EP0641306A1 - Carbocyclic and heterocyclic hiv protease inhibitors - Google Patents

Abstract

Compounds of formula (I) wherein R1 and R4 are OH, (CHR5)mCOR6, (CHR5)mCH(OH)R5 or R5; R2 and R3 are H, C1-8alkyl, Het, C3-10cycloalkyl, Het-C1-8alkyl, C2-8alkenyl, Het-C2-8alkenyl, C3-10cycloalkyl-C1-8alkyl or C3-10cycloalkyl-C2-8alkenyl; R5 is R2 or R2 mono- or di-substituted by G; R6 is H, OH, OR', R2, N(R')2, AA or NHC(=NR7)NHR''; R¿7? is H, CN, COR' or SO2R'; R' is H, C1-6alkyl, C3-10cycloalkyl or C1-8alkyl-C3-10cycloalkyl; R'' is R', COR', C(O)OR' or CON(R')2; G is OR', OC(O)R', OC(O)N(R')2, halogen, COR6, NR'-AA, NHCOR', SO2N(R')2, NHSO2N(R')2, NHC(=NR?7¿)NHR'', CF¿3? or N(R')2; AA is one or two amino acids; Z is CH2, CHOH, CHN(R')2, CHNHCOOR, S, SO, SO2, SONH, O, CHCH2OH, CHCO2H, C=O, NR'', N(O)R' or C=NHOR'; Q is CHOH, S, SO or SO2; m is 0, 1 or 2; n is 0 or 1; and pharmaceutically acceptable salts thereof, inhibit the HIV-1 protease and are useful in the treatment of AIDS.

Description

__ITL__

Carbocycl lc and heterocycl lc HIV protease Inhibitors

Field of he Invention

This invention relates to non-peptide inhibitors of proteases encoded in retroviruses, in particular, to inhibitors of the virally encoded protease of the Human Immunodeficiency Virus.

BACKGROUND

Retroviruses, that is, viruses within the family of Retroviridae, are a class of viruses which transport their genetic material as ribonucleic acid rather than deoxyribonucleic acid. Also known as RNA-tumor viruses, their presence has been associated with a wide range of diseases in humans and animals. They are believed to be the causative agents in pathological states associated with infection by Rous sarcoma virus (RSV) , urine leukemia virus (MLV) , mouse mammary tumor virus (MMTV) , feline leukemia virus (FeLV) , bovine leukemia virus (BLV) , ason-Pfizer monkey virus (MPMV) , simian sarcoma virus (SSV) , simian acquired immunodeficiency syndrome (SAIDS) , human T- lymphotropic virus (HTLV-I, -II) and human immunodeficiency virus (HIV-1, HIV-2) , which is the etiologic agent of AIDS (acquired immunodeficiency syndrome) and AIDS related complexes, and many others. Although the pathogens have, in many of these cases, been isolated, no effective method for treating this type of infection has been developed.

Current treatments for viral diseases generally involve administration of compounds which inhibit reverse transcriptase, such as 3'-azido-3'-deoxythymidine and 2^*,3'- dideoxycytidine. These treatments have not proven effective to arrest or reverse the disease, they may have adverse side effects, and they may lose their efficacy over time. Accordingly, new treatments for viral disease are needed. Virally-encoded proteases function in many of these viruses to hydrolyze viral polyprotein precursors and to yield functional viral proteins. The proteolytic activity provided by the virally-encoded protease in processing the polyproteins cannot be provided by the host and is essential to the life cycle of the retrovirus. It has been demonstrated that retroviruses which lack a protease or contain a mutated form of it, lack infectivity. See Katoh et al . _r Virology, 145, 280-92(1985), Crawford, et al . , J. Virol . , 53, 899-907(1985) and Debouck, et al . , Proc Natl . Read. Sci . USA, 84, 8903-6(1987). Inhibiton of retroviral protease, therefore, presents a method of therapy for retroviral disease.

Methods to express retroviral proteases in E. coli have been disclosed by Debouck, et al . , Proc. Natl . Acad. Sci . USA, 8903-06(1987) and Graves, et al . , Proc. Natl . Acad. Sci . USA, 85, 2449-53(1988) for the HIV-1 virus. The crystal structure of an HIV-1 protease has been disclosed by Miller et al . _r Science, 246, 1149 (1989).

The method of isosteric replacement has been disclosed as a strategy for the development of protease inhibitors for HIV-1. Published European Patent applications EP-A 337 714, EP-A 352 000 and EP-A 357 332, EP-A 346847, EP-A 342 541 and EP-A 393 445 are representative. Similar strategies have also been reported for inhibition of renin in U.S. Patents 4,713,445 and 4,661,473. Other inhibitors of the HIV protease, which contain a unique, symmetrical isostere are reported in EP-A 402 646. There remains a need for novel protease-inhibiting compounds which have a favorable balance of potency and pharmacokinetic properties .

SUMMARY OF THE INVENTION

This invention comprises compounds, hereinafter, of the formula (I), which inhibit the retroviral protease of HIV-1, and are useful for treating Acquired Immunodeficiency Syndrome (AIDS) . This invention is also a pharmaceutical composition, which comprises a compound of formula (I) and a pharmaceutically acceptable carrier.

This invention further constitutes a method for treating retroviral disease, which comprises administering to a mammal in need thereof an effective amount of a compound of formula (I) •

DETAILED DESCRIPTION OF THE INVENTION

The compounds of this invention are illustrated by formula (I) :

(i) wherein,

R_l and R₄ are OH, (CHR₅)_mCOR6, (CHR₅)_mCH(OH)R₅ or R₅; R2 and R3 are H, Ci-βalkyl, Het, C3_ιocycloalkyl, Het- Ci-βalkyl, C2-8alkenyl, Het-C₂-8alkenyl, C3-ιocycloalkyl- Ci-βalkyl or C3_ιocycloalkyl-C2-8alkenyl; R5 is R2 or R2 mono- or di-substituted by G;

R₆ is H, OH, OR', R₂, N(R')₂, AA or NHC(=NR⁷)NHR"; R7 is H, CN, COR' or S02R'; R' is H, Cι-6alkyl, C3_ιocycloalkyl or Cι_8alkylC3_ιocycloalkyl; R" is R', COR^«, C(0)OR' or CON(R')₂;

G is OR¹, OC(0)R^?, OC(0)N(R')2, halogen, CORβ, NR'-AA, NHCOR', S0₂N(R^*)2. NHS0₂N(R')2, NHC(=NR⁷)NHR", CF3 or N(R')₂; AA is one or two amino acids;

Z is CH₂, CHOH, CHN(R') , CHNHCOOR, S, SO, SO2, SONH, O, CHCH2OH, CHC0₂H, C=0, NR", N(0)R' or C=NHOR';

Q is CHOH, S, SO or SO2; m is 0, 1 or 2; n is 0 or 1; or pharmaceutically acceptable salts thereof, provided that:

1) Ri - R₄ are not simultaneously chosen from the group of H, OH and Cι-4alkyl, and

2) no more than two of Ri - R₄ are H.

Preferably i and R2 are not simultaneusly H. Preferably Ri and R₄ are not H.

Preferably m is 0. Suitably n is 0 or 1. Preferably n is 1.

Suitably 2 and R3 are C3-ιocycloalkyl-Cι_6alkyl. Preferably R2 and R3 are benzyl.

Suitably Ri and R₄ are OH, CO2R', C2-salkenyl, (CHR5)_mCH(OH)R₅ or R₂ mono- or di-substituted by G. Preferably Ri and R₄ are OH, CH₂OH or (CHR5)_mCH(OH)R₅.

Suitably Ri and R₄ are the same, and R2 and R3 are the same. Preferably i and R₄ are in a trans configuration relative to one another.

Suitably Q is CHOH or SO2. Preferably Q is CHOH. Suitably Z is CH2, CHOH, C=0, S or SO. Preferably Z is C=0 or SO.

One subgeneric group of compounds is given by formula

(II) wherein Ri to R₄ are as defined in formula (I) and Z is S=0 or C=0.

Another subgeneric group of compounds is given by formula (III) : OH

R

^HOΛ 3

R₂- ^FoH ^z

(III) wherein Ri to R₄ are as defined in formula (I) and Z is CHOH,

S=0 or C=0.

Another subgeneric group of compounds is given by formula (IV) :

(IV) wherein Ri to R₄ are as defined in formula (I) and Q is CHOH or SO2.

