimide (0.18 g) and the mixture refluxed for 15 minutes in the

presence of a 60W light. The reaction was cooled, diluted with hexane (8 ml), filtered and evaporated under vacuum to give the product as an oil which crystallised on standing (0.256 g).

N.M.R. (CDCl₃) δ = 0.95(s,9H); 3.7(m,2H); 4.0(m,2H);

4.5(s,2H); 7.35-7.5(m,4H).

EXAMPLE 110

(S)-5-[(S)-1-t-Butoχycarbonylamino-2-phenylethyl]-(R)-3-[4-(2-t-butyl-1,3-dioxolan-2-yl)benzyl]-gamma-butyrolactone.

The title compound was prepared by the same procedure as described for Intermediate Preparation (2a) by alkylation of the lactone with the product of Example 109.

[α]_D ²⁵ -12° (c = 0.1%, MeOH)

m/e 541.13 (MNH₄)⁺

N.M.R. (CDCl₃) δ = 1.0(S,9H); 1.45(s,9H); 2.0(m,1H);

2.25(m,1H); 2.75(dd,1H); 2.9(d,2H); 3.0(m,1H); 3.15 (dd, 1H) ;

3.7 (m,2H) ; 4.0(m,3H) ; 4.35 (m,1H) ; 4.5 (m,1H) ; 7.0-7.4(m,9H). EXAMPLE 111

(S)-5-t-Butoxycarbonylamino-(S)-4-t-butylolinethylsilyloxy-(R)-2-[4-(2-t-butyl-1,3-dioxolan-2-yl)benzyl]-6-phenylhexanoic acid. The title compound was prepared from the product from Example 110 by the same procedure as described for Intermediate Preparation (2b) . Found: C,67.25; H,8.60; N,2.61. C₃₇H₅₇NO₇Si requires

C,67.75; H,8.76; N,2.14%.

m/e 656.33 (MH) ⁺

[α]_D ²⁵ -27° (c = 0.1%, MeOH)

N.M.R. (CDCl₃ ) δ = 0.10(m,6H) ; 0.90(s,9H) ; 0.95(s,9H) ;

1.35(s,9H) ; 1.6(m,1H) ; 1.9(m,1H) ; 2.5-3.1(m,5H) , 3.70(m,3H) ;

3.9 (m,3H) ; 4.75(d,1H) ; 7.0-7.4 (m,9H) .

EXAMPLE 112

1-[N-((S)-5-t-Butoxycarbonylamino-(S)-4-t-butyldimethylsilyloxy-(R)-2-[4-(2-t-butyl-1,3-dioxolan-2-yl)benzyl]-6-phenylhexanoyl)-(S)-valyl]-4-ketopiperidine.

The title compound was prepared from the product of Example 111 and the product from Intermediate Preparation (5a) by the procedure as described for Intermediate (5b). Found: 0,67.18;

H,8.52; N,4.94. C₄₇H₇₃N₃O₈Si requires C,67.51; H,8.80;

N,5.03%.

m/e 836.64 (MH)⁺

[α]_D ²⁵ +5° (c = 0.1%, MeOH)

N.M.R. (CDCl₃) δ = 0.1(s,6H); 0.9(m,24H); 1.3-1.4(m,2H);

1.35(s,9H); 1.65(m,1H); 1.8(m,1H); 2.0(m,1H); 2.4-2.75(m,8H);

2.9(m,1H); 3.6-3.8(m,4H); 3.8-4.0(m,4H); 4.7(m,2H); 6.4(d,1H); 6.95(d,2H); 7.2-7.35(m,7H).

EXAMPLE 113

1-[N-((S)-5-t-Butoxycarbonylamino-(S)-4-t-butyldimethylsilyloxy-(R)-2-[4-(2-t-butyl-1,3-dioxolan-2-yl)benzyl]-6-phenylhexanoyl)-(S)-valyl]-4-methylaminopiperidine

The title conpound was prepared by the same procedure as described for Example 7 by reacting the product of Example 112 with methylamine. Found: 0, 67.31; H,8.84; N, 6.52. C₄₈H₇₈N₄O₇Si requires C, 67.73 ; H, 9.24; N, 6.58%.

m/e 851.07 (MH) ⁺

[α] +6.0° (c = 0.1%, MeOH)

N.M.R. (CDCl₃) 0.1(s, 6H) ; 0.85 (t,6H) ; 0.95 (s, 18H) ; 1.35 (s, 9H) ; 1.6-1.8 (m,4H) ; 1.85-2.0(m,3H) ; 2.4 (s,3H) ; 2.45-3.2 (m,8H) ;

3.7 (m,3H) ; 3.9-4.1(m,4H) ; 4.4 (m, 1H) ; 4.7-4.85 (m, 2H) ;

6.4 (m,1H) ; 6.95 (m,2H) ; 7.25 (m,2H) ; 7.3 (m,5H) .

EXAMPLE 114

1-[N-((S)-5-t-Butoχycarbonylamino-(R)-2-[4-(2-t-butyl-1,3-dioxolan-2-yl)benzyl]-(S)-4-hydroxy-6-phenylhexanoyl)-(S)-valyl]-4-nethylaminopiperidine

A solution of the product from Example 113 in methylene chloride was cooled to -78°C and saturated with hydrogen chloride for 30 minutes. The excess hydrogen chloride was blown off with nitrogen and the solvent was evaporated under vacuum and the residue partitioned between 1N aqueous sodium hydroxide and ethyl acetate. The organic layer was dried (MgSO₄) and evaporated to give the crude product. A solution of this product in acetonitrile (0.5 ml) was treated with 10 drops of 40% aqueous hydrogen fluoride and the reaction stirred for 10 minutes. The solvent was evaporated and the residue again partitioned between ethyl acetate and 1N aqueous sodium hydroxide. The organic layer was dried (MgSO₄) and

evaporated under vacuum. The residue was purified by

chrαπatography on silica-gel using methylene chloridemethanol-concentrated aqueous ammonia (93:7:1). The clean

fractions were combined, evaporated under vacuum and the solid residue recrystallised from ether to give the title compound as a white solid (0.13 g), m.p. 123-125°. Found: 0,68.48; H,8.59; N,7.97. C₄₀H₆₀N₄O₆.½H₂O requires 0,68.44; H,8.76; N,7.98%.

m/e 693.04 (MH)

[α]_D ²⁵ +2.0° (c = 0.1%, MeOH)

N.M.R. (CDCl₃) 0.8(d,3H); 0.9(d,3H); 1.2(m,1H); 1.3 (s,9H);

1.35(s,9H); 1.4-1.8(m,3H); 1.9(m,3H); 2.45(2xs,3H); 2.6-3.1(m,8H); 3.6(m,1H); 3.75(m,2H); 3.85(m,1H); 4.3(m,1H); 4.7(m,1H);

4.85(m,1H); 6.4 & 6.5(2xd,1H); 7.0(d,2H); 7.25(m,5H); 7.55(d,2H). EXAMPLE 115

(R)-3-(4-Benzenesulphonylbenzyl)-(S)-5-[(S)-1-t-butoxycarbonylamino-2-phenylethyl-gamma-butyrolactone

The title compound was prepared by the same procedure as described for Intermediate Preparation (2a), by the alkylation of the lactone with 4-benzenesulphonylbenzyl bromide. Found: C,67.16;

H ,.6.24; N,2.85. C₃₀H₃₃NO₆S requires C,67.29; H,6.17; N,2.62%. m/e 536 (MH⁺)

N.M.R. (CDCl₃) δ = 1.37(s,9H); 1.86-1.98 (m,1H); 2.25-2.36 (m, 1H); 2.28-3.23(m,5H); 3.95-4.03 (m, 1H); 4.32-4.37(m,1H); 4.49(d,1H); 7.19-7.96(m,14H).

EXAMPLE 116

(R)-2-(4-Benzenesulphonylbenzyl)-(S)-5-(t-butoxycarbonylamino)- (S)-4-(t-butyldimethylsilyloxy)-6-phenylhexanoic acid

The title compound was prepared from the product of Example 115 by the same procedure as described for Intermediate Preparation (2b).

