CZ349899A3 - Inhibitors of viral protease - Google Patents

Description

Viral protease inhibitors Field of the invention

The present invention relates to novel protease inhibitors, in particular inhibitors of aspartate protease, which is present in some retroviruses, particularly in HIV. The invention further relates to the use of such protease inhibitors in the treatment of diseases caused by retroviruses and in the preparation of medicaments for this purpose. The invention also relates to novel synthesis methods to facilitate the preparation of protease inhibitors and similar chemical structures.

BACKGROUND OF THE INVENTION

Many biological processes are dependent on the precise enzymatic processing of polypeptides in particular amino acid sequences. An example of such processing is the posttranslational processing of human immunodeficiency virus (HIV) gag and gag-pol gene products that allow the organization of nuclear structural proteins and the release of viral enzymes. The enzyme responsible for this processing, the HIV protease, is a virus-encoded homodimeric protease belonging to the aspartate-protease family.

The human enzymes renin and pepsin also belong to this family of proteases. Inhibition of HIV protease in cell culture prevents the maturation of the virus and its replication, and therefore this enzyme represents an attractive target for antiviral therapy against HIV in humans.

There are several references in the patent literature describing HIV protease inhibitors, which generally describe peptidomimetics having a large number of chirality centers. Abbott, for example

Laboratories have extensively investigated linear peptidomimetics, as described in a series of patent applications beginning with EP 402654 and culminating in WO 94 14436, which describes optimized linear peptidomimetics and in particular Ritonavir:

compound

Now this compound is known as Norvir, is registered by the FDA and although it has good clinical efficacy, its synthesis is difficult. The difficulty associated with the synthesis described previously in the art is known with respect to the protease inhibitor saquinavir (Inverase, Roche):

According to published reports, synthesis of this compound requires about 20 degrees, resulting in a final compound yield of about 2%. This difficulty of synthesis increases treatment costs and reduces production capacity.

U.S. Pat. U.S. Patent No. 5,413,999 (Merck) discloses indanylpentamine compounds, including the currently marketed indinavir product:

• ·

EP 480714 discloses a symmetrical protease inhibitor having terminal indanolamine groups on both sides of a 7-carbon skeleton:

These compounds are prepared by a complex technique from an alkene diol.

Japanese Patent Application No. 7242613 A (Banyu) also discloses a symmetric protease inhibitor having terminal indanolamine groups on both sides of a 7-carbon skeleton:

wherein R is H or lower alkyl. These compounds are prepared by% BuLi-alkylation of N, O-isopropylidine-N- [2 (R) -hydroxy- (1S) -indynyl] -3-phenylpropanamide with 2-chloro-2-chloromethyl-propene followed by ozonation , reducing and removing protecting groups.

International Patent Application WO 94/13629 (Vertex) describes the use of a mannitol hydrocarbon precursor for the preparation of compounds of the formula:

Obviously, in these inhibitors of benzoyl group esterified to the C-1 and C-6 hydroxyl groups of the mannitol precursor, the PI and PI 'pockets of the HIV protease active site should fill. Amino acid functions such as valyl are an amide bond attached to the C-2 and C-5 hydroxyl groups and are intended to fill the P-2 and P-2 'pockets of the enzyme. These compounds are prepared by bridging 3- and 4-hydroxyl groups using isopropylidine, epoxidizing and ring opening terminal hydroxyl groups using a nucleophilic reagent such as an aryl alcohol, and then amidating the resulting free hydroxyl groups using the appropriate amino acid. Alternatively, it is

Even the isopropylidine protected mannitol was first amidated to the more active

C-1 and C-6 (terminal) hydroxyl groups

φ. amino acid P-2 filling groups and then esterified with benzoyl groups on C-2 and C-5 hydroxyl groups.

One of Abbott Laboratories's first applications relating to protease, EP 402646, describes a large number of potential approaches for the construction of protease inhibitors. One of these approaches also utilizes a hydrocarbon precursor, which becomes the central skeleton of a symteric protease inhibitor. Examples 305 and 307 of EP 402646 describe the ring opening of mannosaccharodilactone and the addition of thi e e o c e b e e;

e «e © © c«?

P (> c o c o c o c o c o c c © c> ® ope ©

e e e e e e e e e e e e e e e e e e e e e e of terminal valine esters to give the 3,4-O-isopropylidine bridged adipamine derivative. The aryl groups that correspond to the PI and PI 'protease pockets are then attached by triflate activation to the C-2 and C-5 positions of the hydrocarbon backbone, and these groups are then converted to phenylthio groups before the isopropylidine bridge is removed.

1. Valine benzyl ester

The disadvantage of this procedure is the undesirable inversion of the C-3 and C-4 configurations and that although reagents such as thiophenyl can be used to remove triflate leaving groups as disclosed in EP 402646, only thioether derivatives can be obtained using such reagents. P1 and P1 'filling groups. It would appear that the triflate cleavable group can be removed using conventional alkylating agents, such as an alkoxide, to yield an O-alkylated P1 / P1 'filling group. However, we have found that in this known process, the alkoxide tends to eliminate olefin-producing triflates instead of 9 9 9 9 9 9 9 9 9 9 • 99 9 9 9 9

9 ttt · 9 · 9 9 9 9 9 9 of the desired O-alkylated substituent.

Magnus Bjorns et al., In the Synthesis of Potential Candidates for Therapeutic Intervention against Human Immunodeficiency Virus, Stockholm University, 1995, discloses a compound

the corresponding benzyl ester and the phenylalanine analog. These compounds are prepared from L-mannonic acid by the steps of:

i) bridging C-3 and C-4 hydroxyls of hexitol with isopropylidine, ii) protecting C1 and C-6 primary hydroxyl groups, iii) O-alkylating C-2 and C-5 hydroxyl groups to aralkyl ethers, iv) oxidizing Cl and C- 6 primary hydroxyl groups per carboxylic acid, and

v) coupling the resulting compound with suitable amino acid (ester) terminal groups. This procedure can be illustrated graphically as follows:

Ph

A suitable valine or phenylalanine (ester) terminal is then condensed. to terminal carboxyl groups in dichloromethane-THF using the HOBt-EDC coupling reaction. Despite the need for protection, oxidation and deprotection steps, the Bjorsne synthesis method is an improvement due to the large number of steps in conventional synthesis of peptidomimetics (see saquinavir above). The Bjorsne synthesis method also avoids tirflat activation, the preferred reactivity of the bad C-3 and C-4 atoms, and other disadvantages of the procedure described in EP 402646 (Abbott). However, the compounds proposed by Bjorsne have inadequate antiviral characteristics. Most preferable compound Bjorsneem proposed in which the terminal methyl valine amine (shown above) has an IC 5 _with μΜ, which should be compared with the current sold protease inhibitors which have an IC _having one or two orders of magnitude.

SUMMARY OF THE INVENTION

We have now discovered a new group of compounds with antiviral properties in the IC _of the order of nanomoles, which is suitable for the synthesis of a new technique based on hydrocarbons, which is advantageous over the technique known in the art which have been described above.

t

Accordingly, in the first aspect, the invention comprises new || compounds of formula I:

where

A and A 'are independently a group of formula II:

• · · ··· · · ·

R '

R

II where

R 1 is H, CH ₃ , C (CH ₃ ) ₂ , -OR ^a , -N (R ^a ) ₂ , -N (R a) OR ^and -DP;

R 10 is H, CH ₃ ; R ^a is H, C 1 -C 4 alkyl;

D is a bond, C 1-4 alkylene, -C (= O) -, -S (O) -, -S (O) - or -S (O). ₂ -;

P is an optionally substituted, mono- or bicyclic cyclic hydrocarbon or heterocycle;

R '' is H, any natural amino acid side chain, carboxacetamide or the (CH ₂ ) JDP group;

M is a bond or -C (= O) N (R ¹¹ ) -;

Q is either absent or is a bond or is -CH (OH) - or -CH ₂ -; or R 1 'together with Q, M and R' form an optionally substituted 5 or 6 membered cyclic hydrocarbon or heterocycle which is optionally fused to another 5 or 6 membered cyclic hydrocarbon or heterocycle;

with the proviso that R 'is -OR ", -N (CH ₃ ) ₂ , -N (R") OR 4, or -DP when M is a bond and Q is absent;

X is H, OH, OCH ₃ ;

Y is H, OH, OCH ₃ , but X and Y are not both H;

Z 'and Z''are independently - (CH ₂ ) _m P, where P is as defined above;

n and m are independently 0, 1 or 2;

And pharmaceutically acceptable salts and prodrugs thereof.

The compounds of formula I are active inhibitors of aspartyl proteases such as HIV protease. Therefore, in another aspect, the invention comprises:

a pharmaceutical composition comprising a compound of formula I in admixture with a pharmaceutically acceptable carrier or diluent;

- the use of a compound of formula I in the manufacture of a medicament for prophylactic medicaments Or treating diseases such as AIDS caused by retroviruses such as HIV; and

- a method of treating conditions caused by retroviruses, in particular AIDS in humans, comprising administering a compound of formula I to a subject afflicted with said disease.

The compounds have a relatively low molecular weight and therefore should have good oral absorption in mammals. Compared to the previously known aspartyl protease inhibitors, the compounds of the present invention can be prepared by small-scale synthesis from readily available and cheap starting materials such as L-mannaro-dilactone or its commercially available precursors and derivatives such as L-mannono-T-lactone .

In another aspect, the invention provides a process for preparing compounds of Formula I

wherein X, Y, Z 'and Z' 'are the same as defined above and A' and A '' are independently:

a group of formula II or a conventional group filling P-2 / P-2 'proteases, said method comprising:

i) O-alkylating L-mannaro-1,4: 6,3-di-lactone to form Z 'and Z' 'groups, ii) opening the lactone with the same or different primary or secondary amines to form the respective A' and A ' groups; and iii) optionally converting C-3 and C-4 into suitable X and Y 'groups.

An example of this aspect of the invention may be illustrated as follows:

The process of the present invention is preferably used to produce compounds of formula I as defined in the claims, but can also be used to prepare protease inhibitors with conventional groups to fill the P-2 / P-2 'protease.

The introduction of Z 'and Z' 'groups as C-2 and C-5 hydroxyl ethers in step i) is preferably performed by O-alkylation with a suitable derivative:

E (CH ₂ ) _n P where E is halogen, mesylate, tosylate etc. and P and _n are the same as defined above in the presence of a base such as carbonate, metal hydride or hydroxide and an aprotic solvent such as N, N dimethylformamide, tetrahydrofuran or acetone. Preferably, the alkylating agent is benzyltrichloroacetimidate together with a proton or Lewis acid, ie trimethylsilyltriflate.

The ring opening in step ii) for insertion of the amino or amino acid derivatives A 'and A' 'is preferably carried out under standard conditions in solvents such as dioxane, nitromethane THF, diglyme, DMF or DMSO, wherein said solvent.

999 999

9 · 9 is preferably selected to dissolve both the hydrocarbon derivative and the particular amine present.

For ease of synthesis it is generally preferred that the terminal 'amines A ¹ and A''are the same. However, although the target enzyme is a symmetric dimer, indicating a close interaction with symmetric compounds, asymmetric terminal amines may be preferred in certain circumstances, for example for resistance or for pharmacokinetic reasons. If it is desired to obtain an asymmetric compound, i.e., compounds with different groups A ¹ and A 1 ', it is most preferred to link the respective groups A 1 and A 1' sequentially. This coupling can be accomplished in conjunction with the attachment of suitable protecting groups for one dilactone ring, but can also be accomplished by adjusting reagent concentrations, reaction conditions, addition rate, etc., to yield a monoamine lactone which is separated by conventional techniques or amine neutralization prior to reaction with a second A 'or A''amine.

Alternatively, the various terminal amination may be performed by solid phase synthesis in which the non-aminated or partially aminated lactone is provided on a solid phase substrate, such as polymer beads known in the art of solid phase synthesis, for example on a Merrifield resin. Such immobilization of the " lactone " allows the amination of only the designated lactone ring. Diagram

1, further, depicts such a synthetic scheme used for the combinatorial synthesis of compounds of the present invention, but it is clear that a single pure compound can be prepared by the same technique using pure reagents.

Scheme l

NH ₂ RNH

H ₂ N (CH ₂ ) _n NH ₂

1. N-Boc-amino acids

2. removal of protecting groups ▼

ý

In Scheme 1, steps 1 and 2 comprise the preparation of linking groups on the carboxyl groups of resin beads. Linkers of different sizes, rigidity and different cleavages (several of which are listed in Step 2) can be used, as are commonly used in the art of solid phase synthesis. In step 3, the free amine on the solid phase bead provided with the linker is an amide that is linked to the N-protected amino acid using standard peptide chemistry conditions. Amino acid reagents include many different, protected amino acids, such as N-Boc valine, N-Boc isoleucine, N-Boc alanine, N-Boc leucine etc., and thus this reaction step leads to the formation of the first combinatorial series. The solid phase beads now carry many randomly spaced amino acids separated by the respective linker from the carboxyl surface of the bead.

In step 4, the free amine (after removal of the N-Boc protecting groups) on the amino acids is used to open the ring of di-O-alkylated τ-dilactone, wherein and R 6 are the same or different optionally substituted (hetero) arylalkyl groups, e.g. , pyridylmethyl, etc. This ring opening is performed using conventional conditions as indicated

Also, in solvents such as dioxane, nitromethane, THF, diglyme,

DM, DMSO and the like. If R 1 and R 2 are different (hetero) arylalkyl groups, a further series of combinatorial variations will occur at this stage, depending on whether the ring containing R 1 or R 2 is open. However, the dilactone reagents themselves may contain many different dilactones with different combinations of R and / or the stereochemical arrangement of the lactone, resulting in even greater combinatorial diversity.

In the fifth step, the remaining ring of the now immobilized lactone is opened in the same manner using another amine reagent. Again, this amine reagent may contain a mixture of different amines, as described above.

for example, L-amino acids or (hetero) cyclic amines, as shown. Thus, a further series of combinatorial diversity can be created at this stage. The combinatorial library is cleaved from the linker using a suitable cleavage reagent, usually a specific amidase, or by changing the pH, etc.

Although the compounds of formula I are preferably prepared by the process of the present invention, it is also possible to use the first steps of Bjorsne technique described above together with the appropriate choice of A 'and A' 'amines, followed by the necessary post-modification of X and Y described above and exemplified in following example 2.

The preparation of compounds of formula I in which X is hydrogen can be conveniently performed by deoxygenation as exemplified in Examples 2 and 26. The preferred stereochemistry is the 2R, 3R, 4R, 5R form.

Cyclic hydrocarbon groups for R 'as -DP and / or Z' / Z '' and / or their optional substituents may be saturated, unsaturated or aromatic and contain monocyclic rings such as phenyl, cyclohexynyl, cyclopentenyl, cyclohexanyl, cyclopentanyl, or bicyclic rings such as indanyl, naphthyl and the like.

Heterocyclic groups for R 'such as -DP and / or Z' / Z '' and / or their optional substituents may be saturated, unsaturated or aromatic and have 1 to 4 heteroatoms and include monocyclic rings such as furyl, thienyl, pyranyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolinidyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, piperidinyl, pyrazinyl, piperazinyl, pyrimidinyl, pyridazinyl, oxyzolyl, oxyzolidinyl, isoxazolidinyl, isoxyzolyl, isothiazolyl, isoxazolidinyl, isoxazolidinyl, isoxazolidinyl, isoxazolidinyl, isoxazolidinyl, isoxazolidinyl, isoxazolidinyl, and the like or bicyclic rings, in particular the aforementioned rings, in particular the above-mentioned rings. 4 fused to a phenyl ring such as indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzothienyl, etc. A hydrocarbon or heterocyclic ring y may be attached via carbon or via heteroatoms, usually a nitrogen atom such as N-piperidyl, N-morpholinyl, etc.