Certain representative compounds of this invention are: trans,trans,trans-2, 6-dibenzyl-2, 6-bis(methoxycarbonyl) 1,4- cyclohexanediol; trans,trans,trans-2, 6-dibenzyl-2, 6-bis(hydroxymethyl)-1,4- cyclohexanediol; trans,trans,cis-2, 6-dibenzyl-2,6-bis(hydroxymethyl)-1,4- cyclohexane-diol; trans,trans-2, 6-dibenzyl-2, 6-bis(hydroxymethyl)-4-oxo-l- cyclohexanol; 1,2,6-trihydroxy-2, 6-dibenzyl, -cyclohexanone;; trans,trans-2,5-dibenzyl-2,5-bis(hydroxymethyl)-1- cyclopentanol; trans,trans-2-5-dibenzyl-2,5-bis-(hydroxymethyl)- tetrahydrothiophene-1,1-dioxide; 4-hydroxy-trans, trans-3,5-dibenzyl-3,5-bis(hydroxymethyl)- tetrahydrothiopyran;

4-hydroxy-trans,trans-3,5-dibenzyl-3,5-bis(hydroxymethyl)- tetrahydrothiopyran-1-oxide;

3,5-dibenzyl-3-hydroxymethyl-5-(l-hydroxy-4- methylpentyl)tetrahydro-4-hydroxy-thiapyran;

4-hydroxy-3,5-dibenzyl-3-hydroxymethyl-5- (l-hydroxy-4- metbylpentyl) tetrahydrothiopyran-1-oxide;

4-hydroxy-2, 6-dibenzyl-2,6-di(hydroxymethyl)- tetrahydrothiopyran-1,1-dioxide; and 4-OXO-2, 6-dibenzyl-2, 6-di(allyl)-cyclohexanol. Preferred compounds of this invention are 1,2,6-trihydroxy- 2,6-dibenzyl,4-cyclohexanone; 4-hydroxy-3,5-dibenzyl-3,5- bis(hydroxymethyl)-tetrahydrothiopyran-1-oxide; and 4-hydroxy-3,5-dibenzyl-3-hydroxymethyl-5-(l-hydroxy-4- methylpentyl) tetrahydrothiopyran-1-oxide.

Also included in this invention are pharmaceutically acceptable addition salts, complexes or prodrugs of the compounds of this invention. Prodrugs are considered to be any covalently bonded carriers which release the active parent drug according to formula (I) in vivo.

The compounds of this invention have favorable pharmacokinetic properties, and are useful, in particular, for the treatment of infections by the human immunodeficiency virus. The definition of any substituent moiety which may occur more than once in formula (I) is independent of any other occurrence. Formula (I) is intended to encompass all unique nonracemic-stereoisomers which may occur due to the presence of asymmetric carbon atoms in the molecule. Ar, or aryl, as applied herein, means phenyl or naphthyl, or phenyl or naphthyl substituted by one to three Cι-₄alkyl, Cι-₄alkoxy, Cι_₄alkthio, trifluoroalkyl, OH, Cl, Br or I.

Het, or heteroaryl, indicates a five or six membered aromatic ring, or a nine or ten-membered aromatic ring containing one to three heteroatoms chosen from the group of nitrogen, oxygen and sulfur, which are stable and available by conventional chemical synthesis. Illustrative heterocycles are imidazole, benzimidazole, pyrrole, indole, pyridinyl, quinoline, benzofuryl, furyl, benzopyranyl, benzothiophene or thiophene. Any accessible combination of up to three substituents on the phenyl, naphthyl or Het ring which is available by chemical synthesis and is stable are within the scope of this invention. C₃_ιocycloalkyl refers to a carbocyclic system of three to ten carbon atoms, which may be monocyclic or bicyclic and contain up to five unsaturated carbon-carbon bonds, which may be substituted with one or more of halogen, hydroxy, amino, Cι_₄alkyl, Cι_₄alkylcarbonyl, Cι-₄alkoxycarbonyl, Cι_₄alkylaminocarbonyl, Cι-₄alkylthio, Cι-₄alkyloxy or trifluromethyl groups. Typical of C₃_ιocycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, indanyl, indenyl, phenyl and naphthyl.

Boc refers to the t-butyloxycarbonyl radical, Cbz refers to the benzyloxycarbonyl radical, Bzl refers to the benzyl radical, Ac refers to acetyl, Ph refers to phenyl, EDTA is ethylenediamine tetraacetic acid, DIEA is diisopropyl ethylamine, DMF is dimethyl formamide and THF is tetrahydrofuran. C-*__galkyl as applied herein is meant to include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, isopentyl and hexyl, isohexyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, and 1-ethylbutyl. C2-6alkenyl as applied herein means C2-6^1kyl wherein one carbon-carbon single bond is replaced by a carbon-carbon double bond. Ar-C-^-galkyl and Ar-C2-6alkenyl mean C^-galkyl or C2-6^al^^enyl wherein a carbon-hydrogen bond is replaced by a carbon-Ar bond. Het-Ci-galkyl and Het-C2-6alke yl mean Cι_galkyl or

C2-6alkenyl wherein a carbon-hydrogen bond is replaced by a carbon-Het bond. C₃-ιocycloalkylCι-₆alkyl means a Ci-βalkyl wherein a carbon-hydrogen bond is replaced by a carbon- C₃-ιocycloalkyl bond.

AA as used herein indicates one or two amino acids, which may be:

When AA is two amino acids, the amino acids are joined by an amide bond, via the amino terminus of one amino acid and the carboxy terminus of the other, to yield a di- or tri-peptide substituent. When G is CO-AA, the amino acid, dipeptide or tripeptide is coupled via its amino terminus to the CO group, and the carboxy terminus of the amino acid/peptide may be a carboxyl, carboxamide or ester group (eg. CO₂H, C0₂ ' or CONR'₂) . When G is NR'-AA, the amino acid, dipeptide or tripeptide is coupled via its carboxy terminus to the N(R')₂ group, and the amino terminus of the amino acid/peptide may be an alkyl, acyl or Ci-galkyl- or aryl-oxycarbonyl amino group (eg. R', R'CO or R'OCO) .

When compounds of formula (I) are administered to an animal infected or potentially infected with a virus, which is dependent upon a virally encoded protease for processing of viral polyproteins, viral replication is inhibited, hence, disease progression is retarded.

The compounds of this invention are prepared by conventional methods of organic chemistry. Representative methods for preparing the compounds of formula (I) wherein n is 1, Q is CHOH, and Ri and R₄ are CH(OH)Rs, C^R' or CON(R')₂ are illustrated in Schemes 1-3. A suitably Z-protected cyclohexanone is functionalized alternately in the 2-position and the 6-position, by base-catalysed nucleophilic addition of an appropriate electrophile to introduce the carboalkoxy or hydroxyl-containing groups Ri and R₄, such as methyl cyanoformate, methyl formate, an acyl halide, such as 4- methyl pentanoyl chloride, or an aldehyde, such as 4- methylpentanal, and an electrophile to introduce the group R₂ and R3, such as an alkyl or aralkyl halide, such as benzyl bromide . Subsequent reduction and deprotection, and optionally further reduction, provides the desired compounds .

Scheme 1

Z Scheme 2

Z 1S2

NaBH₄ MeOH

a a

Scheme 3

11

12 12.

Cyclopentanol-type compounds, wherein n is 0, are prepared in an analogous manner, starting with cyclopentanone or a suitably protected 3-substituted cyclopentanone derivative. Compounds, wherein Q is CHOH and Ri and R₄ are OH, are prepared by a method analogous to Scheme 4.

Scheme 4

DIBAL

CHg -l;?

14 15

l≤ 11

lδ 13.

Compounds wherein Q is S, SO or SO₂ are prepared via a procedure based upon Scheme 5 .

Scheme 5

MCPBA

1.LAH ²- HCOOH

p-TSA = p-toluenesulfonic acid MCPBA = m-chloroperbenzoic acid

The oxidation state of the sulfur moiety is readily controlled by oxidation methods well known in the art. For instance, sulfoxides may be prepared from oxidation of the corresponding sulfide by one equivalent of sodium metaperiodate, while 2 equivalents of m-chloroperbenzoic acid or periodate may be used to prepare the corresponding sulfone. The product of Scheme 5 yields a compound wherein Z is C=0. Reduction of the product of this sequence yields the corresponding compound wherein Z is OH. Starting the reaction sequence with sulfolane yields the corresponding cyclopentyl product wherein Z is CH₂.

Compounds wherein Z is S, SO or SO₂ are prepared by a method based upon Scheme 6. Scheme 6

NalO₄

The oxidation state of the sulfur is controlled via conventional methods for selective oxidation of the sulfur moiety .

Compounds of formula 1 wherein Z is CH₂OH may be prepared by a method based upon Scheme 7 .