Found: C,63.56; H,7.44; N,1.92. C₃₆H₄₉NO₇SSi: 1/5 CH₂Cl₂ requires C,63.51; H,7.22; N,2.04%.

m/e 568 (MH-Boc) ⁺

[α]_D ²⁵ -32° (c = 0.1%, MeOH)

N.M.R. (DMSO-d₆) δ = 0.03(s,3H); 0.08(s,3H); 0.84(s,9H);

1.23(s,9H); 1.85-1.94(m,1H); 2.32-2.46 (m, 1H); 2.61-2.95(m,5H);

3.50-3.58(brm,1H); 3.64-3.69 (m, 1H); 6.82(d,1H); 7.11-7.95 (m, 14H) .

EXAMPLE 117

1-[N-((R)-2-(4-Benzenesulphonylbenzyl)-(S)-5-t-butoxycarbonyl-(S)-4-butyldimethylsilyloxy-6-phenylhexanoyl)-(S)-valyl]-4-ketopiperidine

The title compound was prepared from the product of Example 116 and the product from Interirediate Preparation (3a) by the procedure described for Intermediate (5b). Found: C, 63.25;

H,7.61; N,4.73. C₄₆H₆₅N₃O₈SSi: 2/5 CH₂Cl₂ requires C,63.13;

H,7.46; N,4.76%.

m/e 749 (MH-Boc) ⁺

N.M.R. (DMSO-d₆) δ - 0.07(s,6H); 0.83-0.89 (m,15H); 1.27(s,9H); 1.91-2.95(m,12H); 3.49-3.62 (m, 3H); 3.72-3.79 (m,3H); 4.48-4.54(m, 1H) ; 6.76(d,1H) ; 7.11-7.94 (m, 14H) ; 8.16 (d,1H) .

EXAMPLE 118

1- [N-( (R) -2-(4-Benzenesulphonylbenzyl)-(S)-5-t-butoxycarbonylamino-(S)-4-t-butyldimethylsilyoloxy-6-phenylhexanoyl-(S)-valyl]-4-ethylaminopiperidine

The title conpound was prepared by the same proicedure as

described for Example 7 by reaction of the product of Example 117 with ethylamine.

N.M.R. (DMSO-d₆) δ = 0.08-0.10 (m,6H) ; 0.79-0.86 (m, 15H) ; 0.97-1.21 (m,6H) ; 1.25(s,9H) ; 1.74-1.98 (m,4H) ; 2.29-3.13 (m, 10H) ; 3.51-3.66 (m,2H) ; 3.84-3.97 (m,1H) ; 4.05-4.22 (m,1H) ; 4.41-4.54 (m,1H) ;

6.71 (d, 1H) ; 7.13-8.04 (m, 15H) .

EXAMPLE 119

1-[N-((R)-2-(4-Benzenesulphonylbenzyl)-(S)-5-t-butoxycarbonylamino-(S)-4-hydroxy-6-phenylhexanoyl)-(S)-valyl]-4-methylaminopiperidine

The title compound was prepared from the product of Example 118 by the same procedure as described for Example 2. Found: C, 65.30;

H,7.68; N,7.42. C₄₂H₅₈N₄O₇Si. 1/5 CH₂Cl₂ requires C,65.00;

H,7.45; N,7.08%.

m/e 763 (MH⁺)

[α]_D ²⁵+ 13° (c = 0.1%, MeOH)

N.M.R. (DMSO-d₆) δ = 0.71-0.76(m,6H); 0.92-1.41(m,14H);

1.59-1.88(m,5H); 2.52-3.55(m,12H); 3.76-3.89(m,1H);

4.02-4.09 (m,1H); 4.40-4.58(m,2H); 6.37-6.41(m,1H);

7.11-7.93(m,15H).

EXAMPLE 120

(S)-5-[(S)-1-t-Butoxycarbonylamino-2-phenylethyl]-(R)-3-(4-phenoxybenzyl)-gamma-butyrolactone

The title compound was prepared by the same procedure as described for Intermediate Preparation (2a), by alkylation of the lactone with 4-phenoxybenzyl bromide. Found: C,74.09; H,6.67; N,2.98. C₃₀H₃₃NO₅ requires C,73.92; H,6.77; N,2.87%.

m/e 488 (MH⁺) [α]_D ²⁵ -3° (c = 0.1%, MeOH)

N.M.R. (CDCl₃) δ = 1.38(s,9H); 1.96-2.08 (m, 1H); 2.24-2.33 (m, 1H);

2.74-3.16(m,5H); 3.95-4.03 (m,1H) ; 4.28-4.33 (m,1H); 4.54(d,1H);

6.93-7.40(m,14H).

EXAMPLE 121

(S)-5-Butoxycarbonylamino-(S)-4-(t-butyldimethylsilyloxy)-(R)-2-(4-phenoxybenzyl)-6-phenylhexanoic acid

The title compound was prepared from the product of Example 120 by the same procedure as described for Intermediate Preparation (2b). Found: C,69.78; H,8.10; N,2.31. C₃₆H₄₉NO₆Si requires C, 69.79; H,7.92; N,2.26%.

m/e 619 (MH⁺)

N.M.R. (DMSO-d₆) δ = 0.06(2, 3H); 0.08(s,3H); 0.85(S,9H);

1.18-1.40(m,10H); 1.84-1.95 (m,1H) ; 2.31-2.45 (m,1H);

2.65-2.89(m,5H); 3.54-3.62(m,1H); 3.66-3.73 (m, 1H); 6.34(d,1H); 6.39-7.35(m,14H).

EXAMPLE 122

1-[N-((S)-5-t-Butoxycarbonylamino-(S)-4-t-butyldimethylsilyloxy- (R)-2-(4-thenoxybenzyl)-6-phenylhexanoyl)-(S)-valyl]-4-(N-benzyloxycarbonyl-N-methyl)aminopiperidine

The title cxmpcund was prepared from the product of Example 121 and the product from Intermediate Preparation (3b) by the same procedure as described for Example 3. Found: C,69.23; H,8.30;

N,6.28. C₅₅H₇₆N₄O₈Si requires C,69.54; H,8.00; N,5.90%.

m/e 850 (MH-Boc)

N.M.R. (DMSO-d₆) δ = 0.15(s,6H); 0.85-0.97 (m, 15H) ;

1.20-1.71(m,14H); 1.91-2.05 (m,2H); 2.38-3.15(m,10H);

3.57-3.64 (m, 1H); 3.69-3.75 (m,1H); 4.07-4.18 (m, 2H);

4.45-4.58(m,2H); 5.08(s,2H); 6.73-7.39 (m,20H); 7.83-7.90 (m,1H).

EXAMPLE 123

1-[N-((S)-5-t-Butoxycarbonylamino-(S)-4-hydroxy-(R)-2-(4-phenoxybenzyl)-6-phenylhexanoyl)-(S)-valyl]-4-(N-benzyloxycarbonyl-N-methyl)aminopiperidine The title compound was prepared from the product of Example 122 by the sane procedure as described for Example 4. Found:

C,69.12; H,7.46; N,6.36. C₄₉H₆₂N₄O₈: H₂O requires C,69.01;

H,7.51; N,6.57%.

m/e 835 (MH⁺)

N.M.R. (DMSO-d₆ δ = 0.74-0.79(m,6H); 1.22-1.93 (m,16H);

2.42-3.20(m, 10H); 3.41-3.62 (m,2H) ; 4.03-4.11(m,2H);

4.39-4.62(m,3H); 5.07(s,2H); 6.44(d,1H); 6.83-7.39 (m,19H);

7.78(d,1H).

EXAMPLE 124

1-[N-((S)-5-t-Butoxycarbonylamino-(S)-4-hydroxy-(R)-2-(4-phenoxybenzyl)-6-phenylhexanoyl)-(S)-valyl]-4-metoylaminopiperidine

The title conpound was prepared from the product of Example 123 by the same procedure as described for Example 5. m.p. 101-108°.

