Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
  • C07D213/79—Acids; Esters
  • C07D213/80—Acids; Esters in position 3
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
  • C07C271/06—Esters of carbamic acids
  • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
  • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
  • C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C327/00—Thiocarboxylic acids
  • C07C327/20—Esters of monothiocarboxylic acids
  • C07C327/28—Esters of monothiocarboxylic acids having sulfur atoms of esterified thiocarboxyl groups bound to carbon atoms of hydrocarbon radicals substituted by singly-bound oxygen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C333/00—Derivatives of thiocarbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
  • C07C333/02—Monothiocarbamic acids; Derivatives thereof
  • C07C333/04—Monothiocarbamic acids; Derivatives thereof having nitrogen atoms of thiocarbamic groups bound to hydrogen atoms or to acyclic carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
  • C07D285/01—Five-membered rings
  • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
  • C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
  • C07D285/06—1,2,3-Thiadiazoles; Hydrogenated 1,2,3-thiadiazoles
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
  • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
  • C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
  • C07D295/21—Radicals derived from sulfur analogues of carbonic acid

Definitions

• the present invention relates to a novel class of compounds which are aspartyl protease inhibitors.
• this invention relates to a novel class of mannitol-derived HIV aspartyl protease inhibitors characterized by specific structural and physicochemical features.
• This invention also relates to pharmaceutical compositions comprising these compounds.
• the compounds and pharmaceutical compositions of this invention are particularly well suited for inhibiting the activity of HIV aspartyl protease. Accordingly, they may be advantageously used as anti-viral agents against HIV viruses, including the HIV-1 and HIV-2 viruses.
• HIV human immunodeficiency virus
• AIDS acquired immunodeficiency syndrome
• ARC AIDS-related complex
• HIV encodes the production of a protease which carries out post-translational cleavage of precursor polypeptides in a process necessary for the formation of infectious virions (S. Crawford et al., "A Deletion Mutation in the 5' Part of the pol Gene of Moloney Murine Leukemia Virus Blocks Proteolytic Processing of the gag and pol Polyproteins", J. Virol.. 53, p. 899 (1985)).
• pol which encodes the virion RNA-dependent DNA polymerase (reverse transcriptase) , an endonuclease, HIV protease, and gag, which encodes the core-proteins of the virion
• H. Toh et al. "Close Structural Resemblance Between Putative Polymerase of a Drosophila Transposable Genetic Element 17.6 and pol gene product of Moloney Murine Leukemia Virus", EMBO J.. 4, p. 1267 (1985); L.H. Pearl et al. , “A Structural Model for the Retroviral Proteases", Nature, pp. 329-351 (1987); M.D. Power et al. , "Nucleotide Sequence of SRV-1, a Type D Simian Acquired Immune Deficiency Syndrome Retrovirus", Science. 231, p. 1567 (1986)).
• a number of synthetic anti-viral agents have been designed to target various stages in the replication cycle of HIV. These agents include compounds which block viral binding to CD4 + T-lymphocytes (for example, soluble CD4) , and compounds which interfere with viral replication by inhibiting viral reverse transcriptase (for example, didanosine and zidovudine (AZT) ) and inhibit integration of viral DNA into cellular DNA (M.S. Hirsh and R.T. D'Aqulia, "Therapy for Human Immunodeficiency Virus Infection", N. Eng. J. Med.. 328, p. 1686 (1993)).
• viruses which are directed primarily to early stages of viral replication, do not prevent the production of infectious virions in chronically infected cells. Furthermore, administration of some of these agents in effective amounts has led to cell-toxicity and unwanted side effects, such as anemia and bone marrow suppression.
• the present invention provides a novel class of compounds, including pharmaceutically acceptable derivatives thereof, that have an affinity for aspartyl proteases, in particular, HIV aspartyl proteases.
• these compounds are useful as inhibitors of such proteases.
• These compounds can be used alone or in combination with other therapeutic or prophylactic agents, such as anti-virals, antibiotics, immunomodul tors or vaccines, for the treatment or prophylaxis of viral infection.
• the compounds of this invention are capable of inhibiting HIV viral replication in human CD 4 + T-cells, by inhibiting the ability of HIV aspartyl proteases to catalyze the hydrolysis of peptide bonds.
• These novel compounds can thus serve to reduce the production of infectious virions from chronically infected cells, and can inhibit the initial or further infection of host cells. Accordingly, these compounds are useful as therapeutic and prophylactic agents to treat or prevent infection by HIV-1 and related viruses, which may result in asymptomatic HIV-1 infection, AIDS-related complex ("ARC") , acquired immunodeficiency syndrome
• AIDS AIDS-related dementia
• immune system AIDS-related dementia
• This novel class of mannitol derivatives is represented by formula I:
• each n is independently selected from the group consisting of 0, l and 2; each A and A' is independently selected from the group consisting of a naturally occurring alpha- amino acid and an unnatural alpha-amino acid (e.g., Ala, Asn, Cys, Gly, Gin, His, lie.
• a naturally occurring alpha- amino acid and an unnatural alpha-amino acid e.g., Ala, Asn, Cys, Gly, Gin, His, lie.