Scheme 7

The Ramberg Bakelund rearrangement is performed as generally disclosed by Hartman et al., Synthesis , 504 (1982) and Paquette et al., .T. Am. Cham-Sot... 93, 4516 (1971), proceeding via the α-halo sulfone and a base-catalyzed ring contraction to yield the corresponding 2,2,4,4-substituted 3- methoxycarbonyl-cyclopent-3-enol. Reduction of the methoxycarbonyl groups with lithium aluminum hydride followed by hydrogenation of the olefin with hydrogen over a palladium catalyst yields the 3-hydroxymethyl substituent. Compounds wherein Z is C=NHOH may be prepared from the corresponding ketone precursor (eg. compound 12., _L2.) by reaction with hydroxylamine under dehydrating conditions. Compounds wherein Z is CHCH2OH are also prepared by reacting the appropriate ketone (eg. compound 12 or 19) with methylenetriphenylphosphorane to yield the exo-olefin, followed by hydroboration to yield the alcohol. Compounds wherein Z is CHCO2H may be prepared by oxidation of the hydoxymethylene group introduced in this manner.

Suitable protective groups for functional groups and intermediates are disclosed in Greene, Protective Groups in Organic Chemistry, John Wiley and Sons, New York, 1981.

If the final compound, after it has been deprotected, contains a basic group, an acid addition salt may be prepared. Acid addition salts of the compounds are prepared in a standard manner in a suitable solvent from the parent compound and an excess of an acid, such as hydrochloric, hydrobromic, sulfuric, phosphoric, acetic, maleic, succinic or methanesulfonic. The acetate salt form is especially useful. If the final compound contains an acidic group, cationic salts may be prepared. Typically the parent compound is treated with an excess of an alkaline reagent, such as a hydroxide, carbonate or alkoxide, containing the appropriate cation. Cations such as Na⁺, K⁺, Ca⁺⁺ and NH ⁺ are examples of cations present in pharmaceutically acceptable salts. Certain of the compounds form inner salts or zwitterions which may also be acceptable.

The compounds of formula (I) are used to inhibit the endogenous protease enzyme of viruses, especially retroviruses. In particular, these compounds have been shown to inhibit the endogenous protease of the human immunodeficiency virus. These compounds further have an anti-viral effect and reduce viral infectivity in cell culture. As such they are believed to induce anti-viral activity in patients which are infected with susceptible viruses and require such treatment. The method of treatment comprises the administration orally, parenterally, buccally, trans-dermally, intra-vaginally, rectally or by insufflation, of an effective quantity of the chosen compound, preferably dispersed in a pharmaceutical carrier. Dosage units of the active ingredient are generally selected from the range of 0.1 to 25 mg/kg, but will be readily determined by one skilled in the art depending upon the route of administration, age and condition of the patient. These dosage units may be administered one to ten times daily for acute or chronic infection. The compounds of this invention are particularly useful for the treatment of HIV-1. The compounds of formula (I) are useful in the manufacture of a medicament, particularly a medicament for the treatment of retroviral infections, such as infection by the human immunodeficiency virus. Pharmaceutical compositions of the compounds of this invention, or derivatives thereof, may be formulated as solutions or lyophilized powders for parenteral administration. Powders may be reconstituted by addition of a suitable diluent or other pharmaceutically acceptable carrier prior to use. The liquid formulation is generally a buffered, isotonic, aqueous solution. Examples of suitable diluents are normal isotonic saline solution, standard 5% dextrose in water or buffered sodium or ammonium acetate solution. Such formulation is especially suitable for parenteral administration, but may also be used for oral administration or contained in a metered dose inhaler or nebulizer for insufflation. It may be desirable to add excipients such as polyvinylpyrrolidone, gelatin, hydroxy cellulose, acacia, polyethylene glycol, mannitol, sodium chloride or sodium citrate. A composition for parenteral administration may additionally be comprised of a quantity of the compound encapsulated in a liposomal carrier. The liposome may be formed by dispersion of the compounds in an aqueous phase with phospholipids, with or without cholesterol, using a variety of techniques, including conventional handshaking, high pressure extrusion, reverse phase evaporation and microfluidization. Such a carrier may be optionally directed toward its site of action by an immunoglobulin or protein reactive with the viral particle or infected cells. The choice of such proteins would of course be dependent upon the antigenic determinants of the infecting virus. An example of such a protein is the CD-4 T-cell glycoprotein, or a derivative thereof, such as sCD-4 (soluble CD-4) , which is reactive with the glycoprotein coat of the human immunodeficiency virus (HIV) .

Alternately, these compounds may be encapsulated, tableted or prepared in an emulsion or syrup for oral administration. Pharmaceutically acceptable solid or liquid carriers may be added to enhance or stabilize the composition, or to facilitate preparation of the composition. Liquid carriers include syrup, peanut oil, olive oil, glycerin, saline and water. Solid carriers include starch, lactose, calcium sulfate dihydrate, terra alba, magnesium stearate or stearic acid, talc, pectin, acacia, agar or gelatin. The carrier may also include a sustained release material such as glyceryl monostearate or glyceryl distearate, alone or with a wax. The amount of solid carrier varies but, preferably, will be between about 20 mg to about 1 g per dosage unit. The pharmaceutical preparations are made following the conventional techniques of pharmacy involving milling, mixing, granulating, and compressing, when necessary, for tablet forms; or milling, mixing and filling for hard gelatin capsule forms. When a liquid carrier is used, the preparation will be in the form of a syrup, elixir, emulsion or an aqueous or non-aqueous suspension. Such a liquid formulation may be administered directly p.o. or filled into a soft gelatin capsule. For intra-vaginal or rectal administration, a pulverized powder of the compounds of this invention may be combined with excipients such as cocoa butter, glycerin, gelatin or polyethylene glycols and molded into a suppository. The pulverized powders may also be compounded with an oily preparation, gel, cream or emulsion, buffered or unbuffered, and administered through a transdermal patch. These and other pharmaceutically acceptable formulations are found in Remington's Pharmaceutical Sciences_r 18th Edition, Alfonso R. Gennaro (ed.). Mack Publishing Company, Easton, Pennsylvania (1990) .

Beneficial effects may be realized by co-administering, individually or in combination, other anti-viral agents with the protease inhibiting compounds of this invention. Examples of anti-viral agents include nucleoside analogues, phosphonoformate, rifabutin, ribaviran, phosphonothioate oligodeoxynucleotides, castanospermine, dextran sulfate, alpha interferon and ampligen. Nucleoside analogues, which include 2 ' ,3 '-dideoxycytidine (ddC) , 2 ' ,3'-dideoxyadenine (ddA) and 3'-azido-2 ' ,3'-dideoxythymide (AZT) , are especially usef l. AZT is one preferred agent . Suitably pharmaceutical compositions comprise an anti-viral agent, a protease inhibiting compound of this invention and a pharmaceutically acceptable carrier. The protease inhibiting properties of the compounds of this invention, are demonstrated by their ability to inhibit the hydrolysis of a peptide substrate by rHIV protease in the range of about 1 μM to about 2 mM.

The Examples which follow serve to illustrate this invention. The Examples are intended to in no way limit the scope of this invention, but are provided to show how to make and use the compounds of this invention.

Inhibition of HIV protease activity The ability of the compounds of this invention to inhibit the HIV-1 protease enzyme may be demonstrated by using the assay disclosed by Dreyer et al . , Proc. Natl . Acad. Sci . , U. S.A. , 86, 9752 (1989), Grant et al . , Biochemistry, 30 8441 (1992), and EP-A 352 000. Preferred compounds have Ki's of less than 25 μM.

Tnh-ih-i ion of Viral Infectivitv The ability of the compounds of this invention to gain entry to cells infected with the human immunodeficiency virus, and to inhibit viral replication in vitro may be demonstrated using the assay described by Meek et al . , Nature, 343, 90 (1990), and Petteway et al . , Trends Pharmacol . Sci, 12, 28 (1991) . The compound of Example 6 showed an IC50 for inhibition of viral infectivity in the above assay of less than 100 μM.

The Examples which follow serve to further illustrate this invention. The Examples are intended to in no way limit the scope of this invention, but are representative and are provided to show how to make and use the compounds of this invention.

In the Examples, all temperatures are in degrees Centigrade. FAB indicates fast atom bombardment mass spectrometr . FAB mass spectra were performed upon a VG Zab mass spectrometer using fast atom bombardment. ESMS indicates electrospray ionization mass spectrometry. NMR were recorded at 250 MHz using a Bruker AM 250 spectrometer. Multiplicities indicated are: s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet, dd=doublet of doublets, and br indicates a broad signal.