Preferred embodiments of formula II for groups A '/ A' 'in the compounds of the present invention include groups of formula IIa or Ile:

Ř

Ha wherein n is 1 or 2 and R 'is alkyloxy, preferably methyloxy, or those wherein n is 0 and R' is methyl.

Other preferred groups of formula II are those of formula IIb:

Alternatively, groups A '/ A' 'of the invention are groups of formula IIc:

of the compounds of the present invention

R '

R 1c wherein Q is a bond, methylene or -C (OH) - and R 'is -OR ", -N (R ^a ) ₂ , -NR" OR ", wherein R" is H or C ₁ -C ₃ alkyl, or a cyclic hydrocarbon; or a heterocycle selected from the group consisting of N-piperidine, N-morpholine, N-piperazine, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidyl, pyrazinyl, etc.

A preferred subgroup of compounds of formula IIc is compounds of formula IId:

people where R ^s is hydrogen or methyl (that is a valyl or isoleucyl side chain) and R ^e is or

N 'wherein X is methylene, O, S, S = O, S (= O) ₂ or NH or R ® is N (CH ₃ ) ₂ , -NHOH, -NHOMe, -NHOEt, -NMeOH, -NMeOMe etc.

In each of formulas IIa, IIb and IIc, R ^{11 is} hydrogen, methyl, ethyl, isopropyl, cycloalkyl such as cyclopropyl, cyclobutyl or cyclohexyl, cycloalkenyl, benzyl, carboxacetamide or 4-imidazolylmethyl, each of which may be substituted as described above. Preferred R '' groups include side chains occurring in natural amino acids, particularly leucine, asparagine, histidine or proline. The most preferred R '' groups for the formulas IIa, IIb, IIc and IId are the side chain of isoleucyl and especially valyl.

R 'differs according to the nature of Q and / or M, if present, and may for example be selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, R ® as defined above, valinol, a heterocycle such as pyridyl, thiazole, oxazole, 99 9 99 99 99 imidazole, N-piperidine, N-morpholine, N-piperazine, pyrrolyl, imidazolyl, pyrazolyl, pyrimidyl, pyrazinyl, wherein any R 'group may be substituted as defined for Z' / Z ' ¹ below.

Other preferred A '/ A' 'groups are those of formula II wherein R' ', Q, M and R' together form an optionally substituted 5 or 6 membered hydrocarbon ring or heterocycle. Preferred groups according to this definition are those of formula III:

where

R '' 'is the same as defined above,

R ¹ is H, NR ⁴ R ⁴ , C (= O) R ³ , CR ³ R ⁴ or a monocyclic, optionally substituted hydrocarbon ring or heterocycle,

R ² is OH or together with R ¹ = O, or when R ^{1 is} NR ⁴ R ⁴ , then R ^{2 can} be H,

R ³ is H, halogen, C _i -C ₃ akyl, 0R ^a, NR ⁴ R ^4,

R ⁴ is H, C ₁ -C ₃ alkyl,

R ^is H or a pharmaceutically acceptable ester,

R ⁶ is OH, NH ₂ , carbamoyl or a carboxyl group,

R ⁷ is hydrogen, straight or branched C 1 -C 4 alkyl, or forms a fused phenyl or heteroaromatic ring together with adjacent carbon atoms.

Preferred groups of the formula 1-amino-azaindan-2-ol, i

III are aminoindanol and means groups of the formula:

or

• ·

♦ · • 9 · 9 9 9 * • • 9 « 9 9 9 9 • 9 • * • · * < 99 9 ♦ • · • • • · · • ♦ • · · · · e 9 •

Common groups filling P-2 / P-2 'proteases for Α' / Α ' ¹ include those containing the compounds saquinavir (Roche) and ritonavir (Abbott). Other examples of common P-2 / P-2 'protease filling groups include those contained in VE 478 (Vertex), AG1343 (Agouron, now known as nelfinavir) and indinavir (Merck), as mentioned above.

Optional substituents for the cyclic hydrocarbon or heterocyclic group Z '/ Z' 'or A' / A '' include one to three substituents such as halogen, amino, mercapto, oxo, nitro,

NHC-alkyl, N (C-alkyl), C-alkyl, C-alkenyl,

T 6 1 · o 2 6 3 o

C -C alkynyl, C -C alkanoyl group, C -C alkoxy, thioC -C alkyl, thioC _i -C _e alkoxy, hydroxy, _hydroxyC -C _g alkyl, haloC _i -C _e alkyl, _aminoC -C ₆ alkyl, C ^ -C ^ alkyl, cyano, carboxyl, carbalkoxy, carboxamide, carbamoyl, sulfonamide, benzyloxy, _{morpholyl-C L} -C alkalkyloxy _a monocyclic hydrocarbon or a heterocycle as defined above, a cyclic hydrocarbyl or heterocyclic group separated by an alkyl, a is C ₁ -C ₃ alkylaryl etc.

The preferred definitions for Z 'and Z''is benzyl which is unsubstituted or substituted with 1, 2 or 3 substituents, in particular one substituent selected from the group consisting of fluoro, chloro, hydroxy, amino, -NH (C _i -C _g alkyl), -N (C _i -C _g alkyl) _2,

NPh (C _i -C _g alkyl), -NHPh, methoxy, cyano, hydroxymethyl, aminomethyl, alkylsulfonyl, carbamoyl, morpholinoethoxy, benzyloxy, benzylamide etc. Other possibilities, which in this area, many are exemplified. It should be understood that the substituent on Z 'and / or Z''may contain a ring structure (wherein the ring may itself be substituted as defined herein), such as a phenyl or 5 or 6 membered heterocycle containing one or two heteroatoms, such as, for example, thiophene, pyridine, etc. Preparation of useful heterocyclic substituents for Z 'and Z''such as 4 &apos;

Benzyl is described in Tetrahedron Letters 1997, 6359-6367 and in J. Org. Chem. 62 (1997) 1264 and 6066, and include N-morpholine, N-piperidine, N-piperazine, N'-methyl-N-piperazine, N-pyrrolidone, N-pyrrolidine and the like.

Such substituents may be in the meta-position, but mainly in the ortho- or para- position Z '/ Z' ', where small groups such as fluorine are preferably in the ortho- and meta-position and the various larger groups are in the para-position, such as the (optionally substituted) cyclic substituents, including the N-linked rings mentioned in the previous paragraph. The entire Z 'and Z' 'groups or their respective cyclic hydrocarbon or heterocyclic groups may be different, but for ease of synthesis it is preferred that they be identical.

Suitable pharmaceutically acceptable salts for both A '/ A' 'free acids and other charged groups in the compounds of Formula I include salts of organic carboxylic acids such as acetic, lactic, gluconic, citric, tartaric, maleic, malic, pantothenic acids. , isethionic, oxalic, lactobionic and succinic, organic sulfonic acid salts such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-chlorobenzenesulfonic acid and p-toluenesulfonic acid, and inorganic acid salts such as hydrochloric, hydroiodic, sulfuric, phosphoric and sulfamic acids.

The prodrugs of the present invention are derivatives that release a compound of formula I in vivo, usually by hydrolysis or other metabolic interaction in the small intestine, liver or plasma. Typical prodrugs are esters formed on the free hydroxyl groups of the compounds. Preferred pharmaceutically acceptable esters include C ₁ -C ₂₂ fatty acid esters in which the fatty acid is unsaturated, monounsaturated or polyunsaturated. Among esters of saturated fatty acids

• · · e · · 9 · • • • · t <9 9 • • i 9 ♦ · l • ··· • • • • ♦ · • · « • · · 9 • ·

include those having a short chain, such as acetyl or butyryl, or those having a long chain, such as stearoyl. Unsaturated fatty acid esters are preferably in the--9 series, such as palmitic or linolenic acid esters. Other esters include C _i -C _g alkyl aryl esters such as benzyl or methylpyridyl or esters of phosphoric acid, such as monophosphate. Alternative esters include the carbonate, carbamate or sulfonic esters of the corresponding fatty acids or alkylaryl.

Preferred compounds of formula I are:

N 1, N 6 -di [(1 S) -2-methyl-1- (methylcarbamoyl) propyl] - (2 R, 3 R, 4 R, 5 R) -2,5-di (benzyloxy) -3,4-dihydroxyhexanediamide;

N 1, N 6 -di [(1 S) -2-methyl-1- (methylcarbamoyl) propyl] - (2 R, 3 S, 5 R) -2,5-di (benzyloxy) -3-hydroxyhexanediamide;

N 1, N 6 -di [(1 S) -2-methyl-1- (methylcarbamoyl) propyl] - (2 R, 3 R, 5 R) -2,5-di (benzyloxy) -3-hydroxyhexanediamide;

N1, N6-di [(1S) -2-methyl-1- (methylcarbamoyl) butyl] - (2R, 3R, 4R, 5R) -2,5-di (benzyloxy) -3,4-dihydroxyhexanediamide;

N 1, N 6 -di [(1 S) -1- (methylcarbamoyl) -2-phenylethyl] - (2 R, 3 R, 4 R, 5 R) -2,5-di (benzyloxy) -3,4-dihydroxyhexanediamide;

N 1, N 6 -di [(1 S) -1- (methylcarbamoyl) -2- (4-hydroxyphenyl) ethyl] - (2 R, 3 R, 4 R, 5 R) -2,5-di (benzyloxy) -3,4-dihydroxyhexanediamide ;

N1, N6-di [(1S) -2-methyl-1- (methylcarbamoyl) propyl] - (2R, 3R, 4R, 5R) -2,5-di (4-fluorobenzyl) oxy) -3,4-dihydroxyhexanediamide ;

N 1, N 6 -di [(1 S) -2-methyl-1- (cyclopropylcarbamoyl) propyl] - (2 R, 3 R, 4 R, 5 R) -2,5-di (benzyloxy) -3,4-dihydroxyhexanediamide;

N 1, N 6 -di [(1 S) -2-methyl-1- (methylcarbamoyl) propyl] - (2 R, 3 R, 4 R, 5 R) -2,5-di [(2-methylbenzyl) oxy] -3,4- dihydroxyhexanediamide;

N 1, N 6 -di [(1 S, 2 R) -2-hydroxy-2,3-dihydro-1 H -1-indenyl] - (2 R, 3 R, 4 R, 5 R) -2,5-di (benzyloxy) -3, 4-dihydroxyhexanediamide;

· T 99 99 99 t 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 ··· 999 99 99

N 1 - [(1S, 2R) -2-hydroxy-2,3-dihydro-1H-1-indenyl] -N 6 - [(1S) -2-methyl-1- (methylcarbamoyl) propyl] - (2R, 3R, 4R, 5R) -2,5-di (benzyloxy) -3,4-dihydroxyhexanediamide;

N 1, N 6 -di [(1 S, 2 R) -2-hydroxy-2,3-dihydro-1 H -1-indenyl] - (2 R, 3 R, 4 R, 5 R) -2,5-di (2-fluorobenzyloxy) - 3,4-dihydroxyhexanediamide;

N 1, N 6 -di [(1 S, 2 R) -2-hydroxy-2,3-dihydro-1 H -1-indenyl] - (2 R, 3 R, 4 R, 5 R) -2,5-di (4-fluorobenzyloxy) - 3,4-dihydroxyhexanediamide;

N 1, N 6 -di [(1 S, 2 R) -2-hydroxy-2,3-dihydro-1 H -1-indenyl] - (2 R, 3 R, 4 R, 5 R) -2- (benzyloxy) -5- (4- methylbenzyloxy) -3,4-dihydroxyhexanediamide;

N 1, N 6 -di [(1 S) -2-methyl-1- (methylcarbamoyl) propyl] - (2 R, 3 R, 4 R, 5 R) -2,5-di [(4-phenylbenzyl) oxy] -3,4- dihydroxyhexanediamide;

N 1, N 6 -di [(1 S) -2-methyl-1- (methylcarbamoyl) propyl] - (2 R, 3 R, 4 R, 5 R) -2,5-di [(4- (3-thienyl) benzyl) oxy] -3,4-dihydroxyhexanediamide;

N 1, N 6 -di [(1 S) -1-phenyl-1- (methylcarbamoyl) methyl] - (2 R, 3 R, 4 R, 5 R) -2,5-di (benzyloxy) -3,4-dihydroxyhexanediamide;

N 1, N 6 -di [(1 S) -2-methyl-1- (methylcarbamoyl) propyl] - (2 R, 3 R, 4 R, 5 R) -2,5-di [4- (3-fluorobenzyl) oxy] -3, 4-dihydroxyhexanediamide;

N 1, N 6 -di [(1 S, 2 R) -2-hydroxy-2,3-dihydro-1 H -indenyl] - (2 R, 3 R, 4 R, 5 R) -2,5-di (3-fluorobenzyloxy) -3, 4-dihydroxyhexanediamide;

N 1, N 6 -di [(1 S) -2-methyl-1- (methylcarbamoyl) propyl] - (2 R, 3 R, 4 R, 5 R) -2,5-di [4- (2-fluorobenzyl) oxy] -3, 4-dihydroxyhexanediamide;

N 1, N 6 -di [(1 S) -2-methyl-1- (methylcarbamoyl) propyl] - (2 R, 3 R, 4 R, 5 R) -2,5-di [4- (2,4-difluorobenzyl) oxy] - 3,4-dihydroxyhexanediamide;

N 1, N 6 -di [(1 S, 2 R) -2-hydroxy-2,3-dihydro-1 H -1-indenyl] - (2 R, 3 R, 4 R, 5 R) -2,5-di (2,4-difluorobenzyloxy -3,4-dihydroxyhexanediamide;

N 1, N 6 -di [(1 S) -2-methyl-1- (methylcarbamoyl) propyl] - (2 R, 3 R, 4 R, 5 R) -2,5-di [4- (2-pyridyl) benzyloxy] -3, 4-dihydroxyhexanediamide;

N 1, N 6 -di [(1 S) -2-methyl-1- (methylcarbamoyl) propyl] - (2 R, 3 R, 4 R, 5 R) -2,5-di [4- (2-pyridyl) benzyloxy] -3, 4-dihydroxyhexanediamide;

N 1, N 6 -di [(1 S) -2-methyl-1- (methylcarbamoyl) propyl] - (2 R, 3 R, 4 R, 5 R) -2,5-di [(4- (3-nitrophenyl) benzyl) oxy] -3,4-dihydroxyhexanediamide;

* 9 9 9 9 9 9 9 9 9 999 99 999 999 9 9 9 9 99 99 999 99 99 99 9 9 999 999 99 99 9

ΝΙ, β-di [(1S) -2-methyl-1- (methylcarbamoyl) propyl] - (2R, 3R, 4R, 5R) -2,5-di [4- (2-thienyl) benzyloxy] -3, 4-dihydroxyhexanediamide;

N 1, N 6 -di [(1 S, 2 R) -2-hydroxy-2,3-dihydro-1 H -1-indenyl] - (2 R, 3 R, 5 R) -2,5-di (2,5-dibenzyloxy) - 3-hydroxyhexanediamide;

N1, N6-di [(1S, 2R) -2-hydroxy-2,3-dihydro-1H-1-indenyl] -N6- (2-chloro-6-fluorobenzyl) - (2R, 3R, 4R, 5R) -2,5-di (2-fluorobenzyloxy) -3,4-dihydroxyhexanediamide;

and pharmaceutically acceptable salts thereof.