• each A or A' is bonded to G or G' or to the carboxy group of the adjacent residue A or A' , whichever is appropriate, and the carboxy group of A or A' is bonded to the amino group of the adjacent residue A or A' or to the oxygen of the structure, whichever is appropriate;
• each R 3 is independently selected from the group consisting of: 1) hydrogen; 2) C ⁇ C g alkyl or C 2 -C 6 alkenyl, both of which may be optionally substituted with one or more substituents selected from the group consisting of hydroxyl, chlorine and fluorine; and 3) phenyl or naphthyl, both of which may be optionally substituted with one or more substituents
• each R 4 is independently selected from the group consisting of C 1 -C 1 alkyl, C 2 -C 4 alkenyl, halogen (e.g., F, Cl, Br or I), hydroxyl, nitro, C j - ⁇ alkoxy and -CO-N(R 10 ) (R 10 ) ; each R 5 , R 6 and R ?
• R 5 , R 6 and R 7 of a particular G or G' taken individually, or together in any combination, may be optionally joined to form a monocyclic, bicyclic, or tricyclic ring system, each ring of which is C 3 -C 6 cycloalkyl, with the proviso that R 5 , R g or ⁇ j may not be chlorine, fluorine or hydroxyl if it is present on the carbon adjacent to W; each R 8 is independently selected from the group consisting of hydroxyl; hydrogen; chlorine; fluorine; C 1 ⁇ C 3 alkoxy; a 5-7 membered heterocycle; C ⁇ -C 3 alkyl; phenyl; and naphthyl; said C 1 -C 3 alkyl being optionally substituted with one or more substituents selected from the group consisting of chlorine, fluorine, and hydroxyl; and said phenyl and naphthyl being optionally substituted with one or more substituents R 4 ; or R 5 , R 6
• compositions comprising the mannitol derivatives of formula I and methods for their use as inhibitors of aspartyl proteases, including HIV aspartyl proteases.
• Ar refers to either a saturated or an unsaturated moiety.
• the oxygen of the structure refers to the oxygen of a primary hydroxl group of the mannitol backbone of the compounds of this invention.
• heterocycle refers to a stable 5- 7 membered monocycle or 5-7 membered bicyclic heterocycle, which is either saturated or unsaturated, and which may be optionally benzofused if monocyclic.
• Each heterocycle consists of carbon atoms and from one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur.
• nitrogen and sulfur heteroatoms include any oxidized form of nitrogen and sulfur, and the quaternized form of any basic nitrogen.
• the heterocyclic ring may be attached by any heteroatom or carbon atom of the cycle which results in the creation of a stable structure.
• Preferred heterocycles defined above include, but are not limited to, benzimidazolyl, imidazolyl, imidazolinoyl, imidazolidinyl, quinolyl, isoquinolyl, indolyl, pyridyl, pyrrolyl, pyrrolinyl, pyrazolyl, pyrazinyl, quinoxolyl, piperidinyl, morpho- linyl, thiamorpholinyl, furyl, thienyl, triazolyl, thi- azolyl, ⁇ -carbolinyl, tetrazolyl, thiazolidinyl, benzo- fuanoyl, thiamorpholinyl sulfone, benzoxazolyl, oxopiperidinyl, oxopyrroldinyl, oxoazepinyl, azepinyl, isoxazolyl, tetrahydropyranyl
• HIV protease and “HIV aspartyl protease” are used interchangeably and refer to the aspartyl protease encoded by the human immunodeficiency virus type 1 or 2. In a preferred embodiment of this invention, these terms refer to the human immunodeficiency virus type 1 aspartyl protease.
• pharmaceutically effective amount refers to an amount effective in treating HIV infection in a patient.
• prophylactically effective amount refers to an amount effective in preventing HIV infection in a patient.
• patient refers to a mammal, including a human.
• pharmaceutically acceptable carrier or adjuvant and “physiologically acceptable vehicle” refer to a non-toxic carrier or adjuvant that may be administered to a patient, together with a compound of this invention, and which does not destroy the pharmacological activity thereof.
• the compounds of this invention including the compounds of formula I, are defined to include pharmaceutically acceptable derivatives thereof.
• a "pharmaceutically acceptable derivative” means any pharmaceutically acceptable salt, ester, or salt of such ester, of a compound of this invention or any other compound which, upon administration to a recipient, is capable of providing (directly or indirectly) a compound of this invention or an anti-virally active metabolite or residue thereof.
• Salts derived from appropriate bases include alkali metal (e.g., sodium), alkaline earth metal (e.g., magnesium), ammonium and N-(C
• unnatural alpha-amino acids refers to alpha-amino acids which do not occur in nature but which can be derived from naturally occurring alpha- amino acids or other chemical reagents by methods known to those skilled in the art.
• the compounds of this invention contain one or more asymmetric carbon atoms and thus may occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. All such isomeric forms of these compounds are expressly included in the present invention.
• Each stereogenic carbon may be of the R or S configuration.
• stable refers to compounds- which possess stability sufficient to allow manufacture and administration to a mammal by methods known in the art. Typically, such compounds are stable at a temperature of 40°C or less, in the absence of moisture or other chemically reactive conditions, for at least a week.
• Pharmaceutically acceptable salts of the compounds of this invention include those derived from pharmaceutically acceptable inorganic and organic acids and bases.
• acid salts include: ace ⁇ tate, adipate, alginate, aspartate, benzoate, benzene- sulfonate, bisulfate, butyrate, citrate, camphorate, carophorsulfonate, cyclopentanepropionate, digluconate, dodecylhydrogen-sulfate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycollate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2 -hydroxy-ethanesulfonate, lactate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate,
• This invention also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein.