'Example 1

Preparation of trans.trans-2.6-dibenzyl-2.6-bis(met oxy- carbonyl)-1_r4-cyclohexanedione 1_

a) 2-carhomβthoxy-4. -ethylenedioxycyclohexanone 2_^ The title compound was prepared by a procedure disclosed by Mander et al., Tet . Lett . , 5425 (1983).

Lithium bistrimethylsilylamide (116 mL, 1M in THF, 116 mmol) was added to THF (400 mL) and cooled in a dry-ice acetone bath. To this solution was added 4,4- ethylenedioxycyclohexanone (15.6 g, 100 mmol) in THF (100 mL) over a period of 15 min. The reaction mixture was allowed to warm to 0°C over a period of 2 h. The temperature was lowered again to -78° C, HMPA (917.9 g, 100 mmol) was added, followed by methylcyanoformate (9.35 g, 110 mmol) . After stirring for 30 min, the reaction mixture was poured into cold water (200 mL) . The product was extracted with ether, dried over sodium sulfate, concentrated in vacuo and chromatographed (silica gel, 25% ethyl acetate/hexane) to give the title compound 2 (13.2 g, 63 %) as a colorless oil. •HNMR revealed it to be a mixture of keto and enol tautomers.

b) 2-ben yl-2-carbomethoxy-4.4-ethy„enedloxγcγclohexanon ^ To a suspension of sodium hydride (2.2 g, 3 mmol, 80% in oil) in tetrahydrofuran (200 mL) was added a solution of ketoester 2. (10.8 g, 50.47 mmol) in tetrahydrofuran (100 mL) at 0°C. The reaction mixture was stirred for 0.5 h and benzyl bromide (70 mmol) was added dropwise. The reaction mixture was allowed to warm to room temperature and stirred overnight. Cooled in an ice-bath and quenched with careful addition of water, extracted with ether, washed with water and dried over anhydrous sodium sulfate. Removal of solvents in vacuo followed by filtration through silica gel (eluted with hexane to remove the unreacted benzyl bromide, then with ethyl acetate:hexane 1:4) gave the titled compound 2. as an oil (10.44 g, 81%). ¹H NMR (250 MHz) δ 7.3 (m, 5H) , 4.0 (m,

4H), 3.6 (s, 3H), 3.1 (dd, 2H, J= 13 Hz), 2.95 (m, 1H) , 2.55 (d, 1H, J= 12 Hz), 2.48 (m, 1H) , 1.9 (m, 1H) , 1.75 (d, 1H, J= 12 Hz) .

c) 2-benzyl-2. -bis (methoxycarbonyl) -4.4-ethylenedi oxy- cyclohexanone .4

To a solution of ketone 2. (10.4 g, 34.2 mmol) in tetrahydrofuran (200 L) cooled in a dry ice-acetone bath lithium bistrimethylsilylamide (40 mL, 40 mmol) was added dropwise. The reaction mixture was slowly allowed to warm to 0°C over 2 h and stirred for an additional 30 min. The reaction mixture was recooled to -78°C and HMPA (7 L) was added followed by methyl cyanoformate (3.2 mL) . After 30 min, the reaction mixture was quenched with water, extracted with ether, washed with water and dried over anhydrous sodium sulfate. Removal of solvents in vacuo gave a light yellow oil which was filtered through 100 g silica gel, eluted first with 700 mL of hexane. The product was eluted with 1000 mL of ethyl acetate. Removal of ethyl acetate provided an oil (12.0 g, 98%) which was sufficiently pure for the next step. (Found to be a mixture of isomeric products in the form of keto and enol tautomers) .

d) trans. rans-2. -di enzyl.2 .6-bis (met oxycarbonyl)-4.4- cthylenediQxycyclohexanQne L To a suspension of sodium hydride (1.25 g, 40 mmol, 80% in oil) in tetrahydrofuran (100 mL) at 0°C was added ketodiester ± in THF (100 mL) . After stirring for 30 min at 0°C, benzyl bromide (6 mL, 50 mmol) and HMPA (8 mL, 46 mmol) were added. The reaction mixture was heated in an oil bath at 60°C for 8 h, cooled to 0°C, and quenched with water.

Extraction of the reaction mixture with ether, washing with water, drying over sodium sulfate followed by removal of solvents in vacuo gave an oily residue. Flash chromatography (silica, ethyl acetate:hexane 1:10, and 1:4) gave the titled compound (8.25 g, 66%). Crystallization from ether/hexane mixture provided colorless solid. MS(ESMS) m/z 453 (M+H)⁺; ¹H NMR (CDCI₃, 250 MH) δ 7.30 ( , 10H) , 4.0-3.8 (m, 4H) , 3.4 (d,

2H, J= 12 Hz), 3.3 (s, 6H) , 3.1 (d, 2H, J= 12 Hz), 2.45 (d, 2H, J= 12 Hz), 2.0 (d, 2H, J= 12 Hz).

e) trans,trans-2.6-dibenzγl- .6-bi .<. (methoxycarbonyl) -4.4- ethylenec-Hoxycyclohexanol _

To a solution of ketodiester ϋ (37.5 mg) in methanol (3 mL) was added sodium borohydride (25 mg) . The reaction mixture was stirred at room temperature for 3 h, quenched with water, filtered through celite, washed with ether and the solvents were removed in vacuo to give the titled compound £ as a colorless solid (31.5 mg, 84%) . -'-H NMR (CD₃OD, 400 MHz) δ 7.2(m, 10H) , 4.05 (s, 1H) , 3.6 (s, 3H) , 3.25 (d, 1H, J= 14 Hz), 3.12 (d, 1H, J= 13 Hz), 2.95 (d, 1H, J= 13 Hz), 2.5 (d, 1H, J= 14 Hz), 2.2 (d, 1H, J= 14 Hz), 1.98 (dd, 1H, J= 6, 14 Hz), 1.75 (dd, 1H, J= 9, 14 Hz), 1.45 (dd, 1H, J= 9, 14 Hz) .

f) trans. rans-2.6-dibenzyl-2. -bis ( ethoxvcarbonyl)-1.4- cyclohexanedione 2_.

A suspension of ketal £ (28.5 mg) in 50% aqueous formic acid (2 mL) was heated in an oil bath maintained at 55°C for 3 h. The reaction mixture was cooled and solvents removed in vacuo to give the hydroxy ketone I as a colorless solid (23.9 mg, 95%). ¹H NMR (CDCI₃, 250 MHz) δ 7.3-7.0 (m, 10H) ,

4.75 (s, 1H) , 3.5 (2 singlets, 6H) , 3.15 (dd, 2H, J= 12 Hz), 2.9 (dd, 2H, J=13 Hz), 2.6 (d, 13 Hz) , 2.5 (dd, 2H, J= 6 Hz), 2.3 (d, 1H, J= 13 Hz) .

Example 7.

Preparation of trans. rans-2.6-dibenzyl_r2_f 6-bis (methoxy- carbonyD-1.4-cyclohexanediol j^

Diketone 2 (22 mg) in methanol (2 L) was treated with sodiumborohydride (15 mg) and stirred for 2 h. The reaction mixture was quenched with water, diluted with ether and the solvents were removed in vacuo. The residue was filtered through celite and washed with 50 mL of diethyl ether. Removal of solvents gave the titled compound ϋ as a colorless solid (20 mg, 91%). ¹H NMR (CD₃OD, 400 MHz) δ 7.5-7.0 (m, 10H), 4.2 (m, 1H) , 4.1 (s, 1H) , 3.6 (two overlapping s, 6H) ,

3.3 (d, 1H, J=12 Hz), 3.15 (d, 1H, J=12 Hz), 2.9 (d, 1H, J=12

Hz), 2.5 (d, 1H, J=12 Hz), 2.2 (m, 1H) , 1.9 (m, 1H) , 1.8 (dd, 1H, J=7, 14 Hz), 1.5 (m, 1H, J=7, 14 Hz). Example 3

Preparation of trans _r trans . trans-2 , 6-dibenzvl , 2 - 6- bis (hydroxymethyl ) -1.4-cγclohexanediol .9

To a solution of diol & (25 mg) dissolved in diethyl ether (5 mL) at 0°C was added a IM solution of lithium aluminumhydride (1 mL) in ether. The reaction mixture was warmed to room temperature, stirred overnight, quenched with water (100 mL) and 10% sodium hydroxide (100 mL), diluted with ether, and stirred for 30 min. The mixture was filtered through celite, washed with ethyl acetate and the solvents were removed in vacuo to give the titled compound 1 as a colorless solid (23 mg,100%). __n analytical sample was obtained by HPLC (silica, 3% MeOH/CH₂Cl₂) . ¹H NMR(CT>₃θD, 400 MHz) δ 7.25 (m, 10H) , 4.13 (d, 1H, J=11.3 Hz), 4.0 (m, 1H) ,

3.72 (s, 1H) , 3.5 (d, 1H, J=11.2 Hz), 3.29 (d, 1H, J= 10.3 Hz), 3.1(d, 1H, J=13.5 Hz), 3.07 (d, 1H, J=13 Hz), 2.82 (d, 1H, J=13.5 Hz), 2.80 ( d, 1H, J=10.34 Hz), 2.76 (d, 1H, J=13.1 Hz), 1.5 (m, 2H) , 1.07 (t, 1H, J=12.5 Hz), 0.66 (t, 1H, J=12.5 Hz) .