Found: C,69.09; H,7.89; N,7.85. C₄₁H₅₆N₄O₆: 1/2 H₂O requires

0,69.39; H,8.04; N,7.9%.

m/e 701 (MH⁺)

[α]_D ²⁵+ 19° (c = 0.1%, MeOH)

N.M.R. (DMSO-d₆) δ = 0.73-0.76(m,6H); 0.91-1.15(m,2H);

1.21-1.39(m,10H); 1.61-1.88(m,4H); 2.25(d,3H); 2.45-3.58(m,l1H);

3.82-3.92(m,1H); 4.05-4.11(m,1H); 4.44-4.51(m,2H); 6.43(d,1H);

6.81-7.39 (m,14H) ; 7.69-7.75(m,1H).

EXAMPLE 125

1-(N-t-Butoxycarbonyl)-(S)-valyl-4-hvdroxyazetidine

A solution of N-t-butoxycarbonyl-(S)-valine (5.87 g),

1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (6.21 g), 1-hydroxybenzotriazole hydrate (4.01 g) and N,N-diisopropylethylamine (9 ml) in N,N-dimethylformamide (75 ml) was treated with a solution of 3-hydroxyazetidine hydrochloride (3.8 g) and N,N-diisopropylethylamine (9 ml) in N,N-dimethylformamide (25 ml) at room temperature. After stirring for 18 hours the solvent was evaporated under vacuum and the residual oil dissolved in ethyl acetate (100 ml) and water (100 ml) . The separated organic layer was washed with saturated aqueous sodium bicarbonate (2 × 100 ml), dried (MgSO₄) and evaporated under vacuum to an oil. Purification by silica gel chromatography eluting with methylene chloridemethnol-concentrated aqueous ammonia gave the title compound as a colourless foam (4.5 g) . Found 0,57.70; H,8.95; N,10.34.

C_{1 3}H₂₄N₂O₄ requires 0,57.33; H,8.88; N,10.29%.

m/e 273 (MH⁺)

N.M.R. (DMSO-d₆) δ = 0.82 (m,6H) ; 1.38(s,9H) ; 1.87 (m,1H) ;

3.49-3.75(m,2H) ; 3.82-4.12 (m, 2H) ; 4.31(m,1H) ; 4.45(m,1H) ;

5.73 (m,1H) ; 6.86(m,1H) .

EXAMPLE 126

1-(N-t-Butoxycarbonyl)-(S)-valyl-4-ketoazetidine

A solution of the product from Example 125 (4.5 g) in methylene chloride (25 ml) and triethylamine (11.4 ml) was added to a previously prepared solution of dimethylsulphoxide (4.68 ml) and oxalylchloride (2.9 ml) in methylene chloride (50 ml), cooled to -78°C. After stirring for 1 hour the reaction was allowed to warm to room temperature. The solution was washed with aqueous citric acid (10%, 2 × 50 ml) followed by saturated aqueous sodium chloride (2 × 50 ml), dried (MgSO₄) and evaporated under vacuum to give a yellow oil. Purification by chromatography on silica-gel, eluting with ethyl acetate hexane (30:70) gave the title compound as a colourless foam (2.1 g). Found: C,57.87; H,7.88; N,10.45. C₁₃H₂₂N₂O₄ requires C,57.76; H,8.20; N,10.36%.

m/e 271 (MH)⁺

N.M.R. (DMSO- d₆) δ = 0.88(m,6H); 1.38(s,9H); 1.96(m,1H);

3.87(t,1H); 4.59-5.11(m,4H); 7.01(d,1H).

EXAMPLE 127

1-[N-((R)-2-Benzyl-(S)-5-t-butoxycarbonylamino-(S)-4-t-butyldimethylsilyloxy-6-phenylhexanoyl)-(S)-valyl]-4-ketoazetidine

The title compound was prepared from the product of Example 126 and the product from Intermediate Preparation (2b) by the same procedure as described for Intermediate Preparation (5b) to give a colourless foam (1.95 g). Found: 0,66.16; H,8.24; N,6.20.

C₃₈H₅₇N₃O₆Si. 1/2 H₂O requires 0,66.18; H,8.42; N,6.10%.

m/e 680 (MH⁺) [α]_D ²⁵ -6° (c = 0.17%, MeOH)

N.M.R. (DMSO- d₆) δ = 0.09 (d,6H) ; 0.87 (s,9H) ; 0.90 (m,6H) ;

1.17-1.25(m,1H) ; 1.29(S,9H) ; 1.96(m,2H) ; 2.38-2.77 (m, 3H) ;

2.81-2.95(m,2H) ; 3.56(m,1H) ; 3.70(m,1H) ; 4.08 (m,1H) ;

4.58-4.97 (m,4H) ; 6.l3 (d,1H) ; 7.18 (m,10H) ; 8.12 (d,1H) .

EXAMPLE 128

1-[N-( (R)-2-Benzyl-(S)-5-t-butoxycarbonylamino-(S)-4-t-butyldimethylsilyloxy-6-phenylhexanoyl)-(S) -valyl]-4-ethylaminoazetidine

The title compound was prepared by the same procedure as described for Example 7 by reaction of the product of Example 127 with ethylamine. Found: 0,66.34; H,9.10; N,7.69. C_{4 0}H₆₄N₄O₅Si. H₂O requires 0,66.11; H,9.09; N,7.71%.

m/e 710 (MH⁺)

[α]²⁵ -4° (c = 0.12%, MeOH) .

N.M.R. (DMSO-d₆) δ = 0.11(s,6H); 0.82(m,6H); 0.89(s,9H);

0.99(t,3H); 1.13-1.25(m,1H); 1.28(s,9H); 1.79-2.01(m,2H);

2.14-2.34 (m,1H); 2.36-2.48 (m,2H); 2.51-2.75(m,3H);

2.78-2.96(m,2H); 3.36-3.61(m,3H); 3.63-3.77 (m,2H);

3.79-4.09 (m,2H); 4.13-4.26(m,1H); 6.75(m, 1H); 7.08-7.29 (m,10H); 7.93(m,1H).

EXAMPLE 129

1-[N-(R)-2-Benzyl-(S)-5-t-butoxycarbonylamino-(S)-4-hydroxy-O-phenylhexanoyl)-(S)-valyll-4-ethylamιinoazetidine

The title compound was prepared from the product of Example 128 by the same procedure as described for Example 2 to give the product as a colourless foam. Found: 0,67.03; H,8.13; N,9.08.

C₃₄H₅₀N₄O₅. 2/3 H₂O requires 0,67.32; H,8.41; N,9.24%.

m/e 595(MH⁺)

[α]_D ²⁵-13° (c = 0.1%, MeOH)

N.M.R. (DMSO-d₆) δ = 0.74(m,6H); 0.98(t,3H); 1.18-1.46(m,1H);

1.29(s,9H); 1.61(m,1H); 1.70(m,1H); 2.34-2.61(m,5H);

2.66-2.90(m,4H); 3.36-3.59 (m,4H); 3.67-4.18 (m,3H) ; 4.51(d,1H);

6.38(m,1H); 7.05-7.29(m,10H); 7.77(m,1H). EXAMPLE 130

(S)-5-[ (S)-1-t-Butoxycarbonylamino-2-]-phenylethyl]-(R)-3-(4-iodobenzyl)-gamma-butyrolactone

The title compound was prepared by the same procedure as described for Intermediate Preparation (2a) by alkylation of the lactone with 4-idobenzyl bromide. Found: 0,55.55; H,5.42; N,2.65.

C₂₄H₂₈INO₄ requires 0,55.28; H,5.41; N,2.68%

m/e 522.7 (MH⁺)

[α]_D ²⁵0° (c = 0.1%, MeOH)

N.M.R. (DMSO- d₆) δ = 1.25(s,9H); 2.05(m,2H); 2.65(m,3H);

2.85(m,1H); 3.0(dd,1H); 3.75(m,1H); 4.4(m,1H); 7.05(d,2H);

7.2(m,6H); 7.65(d,2H).