• the basic nitrogen can be quaternized with any agents known to those of ordinary skill in the art including, for example, lower alkyl halides, such as methyl, ethyl, propyl and butyl chloride, bromides and iodides; dialkyl sulfates including dimethyl, diethyl, dibutyl and diamyl sulfates; long chain halides such as decyl, lauryl, yristyl and stearyl chlorides, bromides and iodides; and aralkyl halides including benzyl and phenethyl bromides. Water or oil-soluble or dispersible products may be obtained by such quaternization.
• novel mannitol derivatives of this invention are those of formula I:
• each W is independently selected from the group consisting of -OCO- and -S0 2 ⁇ , with the proviso that W is not -S0 2 - when W is attached to the oxygen of the structure; each R 3 is independently selected from the group consisting of hydrogen; C j -C 8 alkyl; C 2 -C 8 alkenyl; phenyl; and naphthyl; said C j ⁇ -C 8 alkyl and C 2 -
• each R 4 is independently selected from the group consisting of C 1 -C 4 alkyl; C 2 -C 4 alkenyl; halogen; hydroxyl; nitro; C 1 ⁇ C 3 alkoxy; and -CO-N(R 10 ) (R 10 ) ; each R 5 , R g and R 7 is independently selected from the group consisting of hydroxyl; hydrogen; chlorine; fluorine; C 1 ⁇ C 3 alkoxy; a 5-7 membered heterocycle; 1 ⁇ C 3 alkyl; phenyl; and naphthyl; said C ⁇ - C 3 alkyl being optionally substituted with one or more substituents selected from the group consisting of chlorine, fluorine, and hydroxyl; and said phenyl and naphthyl;
• Another embodiment of this invention includes compounds of formula I, as described above, wherein substituents n.
• variables A, A', B, B', D, D 1 , E, E', G, G', n, R 3 -R 12 , m, Ar and W are to be taken as they are defined immediately above.
• each W is independently selected from the group consisting of -OCO- and -S0 2 ⁇ , with the proviso that W is not -S0 2 - when W is attached to the oxygen of the structure;
• each R 3 is selected from the group consisting of hydrogen; ⁇ -C 8 alkyl; C 2 -C 6 alkenyl; phenyl; and naphthyl; said 1 -C 6 alkyl and C 2 -C 6 alkenyl being optionally substituted with one or more substituents selected from the group consisting of hydroxyl, chlorine, and fluorine; and said phenyl and naphthyl being optionally substituted with one or more substituents R 4 ; each R 4 is independently selected from the
• R 5 , R 6 and R 7 of a particular G or G 1 taken individually, or together in any combination, may be optionally joined to form a monocyclic, bicyclic, or tricyclic ring system, each ring of which is C 3 -C 6 cycloalkyl; with the proviso that R 5 , R g , and R 7 may not be chlorine, fluorine, or hydroxyl if it is present on the carbon adjacent to W; each R g is independently selected from the group consisting of hydroxyl; hydrogen; chlorine; fluorine; C 1 -C 3 alkoxy; a 5-7 membered heterocycle; C ⁇ -C 3 alkyl; phenyl; and naphthyl; said C 1 -C 3 alkyl being optionally substituted with one or more substituents selected from the group consisting of chlorine, fluorine and hydroxyl; and said phenyl and naphthyl being optionally substituted with one or more substituents R 4 ; or R 5 , R
• each B and B' is independently selected from the group consisting of oxygen and sulfur
• each D and D' is independently selected from the group consisting of H 2
• each E and E' is independently selected from the group consisting of Ar and N(R l ⁇ R 12 )
• each Ar is selected from the group consisting of phenyl and a 5-7 membered heterocycle; wherein said phenyl and 5-7 membered heterocycle may be optionally substituted with one or more substituents R 4
• each R ⁇ l and R 12 is independently C 1 ⁇ C 6 alkyl.
• R 5 (R g R 7 C) m CO-; R 5 (R g R 7 C) n .W-; and phthaloyl, which may be optionally substituted with one or more substituents R 4 ; wherein m 1-3; each W is independently selected from the group consisting of -OCO- and -S0 2 ⁇ , with the proviso that W is not -S0 2 - when W is attached to the oxygen of the structure; each R 3 is independently selected from the group consisting of C ⁇ -C 6 alkyl; phenyl; and naphthyl; said ⁇ - 1 ⁇ C 6 alkyl being optionally substituted with one or more substituents selected from the group consisting of hydroxyl, chlorine, and fluorine; and said phenyl and naphthyl being optionally substituted with one or more substituents R 4 ; each R 4 is independently selected from the group consisting of C ⁇ -C 4 alkyl; halogen; hydroxyl;
• each B and B 1 is independently selected from the group consisting of oxygen and sulfur
• each D and D' is independently selected from the group consisting of H 2
• each Ar is independently selected from the group consisting of phenyl and a 5-7 membered heterocycle; wherein said phenyl and 5-7 membered heterocycle may be optionally substituted with one or
• a preferred subclass of compounds of this invention are those compounds of formula II:
• each B and B' is independently selected from the group consisting of oxygen and sulfur; each D and D' is independently selected from the group consisting of H 2 ; oxygen and sulfur;- each E and E' is independently selected from the group consisting of Ar and NEt 2 ; and each Ar is selected from the group consisting of phenyl; 3-hydroxyphenyl; 3-pyridyl; 4-(1,2,3- thiadiazol) -yl; and 4-morpholinyl.
• Preferred mannitol derivatives of formula II of this invention are those in which (A) n , (A') n , G and G' are independently CbzVal; and groups B, D and E taken together are selected from the group consisting of: 1) benzoate; 2) 3-hydroxybenzoate; 3) nicotinoate; 4) 4-(l,2,3-thiadiazoate) ; 5) benzyloxy; 6) thiobenzoate; 7) 4-morpholinecarbodithioate; and 8) N,N-diethylcarbodithioate.
