HRP940935A2 - 5,6-dihydropyrone derivatives as protease inhibitors and antiviral agents - Google Patents

Abstract

The present invention relates to novel 5,6-dihydropyrone derivatives and related structures which potently inhibit the HIV aspartyl protease blocking HIV infectivity. The 5,6-dihydropyrone derivatives are useful in the development of therapies for the treatment of bacterial and viral infections and diseases, including AIDS. The present invention is also directed to methods of synthesis of multifunctionalized 5,6-dihydropyrones and of related structures.

Description

Field of invention

The present invention relates to 5, 6-dihydropyrone derivatives that inhibit aspartyl proteases, especially the aspartyl protease found in retroviruses, including the human immunodeficiency virus (HIV). It is expected that 5,6-dihydropyrones can be used as antiviral agents for the treatment of infections caused by HIV or other retroviruses that use aspartyl protease, and to be useful in the treatment of diseases caused by retroviruses, including AIDS.

Knowledge known so far

The name acquired immunodeficiency syndrome (AIDS) was proposed in 1982 with the aim of describing the clinical manifestations of immunodeficiency. The etiological agent for AIDS was only later associated with retroviruses, the human immunodeficiency virus (HIV), or the subfamily of lentiviruses. At least two infectious strains of HIV have been identified, namely HIV-1 and HIV-2. In this proposal, the term HIV will be used as a general term that refers to all strains and mutants of the human immunodeficiency virus. A detailed study of the properties of HIV has enabled various approaches to the development of antiviral drugs, including the inhibition of the viral aspartate protease. (D. Richman, Control of Viral Diseases, 45th Symposium of the Society for General Microbiology, 261-313, (1990).

Aspartate proteases can be found in many retroviruses, including feline immunodeficiency virus (FIV), myeloblastosis-associated virus (MAV), and Rous sarcoma virus (RSV) [H. Toh et al. Nature, 315: 691 (1985); J. Kay, and B.M. Dunn, Biochim. Biophys. Acta, 1: 1048 (1990); C. Cameron, J. Biological. Chem., 168: 11711-720 (1993)]. Because there are structural similarities between known retroviral proteases, compounds that inhibit proteases from HIV may also inhibit proteases from other retroviruses.

Aspartate protease from HIV is responsible for the post-translational shaping of viral polyprotein precursors such as pol and gag. [M. Graves, Structure and Function of Aspartic Proteases, 395-405 (1991)]. Degradation of these polyproteins is fundamental for the maturation of the virus, and the proteolytic activity necessary for the formation of polyproteins cannot be carried out by the action of the host's cellular enzymes. It was found that viruses that do not contain these proteases as well as mutants in which the protease is inactive are not infectious [C.Ping et al., J. Virol., 63: 2550-556 (1989) and N. Kohl et al., Proc. Natl. Acad. Sci. USA, 85: 4686-90 (1987)]. Thus, selective inhibitors of HIV proteases have been found to inhibit the spread of the virus and the formation of cytopathological consequences in culture of acutely infected cells [(J. C. Craig, Antiviral Research, 16: 295-305 (1991)]. For these reasons, inhibition of HIV proteases is considered a promising approach to antiviral therapy. .

HIV protease inhibitors have been extensively reviewed in [e.g. A: Tomasselli et al., Chimica Oggi, 6-27 (1991) and T. Meek, J. Enzyme Inhibition. 6: 65-98 (1992)]. However, most of the mentioned inhibitors are peptides and therefore unsuitable as drugs, due to the well-known pharmacological disadvantages that occur with most peptide drugs (excretion via bile, low bioavailability and instability in the physiological environment, etc.). Non-peptide inhibitors of HIV proteases are therefore very important as they can be used as useful therapeutic agents.

Patent Hei 3-227923 claims that coumarins have anti-HIV activity. However, only 4-hydroxycoumarin was specifically described, but without discussion of the mechanism of action.

World Patent 89/07939 lists eight coumarin derivatives as HlV reverse transcriptase inhibitors with potential antiviral activity. These derivatives are hexachlorocoumarin, 7-acetoxycoumarin, whose structures are shown in the following figure.

[image]

Warfarin, (3-(α-acetonylbenzyl)-4-hydroxycoumarin), shown below was presented by R. Nagorny et al. in AIDS 7: 129-130 (1993) as an inhibitor of cell-mediated and non-cell-mediated HIV infections. However, Warfarin was the only pyrone analogue investigated, and the mechanism of its action in inhibiting HIV was not specified.

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It has been shown by Fairli et al., (Biochem. Biophys. Res. Comm., 188: 631-637, (1992) that selected flavones, which are structurally different from the 5,6-dihydropyrone of the present invention, inhibit HIV-1 protease These compounds are shown below.

[image]

United States Patent No. 3,206,476 describes several pyrones, particularly 3-substituted-4-hydroxy-6-aryl-2-pyrones as pressure lowering agents. However, the type of these substituents in position 3 in these heterocycles is limited only to halogens and amino groups, and alkanoylamino derivatives.

United States Patent No. 3,818,046 describes several pyrone derivatives, particularly 4-hydroxypyrones with carbon chains containing sulfur in the 3-position as growth inhibitors and antimicrobial agents. These pyrones are substituted as follows: R = Me; M = H or alkali metal; R' - H, alkyl, phenyl, halophenyl, nitrophenyl, lower alkylphenyl, benzyl, phenethyl, naphthylmethyl, halobenzyl, lower alkylbenzyl, nitrobenzyl, propargyl, allyl, cyclohexyl, lower alkyl, lower thioalkyl or adamantyl; and n = 0 to 2.

[image]

The pyrone preparation process is described in United States Patent No. 3,931,235. EP 278742 describes several cyclic 2-benzoyl-1,3-diones with herbicidal activity. All these compounds have 3-benzoyl substituents. Their structures in keto tautomeric forms are shown below:

[image]

Summary of the invention

The present invention is based in large part on the inventor's special discoveries that new derivatives of 5,6-dihydroxypyrone, as well as corresponding compounds selected from a wide range of "tailored" molecular structures, potentially inhibit HIV aspartyl protease thereby blocking infection caused by HIV. The present invention is also based on the knowledge of the mechanism of action of antiviral drugs, especially as shown in the structure-activity relationship characteristic of ani-HIV compounds that include 5,6-dihydropyrone derivatives.

The discovered 5,6-dihydropyrones are expected to be extremely useful in the development of treatments for infections caused by viruses, especially retroviruses whose replication and infectivity are based on aspartate protease activity. One such retrovirus is HIV. For these reasons, it is expected that 5,6-dihydropyrones with antiviral activity may be useful in the treatment of diseases and syndromes associated with viral pathogenesis. One such syndrome is AIDS.

The proposed efficient synthesis of biologically active 5,6-dihydroxypyrones involves either de novo formation of 5,6-dihydropyrone cores or modification of 5,6-dihydropyrone with suitable functionality. Furthermore, many of the given working examples show the preparation of specific 5,6-dihydropyrones whose structures contain the desired functional groups with the appropriate geometry.

Testing of specific 5,6-dihydropyrones as inhibitors of aspartate protease from HIV, based on testing the hydrolysis of undecapeptide enzyme substrates, and testing of 5,6-dihydropyrones as inhibitors of virus growth and infectivity, based on testing the infection of the H9 cell line with the HIV-1iiib virus strain, is also covered by this invention.

The present inventors contemplate the preparation of pharmaceutically useful antiviral compositions comprising one or more of the disclosed 5,6-dihydropyrones and the corresponding compounds with pharmaceutically compatible excipients. They are also considering the use of these preparations alone or in combination with other antiviral treatments, in the treatment of infections and diseases caused by retroviruses, including AIDS.

The present inventors contemplate the preparation of pharmaceutically useful antibacterial compositions comprising one or more of the disclosed 5,6-dihydropyrones and corresponding compounds, together with a pharmaceutically compatible excipient.

The present invention relates to the compounds or their pharmaceutically compatible salts of formula 1 shown below.

[image]

where

X represents OR5, NHR5, CH2OR5, CO2R6 or SR5, wherein R5 represents R6 or

COR6, and R6 can independently be H, a straight-chain alkyl group containing 1 to 6 carbon atoms, a branched or cyclic alkyl group containing 3 to 7 carbon atoms, an alkylcycloalkyl group containing 5-9 carbon atoms, benzyl, phenyl or heterocyclyl;

Z represents O or S;

Y represents O, S, C(R 6 ) 2 , NF or NR 6 ;

R1 and R1' are each [CH2]n1-[W1]n2-[Ar]n2-[CH2]n3-[W2]n4-R7;

R2 is independently one of the possible R1 groups, with the restriction that if W1

represents a heteroatom n1 is an integer from 1 to 4;

R3 is independently one of the possible R1 groups, with the restriction that if W1 represents a heteroatom, n1 is an integer from 1 to 4;

R2 and R3 can together form an unsubstituted or substituted three-, four-, five-, six- or seven-membered ring, wherein the substituents represent one or more R7 groups mentioned below;

R4 is [CH2]n2-[W3]n2-[CH2]n3-[W4]n4-[Ar]n2-[CH2]n3-[W2]n4-R7;

n1, n2, n3, n4 and n5 each represent an integer from 0 to 4, 0 to 1, 0 to 4, 0 to 1, and 0 to 2;

W1, W2, and W4 each independently represent O, OCONR7, S(O)n5, CO, C(=NR7)NR7, CR7=CR7, C=C, NR7, CS, C=N-R7, C=NOR7, NR7SO2, SO2NR7, C=C(R7)2, CR7N(R7)2, CR7OR7, C(R7)2, NCO2R7, NR7CO2, CO2, NCON(R7)2, NR7CONR7, NCOR7, NR7CO or CONR7;

W3 represents one of the W1 groups with the restriction that if n1 in R4 is zero, then W3 represents -CO, -CR7=CR7, -C=C, -CS, -C=N-R7, -C=NOR7, -CR7N( R7)2, -C=C(R7)2, -CR7OR7, -C(R7)2, -CO2, -CONR7, where the left dash indicates the bond with the hydropyrone ring;

R7 is independently H, Ar, a straight-chain or branched alkyl or alkenyl group containing 1 to 6 carbon atoms, or two R7 groups can together form a ring of 3 to 7 atoms, or a corresponding substituted derivative in which one or more substituents represent CO2R6, COR6 , CON(R6)2, NR6CON(R6)2, NR6COR6, OR6, S(O)n5R6, N(R6)2, Cl, Br, F, CF3 Ar, OAr or S(O)n5Ar;

Ar independently represents phenyl, naphthyl, a five- or six-membered heterocyclic ring containing 1 to 4 heteroatoms, a cycloalkyl containing 3 to 6 atoms, a fused ring system containing 8-10 atoms or a corresponding substituted derivative, wherein the substituents can be F, Cl , Br, CN, NO2 (CH2)n6R6, (CH2)n6C(Me)=CH2, (CH2)n6N(R6)2, (CH2)n6NR6CON(R6)2, (CH2)n6NR6COR6, (CH2)n6OR6, ( CH2)n6OCOR6, (CH2)n6OCON(R6)2, (CH2)n6CO2R6, (CH2)n6CON(R6)2, (CH2)n6COR6, CF3, (CH2)n6S(O)n5R6, OCH2O or O(CH2)20 ; you

n6 is independently an integer from 0 to 3.

More preferred compounds of formula 1 of the present invention are those in which

X represents R 5 wherein R 5 represents H or COR 6 and R 6 is as defined above;

Z is O;

Y is O, S or CH 2 ;

R1 and R1' each independently represent H, F, (CH2)n1CO2R6, (CH2)n1OR6 or (CH2)n1CON(R6)2;

R2 is [CH2]n1-[W1]n2-[Ar]n2-[CH2]n3-[W2]n4-R7 with the restriction that when W1 represents a heteroatom, then n1 is an integer from 1 to 4;

R 3 is independently one of the groups R 2 ;

R2 and R3 can be part of a five-, six- or seven-membered ring which can be substituted by R7 groups;

R4 is [CH2]n1-[W3]n2-[CH2]n3-[W4]n4-[Ar]n2-[CH2]n3-[W2]n4-R7;

n1, n2, n3, n4 and n5 are as defined above;

W1 and W4 independently represent O, S(O)n5, CO, CR7=CR7, NR7, CR7OR7, C(R7)2, NR7CO2, CO2, NR7CONR7, CONR7 or NR7CO;

W2 is as defined above;

W 3 represents CR 7 OR 7 , C(R 7 ) 2 , or CONR 7 ;

R7 is as defined above;

Ar is as defined above; you

n6 is as defined above.

Even more preferred compounds of formula 1 of the present invention are those in which:

X represents OH;

Z represents O;

Y represents O;

R1 and R1' are H;

R2 is [CH2]n1-[W1]n2-[Ar]n2-[CH2]n3-[W2]n4-R7 with the restriction that when W1 represents a heteroatom, then n1 is an integer from 1 to 4;

R3 is [CH2]n1-[Ar]n2-[CH2]n3-[W2]n4-R7;

R2 and R3 may be part of a five-, six-, or seven-membered ring which may be substituted by R7 groups;

R4 is [CH2]n1-[W3]n2-[CH2]n3-[W4]n4-[Ar]n2-[CH2]n3-[W2]n4-R7;

n1, n2, n3, n4 and n5 are as defined above;

W1 represents O, S(O)n5, NR7, CONR7 or C(R7)2;

W2 is as defined above;

W 3 represents C(R 7 ) 2 ;

W4 is independently CR7=CR7, NR7CONR7, C(R7)2, NR7CO, CO or CO2;

R6 is as defined above;

R7 is as defined above;

Ar is as defined above; you

n6 is as defined above.

Even more than the previous preferred compounds of formula 1 are those in which:

X represents OH;

Z represents O;

Y represents O;

R1 and R1' are H;

R2 is CH2-Ar-(CH2)n3-[W2]n4-R7, CH2-CH2-Ar-(CH2)n3-[W2]n4-R7, CH2OAr-(CH2)n3-[W2]n4-R7, cyclopentylmethyl, (CH2)4-C(=O)N(R7)2, cyclohexylmethyl, 2-(2-or 3-tetrahydrofuranyl)ethyl, 2-(2- or 3-furanyl)ethyl, propyl, butyl, isobutyl, pentyl, isopentyl, 2-(cyclopropyl)ethyl, (CH2)2C(CH3)=CH2, Ar-(CH2)n3-[W2]n4-R7, phenyl or 2-,3-or 4-pyridyl;

R3 represents Ar-(CH2)n3-[W2]n4-R7, phenyl, cyclopentyl, cyclohexyl, 2- or 3-furanyl, 2-or 3-thienyl, 2-, 3- or 4-pyridyl, isobutyl, pentyl, CH2 -CH2Ar or isopentyl;

R2 and R3 can be part of an unsubstituted or substituted five-, six- or seven-membered ring, and the substituents can be R7 groups shown above;

R 4 is as defined above for more preferred compounds of formula 1;

n1, n2, n3, n4 and n5 are as defined above;

W2, W3 and W4 are as defined above for more preferred compounds of formula 1;

R6 is as defined above;

R7 is as defined above;

Ar is as defined above; you

n6 is as defined above.

The following are some of the most preferred compounds of the present invention:

5,6-Dihydro-4-hydroxy-6-phenyl-3-[(phenylmethyl)thio]-2H-pyran-2-one;

5,6-Dihydro-4-hydroxy-6-phenyl-3-[(2-phenylethyl)thio]-2H-pyran-2-one;

5,6-Dihydro-4-hydroxy-6-phenyl-3-[(3-phenylpropyl)thio]-2H-pyran-2-one;

5,6-Dihydro-4-hydroxy-6-phenyl-3-[(2-phenoxyethyl)thio]-2H-pyran-2-one;

5,6-Dihydro-4-hydroxy-6-(2-methylpropyl)-6-phenyl-3-[(phenylmethyl)thio]-2H-pyran-2-one;

5,6-Dihydro-4-hydroxy-6-(2-methylpropyl)-6-phenyl-3-[(2-phenylethyl)thio]-2H-pyran-2-one;

5-(3-Chlorophenyl)-2-(2-phenylethyl)thio]-1,3-cyclohexanedione;

5,6-Dihydro-4-hydroxy-6-(4-methoxyphenyl)-3-[(phenylmethyl)thio]-2H-pyran-2-one;

5,6-Dihydro-4-hydroxy-6-(4-methylthiophenyl)-3-[(phenylmethyl)thio]-2H-pyran-2-one;

5,6-Dihydro-4-hydroxy-6-(4-methylphenyl)-3-[(phenylmethyl)thio]-2H-pyran-2-one;

5,6-Dihydro-4-hydroxy-6-[4-(1,1-dimethylethyl)phenyl]-3-[(phenylmethyl)thio]-2H-pyran-2-one;

6-(4-Chlorophenyl)-5,6-dihydro-4-hydroxy-3-[(phenylmethyl)thio]-2H-pyran-2-one;

6-(3-Chlorophenyl)-5,6-dihydro-4-hydroxy-3-[(phenylmethyl)thio]-2H-pyran-2-one;

5,6-Dihydro-3-[(2-phenylethyl)thio]-6-[4-(phenylmethoxy)phenyl]-2H-pyran-2-one;

5,6-Dihydro-6-(4-methoxyphenyl)-3-[(2-phenylethyl)thio]-2H-pyran-2-one;

5,6-Dihydro-6-(4-methylthiophenyl)-3-[(2-phenylethyl)thio]-2H-pyran-2-one;

5,6-Dihydro-6-(4-methylphenyl)-3-[(2-phenylethyl)thio]-2H-pyran-2-one;

6-[1,1'-Biphenyl]-4-yl-5,6-dihydro-3-[(2-phenylethyl)thio]-2H-pyran-2-one;

5,6-Dihydro-6-[4-(1,1-dimethylethyl)phenyl]-3-[(2-phenylethyl)thio]-2H-pyran-2-one;

6-(3-Chlorophenyl)-5,6-dihydro-3-[(2-phenylethyl)thio]-2H-pyran-2-one;

6-[([1,1'-Biphenyl]-4-yloxy)methyl]-5,6-dihydro-3-[(2-phenylethyl)thio]-2H-pyran-2-one;

6-[1,1'-Biphenyl]-4-yl-6-butyl-5,6-dihydro-4-hydroxy-3-[(2-phenylethyl)thio]-2H-pyran-2-one;

4-[2,3-Dihydro-4-hydroxy-6-oxo-5-[(phenylmethyl)thio]-2H-pyran-2-yl]benzonitrile;

6-(4-Trifluoromethylphenyl)-5,6-dihydro-4-hydroxy-3-[(2-phenylmethyl)thio]-2H-pyran-2-one;

6-(3,5-Dichlorophenyl)-5,6-dihydro-4-hydroxy-3-[(2-phenylmethyl)thio]-2H-pyran-2-one;

6-(Pentafluorophenyl)-5,6-dihydro-4-hydroxy-3-[(phenylmethyl)thio]-2H-pyran-2-one;

5,6-Dihydro-4-hydroxy-6-(3-methylphenyl-3-[(2-phenylethyl)thio]-2H-pyran-2-one;

6-(2-Chlorophenyl)-5,6-dihydro-4-hydroxy-3-[(phenylmethyl)thio]-2H-pyran-2-one;

6-Butyl-5,6-dihydro-4-hydroxy-6-phenyl-3-[(phenylmethyl)thio]-2H-pyran-2-one;

6-[1,1'-Biphenyl]-4-yl-6-butyl-5,6-dihydro-4-hydroxy-3-[(phenylmethyl)thio]-2H-pyran-2-one;

5,6-Dihydro-4-hydroxy-6-phenyl-3-[(phenylmethyl)thio]-6-propyl-2H-pyran-2-one;

5,6-Dihydro-4-hydroxy-6-phenyl-3-[(2-phenylethyl)thio]-6-propyl-2H-pyran-2-one;

5,6-Dihydro-4-hydroxy-6-pentyl-6-phenyl-3-[(phenylmethyl)thio]-2H-pyran-2-one;

5,6-Dihydro-4-hydroxy-6-pentyl-6-phenyl-3-[(2-phenylethyl)thio]-2H-pyran-2-one;

5,6-Dihydro-4-hydroxy-6-(3-methylbutyl)-6-phenyl-3-[(phenylmethyl)thio]-2H-pyran-2-one;

5,6-Dihydro-4-hydroxy-6-(3-methylbutyl)-6-phenyl-3-[(2-phenylethyl)thio]-2H-pyran-2-one;

5,6-Dihydro-4-hydroxy-6,6-diphenyl-3-[(phenylmethyl)thio]-2H-pyran-2-one;

5,6-Dihydro-4-hydroxy-6,6-diphenyl-3-[(2-phenylethyl)thio]-2H-pyran-2-one;

5,6-Dihydro-4-hydroxy-6-phenyl-6-(2-phenylethyl)-3-[(phenylmethyl)thio]-2H-pyran-2-one;

5,6-Dihydro-4-hydroxy-6-phenyl-6-(2-phenylethyl)-3-[(2-phenylethyl)thio]-2H-pyran-2-one;

5,6-Dihydro-4-hydroxy-6-[4-[2-(4-morpholinyl)ethoxy]phenyl]-6-(2-phenylethyl)-3-[(2-phenylethyl)thio]-2H-pyran -2-one;