EXAMPLE 131

(S)-5-[(S)-1-t-Butoxycarbonylamino-2-phenylethyl]-(R)-3-(4-(4-pyridyl)benzyl)-gammabutyrolactone

A heterogeneous solution of 4-bromopyridine hydrochloride (1.95 g) in water (30 ml) and diethyl ether (30 ml) was cooled in an ice bath and treated with solid sodium bicarbonate until the pH of the aqueous layer reached >7.0. The ether layer was separated, dried (MgSO₄) and evaporated under vacuum at 0°C to provide a colourless oil. A solution of the oil in tetxahydrofuran (30 ml) was cooled to -100°C and treated with t-butyllithium (1.7M in pentane, 11.8 ml) dropwise over 20 minutes keeping the temperature below -95°C. After an additional 10 minutes at -100°, a solution of zinc chloride in diethyl ether (1.0 M, 12 ml) was added over 10 minutes and the reaction allowed to warm to room temperature.

Tetrakis(triphenylphosphine)palladium (0.1 g) and a solution of the product from Example 130 (1.05 g) in tetahydrofuran (10 ml) were added and the reaction stirred at room temperature 1.5 hours. A solution of ammonium chloride (2 g in water (10 ml) was added and the resulting mixture poured into a solution of

ethylenediamine tetraacetic acid (9.5 g) in water (100 ml) and the pH adjusted to pH 8 with solid sodium bicarbonate. The solution was extracted with methylene chloride (3 × 100 ml) and the combined organic extracts washed with saturated brine (200 ml), dried (MgSO₄) and evaporated under vacuum. The residue was purified by chromatography on silica-gel with a gradient elution of ethyl acetate-hexane (1:9) through to neat ethyl acetate, to provide the title compound as a colourless foam, (0.59 g). Found:

0,73.3; H,6.78; N,5.84. C₂₉H₃₂N₂O. requires 0,73.71; H,6.83;

N,5.93%.

m/e 473.08 (MH⁺)

[α]_D ²⁵-2° (c = 0.1%, MeOH)

N.M.R. (DMSO-d₆) δ = 1.25(s,9H); 2.1(m,2H); 2.7(m,3H); 2.95(m,1H);

3.1(dd,1H); 3.8(m,1H); 4.4(m,1H); 7.05(d,1H); 7.2(m,5H);

7.4(d,2H); 7.7(d,2H); 7.75(d,2H); 8.6(d,2H).

EXAMPLE 132

(S)-5-t-Butoxycarbonylamino-(S)-4-t-butyldimethylsilyloxy-6-phenyl-(R)-2-(4-(4-pyridyl)benzyl)hexanoic acid

The title compound was prepared from the product of Example 131 by the same procedure as described for Intermediate Preparation (2b).

Found: 0,69.0; H,7.70; N,4.53. C₃₅H₄₈N₂O₅Si requires C,69.5;

H,8.00; N,4.63%.

m/e 605.38 (MH⁺)

[α]_D ²⁵-45° (c = 1%, MeOH)

N.M.R. (DMSO-d₆) δ = 0.1(d,6H); 0.9(s,9H); 1.25(s,9H); 1.4(m,1H);

1.95(m,1H); 2.45(m,1H); 2.8(m,3H); 2.95(m,1H); 3.6(m,1H);

3.75(bd,1H); 6.9(s,1H); 7.2(m,5H); 7.3(d,2H); 7.7(d,2H);

7.75(d,2H); 8.6(d,2H);12.2(6s,1H).

EXAMPLE 133

1-[N-((S)-5-t-Butoxycarbonylamino-(S)-4-t-butyldimethvsilyloxy-6-phenyl-(R)-2-(4-(4-pyridyl)benzyl)hexanoyl)-(S)-valyl]-4-ketopiperidine

The title compound was prepared from the product of Example 132 and the product from Intermediate Preparation (3a) by the same procedure as described for Intermediate Preparation (5b) . Found: 0,68.6; H,8.2; N,6.8. C₄₅H₆₄N₄O₆Si requires 0,68.8; H,8.22;

N,7.14%.

m/e 785.08 (MH⁺) [α]_D ²⁵+12° (c = 0.1%, MeOH)

N.M.R. (DMSO- d₆) δ = 0.1(d,6H); 0.85(dd,6H); 0.9(s,9H);

1.25(m,1H); 1.27(s,9H); 2.0(m,2H); 2.3(m,5H); 2.7(m,2H);

2.9(m,2H); 3.55(m,2H); 3.8(m,4H); 4.55(t,1H); 6.8(d,1H);

7.2(m,5H); 7.35(d,2H); 7.65(m,4H); 8.1(d,1H); 8.6(d,2H).

EXAMPLE 134

1-[N-((S)-5-t-Butoxycarbonylamino-(S)-4-t-butyldimethylsilyloxy-6-phenyl-(R)-2-(4-(4-pyridyl)benzyl)hexanoyl)-(S)-valyl]-4-methylaminopiperidine

The title compound was prepared by the same procedure as

described for Example 7 by the reaction of the product of Example

133 with methylamine.

m/e 800.15 (MH⁺)

[α]_D ²⁵+16° (c = 0.1%, MeOH)

N.M.R. (DMSO- d₆) δ = 0.15(dd,6H); 0.85(dd,6H); 0.9(s,9H);

1.0-1.3 (m,3H); 1.25(s,9H); 1.75-2.05(m,4H); 2.35(d,3H);

2.6-2.95(m,7H); 3.1(t,1H); 3.55(m,1H); 3.7(m,1H); 3.9(bd,1H);

4.05(bd,1H); 4.2(bt,1H); 4.5(dt,1H); 6.75(m,1H); 7.1-7.35(m,7H); 7.65(d,4H); 7.95(dd,1H); 8.7(d,2H).

EXAMPLE 135

1-[N-((S)-5-t-Butoxycarbonylamino-(S)-4-hydroxy-6-phenyl-(R)-2-(4- (4-pyridyl)benzyl)hexanoyl)-(S)-valyl]-4-methylaminopiperidine

The title compound was prepared from the product of Example 134 by the same procedure as described for Example 2 and was obtained as an amorphous solid. Found: C,69.74; H,8.09; N,10.15. C₄₀H₅₅N₅O₅ requires C,70.04; H,8.08; N,10.21%.

m/e 685.95 (MH⁺)

[α]_D ²⁵+33° (c = 0.1%, MeOH)

N.M.R. (DMSO-d₆) δ = 0.8(d,3H); 0.9(d,3H); 1.25(m,3H); 1.4(s,9H);

1.8(m,4H); 2.4(d,3H); 2.9(m,8H); 3.6(m,1H); 3.75(m,1H);

3.9(bd,1H); 4.25(bd,1H); (4.75(q,1H); 4.9(d,1H); 6.5(dd,1H);

7.1(d,2H); 7.25(m,7H); 7.5(m,4H); 8.65(d,2H). EXAMPLE 136

1-[N-(R)-2-Benzyl-(S)-5-cyclobutoxycarbonylamino-(S)-4-hydroxy-6-phenylhexanoyl)-(S)-valyl]-4-methylaminopiperidine hydrate

a) The product from Example 4 (371 mg) was dissolved in dichloromethane (10 ml) and the solution was cooled in an ice bath. Trifluoroacetic acid (2 ml) was added dropwise over 1 minute and the solution stirred at 0°C for 45 minutes. The solvent was evaporated under vacuum and the residue basified with saturated aqueous sodium bicarbonate solution, then extracted with dichloromethane (3 × 50 ml). The combined organic extracts were dried over MgSO₄, filtered and evaporated under vacuum to give 1-[N-((S)-5-amino-(R)-2-benzyl-(S)-4-hydro-xy-6-phenylhexanoyl)-(S)-valyl]-4-(N-benzyloxycarbonyl-N-methylamino)piperidine hemihydrate as a white foam (315 mg). Found: 0,69.84; H,8.00; N,8.42.