• positions l, 1', 2 and 2' is (S) , (S) , (R) and (R) , respectively, and are derived from the starting material, such as from L-mannitol.
• Such preferred compounds include those depicted in Table I. TABLE 1
• B, D, and E taken together may be selected from the group consisting of benzoate; 3-hydroxybenzoate; nicotinoate; 4-(l,2,3-thiadiazoate) ; benzyloxy; thiobenzoate; 4-morpholinecarbodithioate; and N,N- diethylcarbodithioate.
• a and G taken together may form carbobenzyloxyvaline.
• Preferred compounds of this invention are: l,6-Di-0-benzoyl-2,5-di-O-(N-carbobenzyloxyvalyl)- L-mannitol (compound 1) ; l,6-Di- ⁇ -(3-hydroxy)benzoyl-2,5-di-O-(N- carbobenzyloxyvalyl-L-mannitol (compound 2) ; 1,6-Di-0-nicotinoyl-2,5-di-O-(N- carbobenzyloxyvalyl-L-mannitol (compound 3) ;
• the compounds of this invention may be synthesized using conventional techniques.
• these compounds are conveniently synthesized from readily available starting materials.
• the compounds of this invention are among the most readily synthesized HIV protease inhibitors known.
• Previously described HIV protease inhibitors often contain more than six chiral centers, numerous peptide linkages and/or require air-sensitive reagents (such as organo etallic complexes) to effect their syntheses.
• air-sensitive reagents such as organo etallic complexes
• the relative ease with which the compounds of this invention can be synthesized represents an enormous advantage in the large scale production of these compounds.
• mannitol derivatives of formula I and formula II are conveniently obtained from D- or L-mannitol.
• Such enantiomeric or diastereomeric mannitol derivatives may be conveniently prepared from commercially available D-or L-mannitol using known techniques. Although this invention envisions the use of either D- or L-mannitol, or racemic mixtures thereof, as the scaffold upon which to append various functional groups, L-mannitol is preferred.
• D- or L-mannitol may be derivatized according to Scheme I, as depicted below:
• Scheme 1 D- or L-mannitol may be converted to its monoketal using acetone or other ketones known to those skilled in the art (T.W. Greene, Protective Groups in Organic Synthesis. John Wiley and Sons (1991) and references cited therein) .
• the ketal may then be converted to its bis epoxide, first by selective tosylation of the primary hydroxyl groups and then by treatment with potassium carbonate base to effect bis epoxidation with concomitant departure of tosylate.
• An epoxide functionality may then be opened at its least hindered carbon atom with a nucleophile having the general formula E(CD)B, wherein E, D and B are defined as above for the compounds of formula I, giving the monoaddition product (alcohol epoxide) .
• the resulting hydroxyl group may then be esterified in the presence of EDC (l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride) and DMAP (4-dimethylaminopyridine) with an N-protected alpha-amino acid having the general formula G-(A) n -OH, wherein G, A, and n are defined as above for the compounds of formula I, to give an alpha- amino acid-functionalized epoxide.
• EDC l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
• DMAP 4-dimethylaminopyridine
• the remaining epoxide may then be opened with a nucleophile having the general formula E'fCD'JB', wherein E', D' and B* are defined as above for the compounds of formula I, the resulting diol esterified with G'-(A , ) n -OH, wherein G' and A* are defined as above for the compounds of formula I, and the ketal protecting group removed with aqueous acid to give compounds of the general formula I.
• a nucleophile having the general formula E'fCD'JB', wherein E', D' and B* are defined as above for the compounds of formula I
• the resulting diol esterified with G'-(A , ) n -OH wherein G' and A* are defined as above for the compounds of formula I
• the ketal protecting group removed with aqueous acid to give compounds of the general formula I.
• enantiomeric or diastereomeric glycols may be obtained from the oxidation of a suitable olefin-containing precursor with, for example, osmium tetroxide, which may optionally be used in conjunction with another oxidizing agent, such as N-ethylmorpholine N-oxide (see, van Rheenen et al., Tetrahedron Lett.. pp. 1973- 76 (1976) and Evans and Kaldor, J. Pro. Chem.. 55, pp.
• the osmium tetroxide-promoted oxidation may also be carried out in the presence of various chiral ligands to promote asymmetric (i.e., face-selective) oxidation of the olefin (Wai et al., J. Am. Chem. Soc.. Ill, p. 1123 (1989)).
• Another method for constructing the glycol nucleus includes the reductive coupling of two appropriately derivatized aldehydes, which may be the same or different, in a pinacol reaction. This reaction can be carried out using low valent metals, including titanium (J.E. McMurry, Ace. Chem. Res.. 16, pp.
• D- or L-mannitol may be converted to the ketal of formula III (shown below) using acid catalysts known to those skilled in the art and carbonyl compounds of the type ZC(0)Z'; wherein Z and Z' are independently selected from the group consisting of hydrogen, C 1 -C 20 alkyl, C 3 -C 8 cycloalkyl, phenyl, naphthyl, and a 5-7 membered heterocycle; wherein said C j -C ⁇ alkyl, C 3 -c g cycloalkyl, phenyl, naphthyl, and 5-7 membered heterocycle groups may be optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxyl, alkoxyl, phenoxyl, nitro, carboxylate and sulfonate; and wherein Z and Z' may optionally be joined to form a cyclic ketone.