O-alkylated dilactone intermediates are also novel compounds and therefore another aspect of the invention includes compounds of formula IV: Z

wherein Z 'and Z' 'are the same as defined above. Preferably, the compound of formula IV has the following stereochemistry:

OF'

OF

Preferred compounds of formula IV are those wherein Z 'and Z' ¹ are benzyl, 2-fluorobenzyl, 2-methylbenzyl, 2,4-difluorobenzyl,

4-fluorobenzyl, 4-bromobenzyl, 4-phenylbenzyl, 4-thiophenylbenzyl, 4- (4'-nitrophenyl) benzyl, 4-pyridyl) benzyl or benzyl · 4 ··· · 4 ·· · · ··· I • 4 ·· ·· parasubstituovaný primary, secondary or tertiary amine or an N-bonded heterocycle such as piperidine, morpholine, etc. Alternatively, the benzyl may be Z 'and Z''groups different ^^ aryl-alkyl or _{heteroaryl-i2} alkyl, such as pyridylmethylene, quinolylmethylene or naphthylmethylene, as is known in the art for PI proteases.

As in Formula I, Z 'and Z' 'groups may differ in Formula IV, but it is preferred that they be the same due to the bimeric nature of the target enzyme.

Thus, preferred intermediates of formula IV include:

2,5-di-O-benzyl-L-mannaro-1,4: 6,3-dilactone;

2,5-di-O- (2-fluorobenzyl) -L-mannaro-1,4: 6,3-dilactone;

2,5-di-O- (2,4-difluorobenzyl) -L-mannaro-1,4: 6,3-dilactone;

2,5-di-O- (4-fluorobenzyl) -L-mannaro-1,4: 6,3-dilactone;

2,5-di-O- (2-chlorobenzyl) -L-mannaro-1,4: 6,3-dilactone;

2,5-di-O- (4-chlorobenzyl) -L-mannaro-1,4: 6,3-dilactone;

2,5-di-O- (4-thiophen-3'-yl-benzyl) -L-mannaro-1,4: 6,3-dilactone;

2,5-di-O- (4-thiophen-2'-yl-benzyl) -L-mannaro-1,4: 6,3-dilactone;

2,5-di-O- (4- (thiazol-4'-yl) -benzyl) -L-mannaro-1,4: 6,3-dilactone;

2,5-di-O- (4-thiazol-2'-yl-benzyl) -L-mannaro-1,4: 6,3-dilactone;

2,5-di-O- (4-phenylbenzyl) -L-mannaro-1,4: 6,3-dilactone;

2,5-di-O- (4-phenylbenzyl) -L-mannaro-1,4: 6,3-dilactone;

2,5-di-O- (4-phenylbenzyl) -L-mannaro-1,4: 6,3-dilactone;

2,5-di-O- (4- (4'-nitrophenylbenzyl) -L-mannaro-1,4: 6,3-dilactone);

2,5-di-O- (4- (4'-cyanophenylbenzyl) -L-mannaro-1,4: 6,3-dilactone);

2,5-di-O- (4- (4´-halophenylbenzyl) -L-mannaro-1,4: 6,3-dilactone;

2.5- di-0- (4- (4 ¹ -aminofenylbenzyl) -L-Mannar-1,4: 6,3-dilactone;

• 99 · 99

9. 9 9

2,5-di-O- (4- (4'-carboxyphenylbenzyl) -L-mannaro-1,4: 6,3-diacetone);

2,5-di-O- (4- (4'-phenylbenzyl) -L-mannaro-1,4: 6,3-dilactone);

2,5-di-O- (4-pyrid-2-ylbenzyl) -L-mannaro-1,4: 6,3-dilactone;

2,5-di-O- (4-pyrid-3-ylbenzyl) -L-mannaro-1,4: 6,3-dilactone;

2,5-di-O- (4-N-morpholinylbenzyl) -L-mannaro-1,4: 6,3-dilactone;

2,5-di-O- (4-N-piperidinylbenzyl) -L-mannaro-1,4: 6,3-dilactone;

2,5-di-O- (4-N-piperazinylbenzyl) -L-mannaro-1,4: 6,3-dilactone;

2,5-di-O- (4-benzylbenzyl) -L-mannaro-1,4: 6,3-dilactone; and the like.

Intermediates of formula III can be prepared according to the following reaction scheme:

• 9 9 9

9 9 9

999 999

9

The 1-amino-azaindan-2-ol groups filling the P-2 can be prepared analogously to the method disclosed in J. Med. Chem. 1991, 1228-1230.

In the treatment of retroviral-induced diseases, the compounds of formula I are preferably administered in an amount such that plasma concentrations of about 10 to 1000 nM, more preferably 100 to 100 nM, are achieved.

9 9 9 99 99 9 9 9 9 9

9> 9 «9999

9 9 99 99 999999

999,999 9 9

999 «99« 9 9 «99

500 ηΜ. This corresponds to a dose ranging from 0.001 to 100 mg / kg / day, preferably 10 to 50 mg / kg / day, depending on the bioavailability of the composition.

According to the usual practice of using HIV inhibitors, it is preferable to co-administer one to three other antiviral agents such as AZT, ddl, ddC, D4T, ritonavir, saquinavir, indinavir, nelfinavir, DMP 266, delavirdine, nevirapine, trovirdine, PFA, H2G etc. The molar ratio of such co-administered antiviral agents will generally be selected to reflect the EC ₅₀ characteristics of the antiviral agents. Often molar ratios of 25: 1 to 1:25 relative to the compound of formula I will often be preferred.

While it is possible for the active agent to be administered alone, it is preferred that it be administered as part of a pharmaceutical composition. Such compositions will contain the above-defined active agent together with one or more acceptable carriers and optionally other therapeutic ingredients. Carriers must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient of the formulation.

Formulations include those suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration. The compositions are preferably in unit dosage form, for example, in the form of sustained release tablets and capsules, and can be prepared by any technique known in the art of pharmacy.

Such techniques include the step of mixing the above defined active agents with a carrier. Generally, the compositions are prepared by uniformly and intimately mixing the active agent and liquid carriers or finely divided carriers in solid form or both, and

if necessary, a step of shaping the composition.

The compositions of the present invention for oral administration may be formulated as discrete units such as capsules, medical wafers or tablets, each unit containing a predetermined amount of the active agent; furthermore, they may be prepared in powder or granular form; in the form of a solution or suspension of the active agent in an aqueous liquid or a non-aqueous liquid; or in the form of an oil-in-water or water-in-oil emulsion in the form of a bolus and the like.

For compositions for oral administration (e.g., tablets and capsules), the term suitable vehicle carrier includes conventional excipients such as binding agents such as syrup, acacia, gelatin, sorbitol, tragacanth, polyvinylpyrrolidone (Povidone), methylcellulose, ethylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, sucrose and starch; fillers and carriers such as corn starch, gelatin, lactose, sucrose, microcrystalline cellulose, kaolin, mannitol, calcium phosphate, sodium chloride and alginic acid; and glidants such as magnesium stearate and other metal stearates, stearic acid, silicone fluid, talc, waxes, oils and colloidal silica. Flavoring agents such as peppermint, wintergreen oil, cherry flavor and the like can also be used. Addition of a dye may be desirable for easy identification of the dosage form. Tablets may also be coated using well known techniques.

Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing the active agent in a free-flowing form such as a powder or granules, optionally in admixture with a binder, a glidant, an inert diluent, a preservative, a surfactant, or a surfactant; a dispersing agent, in a suitable apparatus. Molded tablets may be prepared by casting a mixture of the compound in the form of a powder wetted with an inert liquid diluent in a suitable machine. The tablets may optionally be coated or scored and may be formulated so as to permit slow or controlled release of the active agent.

Formulations suitable for topical administration include lozenges comprising the active agent in a flavored base, usually sucrose or acacia or tragacanth; pastilles comprising the active agent in an inert base such as gelatin and glycerin, or sucrose and acacia; and mouthwashes containing the active agent in a suitable liquid carrier.

Compositions suitable for topical administration to the skin may be formulated as ointments, creams, gels and pastes comprising an active agent and a pharmaceutically active carrier. An example of a system for topical administration is a transdermal patch containing the active agent.

Compositions suitable for vaginal administration may be formulated as suppositories or pessaries with a suitable base containing, for example, cocoa butter or salicylate. Other vaginal compositions may be formulated as tampons, creams, gels, pastes, foams or sprays containing suitable carriers in addition to the active agent.

Compositions suitable for nasal administration wherein the carrier is in solid form include a coarse powder having a particle size of, for example, from 20 to 500 microns, which is delivered by inhalation into the nose, i.e. by rapid inhalation from a container located in close proximity to the nose. Suitable nasal formulations in which the carrier is a liquid, such as nasal sprays or nasal drops, include aqueous or oily solutions of the active agent.

··························································· · · · · ··· · · · · · · · · ·

Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injectable solutions which may contain antioxidant agents, buffers, bacteriostatic agents and solubilized agents to adjust the isotonicity of the composition with the blood of the recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The compositions may be prepared in single-dose or multi-dose containers, for example, in sealed ampoules and vials, and may be stored in a lyophilized state requiring only the addition of a sterile liquid carrier, for example water for injection, immediately prior to use. Improvised injectable solutions and suspensions may be prepared from sterile powders, granules and tablets by the method previously described.

DETAILED DESCRIPTION OF THE INVENTION

The invention will be further described in the following non-limiting examples.

Example 1: N1, N6-di [(1S) -2-methyl-1- (methylcarbamoyl) propyl] - (2R, 3R, 4R, 5R) -2,5-di (benzyloxy) -3,4-dihydroxyhexanediamide

h ₂ n

CH 3 CN 70 ° C

O

Briefly, oxidation of the α-lactone of mannonic acid with nitric acid affords crystalline L-mannaro-1,4: 6,3-dilactone which is dibenzylated using dibenzyltrichloroacetimidate and trimethylsilyltriflate to give 2,5-di-O-benzyl-L- mannaro-1,4: 6,3-dilactones. This lactone can be opened by the addition of any primary or more often secondary amine, in this case N-methyl-L-valine, to give the title compound in a total yield of 10-30%.

In more detail, the above synthetic scheme is performed as follows:

A. L-Mannonic acid τ-lactone (8.1 g) in aqueous (65%) HNO ₃ (120 mL) was maintained at 98 ° C under a stream of nitrogen for 1-2 hours. After concentrating to the sticky mass, water (50 mL) was added and the solution was concentrated almost to dryness. This material was dried under vacuum for 16 hours and then ethanol (5 ml) and ether (100 ml) were added and the solid material was gently dispersed by sonication and mechanical milling. The solution was removed and the solid material was washed with ethanol (10 mL). The residual solid was recrystallized in ethanol to give 4.3 g of L-mannaro-1,4: 6,3-dilactones.

^{X 3} C-NMR (DMSO-d 6): δ 69.2 (C2, C5), 75.9 (C3, C4), 174.3 (Cl,

C6).

B. Trimethylsilyltriflate or trifluoromethylmethanesulfonic acid (44 drops from Pasteur pipette) was added to a well mixed solution of L-mannaro-1,4: 6,3-dilactones (696 mg) and benzyltrichloroacetimidate (3040 mg) in dioxane (140 mL). After 1.5 hours, the solution was filtered through a 1 cm silica plug, 1 cm NaHCO ₃ and 1 cm silica, washed with dioxane (20 mL), concentrated to dryness and recrystallized from CHCl ₃ to give 1.85 material in solid state. From this solid • 9 · 9 9 9 9 ·

9 9 9 9 9

9 9 99 99 999999

9 9 9 9 9 9

999 999 99 99 99 slurry is formed using hot ether and filtered. The remaining solid material (900 mg) was collected as

2,5-di-O-benzyl-L-mannaro-1,4: 6,3-dilactone.

¹³ C-NMR (DMSO-d 6): δ 72.3, 74.6, 75.1 (CH 2 O, C 2, C 3, C 4, C 5), 128.2, 128.3, 128.7, 137, 2 (Ar), 172 (Cl, C 6).

C. A solution of 2,5-di-O-benzyl-L-mannaro-1,4: 6,3-dilactone (50 mg) and N-methyl-L-valine (110 mg) in acetonitrile (0.5 mg) Heat at 70 ° C for 16 hours. After cooling, the material was purified by silica gel chromatography (CHCl ₃ -MeOH, 9: 1) to give 30 mg.

Example 2: N 1, N 6 -di [(1 S) -2-methyl-1- (methylcarbamoyl) propyl] - (2 R, 3 S, 5 R) -2,5-di (benzyloxy) -3-hydroxyhexanediamide

A. Preparation of (2R, 3S, 4S, 5R) -2,5-di (benzyloxy) -3,4-O-isopropylidene-3,4-dihydroxyhexanoic acid

To a solution of 2,5-di-O-benzyl-3,4-0-isopropylidene-L-iditol (1.84 g, 4.57 mmol) in CH ₂ C1 ₂ (90 ml) was added TEMPO (36 mg, 0.23 mmol), potassium bromide (104 mg, 0.87 mmol), tetrabutylammonium bromide (163 mg, 0.51 mmol) and saturated aqueous sodium bicarbonate (20 mL). The mixture was cooled to 0 ° C and sodium hypochlorite solution (42 mL, 1.2 M, 50.4 mmol) was added over 1.5 hours. After stirring for 30 minutes at 0 ° C, the organic layer was separated and washed with NaHCO ₃ (aqueous) (3 x 40 mL) and water (3 x 40 mL). EtOH (50 mL) was added to the combined aqueous phases and the solution was stirred for 30 minutes. Then EtOAc (100 mL) and the pH was adjusted from 9 to 2 by adding H ^"- -Dowex. The Dowex was filtered off, the phases were separated and the aqueous phase was extracted with EtOAc (4 x 100 mL), dried and concentrated under reduced pressure without heating to give the title compound (1.40 g, 3.25 mmol, 71%).

^{X 3} C-NMR (CD ₃ OD-acetone-d ₆ 2: 1): δ 27.1 (CH ₃ isoprop), 73.7, 77.4, 78.0, 111.0 (isoprop), 128.8 , 129.1, 129.3 and 138.6 (aromatic C), 172.7 (COOH).

B. Preparation of N1, N6-di [(1S) -2-methyl-1- (methylcarbamoyl) propyl] - (2R, 3S, 4S, 5R) -2,5-di (benzyloxy) -3,4-O- isopropylidene-3,4-dihydroxyhexanediamide

The resulting crude material from Step A (1.40 g, 3.25 mmol) was dissolved in dry CH _and CN (21 mL) under a nitrogen atmosphere and pyridine (1.58 mL, 19.5 mmol) and di-N were added. succinylimidyl carbonate (DSC) (3.30 g, 12.9 mmol). The mixture was stirred at ambient temperature for 15 hours, diluted with EtOAc (50 mL), washed with water (3 x 20 mL) and brine (1 x 30 mL), dried, concentrated and purified by silica gel column chromatography.

The activated diacid from the above (974 mg, 1.64 mmol) was dissolved in a 2: 1 mixture of CH ₂ Cl ₂ : THF (7 mL) under a nitrogen atmosphere and L-valine-methylamide (560 mg, 4.30) was added. mmol). The reaction mixture was stirred at ambient temperature for 18 hours, diluted with CH ₂ Cl ₂ (50 mL) and purified by silica gel column chromatography (CHCH ₃ -MeOH 20: 1) to give 844 mg, 1.29 mmol, 79% .

^{X 3} C-NMR (CDC1 ₃₎ δ 16.7 and 19.7 (valCHJ, 26.2 (washboard NH _3), 27.2 (CH _and isoprop), 28.9 (val CHMeJ, 57.8 (val CHNH ), 73.7, 77.1, 77.0, 110.0 isoprop), 128.2, 128.4, 128.7, 129.0 and 135.7 (aromatic C), 169.8 and 170, 9 (CONH and val CO).