Example 4

Preparation of trans_rtrans. is-2.6-dibenzγl-2,6- bis(hydroxymethyl)-l_r4-cyclohexane-diol 10

To a solution of the dione 1_ (100 mg, 0.245 mmol) in diethyl ether (10 mL) cooled in an ice bath was added dropwise a 1 M solution of lithiumaluminium hydride (3 mL, IM in ether) . The reaction mixture was warmed to room temperature and stirred for 10 h. The reaction was quenched with water (200 mL) and 10% aqueous sodium hydroxide (200 L) , diluted with ether (10 mL) , and stirred for 3 h. The mixture was filtered through celite, washed with ethyl acetate (100 mL) and solvents removed in vacuo to give a colorless solid (72 mg, 72%), which was found to be 4:1 mixture of cis _L__ and trans ϋ. diols by ¹HNMR. The two components were separated by HPLC (silica gel, 3%

MeOH/CH₂Cl₂) . The cis diol eluted first. cis diol 1__: ¹HNMR (CD₃OD, 400 MHz) δ 7.4-7.2 (m, 10H) , 4.3

(d, IH, J=11.2 Hz), 3.92 (m, IH) , 3.75 (s, IH) , 3.32 (d, 1 H, J=13 Hz), 3.28 (d, IH, J=13 Hz), 3.1 (d, IH, J=13 Hz), 3.08 (d, IH, J=13 Hz), 3.0 (d, IH, J=13 Hz), 2.75 (d, IH, J=13.23 Hz), 1.6 (dd, IH, J=7, 14 Hz) , 1.4 (dd, IH, J= 4, 14.38 Hz), 1.23 (dd, IH, J=6.5, 14.9 Hz), 1.1 (dd, IH, J= 4, 15.1 Hz).

Example 5

Preparation of tran . rans-2.6-dibenzyl-2.6-bi (hydroxy¬ methyl )-4-oxo-l-cyclohexano„ ^

a) trans. rans-2. -dibenzyl-2. -bis (hydroxymethyl)-4,4-

To a solution of ketodiester ϋ (76 mg, 0.168 mmol) in THF (3 mL) was added lithium aluminumhydride (IM solution in ether, 1.8 mL, 1.8 mmol). The reaction mixture was heated in an oil bath at 50° for 4 h, cooled and quenched with ethyl acetate followed by methanol/water. Diluted with ether and filtered through celite. Removal of solvents gave the titled compound 11 as a colorless solid (42 mg) . ¹H NMR (CD₃OD, 400 MHz) δ 7.2 (m, 10H) , 4.55 (d, IH, J= 6 Hz) , 4.0 (m, 4H) , 3.52 (s, 3H), 3.5 (s, 3H), 3.2 (d, IH, J= 13 Hz) , 3.1 (d, IH, J= 13 Hz), 2.95 (d, IH, J= 13 Hz), 2.8 (d, IH, J= 13 Hz), 2.76 (d, IH, J= 6 Hz), 2.4 (d, IH, J= 14 Hz), 2.2 (d, IH, J= 14 Hz), 1.9 (d, IH, J= 14 Hz), 1.76 (d, IH, J = 14 Hz).

b) trans,trans-2.6-diben?.yl.2.6-bis (hydroxymethyl)-4-oxo-l- cyclohexanol .12

The acetal 11 (19 mg) was dissolved in 35% acetic acid (2 mL) and heated in an oil bath at 60° for 4 h. The reaction mixture was cooled and solvents removed in vacuo to give a solid (15 mg) which was found to be a mixture of the titled product 12. and the hemiketal 12.. ketone - MS (ESMS) m/z 355 (M+H)+. Example 6

Preparation of 1 , 2 , 6-trihydroxy-2 , 6-dibenzyl . 4-cyclohexanone 19

a) 2_r6-bi (benzylidene)-4_r4-ethylenedioxycyclohexanone .15

Sodium hydroxide (2.0 g, 50 mmol) was dissolved in water (20 mL) and ethanol (10 mL) and cooled in an ice bath. To this solution was added 4, -ethylenedioxycyclohexanone 1_L (3.12 g, 20 mmol) and benzaldehyde (4.24 g, 40 mmol) and the reaction was stirred vigorously for 4 h. The precipitated product was suction filtered and washed with ice cold water (100 mL) . The yellow solid was recrystallized from ethanol (95%) to give the title compound ϋ as a yellow solid (3.2 g, 48%). NMR (CDC1 ) δ 7.9 (s, 2H) , 7.5-7.25 (m, 10H), 3.85

(s, 4H), 3.1 (S, 4H) .

b) 2.6-bis(benzyliden .-4.4-ethylenedioxycyclohexanol JL6

Dienone 15. (500 mg, 1.5 mmol) was dissolved in methylene chloride (10 mL) , cooled to -78°C and diisobutylaluminium hydride (1 M in toluene, 3 mL, 3 mmol) was added over a period of 10 min. After 2 h, the reaction was quenched with methanol (1 mL) diluted with methylene chloride (50 mL), washed with aqueous sodium potassium tartrate solution and dried over anhydrous sodium sulfate. Removal of solvents gave the title compound 1__ (510 mg, 100%) as an oil which was found to be sufficiently pure for the next step. ¹H NMR (CDCI₃) δ 7.5-7.1 (m, 10H), 6.7 (s, 2H) , 4.7 (s, IH), 3.8 (m,

4H) , 2.8 (m, 4H) .

c) 1,2,6-trihvdroxy,2,6-dibenzyl,4,4-ethylenedioxy- cyclohexan .18

Dienol lϋ (510 mg, 1.53 mmol) was dissolved in methylene chloride (10 mL) and 3-chloroperoxybenzoic acid (650 mg (80%) , 3 mmol) was added, and the reaction mixture was stirred overnight. The progress of the reaction was followed by ¹HNMR (disappearance of the olefinic protons at 6.7 ppm) . The precipitated acid was removed by filtration and washed with methylene chloride. The filtrate was concentrated in vacuo and the residue was flash chromatographed (silica, ethyl acetate:hexane 1:2) to give 12 (328 mg, 62%) as a white solid. Diepoxide 12 (40 mg, 0.11 mmol) was dissolved in tetrahydrofuran (5 mL) , cooled in an ice bath and lithiumaluminium hydride (1 mL, IM in THF, 1 mmol) was added and allowed to react overnight. The reaction mixture was quenched with sodium hydroxide (10%, 100 mL) , diluted with ether (50 mL) , and filtered through celite. The filter cake was washed with ethyl acetate and the combined organic extracts were concentrated in vacuo. Flash chromatography (silica, 2% methanol/methylene chloride) yielded the title compound' lϋ (10 mg) . ^λE NMR (CD3OD) δ 7.3-7.0 (m, 10H) , 3.8 (m- 4H) , 3.3 (s, IH) , 3.12 (d, IH, J=13.7 Hz), 3.02 (d, IH, J=13.5 Hz), 2.94 (d, IH, J= 13. 7 Hz) , 2.82 ( d, IH, J=13.5 Hz), 1.85 (dd, IH, J=1.6, 14 Hz), 1.68 (d, IH, J=14 Hz), 1.64 (dd, IH, J=1.6, 14 Hz), 1.28 (d, IH, J=14 Hz) .

d) 1.2.6-trihyc.roxy-2_r 6-dibenzyl.4-cyclohexanone ^

A suspension of ketal triol IS. (7 mg) in aqueous formic acid (50%, 0.6 mL) was stirred at room temperature for 4 h. The solvent was removed in vacuo and the residue was triturated with ether/hexane to give the title compound 12. (5 mg) . --H NMR (CD3OD) δ 7.4-7.0 (m, 10H) , 3.6 (s, IH) , 3.05

(two overlapping doublets, 2H, J= 14 Hz), 2.95 (d, IH, J=14 Hz), 2.85 (d, IH, J=14 Hz), 2.7 (d, IH, J= 13 Hz) , 2.4 (q, 2H, J=13 Hz), 2.1 (d, IH, J=13 Hz) .