• ketones may be obtained commercially or may be synthesized by known methods.
• Acetone is especially preferred, using sulfuric acid as the reaction catalyst.
• leaving groups are well known in the art and include halides, hydroxide, alkoxides, phenoxides, and sulfonates.
• the esterification may optionally be run in the presence of an organic base, such as triethylamine, diisopropylamine, ethyldiiso- propylamine, pyridine, 4-dimethylaminopyridine, or mixtures thereof.
• Preferred leaving groups include the halides, and chlorine is especially preferred.
• Preferred organic bases include pyridine and 4- dimethylaminopyridine, and especially preferred are mixtures thereof.
• E-C(D) taken together is benzoate.
• E-C(D) is 3-hydroxyben- zoate.
• E-C(D) is nicotinoate.
• E-C(D) is 1,2, 3-thiadiazole-4-carboxylate.
• Suitable leaving groups are well known in the art and include but are not limited to halides, hydroxyl, alkoxides, phenoxides, and sulfonates.
• the esterification may optionally proceed in the presence of a reaction catalyst such as 4- dimethylamionpyridine, 1-(3-dimethylaminopropy1)-3- ethylcarbodiimide hydrochloride (EDC) , dicyclohexyl- carbodiimide (DCC) , diisopropylcarbodiimide (DIC) , and mixtures thereof.
• a reaction catalyst such as 4- dimethylamionpyridine, 1-(3-dimethylaminopropy1)-3- ethylcarbodiimide hydrochloride (EDC) , dicyclohexyl- carbodiimide (DCC) , diisopropylcarbodiimide (DIC) , and mixtures thereof.
• EDC 1-(3-dimethylaminopropy1)-3- ethylcarbodiimide hydrochloride
• DCC dicyclohexyl- carbodiimide
• DIC diisopropylcarbod
• the compound of. formula V may then be treated with water and acid to remove the ketal protecting group and yield mannitol derivatives of formula I.
• Suitable acids used to remove ketal protecting groups are well known to those skilled in the art and include but are not limited to hydrochloric, sulfuric, acetic, p-toluenesulfonic and trifluoroacetic acid. A preferred acid is trifluoroacetic acid.
• compounds of the present invention may be obtained directly from D- or L- mannose.
• L-mannose is the chosen enantiomer.
• Mannose may be reduced to mannitol by the action of a hydride donor.
• Hydride donors are well known to those skilled in the art and include but are not limited to sodium borohydride, sodium cyanoborohydride, lithium aluminium hydride, lithium tri-sec-butylborohydride and potassium tri-sec-butylborohydride.
• the reduction of mannose to mannitol may take place in a common solvent such as water, methanol, ethanol, 1-propanol, 2- propanol, tetrahydrofuran and mixtures thereof.
• the hydride donor is sodium borohydride and the solvent is methanol.
• Mannitol may then be converted to the ketal of formula III by methods described above.
• the ketal of formula III may then be selectively condensed at the primary hydroxyl positions with an electrophile which, after forming a stable covalent bond with oxygen, can itself serve as a leaving group.
• electrophiles are known to those skilled in the art and include but are not limit-e ⁇ to acid halide and acid annydride derivatives of p-toluenesulfonic acid, 4- bromobenzenesulfonic acid, methanesulfonic acid and trifluoromethanesulfonic acid.
• the resulting bis adduct may be treated with base in a common solvent (defined above) to effect intramolecular bis-epoxidation via attack of the remaining hydroxyl groups at the terminal carbons with concomitant departure of the electrophile- oxygen leaving group.
• bases are well known to those skilled in the art and include, but are not limited to metal hydroxides such as sodium hydroxide, potassium hydroxide and lithium hydroxide, metal carbonates such as sodium carbonate, potassium carbonate and lithium carbonate, and metal hydrogen carbonates such as sodium bicarbonate, potassium bicarbonate and lithium bicarbonate.
• the base is potassium carbonate and the common solvent is methanol.
• Bis epoxides of this type are represented below in formula VI:
• the bis epoxide of formula VI may be alkylated at the least hindered carbon atoms with a nucleophile having the formula E-C(D)-BH, wherein E, D and B are defined as above for the compounds of formula I, to give a diol.
• E-C(D)-BH is benzyl alcohol.
• E-C(D)-BH is thiobenzoic acid.
• E-C(D)-BH is 4- morpholinecarbodithioic acid. Diols obtained by this method are represented below in formula VII:
• Suitable leaving groups are well known in the art and include but are not limited to halides, hydroxyl, alkoxides, phenoxides, and sulfonates.
• the esterification may optionally proceed in the presence of a reaction catalyst, such as 4- dimethylamion-pyridine, 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (EDC) , dicyclohexyl- carbodiimide (DCC) , diisopropylcarbodiimide (DIC) , and mixtures thereof.
• a reaction catalyst such as 4- dimethylamion-pyridine, 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (EDC) , dicyclohexyl- carbodiimide (DCC) , diisopropylcarbodiimide (DIC) , and mixtures thereof.
• EDC 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride
• DCC dicyclohexyl- carbodiimide
• DIC diis
• mannitol derivatives of formula I are defined as above for formula V.
• the compound of formula VIII may then be treated in a similar fashion as the compound of formula V, wherein the ketal protecting group is liberated to afford mannitol derivatives of formula I.
• the acid used in conjunction with water is trifluoroacetic acid.