C. Preparation of NI, N6-di [(1S) -2-methyl-1- (methylcarbamoyl) propyl] - (2R, 3S, 4S, 5R) -2,5-di (benzyloxy) -3,4-dihydroxyhexanediamide

The resulting material from Step B (775 mg, 1.18 mmol) was dissolved in CH ₃ CN-H ₂ O (309 mL), and 2,3-dichloro-5,633 was added. 9 9 99 99 999999

999,999 9 9

999 999 99 99 99 Dicyanobenzoquinone (DDQ) (30 mg, 0.13 mmol) and the temperature was maintained at 75 ° C. After 2 days and 4 days, additional portions (2 x 60 mg) of DDQ were added and after 6 days the reaction mixture was concentrated. The residue was dissolved in EtOAc (50 mL), washed with water (2 x 30 mL), filtered through a pad of charcoal, celite and Na ₂ SO ₄ and purified by silica gel column chromatography (CHCH ₃ -MeOH 20: 1) to give to obtain the title compound (501 mg, 0.81 mmol, 69%). [α] 22.9 ° (c 1, g / 100 mL CHCl ₃ ).

¹³ C-NMR (CDCl ₃ ) δ 16.7 and 19.7 (val CHJ, 26.2 (valCH ₃ NH), 28.6 (val CHNH), 57.7 (val CHNH), 69.6, 73 , 7, 77.6, 128.2, 128.9 and 135.9 (aromatic C), 170.8 and 172.3 (CONH and val CO).

Anal. ^Calcd. for ^C 32 ^H 46 ^N 4 O ₈ ^{: c} 62.52; H, 7.54; N, 9.11.

Found: C, 62.41; H, 7.39; N, 8.98.

D. Preparation of N 1, N 6 -di [(1 S) -2-methyl-1- (methylcarbamoyl) propyl] - (2 R, 3 S, 5 R) -2,5-di (benzyloxy) -3-hydroxyhexanediamide

The resulting material from Step C (58 mg, 94 gmol) was dissolved in dry THF (5 mL) under an argon atmosphere and heated to 45 ° C before N, N-thiocarbonyldiimidazole (40 mg, 0.22 mmol) was added. ). The reaction mixture was heated at reflux for 30 h, concentrated and purified by silica gel chromatography (chloroform-methanol 20: 1) to give thiocarbonate (60 mg, 91 μππίί, 97%).

¹³ C-NMR (CDCl ₃ ) δ 17.2 and 19.5 (val CHJ, 26.4 (val CH ₃ NH), 29.7 (val CHMe ₂ ), 58.7 (val CHNH), 75.6 , 78.0, 83.4, 128.3, 128.9 and 135.2 (aromatic C), 167.7 and 170.6 (CONH and val CO), 189.6 (CS).

Suspension of thiocarbonate (60 mg, 91 μπιοί), tributyltin hydride (50 μΐ, 0.19 mmol) and α, α'-azaisobutyronitrile (15 mg, 91 μπιοί) in

dry toluene (4 mL) was added dropwise to refluxing toluene (2 mL) over 20 minutes. Heat the mixture at reflux for 45 minutes, cool and concentrate. The residue was dissolved in acetonitrile (10 mL) and washed with hexane (2 x 5 mL). The acetonitrile layer was concentrated and purified by silica gel chromatography (toluene-acetone 1: 1) to give the title compound (18 mg, 30 gmol, 33%). [α] _D + 6.1 ° (c 0.7 g / 100 mL CHCl ₃ ).

¹³ C-NMR (CDCl ₃ ) δ 17.3, 17.4 and 19.6 (val CHJ, 26.3 (val CH ₃ NH)),

29.5 (val CHMe ₂ ), 34.5, 58.0 and 58.1 (val CHNH), 68.5, 72.7, 73.7,

76.8, 81.1, 127.9, 128.3, 128.5, 128.6, 128.8, 136.2 and 136.5 (aromatic C), 171.1, 171.4, 171, 6 and 172.5 (NHCO a val CO).

Example 3: Preparation of N 1, N 6 -di [(1 S) -2-methyl-1- (methylcarbamoyl) propyl] - (2 R, 3 R, 5 R) -2,5-di (benzyloxy) -3-hydroxyhexanediamide

Example 1 (144 mg, 0.23 mmol) was dissolved in dry THF (8 mL) under argon and heated to 45 ° C before N, N-thiocarbonyldiimidazole (104 mg, 0.58) was added. mmol). The reaction mixture was heated at reflux for 17 h, concentrated and purified by silica gel chromatography (chloroform-methanol 20: 1) to give thiocarbonate (125 mg, 0.19 mmol, 83%).

¹³ C-NMR (CDCl ₃ ) δ 17.4 and 19.4 (val CHJ, 26.3 (val CH ₃ NH), 30.2 (val CHMe ₂ ), 58.4 (val CHNH), 75.8 , 77.7, 82.4, 128.9, 129.1 and 135.3 (aromatic C), 167.0 and 170.6 (CONH and val CO), 190.7 (CS).

Thiocarbonate (125 mg, 0.19 mmol) was suspended in dry toluene (4 mL) under an argon atmosphere and heated at a temperature of 0 ° C. · 9 9 9 9 9 9 9

9,999 9,999,999,999

9 9 9 9 9 .9

A solution of tributylinhydride (153 g, 0.57 mmol) and α, α'-azaisobutyronitrile (47 mg, 0.28 mmol) in dry toluene (3 mL) was added over 10 minutes. The mixture was heated at reflux for 20 hours, cooled and concentrated. The residue was dissolved in acetonitrile (15 mL) and washed with hexane (2 x 10 mL). The acetonitrile layer was concentrated and purified by silica gel chromatography (CHCl ₃ -MeOH 20: 1) to give the title compound (40 mg, 67 mmol, 35%). [α] _d +1.8 ° (c 0.8 g / 100 mL CHCl 3).

¹³ C-NMR (CDCl ₃ ) δ 17.5, 18.0, 19.4 and 19.6 (val CHJ, 26.1 and 26.3 (val CH ₃ NH), 29.5 and 30.6 ( val CHMeJ, 35.5, 58.2 and 58.3 (val CHNH), 70.2, 73.0, 73.3, 77.2, 83.0, 127.9, 128.0, 128.4 , 128.6, 136.7 (aromatic C), 170.5, 171.3, 121.4, 173.1 (CONH and val CO) Anal calcd for C ₃₂ H ₄₆ N ₄ O ₇ : C 64 H, 7.74; N, 9.36 Found: C, 64.00; H, 7.50; N, 9.15.

Example 4: N 1, N 6 -di [(1 S) -2-methyl-1- (methylcarbamoyl) butyl] (2 R, 3 R, 4 R, 5 R) -2,5-di (benzyloxy) -3,4-dihydroxyhexanediamide

A solution of 2,5-di-O-benzyl-L-mannaro-1,4: 6,3-dilactone of Example 1 (50 mg) and N-methyl-L-isoleucine (120 mg) in acetonitrile was heated at 70 ° C for 16 hours. After cooling, the material was purified by silica gel chromatography (CHCl ₃ -MeOH 19: 1) to give the pure compound.

¹³ C-NMR (CD _and OD) δ 11.7, 16.1, 25.1, 26.3, 37.2, 58.5, 72.3, 73.4,

80.8, 128.7, 129.1, 137.7, 172.7, 173.1.

Example 5: N 1, N 6 -di [(1 S) -2-methyl-1- (methylcarbamoyl) -2-phenylethyl] - (2R, 3R, 4R, 5R) -2,5-di (benzyloxy) -3,4 -dihydroxyhexanediamide

2,5-di-O-benzyl-L-mannaro-1,4: 6,3-dilactone of Example 1 (30);

Dissolve mg (0.085 mmol) in dichloromethane (3 mL) and add phenylalanine-N-methylamide (91 mg, 0.51 mmol) to the stirred solution. The solution was heated at reflux (40 ° C) for 18 hours and then concentrated. The crude material was purified by silica gel chromatography (chloroform-methanol 20: 1).

¹³ C-NMR (CD ₃ OD) δ 72.8, 73.7, 81.9, 127.7, 127.8, 128.4, 128.7,

128.8, 129.0, 135.0, 136.4, 170.0, 172.1.

Example 6: N 1, N 6 -di [(1 S) -1- (methylcarbamoyl) -2- (4-hydroxyphenyl) ethyl] - (2 R, 3 R, 4 R, 5 R) -2,5-di (benzyloxy) -3, 4-dihydroxyhexanediamide

The 2,5-di-O-benzyl-L-mannaro-1,4: 6,3-dilactone of Example 1 (40 mg, 0.113 mmol) was dissolved in dichloromethane (4 mL) and tyrosine-N was added to the stirred solution. methyl amide (132.2 mg, 0.667 mmol). The solution was heated at reflux (40 ° C) for 18 hours and then concentrated. The crude material was purified by silica gel chromatography (chloroform-methanol 20: 1).

¹³ C-NMR (CD ₃ OD) δ 26.1, 37.1, 55.3, 72.9, 72.9, 81.1, 116.1,

128.8, 129.2, 130.9, 138.3, 157.2, 172.9, 173.6.

Example 7: N 1, N 6 -di [(1 S) -2-methyl-1- (methylcarbamoyl) propyl] - (2 R, 3 R, 4 R, 5 R) -2,5-di (4-fluorobenzyl) oxy) -3, 4-dihydroxyhexanediamide

A. To a cold (-10 ° C) solution of 4-fluorobenzyl alcohol (0.85 mL, δ 1.168 g / mL, 7.93 mmol, 1 eq.) In CH ₂ Cl ₂ (10 mL) and KOH (50% aq. solution, 10 ml) was added tetrabutylammonium hydrogen sulphate (0.015 g). After stirring for 5 minutes, trichloroacetonitrile (0,

953 mL, c 1.44 g / mL, 9.51 mmol, 1.2 eq) and the reaction mixture is maintained at -5 ° C for 30 minutes before warming to ambient temperature. The organic phase is separated and the aqueous phase is separated.

Extract CH ₂ Cl ₂ (2 x 10 mL). The combined extracts were dried over MgSO ₄ and concentrated to one third. After filtration through celite, the solvent was removed in vacuo to give the dilactone as a brown-yellow oil (1.82 g, 85%).

1 H-NMR (CHCl ₃ , 250 MHz) δ 5.30 (s, 2H), 7.00-7.15 (m, 2H), 7.40 (m, 2H), 8.40 (b, 1H) .

B. Preparation of 2,5-di-O- (4-fluorobenzyl) -L-mannaro-1,4: 6,3-dilactone

To a solution of the dilactone from Step A (0.200 g, 1.12 mmol) in dioxane (40 mL) was added 4-fluorobenzyltrichloroacetimidate (0.72 g, c 1.353 g / mL, 3.37 mmol, 3.0 eq). The reaction vessel was placed under N ₂ (g) and stirred for 10 minutes. TMS-OTf (0.08 mL, c 1.230 g / mL, 0.45 mmol, 0.4 eq) was added portionwise. After 4 hours the mixture was filtered through a pad of SiO ₂ -NaHCO ₃ -SiO ₂ , recrystallized from CHCl ₃ , slurried with Et ₂ O (2 mL), and filtered to yield (0.315 g, 71.8%) .

¹ H-NMR (DMSO-d _e, 250 MHz) δ 4.75, 4.80 (d, J = 7.1 Hz, 4H), 4.90 (d, J = 3.7, 2H), 5 Δ (d, J = 5.8 Hz, 2H), 7.15-7.25 (m, 4H), 7.40-7.55 (m, 4H). ¹³ C-NMR (DMSO-d, 62.9 MHz) δ 71.4, 74.4, 74.7, 115.1, 115.5, 130.2, 130.3, 133.3, 160.0 , 164.0, 171.8.

C. To the benzylated dilactone from step B (0.050 g, 0.128 mmol, 1.0 eq.) In CH ₃ CN (pa, 2 mL) was added L-valine-N-methylamide (0.050 g, 3.84 mmol, 3 mL). , 0 eq). The reaction mixture was heated and stirred at 70 ° C for 24 hours. Concentration gave a brown oil (crude, 0.107 g). Purification by flash chromatography on silica gel (9: 1 CHCl ₃ : MeOH) (12: 1 CHCl ₃ : MeOH + 1% HOAc) and (12: 1 CHCl ₃ : MeOH) afforded 0.006 g of the title compound (7.2%). .

H-NMR (DMSO-d _e, 250 MHz) δ 0.90 to 0.95 (m, 6H), 1.90 - 2.05 (m,

2H), 2.55 (m, 6H), 3.80-3.90 (m, 2H), 3.95-4.05 (d, J = 7.8 Hz, 2H), 4.10-4 20 (m, 2H), 4.40-4.45 (m, 4H), 4.75-4.65 (d, J = 7.47, 2H), 7.10-7.20 (m, 4H), 7.25-7.40 (m, 4H), 7,

- 7.80 (d, J = 8.94 Hz, 2H), 7.85 - 7.90 (d, J = 4.64 Hz, 2H). ^{X 3} C-NMR (DMSO-d _6, 62.9 MHz) δ 18.0, 19.1, 25.3, 57.5, 69.6,

70.26, 79.2, 93.0, 114.7, 115.0, 129.5, 129.6, 134.1, 159.5, 163.4, 170.3, 171.0, 115, 1, 115.5, 130.2, 130.3, 133.3, 160.0, 164.0, 171.8.

Example 8: N 1, N 6 -di [(1 S) -2-methyl-1- (cyclopropylcarbamoyl) propyl] - (2 R, 3 R, 4 R, 5 R) -2,5-di (benzyloxy) -3,4-dihydroxyhexanediamide

In a similar manner to Example 2B, but using L-valine-N-cyclopropylamide (117 mg, 0.27 mmol) gave the corresponding intermediate as an off-white solid (147 mg, 0.25 mmol, 93%).

^{X 3} C-NMR (CDC1 ₃₎ δ 6.1, 6.7 _(CH2 cyclopropyl), 17.4, 19.4 (washboard _3), 22.6 (val CHMeJ, 27.1 _(CH3 isoprop) 30.1 (CHNH-cyclopropyl), 57.8 (NHCH), 74.2 (C3, C4), 76.6 (C2, C5), 78.9 (OCH ₂ Ph), 110.3 (isoprop) 128.4, 128.7, 128.9, 136.5 (arom. C), 169.3 (val C = O), 172.1 (NHC = O).

This intermediate (86 mg, 0.16 mmol) was treated as in Example 2C to give the title compound (52 mg, 0.010 mmol, 65%) as an off-white solid. [α] D - 17 ° (c. 0.86 CHCl ₃ ).

^{X 3} C-NMR (CDC1 ₃₎ δ 5.8, 6.3 _(CH2 -cyclopropyl), 16.8, 19.5 (washboard _3), 22.8 (val _CHMe2), 28.9 (CHNH- cyclopropyl), 58.0 (NHCH), 73.4 (C3, C4), 73.4 (C2, C5), 82.2 (OCH ₂ Ph), 128.6, 128.8, 129.3, 136 2 (arom. C), 171.1 (val C = O), 172.0 (NHC = O).

• · · · ·

Example 9: N 1, 6-di [(1S) -2-methyl-1- (methylcarbamoyl) propyl] (2R, 3R, 4R, 5R) -2,5-di [(2-methylbenzyl) oxy] -3, 4-dihydroxyhexanediamide

A. Dissolve 1,6-di- (dimethyl-tert-butylsilyl) -3,4-O-isopropyl-L-mannitol (1.834 g, 4.07 mmol) in dry tetrahydrofuran (25 mL). The solution was then cooled to 0 ° C and sodium hydroxide (60% aqueous solution, 0.556 g, 13.44 mmol, 3.3 eq) was added. Remove the cooling bath and stir the reaction mixture at room temperature for 15 minutes. 2-Methylbenzyl bromide (120 mL, 8.96 mmol, 2.2 eq) and tetrabutylammonium iodide (0.285 g, 0.77 mmol, 0.19 eq) were added and the reaction mixture was stirred at ambient temperature overnight. The solution was then diluted with diethyl ether (200 mL) and washed three times with water (200 mL). The organic phase was dried and concentrated. The material was purified by flash chromatography on silica gel (toluene) to afford disilyl ether (1.86 g, 70%).