C₃₈H₅₀N₄O₅. 0.5 H₂O requires 0,70.02; H;7.89; N,8.60%. b) The above product (0.45 mmole, 290 mg) was dissolved in dichloromethane (20 ml) and cyclobutoxycarbonyloxysuccinimide (0.5 mmole, 107 mg) added. The mixture was stirred at room temperature for 4 hours and the solvent removed under vacuum. The residue was redissolved in ethyl acetate (100 ml) and the solution was washed with dilute hydrochloric acid (0.2 M, 50 ml), saturated aqueous sodium bicarbonate (50 ml) brine (10 ml) and then dried over sodium sulphate, filtered and the filtrate evaporated to dryness.

The residue was purified by column chroiratcgraphy on silica, eluting with dichlo-rcmethane:methanol (98:2), and crystallised from diethyl ether to give 1-[N-((R)-2-benzyl-(S)-5-cyclobutoxy¬carbonylamino-(S)-4-hydroxy-6-phenylhexanoyl)-(S)-valyl]-4-(N-benzyloxycarbonyl-N-methylamino)piperidine (262 mg), m.p.

162-164°C. Found: 0,69.52; H,7.73; N,7.41. C₄₃H₅₆N₄O₇ requires

0,69.71; H,7.62; N,7.56%. (c = 0.1, MeOH).

c) A solution of the above product (0.31 mmol, 227 mg) in methanol (25 ml) was treated with 10% palladium on charcoal (60 mg). The mixture was stirred at room temperature under hydrogen at a pressure of 2.76 bar (40 p.s.i.) for 2 hours. The catalyst was removed by filtration and the solvent evaporated under vacuum to give an oil which was purified by column chromatography on silica-gel eluting with dichloromethane:methanol:880 ammonia

(93:6:1) . After evaporation of the product fractions the residue crystallised on trituration with diethylether to afford the title compound (162 mg) , m.p. 168-170°C. Found: 0,68.47; H,8.16;

N,9.04; C₃₅H₅₀N₄O₅. 0.4 H₂O requires 0,68.47; H,8.34; N,9.13%. m/e [MH]⁺ 607

(c = 0.1 MeOH)

N.M.R. (DMSO-d₆) δ = 0.75(d,6H) ; 1.08(m,2H) ; 1.30(m,1H) ;

1.50(q,1H) ; 1.64(m,2H) ; 1.72-1.90 (m,6H) ; 2.15(m,2H) ; 2.32 (s,3H) ; 2.50-2.90(m,8H) ; 3.42 (m,1H) ; 3.55(m,1H) ; 3.84(m,1H) ; 4.l3 (m,1H) ; 4.47(dt,1H) ; 4.65(m,2H) ; 6.68(m,1H) ; 7.05-7.30(m,10H) ; 7.75(d,1H) .

EXAMPLE 137

1-[N-((S)-5-AminocarbonyImethoxycarbonylamino -(R)-2-benzyl-(S)-4-hydroxy-6-phenylhexanoyl)-(S)-valyl]-4-(N-methylamino)piperidine hemihydrate

a) To a solution of 1-[N-( (S)-5-amino-(R)-2-benzyl-(S)-4-hydroxy-6-phenylhexanoyl)-(S)-valyl]-4-(N-benzoyloxycarbonyl-N-methylamino)piperidine, (from Example 136(a) , 0.5 mmole, 321 mg) in dichloromethane (20 ml) was added methoxycarbonylmethoxycarbonylsuccinimide (0.6 mmol, 139 mg) and the resulting solution stirred at room temperature for 18 hours. The solvent was removed under vacuum and the residue was redissolved in ethyl acetate (100 ml) . The solution was washed with 0.2N hydrochloric acid (50 ml) , saturated aqueous sodium bicarbonate (25 ml) and brine (10 ml) . The organic phase was then dried over magnesium sulphate, filtered and evaporated to dryness. The residue was purified by column chromatography on silica gel eluting with dichloro0ethane-methanol (98:2) . Evaporation of the product containing fractions gave 1-[N-((R)-2-benzyl-(S)-4-hydroxy-(S)-5-methoxycarbonylmethoxycarbonylamino-6-phenyhexanoyl-(S)-valyl]-4-(N-benzyloxycarbonyl-N-methylamino)piperidine as a white foam (374 mg) , m/e [MH⁺] 759. b) A solution of the above product (0.43 mmole, 330 mg) was dissolved in methanolic ammonia (10 ml) at 0°C. After 40 minutes the solvent was removed under vacuum and the residue purified by column chromatography on silica-gel eluting ethyl acetate:methanol (98:2) . Evaporation of the product containing fractions gave 1-[N-( (S)-5-aminocarbonyl metooxycarbonylamino-(R) -2-benzyl-(S)-4-hydroxy-6-phenylhexanoyl)-(S)-valyl) ]-4-(N-benzyloxycarbonyl-N-methylamino)piperidine as a white foam. (155 mg) , m/e [MH]⁺ 744. c) Catalytic hydrogenation of the above product over palladium on charcoal as described for Example 136 step (c) gave the title compound, m.p. 130-135°C dec. Found: 0,63.98; H,7.82; N,11.02;

C₃₃H₄₇N₅O₆· 0.5 H₂O requires C,64.06; H,7.82; N,11.32%.

(c = 0.1 MeOH) .

N.M.R. (DMSO-d ₆) δ = 0.74 (m, 6H) ; 0.83 (m,1H) ; 0.95-1.90 (m,7H) ;

2.12 (m,1H) ; 2.25(s,3H) ; 2.50-2.90 (m, 7H) ; 3.46 (m,1H) ; 3.53 (m,1H) ; 3.70(m,1H) ; 4.07 (m,1H) ; 4.2l(s,2H) ; 4.48 (m,1H) ; 4.78 (dbs,1H) ;

7.00(d,1H) ; 7.05-7.30 (m,12H) ; 7.73 (d,1H) .

EXAMPLE 138

1-[N-((S)-5-(1-Aminocarbonylethoxy)carbonylamino-(R)-2-benzyl- (S)-4-hydroxy-6-phenylhexanoyl)-S-valyl]-4-(N-methylamino)piperidine hydrochloride.

a) The procedure of Example 137 step (a) was followed using

1-(methoxycarbonyl)ethoxycarbonyloxysuccinimide (2 mmole, 490 mg) and the same amine (1 mmole, 642 mg) to give 1-[N-((R)-2-benzyl- (S)-4-hydroxy-(S)-5-(1-methoxycarbonylethoxy)carbonylamino-6-phenylhexanoyl)-S-valyl]-4-(N-benzyloxycarbonyl-N-methylamino)piperidine, (598 mg) m/e [MH] 773.

b) The above product (0.74 mmole, 572 mg) was dissolved in 2,2-dimethoxypropane (5 ml) and p-toluenesulphonic acid (5 mg) was added. The solution was heated at 50°C for 2 hours and the solvent was then removed under vacuum. The residue was

redissolved in ethyl acetate (100 ml) and washed with saturated aqueous sodium bicarbonate solution (25 ml) then brine (10 ml) . The organic layer was dried over magnesium sulphate, filtered and evaporated to dryness. The compound was further purified by column chromatography on silica-gel eluting with hexane:ethyl acetate (60:40). Evaporation of the product conteining fractions gave 1-[N-((S)-4-benzyl-2,2-dimethyl-3-(1-methoxycarbonylethoxy )carbonyloxazolidine-5-(S)-((R)-2-benzyl)-3-propanoyl)-(S)

-valyl)]-4-(N-benzyloxycarbonyl-N-methylamino)-piperidine (408 mg). m/e [MH]⁺ 813. c) The above product (230 mg) was dissolved in methanolic ammonia (10 ml) and the solution was stirred at roam temperature for 18 hours. The solvent was removed under vacuum and the residue was purified by column chromatography on silica-gel, eluting with hexane: ethyl acetate (40:60) . The product containing fractions were evaporated to dryness to give 1-[N-((3-(1-aminocarbonylethoxy)carbonyl)-(S)-4-benzyl-2,2-dimethyloxazolidine-5- ( (S)-((R)-2-benzyl)-3-propanoyl) )-(S)-valyl]-4-(N-benzyloxycarbonyl-N-methylamino) piperidine as a white foam (145 mg) . m/e [MH]⁺ 798.

d) The above product from step (c) (0.18 mmole, 145 mg) was dissolved in methanol (10 ml) and p-toluenesulphonic acid (0.05 mmole, 10 mg) was added. The solution was heated at reflux, under nitrogen, for 2.5 hours. The cooled solution was jpαured into ethyl acetate (100 ml) and washed with saturated aqueous sodium bicarbonate (25 ml) and brine (10 ml) . The organic layer was then dried over magnesium sulphate, filtered and evaporated to dryness. The residue was purified by column chromatography on silica-gel, eluting with ethyl acetete:methanol (19:1) .