• Mannitol derivatives of the preferred embodiment of the invention were synthesized from 3,4- O-isopropylidine-L-mannitol (IC) , which was derived from L-mannitol (see Schemes 2-3 below) , according to procedures described by L.F. Wiggins, J. Chem. Soc.. p.
• L-mannitol derivatives 1-4 were obtained by selective acylation of both primary hydroxyl groups of compound IC with an either a carboxylie acid halide in the presence of pyridine, or a carboxylie acid in the presence of EDC and DMAP, followed by coupling the resulting diol with carbobenzyloxy-L-valine (CbzVal-OH) in the presence of EDC and DMAP. Subsequent treatment with aqueous trifluoroacetic acid to remove the acetonide protecting group yielded L-mannitol derivatives 1-4 (Scheme 2) .
• L-mannitol derivatives 5-8 were similarly derived from compound IC, which was obtained from the sodium borohydride reduction of L-mannose, followed by tris ketalization with acetone and sulfuric acid, and subsequent removal of the terminal ketals with acetic acid and water (Scheme 3).
• RX SCSN(CH 2 CH 2 ) 2 0. 7
• Acetonide IC was then selectively tosylated at each primary hydroxyl site with p-toluenesulfonyl chloride in pyridine, and then treated with potassium carbonate in methanol to afford bis epoxide 5A (see, L.F. Wiggins, J. Chem. Soc.. p. 13, (1946); Le Merrer et al., Tetrahedron Lett.. 26, 319 (1985) and Le Merrer et al., Heterocvcles. 25, p. 541 (1987)).
• Mannitol derivatives 5 and 6 were obtained by treating bis epoxide 5A with either an alcohol or a thiocarboxylic acid using aluminum oxide as a catalyst (see, Posner et al.. Tetrahedron Lett.. 42, p. 3596 (1975) and Posner et al. , J. Am. Chem. Soc.. 99, pp. 25 and 8208 (1977)), esterifying the resulting diols with CbzVal- OH in the presence of EDC and DMAP, and removing the acetonide protecting group with TFA/water.
• Mannitol derivatives 7 and 8 were obtained by treating bis epoxide 5A with a dithioic acid salt, in the presence dimethyIformamide solvent (for an analogous reaction wherein an N-acylaziridine is ring-opened with mercaptan nucleophiles, see Kempf et al. , European patent application 402646 Al) .
• the dithioic acid salt may be used directly or generated in situ from reaction with an amine base.
• the resulting diols were then esterified with CbzVal-OH in the presence of EDC and DMAP, and the acetonide protecting group was removed with TFA and water.
• the compounds of this invention may be modified by appending appropriate functionalites to enhance selective biological properties.
• modifications are known in the art and include those which increase biological penetration into a given biological system (e.g., blood, lymphatic system, central nervous system) , increase oral availability, increase solubility to allow administration by injection, alter metabolism and alter rate of excretion.
• the novel compounds of the present invention are excellent ligands for aspartyl proteases, particularly HIV-1, HIV-2 and HTLV- 1 proteases. Accordingly, these compounds are capable of targeting and inhibiting late stage events in HIV replication, i.e., the processing of the viral polyproteins by HIV encoded proteases.
• Compounds according to this invention advantageously inhibit the ability of the HIV-i virus to infect immortalized human T cells over a period of days, as determined by an assay of extracellular p24 antigen — a specific marker of viral replication (see. Meek et al.. Nature, 343, pp. 90-92 (1990)).
• the compounds according to this invention may also be used as inhibitory or interruptive agents for other viruses which depend on aspartyl proteases, similar to HIV or
• HTLV aspartyl proteases for obligatory events in their life cycle.
• Such compounds inhibit the proteolytic processing of viral polyprotein precursors by inhibiting aspartyl protease.
• aspartyl protease is essential for the production of mature virions, inhibition of that processing effectively blocks the spread of virus by inhibiting the production and reproduction of infectious virions, particularly from chronically infected cells.
• the compounds of this invention advantageously inhibit enzymatic activity of aspartyl proteases and inhibit the ability of aspartyl proteases to catalyze the hydrolysis of peptide bonds.
• the compounds of this invention may be employed in a conventional manner for the treatment or prevention of HIV, HTLV, and other viruses which depend on aspartyl proteases for obligatory events in their life cycle. Such methods of treatment, their dosage levels and requirements may be selected by those of ordinary skill in the art from available methods and techniques.
• a compound of this invention may be combined with a pharmaceutically acceptable adjuvant for administration to a virally-infected patient in a pharmaceutically acceptable manner and in an amount effective to lessen the severity of the viral infection.
• the compounds of this invention may be used in vaccines and methods for protecting individuals against viral infection over an extended period of time.
• the compounds may be employed in such vaccines either alone or together with other compounds of this invention in a manner consistent with the conventional utilization of protease inhibitors in vaccines.
• a compound of this invention may be combined with pharmaceutically acceptable adjuvants conventionally employed in vaccines and administered in prophylactically effective amounts to protect individuals over an extended period time against viral infections, such as HIV infection.
• the novel protease inhibitors of this invention can be administered as agents for treating or preventing viral infections, including HIV infection, in a mammal.
• the compounds of this invention may be administered to a healthy or HIV-infected patient either as a single agent or in combination with other anti-viral agents which interfere with the replication cycle of HIV.
• the compounds of this invention may be administered with other anti-viral agents which target different events in the viral life cycle, the therapeutic effect of these compounds is potentiated.
• the co-administered anti-viral agent can be one which targets early events in the life cycle of the virus, such as cell entry, reverse transcription and viral DNA integration into cellular DNA.