1-[4-[3,6-Dihydro-4-hydroxy-6-oxo-5-[(2-phenylethyl)thio]-2H-pyran-2-yl]phenyl-5-phenyl-1H-pyrrole-2 -propionic acid;

5,6-Dihydro-4-hydroxy-6-(3-methylbutyl)-3-[[2-(1-methylethyl)phenyl]thio]-6-phenyl-2H-pyran-2-one;

5,6-Dihydro-4-hydroxy-6-phenyl-6-(2-phenylethyl)-3-[[3-phenylmethoxy)phenyl]methyl]-2H-pyran-2-one;

5,6-Dihydro-4-hydroxy-3-[5-methyl-2-(1-methylethyl)phenoxy]-6-phenyl-6-(2-phenylethyl)-2H-pyran-2-one;

N-(1,1-Dimethylethyl)-1-[[3,6-dihydro-4-hydroxy-6-oxo-2-phenyl-5-[(2-phenylethyl)thio]-2H-pyran-2-yl ]methyl]-cyclohexanecarbodylimide;

6-Butyl-3-[(1-ethyl-1H-indol-3-yl)thio]-5,6-dihydro-4-hydroxy-6-phenyl-2H-pyran-2-one;

5,6-Dihydro-4-hydroxy-6-(4-hydroxyphenyl)-3-[(phenylmethyl)thio]-2H-pyran-2-one;

5,6-Dihydro-4-hydroxy-6-(4-hydroxyphenyl)-3-[(2-phenylethyl)thio]-2H-pyran-2-one;

[4-[5,6-Dihydro-4-hydroxy-2-oxo-3-[(phenylmethyl)thio]-2H-pyran-6-yl]phenoxy]acetic acid;

[4-[5,6-Dihydro-4-hydroxy-2-oxo-3-[(2-phenylethyl)thio]-2H-pyran-6-yl]phenoxy]acetic acid;

Ethyl [4-[5,6-dihydro-4-hydroxy-2-oxo-3-[(phenylmethyl)thio]-2H-pyran-6-yl]phenoxy]-acetate;

Ethyl [4-[5,6-dihydro-4-hydroxy-2-oxo-3-[(2-phenylethyl)thio]-2H-pyran-6-yl]phenoxy]-acetate;

5,6-Dihydro-4-hydroxy-6-[4-(2-hydroxyethoxy)phenyl]-3-[(phenylmethyl)thio]-2H-pyran-2-one;

5,6-Dihydro-4-hydroxy-6-[4-(2-hydroxyethoxy)phenyl]-3-[(2-phenylethyl)thio]-2H-pyran-2-one;

5,6-Dihydro-4-hydroxy-3-[(phenylmethyl)thio]-6-[4-[2-(4-thiomorpholinyl)ethoxy]phenyl]-2H-pyran-2-one-S,S-dioxide ;

5,6-Dihydro-4-hydroxy-3-[(2-phenylethyl)thio]-6-[4-[2-(4-thiomorpholinyl)ethoxy]phenyl]-2H-pyran-2-one-S,S -dioxide;

[4-[5,6-Dihydro-4-hydroxy-2-oxo-3-[(phenylmethyl)thio]-2H-pyran-6-yl]phenoxy]-benzoic acid;

[4-[5,6-Dihydro-4-hydroxy-2-oxo-3-[(2-phenylethyl)thio]-2H-pyran-6-yl]phenoxy]-benzoic acid;

5,6-Dihydro-4-hydroxy-6-[4-(hydroxymethyl)phenyl]-3-[(phenylmethyl)thio]-2H-pyran-2-one;

5,6-Dihydro-4-hydroxy-6-[4-(hydroxymethyl)phenyl]-3-[(2-phenylethyl)thio]-2H-pyran-2-one;

5,6-Dihydro-4-hydroxy-6-(3-methylbutyl)-3-[5-methyl-1-(phenylmethyl)hexyl]-6-phenyl-2H-pyran-2-one;

3-[1-(cyclohexylthio)-5-methylhexyl]-5,6-dihydro-4-hydroxy-6-(3-methylbutyl)-6-phenyl-2H-pyran-2-one;

3-[2-(Cyclohexyl-1-[(3-methylbutyl)amino]ethyl]-5,6-dihydro-4-hydroxy-6-(3-methyl-butyl)-6-phenyl-2H-pyran-2 -he;

5,6-Dihydro-4-hydroxy-6-(3-methylbutyl)-3-[(4-methylpentyl)(phenylmethyl)amino]-6-phenyl-2H-pyran-2-one;

5,6-Dihydro-4-hydroxy-6-phenyl-3-[(phenylmethyl)thio]-6-[(tetrahydro-3-furanyl(methyl)-2H-pyran-2-one;

2,3-Dihydro-4-hydroxy-6-oxo-2-phenyl-5-[(phenylmethyl)thio]-2H-pyran-3-acetamide;

2,3-Dihydro-4-hydroxy-6-oxo-2-phenyl-5-[(phenylmethyl)thio]-2H-pyran-3-butanamide;

5-(4-Hydroxybutyl)-5,6-dihydro-4-hydroxy-6-phenyl-3-[(phenylmethyl)thio]-2H-pyran-2-one;

5,6-Dihydro-4-hydroxy-6-phenyl-3-[(2-phenylethyl)thio]-2(1H)-pyridinone;

5,6-Dihydro-4-hydroxy-1-methyl-6-phenyl-3-[(2-phenylethyl)thio]-2(1H)-pyridinone;

Phenylmethyl 2-(1-methylethyl)-2-[[3,6-dihydro-4-hydroxy-6-oxo-2-phenyl-5-[(2-phenylethyl)-thio]-2H-pyran-2

-yl]methyl]hydrazinecarboxylate;

N-[1-[[3,6-Dihydro-4-hydroxy-6-oxo-2-phenyl-5-[(2-phenylethyl)thio]-2H-pyran-2-yl]-methyl]cyclopentyl]urea ;

N-[1-[[3,6-Dihydro-4-hydroxy-6-oxo-2-phenyl-5-[(2-phenylethyl)thio]-2H-pyran-2-yl]-methyl]cyclopentyl]- N'-(phenylmethyl)urea;

Phenylmethyl [1-[[3,6-dihydro-4-hydroxy-6-oxo-2-phenyl-5-[(2-phenylethyl)thio]-2H-pyran-2-yl]methyl]cyclopentyl]carbamate;

6-[(2,3-Dimethyl-1H-pyrrol-1-yl)methyl]-5,6-dihydro-4-hydroxy-6-phenyl-3-[(2-phenylethyl)-thio]-2H-pyran -2-one;

5,6-Dihydro-4-hydroxy-6-[2-(1-piperazinyl)ethyl]-6-phenyl-3-[(2-phenylethyl)thio]-2H-pyran-2-one;

5,6-Dihydro-4-hydroxy-6-[2-(4-morpholinyl)ethyl]-6-phenyl-3-[(phenylmethyl)thio]-2H-pyran-2-one;

5,6-Dihydro-4-hydroxy-6-[3-(4-morpholinyl)propyl]-6-phenyl-3-[(phenylmethyl)thio]-2H-pyran-2-one;

5,6-Dihydro-4-hydroxy-6-[4-(4-morpholinyl)butyl]-6-phenyl-3-[(phenylmethyl)thio]-2H-pyran-2-one;

5,6-Dihydro-4-hydroxy-6-[2-(4-thiomorpholinyl)ethyl]-6-phenyl-3-[(phenylmethyl)thio]-2H-pyran-2-one;

5,6-Dihydro-4-hydroxy-6-[3-(4-thiomorpholinyl)propyl]-6-phenyl-3-[(phenylmethyl)thio]-2H-pyran-2-one;

5,6-Dihydro-4-hydroxy-6-[4-(4-thiomorpholinyl)butyl]-6-phenyl-3-[(phenylmethyl)thio]-2H-pyran-2-one;

5,6-Dihydro-4-hydroxy-6-[2-(1-piperazinyl)ethyl]-6-phenyl-3-[(phenylmethyl)thio]-2H-pyran-2-one;

5,6-Dihydro-4-hydroxy-6-[3-(1-piperazinyl)propyl]-6-phenyl-3-[(phenylmethyl)thio]-2H-pyran-2-one;

5,6-Dihydro-4-hydroxy-6-[4-(1-piperazinyl)butyl]-6-phenyl-3-[(phenylmethyl)thio]-2H-pyran-2-one;

5,6-Dihydro-4-hydroxy-6-[2-(4-methyl-1-piperazinyl)ethyl]-6-phenyl-3-[(phenylmethyl)thio]-2H-pyran-2-one;

5,6-Dihydro-4-hydroxy-6-[3-(4-methyl-1-piperazinyl)propyl]-6-phenyl-3-[(phenylmethyl)-thio]-2H-pyran-2-one;

5,6-Dihydro-4-hydroxy-6-[4-(4-methyl-1-piperazinyl)butyl]-6-phenyl-3-[(phenylmethyl)thio]-2H-pyran-2-one;

5,6-Dihydro-4-hydroxy-6-[2-(4-morpholinyl)ethyl]-6-phenyl-3-[(2-isopropylphenyl)thio]-2H-pyran-2-one;

5,6-Dihydro-4-hydroxy-6-[3-(4-morpholinyl)propyl]-6-phenyl-3-[(2-isopropylphenyl)thio]-2H-pyran-2-one;

5,6-Dihydro-4-hydroxy-6-[4-(4-morpholinyl)butyl]-6-phenyl-3-[(2-isopropylphenyl)thio]-2H-pyran-2-one;

5,6-Dihydro-4-hydroxy-6-[2-(4-morpholinyl)ethyl]-6-phenyl-3-[(2-isopropylphenyl)thio]-2H-pyran-2-one;

5,6-Dihydro-4-hydroxy-6-[3-(4-morpholinyl)propyl]-6-phenyl-3-[(2-isopropylphenyl)thio]-2H-pyran-2-one;

5,6-Dihydro-4-hydroxy-6-[4-(4-thiomorpholinyl)butyl]-6-phenyl-3-[(2-isopropylphenyl)thio]-2H-pyran-2-one;

5,6-Dihydro-4-hydroxy-6-[2-(1-piperazinyl)ethyl]-6-phenyl-3-[(2-isopropylphenyl)thio]-2H-pyran-2-one;

5,6-Dihydro-4-hydroxy-6-[3-(1-piperazinyl)propyl]-6-phenyl-3-[(2-isopropylphenyl)thio]-2H-pyran-2-one;

5,6-Dihydro-4-hydroxy-6-[4-(1-piperazinyl)butyl]-6-phenyl-3-[(2-isopropylphenyl)thio]-2H-pyran-2-one;

5,6-Dihydro-4-hydroxy-6-[2-(4-methyl-1-piperazinyl)ethyl]-6-phenyl-3-[(2-isopropylphenyl)-thio]-2H-pyran-2-one ;

5,6-Dihydro-4-hydroxy-6-[3-(4-methyl-1-piperazinyl)propyl]-6-phenyl-3-[(2-isopropyl-phenyl)thio]-2H-pyran-2- he;

5,6-Dihydro-4-hydroxy-6-[4-(4-methyl-1-piperazinyl)butyl]-6-phenyl-3-[(2-isopropyl-phenyl)thio]-2H-pyran-2- he;

5,6-Dihydro-4-hydroxy-3-[(2-isopropylphenyl)thio]-6-(3-morpholin-4-yl-3-oxopropyl)-6-phenyl-2H-pyran-2-one;

5,6-Dihydro-4-hydroxy-3-[(2-isopropylphenyl)thio]-6-(4-morpholin-4-yl-4-oxobutyl)-6-phenyl-2H-pyran-2-one;

5,6-Dihydro-4-hydroxy-3-[(2-isopropylphenyl)thio]-6-(5-morpholin-4-yl-5-oxopentyl)-6-phenyl-2H-pyran-2-one;

5,6-Dihydro-4-hydroxy-3-[(2-isopropylphenyl)thio]-6-(3-thiomorpholin-4-yl-3-oxo-propyl)-6-phenyl-2H-pyran-2-one ;

5,6-Dihydro-4-hydroxy-3-[(2-isopropylphenyl)thio]-6-(4-thiomorpholin-4-yl-4-oxobutyl)-6-phenyl-2H-pyran-2-one;

5,6-Dihydro-4-hydroxy-3-[(2-isopropylphenyl)thio]-6-(5-thiomorpholin-4-yl-5-oxopentyl)-6-phenyl-2H-pyran-2-one;

5,6-Dihydro-4-hydroxy-3-[(2-isopropylphenyl)thio]-6-(3-piperazin-1-yl-3-oxopropyl)-6-phenyl-2H-pyran-2-one;

5,6-Dihydro-4-hydroxy-3-[(2-isopropylphenyl)thio]-6-(4-piperazin-1-yl-4-oxobutyl)-6-phenyl-2H-pyran-2-one;

5,6-Dihydro-4-hydroxy-3-[(2-isopropylphenyl)thio]-6-(5-piperazin-1-yl-5-oxopentyl)-6-phenyl-2H-pyran-2-one;

5,6-Dihydro-4-hydroxy-3-[(2-isopropylphenyl)thio]-6-[3-(4-methylpiperazin-1-yl)-3-oxo-propyl)-6-phenyl-2H-pyran -2-one;

5,6-Dihydro-4-hydroxy-3-[(2-isopropylphenyl)thio]-6-[4-(4-methylpiperazin-1-yl)-4-oxo-butyl)-6-phenyl-2H-pyran -2-one;

5,6-Dihydro-4-hydroxy-3-[(2-isopropylphenyl)thio]-6-[5-(4-methylpiperazin-1-yl)-5-oxo-pentyl)-6-phenyl-2H-pyran -2-one;

5,6-Dihydro-4-hydroxy-3-[(phenylmethyl)thio]-6-(3-morpholin-4-yl-3-oxopropyl)-6-phenyl-2H-pyran-2-one;

5,6-Dihydro-4-hydroxy-3-[(phenylmethyl)thio]-6-(4-morpholin-4-yl-4-oxobutyl)-6-phenyl-2H-pyran-2-one;

5,6-Dihydro-4-hydroxy-3-[(phenylmethyl)thio]-6-(5-morpholin-4-yl-5-oxopentyl)-6-phenyl-2H-pyran-2-one;

5,6-Dihydro-4-hydroxy-3-[(phenylmethyl)thio]-6-(3-morpholin-4-yl-3-oxopropyl)-6-phenyl-2H-pyran-2-one;

5,6-Dihydro-4-hydroxy-3-[(phenylmethyl)thio]-6-(4-thiomorpholin-4-yl-4-oxobutyl)-6-phenyl-2H-pyran-2-one;

5,6-Dihydro-4-hydroxy-3-[(phenylmethyl)thio]-6-(5-thiomorpholin-4-yl-5-oxopentyl)-6-phenyl-2H-pyran-2-one;

5,6-Dihydro-4-hydroxy-3-[(phenylmethyl)thio]-6-(3-piperazin-1-yl-3-oxopropyl)-6-phenyl-2H-pyran-2-one;

5,6-Dihydro-4-hydroxy-3-[(phenylmethyl)thio]-6-(4-piperazin-1-yl-4-oxobutyl)-6-phenyl-2H-pyran-2-one;

5,6-Dihydro-4-hydroxy-3-[(phenylmethyl)thio]-6-(5-piperazin-1-yl-5-oxopentyl)-6-phenyl-2H-pyran-2-one;

5,6-Dihydro-4-hydroxy-3-[(phenylmethyl)thio]-6-[3-(4-methylpiperazin-1-yl)-3-oxo-propyl)-6-phenyl-2H-pyran-2 -he;

5,6-Dihydro-4-hydroxy-3-[(phenylmethyl)thio]-6-[4-(4-methylpiperazin-1-yl)-4-oxobutyl)-6-phenyl-2H-pyran-2-one ;

5,6-Dihydro-4-hydroxy-3-[(phenylmethyl)thio]-6-[5-(4-methylpiperazin-1-yl)-5-oxo-pentyl)-6-phenyl-2H-pyran-2 -he;

Methyl 2-t-butyl-3-[[5,6-dihydro-4-hydroxy-2-oxo-6-phenyl-6-(2-phenylethyl)-2H-pyran-3-yl]thio]benzoate;

5-[3,6-Dihydro-4-hydroxy-5-[5-methyl-3-(3-pyridinylmethoxy)-2-isopropylphenyl]thio]-6-oxo-2-phenyl-2H-pyran-2-yl ]pentanoic acid;

3-[[5-Ethyl-2-(1-methyl-2-hydroxyethyl)phenyl]thio]-5,6-dihydro-4-hydroxy-6,6-diphenylmethyl-2H-pyran-2-one;

5-[5-[(2-Cyclopentyl-5-isopropylphenyl)thio]-3,6-dihydro-4-hydroxy-6-oxo-2-phenyl-2H-pyran-2-yl]pentanoic acid;

5,6-Dihydro-4-hydroxy-6-(3-methylbutyl)-6-phenyl-3-[[2-[2-(3-pyridinyl)ethyl]phenyl]thio]-2H-pyran-2-one ;

5,6-Dihydro-4-hydroxy-3-[[5-(2-hydroxyethyl)-3-(2-phenylethyl)-2-isopropylphenyl]thio]-6-phenyl-6-(2-phenylethyl)-2H -pyran-2-one;

4-[[5,6-Dihydro-4-hydroxy-2-oxo-6,6-diphenyl-2H-pyran-3-yl]thio]-2-hydroxyindane;

3-[[4,5-Diethyl-2-(1-hydroxyethyl)phenyl]thio]-5,6-dihydro-4-hydroxy-6-phenyl-6-(2-phenyl-ethyl)-2H-pyran2- he;

5,6-Dihydro-4-hydroxy-3-[(2-isopropyl-5-methylphenyl)methyl]-6-(2-phenylethyl)-6-phenyl-2H-pyran-2-one;

5,6-Dihydro-4-hydroxy-3-[(3-hydroxymethyl-2-isopropyl-5-methylphenyl)methyl]-6,6-diphenyl-2H-pyran-2-one;

5,6-Dihydro-4-hydroxy-3-[[4-(hydroxymethyl)phenyl]methyl]-6-pentyl-6-phenyl-2H-pyran-2-one;

5,6-Dihydro-4-hydroxy-3-[(3-hydroxyphenyl)methyl]-6-(2-phenylethyl)-6-phenyl-2H-pyran-2-one;

5,6-Dihydro-4-hydroxy-6-pentyl-6-phenyl-3-[[4-(pyridin-3-ylmethoxy)phenyl]methyl]-2H-pyran-2-one;

5,6-Dihydro-4-hydroxy-3-[[(2-isopropyl-3-[2-(morpholin-4-yl)ethoxy]phenyl]methyl]-6-(2-phenylethyl)-6-phenyl- 2H-pyran-2-one;

5,6-Dihydro-4-hydroxy-3-(3-methyl-1-phenyl-but-2-enyl)-6,6-diphenyl-2H-pyran-2-one;

3-[(1,4-di-tert-Butyl-1H-imidazol-2-yl)thio]-5,6-dihydro-4-hydroxy-6-(2-phenylethyl)-6-phenyl-2H-pyran -2-one;

5,6-Dihydro-4-hydroxy-6-(3-methylbutyl)-3-(3-methyl-1-propyl-but-2-enyl)-6-phenyl-2H-pyran-2-one;

5,6-Dihydro-4-hydroxy-3-[[2-(hydroxymethyl)phenyl]methyl]-6-(2-phenylethyl)-6-phenyl-2H-pyran-2-one;

Diisobutylamino-5,6-dihydro-4-hydroxy-6,6-diphenyl-2H-pyran-2-one;

5,6-Dihydro-4-hydroxy-6-(2-phenylethyl)-6-phenyl-3-(N-phenyl-N-propylamino)-2H-pyran-2-one;

3-(3,4-Dihydro-2H-quinolin-1-yl)-6-hexyl-5,6-dihydro-4-hydroxy-6-phenyl-2H-pyran-2-one;

5,6-Dihydro-4-hydroxy-3-[(2-isopropyl-5-methylphenyl)amino]-6,6-diphenyl-2H-pyran-2-one;

6-Butyl-3-[(1,4-di-tert-butyl-1H-imidazol-2-yl)amino]5,6-dihydro-4-hydroxy-6-phenyl-2H-pyran-2-one;

6-Butyl-3-3,5-dimethylphenyl)-5,6-dihydro-4-hydroxy-6-phenyl-2H-pyran-2-one;

3-[4-[Phenylmethoxy)methyl]-1-tert-butyl-1H-imidazol-2-yl)amino]-5,6-dihydro-4-hydroxy-6-(2-phenylethyl)-6-phenyl- 2H-pyran-2-one;

3-(1-tert-Butyl-4-methyl-1H-pyrrol-2-yl)-5,6-dihydro-4-hydroxy-6,6-diphenyl-2H-pyran-2-one;

6-[2-[4-(5,5-Dimethyl-4,5-dihydro-oxazol-2-yl)phenyl]ethyl]-5,6-dihydro-4-hydroxy-3-[(2-isopropyl- 5-methylphenyl)thio]-6-phenyl-2H-pyran-2-one;