Evaporation of the product-conteining fractions gave

1-[N-((S)-5-(1-aminocarbonylethoxy)carbonylamino-(R)-2-benzyl- (S)-4-hydroxy-6-phenyl-hexanoyl)-(S)-valyl]-4-(N-benzyloxy¬carbonyl-N-methylamino)piperidine (73 mg) . m/e [MH] 758.

e) The above product from step (d) (70 mg, 0.09 mmole) was hydrogenated using the same conditions as described in Example 136(c) to give the title conpound (43 mg) . This was redissolved in ethyl ac etate:methanol 2:1 (10 ml) and treated with ethereal hydrogen chloride to give the hydrochloride as a white crystalline solid (43 mg) , m.p. >142°C dec. Found C,58.98; H,7.42; N,9.45.

C₃₄H₄₉N₅O₆· HCl. 1.5 H₂O. 0.5 C₄H₈O₂ re quires C,59.12; H,7.86; N,9.58%. m/e [MH]⁺ 624

N.M.R. (DMSO-d₆) δ = 0.75(m,6H); 1.13-1.70(m,8H); 1.62(m,1H);

1.87(m,1H); 2.02 (broad 1H) ; 2.44-2.88 (m,10H); 3.43 (m,1H) ;

3.52(m,1H); 4.42(m,3H); 4.66(m,2H); 6.90(m,1H); 7.05-7.30(m,12H);

7.84(m,1H); 8.97(broad s,2H) . EXAMPLE 139

1-[-N((S)-5-(1-Aminocarbonyl-1-methylethoxy)carbonylamino-(R)-2-benzyl-(S)-4-hydroχy-6-phenylhexanoyl)-(S)-valyl]-4-(N-methylamino)piperidine hydrochloride

a) The product from Example 136(a) (0.93 mmole, 594 mg) was dissolved in dichloromethane (20 ml) and the solution was treated with pyridine (1.5 mmole, 119 mg) and 1-methoxycarbonyl-1-nethylethylchlorofornate (1.1 mmole, 199 mg) . The solution was stirred at room temperature for 1 hour and the solvent was then removed under vacuum. The residue was redissolved in ethyl acetate (100 ml) and washed with 0.5 N hydrochloric acid (25 ml), saturated aqueous sodium bicarbonate (25 ml) and brine (10 ml). The organic layer was dried over magnesium sulphate, filtered and the filtrate was evaporated to dryness. The residue was further purified by column chromatography on silica-gel eluting with cUchloro-nethane: methanol (98:2). The product containing fractions were evaporated to give 1-[N-( (R)-2-benzyl-(S)-4-hydroxy-(S)-5-(1-methoxycarbonyl-1-methylethoxy)cartonylamιino-6-phenylhexanoyl)-(S)-valyl]-4-N-benzyloxycarbonyl-N-methylamino)piperidine, (554 mg), m/e [MH]⁺ 787.

b) The above product from step (a) (540 mg) was dissolved in 2,2-di.rιethoxypropane following the procedure of Example 138 step (b) to give the oxazolidine derivative (483 mg).

c) The product from step (b) above (483 mg) was dissolved in dioxan (10 ml) and 1M sodium hydroxide solution (0.6 ml) was added. The solution was heated at 50°C for 24 hours and then poured into water (50 ml) and the mixture was then acidified with 1M hydrochloric acid (1.0 ml) and extracted with ethyl acetate (3 × 50 ml). The combined organic extracts were dried over magnesium sulphate, filtered and evaporated to dryness. The residue was further purified by column chromatography on silica gel, eluting with ethyl acetate:glacial acetic acid (99:1). The product containing fractions were evaporated to give 1-[N-((S)-4-benzyl-3-(1-carboxy-1-methylethoxy)carbonyl-2,2-dimethyloxazolidine-5- ((S)-((R)-2-benzyl)-3-propanoyl))-(S)-valyl]-4-(N-benzyloxycarbonyl-N-methylamino)-piperidine as a white foam (183 mg). m/e [MH]⁺ 813 d) The product from step (c) above (175 mg, 0.22 mmole) was dissolved in dry dichloromethane (10 ml) and 1-hydroxybenzotriazole (0.35 mmole, 47 mg) was added. 1-(3-Dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (0.30 mmole, 58 mg) was then added and the solution stirred at room teirperature for 45 minutes. Methanolic ammonia (1 ml) was introduced and after a further 20 minutes at roam teπperature the solution was evaporated to dryness. The residue was redissolved in ethyl acetate (100 ml) and the solution was washed with hydrochloric acid (0.1 mmole, 50 mg), saturated aqueous sodium bicarbonate (25 ml) and brine (10 ml). The solution was dried over magnesium sulphate, filtered and the filtrate was evaporated to give 1-[N-(3-(1-aminocarbonyl-1-methylethαxy)carbonyl-(S)-4-benzyl-2,2-dimethyl-oxazolidine-5- ((S)-((R)-2-benzyl)-3-propanoyl))-(S)-valyl]-4-(N-benzyloxycarbonyl-N-methylamino)-piperidine. m/e [MH] 812.

e) The product from step (d) above was treated with p-toluene sulphonic acid in methanol and the product then hydrogenated following the procedures of Example 138 steps (d) and (e) to give the title compound (64 mg) m.p. >125°C dec. Found: C,60.23;

H,7.85; N,9.51. C₃₅H₅₁N₅O₆. HCl.H₂O. 0.25 C₄H₈O₂ requires

C,60.58; H,7.90; N,9.80%. m/e [MH]⁺ 638

[α]²⁵13° (c = 0.1 MeOH)

589

N.M.R. (DMSO-d₆) δ = 0.75(m,6H); 1.21-1.45(m,l1H); 1.56(m,1H);

1.86(m,1H); 2.42-2.87(m,9H); 3.05-3.53 (m,4H) ; 4.10(m,1H);

4.48(m,2H); 4.70(bs,1H); 6.86(t,1H); 7.17(m,12H); 7.88(dd,1H); 8.9(b,sH).

EXAMPLE 140

1-[N-((R)-2-Benzyl-(S)-4-hydroxy-(S)-5-(1-methylaminocarbonylethoxy)carbonylamιino-6-phenylhexanoyl)-(S)-valyl]-4-(N-methylamino)piperidine- hydrochloride, hydrate.

The procedure of Example 139 was followed but using πethylamine in step (d) instead of ammonia. Subsequent deprotection as described in Example 138 gave the title ccampound (258 mg) , m.p. 166-172°C dec. Found: 0,60.80; H,7.77; N,9.86. C₃₅H₅₁N₅O₆. HCl. H₂O requires C,60.72; H,7.86; N,10.12%.

m/e [MH]⁺ 638 (c = 0.1 MeOH) .

N.M.R. (DMSO-d₆) c5 = 0.75(m,6H); 1.20-1.68 (m,7H); 1.88(m,1H);

2.05(m,2H); 2.40-2.90 (m, 13H) ; 3.17(m,1H); 3.43(m,1H); 3.52(m,1H);

4.07(m,1H); 4.45(m,2H); 4.70(m,2H); 6.88(m,1H); 7.07-7.30(m,10H);

7.82(m,2H); 8.98(bs,2H).