• Anti-HIV agents targeting such early life cycle events include, didanosine (ddl) , alcitabine (ddC) , d4T, zidovudine (AZT) , polysulfated polysaccharides, sT4 (soluble CD4) — which blocks attachment or adsorption of the virus to host cells — and other compounds which block binding of virus to CD4 receptors on CD4-bearing T- lymphocytes.
• Other retroviral reverse transcriptase inhibitors, such as derivatives of AZT may also be co- administered with the compounds of this invention to provide therapeutic treatment for substantially reducing or eliminating viral infectivity and the symptoms associated therewith.
• anti ⁇ viral agents examples include ganiclovir, dideoxycytidine, trisodium phosphonoformate, eflornithine, ribavirin, acyclovir, alpha interferon and trimenotrexate.
• non-nucleoside inhibitors of reverse transcriptase such as TIBO or nevirapine, may be used to potentiate the effect of the compounds of this invention, as may viral uncoating inhibitors, inhibitors of trans-activating proteins such as tat or rev, or inhibitors of the viral integrase. These compounds may also be co-administered with other inhibitors of HIV aspartyl protease.
• Combination therapies according to this invention exert a synergistic effect in inhibiting HIV replication because each component agent of the combination acts on a different site of HIV replication.
• the use of such combinations also advantageously reduces the dosage of a given conventional anti-retroviral agent which would be required for a desired therapeutic or prophylactic effect as compared to when that agent is administered as a monotherapy.
• These combinations may reduce or eliminate the side effects of conventional single anti- retroviral agent therapies while not interfering with the anti-retroviral activity of those agents.
• These combinations reduce potential of resistance to single agent therapies, while minimizing any associated toxicity.
• These combinations may also increase the efficacy of the conventional agent without increasing the associated toxicity.
• Preferred combination therapies include the administration of a compound of this invention with AZT, ddl, ddC or d4T.
• the compounds of this invention may also be co-administered with other HIV protease inhibitors such as Ro 31-8959 (Roche) , L-735,524 (Merck), XM 323 (Du-Pont Merck) and A-80,987 (Abbott) to increase the effect of therapy or prophylaxis against various viral mutants or members of other HIV quasi species.
• HIV protease inhibitors such as Ro 31-8959 (Roche) , L-735,524 (Merck), XM 323 (Du-Pont Merck) and A-80,987 (Abbott) to increase the effect of therapy or prophylaxis against various viral mutants or members of other HIV quasi species.
• retroviral reverse transcriptase inhibitors such as derivatives of AZT, or other HIV aspartyl protease inhibitors.
• retroviral reverse transcriptase inhibitors such as derivatives of AZT, or other HIV aspartyl protease inhibitors.
• retroviral reverse transcriptase inhibitors such as derivatives of AZT, or other HIV aspartyl protease inhibitors.
• the compounds of this invention can also be administered in combination with immunomodulators (e.g., bropirimine, anti-human alpha interferon antibody, IL-2, GM-CSF, methionine enkephalin, interferon alpha, diethyldithiocarba ate, tumor necrosis factor, naltrexone and rEPO) ; antibiotics (e.g., pentamidine isethiorate) or vaccines to prevent or combat infection and disease associated with HIV infection, such as AIDS and ARC.
• immunomodulators e.g., bropirimine, anti-human alpha interferon antibody, IL-2, GM-CSF, methionine enkephalin, interferon alpha, diethyldithiocarba ate, tumor necrosis factor, naltrexone and rEPO
• antibiotics e.g., pentamidine isethiorate
• vaccines to prevent or combat infection and disease associated with HIV infection, such
• compositions according to this invention may be comprised of a combination of an aspartyl protease inhibitor of this invention and another therapeutic or prophylactic agent.
• the compounds of this invention can also be used as inhibitory agents for other viruses which depend on similar aspartyl proteases for obligatory events in their life cycle. These viruses include, but are not limited to, other AIDS-like d iseases caused by retroviruses, such as simian immunodeficiency viruses, HTLV-I and HTLV-II.
• viruses include, but are not limited to, other AIDS-like d iseases caused by retroviruses, such as simian immunodeficiency viruses, HTLV-I and HTLV-II.
• the compounds of this invention may also be used to inhibit other aspartyl proteases, and in particular, other human aspartyl proteases, including renin and aspartyl proteases that process endothelin precursors.
• compositions of this invention comprise any of the compounds of the present invention, and pharmaceutically acceptable salts thereof, with any pharmaceutically acceptable carrier, adjuvant or vehicle.
• Pharmaceutically acceptable carriers, adjuvants and vehicles that may be used in the pharmaceutical compositions of this invention include, but are nor limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.
• compositions of this invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. We prefer oral administration or administration by injection.
• the pharmaceutical compositions of this invention may contain any conventional non-toxic pharmaceutically-acceptable carriers, adjuvants or vehicles.
• parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.
• the pharmaceutical compositions may be in the form of a sterile injectable preparation, for example, as a sterile injectable aqueous or oleaginous suspension.
• This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents.
• the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally- acceptable diluent or solvent, for example, as a solution in l,3-butanediol.
• suitable vehicles and solvents that may be employed are mannitol, water, Ringer's solution and. isotonic sodium chloride solution.
• sterile, fixed oils are conventionally employed as a solvent or suspending medium.
• any bland fixed oil may be employed, including synthetic mono- or diglycerides.
• Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
• These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as Ph. Helv or a similar alcohol.
• compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, and aqueous suspensions and solutions.
• carriers which are commonly used include lactose and corn starch.