6-[2-[4-(4,4-Dimethyl-4,5-dihydro-oxazol-2-yl)phenyl]ethyl]-5,6-dihydro-4-hydroxy-3-[(2-isopropyl- 5-methylphenyl)thio]-6-phenyl-2H-pyran-2-one;

6-[2-[4-(1,1-Dioxothiomorpholin-4-yl)phenyl]ethyl]-5,6-dihydro-4-hydroxy-3-[(2-iso-propyl-5-methylphenyl)thio] -6-phenyl-2H-pyran-2-one;

1-Hydroxy-4-[2-[4-hydroxy-5-[(2-isopropyl-5-methylphenyl)thio]-6-oxo-2-phenyl-3,6-dihydro-2H-pyran-2-one ;

5,6-Dihydro-4-hydroxy-6-[2-1H-indol-5-yl)ethyl]-3-[(2-isopropyl-5-methoxyphenyl)thio]-6-phenyl-2H-pyran-2 -he;

5,6-Dihydro-4-hydroxy-6-(2-phenylethyl)-6-phenyl-3-(2-phenyl-[1,3]dithiolan-2-yl)-2H-pyran-2-one;

5,6-Dihydro-4-hydroxy-3-[(2-isopropyl-5-methylphenyl)thio]-6-(2-phenylethyl)-6-[4-[(pyridin-3-yl)methoxy]phenyl] -2H-pyran-2-one;

5,6-Dihydro-4-hydroxy-3-[(2-isopropylphenyl)thio]-6-phenyl-6-[5-(phenylmethyl)amino-2,2-dimethyl-pentyl]-2H-pyran-2- he;

N-Benzyl-5-[4-Hydroxy-5-[(2-isopropyl]phenyl]thio]-6-oxo-2-phenyl-3,6-dihydro-2H-pyran-2-yl]-4,4 -dimethyl-pentanamide;

1-[2-[4-Hydroxy-5-[(2-isopropylphenyl)thio]-6-oxo-2-phenyl-3,6-dihydro-2H-pyran-2-yl]-1-phenylethyl]-3 -pyridin-2-ylmethylurea;

5,6-Dihydro-4-hydroxy-6-(5-hydroxypentyl)-3-[(2-isopropylphenyl)thio]-6-phenyl-2H-pyran-2-one;

tert-Butyl 5-[4-hydroxy-5-[(2-isopropyl-5-methylphenyl)thio]-6-oxo-2-phenyl-3,6-dihydro-2H-pyran-2-yl]pentanoate;

6-[4-[4,4-Dimethyl-4,5-dihydro-oxazol-2-yl)butyl]-5,6-dihydro-4-hydroxy-3-[(2-iso-propylphenyl)thio]- 6-phenyl-2H-pyran-2-one;

Phenylmethyl 1-[[3,5-Dihydro-4-hydroxy-5-[(2-isopropylphenyl)thio]-6-oxo-2-phenyl-2H-pyran-2-yl]methyl]cyclohexyl]methyl-carbamate;

5,6-Dihydro-4-hydroxy-6-phenyl-3-[(phenylmethyl)thio]-6-[2-(4-pyridyl)ethyl]-2H-pyran-2-one;

5,6-Dihydro-4-hydroxy-6-[2-(5-hydroxy-2-methylphenyl)ethyl]-6-phenyl-3-[(phenylmethyl)thio]-2H-pyran-2-one;

5,6-Dihydro-4-hydroxy-6-[2-(3-morpholin-4-yl)phenyl)ethyl]-6-phenyl-3-[(phenylmethyl)thio]-2H-pyran-2-one;

5,6-Dihydro-4-hydroxy-6-[2-phenylethyl]-3-[(phenylmethyl)thio]-6-(4-pyridyl)-2H-pyran-2-one;

5,6-Dihydro-4-hydroxy-6-phenyl-3-[(phenylmethyl)thio]-6-[2-(2-thienyl)ethyl]-2H-pyran-2-one;

6-[2-(2-Furyl)ethyl]-5,6-dihydro-4-hydroxy-6-phenyl-3-[(phenylmethyl)thio]-2H-pyran-2-one;

5,6-Dihydro-4-hydroxy-6-phenyl-3-[(phenylmethyl)thio]-6-[2-(1H-pyrrol-2-yl)ethyl]-2H-pyran-2-one;

Methyl 5-[4-Hydroxy-5-[(2-isopropylphenyl)thio]-6-oxo-2-phenyl-3,6-dihydro-2H-pyran-2-yl]pentanoate;

Ethyl 5-[4-Hydroxy-5-[(2-isopropylphenyl)thio]-6-oxo-2-phenyl-3,6-dihydro-2H-pyran-2-yl]pentanoate;

Propyl 5-[4-Hydroxy-5-[(2-isopropylphenyl)thio]-6-oxo-2-phenyl-3,6-dihydro-2H-pyran-2-yl]pentanoate;

Isopropyl 5-[4-Hydroxy-5-[(2-isopropylphenyl)thio]-6-oxo-2-phenyl-3,6-dihydro-2H-pyran-2-yl]pentanoate;

tert-Butyl 5-[4-Hydroxy-5-[(2-isopropylphenyl)thio]-6-oxo-2-phenyl-3,6-dihydro-2H-pyran-2-yl]pentanoate;

Benzyl 5-[4-Hydroxy-5-[(2-isopropylphenyl)thio]-6-oxo-2-phenyl-3,6-dihydro-2H-pyran-2-yl]pentanoate;

tert-Butyl 3-[4-Hydroxy-5-[(2-isopropylphenyl)thio]-6-oxo-2-phenyl-3,6-dihydro-2H-pyran-2-yl]carbamate;

Benzyl 3-[4-Hydroxy-5-[(2-isopropylphenyl)thio]-6-oxo-2-phenyl-3,6-dihydro-2H-pyran-2-yl]carbamate;

1-Benzyl-3-{3-[4-hydroxy-5-[(2-isopropylphenyl)thio]-6-oxo-2-phenyl-3,6-dihydro-2H-pyran-2-yl]-propyl} -urea;

N-Benzyl-4-[4-Hydroxy-5-[(2-isopropylphenyl)thio]-6-oxo-2-phenyl-3,6-dihydro-2H-pyran-2-yl]butane-1-sulfonamide;

4-[4-Hydroxy-5-[(2-isopropylphenyl)thio]-6-oxo-2-phenyl-3,6-dihydro-2H-pyran-2-yl]-butane-1-sulfonamide;

4-[4-Hydroxy-3-[(2-isopropyl-5-methylphenyl)thio]-6-phenyl-5,6-dihydro-1H-pyridin-2-one;

4-[4-Hydroxy-3-[(2-isopropyl-5-methylphenyl)thio]-6-phenyl-6-(2-phenylethyl)-5,6-dihydro-1H-pyridin-2-one;

3-Hydroxy-2-[(2-isopropyl-5-methylphenyl)thio]-5-phenyl-5-(2-phenylethyl)-cyclohex-2-enone;

3-Hydroxy-2-[(2-isopropyl-5-methylphenyl)thio]-5-phenylcyclohex-2-enone;

4-Hydroxy-3-[(2-isopropyl-5-methylphenyl)sulfonyl]-6-phenyl-6-(2-phenylethyl)-5,6-dihydro-2H-pyran-2-one;

4-Hydroxy-3-(2-isopropylbenzoyl)-6-phenyl-6-(2-phenylethyl)-5,6-dihydro-2H-pyran-2-one;

4-Hydroxy-3-[methoxylamino(phenyl)methyl]-6-phenyl-6-(2-phenylethyl)-5,6-dihydro-2H-pyran-2-one;

4-Hydroxy-3-[methylimino(phenyl)methyl]-6-phenyl-6-(2-phenylethyl)-5,6-dihydro-2H-pyran-2-one;

2,3-Dihydro-4'-hydroxy-3,3-dimethyl-5'-[2-isopropylphenyl)thio]-spiro[4H-1-benzopyran-4,2'-[2H]pyran]-6'( 3'H)-one;

2,3-Dihydro-4'-hydroxy-2,2-dimethyl-5'-[(5-methyl-2-isopropylphenyl)thio]-spiro[1H-indene-1,2'-[2H]pyran]- 6'(3'H)-one;

2,3-Dihydro-4'-hydroxy-5'-[(5-methyl-2-isopropylphenyl)thio]-spiro[1H-inden-1,2'-[2H]pyran]-6'(3'H )-he;

4"-Hydroxy-5"-[(5-methyl-2-isopropylphenyl)thio]-dispiro[cyclopropane-1,2'(3'H)-[1H]-inden-1',2"-[2H] pyran]-6"(3"H)-one;

3,4-Dihydro-4'-hydroxy-5'-[(5-methyl-2-isopropylphenyl)thio]-spiro[naphthalene-1(2H),2'-[2H]pyran]-6'(3' H)-one;

3,4-Dihydro-4'-hydroxy-2,2-dimethyl-5'-[(5-methyl-2-isopropylphenyl)thio]-spiro[naphthalene-1,2'-[2H]pyran]-6' (3'H)-one;

3',4'-Dihydro-4"-hydroxy-5"-[(5-methyl-2-isopropylphenyl)thio]-dispiro[cyclopropane-1,2'(1'H)-naphthalene-1,2"[ 2H]pyran]-6"(3"H)-one;

4-Hydroxy-3-(2-isopropylphenoxy)-6-phenyl-6-(2-phenylethyl)-5,6-dihydro-2H-pyran-2-one;

4-Hydroxy-3-(2-isopropyl-5-methylphenoxy)-6-phenyl-6-(2-phenylethyl)-5,6-dihydro-2H-pyran-2-one;

3-(2-tert-Butylphenoxy-4-hydroxy-6-phenyl-6-(2-phenylethyl)-5,6-dihydro-2H-pyran-2-one;

5-[5-(2-Cyclopentylphenoxy)-4-hydroxy-6-oxo-2-phenyl-3,6-dihydro-2H-pyran-2-yl]pentanoic acid;

4-Hydroxy-3-(2-isopropyl-5-methylphenoxy)-6-(2-phenylethyl)-6-propyl-5,6-dihydro-2H-pyran-2-one;

6-Cyclopentylmethyl-4-hydroxy-3-(2-isopropylphenoxy)-6-phenyl-5,6-dihydro-2H-pyran-2-one;

3-(Cyclopropylphenylamino)-4-hydroxy-6-phenyl-6-(2-phenylethyl)-5,6-dihydro-2H-pyran-2-one;

N-[3-[Cyclopropyl[4-hydroxy-2-oxo-6-phenyl-6-(2-phenylethyl)-5,6-dihydro-2H-pyran-3-yl]amino]phenyl]benzenesulfonamide;

[3-[Cyclopropyl[4-hydroxy-2-oxo-6-(2-phenylethyl)-6-propyl-5,6-dihydro-2H-pyran-3-yl]amino]phenyl]quinoline-8-sulfonic acid acid;

3-[(Cyclopropylphenylamino)-4-hydroxy-6-(2-phenylethyl)-6-propyl-5,6-dihydro-2H-pyran-2-one;

4-Hydroxy-6-isobutyl-6-(2-phenylethyl)-3-(phenylpropylamino)-5,6-dihydro-2H-pyran-2-one;

N-[4-Hydroxy-2-oxo-6-phenyl-6-(2-phenylethyl)-5,6-dihydro-2H-pyran-3-yl]-N-phenyl-methanesulfonamide;

N-[6-(2-Benzo[1,3]dioxol-5-yl-ethyl)-4-hydroxy-2-oxo-6-phenyl-5,6-dihydro-2H-pyran-3-yl]- N-3-(methylbutyl))benzenesulfonamide;

3-[Cyclopentyl(cyclopentylmethyl)amino]-4-hydroxy-6-phenyl-6-(2-phenylethyl)-5,6-dihydro-2H-pyran-2-one;

4-Hydroxy-3-[methoxy(phenyl)methyl]-6-phenyl-6-(2-phenylethyl)-5,6-dihydro-2H-pyran-2-one;

3-[Cyclopentyl(cyclopentyloxy)methyl]-4-hydroxy-6-(2-phenylethyl)-6-propyl-5,6-dihydro-2H-pyran-2-one;

3-(1-Cyclopentyloxy-3-methylbutyl]-4-hydroxy-6-(3-methylbutyl)-6-phenyl-5,6-dihydro-2H-pyran-2-one;

6-Cyclopentyl-3-[cyclopentyl(isopropoxy)methyl]-4-hydroxy-6-methylbutyl-5,6-dihydro-2H-pyran-2-one;

4-Hydroxy-3-[(2-isopropylphenyl)thio]-6-(2-phenylethyl)-6-propyl-5,6-dihydro-2H-pyran-2-one;

4-Hydroxy-6-isobutyl-3-[2-isopropyl-5-methylphenyl)thio]-6-[(2-phenylethyl)-5,6-dihydro-2H-pyran-2-one;

3-[(2-tert-Butyl-furan-3-yl)thio]-4-hydroxy-6-phenyl-6-(2-phenylethyl)-5,6-dihydro-2H-pyran-2-one;

4-Hydroxy-3-[(3-isopropyl-pyridin-4-yl)thio]-6-phenyl-6-(2-phenylethyl)-5,6-dihydro-2H-pyran-2-one;

3-[(2-Cyclopentyl-pyridin-3-yl)thio]-4-hydroxy-6-pentyl-6-phenyl-5,6-dihydro-2H-pyran-2-one;

4-Hydroxy-6-isobutyl-3-[(3-isopropyl-isoxazol-4-yl)thio]-6-(2-phenylethyl)-5,6-dihydro-2H-pyran-2-one;

5-[(2-Isopropyl-5-methylphenyl)thio]-6-oxo-2-phenyl-2-(2-phenylethyl)-3,6-dihydro-2H-pyran-4-ylacetate;

2-[2-(benzo[1,3]dioxol-5-yl)ethyl]-5-[(2-isopropyl-5-methylphenyl)thio]-6-oxo-2-phenyl-3,6-dihydro2H- pyran-4-ylpropionate;

5-[4-Isobutyryloxy-5-[(2-isopropylphenyl)thio]-6-oxo-2-phenyl-3,6-dihydro-2H-pyran-2-yl]pentanoic acid;

N-[3-[Cyclopropyl[4-(acetoxy)-5,6-dihydro-2-oxo-6-phenyl-6-(2-phenylethyl)-2H-pyran-3-yl]methyl]phenyl]benzenesulfonamide;

5-[Cyclopropyl[3-[(phenylsulfonyl)amino]phenyl]methyl]-3,6-dihydro-6-oxo-2,2-diphenyl-2H-pyran-4-yl propionate;

3,5-Dihydro-6-oxo-2-(2-phenylethyl)-5-(1-phenylpropyl)-2-propyl-2H-pyran-4-yl 2,2-dimethylbutanoate; you

5-[Cyclopropyl[3-[(ethylsulfonyl)amino]phenyl]methyl]-3,6-dihydro-6-oxo-2-(2-phenylethyl)-2-propyl-2H-pyran-4-yl benzeneacetate;

Detailed description of the invention

The term "alkyl" herein refers to a straight or branched chain hydrocarbon radical which, unless otherwise specified, contains from 1 to 12 carbon atoms, and includes, for example, methyl, ethyl, butyl, n-propyl, isopropyl, n-butyl, s-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, udecyl and dodecyl. Alkyl groups can have one or more sites of unsaturation, such as double and triple bonds. The alkyl group is substituted or unsubstituted, and it can be with 1 to 3 of the following substituents: alkyl, alkoxy, thioalkoxy, all as defined here, hydroxy, thiol, nitro, halogen, amino, formyl, carboxyl, nitrile, -NH-CO -R, -CO-NH-, -CO2R, -COR, aryl or heteroaryl wherein alkyl (R), aryl and heteroaryl are also as defined herein.

The term "cycloalkyl" means, unless otherwise specified, a hydrocarbon ring containing 3 to 12 carbon atoms, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and adamantyl. When possible, the cycloalkyl group may contain a double bond. The cycloalkyl ring may be unsubstituted or substituted with 1 to 3 of the following groups: alkyl, alkoxy, thioalkoxy, all of which are as defined herein, hydroxy, thiol, nitro, halogen, amino, formyl, carboxyl, nitrile, -NH-CO -R, -CO-NHR-, -CO2R, -COR, aryl or heteroaryl, wherein alkyl (R), aryl and heteroaryl are as defined herein.

The term alkylcycloalkyl refers to a cycloalkyl group, as defined herein, which is directly attached to an alkyl group, as defined herein.

The terms "Alkoxy" and "ThioAlkoxy" refer to O-alkyl or S-alkyl, and alkyl is as defined above.

The term spirocyclyl refers to a carbocyclic or heterocyclic ring whose ends meet at the only carbon atom of the chain or other ring.

The term "aryl" refers to an aromatic radical that is a phenyl group, a benzyl group, a naphthyl group, a fluarenyl group, a pyrenyl group, an anthracylic group, or fused rings derived from two phenyl, naphthyl, and a five- or six-membered ring containing 0 to 3 heteroatoms, and may be selected from quinoline, isoquinolone, indole, indane, benzofuran, benzothiophene, benzoxazole, benzothiazole, bezisoxazole, coumarin, benzimidazole and the like, and may be unsubstituted or substituted with 1 to 3 of the following substituents: alkyl as defined above, alkoxy as defined above, thioalkoxy as defined above, hydroxy, thiol, nitro, halogen, amino, formyl, carboxy, nitrile, -NHCOR, -CONHR, -CO2R, -COR, aryl or heteroaryl, wherein alkyl (R), aryl and heteroaryl as defined above.

The term "heteroaryl" and "heterocyclyl" represented by "Ar" refers to a heterocyclic radical that is 2- or 3-thienyl, 2- or 3-furanyl, 2- or 3-pyrrolyl, 2-, 4- or 5-imidazolyl, 3 -, 4- or 5-pyrazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isotoazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 3 - or 5- 1,2,4-triazolyl, 4- or 5- 1,2,3-triazolyl, tetrazolyl, 2-, 3- or 4-pyridinyl, 3-, 4- or 5-pyridazinyl, 2-pyrazinyl , 2-,4- or 5-pyrimidinyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolinyl, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 2-, 3-, 4-, 5-, 6- or 7-benzo[b]thienyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl, 2-, 4-, 5-, 6- or 7-benzimidazolyl, 2-, 4-, 5, 6- or 7-benzothiazolyl, 1- or 2-piperazinyl , 2-, 3- or 4-morpholinyl, 2-, 3- or 4-thiomorpholinyl, 1-, 2- or 3-pyrrolidinyl, 2- or 3-tetrahydrofuranyl, 2-, 3- or 4-tetrahydropyranyl, 2- , 3- or 4-piperidinyl, 1-, 2-, 4-, 5- or 6-tetrahydropyrimidinyl, 2-dioxolinyl, 2-, 4 or 5-imidazolidinyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolinyl, unsubstituted or substituted with 1 or 2 substituents which may be alkyl as defined above, aryl as defined above, alkoxy as defined above, thioalkyl as defined above defined, hydroxy thiol, nitro, halogen, formyl, amino, carboxyl, nitrile, -NHCOR, -CO2R, -COR wherein alkyl is as defined above. "Halogen" means fluorine, chlorine, bromine or iodine.

Some compounds of formula I can further form pharmaceutically compatible salts formed by acid and/or base addition. All these forms are covered by this invention.

Pharmaceutically compatible acid addition salts of formula I are derived from non-toxic inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydroiodic, hydrofluoric, phosphoric acid and the like, as well as salts derived from non-toxic organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkane diacids, aromatic aliphatic and aromatic sulfonic acids, etc. Such salts include sulfates, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides , acetates, trifluoroacetates, propionates, caprylates, isobutyrals, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, maleate tartrates, methanesulfonates and the like. Also contemplated are amino acid salts such as arginates and the like, gluconates galacturonates (see, for example, Berge, S. M. et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science, 66: 1-19(1977).

Salts formed by the addition of acid from the mentioned basic compounds are prepared by combining the free base with the required amount of acid in a conventional way.

Pharmaceutically compatible base addition salts are formed with a metal or amine, such as alkali metals, alkaline earth metals or organic amines. Examples of metals that have been used as cations are: sodium, potassium, magnesium, calcium and the like. Examples of suitable amines are: N,N'-dibenzylethylenediamine, chlorprocaine, choline, diethanolamine, dicyclohexylamine, ethylenediamine, N-methylglucamine and procaine (see for example Berge, S. M. et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science, 66: 1 -19 (1977).

Salts formed by the addition of a base from the mentioned acidic compounds are prepared by combining the free acid group with the required amount of base in a conventional way.

Some compounds of the present invention can exist in unsolvated form as well as in solvated form, including hydrate forms. In general, solvated forms including hydrates are equivalent to unsolvated forms and are intended to be encompassed by the present invention.

Certain compounds of the present invention can be prepared and administered in a wide variety of oral and parenteral dosage forms. Thus, the compounds of the present invention can be administered by injection, which can be intravenous, intramuscular, subcutaneous, intraduodenal or intraperitoneal. The compounds of the present invention can also be administered by inhalation, for example intranasally. Furthermore, the compounds of the present invention can be administered transdermally. It will be apparent to those skilled in the art that the following dosage forms may contain as an active component either a compound of formula 1 or a corresponding pharmaceutically compatible salt of formula 1. For the preparation of pharmaceutical preparations from the compounds of the present invention, pharmaceutically compatible excipients may be either solid or liquid. Solid forms of preparations include powders, tablets, pills, capsules, sachets, suppositories and dispersible granules. A solid excipient may be one or more substances that may also act as diluents, flavor enhancers, binders, preservatives, tablet disintegrants, or encapsulating agents.