EXAMPLE 141

1-[N-((R)-2-Benzyl-(S)-4-hydroxy-(S)-5-oxeton-3-oxycarbonylamino- 6-phenylhexanoyl)-(S)-valyl]-4-(N-methylamino)piperidine

The product from Example 136 step (a) (642 mg, 1 mmole) was dissolved in dichloromethane (20 ml) and oxetan-3-oxycarbonyloxysuccinimide (from Preparation 12, 221 mg, 1 mmole) added using the procedure outlined in Example 136 step (b). Subsequent

deprotection using the procedure of Example 136 step (c) gave the title compound (168 mg) m.p. 125-129°C dec. Found: 0,66.80;

H,8.09; N,8.77. C₃₄ H₄₈N₄O₆ requires C,67.08; H,7.95; N,9.20%. m/e [MH]⁺ 609. (c = 0.1 MeOH)

N.M.R. (DMSO-d₆) 5 = 0.75 (m,6H); 1.00-1.94 (m,7H);

2.10-2.25(m,3H); 2.42-2.90(m,9H); 3.47(m,1H); 3.57(m,1H);

3.82(m,1H); 4.07(m,1H); 4.43(dq,2H); 4.50

(m,1H); 4.68(m,3H); 5.12(p,1H); 7.09-7.27(m,l1H); 7.77(m,1H).

EXAMPLE 142

1-[N-((R)-2-Benzyl-(S)-5-(1,1-dioxothietan-3-oxycarbonylamino)-(S)-4-hydroxy-6-phenylhexanoyl)-(S)-valyl]-4-(N-methylaminolpiperidine

a) The product from Example 136 step (a) (2.57 g, 4 mmole) was dissolved in dichloromethane (100 ml) and the product from

Preparation 11 (1.04 g, 45 mmol) added using the procedure outlined in Example 136 step (b). The product, 1-[N-((R)-2-benzyl-(S)-4-hydroxy-(S)-6-phenyl-(S)-5-(thietan-3-oxycarbonylamino)hexanoyl)-(S)-valyl]-4-(N-benzyloxycarbonyl-N-metoylamino)piperidine was obtained as a glass (2.42 g). m/e [MH] 759.

b) The product from step (a) above (1.60 g, 2.11 mmole) was dissolved in dichloromethane (100 ml) and the solution was cooled in an ice bath. 3-Chloroperbenzoic acid (85%, 430 mg, 2.11 mmole) was added portionwise over 1 minute and the solution stirred at 0°C for 20 minutes. The solvent was removed under vacuum and the residue redissolved in ethyl acetate (100 ml) and washed with saturated aqueous sodium bicarbonate solution (25 ml) and brine (10 ml). The organic layer was then dried over magnesium sulphate, filtered and the filtrate was evaporated to dryness. Trituration of the residue with ether gave the 1-oxo-thietanyl derivative as a white solid (1.38 g), m.p. 125-129°C dec. m/e [MH]⁺ 775.

c) The product from step (b) above (700 mg, 0.9 mmole) was dissolved in dichloromethane (50 ml) and 3-chloroperbenzoic acid (85%, 183 mg, 0.9 mmole) was added portionwise over 1 minute. The solution was stirred at room temperature for 2 hours and the solvent removed under vacuum. The residue was redissolved in ethyl acetate (50 ml) and washed with saturated aqueous sodium bicarbonate solution (20 ml) and brine (10 ml). The organic extract was dried over magnesium sulphate, filtered and the filtrate evaporated to dryness to give the 1,1,dioxo-thietanyl derivative as a white solid. (609 mg). m.p. 203-205°C. m/e [MH]⁺ 791.

d) The product from step (c) above (500 mg, 0.63 mmole) was hydrogenated by the method described in 136 step (c) using a 1:1 mixture of methanol:ethyl acetate as solvent to give the title product (202 mg), m.p. 189-191°C dec. Found: C,61.79; H,7.59; N,8.39. C₃₄H₄₈N₄O₇S requires 0,62.17; H,7.37; N,8.53%.

m/e [MH]⁺ 657.

(c = 0.1 MeOH)

N.M.R. (DMSO-d₆) δ = 0.75(m,6H); 1.05(m,1H); 1.30(m,1H);

1.62-1.92(m,5H); 2.28(S,3H); 2.50-3.10(m,8H); 347(m,1H);

3.55(m,1H); 3.78-4.15(m,4H); 4.44-4.72 (m,4H); 5.04(m,1H);

7.05-7.34(m,12H); 7.81(d,1H).

EXAMPLE 143

1-[N-((S)-4-Hydroxy-(S)-5-((S)-1-methylaminocarbonylethoxy)carbonylamino-6-phenyl-(R)-2-(4-trifluoromethoxybenzyl)hexanoyl)(S)-valyl]-4-(N-ethylamino)piperidine, hydrochloride, hydrate a) (S)-5-t-Butoxycarbonylamino-(S)-4-(t-butyldimethylsilyloxy)- 6-phenyl-(R)-2-(4-trifluoronethoxybenzyl)hexanoic acid (from Example 79, 5.0 g, 8.17 mmole) was reacted with 1-(N-t-butoxycartonyl-(S)-valyl-4-ketopiperidine (from Intermediate Preparation 3(a)), following the procedure of Intermediate Preparation 5(b) to give 1-[N-((S)-5-t-tutoxycarbonylamino-(S)-4-t-butyldimethylsilyloxy-6-phenyl-(R)-2-(4-trifluoromethoxybenzyl)hexanoyl)-(S)-valyl]-4-ketopiperidine, (6.46 g). m/e [MH] 793.

b) Reaction of the product from step (a) above with ethylamine following the procedure described in Example 7 gave

1-[N-((S)-S-t-butoxycartonylamino-(S)-4-t-tutyldiιtetftylsilyloxy-6-phenyl-(R)-2-(4-trifluoromethoxybenzyl)hexanoyl)-(S)-valyl]-4-ethylaminopiperidine. m/e [MH]⁺ 822.

c) The product from step (b) above (5.94 g, 7.24 mmole) was dissolved in dichloromethane and benzyloxycarbonyloxysuccinimide (1.87g, 7.50 mmole) was added. The solution was stirred at room teirperature for 2 hours and the solvent was then removed under vacuum. The residue was redissolved in ethyl acetate (100 ml) and washed with 0.25M hydrochloric acid (50 ml), saturated aqueous sodium bicarbonate (25 ml) and brine. The organic layer was dried over magnesium sulphate, filtered and the filtrate evaporated to dryness. Further purification was carried out by column

chromatography on silica gel eluting with dαchlorcmethane:methanol (98:2). Evaporation of the product containing fractions gave

1-[N-((S)-5-t-butyloxycarbonylamino-(S)-4-t-butyldimethylsilyloxy-6-phenyl-(R)-2-(4-trifluoromethoxybenzyl)hexanoyl)-(S)-valyl]-4-[N-benzyloxycarbonyl-N-etoylamino)piperidine (6.30 g). m/e [MH]⁺ 955.

d) The product from step (c) above was reacted with tetra-n-butylammonium fluoride as described in Example 2 to give 1-[N- ((S)-5-t-butyloxycarbonylamino-(S)-4-hydroxy-6-phenyl-(R)-2-(4-trifluoromethoxybenzyl)hexanoyl)-(S)-valyl]-4-[N-benzyloxycartonyl-N-ethylamino)piperidine, m.p. 164-167°C. Found: 0,63.98; H,7.36; N,6.41. C₄₅H₅₉F₃N₄O₈ requires C,64.27; H,7.07; N,6.66%. m/e [MH]⁺ 841

e) The N-t-tutyloxycarbonyl group was removed by treatment with trifluoroacetic acid following the procedure of Example 136 step (a) to give 1-[N-((S)-5-amino-(S)-4-hydroxy-6-phenyl-(R)-2-(4-trifluoromethoxybenzyl)hexanoyl)-(S)-valyl]-4-[N-benzyloxycarbonyl-N-ethylamino)piperidine, m/e [MH]⁺ 741. f) The product from step (e) above was reacted with (S)-(1-methoxycarbonylethoxy)carbonyloxysuccinimide (from Intermediate Preparation 9) following the procedure of Example 136 step (b) to give 1-[N-( (S)-4-hydroxy-(S)-5-( (S)-1-methoxycarbonylethoxy)¬carbonylamino-6-phenyl-2-(4-trifluoromethoxybenzyl)hexanoyl)-(S)-valyl]-4-(N-benzyloxycarbonyl-N-ethylamino)piperidine. m/e [MH] ⁺ 871.

g) Reaction of the product from step (f ) above with

2,2-diπethoxypropane as described in Example 138 step (b) gave the oxazolidine derivative which was reacted with methylamine and subsequently deprotected as described in Example 140 to give the title coipound. m.p. 223-226°C. Found: C,56.68; H,7.00; N,8.53. C₃₇H₅₂F₃N₅O₇. HCl. H₂O requires 0,56.32; H,7.01; N,8.86%.

m/e MH] 736.