H-NMR (CDC1 _3, 250 MHz) δ 0.10 (s, 12H, 2 x CH ₃ C (CH _{3) 2} -Si), 0.90 (s, 12H, 2 x (CH _{3) 2} -Si), 1.30 (s, 6H, 2 x CH _and C (CH _{3) 2} Si), 1.40 (s, 6H, 2x isoprop., CHJ, 2.30 (s, 6H, 2x Ph- CH ₃ ), 3.63-3.78 (m, 4H, H1, H-6), 3.86-3.94 (dd, 2H, H-2, H-5, J = 7.47, 3) , 20

Hz), 4.17-4.24 (dd, 2H, H-3, H-4, J = 1.72, 1.29 Hz), 4.50 4 _V: 82 (dd, 4H, 2x O- CH ₂ -Ph, J = 52.55, 11.86 Hz), 7.08-7.36 (m, 2x Ph).

¹³ C-NMR (CDCl ₃ , 62.9 MHz): δ 5.47 ((CH ₃ ) ₂ Si), 18.61 (CH ₃ C (CH ₃ ) ₂ -Si), 25.90 (2x CH ₃₎ C (CH ₃ ) ₂ -Si), 27.25 (isoprop.C), 29.72 (2xPh-CH ₃ ), 63.70 (Cl, C-6), 71.38 (C-2, C- 5), 78.29 (2x

O-CH ₂ -Ph), 81.47 (C-3, C-4), 109.49 (isoprop. C), 125.65,

127.42, 128.32, 129.31 (2x Ph).

B. Preparation of 2,5-di-O- (2-methylbenzyl) -3,4-isopropylidene-L-mannitol

The disilyl ether from step A (1.749 g, 2.65 mmol) was dissolved. 9 9 9 9 9 9 9 9 9 9 9 9 9 9 999 999 9 99 99 99 9 · · 9 in dry tetrahydrofuran. Tetrabutylammonium fluoride in THF (6.92 mL, 1.0 M, 2.6 eq) was added. The solution was stirred at ambient temperature for 2.5 hours and concentrated. The material was purified by flash chromatography on silica gel (toluene: ethyl acetate 1: 1) to give the title diol (0.99 g, 88%).

1 H-NMR (CDCl ₃ , 250 MHz) δ (s, 6H, 2x Ph-CH ₃ ), 3.60 (m, 2H, H-2, H-5), 4.19 Hz), 4, 52 - 4.71 (dd, 4H,

7.25 (m, 8H, 2.times.Ph). ¹³ C-NMR (CDCl ₃ , 62.9 MHz): 78.95 (2x O-CH ₂ -Ph), 80.94 129.32 (2x Ph).

1.40 (s, 6H, 2x isoprop., CH _3), 2.35 3.68 (m, 4H, H, H-6), 3.75 to 3.85

4.25 (dd, 2H, H-3, H-4, J = 2.40, 1.35)

Ph-CH ₂ -O, J = 13.49, δ 61.26 (C-2, C-5), (C-3, C-4), 125.92,

11.58 Hz), 7.10

70.68 (C-1, C-6), 127.47, 128.69,

C. Preparation of 2,5-di-O- (2-methylbenzyl) -isopropylidene-L-mannonic acid

To the diol from step B (0.126 g, 0.51 mmol) in dichloromethane (3.6 mL was added 2,2,6,6-tetramethylpiperidin-1-yloxyl, free radical (0.003 g, 0.02 mmol, 0, 03 equiv) and add potassium bromide solution (0.006 g, 0.05 mmol, 0.09 equiv) and tetramethylammonium bromide (0.008 g, 0.03 mmol, 0.05 equiv) and saturated aqueous sodium bicarbonate solution (2 equiv.). , 20 ml).

This solution was cooled to 0 ° C and sodium hypochlorite solution (14%, 4.32 mL, 10.2 mmol, 20 eq.), Saturated aqueous sodium chlorite solution (2.30 mL) and saturated aqueous aq. sodium bicarbonate solution (1.20 mL). After stirring for an additional hour, the organic phase was washed with 3 x 15 ml H ₂ O and the combined aqueous phases were acidified with 1M hydrochloric acid to pH 2. The acidified aqueous phase was then washed three times with ethyl acetate (15 ml), the organic phase was dried and concentrate to give the title diacid. The resulting compound can be used directly in the next step.

D. (i). Preparation of N- (benzyloxycarbonyl) -1'-methyl-L-valinamide

Cbz-valine (2.55 g, 10.17 mmol), methylamine hydrochloride (0.824 g, 12.20 mmol, 1.2 eq) and 1-hydroxybenzotriazole (2.06 g, 15.25 mmol) were dissolved in dichloromethane (125 mL) and triethylamine (5.52 mL, 39.65 mmol, 3.9 eq) was added to adjust the pH to 7.5. The solution was cooled to 0 ° C and added

N, N'-dicyclohexylcarbodiimide (2.94 g, 14.24 mmol, 1.4 eq.) And the solution was stirred for an additional hour in a cooling bath.

The solution was then stirred overnight at ambient temperature. The reaction mixture was filtered, concentrated, and dissolved in ethyl acetate (176 mL). The organic phase was washed with water (125 mL) and sodium bicarbonate (125 mL), dried and concentrated. The material was purified by recrystallization in ethyl acetate-hexane to give the title compound (2.04 g, 75%).

1 H-NMR (CDCl ₃ , 250 MHz) δ 0.90-1.00 (m, 6H, <CH ₃ ) ₂ CH-CH), 1.66 (s, 1H, CH-CH (CH ₃ ) ₂ ) 3.80 (d, 3H, J = 4.82 Hz), 3.88-3.99 (m, 1H, H-3), 5.10 (S, 2H, H-5), 5, 25-5.41 (d, 1H, NH-CO, J = 7.67 MHz), 5.90-6.05 (S, 1H, NH-COO), 7.30-7.42 (m, 5H) , Ph). ¹³ C-NMR (CDC1 _3, 62.9 MHz): δ 19.24 (C), 26.14 (CH-CH _{(CH3) z)}

30.67 (CH-CH (CH ₃ ) ₂ ), 60.67 (C-3), 67.06 (C-5), 128.02, 128.20, 128.54, 136.19 (Ph) 156.45 (C-2), 171.80 (C-4).

D. (ii). Preparation of N-methyl-valinamide

N- (benzyloxycarbonyl) -4'-methyl-L-valinamide from step (i) (2.49 g, 9.42 mmol) was dissolved in ethanol (100 mL) and palladium on carbon (10%, 0.399 g) was added. ). The mixture was then hydrogenated (approx. 230 mL H ₂ ) at ambient temperature overnight. The Pd / C was then filtered through a pad of celite and concentrated.

· 9 $ • 9 «9 · 9« 9 9

The material was purified by flash chromatography on silica gel (dichloromethane-acetone 1: 1) to give N-methyl-valinamide (0.87 g, 71%).

^X H-NMR (CDC1 _3, 250 MHz) 6 .79-.85 (m, 6H, CH-CH _{(CH3) z),} 1.76 (m, 1H, CH-CH (CH ₃₎ _ 2.74 - 2.76 (d, 2H, H1, J = 4.99 Hz), 3.75 - 3.77 (d, 1H, H-3, J = 4.43), 6, 76 (s, 2H, NH 3, 7.26 (s, 1H, n H -CH ₃ )).

¹³ C-NMR (CDCl ₃ , 69.2 MHz) δ 19.68 (Cl), 26.23 (CH-CH (CH ₃ ) ₂ ),

30.77 (CH-CH _{(CH3) 2),} 60.21 (C-3), 166.10 (C-2).

D. (iii). Preparation of N1, N6-di [(1S) -2-methyl-1- (methylcarbamoyl) propyl] - (2R, 3R, 4R, 5R) -3,4-O-isopropylidene-2,5-di [(2- methylbenzyl) oxy] -3,4-dihydroxyhexanediamide

The acid from step C (0.247 g, 0.56 mmol) and the amide from step D (ii) (0.211 g, 1.62 mmol, 2 eq) were dissolved along with 1-hydroxybenztriazole (0.27 g, 2, 00 mmol, 3.6 eq) in dichloromethane (5.8 mL) and tetrahydrofuran (2.9 mL). Triethylamine (0.18 mL, 1.28 mmol, 2.3 eq) was added to adjust the pH to 7.5. The reaction mixture was cooled to 0 ° C and added

1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, hydrochloride salt (0.287 g, 1.50 mmol, 2.7 eq) and the solution was stirred in the cooling bath for 1 hour. The reaction mixture was then stirred for an additional 2 hours at ambient temperature. The reaction mixture was then diluted with dichloromethane (30 mL) and washed with sodium bicarbonate (3 x 30 mL), dried and concentrated. The material was purified by flash chromatography on silica gel (dichloromethane: methanol 3:

1) to give the title diamond (0.291 g).

¹ H-NMR (DMSO-d _e, 250 MHz) δ 0.78 to 0.94 (m, 12H, 2x H-CH _{(CH3) 2),} 1.22 (s, 6H, isoprop.CH ₃₎ , 1.87 to 1.93 (m, 2H, H-4, H-13), 2.24 (s, 6H, 2x _Ph-CH3), 2.56 (d, 6H, Hl, H-16 , J = 4.38 Hz), 4.11 -

·· ·· • 9 9 O

I »9 999

9

99

4.14 (m, 6H, 2x CH-CH _{(CH3) 2),} H-7, (d, 4H, _Ph-CH2 -O, J = 9.92), 6.48 (d, 2H, 2x CH-NH-CO, J = 11.32 Hz) 4.44).

H-8, H-9, 7.05 (m, 8.00 (d,

H-10), 4.46-4.50 8H, Ph), 7.70-7.75 2H, 2x CH -NH, J =

E. Preparation of N1, N6-di [(1S) -2-methyl-1- (methylcarbamoyl) propyl] (2R, 3R, 4R, 5R) -2,5-di [(2-methylbenzyl) oxy] -3, Of 4-dihydroxyhexanediamide

Hydrochloric acid, 45% in methanol (2 mL) was added to the diamine grade D (0.060 g, 0.090 mmol). The reaction mixture was stirred at ambient temperature for 60 minutes and then concentrated. The material was purified by flash chromatography on silica gel (dichloromethane: methanol 9: 1) to give the title diamide (0.042 g, 74%).

@ 1 H-NMR (DMSO-d, 250 MHz) .delta. 0.82 - 0.87 (t, 12H, 2x CH-CH (CH)),

J = 6.06), 1.94-2.02 (m, 2H, CH-CH (CH ₂ )), 2.25 (s, 6H, 2x Ph-CH ₃ ), 2.60 (d, 6H, H1, H-16, J = 4.42 Hz), 3.86-3.88 (m,

2H, H-4, H-13), 4.01-4.04 (d, 2H, H-8, H-9, J = 7.27), 4.18

- 4.19 (m, 2H, H-7, H-10), 4.47 (s, 4H, _Ph-CH2 -O), 7.15 - 7.31 (m, 8H, Ph), 7 70-7.74 (d, 2H, 2 * CH-NH-CO, J = 8.82 Hz), 7.90

7.92 (d, 2H, 2x CH _and -NH, J = 4.49).

¹³ C-NMR (DMSO-d, 69.2 MHz) δ 17.99 (CH-CH (CH)), 19.13 (Ph-CH ₃ ), 25.31 (CH-CH (CH ₃ ) ₂ ) , 30.40 (C, C-16), 57.57 (C-4, C-13), 69.37 _(Ph-CH2 -O), 69.80 (C-7, C-10) 79.29 (C-8, C-9), 125.47, 127.59, 128.30, 129.78, 131.48, 136.42 (Ph), 170.38 (C-3, C- 14), 172.03 (C-6, C-11).

Example 10: N 1, N 6 -di [(1 S, 2 R) -2-hydroxy-2,3-dihydro-ΙΗ-1-indenyl] - (2 R, 3 R, 4 R, 5 R) -2,5-di (benzyloxy) -3,4-dihydroxyhexanediamide

0.915 g (2.2 eq., Mmol) of (1S, 2R) -1-amino-2-indanol were added with (1S, 2R) -1-amino-2-indanol. Suspend in 12 ml CHCl ₃ and heat at 45 ° C. 2,5-di-O-benzyl-L-mannaro-1,4: 6,3-dilactone (1.0 g, 1.0 eq., 2.82 mmol) was added in one portion and the mixture was stirred at 50 ° C for another 4 hours. Then, the reaction mixture was extracted with saturated aqueous NH 4 Cl (2x) and water (2x), dried over MgSO _4, and concentrated.

Recrystallization from methanol gave the title compound as a white solid (0.65 g, 35%).

¹³ C-NMR (CDCl ₃ ) δ 39.2, 57.8, 71.6, 72.5, 73.5, 81.5, 124.0, 125.3, 127.0, 128.2, 128 , 3, 128.6, 136.7, 139.8, 140.8, 171.6. (CH NO) C, H, N. [α] -20.7 (c 0.68, CHCl).

Example 11: N 1 - [(1S, 2R) -2-hydroxy-2,3-dihydro-1H-1-indenyl] -N 6 - [(1S) -2-methyl-1- (methylcarbamoyl) propyl- (2R, 3R, 4R, 5R) -2,5-Di (benzyloxy) -3,4-dihydroxyhexanediamide

208 mg (1.0 eq, 1.41 mmol) of (1S, 2R) -1-amino-2-indanol was suspended in 4 mL of CH ₃ CN and heated at 55 ° C. 2,5-Di-O-benzyl-L-mannaro-1,4: 6,3-dilactone (0.5 g, 1.0 eq., 1.41 mmol) was added in one portion and the mixture was stirred at 50 ° C for an additional 1.5 hours along with 1 mL CH ₃ CN. After 3.5 hours, an additional portion of L-valine-methylamide (184 mg, 1.0 eq., 1.41 mmol) was added. After 22 hours, the reaction mixture was concentrated and purified by flash chromatography on silica gel (CHCl: MeOH 30: 1, CHCl: MeOH 20: 1 and EtOAc: MeOH * 3 3).

10: 1) to afford the title compound (14 mg, 1.6%).

♦ ¹³ C-NMR (CDCl ₃ ) δ 17.2, 19.5, 39.3, 58.0, 58.4, 72.2, 72.4, 72.8, 73.4, 81.4, 81.8, 123.9, 125.4, 127.0, 128.1, 128.2, 128.4,

128.5, 128.7, 128.8, 136.4, 139.6, 140.8, 170.9, 172.0.

Example 12: N 1, N 6 -di [(1 S, 2 R) -2-hydroxy-2,3-dihydro-1 H -1-indenyl] - (2 R, 3 R, 4 R, 5 R) -2,5-di (2- fluorobenzyloxy) -3,4-dihydroxyhexanediamide

· # # # # # # # # # # # # # # # #

A. Preparation of 2-fluorobenzyltrichloroacetimidate

The title compound was prepared according to the procedure for EXAMPLE 7A, using 2-fluoro-benzyl alcohol (2.79 g, 74%).

1 H-NMR (CHCl ₃ , 250 MHz) δ 5.36 (s, 2H, H-4), 7.23-7.49 (m, 6H,

Ph), 8.45 (s, 1H, NH).

¹³ C-NMR (CDCl ₃ , 62.9 MHz) δ 64.65 (C-4), 91.14 (Cl), 115.14, 115.45, 123.97, 128.97, 128.90, 129.97, 130.11 (Ph), 162.18 (C-2).

B. Preparation of 2,5-di-O- (2-fluorobenzyl) -L-mannaro-1,4: 6,3-dilactone

The title compound as a white solid was prepared as in Example 7B using 2-fluorobenzyltrichloroacetimidate (0.303 g, 73%).