Example 7

Preparation Qf t,rans.t.ranfi-2,5-tiibenzy-.-2,5- bis (hydroxymethyl )-1-oyolopentanol .24.

a) 2.5-his (ethoxycarbony.. -pentan-1-one

The title compound was prepared by the procedure of Kierstead et al., J. Che-m. Soc. 3616-3621 (1952) . b) trans-2.5-bis(ethoxycarbonyl)-2,5-dibenzγl-cγclQ-pentan-l- one ^0_

The product of step (7a) (2.28 g, 10 mmol) was added to a slurry of 100 mmol NaH in THF (50 ml) . Benzyl bromide (5.9 ml, 50 mmol) was added and the mixture was stirred under Ar for 20 hr. The mixture was poured into cold 0.3 N HCl (300 ml), then extracted with ethyl acetate (3 x 150 ml) . Concentration of the organic layer and flash chromatography of the residue (silica gel, gradient elution, 0% - 4% ethyl acetate/hexane) provided the title compound (2.15 g, 53%). MS (CI/NH₃) : m/z 409 ( +H)+.

c) trans-2.5-bis(ethoxycarbonyl)-2.5-dibenzyl-l- cyclopentano. _2i The product of step (7b) (309 mg) was reacted with aBH₄

(40 mg) in ethanol (3 ml) for 12 h. The mixture was diluted with 0.3 N HCl and extracted with ethyl acetate.

Concentration of the organic layer and flash chromatography of the residue (silica gel, gradient*elution, 0% - 16% ethyl acetate/hexanes) provided the title compound (0.206 g, 50%).

MS (CI/NH₃) m/z 411 (M+H)+.

d) trans,trans-2,5-dibenzγl-2_r5-bis (ethoxycarbonyl)-1- benzyloxy-cyclopentane 22 The product of step (7c) (494 mg, 1.2 mmol) was added to a mixture of NaH (3 mmol) and benzyl bromide (0.6 ml, 5 mmol) in THF (2 ml) at 5°C. The mixture was stirred with warming to 25°C over 5 h, poured into 0.3N HCl (10 ml), and extracted with ethyl acetate (3 x 25 ml) . Concentration and flash chromatography (silica gel, hexane followed by 2% ethyl acetate/hexane) provided the title compound (0.321 g) . e) trans _r trans-2.5-bis (hydroxymethyl) -2.5-dibenzyl-l- ftenzylpxy-cyπlppentane 3.

To a solution of the product of step (7d) (250 mg, 0.50 mmol) in methylene chloride (2.5 ml) at -30°C under Ar was added diisobutylaluminum hydride (4 mmol) in toluene (4 ml) . The solution was stirred 45 min, then water (1 ml) was added. After 5 min the mixture was diluted with methylene chloride and filtered through Celite. The filtrate was washed with water, dried over sodium sulfate, and concentrated to provide the title compound (200 mg, 96%) .

f) trans-trans-2,5-dibenzyl-2 , 5-bis (hydroxymethyl)-1- cyclopentanp] 24

The product of step (7e) (19 mg) was stirred with Pd(0H)2 (14 mg) in methanol (2 ml) under H2 (1 atm) for 1 h. Filtration and removal of solvent provided the title compound. Mp 151-152°C; ¹H NMR(CDCl3) δ 7.19 (m, 10H) , 4.10 (s, IH) , 3.84 (d, IH, J=ll Hz), 3.49 (d, 1, J =10Hz) , 3.40 (d, IH, J=ll Hz), 3.09 (m, 3H) , 2.58 (t, 2, J=14 Hz), 1.4 (m, 3H) , 0.79 (m, IH) ; MS (ES/MS) m/z 327.2 (M+H)⁺; Anal.

(C21H26O3) calc: C, 77.27; H, 8.03. found: C, 77.07; H, 8.08.

Example 8

Preparation of trans-trans-2-5-dibenzyl-2_f 5-bis-

(hydroxymethyl) e rahydrQthipp ene-l, l-dioxide .gj.

a) 2-carbethoxytetrahydrothiophene-l. l-dioxide 25 To a solution of sulfolane (24.03 g, 0.20 mol) in dry

THF (400 mL) at -78°C was added dropwise 2.5 M butyl lithium (80 mL, 0.20 mol) and the solution stirred for 30 min at -78°C. Ethyl chloroformate (10.9 g, 0.10 mol) was added dropwise to this solution causing precipitation. The mixture was warmed to 0°C, quenched with saturated ammonium chloride (300 mL) and extracted with ether. The ether solution was dried with magnesium sulfate, filtered and the filtrate was evaporated to yield the title compound as an oil (26.4 g) containing a very small amount of starting material by TLC (silica, Et₂θ) .

b) 2-benzyl-2-carbethoxytetrahydrothiophene l_fl-dioxide j_6 To a suspension of sodium hydride (1.29 g, 0.051 mol) in dry THF (200 mL) at 0°C under argon was added 2- carbethoxytetrahydrothiophene 1,1-dioxide (9.6 g, 0.05 mol) in THF (20 mL) dropwise and stirring was continued until gas evolution ceased. A solution of benzyl bromide (8.9 g, 0.051 mol) in THF (20 L) was added dropwise at 0°C and the solution was stirred at 25°C for 16 h. The solution was quenched with water (150 mL) and extracted with ethyl acetate (2x100 mL) . The organic solution was washed with water (50 mL) and brine (100 mL) and the solvent removed at reduced pressure to give an oil which was purified by flash chromatography (silica gel, 2:8 hexane:ethyl acetate) to yield the title compound as an oil (13.3 g, 94%) .

C) 2-ben7.y1.-2.5-dioarbethoxytetrahydrothiophene-1.1-dioxide 2^

To a solution of diisopropylamine (2.26 g, 22.3 mmol) in dry THF (150 mL) under argon at -78, butyl lithium (2.5 M in hexane, 8.92 mL, 22.3 mmol) was added dropwise. The solution was stirred for 10 min at -78°C. A solution of 2- benzyl-2-carbethoxytetrahydrothiophene 1,1-dioxide (6.0 g, 21.2 mmol) in THF (30 mL) was added dropwise and the yellow solution was stirred for 10 min at -78°C. A solution of ethyl chlorofor ate (2.42 g, 22.3 mmol) in THF (20 mL) was added and the reaction was stirred for 1 h at -78°C. The reaction was quenched with saturated aqueous ammonium chloride (200 mL) and the solution was extracted with ether (2x100 mL) . The ether solution was washed with brine, dried with magnesium sulfate, filtered and evaporated to an oil which was then purified by flash column chromatography (silica, 7:3 hexane:ethyl acetate) to give the product as an oil (5.94 g, 79%) . d) 2-5-dibenzyl-2.5-dicarbethoxytetrahydrothiophene-l.1- dipxide 2

2-Benzyl-2, 5-dicarbethoxytetrahydrothiophene-l, 1-dioxide (4.94 g, 0.0139 mol) in dry THF (35 mL) dropwise at 25°C was added to a suspension of sodium hydride (0.44 g, 17.4 mmol) in dry THF (150 mL) under argon added. The reaction mixture was warmed to 50°C and stirred for 15 min. Benzyl bromide (3.04 g, 17.4 mmol) was added, and the reaction was stirred for 24 h at 25°C and 24 h at 50°C. The reaction was quenched with ice water (200 mL) and extracted with ether (2x150 mL) . The ether extracts were washed with brine, dried with magnesium sulfate, filtered and evaporated to give an oil. The oil was dissolved in hexane:ethyl acetate (1:1) and purified by flash chromatography (silica gel, 8:2 hexane:ethyl acetate) to yield the title compound as a solid (231 mg, 4%) .

e) trans,trans-2-5-dibenzyl-2, 5-bis (hydroxymethyl) - tetrahydrothiophene-1_r 1-dioxid .2^ To a solution of 2-5-dibenzyl-2, 5-dicarbethoxytetra- hydrothiophene-1, 1-dioxide (100 mg, 0.225 mmol) in dry ether (10 mL) at 0°C was added lithium aluminum hydride (IM in ether, 0.56 mL, 0.56 mol) and the reaction mixture was stirred for 2.5 h at 25. The reaction was cooled in an ice bath and quenched with 10% sodium hydroxide (0.10 mL) and the mixture was stirred for 30 min at 25°C. The suspension was filtered through Celite and the filter cake was washed with additional ether. The solvent was removed under reduced pressure and the resultant oil was triturated with hexane:ether (3:1) to give the title compound as a solid (33 mg, 41%) . Anal. (C20H24θ4S«l/8 H2O) calcd: C, 66.23; H, 6.74. found: C, 66.21; H, 6.71. ¹H NMR (CD3OD) δ 1.80 (4H, m) ,

3.08 (4H, dd), 3.62 (4H, dd) , 7.25 (10H, m) .