(c = 0.1 MeOH) .

N.M.R. (DMSO-d₆) δ = 0.75(m,6H) ; 1.15-1.68 (m, 12H) ; 1.85(m,1H) ;

2.55-3.13 (m,12H) ; 3.25(m,1H) ; 3.48(m,5H) ; 4.13 (m,1H) ; 4.43 (m,2H) ;

4.71(m,1H) ; 6.88(t,1H) ; 7.22(m,9H) ; 7.75(d,1H) ; 7.90(t,1H) ;

8.95(bs 2H) ;

EXftMPLE 144

1-[N-(S)-4-Hydroxy-(S)-5-((R)-1-methylaminocarbonylethoxy)carbonylamino-6-phenyl-(R)-2-(4-trifluoromethoxybenzyl)hexanoyl)- (S)-valyl]-4-(N-ethylamino)-piperidine, hydrochloride, hydrate

The procedure described in Example 143 was followed but using

(R)-(1-methoxycarbonylethoxy) cartonyloxysuccinimide from

Intermediate Preparation 10 in step (f). The product was obtained as a white solid, m.p. 198-200°C dec. Found: 0,55.89; H,7.06;

N,8.78. C₃₇H₅₂F₃N₅O₇. HCl. H₂O requires C,56.23; H,7.01; N,8.86%. m/e [MH]⁺ 736. 0° (c = 0.1 MeOH)

25

[α] +15° (c = 0.1 MeOH) .

365

N.M.R. (DMSO-d₆) δ = 0.75(m,6H); 1.16-1.68(m,10H); 1.86(m,1H);

2.08(m,2H); 2.56-3.08(m,12H); 3.25(m,1H); 3.40(m,4H); 3.55(m,1H);

4.16(m,1H); 4.45(m,2H); 4.70(m,1H); 6.90(t,1H); 7.18(m,9H);

7.80(d,1H); 7.91(t,1H); 8.83(bs,2H).

Claims

1. A compound having the formula:-

or a pharmaceutically acceptable salt thereof or bioprecursor therefor, wherein:

R¹ is C₁-C₆ alkyl, C₃-C₈ cycloalkyl, aryl, heterocyclyl, or

R⁷R⁸NCO;

R² is C₁-C₆ alkyl, C₃-C₈ cycloalkyl(C₁-C₄)alkyl, aryl(C₁-C₄)alkyl, or heterocyclyl(C₁-C₄)alkyl;

R³ is C₁-C₆ alkyl, C₃-C₈ cycloaUcyl, C₃-C₈ cycloalkyl (C₁-C₄)alkyl, aryl(C₁-C₄)alkyl, aryl(C₂-C₄)alkenyl, heterocyclyl (C₁-C₄)alkyl or heterocyclyl (C₁-C₄)alkenyl;

R⁴ is C₁-C₆ alkyl, C₃-C₈ cycloalkyl, aryl or heterocyclyl;

R and R are each independently H, C₁-C₆ alkyl, C₃-C₇ cycloalkyl, or C₁-C₆ alkyl substituted by C₁-C₄ alkoxy, hydroxy or N R⁷ R⁸; or

R⁵ and R⁶ are linked to form, together with the nitrogen atom to which they are attached, a pyrrolidine, piperidine, morpholine, piperazine or N-(C₁-C₄ alkyl) piperazine group;

each of R ⁷ and R⁸ is independently H, C₁-C₆ alkyl or C₃-C₈ cycloalkyl; or R⁷ and R⁸ may be joined together to form, with the nitrogen to which they are attached, a 4 to 8 membered

nitrcgen-containing heterocyclic group;

each of R⁹, R¹⁰, R¹¹ and R¹² is independently H, C₁-C₆ alkyl or C₃-C₈ cycloalkyl; or R ⁹ and R¹⁰, or R¹¹ and R¹² may be joined together to form a 3 to 8 -membered carbocyclic ring;

X is a 4-10 membered mono- or bicyclic heterocyclic group conraining carbon ring atoms and one 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 -(CR¹¹R¹²)_m -NR⁵R⁶ substitutent, it may be substituted by up to 4 further substitutents each independently chosen from F, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, OH, C₁-C₆ alkoxy or NR⁷R⁸;

and n and m are each independently 0, 1 or 2;

and wherein any alkyl or cycloalkyl group included in the aforementioned definitions may optionally be fully or partially substituted by fluorine.

2. A compound as claimed in claim 1 having the stereochemistry-:

wherein R¹ to R⁶, R⁹ to R¹², n, m and X are as previously defined in claim 1.

3. A compound as claimed in claim 1 or claim 2 wherein R¹ is t-butyl, and n is O, or R¹-(C R⁹ R¹⁰)_n- is benzyl.

4. A compound as claimed in claim 3 wherein R² is benzyl.

4

5. A compound as claimed in claim 3 or claim 4 wherein R is isopropyl or sec-butyl.

3

6. A compound is claimed in any one of claims 3 to 5 wherein R is benzyl optionally substituted in the pAienyl ring by methyl, chloro, CF₃ , OCF₃, pivaloyl, OH, OONMe₂ , phenoxy, phenylsulphonyl or pyridyl or R is 3-phenylpropyl or 3-phenyl-prop-2-enyl.

7. A compound as claimed in any one of claims 3 to 6 wherein each of R⁹, R¹⁰, R¹¹ and R¹² is H.

8. A conpound as claimed in any one of claims 3 to 7 wherein X is piperidinyl.

9. A cxsnpound as claimed in claim 1 wherein said compound is: 1-[N-( (S)-5-t-butoxycarbonylaιrιino-(S)-4-hydroxy-6-phenyl-(R)-2- (4-trifluoromethoxybenzyl)hexanoyl)-(S)-valyl]-4-methylaminopiperidine; 1-[N-( (S)-5-t-butoxycarbonylaιrdno-(S)-4-hydroxy-6-phenyl-(R) -2- (3-phenylprop-2-en-1-yl)hexanoyl-(S)-isoleucyl]-4-ethylaminopiperidine; or

1-[N-( (R)-2-benzyl-(S)-5-t-butoxycarbonylamino-(S)-4-hydroxy- 6-phenylhexanoyl)-(S)-α-cyclohexylglycyl]-4-(2-methoxyethylamino)piperidine.

10. A process for preparing a compound of the formula (I) as claimed in claim 1 which comprises removing the protecting groups from a compound of the formula:

wherein X¹ is either H or a selectively removable hydroxyprotecting group and Y is either R⁶, or a selectively removable nitrogen-protecting group and R ¹ to R⁶ and R⁹ to R¹² are as previously defined with the proviso that at least one of X¹ and Y¹ is a protecting group, and isolating the compound of formula (I) and optionally forming a pharmaceutically acceptable salt thereof.

11. A pharmaceutical composition comprising a compound of the formula (I) or (Ia) or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 9, together with a pharmaceutically acceptable diluent or carrier.

12. A conpound of the formula (I), or (Ia) or a pha-t-maceutically acceptable salt thereof, as claimed in any one of claims 1 to 9 for use in medicine , in particular for use in the treatment or prophylaxis of human retroviral infections.

13. The use of a compound of the formula (I) or (Ia) as claimed in any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for use in the treatment or pjrophylaxis of human retroviral infections.

14. A method of treating human rotrσviral infections which comprises administering an effective amount of a compound of the formula (I) or (Ia) as claimed in any one of claims 1 to 9.