1 H-NMR (DMSO-d, 250 MHz) δ 4.83 (d, 4H, 2x Ph-CH, J = 8.00), 4.93 (d, 2H, H-3, H-4, J) = 3.72), 5.31 (d, H-2, H-5, J = 3.78),

7.19 - 7.54 (m, 8H, 2x Ph).

¹³ C-NMR (DMSO-d _e, 62.9 MHz) δ 65.78 (C-3, C-4), 74.22 (C-2, C-5), 74.95 _(2xPh-CH2 ), 115.04, 124.41, 130.25, 130.38, 130.58 (2x Ph), 170.41 (Cl, C-6).

*

C. The title compound was prepared according to the procedure for EXAMPLE 10, starting from

Using 2,5-di-O- (2-fluorobenzyl) -L-mannaro-1,4: 6,3-dilactone (0.056 g, 33%).

¹H-NMR (DMSO-d _e, 250 MHz) δ 2.77 to 3.11 (d + dd, 4H, HI, H-14, J = 4.58, 11.56, 16.07), 3 96 (t, 2H, H-3, H-12, J = 7.28), 4.16 (d, 2H, H-7, H-8, J = 7.96), 4.44 (q , 2H, H-6, H-9, J = 3.83, 4.43), 4.62 (d, 4H, 2x _Ph-CH2, J = 3.40), 4.92 (d, 2H , 2x OH-CH, J = 7.23), 5.08 (d, 2H, CH ₂ OH, J = 4.10), 5.27 (q, 2H, C-23, C-13, J • 9

9 V 9 9 9 9 9 • 9 9 9 9 9 9 * • 9 9 9 9 9 « • • «9 9 9 9 9 9 9 9 9 9 9

9 9 9 ·

= 3.61, 5.53), 7.11 - 7.51 (m, 16H, 4x Ph), 7.82 (d, 2H, NH, J = 8.72).

¹³ C-NMR (DMSO-d _g, 62.9 MHz) δ 54.79 (C, C-14), 56.57 (C-3, C-12), 64.88 _(2xPh-CH2) 69.81 ((C-7, C-8), 72.01 (C-2, C-13), 79.53 (C-6, C-9), 114.80, 115.15, 124, 18, 125.70, 124.91, 126.09, 127.16, 129.55, 129.68, 130.10, 140.55, 141.90, 157.86, 161.76 (4x Ph), 170.64 (C-5, C-10).

Example 13: N 1, N 6 -di [(1 S, 2 R) -2-hydroxy-2,3-dihydro-1 H -1-indenyl] - (2 R, 3 R, 4 R, 5 R) -2,5-di (4- fluorobenzyloxy) -3,4-dihydroxyhexanediamide

A. Preparation of 4-fluorobenzyltrichloroacetimidate

The title compound was prepared according to the procedure for EXAMPLE 7A, using 4-fluoro-benzyl alcohol (3.036 g, 81%).

Δ-NMR (CHCl ₃ , 250 MHz) δ 5.29 (s, 2H, H-4), 7.18-7.43 (m, 6H, Ph), 8.45 (s, 1H, NH).

¹³ C-NMR (CDCl _a, 62.9 MHz) δ 70.02 (C-4), 91.35 (C), 115.32, 115.67, 129.77, 129.90, 131.26 ( Ph), 162.40 (C-2).

B. Preparation of 2,5-di-O- (4-fluorobenzyl) -L-mannaro-1,4: 6,3-dilactone

The title compound as a white solid was prepared as in Example 7B using 4-fluorobenzyltrichloroacetimidate (0.242 g, 54%).

1 H-NMR (DMSO-d. 250 MHz) δ 4.74 (d, 4H, 2x Ph-CH, J = 6.87),

2

4.87 (d, 2H, H-3, H-4, J = 4.00), 5.24 (d, H-2, H-5, J = 4.02), 7.18-7, 47 (m, 8H, 2x Ph).

¹³ C-NMR (DMSO-d _e, 62.9 MHz) δ 71.17 (C-3, C-4), 74.25 (C-2, C-5),

74.68 _(2xPh-CH2), 114.92, 115.27, 130.00, 130.13, 133.07 (2x Ph), 171.54 (C, C-6).

• «♦« «» »» »» »» »» »

C. The title compound was prepared according to the procedure for EXAMPLE 10, using 2,5-di-O- (4-fluoro-benzyl) -L-mannaro-1,4: 6,3-dilactone (0.053 g, 40%).

^ • H-NMR _(DMSO-dg, 250 MHz) δ 2.78 to 3.11 (d + dd, 4H, HI, H-14

J = 4.63, 11.53, 16.08), 3.95 (t, 2H, H-3, H-12, J = 7.64), 4.11 (d, 2H, H-7, H-8, J = 8.04), 4.45 (m, 2H, H-6, H-9), 4.51 (d, 4H, 2x _Ph-CH2, J = 6.02), 4 89 (d, 2H, 2x OH-CH, J = 7.45), 5.10 (d, 2H, CH ₂ OH, J = 4.16), 5.27 (q, 2H, C-23 C-13, J = 3.59, 4.96), 7.09-7.84 (m, 16H, 4x Ph), 8.30 (d, 2H, NH, J = 8.74).

¹³ C-NMR (DMSO-d _g, 62.9 MHz) δ 54.80 (C, C-14), 56.56 (C-3, C-12), 69.72 _(2xPh-CH2) 70.38 ((C-7, C-8), 72.02 (C-2, C-13), 79.36 (C-6, C-9), 114.68, 115.01, 124, 23, 124.71, 126.09, 127.18, 129.62, 129.74, 134.15, 140.56, 141.92, 159.55, 163.40 (4x Ph), 170.81 ( C-5, C-10).

Example 14: N 1, N 6 -di [(1 S) -2-methyl-1- (methylcarbamoyl) propyl] - (2 R, 3 R, 4 R, 5 R) -2,5-di (4-phenylbenzyl) oxy) -3, 4-dihydroxyhexanediamide

A. Preparation of 4-bromobenzyltrichloroacetimidate

The title compound was prepared according to the procedure for EXAMPLE 7A, using 4-bromo-benzyl alcohol (3.2 g, 90%).

H-NMR _(CDCl, 250 MHz) δ 5.3 (s, 2H), 7.3 (d), 8.4 (s).

¹³ C-NMR (CDCl ₃ , 62.9 MHz) δ 69.84, 122.32, 131.65, 134.38, 132.32.

B. Preparation of 2,5-di-O- (4-bromobenzyl) -L-mannaro-1,4: 6,3-dilactone

The title compound was prepared according to the procedure for EXAMPLE 7B using 4-bromo-benzyltrichloroacetimidate (0.739 g, 83%).

• · · · 9 · 9999 ··

9 · ¹H-NMR (DMSO-d _e, 250 MHz) δ 4.7 (d), 4.8 (d), 4.9 (d), 5.3 (d), 7.4 (d ), 7.6 (d).

¹³ C-NMR (DMSO-d _e, 62.9 MHz) δ 71.27, 74.40, 74.92, 130.08,

131.36, 136.44, 171.68.

C. Preparation of N 1, N 6 -di [(1 S) -2-methyl-1- (methylcarbamoyl) propyl] - (2 R, 3 R, 4 R, 5 R) -2,5-di (4-bromobenzyl) oxy) -3, Of 4-dihydroxyhexanediamide

The title compound was prepared according to the procedure for EXAMPLE 10 using 2,5-di-O- (4-bromo-benzyl) -L-mannaro-1,4: 6,3-dilactone (0.0746 g, 66%).

¹³ C-NMR (DMSO-d _g, 62.9 MHz) δ 17.93, 19.81, 26.32, 30.84, 58.93, 72.11, 72.51, 80.72, 122, 67, 130.36, 132.29, 136.80, 172.35, 172.88.

D. Preparation of the title compound

Material from Step C (30 mg, 0.039 mmol), Phenylboronic acid (23.6 mg, 0.194 mmol), Pd (PPh ₃ ) ₄ (2.2 mg, 0.0019 mmol), NaCO ₃ (77.6 μΐ, 2M), EtOH (60 μΐ), H ₂ O (80 μΐ) and dimethoxyethane (240 μΐ) are mixed in a reaction tube fitted with screw plugs in an N ₂ atmosphere. The tube was irradiated with microwave irradiation for 4 minutes at 45 W. The tube was cooled in water before the reaction mixture was concentrated and purified by silica gel chromatography (CHCl ₃ -MeOH 2 O: 1) to give the title compound (28 rtig).

¹³ C-NMR (CDCl _a, 62.9 MHz) δ 17.08, 19.79, 26.18, 29.04, 58.42, 73.28, 73.64, 81.96, 127.20, 127.68, 128.96, 129.01, 135.26, 140.51, 141.71, 170.55, 172.53.

• · ·

Example 15: N 1, N 6 -di [(1 S) -2-methyl-1- (methylcarbamoyl) propyl] - (2 R, 3 R, 4 R, 5 R) -2,5-di [4- (3-thienyl) benzyloxy] -3,4-dihydroxyhexanediamide

Preparation of the title compound. Example 14C material (33 mg, 0.043 mmol), 3-thiopheneboronic acid (23.9 mg, 0.214 mmol), Pd (PPh ₃ ) ₄ (2.5 mg, 0.00214 mmol), NaCO ₃ (85.0 μΐ, 2M), EtOH (65 μΐ), H ₂ O (90 μΐ) and dimethoxyethane (270 μΐ) are mixed in a reaction tube fitted with screw plugs in an N ₂ atmosphere. The tube was irradiated by microwave irradiation for 4 minutes at 45 W. The tube was cooled in water before the reaction mixture was concentrated and purified by silica gel chromatography (CHCl ₃ -MeOH 20: 1) to give the title compound (30 mg).

¹³ C-NMR (CDCl ₃ / MeOH-d ₄ , 62.9 MHz) δ 16.55, 18.42, 24.91, 29.54, 57.64, 70.96, 71.77, 79.38 , 119.70, 125.34, 125.63, 125.76,

128.00, 135.14, 141.08, 171.32, 171.66.

Analysis: Calcd: C 61.61; H, 6.47; N, 7.19. Found: C, 61.2; H, 6.5; N, 7.2.

Example 16: N 1, N 6 -di [(1 S) -2-phenyl-1- (methylcarbamoyl) methyl] - (2 R, 3 R, 4 R, 5 R) -2,5-di (benzyloxy) -3,4-dihydroxyhexanediamide

The 2,5-di-O-benzyl-L-mannaro-1,4: 6,3-di-lactone of Example 1 (150 mg, 0.423 mmol) was dissolved in acetonitrile (1 mL) and phenylglycine was added to the stirred solution. N-methylamide (271 mg, 1.67 mmol). Heat the solution at 65 ° C for 14 hours and then concentrate. The crude material was purified by silica gel chromatography (chloroform: methanol 9: 1).

¹³ C-NMR (CDOD ₃ and CDCl ₃ ) δ 26.3, 26.4, 57.1, 71.8, 73.4, 80.3,

127.4, 128.3, 128.4, 128.5, 128.6, 129.0, 136.5, 137.2, 170.3,

171.3.

Analysis: Calculation: C 66.85; H, 6.20; N, 8.21. Found: C, 66.74; H, 6.34; N, 8.12.

Example 17: N 1, N 6 -di [(1 S) -2-methyl-1- (methylcarbamoyl) propyl] - (2 R, 3 R, 4 R, 5 R) -2,5-di [4- (3-fluorobenzyl) oxy] -3,4-dihydroxyhexanediamide

A. Tetrabutylammonium hydrogen sulphate (30 mg, 0.09 mmol) was added to 3-fluorobenzyl alcohol (1.6 g, 12.4 mmol) in CH ₂ Cl ₂ (15 mL) and KOH (50%, 15 mL). This mixture was cooled to -15 ° C before addition of trichloroacetonitrile (1.5 mL, 14.9 mmol). After 30 minutes at -10 ° C and 2.5 hours at ambient temperature, the phases are separated. The aqueous phase was extracted twice with CH ₂ C1 _2nd The combined organic phases were dried over MgSO ₄ and purified by silica gel column chromatography (toluene) to give 3-fluorobenzyltrichloroacetimidate (3.27 g, 95%) as a clear oil.

¹ H-NMR (CDCl ₃ ) δ 5.3 (s), 7.0-7.15 (m), 7.3-7.45 (m), 8.4 (s).

B. Preparation of 2,5-di-O- (3-fluorobenzyl) -L-mannaro-1,4: 6,3-dilactone

The title compound in a white solid melt was prepared as in Example 7B using 3-fluorobenzyltrichloroacetimidate (0.220 g, 33%).

¹H-NMR (DMSO-d _e, 250 MHz) δ 4.8 (d, 4H, J = 5.8), 4.9 (d, 2H, J = 4.1), 5.25 (d 2H, J = 3.9), 7.15-7.25 (m, 8H), 7.3-7.35 (m, 2H).

¹³ C-NMR (DMSO-d _g, 62.9 MHz) δ 71.08, 74.27, 74.67, 114.45,

123.59, 130.30, 130.53, 139.8, 171.55.

C. Following the procedure of Example 7C, using 2,5-di-O- (3-fluorobenzyl) 51

• * · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

-L-mannaro-1,4: 6,3-dilactone gives N1, N6-di [(1S) -2-methyl-1- (methylcarbamoyl) propyl] - (2R, 3R, 4R, 5R) -2 5-di [4- (3-fluorobenzyl) oxy] -3,4-dihydroxyhexanediamide (0.030 g, 16%) as a white solid.

Example 18: N 1, N 6 -di [(1 S, 2 R) -2-hydroxy-2,3-dihydro-1 H -1-indenyl] - (2 R, 3 R, 4 R, 5 R) -2,5-di (3- fluorobenzyloxy) -3,4-dihydroxyhexanediamide

Following the procedure of Example 10, using 2,5-di-O- (3-fluorobenzyl) -L-mannaro-1,4: 6,3-dilactone from Example 17B (0.03 g, 0.08 mmol) and ( 1S, 2R) -1-amino-2-indanol (0.046 compound (0.04 g, 76%)).

¹³ C-NMR (DMSO-d _e, 62.9 MHz) δ 39.4

113.8, 113.9, 114.2, 114.3, 123.2, 130.0, 130.1, 140.6, 141.0, 141.1,, 0.31 mmol) to give the title compound

56.6, 69.7, 70.2, 72.0, 79.5,

124.2, 124.7, 126.1, 127.2,

141.9, 160.1, 164.0, 170.7.

Example 19: N 1, N 6 -di [(1 S) -2-methyl-1- (methylcarbamoyl) propyl] - (2 R, 3 R, 4 R, 5 R) -2,5-di [4- (2-fluorobenzyl) oxy] -3,4-dihydroxyhexanediamide

Following the procedure of Example 7C, using 2,5-di-O- (2-fluorobenzyl) -L-mannaro-1,4: 6,3-dilactone (Example 12B), the title compound (0.062 g, 38%) was obtained. as a white solid substance.

^{X 3} C-NMR (DMSO-d _e, 62.9 MHz) δ 17.90, 19.11, 25.29, 30.43, 57.49, 64.78, 69.74, 79.38, 114, 82, 115.15, 124.18, 124.59, 129.59,

130.14, 170.14, 170.93.

Example 20: N 1, N 6 -di [(1 S) -2-methyl-1- (methylcarbamoyl) propyl] - (2 R, 3 R, 4 R, 5 R) -2,5-di [4- (2,4-difluorobenzyl) oxy] -3,4-dihydroxyhexanediamide • 9 · · ···

9

999 99 99 99

A. Tetrabutylammonium hydrogen sulphate (15 mg) was added

2,4-difluorobenzyl alcohol (1.0 g, 6.94 mmol) in CH ₂ Cl ₂ KOH (50%, 10 mL). The mixture was cooled to -15 ° C before being stirred

(10 mL) and addition of trichloroacetonitrile (1.2 mL, 8.32 mmol). After 30 minutes at -15 ° C and 3 hours at ambient temperature, the phases are separated. The aqueous phase was extracted twice with CH ₂ C1 _2nd The combined organic phases were dried over MgSO ₄ and reduced to one third. The residue was filtered through celite and concentrated to give crude

2,4-difluorobenzyltrichloroacetimidate (1.83 g, 92%) as a yellow oil.