Example 9

Preparation of 4-hydroxy-trans.trans-3.5-dibenzyl-3.5- bis (hydroxymethyl ■• -tetrahydrothiopyran _3_3 a) 3-benzyl-3-carbomethoxytetrahydro-l.4-thianvrone

To a suspension of sodium hydride (0.477 g, 18.9 mmol) in dry THF (50 mL) at 0°C was added 3-carbomethoxytetrahydro- 1,4-thiapyrone (2.74 g, 15.7 mmol) [prepared by the method of Fehnel et al . , J. Am. Chem. Soc, 70, 1813 (1948)] in THF dropwise and stirred for 15 min. A solution of benzyl bromide (3.29 g, 18.9 mmol) was added in THF (5 mL) and the solution was stirred at 25°C for 17 h. The reaction was poured into ice water and extracted with ethyl acetate (3x60 mL) . The ethyl acetate solution was washed with brine, dried with magnesium sulfate, filtered and evaporated to give an oil which was purified by flash column chromatography (silica gel, 9:1 hexaned:ethyl acetate) to give the title compound as a solid (1.28 g, 31%) .

b) 3-benzyl-3.5-dicarbomethoxytetrahydro-l,4-thiapyrone 2

To a solution of diisopropylamine (0.588 g, 5.81 mmol) in dry THF (12 mL) at -20°C under argon was added dropwise n- butyllithium (2.5 M in hexane, 2.32 ml, 5.81 mmole) and the solution was stirred for 30 min. The solution was cooled to -78°C and a solution of 3-benzyl-3-carbomethoxytetrahydro- 1, -thiapyrone (1.28 g, 4.84 mmole) in dry THF (5 mL) was added dropwise. The reaction was warmed to 0°C and stirred for lh. After cooling to -78°C, HMPA (0.87 g, 4.84 mmole) followed by methyl cyanoformate 0.494 g, 5.81 mmole) was added and the solution was stirred at -78°C for 30 min. The reaction was quenched with ice water (50 mL) and extracted with ether (3x40 mL) . The ether was dried with magnesium sulfate, filtered and the solvent was removed at reduced pressure. The resultant oil was purified by flash column chromatography (silica gel, 8:2 hexane:ethylacetate) to yield the title compound as an oil (1.33 g, 85%) .

C) 3, 5-dibenzyl-3, 5-dicarbomethoxytetrahγdro-l.4-thiapyrone 32

To a suspension of sodium hydride (0.125 g, 4.95 mmol) in dry THF (19 mL) at 25°C was added dropwise 3-benzyl-3,5- dicarbomethoxytetrahydro-1,4-thiaρyrone (1.33 g, 4.13 mmol) in dry THF (10 mL) and the reaction was stirred for 30 min. Benzyl bromide (0.864 g, 4.95 mmol) was added and the reaction was stirred at 50°C for 17 h. The reaction was quenched with ice water (50 mL) and extracted with ether (3x50 mL) . The ether was washed with brine, dried with magnesium sulfate, filtered and evaporated to an oil. The crude oil was purified by flash column chromatography (silica gel, 8:2 hexane:ethyl acetate) to give an oil which was triturated with hexane-ether to yield the title compound as a solid (0.501 g, 29%). Mp 115-116°C.

d) 4-hydroxy-trans.trans-3.5-dibenzyl- _r5-bi (hydroxymethyl)- tetrahydrothiopyran To a solution of 3,5-dibenzyl-3,5-dicarbomethoxy- tetrahydro-1,4-thiapyrone (203 mg, 0.492 mmole) in dr,y ether (20 mL) was added lithium aluminum hydride (1.0 M in ether, 2.5 L, 2.5 mmol) and the reaction was stirred at 33°C for 16 h. The reaction was cooled in ice, quenched with 10% aqueous sodium hydroxide (0.18 mL) , diluted with ethyl acetate, and the inorganic salts were filtered off. The filtercake was triturated with ether, filtered, and the filtrate was combined with the ethyl acetate extract. The solvent was removed under reduced pressure and the resultant semi-solid residue was triturated with hexane:ethyl acetate (3:1) to yield the title compound as a solid (72 mg + 18 mg (2nd crop), 51%). ¹H NMR (CD3OD) δ 2.1 (IH, d) , 2.23 (4H, m) , 2.54

(IH, d), 2.91 (IH, d), 3.0 (IH, d) , 3.1 (IH, d) , 3.2 (IH, d) , 3.48 (IH, s), 3.51 (IH, m)^', 3.77 (IH, s) , 3.82 (IH, d) , 4.50 (IH, d), 7.27 (10H, m) .

Example 10

Preparation of 4-hγdroxy-trans. rans-3.5-d benzγl-3.5- bis (hydroxymethyl)tetrahydrothiopyran-1-oxide ^

To a suspension of 4-hydroxy-trans,trans-3,5-dibenzyl- 3, 5-tis(hydroxymethyl) tetrahydrothiopyran (15 mg, 41.8 μmole) in methanol: ater (5:4, 5 mL) at 50°C was added sodium metaperiodate (9.4 mg, 43.9 μmole) in methanol:water (5:4, ~1 mL) and the reaction was heated at 50°C for 17 h. The solvent was removed at reduced pressure and the residue was triturated with methanol:chloroform (-1:1) . The solution was evaporated to dryness and the resultant solid was triturated with ether and filtered to yield the title compound as a solid (9.7 mg, 62%). MS m/z 374 (M+H)+; ¹H NMR (CD3OD) δ 2.37

(2H dd), 2.9-3.2 (6H, m) , 3.59 (IH, d) , 3.98 (2H, dd), 4.04 (IH, s), 7.27 (10H, m) .

Example 11

Preparation of 3. -dibenzyl-3-hydroxymethyl-5-(l-hydroxy-4- methylpentyl ) e rahydrp-4-hydroxy-thiapyran 1

a) 3-benzyl-3-carbpn.et_-0_.y-5- (4-methylyaleryl) tetrahydro-1 , - t.hiapyrone 3_5

To a solution of lithium bis(trimethylsilyl)amide (1.0 M, 11.0 mL, 11.0 mmol) in dry THF (100 mL) under argon at

-78°C, added 3-benzyl-3-carbomethoxytetrahydro-l,4-thiapyrone (2.33 g, 8.80 mmole) in dry THF (6 mL) dropwise. The temperature of the solution was raised to -10°C over a period of 1 h and stirred for an additional 30 min. The reaction was cooled to -78°C and 4-methyl valeryl nitrile (1.43 g,

11.5 mmole) was added and the solution was stirred for 15 min and then allowed to warm to -20°C over 1.5 h. The reaction was quenched with water (50 mL) and extracted with ethyl acetate (2x100 mL) . The ethyl acetate solution was dried with magnesium sulfate, filtered and the solvent was removed under reduced pressure. The resultant oil was purified by flash chromatography (silica gel, 9:1 hexane:ethyl acetate) to yield the title compound as an oil (2.60 g, 81%) . b) 3.5-dibenzyl-3-carbnmethoxy-5-(4-methvlvalervl)tetrahvdro- 1 -4-thiapyrone .36

3-Benzyl-3-carbomethoxy-5- (4-methylvaleryl)tetrahydro- 1,4-thiapyrone (2.59 g, 7.15 mmol) in dry THF (10 mL) was added dropwise to a suspension of sodium hydride (0.343 g, 14.3 mmol) in dry THF (40 mL) under argon. The reaction was stirred for 30 min at 25°C. Benzyl bromide (3.05 g, 17.9 mmol) was added followed by HMPA (1.92 g, 10.7 mmol) and the reaction mixture was heated at 50°C for 17 h. The reaction was cooled in ice and quenched with water (35 mL) and extracted with ethyl acetate (35 mL) . The ethyl acetate was washed with water and brine, dried over magnesium sulfate, filtered, and the solvent was removed under reduced pressure. The resultant oil was purified by flash column chromatography (silica gel, 19:1 hexane:ethyl acetate) to yield the title compound as an oil (1.90 g, 59%) .

c) 4-hydroxy-3_r5-dibenzyl-3-hydroxymethyl-5- (l-hydroxy-4- ethylpentyl )tetrahydrothiopyran J7

To a solution of 3,5-dibenzyl-3-carbomethoxy-5- (4- methylvaleryl)tetrahydro-1, 4-thiapyrone (220 mg, 0.486 mmol) in dry ether (35 mL) was added a THF solution of lithium aluminum hydride (1.0 M, 2.5 ml, 2.5 mmol) and the reaction was stirred at 31° for 3 hours. The reaction was cooled in ice, quenched with 10% sodium hydroxide (0.20 mL) and diluted with ethyl acetate. The inorganic salts were filtered off. The filter cake was washed with additional ethyl acetate. The solvent was removed under reduced pressure and the residual oil was purified by flash chromatography (silica gel, 85:15 hexane:ethyl acetate) to yield the title compound as an oil (63 mg, 30%) .