The powders contain finely divided four hundred auxiliary agents in a mixture with a finely divided active component.

In tablets, the active component is mixed with an auxiliary agent that has the necessary binding properties in a suitable ratio and the mixture is pressed into the desired shape and size.

Powders and tablets preferably contain from about five or ten to about seventy percent of the active substance. Suitable excipients are: magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, corn starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low-melting wax, cocoa butter, and the like. The term "preparation" includes the formulation of the active compound with an encapsulating agent as an auxiliary agent, forming a capsule with or without other auxiliary agents, which is surrounded by the auxiliary agent, so that the agent is an integral part of the capsule. Similarly, a bag is included in oriblets. Tablets, powders, capsules, pills, sachets and tablets can be used as solid dosage forms suitable for oral administration.

A low-melting wax, such as a mixture of glycerides of fatty acids or cocoa butter, is used for the preparation of suppositories, which are melted first, and the active component is homogeneously dispersed in it. Then the melted homogeneous mixture is transferred into suitable molds, left to cool until solidification.

Liquid form preparations include solutions, suspensions and emulsions, for example an aqueous solution or an aqueous propylene glycol solution. For parenteral injection, liquid preparations can be formulated in an aqueous polyethylene glycol solution.

Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and optionally adding suitable coloring and flavoring agents, stabilizers and thickeners.

Aqueous suspensions suitable for oral use can be prepared by dispersing the finely divided active component in water with a viscous material such as natural or artificial gums, resins, methylcellulose, sodium carboxymethylcellulose and other well-known suspending substances.

Also included in the invention are solid preparations that are converted into liquid forms for oral administration prior to use. Such liquid forms include solutions, suspensions and emulsions. In addition to the active component, these preparations may also contain coloring and flavoring agents, stabilizers, buffers, artificial and natural sweeteners, disintegrants, thickeners, solubilizers and the like.

The pharmaceutical preparations are preferably in dosage units. In such forms, the preparation is divided into dosage units, each of which contains an appropriate amount of active substance. A dosage unit may be a packaged preparation or a package that may contain multiple unit preparations, such as packaged tablets, capsules, and powders in vials or ampoules. The unit dosage form may also be a capsule, sachet, or capsule by itself or may be present in a corresponding number from any packaging form.

The amount of the active component in a unit dose of the preparation can range from 0.1 mg to 100 mg, preferably 0.5 mg to 100 mg, depending on the needs of the specific application and the availability of the active substance. The preparation may optionally contain other compatible therapeutic substances.

For therapeutic purposes as protease antagonists of retroviruses including HIV, or as agents for the treatment of AIDS, the compounds used in the pharmaceutical method of this invention are administered daily in an initial dose of about 0.01 mg to about 100 mg/kg. A daily dose range of about 0.2 mg to about 10 mg/kg is preferred. The dose, however, can be changed, depending on the patient's requirements, the severity of the condition being treated and the compound used. Determining the appropriate dose for a particular case is left to the expert. In general, treatment is initiated with lower doses that are less than the optimal dose of the compound. Then the dose is gradually increased until the optimal effect under the given conditions. If desired, the daily dose can be divided and given in portions during the day.

General synthesis of 5,6-dihydropyrone derivatives

Scheme I shown below illustrates the preparation of substituted dihydropyrones III.

[image]

Methyl acetoacetate (I) is added with a metal hydride, preferably sodium hydride in THF or ether at -20°C to +10°C, and then strengthened with a base, usually n-BuLi in a solvent such as THF or ether at -20° C to +10°C, during which the dianion is formed. The corresponding substituted aldehyde or ketone was added to the reaction mixture, it was left to react for an additional 15 minutes to 24 days, and finally processed, whereby β-ketolactone (dihydropyrone) II was formed. Compound II is converted to the desired pyrones III by the action of a suitable electrophile such as thiotosylate, alkyl halide and the like in an ethanol or DMF solution containing an inert base such as triethylamine and/or sodium bicarbonate at 25°C to 80°C.

For the purpose of the above and other syntheses of compounds from the presented invention, reactive functional groups present in starting compounds, reaction intermediates or reaction products can be protected during chemical reactions by using protective groups that convert the reactive functional group into sufficiently inert for the reaction conditions. (See for example Protective Groups in Organic Synthesis, 2nd ed., T.W. Green and P.G. Wuts, John Wiley & Sons, New York, NY 1991). For example, the following protective groups suitable for reducing the reactivity of amino, hydroxyl and other groups can be used: carboxylic acyl groups, such as froml, acetyl, trifluoroacetyl; alkoxycarbonyl groups, such as ethoxycarbonyl, t-butoxycarbonyl (BOC), β,β,β,-trichloroethoxycarbonyl (TCEC), β-iodoethoxycarbonyl; aryloxycarbonyl groups such as benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, phenoxycarbonyl; trialkylsilyl groups such as trimethylsilyl and t-butyldimethylsilyl (TBDMS); and groups such as trityl, tetrahydropyranyl, vinyloxycarbonyl, o-triphenylsulfenyl, diphenylphosphinyl, p-toluenesulfonyl and benzyl. After completion of the reaction, protective groups can be removed by known procedures. For example, the BOC group can be removed by acidolysis, the trityl group by hydrogenolysis, TBDMS by the action of fluoride ions, and TCEC by the action of zinc.

Scheme II describes an alternative synthesis of dihydropyrones substituted at the C-3 position.

[image]

A base such as sodium hydride or sodium ethoxide is added to acetoacetate I in a suitable solvent such as THF, ether or alcohol at -20°C to 10°C, and the resulting anion is "trapped" with an appropriately substituted alkyl or benzyl halide. , usually with bromide or iodide, resulting in the ketoester V (Y = CH2). Alternatively, chloroacetoacetate IV is treated with a thiol, preferably in the presence of a suitable base such as triethylamine, piperidine or pyridine in a suitable solvent such as dichloromethane at -10°C to +25°C to give the ketoester V (Y = S) ( see Z. Voshida et al, Tetrahedrom 26: 2987 (1970)). The required thiol can be prepared from the corresponding phenol via a Newman-Kwart rearrangement (see, for example, H. Kwart and H. Omura, J. Am. Chem. Soc. 93: 7250 (1971); M. S. Newman and F. W. Hetzel, Org. Syn. Coll. . Voll. VI: 825 (1988); M. S. Newman and H. A. Karnes, J. Org. Chem. 31: 3980 (1966)) or from the corresponding iodobenzene via nucleophilic substitution with thiourea in the presence of nickel as a catalyst (K. Takagi, Chem. Letters, 1307 (1985)). Similarly, reaction of compound IV with an alkoxide in a suitable solvent such as benzene, DMF, or a mixture of THF and HMPA at -10°C to 25°C affords acetoacetate V (Y = O) (see T. Sasaki et al., Tetrahedron 38: 85 (1982)). Intermediate V is then converted to dihydropyrone VI using the general procedure shown in Scheme III.

[image]

A suitable base such as lithium diisopropylamide is added to ester VII in a suitable solvent such as THF or ether at -78°C to 0°C, and the resulting anion is treated with a suitable acylating agent such as ester VIII at which results in ketoester IX. By cyclization of compound IX, for example by treatment with a suitable base such as sodium hydroxide or sodium alkoxide, the desired dihydropyrone X is formed.

Any of the 4-hydroxy-2H-pyran-2-ones such as III, VI or X can be constructed to contain a suitable leaving group (such as halogen, acetate, tosylate, etc.) and one of the R1 or R2 substituents . Such reaction may involve esterification or amide formation using well known methods.

Furthermore, 4-hydroxy-2(1H)-pyridinones such as XI shown below are already known (eg, see M.J. Ashton et al., Helerocyclies 28: (2) 1015 (1989)), can be translated into the desired protease inhibitor and an antiviral agent analogous to 5,6-dihydropyrones using reactions similar to those used for the conversion of II → III in Scheme I above.

[image]

Substituted 1,3-cyclohexadiones can be prepared as described by Werbel (see J. Med. Chem, 35: 3429-47 (1992) and citations therein). 1,3-Cyclohexanediones can be converted to substituted analogues using reactions similar to those for the II → III conversion.

Tetrahydro(thio)pyran-2,4-dione derivatives can be prepared as described in US Patent 4,842,638 and references therein. Tetrahydro(thio)pyran-2,4-diones can be converted into various substituted analogues using reactions similar to those for the II → III conversion.

Derivatives containing a thio group in the 3-position can also be prepared as shown in Scheme IV.

[image]

A suitable brominating agent such as N-bromosuccinimide was added to the dihydropyrone II in a suitable solvent such as t-butanol for 1 to 18 hours. The resulting brominated intermediate XII is reacted with a thiol, usually in the presence of a suitable base such as pridine or piperidine, in a suitable solvent such as dichloromethane at 0°C to 25°C to give the desired product XIII.

An alternative synthesis of derivatives containing carbon in the 3-position is shown in Scheme V.

[image]

A suitable acid was added to the dihydropyrone II, and the product was converted to intermediate XV according to the procedure described in U.S. Patent 4,842,638 (1989). The keto group of compound XV is reduced to methylene with a suitable reducing agent such as cyanoborohydride or hydrogen, in the presence of a catalyst, whereby compound XVI is formed.

Scheme VI shows a possible method for the preparation of some 4-hydroxy-2H-pyran-2-ones (such as III or VI) with side chains R1 or R2 containing an amide group.

[image]

The required acid XVII, which was prepared according to literature conditions, cyclizes to lactone XVIII in DMF and dichloromethane at a temperature from 0°C to 75°C. The lactone ring is opened with the corresponding substituted amine alone or in a solvent such as toluene at 75-110°C to form the keto amide XIX. This amide XIX was treated with the dianion described in Scheme I and lactone XX is formed which is identical to compound II where R1 represents a chain containing a new amide group. XX can be converted to the desired compound using the conditions described in Scheme I.

The compounds of the present invention may exist in their tautomeric form, i.e., in the enol and keto forms of the compounds shown in Scheme I. Both forms as well as mixtures thereof are preferred forms of the present invention.

Substituted propiophenones were prepared by hydrogenation of the corresponding chalcones in tetrahydrofuran with 5% Pd on BaSO4 as a catalyst.

Chalcones were prepared according to Kohler and Chadwell Org. Synth. Coll. Vol. I, 78, 1941.

Procedures for the preparation of 5,6-dihydropyrone derivatives

General method 1

Methylacetoacetate was added dropwise to a mixture of hexane-washed sodium hydride and anhydrous tetrahydrofuran at 0°C, and the reaction mixture was stirred at 0°C (15 minutes to 1 hour). N-butyl lithium was then added at 0°C and the reaction mixture was stirred at 0°C (15 minutes to 1 hour). An aldehyde or ketone in tetrahydrofuran was added to the dianion, the mixture was stirred at 0°C (15 minutes to 24 hours), and allowed to warm to room temperature (15 minutes to 24 hours). Water was added to the reaction mixture and left with stirring for 15 minutes to overnight. After extraction with diethyl ether, the aqueous layer was acidified with acid (2-6 M HCl) at 0°C to pH 1-2, and the aqueous layer was extracted with ethyl acetate or CH2Cl2- The organic extracts of the acid solution were combined, dried over MgSO4 and concentrated.

Example A

5,6-Dihydro-4-hydroxy-6-phenyl-2H-pyran-2-one (±)

The title compound was prepared as described in General Method 1, using 13.67 g of methyl acetoacetate, 8.5 g of 60% dispersed NaH in oil, 73.6 mL of 1.6 M n-butyllithium in hexane, 10 g of benzaldehyde, and 300 mL of tetrahydrofuran. After the addition of aldehyde, the reaction mixture was stirred for 15 minutes at -78°C, and was allowed to warm to room temperature, where it was stirred overnight. The solid was filtered off during concentration, (melting point 145-146°C).

1H NMR (CDCl3) δ 2.8-3.05 (m, 2H), 3.5 (d, 1H), 3.7 (d, 1H), 5.7 (dd, 1H), 7.3-7.5 (m, 5H).

Example B

5,6-Dihydro-4-hydroxy-6-(2-methylpropyl)-6-phenyl-2H-pyran-2-one (±)

The title compound was prepared as described in General Method 1, using 12 g of methyl acetoacetate, 4.3 g of 60% dispersed NaH in oil, 64.5 mL of 1.6 M n-butyllithium in hexane, 10 g of isovalerophenone, and 300 mL of tetrahydrofuran. After the addition of phenone, the reaction mixture was stirred for 15 minutes at -78°C, and for 2 hours at room temperature. The crude product was purified by flash chromatography using hexane/ethyl acetate 6/40-40/60 as eluent. The solid was slurried in diethyl ether. (melting point 123.5-125 °C).

1H NMR (CDCl3) δ 0.81 (d, 3H), 0.89 (d, 3H), 1.6-1.7 (m, 1H), 1.91 (m, 2H), 2.90 (d, 1H), 2.95 (d, 1H), 3.25 (d, 1H), 3.35 (d, 1H), 7.25-7.45 (m, 5H).

Example C

5,6-Dihydro-4-hydroxy-6-(4-methoxyphenyl)-2H-pyran-2-one (±)

The title compound was prepared as described in General Method 1, using 5 mL of methyl acetoacetate, 2.0 g of 60% dispersed NaH in oil, 25 mL of 2.0 M n-butyllithium in hexane, 7.0 mL of 4-methoxybenzaldehyde, and 150 mL of tetrahydrofuran. After the addition of aldehyde, the reaction mixture was stirred for 15 minutes at 0°C and allowed to warm to room temperature, where it was stirred overnight. The crude product was slurried in diethyl ether, whereby a solid was obtained (melting point 159-162°C with decomposition).

1H NMR (CDCl3) δ 2.91 (dd, 2H), 3.57 (dd, 2H), 3.83 (s, 3H), 5.66 (dd, 1H), 6.93-6.97 (m, 2H), 7.30-7.34 (m, 2H) ).

Example D

5,6-Dihydro-4-hydroxy-6-[4-(methylthio)phenyl]-2H-pyran-2-one (±)

The title compound was prepared as described in General Method 1, using 10 mL of methyl acetoacetate, 4.0 g of 60% dispersed NaH in oil, 60 mL of 1.6 M n-butyllithium in hexane, 18.8 mL of 4-methylthiobenzaldehyde, and 200 mL of tetrahydrofuran. After the addition of aldehyde, the reaction mixture was stirred for 15 minutes at -78 °C, and was allowed to warm to room temperature, where it was stirred overnight. The crude product was slurried in diethyl ether, whereby a solid was obtained (melting point 139-141°C).

1H NMR (CDCl3) δ 2.51 (s, 3H), 2.92 (dd, 2H), 3.58 (dd, 2H), 5.68 (dd, 1H), 7.27-7.31 (m, 4H).

Example E

5,6-Dihydro-4-hydroxy-6-(4-(methylphenyl)-2H-pyran-2-one (±)

The title compound was prepared as described in General Method 1, using 10 mL of methyl acetoacetate, 3.7 g of 60% dispersed NaH in oil, 58 mL of 1.6 M n-butyllithium in hexane, 10.9 mL of p-tolualdehyde, and 250 mL of tetrahydrofuran. After the addition of aldehyde, the reaction mixture was stirred for 1:5 minutes at -78°C, and was allowed to warm to room temperature, where it was stirred overnight. The crude product was slurried in diethyl ether, whereby a solid was obtained (melting point 138-139°C).

1H NMR (CDCl3) δ 2.39 (s, 3H), 2.93 (dd, 2H), 3.58 (dd, 2H), 5.69 (dd, 1H), 7.23-7.32 (m, 4H).

Example F

6-[4-(1,1-Dimethylethyl)phenyl]-5,6-dihydro-4-hydroxy-2H-pyran-2-one (±)

The title compound was prepared as described in General Method 1, using 5.0 mL of methyl acetoacetate, 2.0 g of 60% dispersed NaH in oil, 31.5 mL of 1.6 M n-butyllithium in hexane, 9.0 g of 4-(1,1-dimethylethyl ) of benzaldehyde in 100 mL of tetrahydrofuran. After the addition of aldehyde, the reaction mixture was stirred for 15 minutes at 0°C and allowed to warm to room temperature, where it was stirred overnight. The crude product was slurried in diethyl ether, whereby a solid was obtained (melting point 164-165°C).

1H NMR (CDCl3) δ 1.33 (s, 9H), 2.94 (dd, 2H), 3.59 (dd, 2H), 5.69 (dd, 1H), 7.31-7.47 (m, 4H).

Example G

6-(4-Chlorophenyl]-5,6-dihydro-4-hydroxy-2H-pyran-2-one (±)

The title compound was prepared as described in General Method 1, using 10 mL of methyl acetoacetate, 3.9 g of 60% dispersed NaH in oil, 58 mL of 1.6 M n-butyllithium in hexane, 13.5 g of 4-chlorobenzaldehyde, and 250 mL of tetrahydrofuran. After the addition of aldehyde, the reaction mixture was stirred for 15 minutes at -78°C, and was allowed to warm to room temperature, where it was stirred overnight. The crude product was slurried in diethyl ether, whereby a solid was obtained (melting point 149-150°C).

1H NMR (CDCl3) δ 2.83 (dd, 1H), 2.95 (dd, 1H), 3.60 (dd, 2H), 5.67 (dd, 1H), 7.33-7.44 (m, 4H).

Example H

6-(3-Chlorophenyl]-5,6-dihydro-4-hydroxy-2H-pyran-2-one (±)

The title compound was prepared as described in General Method 1, using 5.0 mL of methyl acetoacetate, 2.0 g of 60% dispersed NaH in oil, 25 mL of 2.0 M n-butyllithium in hexane, 6.5 g of 3-chlorobenzaldehyde, and 250 mL of tetrahydrofuran. After the addition of aldehyde, the reaction mixture was stirred for 15 minutes at -78°C, and was allowed to warm to room temperature, where it was stirred overnight. The crude product was slurried in diethyl ether, whereby a solid was obtained (melting point 122-124°C).

1H NMR (CDCl3) δ 2.83 (dd, 1H), 2.96 (dd, 1H), 3.60 (dd, 2H), 5.68 (dd, 1H), 7.25-7.42 (m, 4H).

Examples

5,6-Dihydro-4-hydroxy-6-[4-(phenylmethoxy)phenyl]-2H-pyran-2-one (±)

The title compound was prepared as described in General Method 1, using 5.0 mL of methyl acetoacetate, 2.0 g of 60% dispersed NaH in oil, 25 mL of 2.0 M n-butyllithium in hexane, 12.0 g of 4-benzyloxybenzaldehyde, and 150 mL of tetrahydrofuran. After the addition of aldehyde, the reaction mixture was stirred for 15 minutes at 0°C and allowed to warm to room temperature, where it was stirred overnight. The crude product was slurried in diethyl ether, whereby a solid was obtained (melting point 165-166°C).

1H NMR (CDCl3) δ 2.91 (dd, 1H), 3.56 (dd, 1H), 5.09 (s, 2H), 5.65 (dd, 1H), 6.98-7.04 (m, 2H), 7.30-7.44 (m, 7H) ).

Example J

6-[1,1'-Biphenyl]-4-yl-5,6-dihydro-4-hydroxy-2H-pyran-2-one (±)

The title compound was prepared as described in General Method 1, using 13.0 mL of methyl acetoacetate, 5.3 g of 50% dispersed NaH in oil, 60 mL of 1.6 M n-butyllithium in hexane, 16.3 g of 4-biphenylcarboxaldehyde, and 300 mL of tetrahydrofuran. After the addition of aldehyde, the reaction mixture was stirred for 15 minutes at 0°C and allowed to warm to room temperature, where it was stirred overnight. The crude product was slurried in diethyl ether, whereby a solid was obtained (melting point 150-152°C).

1H NMR (CDCl3) δ 2.97 (dd, 1H), 3.60 (dd, 2H), 5.77 (dd, 1H), 7.27-7'.68 (m, 9H).

Example K

6-[[(1,1'-Biphenyl)-4-yloxy]methyl]-5,6-dihydro-4-hydroxy-2H-pyran-2-one (±)

The title compound was prepared as described in General Method 1, using 4.76 mL of methyl acetoacetate, 1.97 g of 50% dispersed NaH in oil, 19.5 mL of 2.1 M n-butyllithium in hexane, 8.7 g of [[1,1'-biphenyl ]-4-yloxy]-acetaldehyde and 200 mL tetrahydrofuran. After the addition of aldehyde, the reaction mixture was stirred for 60 minutes at -78°C, and was allowed to warm to room temperature, where it was stirred overnight. The crude product was slurried in diethyl ether, whereby a solid was obtained (melting point 152-154 °C).

1H NMR (CDCl3) δ 2.83 (dd, 1H), 2.95 (dd, 1H), 3.61 (dd, 2H), 4.23 (dd, 1H), 4.38 (dd, 1H), 5.03-5.07 (m, 1H), 6.94-6.98 (m, 2H), 7.30-7.57 (m, 7H).