¹ H-NMR (CDCl 3) δ 5.35 (s), 6.75-6.90 (m), 7.50 (m), 8.50 (s). ^X3 C-NMR (CDCl3, 62.9 MHz) δ 64.1, 91.1, 103.9, 111.1, 118.6,

131.2, 158.9, 161.0, 162.3, 162.9, 165.2.

B. Preparation of 2,5-di-O- (2,4-difluorobenzyl) -L-mannaro-1,4: 6,3-dilactone

The title benzylated dilactone as a white solid (0.97 g, 99%) was prepared according to the procedure of Example 7B, using

2,4-difluorobenzyltrichloroacetimidate.

(t, 4H, J = 2.1, 3.3), 5.20 (d,

7.5-7.65 (m, 2H).

B (0.11 g, 0.28 mmol) a

N-methyl-L-valine (0.22 g, 1.66 mmol) was heated at reflux in dichloromethane (1 mL) overnight. Concentration and purification by silica gel column chromatography gave the title diamide (0.042 g, 23%) as a white solid.

^{X 3} C-NMR (MeOH-d ₄ , 62.9 MHz) δ 18.4, 19.7, 26.2, 31.2, 59.9, 66.8, 72.1, 81.4, 104, 2, 104.6, 104.9, 112.0, 112.4, 121.7, 122.1,

H-NMR (DMSO-d _s, 250MHz) δ 4.75 4H, J = 6.6), 6.9 - 7.1 (m, 4H),

C. benzylated dilactone of step

I · · · ··· ···

133.1, 133.2, 173.3, 173.8.

Example 21: N 1, N 6 -di [(1 S, 2 R) -2-hydroxy-2,3-dihydro-1 H -1-indenyl] - (2 R, 3 R, 4 R, 5 R) -2,5-di (2 4-difluorobenzyloxy) -3,4-dihydroxyhexanediamide

Following the procedure of Example 20C, using (1S, 2R) -1-amino-2-indanol (0.16 g, 1.09 mmol) to give the title compound (0,

048 g, 25%) as a white solid.

1 H-NMR (MeOH-d ₄ , 62.9 MHz) δ 2.90 (2d, 2H), 3.15 (2d, 2H), 4.20 (d, 2H), 4.62 (m, 4H), 4.7 (s, 2H), 5.4 (d, 2H), 6.8-7.0 (m,

4H), 7.2-7.4 (m, 8H), 7.45-7.65 (m, 6H).

Example 22: N 1, N 6 -di [(1 S) -2-methyl-1- (methylcarbamoyl) propyl] - (2 R, 3 R, 4 R, 5 R) -2,5-di [4- (2-pyridyl) benzyloxy] -3,4-dihydroxyhexanediamide

Example 14C material (30 mg, 0.039 mmol), trimethyl-2-pyridyltin (47.0 mg, 0.194 mmol), Pd (PPh ₃ ) ₄ (2.25 mg, 0.0010 mmol), DMF (1 mL) and CuO (3.1 mg, 0.039 mmol) was mixed in a reaction tube equipped with screw plugs under an N ₂ atmosphere. The tube was irradiated with microwave for 2 minutes at 60 W. The mixture was diluted with CH ₂ Cl ₂ (50 mL), washed with brine (3 x 20 mL), concentrated and purified by silica gel chromatography (CH ₂ Cl ₂ -MeOH 15: 1), yielding the title compound (16 mg).

¹³ C-NMR (CDCl ₃ / MeOH-d ₄ , 62.9 MHz) δ 18.6, 20.0, 26.4, 31.9, 60.1,

72.3, 73.2, 81.6, 122.7, 123.9, 128.3, 129.7, 139.1, 140.1,

150.4, 158.7, 173.7, 174.1.

···························

Example 23: N 1, N 6 -di [(1 S) -2-methyl-1- (methylcarbamoyl) propyl] - (2 R, 3 R, 4 R, 5 R) -2,5-di [4- (3-pyridyl) benzyloxy] -3,4-dihydroxyhexanediamide

Following the procedure of Example 22, using trimethyl-3-pyridyltin (47 mg, 0.194 mmol) and purification by silica gel column chromatography (CHCl ₃ -MeOH 9: 1) gave the title compound (15 mg).

^{X 3} C-NMR (CDCl ₃ / _MeOH-d4, 62.9 MHz) δ 18.1, 20.0, 31.1, 59.2, 72.4, 73.0, 81.0, 125.1 , 128.1, 129.7.

Example 24: N 1, N 6 -di [(1 S) -2-methyl-1- (methylcarbamoyl) propyl] - (2 R, 3 R, 4 R, 5 R) -2,5-di [(4- (3-nitrophenyl) benzyl) oxy] -3,4-dihydroxyhexanediamide

Example 14C material (200 mg, 0.259 mmol), 3-thiopheneboronic acid (216.1 mg, 1.294 mmol), Pd (PPh ₃ ) ₄ (15.0 mg, 0.0229 mmol), NaCO ₃ (259 µΐ, 2M), EtOH (773 μΐ), H ₂ O (1288 μΐ) and dimethoxyethane (3091 μΐ) are mixed in a reaction tube fitted with screw plugs under N ₂ atmosphere. Heat the tube at 80 ° C overnight. The mixture was diluted with CH ₂ Cl ₂ (50 mL), washed with brine (3 x 20 mL), concentrated and purified by silica gel column chromatography (CHCl ₃ -MeOH 20: 1) to give the title compound (206 mg).

¹³ C-NMR (DMSO-d _e, 62.9 MHz) δ 18.1, 19.2, 25.4, 30.5, 57.6, 69.8,

70.7, 79.5, 120.9, 122.0, 126.8, 128.4, 130.4, 133.1, 137.0,

138.5, 141.4, 148.4, 170.0, 171.1.

Example 25: N 1, N 6 -di [(1 S) -2-methyl-1- (methylcarbamoyl) propyl] - (2 R, 3 R, 4 R, 5 R) -2,5-di [4- (2-thienyl) benzyloxy] -3,4-dihydroxyhexanediamide

Example 14C material (100 mg, 0.129 mmol), 2-thiopheneboronic acid (82.8 mg, 0.647 mmol), Pd (PPh ₃ ) ₄ (7.49 mg, 0,

0065 mmol), NaCO ₃ (129 μΐ, 2M), EtOH (386 μΐ), H ₂ O (644 μΐ) and dimethoxyethane (1546 μΐ) are mixed in a reaction tube fitted with screw plugs under N ₂ atmosphere. Heat the tube at 80 ° C overnight. The mixture was diluted with CHCl ₃ (50 mL), washed with brine (3 x 20 mL), concentrated, and purified by silica gel column chromatography (CHCl ₃ -MeOH 20: 1) to give the title compound (88.8 mg).

¹³ C-NMR (CDCl ₃ / MeOH-d ₄ , 62.9 MHz) δ 17.0, 18.3, 19.6, 26.0, 29.0,

50.7, 58.3, 72.9, 73.0, 81.4, 123.4, 125.2, 126.2, 128.1, 128.6,

131.9, 134.6, 135.3, 143.5, 170.7, 172.1,

Analysis: Found: C 68.9; H, 6.33; N, 7.36.

Example 26: N 1, N 6 -di [(1 S, 2 R) -2-hydroxy-2,3-dihydro-1 H -1-indenyl] - (2 R, 3 R, 5 R) -2,5-di (benzyloxy) -3 -hydroxyhexanediamide

A. To a stirred solution of the material of Example 10 (400 mg, 620 mmol) in CH ₂ Cl ₂ (3 mL) at 0 ° C under argon was added lutidine (142 µΐ, 1.22 mmol) and t-butyldimethylsilyltriflate (296 mL). μΐ, 1.29 mmol). After 4 hours, 1M NaOH (0.5 mL) was added and the mixture was washed with 1M HCl and brine. The organic layer was dried, concentrated, and purified by silica gel column chromatography (CHCl ₃ -MeOH 80: 1) to give the disilylated compound (313 mg, 355 μΐηοΐ, 57%).

¹³ C-NMR (CDCl ₃ ) δ -4.8, 17.9, 25.7, 40.6, 56.3, 71.1, 74.0, 77.2,

124.5, 124.8, 126.9, 127.9, 128.2, 128.5 136.7, 139.8, 140.9,

176.2.

B. To a solution of the material from step a) (922 mg, 1.05 mmol) in CH ₂ C1 ₂ (21 mL) was added N, N-thiocarbonyldiimidazole (598 mg, 3.36 mmol). The mixture is heated at reflux for 22 hours,

·· ··

9 9 · • 9 9 9 • 999 999 ·

Concentrate and purify by silica gel column chromatography (toluene: EtOAc 3: 1) to give intermediate (887 mg, 0.961 mmol, 92%).

^{X 3} C-NMR (CDC1 ₃₎ δ -4.8, -4.9, 17.8, 25.6, 40.5, 56.9, 74.3, 75.2,

78.2, 82.7, 124.6, 124.8, 126.6, 128.6, 128.8, 129.0, 135.6, 140.0, 141.5, 165.7, 192, 0.

C. To a refluxing solution of the material from step b) in toluene (84 mL) under an argon atmosphere was added tributyltin hydride (0.70 mL, 2.6 mmol) and α, α'-azoisobutyronitrile (284 mg, 1 mL) over 20 min. 73 mmol) in toluene. After 20 hours, additional tributyltin hydride (0.23 mL) and α, α'-azoisobutyronitrile (71 mg) were added. After an additional 4 hours, the mixture was concentrated, dissolved in toluene and washed

2.5 M NaOH and water, dried and concentrated. The residue was purified by silica gel column chromatography (toluene: EtOAc 3: 1) to give 150 mg (0.17 mmol, 20%).

¹³ C-NMR (CDCl ₃ ) δ -4.7, -4.8, 18.0, 25.7, 36.4, 40.5, 40.6, 56.3,

56.4, 69.8, 73.3, 74.0, 74.5, 82.0, 124.5, 124.7, 124.8, 126.9, 127.0, 127.1, 127.7, 127.9, 128.0, 128.2, 128.3, 128.4, 128.5,

136.7, 139.7, 141.2, 141.3, 171.3, 173.4.

D. To a stirred solution of the material from step c) (150 mg, 0.17 mmol) in MeOH (6 mL) was added H + -Dowex. After 3 days at ambient temperature, the mixture was filtered, concentrated, and purified by silica gel column chromatography (CHCl ₃ -MeOH 20: 1), followed by recrystallization from MeOH, to give N1, N6-di [(1S, 2R) - 2-hydroxy-2,3-dihydro-1H-1-indenyl] - (2R, 3R, 5R) -2,5-di (benzyloxy) -3-hydroxyhexanediamide (38 mg, 0.060 mmol, 34%).

¹³ C-NMR (CDCl ₃ -MeOH-d ₆ ) δ 35.9, 39.8, 39.9, 57.2, 57.3, 69.2,

72.5, 72.7, 73.4, 74.0, 77.6, 84.0, 124.1, 124.2, 125.5, 127.2, «· · · · · · · «« * * * * * * * * * » · «·· ··

128.3, 128.4, 128.5, 128.8, 137.1, 140.2, 140.4, 140.6, 140.7,

171.4.

Example 27: N 1 - [(1S, 2R) -2-hydroxy-2,3-dihydro-1H-1-indenyl] -N 6 (2-chloro-6-fluorobenzyl) - (2R, 3R, 4R, 5R) - 2,5-di (2-fluorobenzyloxy) -3,4-dihydroxyhexanediamide

A. Preparation of (1S, 2R) -1-phthalimido-2-indanol on a solid support

The dry Merrfield resin with dihydropyran linker (300 mg, 2.1 mmol / g, 0.65 mmol linker) was swelled in 1,2-dichloroethane (4.2 mL) under argon. Anhydrous PPTS (300 mg, 1.2 mmol) and (1S, 2R) -1-phthalimido-2-indanol (501 mg, 1.8 mmol) were added and the mixture was heated to 75 ° C. After 20 h, the mixture was cooled to ambient temperature and the solid was rinsed with CH ₂ Cl (20 mL), THF (10 mL) and dried in vacuo.

B. Preparation of (1S, 2R) -1-amino-2-indanol on a solid support

Polymer 99 * - 9 · 9 «9» 9 ··· ·· · · ··

Methylamine in ethanol (4.0 mL, 33%) was added to the solid material from the previous step and mixed for 16 hours. The resulting solid was rinsed with CH ₂ Cl ₂ (10 mL), THF (10 mL), MeOH (10 mL), and CHCl ₃ (10 mL) and dried in vacuo.

C. Preparation of N1- (2,5-di-O- (2-fluorobenzyl)) - 1,4-mannolactone-6-amide-N6 - [(1S, 2R) -2-hydroxy-2,3-dihydro-1H- 1-indenyl] on a solid support

The solid material from the previous step was swelled in 1,2-dichloroethane (4.5 mL ·) for 40 minutes under an argon atmosphere. 2,5-Di-O- (2-fluorobenzyl) -L-mannaro-1,4: 6,3-dilactone (Example 12B) (502 mg, 1.29 mmol) was added and the mixture was heated for 16 h at 50 ° C, then allowed to cool and rinsed with CH ₂ C1 ₂ (10 mL) and CHCl _and (10 mL).

D. Preparation of N1 - [(1S, 2R) -2-hydroxy-2,3-dihydro-1H-1-indenyl] -N6 (2-chloro-6-fluorobenzyl) - (2R, 3R, 4R, 5R) - 2,5-di (benzyloxy) -3,4-dihydroxyhexanediamide on a solid support

\\ // • 9 • 9

9 9 9

9 9 9 9

9

999 999

9 9 9

99 99 99

The solid material from the previous step was swelled in CH _and CN (4.5 mL) for 40 minutes under argon. 2-Chloro-6-fluorobenzylamine (249 mg, 1.56 mmol) was added and the mixture was heated at 50 ° C for 16 h, then allowed to cool and rinsed with CH ₂ Cl ₂ (10 mL) and CHCl ₃ ( 10 ml).

E. Preparation of N 1 - [(1S, 2R) -2-hydroxy-2,3-dihydro-1H-1-indenyl] -N 6 (2-chloro-6-fluorobenzyl) - (2R, 3R, 4R, 5R) - 2,5-di (2-fluorobenzyloxy) -3,4-dihydroxyhexanediamide

2.3 M HCl in methanol (8.5 mL) was added to the solid material from the previous step. After 4 h under argon, the solid material was rinsed with CH ₂ Cl ₂ (20 mL) and MeOH (20 mL). The combined organic layers were collected and combined and then diluted with CHCl ₃ (20 mL) and washed with saturated aqueous NaHCO ₃ (2 x 30 mL). The combined aqueous layers were extracted with CHCl ₃ (2 x 40 mL). The combined organic layer was concentrated and purified by silica gel column chromatography (CHCl ₃ -MeOH 40: 1) to give the title compound (68 mg, 23% yield based on packing).

¹³ C-NMR (CDCl ₃ ) δ 34.3, 34.3, 39.2, 57.8, 67.4, 68.2, 71.3, 71.5,

72.4, 72.5, 79.8, 80.9, 114-140, 159.1, 159.2, 159.7, 162.8,

162.9, 163.4, 171.2, 172.1.