• Lubricating agents such as magnesium stearate, are also typically added.
• useful diluents include lactose and dried corn starch.
• aqueous suspensions are administered orally, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavoring and/or coloring agents may be added.
• compositions of this invention may also be administered in the form of suppositories for rectal administration.
• These compositions can be prepared by mixing a compound of this invention with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the active components.
• suitable non-irritating excipient include, but are not limited to, cocoa butter, beeswax and polyethylene glycols.
• Topical administration of the pharmaceutical compositions of this invention is especially useful when the desired treatment involves areas or organs readily accessible by topical application.
• the pharmaceutical composition should be formulated with a suitable ointment containing the active components suspended or dissolved in a carrier.
• Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petroleum, white petroleum, propylene glycol, polyoxy- ethylene polyoxypropylene compound, emulsifying wax and water.
• the pharmaceutical compositions can be formulated with a suitable lotion or cream containing the active compound suspended or dissolved in a carrier.
• Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol,
• compositions of this invention may also be topically applied to the lower intestinal tract by rectal suppository formulation or in a suitable enema formulation. Topically-transdermal patches are also included in this invention.
• the pharmaceutical compositions of this invention may be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance ioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art. Dosage levels of between about .01 and about
• the pharmaceutical compositions of this invention will be administered from about 1 to about 5 times per day or alternatively, as a continuous infusion. Such administration can be used as a chronic or acute therapy.
• the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the patient treated and the particular mode of administration.
• a typical preparation will contain from about 5% to about 95% active compound (w/w) .
• such preparations contain from about 20% to about 80% active compound.
• a maintenance dose of a compound, composition or combination of this invention may be administered, if necessary. Subsequently, the dosage or frequency of administration, or both, may be reduced, as a function of the symptoms, to a level at which the improved condition is retained. When the symptoms have been alleviated to the desired level, treatment should cease. Patients may, however, require intermittent treatment on a long-term basis, upon any recurrence of disease symptoms.
• the compounds of this invention are also useful as commercial reagents which effectively bind to aspartyl proteases, particularly HIV aspartyl protease.
• the compounds of this invention, and their derivatives may be used to block proteolysis of a target peptide, such as an aspartyl protease, or may be derivatized to bind to a stable resin as a tethered substrate for affinity chromatography applications.
• a target peptide such as an aspartyl protease
• This invention also includes methods for synthesizing aspartyl protease inhibitors.
• One method comprises the steps of:
• step (f) treating said diester with a mixture of water and said acid of step (a) to yield said aspartyl protease inhibitor.
• Another method for synthesizing aspartyl protease inhibitors according to this invention comprises the steps of:
• step (d) treating said diester with a mixture of water and said acid of step (a) to yield said aspartyl protease inhibitor.
• the Al 2 0 3 employed for epoxide ring-opening reactions with heteroatom nucleophiles was preferably Brockman Super I, Woelm 200 neutral (from ICN flow).
• L-mannitol was prepared by the reduction of L-mannose which was purchased from Sigma. Commercial L-amino acid derivatives were employed where relevant.
• Analytical thin layer chromatography (TLC) was carried out with 0.25 mm silica gel E. Merck 60 F 254 plates and eluted with the indicated solvent systems. Preparative chromatography was performed either by flash chromatography, using Silica Gel 60 (EM Science) with the indicated solvent systems and a positive N 2 pressure for elutions, or by thick layer chromatography, again employing E.
• Nuclear magnetic resonance (NMR) spectra were recorded on a Bruker AMX 500 equipped with a reverse or QNP probe. Samples were dissolved in deuteriochloroform or deuteriomethanol for data acquisition, using the respective internal protic solvent frequencies as standards. Chemical shifts (in parts per million) and multiplicities (denoted as s for singlet, d for doublet, dd for doublet of doublets, t for triplet, q for quartet, m for ultiplet, and br for broad) are provided herein, and the number of hydrogens listed for all C 2 -symmetric compounds is half of that present in the molecule.
• Nicotinoyl chloride hydrochloride (324.1 mg, 1.82 mmol) was added in one portion to a -78°C solution of compound IC (202.4 mg, 0.91 mmol) in pyridine (3.6 ml) and CH 2 C1 2 (3.6 ml). The reaction was allowed to stir for 5 hours, while slowly warming to room temperature. The reaction was poured onto CH 2 C1 2 (40 ml) and washed with H 2 0 (three times) and saturated aqueous NaCl, then dried over Na 2 S0 4 and concentrated in vacuo. Flash chromatography using 15% isopropa- nol/CH 2 Cl 2 as eluent gave compound 3A (209 mg) .
• Benzyl alcohol (104 ⁇ l, 1.00 mmol) was added to a slurry of Al 2 0 3 (1.35 g) in Et 2 0 (3 ml), and after stirring for 5 minutes, a solution of the bis-epoxide compound 5A (34.2 mg, 0.18 mmol) in Et 2 0 (2 ml) was added. The reaction proceeded at room temperature for 12 hours, then MeOH (20 ml) was added to the reaction mixture and the solution was allowed to stand for 4 hours.
• Acetonide removal was effected by stirring compound 5C (1.9 mg, 2.19 ⁇ mol) with 90% aqueous trifluoroacetic acid (1.5 ml) at 0°C for 75 minutes, then removing the solvent in vacuo. The resulting residue was purified by thick layer chromatography (0.5 mm) using 17% Et 2 0/CH 2 C1 2 as eluent, which afforded compound 5 (1.6 mg) as a white solid.

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