Example L

6-[1,1'-Biphenyl)-4-yl-6-butyl-5,6-dihydro-4-hydroxy-2H-pyran-2-one (±)

The title compound was prepared as described in General Method 1, using 13 mL of ethyl acetoacetate, 5.3 g of 60% dispersed NaH in oil, 60 mL of 1.6 M n-butyllithium in hexane, 21 g of 1-[1,1'- biphenyl]-4-yl 1 pentanone and 300 mL of tetrahydrofuran. After the addition of ketones, the reaction mixture was stirred for 60 minutes at -78°C, and for two hours at room temperature. The solid crude product was washed twice with CH2Cl2 and twice with ethyl acetate (melting point 165-170°C).

1H NMR (d6-DMSO) δ 0.7-1.9 (m, 7H), 2.0 (m, 2H), 3.0 (s, 2H), 4.9 (s, 1H), 7.3-7.8 (m, 9H), 11.3 (s , 1H).

Example M

4-[2,3-Dihydro-4-hydroxy-6-oxo-2H-pyran-2-yl]-benzonitrile (±)

The title compound was prepared as described in General Method 1, using 5.0 mL of methyl acetoacetate, 2.0 g of 60% dispersed NaH in oil, 25 mL of 2.0 M n-butyllithium in hexane, 7.6 g of 4-cyanobenzaldehyde, and 150 mL of tetrahydrofuran. After the addition of aldehyde, the reaction mixture was stirred for 10 minutes at 0°C and left at room temperature overnight. The crude product was slurried in diethyl ether, whereby a solid was obtained (melting point 149-152°C).

1H NMR (CDCl3) δ 2.80 (dd, 1H), 2.99 (dd, 1H), 3.65 (dd, 2H), 5.75 (dd, 1H), 7.55 (d, 2H), 7.75 (d, 2H).

Example N

6-(4-Trifluoromethylphenyl)-5,6-dihydro-4-hydroxy-2H-pyran-2-one (+/-)

The title compound was prepared as described in General Method 1 using 10 mL of methyl acetoacetate, 3.7 g of 60% dispersed NaH in oil, 58 mL of 1.6 M n-butyllithium in hexane, 11.5 g of 4-trifluoromethylbenzaldehyde, and 250 mL of tetrahydrofuran. After the addition of aldehyde, the reaction mixture was stirred for 10 minutes at 0°C and 30 minutes at room temperature. The crude product was slurried in diethyl ether, whereby a solid was obtained (melting point 155-156°C).

1H NMR (CDCl3) δ 2.83 (dd, 1H), 2.99 (dd, 1H), 3.38 (dd, 2H), 5.76 (dd, 1H), 7.50-7.76 (m, 4H).

Example O

6-(3,5-Dichlorophenyl)-5,6-dihydro-4-hydroxy-2H-pyran-2-one (+/-)

The title compound was prepared as described in General Method 1, using 2.5 mL methyl acetoacetate, 1.0 g 60% dispersed NaH in oil, 12.5 mL 2.0 M n-butyllithium in hexane, 5.1 g 3,5-dichlorobenzaldehyde, and 75 mL tetrahydrofuran. After the addition of aldehyde, the reaction mixture was stirred for 10 minutes at 0°C, and allowed to warm to room temperature, where it was stirred overnight. The crude product was slurried in diethyl ether, whereby a solid was obtained (melting point 135-137°C).

1H NMR (CDCl3) δ 2.78 (dd, 1H), 2.97 (dd, 1H), 3.63 (dd, 2H), 5.64 (dd, 1H), 7.31-7.40 (m, 3H).

Example P

5,6-Dihydro-4-hydroxy-6-(pentafluorophenyl)-2H-pyran-2-one (+/-)

The title compound was prepared as described in General Method 1, using 2.5 mL of methyl acetoacetate, 1.0 g of 60% dispersed NaH in oil, 12.5 mL of 2.0 M n-butyllithium in hexane, 3.4 mL of pentafluorobenzaldehyde, and 75 mL of tetrahydrofuran. After the addition of aldehyde, the reaction mixture was stirred for 10 minutes at 0°C, and allowed to warm to room temperature, where it was stirred overnight. The crude product was slurried in diethyl ether, whereby a solid was obtained (melting point 176-178°C).

1H NMR (CDCl3) δ 2.89 (dd, 1H), 3.15 (dd, 1H), 3.70 (dd, 2H), 6.02 (dd, 1H).

Example Q

5,6-Dihydro-4-hydroxy-6-(3-methylphenyl)-2H-pyran-2-one (+/-)

The title compound was prepared as described in General Method 1, using 2.0 mL of methyl acetoacetate, 0.8 g of 60% dispersed NaH in oil, 10 mL of 2.0 M n-butyllithium in hexane, 2.6 mL of 3-methylbenzaldehyde in 100 mL of tetrahydrofuran. After the addition of aldehyde, the reaction mixture was stirred for 10 minutes at 0°C, and allowed to warm to room temperature, where it was stirred overnight. The crude product was slurried in diethyl ether, whereby a solid was obtained (melting point 137-138°C).

1H NMR (CDCl3) δ 2.38 (s, 3H), 2.88 (dd, 1H), 2.95 (dd, 1H), 3.57 (dd, 2H), 5.68 (dd, 1H), 7.16-7.33 (m, 4H).

An example of R

6-(2-Chlorophenyl)-5,6-dihydro-4-hydroxy-2H-pyran-2-one (+/-)

The title compound was prepared as described in General Method 1, using 2.5 mL of methyl acetoacetate, 1.0 g of 60% dispersed NaH in oil, 12.5 mL of 2.0 M n-butyllithium in hexane, 3.3 mL of 2-chlorobenzaldehyde, and 75 mL of tetrahydrofuran. After the addition of aldehyde, the reaction mixture was stirred for 10 minutes at 0°C, and for 2 hours at room temperature. The crude product was slurried in diethyl ether, whereby a solid was obtained (melting point 124-125°C).

1H NMR (CDCl3) δ 2.63 (dd, 1H), 3.10 (dd, 1H), 3.68 (dd, 2H), 6.07 (dd, 2H), 7.3-7.65 (m, 4H).

Example of S

6-Butyl-5,6-dihydro-4-hydroxy-6-phenyl-2H-pyran-2-one (+/-)

The title compound was prepared as described in General Method 1, using 2.7 mL of methyl acetoacetate, 1.1 g of 60% dispersed NaH in oil, 12.5 mL of 2.0 M n-butyllithium in hexane, 5.1 mL of valerophenone, and 75 mL of tetrahydrofuran. After the addition of ketones, the reaction mixture was stirred for 10 minutes at 0°C and allowed to warm to room temperature, before which it was stirred overnight. The crude product was slurried in diethyl ether, whereby a solid was obtained (melting point 124-126°C).

1H NMR (CDCl3) δ 0.85 (t, 3H), 1.28 (m, 4H), 1.97 (m, 2H), 2.90 (dd, 1H), 3.30 (dd, 2H), 7.28-7.42 (m, 5H).

Example T

5,6-Dihydro-4-hydroxy-6-phenyl-6-propyl-2H-pyran-2-one (+/-)

The title compound was prepared as described in General Method 1, using 5 mmol of methyl acetoacetate, 5.5 mmol of 60% dispersed NaH in oil, 5.5 mmol of 1.6 M n-butyllithium in hexane, 5.5 mmol of butyrophenone and 14 mL of tetrahydrofuran. After the addition of ketone, the reaction mixture was stirred for 90 minutes at 0°C. The reaction mixture was poured into a saturated solution of NH4Cl and extracted with ethyl acetate. The organic layer was dried over MgSO4, concentrated, and the residue was purified by flash chromatography using hexane/ethyl acetate 80/20 as eluent. The aldol product was mixed at room temperature with 100 mL of 0.1 M NaOH for 3.5 hours. The reaction mixture was processed according to General Method 1, and the product was slurried in diethyl ether, whereby a solid was obtained (melting point 124-126°C).

1H NMR(CDCl3) δ 0.88(t,3H), 1.1-1.4 (m, 2H), 1.95 (m, 2H), 2.90 (d, 1H), 2.92 (d, 1H), 3.25 (d, 1H), 3.35 (d, 1H), 7.2-7.4 (m, 5H).

Example of U

5,6-Dihydro-6-pentyl-6-phenyl-2H-pyran-2-one (+/-)

The title compound was prepared as described in General Method 1, using 10 mmol of methyl acetoacetate, 11 mmol of 60% dispersed NaH in oil, 10.5 mmol of 1.6 M n-butyllithium in hexane, 10.5 mmol of hexanophenone and 28 mL of tetrahydrofuran. During concentration, a solid substance is precipitated, which is slurried in diethyl ether and filtered (melting point 123-124°C).

1H NMR (CDCl3) δ 0.83 (t, 3H), 1.1-1.4 (m, 6H), 1.9-2.0 (m, 2H), 2.90 (d, 1H), 2.92 (d, 1H), 3.25 (d, 1H) ), 3.35 (d, 1H), 7.2-7.5 (m, 5H).

Example V

5,6-Dihydro-6-(3-methylbutyl)-6-phenyl-2H-pyran-2-one (+/-)

The title compound was prepared as described in General Method 1, using 25 mmol of methyl acetoacetate, 27.5 mmol of 60% dispersed NaH in oil, 26.25 mmol of 1.6 M n-butyllithium in hexane, 25 mmol of isohexanophenone and 70 mL of tetrahydrofuran. During concentration, a solid substance is precipitated, which is slurried in diethyl ether and filtered (melting point 134-136°C).

1H NMR (CDCl3) δ 0.83 (dd, 6H), 1.1-1.3 (m, 2H), 1.4-1.6 (m, 1H), 1.9-2.1 (m, 2H), 2.90 (d, 1H), 2.92 (d , 1H), 3.25 (d, 1H), 3.35 (d, 1H), 7.2-7.5 (m, 5H).

Example of W

5,6-Dihydro-6,6-diphenyl-2H-pyran-2-one

The title compound was prepared as described in General Method 1, using 20 mmol of methyl acetoacetate, 22 mmol of 60% dispersed NaH in oil, 21 mmol of 1.6 M n-butyllithium in hexane, 20 mmol of benzophenone and 70 mL of tetrahydrofuran. During concentration, a solid substance is precipitated, which is slurried in diethyl ether and filtered (melting point 170.5-173°C).

1H NMR (CDCl3) δ.18 (s, 2H), 3.4 (s, 2H), 7.3-7.5 (m, 10H).

Example X

5,6-Dihydro-6-phenyl-6-(2-phenylethyl)-2H-pyran-2-one (+/-)

The title compound was prepared as described in General Method 1, using 25 mmol of methyl acetoacetate, 27.5 mmol of 60% dispersed NaH in oil, 26.25 mmol of 1.6 M n-butyllithium in hexane, 25 mmol of 3-phenylpropiophenone and 70 mL of tetrahydrofuran. During concentration, a solid substance is precipitated, which is slurried in diethyl ether and filtered (melting point 130-130.5°C).

1H NMR (CDCl3) δ 2.2-2.4 (m, 2H), 2.4-2.6 (m, 1H), 2.6-2.8 (m, 1H), 2.9 (d, 1H), 3.0 (d, 1H), 3.3 (d , 1H), 3.4 (d, 1H), 7.0-7.5 (m, 15H).

Example Y

5,6-Dihydro-4-hydroxy-6-phenyl-2(1H)-pyridinone (±)

The title compound was prepared by decarboxylation of 6-phenyl-2,4-dioxopiperidine-3-carboxylate (prepared according to Ashton et al., Heterocycles 28: (2) 1015 (1989)) by refluxing in acetonitrile (according to Toda et al., J. Antibiotics 23: (2) 173 (1980)). Removal of the solvent results in a solid (melting point 166-169°C).

1H NMR (CDCl3) δ 2.77 (dd, 1H), 2.90 (dd, 1H), 3.38 (s, 2H), 4.80 (dd, 1H), 6.40 (s, 1H), 7.32-7.46 (m, 5H).

Example Z

5,6-Dihydro-4-hydroxy-6-phenoxymethyl-6-phenyl-2H-pyran-2-one (+/-)

The title compound was prepared as described in General Method 1, using 0.85 mL of methyl acetoacetate, 350 mg of 60% dispersed NaH in oil, 5 mL of 1.6 M n-butyllithium in hexane, 2.0 g of 2-phenoxy-1-phenyl- of ethanone and 60 mL of tetrahydrofuran. After the addition of ketone, the reaction mixture was stirred for 10 minutes at 0°C, and was stirred for 1 hour at room temperature. The crude product was slurried in diethyl ether, whereby a solid was obtained (melting point 133-135°C).

1H NMR (CDCl3) δ 3.03 (d, 1H), 3.35 (d, 1H), 4.18 (dd, 2H), 4.90 (s, 1H), 6.92-6.95 (m, 3H), 7.24-7.49 (m, 7H) ), 11.56 (s, 1H).

Example A1

6-(2-Benzo[1,3]dioxol-5-yl-ethyl)-5,6-dihydro-4-hydroxy-6-phenyl-2H-pyran-2-one (+/-)

The title compound was prepared as described in General Method 1, using 0.22 mL of methyl acetoacetate, 90 mg of 60% dispersed NaH in oil, 1 mL of 2.1 M n-butyllithium in hexane, 500 mg of 3-(3,4 -methylenedioxyphenyl)propiophenone and 15 mL of tetrahydrofuran. After the addition of ketone, the reaction mixture was stirred for 10 minutes at 0°C, and was stirred for 2 hours at room temperature. The crude product was slurried in diethyl ether, whereby a solid was obtained (melting point 112-114°C).

1H NMR (CDCl3) δ 2.20-2.28 (m, 2H), 2.37-2.44 (m, 1H), 2.61-2.69 (m, 1H), 2.95 (dd, 2H), 3.32 (dd, 2H), 5.90 (s , 2H), 6.52-6.70 (m, 3H), 7.33-7.44 (m, 5H).

Example B1

6-[2-(3,4-Dichlorophenyl)-ethyl]-5,6-dihydro-4-hydroxy-6-phenyl-2H-pyran-2-one (+/-)

The title compound was prepared as described in General Method 1, using 1.7 mL of methyl acetoacetate, 630 mg of 60% dispersed NaH in oil, 9.85 mL of 1.6 M n-butyllithium in hexane, 4.0 g of 3-(3,4-dichlorophenyl) ) of propiophenone and 150 mL of tetrahydrofuran. After the addition of ketones, the reaction mixture was stirred for 15 minutes at 0°C and allowed to warm to room temperature while stirring for 4 hours. The crude product was slurried in diethyl ether, whereby a solid was obtained (melting point 145-147°C).

1H NMR (CDCl3) δ 2.18-2.35 (m, 2H), 2.39-2.50 (m, 1H), 2.68-2.80 (m, 1H), 2.96 (dd, 2H), 3.36 (dd, 2H), 6.90-7.50 (m, 8H).

Example C1

6-[2-(4-Fluorophenyl)-ethyl)-5,6-dihydro-4-hydroxy-6-phenyl-2H-pyran-2-one (+/-)

The title compound was prepared as described in General Method 1, using 3.4 mL of methyl acetoacetate, 1.2 mg of 60% dispersed NaH in oil, 18 mL of 1.6 M n-butyllithium in hexane, 6.0 g of 3-(4-fluorophenyl)propiophenone. and 200 mL tetrahydrofuran. After the addition of ketone, the reaction was stirred for 15 minutes at 0°C, and for 4 hours at room temperature. The crude product was slurried in diethyl ether, whereby a solid was obtained (melting point 155-157°C).

1H NMR (CDCl3) δ 2.23-2.29 (m, 2H), 2.41-2.52 (m, 1H), 2.67-2.78 (m, 1H), 2.97 (dd, 2H), 3.35 (dd, 2H), 7.34-7.47 (m, 5H), 6.91-7.07 (m, 4H).

Example D1

5,6-Dihydro-6-hexyl-4-hydroxy-6-phenyl-2H-pyran-2-one (±)

The title compound was prepared as described in General Method 1, using 25 mmol of methyl acetoacetate, 27.5 mmol of 60% dispersed NaH in oil, 26.25 mmol of 1.6 M n-butyllithium in hexane, 25 mmol of heptanophenone and 70 mL of tetrahydrofuran. During concentration, a solid substance is precipitated, which is slurried in diethyl ether and filtered (melting point 119-120.5°C).

1H NMR (CDCl3) δ 0.84 (t, 3H), 1.1-1.4 (m, 8H), 1.9-2.0 (m, 2H), 2.89 (d, 1H), 2.93 (d, 1H), 3.24 (d, 1H) ), 3.35 (d, 1H), 7.2-7.5 (m, 5H).

Example E1

5,6-Dihydro-6-hexyl-4-hydroxy-6-(4-methylpentyl)-6-phenyl-2H-pyran-2-one (±)

The title compound was prepared as described in General Method 1, using 14.2 mmol of methyl acetoacetate, 15.6 mmol of 60% dispersed NaH in oil, 14.9 mmol of 1.6 M n-butyllithium in hexane, 14.2 mmol of isoheptanophenone and 50 mL of tetrahydrofuran. Isoheptanophenone is prepared by reacting the appropriate acid chloride with AlCl3 in benzene as described by Vogel in Practical Organic Chemistry 1978, 770-775. During concentration, a solid substance is precipitated which was recrystallized from ethyl acetate (melting point 124-125°C).

1H NMR (CDCl3) δ 0.80 (dd, 6H), 1.1-1.2 (m, 2H), 1.15-1.40 (m, 2H), 1.4-1.5 (m, 1H), 1.9-2.0 (m, 2H), 2.88 (d, 1H), 2.9 (d, 1H), 3.2 (d, 1H), 3.3 (d, 1H), 7.2-7.5 (m, 5H).

Example F1

6-(Cyclopentylmethyl)-5,6-dihydro-6-hexyl-4-hydroxy-6-phenyl-2H-pyran-2-one (±)

The title compound was prepared as described in General Method 1, using 25 mmol of methyl acetoacetate, 27.5 mmol of 60% dispersed NaH in oil, 26.25 mmol of 1.6 M n-butyllithium in hexane, 25 mmol of 2-cyclopentyl-1-phenyl- of ethanone and 70 mL of tetrahydrofuran. 2-Cyclopentyl-1-phenyl-ethanone was prepared by reacting the appropriate acid chloride with AlCl3 in benzene as described by Vogel in Practical Organic Chemistry 1978, 770-775. During concentration, a solid substance is precipitated which was recrystallized from ethyl acetate (melting point 158-160°C).

1H NMR (DMSO-d6) δ 0.8-0.9 (m, 1H), 1.0-1.1 (m, 1H), 1.2-1.8 (m, 7H), 1.9-2.1 (m, 2H), 2.9 (ABq, 2H) , 4.8 (s, 1H), 7.2-7.4 (m, 5H), 11.3 (s, 1H).

Example G1

3,4-Dihydro-4'-hydroxy-spiro[naphthlen-1(2H),2'-[2H]pyran]-6' (3'H)-one (±)

The title compound was prepared as described in General Method 1, using 25 mmol of methyl acetoacetate, 27.5 mmol of 60% dispersed NaH in oil, 26.25 mmol of 1.6 M n-butyllithium in hexane, 25 mmol of α-tetralone and 70 mL of tetrahydrofuran. The product was recrystallized from ethyl acetate/diethyl ether (melting point 117-119°C).

1H NMR (DMSO-d6) δ 1.7-1.9 (m, 1H), 1.9-2.1 (m, 2H), 2.1-2.3 (m, 1H), 2.7-3.0 (m, 2H), 2.95 (d, 1H) , 3.1 (d, 1H), 3.5 (s, 2H), 7.1-7.2 (m, 1H), 7.2-7.3 (m, 2H), 7.4-7.5 (m, 1H).

Example H1

3-(3,6-Dihydro-4-hydroxy-6-oxo-2-phenyl-2H-pyran-2-yl)-propionic acid (±)

The title compound was prepared as described in General Method 1, using 25 mmol of methyl acetoacetate, 27.5 mmol of 60% dispersed NaH in oil, 26.25 mmol of 1.6 M n-butyllithium in hexane in 50 mL of tetrahydrofuran, and 25 mmol of sodium 3- of benzoylpropionate in 60 mL of tetrahydrofuran. Sodium 3-benzoylpropionate was prepared by reacting the acid (25 mmol) with NaH in hexane (26.25 mmol) in tetrahydrofuran at 0°C for 30 minutes. The crude product was purified by flash chromatography using CH2Cl2/MeOH/CH3CO2H (90/10/0.2) to give a viscous gum.

1H NMR (CDCl3) δ 2.1-2.6 (m, 4H), 2.9 (d, 1H), 3.0 (d, 1H), 3.3 (d, 1H), 3.4 (d, 1H), 7.2-7.5 (m, 5H ).