Example 12

Preparation of 4-hydroxy-3.5-dibenzyl-3-hydroxymethyl-5- (1- hydroxy-4-methγlpentyl )-tetrahydrothiopyran-l-oxide .38_. Sodium metaperiodate (12.0 mg, 56.3 μmol) was added to a suspension of 4-hydroxy-3,5-dibenzyl-3-hydroxymethyl-5-(2- hydroxy-4-methylpentyl) tetrahydrothiopyran (19.3 mg, 45 μmol) in 5 ml methanol:water (5:4) and the reaction mixture was stirred at 50°C. Additional sodium metaperiodate (6 mg, 28 μmol) was added and the reaction was stirred for 17 h. The solvent was removed under reduced pressure and the resultant solid was stirred with a chloroform-methanol mixture (1:1) and the inorganic salts were filtered off. The solvent was evaporated and the solid was stirred with chloroform and then filtered. The solvent was again removed at reduced pressure and the residue was triturated with hexane-ether and filtered to give the product as a solid (12.1 mg, 61%). MS m/z 444; H NMR δ 0.995 (6H, m) , 1.32 (2H, m), 1.55 (2H, m) , 1.69 (2H, m) , 1.90 (IH, m) , 2.25 (2H, m) ,

2.95 (2H, m), 3.10 (2H, dd) , 3.49 (2H, m) , 3.57 (IH, d) , 3.97 (IH, s), 4.47 (IH, d), 7.31 (10H, m) .

Example 13

using the general methods disclosed herein, the following compounds were prepared: a) 4-hydroxy-2,6-dibenzyl-2,6-di(hydroxymethyl)- tetrahydrothiopyran-1,1-dioxide; and b) 4-oxo-2,6-dibenzyl-2,6-di(allyl)-cyclohexanol. IH NMR

(CDC13) δ 7.2-7.4 (m 10H), 6.2 ( , IH), 5.6 (m, IH) , 5.25 (s,

IH), 5.2 (s, IH), 4.9-5.2 (m, 2H) , 3.9 (d, IH, J=6 Hz), 3.1

(d, 2H, J=12 Hz), 2.9 (q, 2H, J=12 Hz), 2.6 (q, IH, J=12 Hz),

2.5 (d, IH, J=12 Hz), 2.3 (m, 4H) , 2.0 (d, IH, J=12 Hz), 1.9 (d, IH, J=6 Hz), 1.52 (q, IH, J=12 Hz).

Example 14

Parenteral Dosage Unit Composition A preparation which contains 25 mg of a compound of this invention is prepared as follows:

25 mg of the compound is dissolved in 15 mL of distilled water. The solution is filtered under sterile conditions into a 25 mL multi-dose ampoule and lyophilized. The powder is reconstituted by addition of 20 L of 5% dextrose in water(D5W) for intravenous or intramuscular injection. The dosage is thereby determined by the injection volume. This solution is also suitable for use in other methods for administration, such as addition to a bottle or bag for IV drip infusion.

Example 15

Oral Dosage Unit Composition

A capsule for oral administration is prepared by mixing and milling 200 mg of the compound with 450 mg of lactose and 30 mg of magnesium stearate. The resulting powder is screened and filled into a hard gelatin capsule.

The above description fully discloses how to make and use this invention. This invention, however, is not limited to the precise embodiments described herein, but encompasses all modifications within the scope of the claims which follow.

Claims

What is claimed is:

1. A compound of the formula:

(I) wherein,

R_l and R are OH, (CHR₅)_mCOR6, (CHR₅)_mCH(OH)R₅ or R₅; 2 and R3 are H, Ci-salkyl, Het, C3_ιocycloalkyl, Het- Ci-βalkyl, C2-salkenyl, Het-C2-8alkenyl, C3-χocycloalkyl- Cι_8alkyl or C3_ιocycloalkyl-C2-8-a*lkenyl;

R5 is R₂ or R2 mono- or di-substituted by G; Rδ is H, OH, OR', R2, N(R')2_. AA or NHC (=NR⁷)NHR"; R₇ is H, CN, COR' or SO2R';

R' is H, Cι-6alkyl, C3_ιocycloalkyl or Cι_8alkylC3-ιocycloalkyl;

R" is R', COR', C(0)OR' or CON(R')₂;

G is OR*, OC(0)R', OC(0)N(R')2, halogen, CORβ, NR'-AA, NHCOR*, Sθ2N(R*)₂. NHS02N(R')₂, NHC(=NR⁷)NHR", CF3 or N(R')₂; AA is one or two amino acids;

Z is CH2, CHOH, CHN(R')2, CHNHCOOR, S, SO, SO2, SONH, 0, CHCH2OH, CHCO2H, C=0, NR", N(0)R* or C=NH0R'; Q is CHOH, S, SO or SO2; m is 0, 1 or 2; n is 0 or 1; or pharmaceutically acceptable salts thereof, provided that:

1) Ri - R₄ are not simultaneously chosen from the group of H, OH and Cι_₄alkyl, and

2) no more than two of Ri - R₄ are H.

2. A compound according to claim 1 in which Ri and R4 are OH, CO2R', C2-8alkenyl, (CHR5)_mCH(OH)Rs or R2 mono- or di- substituted by G.

3. A compound according to claim 1 in which R₂ and R₃ are C₃-ιocycloalkyl-Cι-₆alkyl.

4. A compound according to claim 1 in which Z is CH₂, CHOH, C=0, S or SO.

5. A compound according to claim 1 in which Q is CHOH.

6. A compound according to claim 5 in which Z is C=0 or S=0.

7. A compound according to claim 6 in which Ri and R₄ are OH, CH₂OH or (CHR₅)_mCH(OH)R₅.

8. A compound according to claim 1 in which the compound is: trans,trans,trans-2, 6-dibenzyl-2, 6- bis (methoxycarbonyl)1,4-cyclohexanediol; trans,trans,trans-2, 6-dibenzyl-2, 6-bis (hydroxymethyl)- 1, -cyclohexanediol; trans,trans,cis-2,6-dibenzyl-2,6-bis(hydroxymethyl)-1,4- cyclohexane-diol; y trans,trans-2,6-dibenzyl,2, 6-bis (hydroxymethyl)-4-oxo-l- cyclohexanol;

1,2, 6-trihydroxy-2,6-dibenzyl,4-cyclohexanone; trans,trans-2,5-dibenzyl-2,5-bis(hydroxymethyl)-1- cyclopentanol; trans,trans-2-5-dibenzyl-2,5-bis-(hydroxymethyl)- tetrahydrothiophene-1,1-dioxide;

4-hydroxy-trans, trans-3,5-dibenzyl-3,5- bis(hydroxymethyl)-tetrahydrothiopyran; 4-hydroxy-trans,trans-3,5-dibenzyl-3,5- bis(hydroxymethyl)-tetrahydrothiopyran-1-oxide;

3,5-dibenzyl-3-hydroxymethyl-5-(l-hydroxy-4- methylpentyl)tetrahydro-4-hydroxy-thiapyran;

4-hydroxy-3,5-dibenzyl-3-hydroxymethyl-5-(l-hydroxy-4- methylpentyl) tetrahydrothiopyran-1-oxide;

4-hydroxy-2, 6-dibenzyl-2, 6-di (hydroxymethyl)- tetrahydrothiopyran-1,1-dioxide; or

4-0x0-2, 6-dibenzyl-2,6-di(allyl)-cyclohexanol.

9. A pharmaceutical composition which comprises a compound according to claim 1 and a pharmaceutically acceptable carrier.

10. The use of a compound according to claims 1-9 in the manufacture of a medicament.

11. A method of treating disease states associated with infection by a retrovirus which comprises administering an effective amount of a compound according to claim 1.

12. A method of treating disease states associated with HIV infection which comprises administering an effective amount of a compound according to claim 1.

13. A method of treating disease states associated with HIV infection which comprises administering an effective amount of a compound according to claim 1 and AZT.