• ·

t · · · · »· · · ·

Example 28: N 1 - [(1S, 2R) -2-hydroxy-2,3-dihydro-1H-1-indenyl] -N 6 [(1S) -2-methyl-1 - ([2-pyridylmethyl] carbamoyl) propyl ] - (2R, 3R, 4R, 5R) -2,5-di (benzyloxy) -3,4-dihydroxyhexanediamide

A. Preparation of N 1 - (2,5-di-O-benzyl) -1,4-mannolactone-6-amide-N 6 [t-butylvaline ester] t-butylvaline ester (0.4 g) and material from step 1B in CH ₂ Cl ₂ (50 mL) was kept at 4 ° C for 16 hours. Concentration and purification by silica gel column chromatography (EtOAc-hexane 1: 2) gave the title compound (120 mg).

B. Preparation of NI - [(1S, 2R) -2-Hydroxy-2,3-dihydro-1H-1-indenyl] -N6 [t-butylvaline ester] - (2R, 3R, 4R, 5R) -2,5 di (benzyloxy) -3,4dihydroxyhexandiamidu (1S, 2R) -l-amino-2-indanol was added to a solution of the material from the previous step in CH ₂ C1 ₂ and the reaction continued for 16 hours. Concentration and purification by silica gel column chromatography (EtOAc-hexane 1: 2) gave the title compound (135 mg).

C. Preparation of NI - [(1S, 2R) -2-hydroxy-2,3-dihydro-1H-1-indenyl] -N6 [valinic acid] - (2R, 3R, 4R, 5R) -2,5-di (benzyloxy) -3.4. dihydroxyhexanediamide * The material (120 mg) from the previous step was treated with TFA (5 mL) for 20 minutes. Concentration and drying in vacuo gave the title compound (96 mg).

D. Preparation of the title compound

To the material from the previous step in CH ₂ C1 ₂ was added 1-hydroxybenzotriazole hydrate (14 μΐ), 2-aminomethylpyridine (20 mg) and 1, • ·

3-Dicyclohexylcarbodiimide (35 mg). After one hour, the mixture was directly purified by silica gel column chromatography (EtOAc-MeOH 9: 1) to give the title compound (38 mg).

Example 29:

The groups filling the P1 and P1 'para -brominated analog of the compound of Example 7 were extended according to the above formula. Styrene (12.1 mg, 0.1165 mmol) and a small amount of THF were added to the dried tube under nitrogen in an ice bath. 9-BBN is added by syringe with shaking. The mixture was allowed to warm to ambient temperature and stirred for 4 hours. A brominated intermediate prepared in a manner analogous to that described in Example 7 (30 mg, 0.002 mmol), K ₂ CO ₃ , was added under a nitrogen atmosphere.

• • »· 9 · • • * • • · · • » • · • • ·· * • • · • • • · · ··· ·· * »

(21.45 mg, 0.155 mmol), and Pd (PPh ₃ ) (2.70, 0.002 mmol) in 1 mL DMF and the mixture was heated at 50 ° C overnight. Approximately 50 mL of chloroform was added and the mixture was shaken with 3 x 30 mL of brine, dried and evaporated overnight in vacuo. The material shown above was purified by silica gel column chromatography.

¹³ C-NMR (CDCl ₃ ) δ 172.5, 170.2, 142.4, 141.4, 133.6, 128.9,

128.3, 128.1, 126.0, 82.0, 73.6, 73.3, 58.3, 37.5, 28.7, 25.9, 19.7, 16.8.

Example 30

Tributyl-2-thiazolyltin (72.6 mg, 0.19 mmol), Pd (PPh ₃ ) ₄ (2.25 mg, 0.002 mmol), brominated analog of Example 7 (30 mg, 0.034 mmol), «· 99 ·

Ag ₂ O (9.0 mg, 0.04 mmol) in 1 mL DMF was placed in a test tube and microwave irradiated at 60 W for 2 min. 50 mL of chloroform was added and the mixture was washed with 3 x 20 mL brine. . The organic phase was dried and evaporated to give the title compound.

^{X 3} C-NMR (CDC1 ₃₎ δ 173.3, 172.7, 144.0, 140.4, 133.8, 129.4,

127.5, 120.4, 81.2, 72.8, 72.2, 59.3, 31.1, 26.5, 19.9, 18.1.

Example 31

A mixture of the thickened analog from Example 7 (38.6 mg, 0.05 mmol), methyl acrylate (21.5 mg, 0.25 mmol), diisopropylethylamine (25.8 mg, 0.2 mmol), Pd (OAc) ₂ ( 1.12 mg, 0.05 mmol), (o-tol) ₃ P (3.65 mg, 0.012 mmol) and water (0.15 mL) in DMF (0.85 mL) are degassed under «· · · With a nitrogen stream within 10 minutes. The reaction mixture was stirred and heated at 100 ° C for 48 hours. The reaction mixture was allowed to cool and added to saturated aqueous sodium chloride solution (10 mL). The aqueous layer was extracted with dichloromethane (3 x 10 mL) and the combined organic phases were washed with saturated aqueous sodium chloride solution (3 x 5 mL), dried over MgSO ₄ , filtered, and concentrated under reduced pressure. The residue was purified on a silica gel column to give the above material (27 mg,

69%).

^{X 3} C-NMR (CDCl ₃ ) 5171.7, 171.6, 171.5, 167.7, 14.4, 139.2, 134.3, 131.7, 129.6, 128.4, 118, 0, 80.5, 77.7, 77.2, 76.7, 72.4, 71.8, 51.8, 49.7, 49.4, 49.1, 48.8, 48.5, 29.8, 25.9, 19.4, 17.3.

Example 32

• · «> 9 · 9 ··· ··

By repeating the reaction conditions of Example 31, using 2-ethoxy-3-keto-1-cyclohexanediene, a mixture of compounds was obtained which was separated by 7% MeOH in dichloromethane (preparative plate) to give 66 mg of the crude compound mentioned above.

^a - ³ C-NMR (CDCl ₃ ) δ 171.5, 137.3, 137.0, 128.5, 128.2, 128.0,

127.4, 80.5, 77.5, 77.2, 77.0, 76.5, 72.4, 71.8, 67.9, 58.0,

50.0, 49.7, 49.3, 49.0, 48.7, 48.4, 48.1, 38.7, 30.6, 29.5, 25.6, 22.3, 19, 3, 17.1, 15.1.

Example 33

To a solution of the compound of Example 32 (18 mg, 0.02 mmol) in CH ₂ Cl ₂ was added dropwise 1-N-boron tribromide (0.1 mL) at -78 ° C over 5 minutes. The reaction mixture was stirred at this temperature for 30 minutes and then left in the refrigerator at room temperature for 2 hours

9 ··> 10 · «

999 999

5 ° C. Add the reaction mixture to saturated aqueous NaCl (5 mL), extract with dichloromethane (3 x 5 mL) and wash the combined organic extracts with saturated aqueous NaCl (2 x 5 mL), dry over MgSO ₄ , filter and concentrate under reduced pressure. The residue was purified on a silica gel column to give the crude material of the above formula (9.8 mg, 58%).

¹³ C-NMR (CDCl ₃ ) δ 171.5, 136.5, 128.4, 127.9, 127.6, 80.3, 77.5,

76.5, 72.4, 71.8, 58.0, 49.9, 49.6, 49.3, 48.6, 48.3, 48.0, 35.7,

29.5, 28.6, 25.7, 22.4, 19.3, 17.1.

Biological Example 1

Representative compounds were tested for affecting HIV protease activity in a spectrophotometric enzyme assay using the chromogenic substrate His-Lys-Ala-Arg-Val-Leu-p-nitro-Phe-Glu-Ala-Nle-Ser-amide and purified HIV protease. The rate of cleavage is continuously monitored by recording the change in absorbance at 300 nm. IC represents such a concentration _of compound which inhibits enzyme activity by 50%, as determined from dose response curves. However, the compounds of the present invention are so extremely active that the affinity constants (K i.

The compounds are also tested to affect HIV protease activity in cell culture. MT4 cells cultured in RPMI 1640 cell culture medium containing 10% fetal calf serum are infected with 10 TCID HIV-1 per 2 x 10 ⁵ cells and cultured for 6 days. XTT is added and the amount of XTT-formazan produced in the next 6 hours represents the number of surviving cells. Results are expressed as ED _so, i.e. the concentration of compound of the present invention, in mcg / ml which inhibits viral ··· ··· ·· · • «· replication by 50%.

The antiviral activities of the exemplary compounds of the present invention are shown in Table 1.

Table 1

IC _with μΜ (Κ _± μΜ) ^ed 50 Msr / ^ml Example 1 0.015 0.5 Example 3 0.004 0.5 Example 4 (0,009) 1 Example 7 (0,0023) 5 Example 8 (0,0034) 6 Example 9 (0,0035) 0.4 Example 10 (0,0016) 0.05 Example 11 0,0012 0.2 Example 12 (0,00013) 0.04 Example 13 (0,00007) 0.2 Example 14 (0,00067) 0.04 Example 15 (0,0012) 0.03 Example 16 (0,0023) 1 Example 17 (0,002) 0.8 Example 18 (0,050) 0.5 Example 19 (0,0005) 0.8 Example 20 (0,0001) 0.9 Example 21 (0,00038) 0.1 Example 22 (0,00061) 0.4 Example 23 (0,0019) 2 Example 24 (0,0014) 0.4 Example 25 (0,00017) 0.02 Example 26 (0,00097) 0.8

* ·

Table 1 (continued)

IC _with μΜ (Κ _χ μΜ) ^ED 50 / ml Example 27 (0,0014) 0.8 Example 28 ND 0.2 Example 31 (0,00009) 0.3 Example 32 (0,0003) 0.2 Example 33 (0,0005) 0.2

• r ¹

Claims (20)

1. A compound of formula I: where A and A 'are independently the same or different groups of formula II: R ⁿ Y ^q -m ^{/ R} R (II) wherein R 1 is H, CH ₃ , C (CH ₃ ) ₂ , -OR ^a , -N (R ^a ) ₂ , -N (R ^a ) OR ^and -DP; R 10 is H, CH ₃ ; R ^a is H, C ₁ -C ₃ alkyl; D is a bond, C 1-4 alkylene, -C (= O) -, -S (O) - or -S (O) ₂ -; P is an optionally substituted, mono- or bicyclic carbone or heterocycle; R '' is H, any naturally occurring amino acid side chain, carboxacetamide, or (CH ₂ ) _n DP; M is a bond or -C (= O) N (R '') -; Q is either absent, or is a bond, or is -CH (OH) - or -CH ₂ -; or form R '' together with Q, M and R 'optionally substituted with 5 or A 6-membered carbo- or heterocycle which is optionally fused to another 5- or 6-membered cyclic hydrocarbon or heterocycle; with the proviso that R 1 is -OR ^a , -N (CH ₃ ) ₂ , -N (R ^a ) OR ^and -DP when M is a bond and Q is absent; · · • »· X is H, OH, OCH ₃ ; Y is H, OH, OCH ₃ , but X and Y are not both H; Z 'and Z''are independently - (CH ₂ ) _m P, wherein P is as defined above; n and m are independently 0, 1 or 2; and pharmaceutically acceptable salts and prodrugs thereof. A compound according to claim 1, wherein A 'and / or A' 'are groups of formula IIa: R (IIa) wherein n is 0, 1 or 2; R 1 is methyl or methyloxy; and R '' is hydrogen, methyl, ethyl, isopropyl, cycloalkyl such as cyclopropyl, cyclobutyl or cyclohexyl, cycloalkenyl, benzyl, carboxacetamide or 4-imidazolylmethyl or a side chain occurring in natural amino acids. The compound of claim 2, wherein n is 0aR 'is methyl. A compound according to claim 1, wherein A 'and / or A' 'are groups of formula IIb: R (lib) where R '' is as defined in claim 2; and R 10 is hydrogen or methyl. A compound according to claim 1, wherein A 'and / or A' 'are groups of formula IIc: R '(IIc) where Q is a bond, methylene or -C (OH) -; R 'is an optionally substituted carbo- or heterocycle; and _R 1 _{and R} 1 _are as defined in claim 2. A compound according to any one of claims 3, 4 or 5, wherein R '' is a side chain of leucine, isoleucine, asparagine, histidine or proline, and preferably valine. A compound according to claim 1, wherein A 'and / or A' 'are groups of formula III: (III) where R 11 is H or R ¹ is H, NR ⁴ R is H or CH ₃ ; u κτη4π4 γΊ - C (= O) R ³ , CR ³ R ⁴ or a monocyclic, optionally substituted carbo- or heterocycle; R ² is OH or together with R ¹ = O, or when R ^{1 is} NR ⁴ R ⁴ , then R ^{2 can} be H; R ³ is H, halogen, C ₁ -C ₃ alkyl, OR ⁵ , NR ⁴ R ⁴ ; R ⁴ is H, C ₁ -C ₃ alkyl; R ⁵ is H or a pharmaceutically acceptable ester; R ⁶ is OH, NH ₂ , carbamoyl or carboxyl; R ⁷ is hydrogen, straight or branched C ₁ -C ₄ alkyl, or forms fused phenyl or pyrimidine together with adjacent carbon atoms. A compound according to claim 8, the structure: wherein the group of formula III has or The compound of claim 1, wherein A 'and A' 'are the same. A compound according to claim 1, wherein Z 'and / or Z' 'is benzyl unsubstituted or substituted by one to three substituents selected from the group consisting of halogen, methoxy, hydroxy, amino, cyano, hydroxymethyl, aminomethyl, morpholinethoxy, alkylsulfonyl, carbamoyl, benzyloxy , phenyl (itself substituted as defined herein), or a 5- to 6-membered heterocycle containing one or two heteroatoms such as thiophene, pyrimidine, N-morpholine, N-piperidine, N-piperazine, N'-methyl-N-piperazine, N-pyrrolidone, N-pyrrolidine and the like, which is optionally substituted as defined herein. ··· · · ···· · · · t · t · t · t · «· t · t · t · A compound according to claim 10, wherein Z 'and / or Z' 'is benzyl, 2-fluorobenzyl, 2-methylbenzyl, 2,4-difluorobenzyl, 4-fluorobenzyl, 4-bromobenzyl, 4-phenylbenzyl, 4-thiophenylbenzyl, 4- (4'-nitrophenyl) benzyl), 4-thienylbenzyl, 4-thiazolylbenzyl or 4- (pyridyl) benzyl. The compound of claim 1, wherein Y is H and / or X is OH. The compound of claim 1 having the 2R, 3R, 4R, 5R configuration. A pharmaceutical composition comprising a compound according to any one of the preceding claims and a pharmaceutically acceptable carrier or diluent. A method for inhibiting HIV replication comprising administering an effective amount of a compound of any one of claims 1 to 13 to a subject afflicted with said disease. A process for the preparation of compounds of formula I wherein X, Y, Z 'and Z' 'are the same as defined in claim 1 and A' and A '' are independently a group of formula II or a conventional group filling P-2 / P- 2 'proteases, comprising: i) O-alkylating L-mannaro-1,4: 6,3-di-lactone to form Z 'and Z' 'groups, ii) opening the lactone with the same or different primary or secondary amines to form the respective A' and A ' groups; and iii) optionally correcting C-3 and C-4 to suitable X and Y 'groups. Ί4 · # # # # # # # # # # # # # # A compound of formula IV wherein Z 'and Z ¹ ' are the same as defined in claim 1. A compound according to claim 17 having the following stereochemistry: A compound according to claim 17, wherein Z 'and / or Z ¹ ' are each independently benzyl, 2-fluorobenzyl, 2-methylbenzyl, 2, 4-difluorobenzyl, 4-fluorobenzyl, 4-bromobenzyl, 4-phenylbenzyl, Thiofenylbenzyl 4-4- (4-nitrophenyl ¹⁾ benzyl), 4-thienylbenzyl, 4-thiazolylbenzyl or 4- (pyridyl) benzyl. The compound of claim 17, wherein Z 'and Z' 'are the same.