Example I1

4-(3,6-Dihydro-4-hydroxy-6-oxo-2-phenyl-2H-pyran-2-yl)-butyric acid (±)

The title compound was prepared as described in General Method 1, using 25 mmol of methyl acetoacetate, 27.5 mmol of 60% dispersed NaH in oil, 26.25 mmol of 1.6 M n-butyllithium in hexane in 50 mL of tetrahydrofuran, and 25 mmol of sodium 4- of benzoyl butyrate in 100 mL of tetrahydrofuran. Sodium 4-benzoylbutyrate was prepared by reacting the acid (25 mmol) with NaH in hexane (17.5 mmol) in tetrahydrofuran at 0°C for 25 minutes. The crude product was purified by flash chromatography using CH2Cl2/MeOH/CH3CO2H (99/0.1-97.5/2.5/0.1) to give a solid which was recrystallized from ethyl acetate (mp 134-137°C).

1H NMR (DMSO-d6) δ 1.1-1.2 (m, 1H), 1.4-1.6 (m, 1H), 1.8-2.0 (m, 2H), 2.0-2.2 (m, 2H), 2.9 (ABq, 2H) , 4.85 (s, 1H), 7.2-7.4 (m, 5H).

Example J1

5-(3,6-Dihydro-4-hydroxy-6-oxo-2-phenyl-2H-pyran-2-yl)-pentanoic acid (±)

The title compound was prepared as described in General Method 1, using 25 mmol of methyl acetoacetate, 27.5 mmol of 60% dispersed NaH in oil, 26.25 mmol of 1.6 M n-butyllithium in hexane in 50 mL of tetrahydrofuran, and 25 mmol of sodium 5- benzoylpentanoate in 100 mL of tetrahydrofuran. Sodium 5-benzoylpentanoate was prepared by reacting the acid (25 mmol) with NaH in hexane (27.5 mmol) in tetrahydrofuran at 0°C for 25 minutes. The crude product was recrystallized from ethyl acetate (melting point 136-140°C).

1H NMR (DMSO-d6) δ 0.8-2.0 (m, 1H), 1.1-1.3 (m, 1H), 1.3-1.5 (m, 2H), 1.8-2.0 (m, 2H), 2.1 (t, 2H), 2.9 (ABq, 2H), 4.85 (s, 1H), 7.2-7.4 (m, 5H), 11.4 (broad s, 1H), 12.0 (broad s, 1H).

Example K 1

5,6-Dihydro-4-hydroxy-6-phenyl-6-pyridin-4-yl-2H-pyran-2-one (±)

The title compound was prepared as described in General Method 1, using 90 mmol ethyl acetoacetate, 99 mmol 60% dispersed NaH in oil, 95 mmol 1.6 M n-butyllithium in hexane, 90 mmol 4-benzoylpyridine and 250 mL tetrahydrofuran. The reaction mixture was acidified with acetic acid, and the solid product was washed with a mixture of ice and water (melting point 148-150°C).

Example L 1

5,6-Dihydro-4-hydroxy-6-[(inethylphenylamino)methyl]-6-phenyl-2H-pyran-2-one (±)

2-(Methylphenylamino)-1-phenylethanone was prepared by reacting N-methylamine (50 mmol), α-bromoacetophenone (50 mmol), triethylamine (55 mmol) in diethyl ether at room temperature overnight. The diethyl ether was evaporated, p-dioxane was added and the mixture was refluxed for 15 hours. The solid triethylamine hydrochloride was filtered off. The filtrate was concentrated, and the solid was recrystallized from ethyl acetate, whereby the desired solid compound was obtained (melting point 118-120°C).

The title compound was prepared as described in General Method 1, using 6.7 mmol of methyl acetoacetate, 7.3 mmol of 60% dispersed NaH in oil, 7.0 mmol of 1.6 M n-butyllithium in hexane, 6.7 mmol of 2-(methyl phenylamino)-1 -phenylethanone and 40 mL of tetrahydrofuran. The reaction mixture is acidified conc. HCl to pH 7 and then acidified with acetic acid to pH 3. The product was purified by flash chromatography using CH2Cl2/MeOH (99/1) to give a solid (mp 152-153°C).

1H NMR (CDCl3) δ 2.9 (d, 1H), 3.05 (s, 3H), 3.1 (d, 1H), 3.2 (d, 1H), 3.3 (d, 1H), 3.7 (ABq, 2H), 6.7- 6.8 (m, 3H), 7.2-7.3 (m, 2H), 7.3-7.5 (m, 5H).

Example M 1

N-Benzyl-4-(3,6-dihydro-4-hydroxy-6-oxo-2-phenyl-2H-pyran-2-yl)-N-methylbutyramide (±)

N-Benzyl-5-oxo-5-phenylpentanamide was prepared by refluxing N-methyl-benzylamine (10.5 mmol) and 6-phenyl-3,4-dihydro-pyran-2-one (10.5 mmol) in toluene for one hour. The reaction was allowed to stir overnight at room temperature. The mixture was poured into 100 mL of ethyl acetate and 100 mL of 1M HCl. The organic extracts were washed with 100 mL of 1M NaOH, 100 mL of water and dried over MgSO4. The crude product was purified by "flash" chromatography (CH2Cl2/MeOH 98/2), whereby a liquid was formed.

1H NMR (CDCl3) δ 2.0-2.2 (m, 2H), 2.5 (t, 2H), 2.93/2.96 (s/s, 3H), 3.0-3.2 (m, 2H), 4.5/4.6 (s/s, 2H), 7.1-7.6 (m, 8H), 7.8-8.0 (m, 2H).

The title compound was prepared as described in General Method 1, using 5.6 mmol of methyl acetoacetate, 6.1 mmol of 60% dispersed NaH in oil, 5.9 mmol of 1.6 M n-butyllithium in hexane, 5.6 mmol of N-benzyl-5-oxo- of 5-phenylpentanamide and 25 mL of tetrahydrofuran. The product was purified by flash chromatography using CH2Cl2/MeOH (98/2) to give a solid (mp 47-51°C).

1H NMR (CDCl3) δ 1.1-1.3 (m, 1H), 1.4-1.6 (m, 1H), 1.8-2.0 (m, 2H), 2.2-2.4 (m, 2H), 2.75/2.81 (s/s 3H ), 2.85-3.1 (m, 2H), 4.4/4.5 (s/s, 2H), 4.85/4.9 (s/s, 1H), 7.1-7.4 (m, 10h), 11.36/11.38 (s/s, 1H).

General method 2

The thiotosylate reagent was prepared by reacting the same molar ratios of alkyl halides to sodium thiotosylate in absolute ethanol, and by refluxing for 24 hours in DMF and stirring at room temperature for 12 to 72 hours. The solvent was removed, and the residue was treated with ethyl acetate and washed with water. Alternatively, water was added and the aqueous layer was extracted with diethyl ether or ethyl acetate. The organic extracts were dried over MgSO4 and concentrated in vacuo.

Alternatively, the thiotosylate reagent is prepared as described by M. G. Ranasinghe and P. L. Fuchs in Syn. Comm. 18(3): 227 (1988).

Example AA

Benzyl p-toulenthiosulfonate

The title compound was prepared as described in General Method 2, using 0.05 mol benzyl chloride, 0.05 mol potassium thiotosylate in 150 mL ethanol. The residue was dissolved in hexane and crystallized, whereby 10.8 (77%) of benzyl-p-toluene-thiosulfonate (melting point 52-56.5°C) was obtained.

1H NMR (CDCl3) δ 2.45 (s, 3H), 4.26 (s, 2H), 7.18-7.30 (m, 7H), 7.74 (d, 2H).

Example BB

2-Phenylethyl-p-toulenthiosulfonate

The title compound was prepared as described in General Method 2, using pentenyl bromide (0.088 mol), potassium thiosulfate (0.088 mol) and absolute ethanol (250 mL). A pure liquid was obtained, which was further used without purification.

1H NMR (CDCl3) δ 2.47 (s, 3H), 2.92 (t, 2H), 3.24 (t, 2H), 7.1-7.4 (m, 7H), 7.84 (d, 2H).

Example CC

3-Phenylpropyl-p-toulenthiosulfonate

The title compound was prepared as described in General Method 2, using 1-bromo-3-phenylpropane (0.044 mol), potassium thiotosylate (0.044 mol) and absolute ethanol (125 mL), yielding an oil which was used further without purification.

1H NMR (CDCl3) δ 1.95 (quintet, 2H), 2.459 (s, 3H), 2.63 (t, 2H), 2.95 (t, 2H), 7.0-7.4 (m, 8H), 7.7 (d, 2H).

Example of DD

2-Phenoxyethyl-p-toulenthiosulfonate

The title compound was prepared as described in General Method 2, using 2-phenoxoethyl bromide (0.025 mol), potassium thiosilyl (0.025 mol) and DMF (100 mL), to give a solid.

1H NMR (CDCl3) δ 2.45 (s, 3H), 3.34 (t, 2H), 4.14 (t, 2H), 6.80 (d, 2H), 6.95 (t, 1H), 7.26 (t, 2H), 7.35 ( d, 2H), 7.82 (d, 2H).

General method 3

3-Bromo-5,6-dihydro-4-hydroxy-2H-pyran-2-one intermediates were prepared by reacting the same molar ratios of the required 6-substituted 5,6-dihydro-4-hydroxy-2H-pyran-2-one ( prepared according to General Method 1), and N-bromosuccinimide (1.0 equivalent) in dry t-butanol in a dark place. The solvent was evaporated, the residue was partitioned between chloroform and water. The organic layer was washed with sodium chloride solution, dried (MgSO4) and concentrated.

Example AAA

3-Bromo-5,6-dihydro-4-hydroxy-6,6-diphenyl-2H-pyran-2-one

The title compound was prepared as described in General Method 3, using 4.0 mmol of 5,6-dihydro-4-hydroxy-6,6-diphenyl-2H-pyran-2-one (prepared in Example W) and 4.0 mmol of NBS. A solid was obtained.

1H NMR (DMSO-d6) δ 3.68 (s, 2H), 7.27-7.40 (m, 10H).

Example BBB

3-Bromo-5,6-dihydro-4-hydroxy-6-phenyl-6-(2-phenylethyl)-2H-pyran-2-one (+/-)

The title compound was prepared as described in General Method 3, using 2.0 mmol of 5,6-dihydro-4-hydroxy-6-phenyl-6-(2-phenylethyl)-2H-pyran-2-one (prepared in Example X ) and 2.0 mmol NBS.

1H NMR (DMSO-d6) δ 2.16-2.58 (m, 4H), 3.30 (m, 2H), 7.04-7.60 (m, 10H).

Example CCC

3-Bromo-5,6-dihydro-4-hydroxy-6-phenyl-(3-methylbutyl)-2H-pyran-2-one (+/-)

The title compound was prepared as described in General Method 3, using 2.0 mmol of 5,6-dihydro-4-hydroxy-6-phenyl-6-(3-methylbutyl)-2H-pyran-2-one (prepared in Example V ) and 2.0 mmol NBS.

1H NMR (DMSO-d6) δ 0.80, (m, 6H), 1.00 (m, 1H), 1.14 (m, 1H), 1.42 (m, 1H), 1.95 (m, 2H), 3.35 (m, 2H) , 7.25-7.52 (m, 5H).

Example of DDD

5-[5-Bromo-4-hydroxy-6-oxo-2-phenyl-3,6-dihydro-2H-pyran-2-yl]pentanoic acid (+/-)

The title compound was prepared as described in General Method 3, using 1.4 mmol of 5-[4-hydroxy-6-oxo-2-phenyl-3,6-dihydro-2H-pyran-2-yl]pentanoic acid (prepared in Example J1) and 1.4 mmol NBS.

1H NMR (DMSO-d6) δ 0.94, (m, 1H), 1.22-1.40 (m, 3H), 1.92 (m, 2H), 2.13 (t, 2H), 3.28 (q, 2H), 7.16-7.52 ( m, 5H).

General method 4

The desired compounds were prepared by adding 5,6-dihydro-2H-pyran-2-one, absolute ethanol, p-toluenethiosulfonate reagent and Et3N to the reaction vessel. The solution was stirred from room temperature to reflux for 4 hours to one week. The solvent was removed, and the residue was partitioned between 1M HCl and CH2Cl2 or ethyl acetate. The layers were separated, and the aqueous layer was extracted with CH2Cl2 or ethyl acetate. The organic layers were combined and dried over MgSO4.

Example 1

5,6-Dihydro-4-hydroxy-6-phenyl-3-[(phenylmethyl)thio]-2H-pyran-2-one (±)

The title compound was prepared as described in General Method 4, using 2.1 mmol of 5,6-dihydro-4-hydroxy-6-phenyl-2H-pyran-2-one, 10 mL of absolute ethanol, 2.3 mmol of benzyl-p -toluenethiosulfonate and 2.3 mmol of Et3N in 5 mL of absolute ethanol. The solution was stirred for 3 days at room temperature. Concentration in vacuum gives a solid which is slurried in diethyl ether and ethyl acetate. The solid was filtered off, the mother liquor was evaporated and the product was purified by flash chromatography on silica gel using CH2Cl2/MeOH (99/1 to 97/3) as eluent. By combining the fractions, 0.365 g (55%) of the desired product was obtained in the form of a solid (melting point 150-151.5°C).

1H NMR (CDCl3) δ 2.65 (dd, 1H), 2.78 (dd, 1H), 3.85 (d, 1H), 3.94 (d, 1H), 5.29 (dd, 1H), 7.2-7.4 (m, 11H).

Example 2

5,6-Dihydro-4-hydroxy-6-phenyl-3-[(2-phenylmethyl)thio]-2H-pyran-2-one (±)

The title compound was prepared as described in General Method 4, using 2.1 mmol of 5,6-dihydro-4-hydroxy-6-phenyl-2H-pyran-2-one, 6 mL of absolute ethanol, 2.3 mmol of 2-phenylethyl-p -toluenethiosulfonate in 6 mL of absolute EtOH and 2.3 mmol of triethylamine in 3 mL of absolute EtOH. The reaction was stirred for 4 days at room temperature. The product was purified by flash chromatography on silica gel using CH2Cl2/MeOH (99/1 to 97/3) as eluent. The resulting viscous paste was isolated and slurried in ether, resulting in a solid (melting point 98-99°C).

1H NMR (CDCl3) δ 2.8-3.1 (m, 6H), 5.3 (dd, 1H), 7.1-7.7 (m, 11H).

Example 3

5,6-Dihydro-4-hydroxy-6-phenyl-3-[(3-phenylpropyl)thio]-2H-pyran-2-one (±)

The title compound was prepared as described in General Method 4, using 2.63 mmol of 5,6-dihydro-4-hydroxy-6-phenyl-2H-pyran-2-one, 7 mL of absolute EtOH, 2.76 mmol of 2-phenylpropyl-p -toluenethiosulfonate in 6 mL of absolute EtOH and 2.89 mmol of triethylamine in 2 mL of absolute EtOH. The reaction was stirred for 2 days at room temperature. The product was slurried in ethyl acetate, whereby a solid was obtained (melting point 134-135°C).

1H NMR (CDCl3) δ 1.8 (quintet, 2H), 2.6-2.8 (m, 4H), 2.87 (dd, 1H), 3.01 (dd, 1H), 5.43 (dd, 1H), 7.1-7.5 (m, 10H ), 7.81 (wide s, 1H).

Example 4

5,6-Dihydro-4-hydroxy-6-phenyl-3-[(2-phenoxyethyl)thio]-2H-pyran-2-one (±)

The title compound was prepared as described in General Method 4, using 0.54 mmol of 5,6-dihydro-4-hydroxy-6-phenyl-2H-pyran-2-one, 7 mL of absolute EtOH, 0.57 mmol of 2-phenoxyethyl-p -toluenethiosulfonate in 6 mL absolute EtOH and 0.06 mmol triethylamine in 2 mL absolute EtOH. The reaction was stirred for 2 days at room temperature.

The product was purified by "flash" chromatography, and was slurried in diethyl ether, whereby a solid was obtained (melting point 107-108°C).

1H NMR (DMSO-d6) δ 2.80 (dd, 1H), 2.9-3.0 (m, 2H), 3.08 (dd, 1H), 4.07 (t, 2H), 5.47 (dd, 1H), 6.9-7.0 (m , 3H), 7.2-7.5 (m, 7H).

Example 5

5,6-Dihydro-4-hydroxy-6-(2-methylpropyl)-6-phenyl-3-[(phenylmethyl)thio]-2H-pyran-2-one (±)

The title compound was prepared as described in General Method 4, using 0.61 mmol of 5,6-dihydro-4-hydroxy-6-(2-methylpropyl)-6-phenyl-2H-pyran-2-one, 5 mL of absolute EtOH , 0.67 mmol of benzyl-p-toluenethiosulfonate in 3 mL of absolute EtOH and 0.67 mmol of triethylamine in 2 mL of absolute EtOH. The reaction was stirred for 18 hours at room temperature. The product was purified by "flash" chromatography (CH2Cl2/MeOH) 99.5/0.5), whereby a viscous oil was formed.

1H NMR (CDCl3) δ 0.72 (d, 3H), 0.90 (d, 3H), 1.5-1.7 (m, 1H), 1.81 (dd, 1H), 1.91 (dd, 1H), 2.95 (ABq, 2H), 3.53 (d, 1H), 3.75 (d, 1H), 6.8-6.9 (m, 2H), 7.1-7.4 (m, 8H).

Example 6

5,6-Dihydro-4-hydroxy-6-(2-methylpropyl)-6-phenyl-3-[(2-phenylmethyl)thiol-2H-pyran-2-one (±)

The title compound was prepared as described in General Method 4, using 0.61 mmol of 6-i-butyl-5,6-dihydro-4-hydroxy-6-(2-methylpropyl)-6-phenyl-2H-pyran-2- it, 5 mL of absolute EtOH, 0.67 mmol of 2-phenylethyl-p-toluenethiosulfonate in 3 mL of absolute EtOH and 0.67 mmol of triethylamine in 2 mL of absolute EtOH. The reaction was stirred for 18 hours at room temperature. The product was purified by "flash" chromatography (CH2Cl2/MeOH) 99.5/0.5), whereby a viscous oil was formed.

1H NMR (CDCl3) δ 0.75 (d, 3H), 0.89 (d, 3H), 1.5-1.7 (m, 1H), 1.87 (dd, 1H), 1.95 (dd, 1H), 2.2-2.3 (m, 1H ), 2.4-2.5 (m, 1H), 2.6-2.8 (m, 1H), 3.13 (ABq, 2H), 6.90-6.95 (m, 2H), 7.1-7.4 (m, 8H).

Example 7

5-(3-Chlorophenyl)-2-[2-phenylethyl)thio]-1,3-cyclohexanedinone)

5-(3-Chlorophenyl)-1,3-cyclohexanedinone can be prepared as described in J. Med. Chem. 1992, 35, 19, 3429-3447. 0.03 g (1.35 mmol) of 5-(3-chlorophenyl)-1,3-cyclohexanedinone in 5 mL of absolute EtOH, 0.43 (1.48 mmol) of 2-phenylethyl-p-toluenethiosulfonate in 3 mL of absolute EtOH were added to a 50 mL reaction flask. and 0.16 g (1.62 mmol) of Et3N in 2 mL of absolute EtOH. The reaction was stirred for 27 hours at room temperature. Ethanol was removed in vacuo and the residue was dissolved in 200 mL of diethyl ether and 100 mL of HCl. The aqueous layer was extracted with 2x100 mL of diethyl ether. The organic extracts were combined, dried over MgSO4 and concentrated. The residue was purified by flash chromatography using CH2Cl2/MeOH 99/1 to give a solid (mp 69-73°C).

1H NMR (CDCl3) δ 2.5-3.1 (m, 8H), 3.3 (m, 1H), 7.1-7.4 (m, 9H), 7.9 (broad s, 1H).

Example 8

5,6-Dihydro-4-hydroxy-6-(4-methoxyphenyl)-3-[(phenylmethyl)thio]-2H-pyran-2-one (+/-)

The title compound was prepared as described in General Method 4, using 300 mg of 5,6-dihydro-4-hydroxy-6-(4-methoxyphenyl)-2H-pyran-2-one, 500 mg of benzyl p-toluenethiosulfonate and 1.0 mL of triethylamine in 10 mL of absolute ethanol. The solution was stirred overnight at room temperature. Purification by flash chromatography using CH2Cl2/MeOH (100/0 to 95/5) gave a viscous oil which was triturated in diethyl ether to give a solid (mp 168-170°C).

1H NMR (CDCl3) δ 2.60 (dd, 1H), 2.77 (dd, 1H), 3.82 (s, 3H), 3.89 (dd, 2H), 5.23 (dd, 1H), 6.89-7.33 (m, 10H).

Example 9

5,6-Dihydro-4-hydroxy-6-(4-methylthiophenyl)-3-[(phenylmethyl)thio]-2H-pyran-2-one (+/-)

The title compound was prepared as described in General Method 4, using 480 mg of 5,6-dihydro-4-hydroxy-6-(4-methylthiophenyl)-2H-pyran-2-one, 620 mg of benzyl p-toluenethiosulfonate and 0.34 mL of triethylamine in 10 mL of absolute ethanol. The solution was stirred for 3 days at room temperature. Purification by flash chromatography using CH2Cl2/MeOH (100/0 to 95/5) gave a viscous oil which was triturated in diethyl ether to give a solid (mp 185-188°C).

1H NMR (CDCl3) δ 2.49 (s, 3H), 2.62 (dd, 1H), 2.75 (dd, 1H), 3.90 (dd, 2H), 5.25 (dd, 1H), 7.19-7.32 (m, 10H).

Example 10

5,6-Dihydro-4-hydroxy-6-(4-methylphenyl)-3-[(phenylmethyl)thio]-2H-pyran-2-one (+/-)

The title compound was prepared as described in General Method 4, using 123 mg of 5,6-dihydro-4-hydroxy-6-(4-methylphenyl)-2H-pyran-2-one, 170 mg of benzyl p-toluenethiosulfonate and 0.90 mL of triethylamine in 3 mL of absolute ethanol. The solution was stirred for 18 hours at room temperature. The crude product was slurried in diethyl ether, whereby a solid was obtained (melting point 166-167°C).

1H NMR (CDCl3) δ 2.36 (s, 3H), 2.62 (dd, 1H), 2.77 (dd, 1H), 3.94 (dd, 2H), 5.25 (dd, 1H), 7.19-7.32 (m, 10H).

Example 11

5,6-Dihydro-4-hydroxy-6-[4-(1,1-dimethylethyl)phenyl)-3-[(phenylmethyl)thio]-2H-pyran-2-one (+/-)

The title compound was prepared as described in General Method 4, using 445 mg of 5,6-dihydro-4-hydroxy-6-[4-(1,1-dimethylethyl)phenyl]-2H-pyran-2-one, 550 mg of benzyl-p-toluenethiosulfonate and 0.3 mL of triethylamine in 10 mL of absolute ethanol. The solution was stirred for 3 days at room temperature. The crude product was slurried in diethyl ether, whereby a solid was obtained (melting point 140-142°C).

1H NMR (CDCl3) δ 1.32 (s, 9H), 2.65 (dd, 1H), 2.79 (dd, 1H), 3.89 (dd, 2H), 5.27 (dd, 1H), 7.18-7.43 (m, 10H).

Example 12

6-(4-Chlorophenyl)-5,6-dihydro-4-hydroxy-3-[(phenylmethyl)thio]-2H-pyran-2-one (+/-)

The title compound was prepared as described in General Method 4, using 250 mg of 6-(4-chlorophenyl)-5,6-dihydro-4-hydroxy-2H-pyran-2-one, 315 mg of benzyl p-toluenethiosulfonate and 0.16 mL of triethylamine in 8 mL of absolute ethanol. The solution was stirred overnight at room temperature. Purification by flash chromatography using CH2Cl2/MeOH (100/0 to 95/5) gave a viscous oil which was triturated in diethyl ether to give a solid (mp 167-170°C).

1H NMR (CDCl3) δ 2.62 (dd, 1H), 2.74 (dd, 1H), 3.90 (dd, 2H), 5.21 (dd, 1H), 7.23-7.41 (m, 10H).

Example 13

6-(3-Chlorophenyl)-5,6-dihydro-4-hydroxy-3-[(phenylmethyl)thio]-2H-pyran-2-one (+/-)

The title compound was prepared as described in General Method 4, using 300 mg of 6-(3-chlorophenyl)-5,6-dihydro-4-hydroxy-2H-pyran-2-one, 450 mg of benzyl p-toluenethiosulfonate and 1.0 mL of triethylamine in 10 mL of absolute ethanol. The solution was stirred overnight at room temperature. Purification by flash chromatography using CH2Cl2/MeOH (100/0 to 95/5) gave a viscous oil which was triturated in diethyl ether to give a solid (mp 139-142°C).

1H NMR (CDCl3) δ 2.64 (dd, 1H), 2.73 (dd, 1H), 3.89 (dd, 2H), 5.25 (dd, 1H), 7.18-7.41 (m, 10H).

Example 14

5,6-Dihydro-[(2-phenylethyl)thio]-6-[4-(phenylmethoxy)phenyl]-2H-pyran-2-one (+/-)

The title compound was prepared as described in General Method 4, using 109 mg of 5,6-dihydro-4-hydroxy-6-[4-(phenylmethoxy)phenyl)]-2H-pyran-2-one, 114 mg of 2- of phenylethyl-p-toluenethiosulfonate and 0.06 mL of triethylamine in 3 mL of absolute ethanol. The solution was stirred overnight at room temperature. Purification by flash chromatography using CH2Cl2/MeOH (100/0 to 95/5) gave a viscous oil which was triturated in diethyl ether to give a solid (mp 99-101°C).

1H NMR (CDCl3) δ 2.78 (dd, 1H), 2.85 (dd, 1H), 2.92-3.11 (m, 4H), 5.07 (s, 2H), 5.30 (dd, 1H), 6.97-7.44 (m, 14H) ), 7.62 (s, 1H).

Example 15

5,6-Dihydro-6-(4-methoxyphenyl)-3-[(2-phenylethyl)thio]-2H-pyran-2-one (+/-)

The title compound was prepared as described in General Method 4, using 300 mg of 5,6-dihydro-4-hydroxy-6-(4-methoxyphenyl)-2H-pyran-2-one, 500 mg of 2-phenylethyl-p- toluenethiosulfonate and 1.0 mL of triethylamine in 10 mL of absolute ethanol. The solution was stirred overnight at room temperature. The crude product was slurried in diethyl ether, whereby a solid was obtained (melting point 112-115°C).

1H NMR (CDCl3) δ 2.78 (dd, 1H), 2.86 (dd, 1H), 2.92-3.11 (m, 4H), 3.81 (s, 3H), 5.31 (dd, 1H), 6.91-7.35 (m, 10H) ).

Example 16

5,6-Dihydro-6-(4-methylthiophenyl)-3-[(2-phenylethyl)thio]-2H-pyran-2-one (+/-)

The title compound was prepared as described in General Method 4, using 430 mg of 5,6-dihydro-4-hydroxy-6-(4-methylthiophenyl)-2H-pyran-2-one, 585 mg of 2-phenylethyl-p- toluenethiosulfonate and 0.3 mL of triethylamine in 10 mL of absolute ethanol. The solution was stirred for 3 days at room temperature. The crude product was slurried in diethyl ether, whereby a solid was obtained (melting point 135-137°C).

1H NMR (CDCl3) δ 2.48 (s, 3H), 2.77-3.10 (m, 6H), 5.32 (dd, 1H), 7.16-7.33 (m, 9H), 7.63 (s, 1H).

Example 17

5,6-Dihydro-6-[4-methylphenyl)-3-[(2-phenylethyl)thio]-2H-pyran-2-one (+/-)

The title compound was prepared as described in General Method 4, using 500 mg of 5,6-dihydro-4-hydroxy-6-(4-methylphenyl)-2H-pyran-2-one, 720 mg of 2-phenylethyl-p- toluenethiosulfonate and 0.4 mL of triethylamine in 12 mL of absolute ethanol. The solution was stirred overnight at room temperature. Purification by flash chromatography using CH2Cl2/MeOH (100/0 to 95/5) gave a viscous oil which was triturated in diethyl ether to give a solid (mp 112-113°C).

1H NMR (CDCl3) δ 2.36 (s, 3H), 2.79 (dd, 1H), 2.84 (dd, 1H), 2.91-3.10 (m, 4H), 5.33 (dd, 1H), 7.16-7.33 (m, 9H) ), 7.61 (s, 1H).

Example 18

6-[1,1'-Biphenyl]-4-yl-5,6-dihydro-3-[(2-phenylethyl)thio]-2H-pyran-2-one (+/-)

The title compound was prepared as described in General Method 4, using 200 mg of 5,6-dihydro-4-hydroxy-6-[1,1'-biphenyl]-4-yl-2H-pyran-2-one, 300 mg of 2-phenylethyl-p-toluenethiosulfonate and 1.0 mL of triethylamine in 10 mL of absolute ethanol. The solution was stirred overnight at room temperature. Purification by flash chromatography using CH2Cl2/MeOH (100/0 to 95/5) gave a viscous oil which was triturated in diethyl ether to give a solid (mp 130-133°C).

1H NMR (CDCl3) δ 2.84-2-89 (m, 2H), 2.96-3.12 (m, 4H), 5.42 (dd, 1H), 7.08-7.67 (m, 15H).

Example 19

5,6-Dihydro-6-[4-(1,1-dimethylethyl)phenyl)-3-[(2-phenylethyl)thio]-2H-pyran-2-one (+/-)

The title compound was prepared as described in General Method 4, using 430 mg of 5,6-dihydro-4-hydroxy-6-[4-(1,1'-dimethylethyl)phenyl]-2H-pyran-2-one, 560 mg of 2-phenylethyl-p-toluenethiosulfonate and 0.28 mL of triethylamine in 10 mL of absolute ethanol. The solution was stirred for 3 days at room temperature. The crude product was slurried in diethyl ether, whereby a solid was obtained (melting point 130-131°C).

1H NMR (CDCl3) δ 1.31 (s, 9H), 2.79-2.88 (m, 2H), 2.94-3.11 (m, 4H), 5.34 (dd, 1H), 7.16-7.43 (m, 9H), 7.61 (s , 1H).

Example 20

6-(3-Chlorophenyl)-5,6-dihydro-3-[(2-phenylethyl)thio]-2H-pyran-2-one (+/-)

The title compound was prepared as described in General Method 4, using 300 mg of 6-(3-chlorophenyl)-5,6-dihydro-4-hydroxy-2-one, 500 mg of 2-phenylethyl-p-toluene-thiosulfonate and 1.0 mL of triethylamine in 10 mL of absolute ethanol. The solution was stirred overnight at room temperature. Purification by flash chromatography using CH2Cl2/MeOH (100/0 to 95/5) gave a viscous oil which was triturated in diethyl ether to give a solid (mp 99-100°C).

1H NMR (CDCl3) δ 2.78-2.91 (m, 2H), 2.97-3.13 (m, 4H), 5.32 (dd, 1H), 7.17-7.43 (m, 9H), 7.62 (s, 1H).

Example 21

6-[([1,1'-Biphenyl]-4-yloxy)methyl]-5,6-dihydro-3-[(2-phenylethyl)thio]-2H-pyran-2-one (+/-)

The title compound was prepared as described in General Method 4, using 150 mg of 6-[[(1,1'-biphenyl)-4-yloxy]methyl]-5,6-dihydro-4-hydroxy-2-one, 185 mg of 2-phenylethyl-p-toluenethiosulfonate and 1.0 mL of triethylamine in 5 mL of absolute ethanol. The solution was stirred overnight at room temperature. Purification by flash chromatography using CH2Cl2/MeOH (100/0 to 95/5) gave a viscous oil which was triturated in diethyl ether to give a solid (mp 124-126°C).

1H NMR (CDCl3) δ 2.77 (dd, 1H), 2.88 (dd, 1H), 2.95-3.10 (m, 4H), 4.19-4.28 (m, 2H), 4.71-4.76 (m, 1H), 6.96-7.56 (m, 14H), 7.65 (s, 1H).

Example 22

6-[1,1'-Biphenyl]-4-yl-6-butyl-5,6-dihydro-4-hydroxy-3-[(2-phenylethyl)thio]-2H-pyran-2-one (±)

The title compound was prepared as described in General Method 4, using (0.388 mmol) 6-[1,1'-biphenyl]-4-yl-6-butyl-5,6-dihydro-4-hydroxy-2H-pyran -2-one, 5 mL absolute EtOH, (0.407 mmol) 2-phenylethyl-p-toluenethiosulfonate in 5 mL absolute EtOH and (0.426 mmol) triethylamine in 2 mL absolute ethanol. The reaction was stirred overnight at room temperature. Purification by "flash" chromatography (CH2Cl2/MeOH 99/1) gave a solid which was recrystallized from ethyl acetate/diethyl ether (melting point 100-104°C).

1H NMR (CDCl3) δ 0.86 (t, 3H), 1.15-1.5 (m, 4H), 1.9-2.1 (m, 2H), 2.2-2.5 (m, 2H), 2.5-2.8 (m, 2H), 3.2 (ABq, 2H), 6.8-6.9 (m, 2H), 7.1-7.2 (m, 3H), 7.3-7.7 (m, 9H).

Example 23

4-[2,3-dihydro-4-hydroxy-6-oxo-5-[(phenylmethyl)thio]-2H-pyran-2-yl]benzonitrile (+/-)

The title compound was prepared as described in General Method 4, using 250 mg of 4-[2,3-dihydro-4-hydroxy-6-oxo-2H-pyran-2-yl]benzonitrile, 385 mg of benzyl p-toluenethiosulfonate and 1.0 mL of triethylamine in 10 mL of absolute ethanol. The solution was stirred overnight at room temperature. Purification by flash chromatography using CH2Cl2/MeOH (100/0 to 95/5) as eluent gave a viscous oil which was slurried in diethyl ether to give a solid (melting point 148-151°C).

1H NMR (CDCl3) δ 2.66-2.75 (m, 2H), 3.91 (dd, 2H), 5.33 (dd, 1H), 7.20-7.72 (m, 10H).

Example 24

6-(4-Trifluoromethylphenyl)-5,6-dihydro-4-hydroxy-3-[(phenylmethyl)thio]-2H-pyran-2-one (+/-)

The title compound was prepared as described in General Method 4, using 211 mg of 6-(4-trifluoromethylphenyl)-5,6-dihydro-4-hydroxy-2H-pyran-2-one, 273 mg of benzyl p-toluenethiosulfonate and 1.0 mL of triethylamine in 10 mL of absolute ethanol. The solution was stirred overnight at room temperature. Purification by flash chromatography using CH2Cl2/MeOH (100/0 to 95/5) as eluent gave a viscous oil which was slurried in diethyl ether to give a solid (melting point 183-186°C).

1H NMR (CDCl3) δ 2.65-2.77 (m, 2H), 3.92 (dd, 2H), 5.35 (dd, 1H), 7.19-7.68 (m, 10H).

Example 25

6-(3,5-Dichlorophenyl)-5,6-dihydro-4-hydroxy-3-[(phenylmethyl)thio]-2H-pyran-2-one (+/-)

The title compound was prepared as described in General Method 4, using 250 mg of 6-(3,5-dichlorophenyl)-5,6-dihydro-4-hydroxy-2H-pyran-2-one, 320 mg of benzyl-p- toluenethiosulfonate and 1.0 mL of triethylamine in 10 mL of absolute ethanol. The solution was stirred overnight at room temperature. Purification by flash chromatography using CH2Cl2/MeOH (100/0 to 95/5) as eluent gave a viscous oil which was slurried in diethyl ether to give a solid (melting point 147-149°C).

1 H NMR (CDCl 3 ) 62.61-2.74 (m, 2H), 3.90 (dd, 2H), 5.21 (dd, 1H), 7.18-7.36 (m, 9H).

Example 26

6-(Pentafluorophenyl)-5,6-dihydro-4-hydroxy-3-[(phenylmethyl)thio]-2H-pyran-2-one (+/-)

The title compound was prepared as described in General Method 4, using 226 mg of 6-(pentafluorophenyl)-5,6-dihydro-4-hydroxy-2H-pyran-2-one, 269 mg of benzyl p-toluenethiosulfonate and 1.0 mL of triethylamine in 10 mL of absolute ethanol. The solution was stirred overnight at room temperature. Purification by "flash" chromatography using CH2Cl2/MeOH (100/0 to 95/5) as eluent gives a viscous oil which is slurried in diethyl ether to give a solid (melting point 113-115°C).

1H NMR (CDCl3) δ 2.5 (dd, 1H), 3.14 (dd, 1H), 3.90 (dd, 2H), 5.57 (dd, 1H), 7.19-7.365 (m, 6H).

Example 27

5,6-Dihydro-4-hydroxy-6-(3-methylphenyl-3-[(2-phenylethyl)thio]-2H-pyran-2-one (+/-)

The title compound was prepared as described in General Method 4, using 300 mg of 5,6-dihydro-4-hydroxy-6-(3-methylphenyl)-2H-pyran-2-one, 515 mg of 2-phenylethyl-p- toluenethiosulfonate and 1.0 mL of triethylamine in 10 mL of absolute ethanol. The solution was stirred overnight at room temperature. Purification by flash chromatography using CH2Cl3/MeOH (100/0 to 95/5) as eluent gave a viscous oil which was slurried in diethyl ether to give a solid (melting point 81-83°C).

1H NMR (CDCl3) δ 2.38 (s, 3H), 2.78-3.10 (m, 6H), 5.35 (dd, 1H), 7.17-7.34 (m, 9H), 7.61 (s, 1H).

Example 28

6-(2-Chlorophenyl)-5,6-dihydro-4-hydroxy-3-[(phenylmethyl)thio]-2H-pyran-2-one (+/-)

The title compound was prepared as described in General Method 4, using 200 mg of 6-(2-chlorophenyl)-5,6-dihydro-4-hydroxy-2H-pyran-2-one, 300 mg of benzyl p-toluenethiosulfonate and 1.0 mL of triethylamine in 10 mL of absolute ethanol. The solution was stirred overnight at room temperature. Purification by flash chromatography using CH2Cl3/MeOH (100/0 to 95/5) as eluent gave a viscous oil which was slurried in diethyl ether to give a solid (melting point 89-91°C).

1Η NMR (CDCl3) δ 2.58 (dd, 1H), 2.80 (dd, 1H), 3.92 (dd, 2H), 5.64 (dd, 1H), 7.20-7.67 (m, 10H).

Example 29

6-Butyl-5,6-dihydro-4-hydroxy-6-phenyl-3-[(phenylmethyl)thio]-2H-pyran-2-one (+/-)

The title compound was prepared as described in General Method 4, using 400 mg of 6-butyl-5,6-dihydro-4-hydroxy-2H-pyran-2-one, 540 mg of benzyl-p-toluene-thiosulfonate and 1.0 mL of triethylamine in 10 mL of absolute ethanol. The solution was stirred overnight at room temperature. Purification by flash chromatography using CΗ2Cl2/MeOH (100/0 to 95/5) as eluent gave a viscous oil.

1H NMR (CDCl3) δ 0.82 (t, 3H), 1.0-1.4 (m, 4H), 1.83-1.99 (m, 2H), 2.97 (dd, 2H), 3.63 (dd, 2H), 6.83-7.41 (m , 11H).

Example 30

6-[1,1'-Biphenyl]-4-yl-6-butyl-5,6-dihydro-4-hydroxy-3-[(phenylmethyl)thio]-2H-pyran-2-one (±)

The title compound was prepared as described in General Method 4, using (0.388 mmol) 6-[1,1'-biphenyl]-4-yl-6-butyl-5,6-dihydro-4-hydroxy-2H-pyran -2-one, 5 mL absolute EtOH, (0.407 mmol) benzyl-p-toluenethiosulfonate in 3 mL absolute EtOH and (0.426 mmol) triethylamine in 2 mL absolute ethanol. The reaction was stirred overnight at room temperature. Purification by "flash" chromatography (CH2Cl2/MeOH 99/1) gave a solid (melting point 45-52°C).

1H NMR (CDCl3) δ 0.85 (t, 3H), 1.15-1.7 (m, 5H), 1.9-2.1 (m, 2H), 3.0 (ABq, 2H), 3.5 (d, 1H), 3.7 (d, 1H) ), 6.8-6.9 (m, 2H), 7.0-7.7 (m, 12H).

Example 31

5,6-Dihydro-4-hydroxy-6-phenyl-3-[(phenylmethyl)thio]-6-propyl-2H-pyran-2-one (±)

The title compound was prepared as described in General Method 4, using 1.08 mmol of 5,6-dihydro-4-hydroxy-6-phenyl-6-propyl-2H-pyran-2-one, 5 mL of absolute EtOH, 1.29 mmol of benzyl -p-toluenethiosulfonate in 10 mL of absolute EtOH and 1.51 mmol of triethylamine in 5 mL of absolute ethanol. The reaction was stirred overnight at room temperature. Purification by "flash" chromatography (hexane/ethyl acetate 75/25) gave a viscous oil.

1H NMR (CDCl3) δ 0.83 (t, 3H), 1.0-1.2 (m, 1H), 1.3-1.5 (m, 1H), 1.8--2.0 (m, 2H), 2.97 (ABq, 2H), 3.5 ( d, 1H), 3.7 (d, 1H), 6.8-6.9 (m, 2H), 7.0-7.5 (m, 9H).

Example 32

5,6-Dihydro-4-hydroxy-6-phenyl-3-[(2-phenylethyl)thio]-6-propyl-2H-pyran-2-one (±)

The title compound was prepared as described in General Method 4, using 1.08 mmol of 5,6-dihydro-4-hydroxy-6-phenyl-6-propyl-2H-pyran-2-one, 5 mL of absolute EtOH, 1.29 mmol of 2 -phenylethyl-p-toluenethiosulfonate in 10 mL absolute EtOH and 1.51 mmol triethylamine in 5 mL absolute ethanol. The reaction was stirred overnight at room temperature. Purification by "flash" chromatography (hexane/ethyl acetate 75/25) gave a viscous oil.

1H NMR (CDCl3) δ 0.85 (t, 3H), 1.1-1.3 (m, 1H), 1.3-1.5 (m, 1H), 1.8-2.0 (m, 2H), 2.2-2.3 (m, 1H), 2.3 -2.5 (m, 1H), 2.6-2.8 (m, 2H), 3.1 (ABq, 2H), 6.9 (d, 2H), 7.1-7.5 (m, 9H).

Example 33

5,6-Dihydro-4-hydroxy-6-pentyl-6-phenyl-3-[(phenylmethyl)thio]-6-propyl-2H-pyran-2-one (±)

The title compound was prepared as described in General Method 4, using 0.96 mmol of 5,6-dihydro-6-pentyl-6-phenyl-6-propyl-2H-pyran-2-one, 5 mL of absolute EtOH, 1.05 mmol of benzyl -p-toluenethiosulfonate in 10 mL absolute EtOH and 1.05 mmol triethylamine in 5 mL absolute ethanol. The reaction was stirred overnight at room temperature. Purification by "flash" chromatography (hexane/ethyl acetate 75/25) gave a viscous oil.

1H NMR (CDCl3) δ 0.81 (t, 3H), 1.0-1.4 (m, 6H), 18-2.0 (m, 2H), 2.97 (ABq, 2H), 3.5 (d, 1H), 3.7 (d, 1H) ), 6.8-6.9 (m, 2H), 7.0-7.4 (m, 9H).

Example 34

5,6-Dihydro-4-hydroxy-6-pentyl-6-phenyl-3-[(2-phenylethyl)thio]-2H-pyran-2-one (±)

The title compound was prepared as described in General Method 4, using 0.96 mmol of 5,6-dihydro-6-pentyl-6-phenyl-2H-pyran-2-one, 5 mL of absolute EtOH, 1.05 mmol of phenethyl-p-toluenethiosulfonate in 10 mL absolute EtOH and 1.05 mmol triethylamine in 5 mL absolute ethanol. The reaction was stirred overnight at room temperature. Purification by "flash" chromatography (hexane/ethyl acetate 70/30) gave a viscous oil.

1H NMR (CDCl3) δ 0.82 (t, 3H), 1.0-1.4 (m, 6H), 1.8-2.0 (m, 2H), 2.2-2.3 (m, 1H), 2.3-2.5 (m, 1H), 2.6 -2.8 (m, 2H), 3.13 (ABq, 2H), 6.8-6.9 (m, 2H), 7.1-7.5 (m, 9H).

Example 35

5,6-Dihydro-4-hydroxy-6-(3-methylbutyl)-6-phenyl-3-[(phenylmethyl)thio]-2H--pyran-2-one (±)

The title compound was prepared as described in General Method 4, using 0.96 mmol of 5,6-dihydro-6-(3-methylbutyl)-6-phenyl-2H-pyran-2-one, 5 mL of absolute EtOH, 1.05 mmol of benzyl -p-toluenethiosulfonate in 10 mL absolute EtOH and 1.15 mmol triethylamine in 5 mL absolute ethanol. The reaction was stirred overnight at room temperature. Purification by "flash" chromatography (hexane/ethyl acetate 80/20) gave a viscous oil.

1H NMR (CDCl3) δ 0.80 (dd, 6H), 0.9-1.1 (m, 1H), 1.2-1.3 (m, 1H), 1.3-1.5 (m, 1H), 1.8-2.0 (m, 2H), 2.97 (ABq, 2H), 3.5 (d, 1H), 3.7 (d, 1H), 6.8-6.9 (m, 2H), 7.0-7.4 (m, 9H).

Example 36

5,6-Dihydro-4-hydroxy-6-(3-methylbutyl)-6-phenyl-3-[(2-phenylethyl)thio]-2H-pyran-2-one (±)

The title compound was prepared as described in General Method 4, using 0.96 mmol of 5,6-dihydro-6-(3-methylbutyl)-6-phenyl-2H-pyran-2-one, 5 mL of absolute EtOH, 1.05 mmol of 2 -phenylethyl-p-toluenethiosulfonate in 10 mL absolute EtOH and 1.05 mmol triethylamine in 5 mL absolute ethanol. The reaction was stirred overnight at room temperature. Purification by "flash" chromatography (hexane/ethyl acetate 80/20) gave a viscous oil.

1H NMR (CDCl3) δ 0.80 (dd, 6H), 1.0-1.15 (m, 1H), 1.2-1.3 (m, 1H), 1.4-1.5 (m, 1H), 1.9-2.0 (m, 2H), 2.2 -2.3 (m, 1H), 2.3-2.5 (m, 1H), 2.6-2.8 (m, 2H), 3.15 (ABq, 2H), 6.8-6.9 (m, 2H), 7.1-7.5 (m, 9H) .

Example 37

5,6-Dihydro-4-hydroxy-6,6-diphenyl-3-[(phenylmethyl)thio]-2H-pyran-2-one

The title compound was prepared as described in General Method 4, using 0.94 mmol of 5,6-dihydro-4-hydroxy-6,6-diphenyl-2H-pyran-2-one, 5 mL of absolute EtOH, 1.13 mmol of benzyl-p -toluenethiosulfonate in 10 mL of absolute EtOH and 1.31 mmol of triethylamine in 5 mL of absolute ethanol. The reaction was stirred overnight at room temperature. Purification of the product by "flash" chromatography (CH2Cl2/MeOH 100/0-98/2) gave a solid (melting point 44-47.5°C).

1 H NMR (CDCl 3 ) δ 3.34 (s, 2H), 3.63 (s, 2H), 6.8-6.9 (m, 2H), 7.1-7.5 (m, 14H).

Example 38

5,6-Dihydro-4-hydroxy-6,6-diphenyl-3-[(2-phenylethyl)thio]-2H-pyran-2-one

The title compound was prepared as described in General Method 4, using 0.94 mmol of 5,6-dihydro-4-hydroxy-6,6-diphenyl-2H-pyran-2-one, 5 mL of absolute EtOH, 1.13 mmol of 2-phenylethyl -p-toluenethiosulfonate in 10 mL absolute EtOH and 1.31 mmol triethylamine in 5 mL absolute ethanol. The reaction was stirred overnight at room temperature. The crude solid product was slurried in diethyl ether to give a solid (melting point 153-154.5°C).

1H NMR (CDCl3) δ 2.3 (t, 2H), 2.6 (t, 2H), 3.49 (s. 2H), 6.8-6.9 (m, 2H), 7.1-7.6 (m, 14H).

Example 39

5,6-Dihydro-4-hydroxy-6-phenyl-6-(2-phenylethyl)-3-[(phenylmethyl)thio]-2H-pyran-2-one (±)

The title compound was prepared as described in General Method 4, using 0.85 mmol of 5,6-dihydro-4-hydroxy-6-phenyl-6-(2-phenylethyl)-2H-pyran-2-one, 5 mL of absolute EtOH , 1.02 mmol of benzyl-p-toluenethiosulfonate in 10 mL of absolute EtOH and 1.19 mmol of triethylamine in 5 mL of absolute ethanol. The reaction was stirred overnight at room temperature. Purification by "flash" chromatography (hexane/ethyl acetate 80/20) gave a viscous oil.

1H NMR (CDCl3) δ 2.1-2.4 (m, 3H), 2.7-2.8 (m, 1H), 3.10 (ABq, 2H), 3.5 (d, 1H), 3.8 (d, 1H), 6.8-6.9 (m , 2H), 7.0-7.5 (m, 14H).

Example 40

5,6-Dihydro-4-hydroxy-6-phenyl-6-(2-phenylethyl)-3-[(2-phenylethyl)thio]-2H-pyran-2-one (±)

The title compound was prepared as described in General Method 4, using 0.85 mmol of 5,6-dihydro-4-hydroxy-6-phenyl-6-(2-phenylethyl)-2H-pyran-2-one, 5 mL of absolute EtOH , 1.02 mmol of 2-phenylethyl-p-toluenethiosulfonate in 10 mL of absolute EtOH and 1.19 mmol of triethylamine in 5 mL of absolute ethanol. The reaction was stirred overnight at room temperature. The crude solid product was triturated with diethyl ether to give a solid (melting point 56-58°C).

1H NMR (CDCl3) δ 2.2-2.5 (m, 5H), 2.6-2.8 (m, 3H), 3.2 (ABq, 2H), 6.8-6.9 (m, 2H), 7.0-7.5 (m, 14H).

Example 41

5,6-Dihydro-4-hydroxy-6-phenyl-3-[(2-phenylethyl)thio]-2(1H)-pyridinone (±)

The title compound was prepared as described in General Method 4, using 105 mg of 5,6-dihydro-4-hydroxy-6-phenyl-2(1H)-pyridinone, 175 mg of 2-phenylethyl-p-toluene-thiosulfonate and 0.1 mL of triethylamine in 5 mL of absolute ethanol. The solution was stirred overnight at room temperature. Purification by flash chromatography using CH2Cl2/McOH (100/0 to 97/3) gave a viscous oil which was triturated in diethyl ether to give a solid (mp 111-113°C).

1H NMR (CDCl3) δ 2.80-3.03 (m, 6H), 4.70 (t, 1H), 5.75 (s, 1H), 7.16-7.40 (m, 11H).

Example 42

5,6-Dihydro-4-hydroxy-6-phenoxymethyl-6-phenyl-3-[(phenylmethyl)thio]-2H-pyran-2-one (+/-)

The title compound was prepared as described in General Method 4, using 200 mg of 5,6-dihydro-4-hydroxy-6-phenoxymethyl-6-phenyl-2H-pyran-2-one, 210 mg of benzyl p-toluenethiosulfonate and 0.125 mL of triethylamine in 5 mL of absolute ethanol. The solution was stirred overnight at room temperature. Purification by flash chromatography using CH2Cl2/MeOH (100/0 to 95/5) afforded a solid (mp 161-163°C).

1H NMR (CDCl3) δ 3.10 (d, 1H), 3.52 (d, 1H), 3.54 (d, 1H), 3.75 (d, 1H), 3.97 (d, 1H), 4.23 (d, 1H), 6.84- 7.52 (m, 16H).

Example 43

6-[2-Benzo[1,3]dioxol-5-yl)ethyl]-5,6-dihydro-4-hydroxy-6-phenyl-3-[(phenylmethyl)thio]-2H-pyran-2-one (+/-)

The title compound was prepared as described in General Method 4, using 165 mg of 6-[2-benzo[1,3]dioxol-5-yl)ethyl]-5,6-dihydro-4-hydroxy-6-phenyl- 2H-pyran-2-one, 150 mg of benzyl-p-toluenethiosulfonate and 0.075 mL of triethylamine in 5 mL of absolute ethanol. The solution was stirred overnight at room temperature. Purification by flash chromatography using CH2Cl2/MeOH (100/0 to 95/5) afforded a solid (mp 45-50°C).

1H NMR (CDCl3) δ 2.08-2.30 (m, 3H), 2-62-2.71 (m, 1H), 2.98 (dd, 2H), 3.53 (d, 1H), 3.76 (d, 1H), 5.89 (s , 1H), 6.50-6.86 (m, 5H), 7.06-7.26 (m, 4H), 7.33-7.44 (m, 5H).

Example 44

6-[2-(3,4-Dichlorophenyl)ethyl]-5,6-dihydro-4-hydroxy-6-phenyl-3-[(phenylmethyl)-thio]-2H-pyran-2-one (+/- )

The title compound was prepared as described in General Method 4, using 365 mg of 6-[2-(3,4-dichlorophenyl)ethyl]-5,6-dihydro-4-hydroxy-6-phenyl-2H-pyran-2 -on, 310 mg of benzyl-p-toluenethiosulfonate and 0.15 mL of triethylamine in 5 mL of absolute ethanol. The solution was stirred overnight at room temperature. Purification by flash chromatography using CH2Cl2/MeOH (100/0 to 95/5) as eluent gave a solid (mp 43-50°C).

1H NMR (CDCl3) δ 2.07-2.16 (m, 1H), 2.21-2.28 (m, 2H), 2.71-2.77 (m, 1H), 2.99 (dd, 2H), 3.54(d, 1H), 3.78 (d , 1H), 6.84-6.91 (m, 3H), 7.10-7.45 (m, 11H).

Example 45

6-[2-(4-Fluorophenyl)ethyl]-5,6-dihydro-4-hydroxy-6-phenyl-3-[(phenylmethyl)thio]-2H-pyran-2-one (+/-)

The title compound was prepared as described in General Method 4, using 312 mg of 6-[2-(4-fluorophenyl)ethyl]-5,6-dihydro-4-hydroxy-6-phenyl-2H-pyran-2-one , 310 mg of benzyl-p-toluenethiosulfonate and 0.15 mL of triethylamine in 5 mL of absolute ethanol. The solution was stirred overnight at room temperature. Purification by flash chromatography using CH2Cl2/MeOH (100/0 to 95/5) as eluent gave a solid (mp 86-90°C).

1H NMR (CDCl3) δ 2.08-2.35 (m, 3H), 2.08-2.35 (m, 2H), 2.70-2.77 (m, 1H), 2.99 (dd, 2H), 3.54 (d, 1H), 3.77 (d , 1H), 6.85-7.44 (m, 15H).

Example 46

5,6-Dihydro-6-hexyl-4-hydroxy-6-phenyl-3-[(phenylmethyl)thio]-2H-pyran-2-one (±)

The title compound was prepared as described in General Method 4, using 0.91 mmol of 5,6-dihydro-6-hexyl-4-hydroxy-6-phenyl-2H-pyran-2-one (±), 5 mL of absolute EtOH, 1.1 mmol of benzyl-p-toluenethiosulfonate in 10 mL of absolute EtOH and 1.27 mmol of triethylamine in 5 mL of absolute ethanol. The reaction was stirred overnight at room temperature. By purifying the product by "flash" chromatography (CH2Cl2/MeOH 99.5/0.5), a viscous rubber was obtained.

1H NMR (CDCl3) δ 0.81 (t, 3H), 1.0-1.4 (m, 8H), 1.8-2.0 (m, 2H), 2.97 (ABq, 2H), 3.5 (d, 1H), 3.7 (d, 1H) ), 6.8-6.9 (m, 2H), 7.0-7.4 (m, 9H).

Example 47

5,6-Dihydro-6-hexyl-4-hydroxy-6-phenyl-3-[(2-phenylethyl)thio]-2H-pyran-2-one (±)

The title compound was prepared as described in General Method 4, using 0.91 mmol of 5,6-dihydro-6-hexyl-4-hydroxy-6-phenyl-2H-pyran-2-one (±), 5 mL of absolute EtOH, 1.09 mmol of benzyl-p-toluenethiosulfonate in 5 mL of absolute EtOH and 1.27 mmol of triethylamine in 5 mL of absolute ethanol. The reaction was stirred overnight at room temperature. Purification of the product by "flash" chromatography (CH2Cl2/MeOH 99.75/0.25-99/1) resulted in a viscous rubber.

1H NMR (CDCl3) δ 0.84 (t, 3H), 1.0-1.4 (m, 8H), 1.8-2.0 (m, 2H), 2.2-2.3 (m, 1H), 2.3-2.5 (m, 1H), 2.6 -2.8 (m, 2H), 3.13 (ABq, 2H), 6.9 (dd, 2H), 7.1-7.5 (m, 8H).

Example 48

5,6-Dihydro-4-hydroxy-6-(4-methylpentyl)-6-phenyl-3-[(phenylmethyl)thio]-2H-pyran-2-one (±)

The title compound was prepared as described in General Method 4, using 1 mmol of 5,6-dihydro-4-hydroxy-6-(4-methylpentyl)-6-phenyl-2H-pyran-2-one (±), 5 mL absolute EtOH, 1.2 mmol benzyl-p-toluenethiosulfonate in 5 mL absolute EtOH and 4 mmol NaHCO3 in 5 mL absolute ethanol. The reaction was heated for 1.5 hours at 50°C and stirred overnight at room temperature. By cleaning the product by "flash" chromatography (CH2Cl2/MeOH 100/0 - 99/1), a viscous rubber was obtained.

1H NMR (CDCl3) δ 0.78 (d, 6H), 1.0-1.5 (m, 5H), 1.8-2.0 (m, 2H), 2.97 (ABq, 2H), 3.5 (d, 1H), 3.7 (d, 1H ), 6.8-6.9 (m, 2H), 7.0-7.4 (m, 9H).

Example 49

5,6-Dihydro-4-hydroxy-6-(4-methylpentyl)-6-phenyl-3-[(2-phenylethyl)thio]-2H-pyran-2-one (±)

The title compound was prepared as described in General Method 4, using 1 mmol of 5,6-dihydro-4-hydroxy-6-(4-methylpentyl)-6-phenyl-2H-pyran-2-one (±), 5 mL of absolute EtOH, 1.2 mmol of phenylethyl-p-toluenethiosulfonate in 5 mL of absolute EtOH and 1.4 mmol of triethylamine in 5 mL of absolute ethanol. The reaction was heated for 1.5 hours at 50°C. Purification of the product by flash chromatography using hexane/ethyl acetate (80/20) gave a viscous gum.

1H NMR (CDCl3) δ 0.79 (d, 6H), 1.0-1.5 (m, 5H), 1.8-2.0 (m, 2H), 2.2-2.3 (m, 1H), 2.3-2.5 (m, 1H), 2.6 -2.8 (m, 2H), 3.14 (ABq, 2H), 6.9 (d, 2H), 7.1-7.5 (m, 8H).

Example 50

6-Cyclopentylmethyl-5,6-dihydro-4-hydroxy-6-phenyl-3-[(phenylmethyl)thio]-2H-pyran-2-one (±)

The title compound was prepared as described in General Method 4, using 1 mmol of 6-cyclopentylmethyl-5,6-dihydro-4-hydroxy-6-phenyl-2H-pyran-2-one (±), 5 mL of absolute EtOH, 1.2 mmol of benzyl-p-toluenethiosulfonate in 5 mL of absolute EtOH and 4 mmol of NaHCO3 in 5 mL of absolute ethanol. The reaction was heated for 15 minutes at 120 °C. Purification of the product by flash chromatography using hexane/ethyl acetate (75/25) gave a viscous gum.

1H NMR (CDCl3) δ 0.8-1.0 (m, 2H), 1.0-1.2 (m, 1H), 1.3-1.6 (m, 5H), 1.6-1.8 (m, 2H), 1.97 (dd, 1H), 2.07 (dd, 1H), 2.97 (ABq, 2H), 3.5 (d, 1H), 3.7 (d, 1H), 6.8-6.9 (m, 2H), 7.0-7.4 (m, 9H).

Example 51

6-Cyclopentylmethyl-5,6-dihydro-4-hydroxy-6-phenyl-3-[(2-phenyl-ethyl)thio]-2H-pyran-2-one (±)

The title compound was prepared as described in General Method 4, using 1 mmol of 6-cyclopentylmethyl-5,6-dihydro-4-hydroxy-6-phenyl-2H-pyran-2-one (±), 5 mL of absolute EtOH, 1.2 mmol of phenylethyl-p-toluenethiosulfonate in 5 mL of absolute EtOH and 1.4 mmol of triethylamine in 5 mL of absolute ethanol. The reaction was stirred for 2 days at room temperature. Purification of the product by flash chromatography using hexane/ethyl acetate (75/25 - 60/40) gave a viscous rubber.

1H NMR (CDCl3) δ 0.8-1.0 (m, 1H), 1.0-1.1 (m, 1H), 1.2-1.8 (m, 7H), 1.9-2.1 (m, 2H), 2.3 (t, 2H), 2.5 -2.6 (m, 2H), 3.25 (s, 2H), 6.95 (d, 2H), 7.1-7.4 (m, 8H).

Example 52

3,4-Dihydro-4'-hydroxy-5'-[(phenylmethyl)thio]-spiro[naphthalene-1(2H),2'-[2H]-pyran-6'(3'H)-one (± )

The title compound was prepared as described in General Method 4, using 1.1 mmol of 3,4-Dihydro-4'-hydroxy-spiro[naphthalene-1(2H),2'-[2H]pyran-6'(3'H )-one (±), 5 mL absolute EtOH, 1.3 mmol benzyl-p-toluenethiosulfonate in 5 mL absolute EtOH and 1.5 mmol triethylamine in 5 mL absolute ethanol. The reaction was stirred overnight at room temperature. The product was purified by flash chromatography using hexane/ethyl acetate (90/10 - 60/40), and was triturated in ether to give a solid (mp 143-145).

1H NMR (CDCl3) δ 1.5-1.8 (m, 2H), 1.8-2.1 (m, 2H), 2.6 (d, 1H), 2.7-2.9 (m, 2H), 3.0 (dd, 1H), 3.9 (ABq , 2H), 7.0-7.2 (m, 1H), 7.2-7.4 (m, 7H), 7.4-7.5 (m, 1H).

Example 53

3,4-Dihydro-4'-hydroxy-5'-[(2-phenylethyl)thio]-spiro[naphthalene-1(2H),2'-[2H]pyran-6'(3'H)-one ( ±)

The title compound was prepared as described in General Method 4, using 1.1 mmol of 3,4-Dihydro-4'-hydroxy-spiro[naphthalene-1(2H),2'-[2H]pyran-6'(3'H )-one (±), 5 mL of absolute EtOH, 1.3 mmol of phenethyl-p-toluenethiosulfonate in 5 mL of absolute EtOH and 1.5 mmol of triethylamine in 5 mL of absolute ethanol. The reaction was stirred overnight at room temperature. The product was purified by flash chromatography using CH2Cl2/MeOH (100/0 - 98/2) to give a solid which was recrystallized from CH2Cl2/diethyl ether (mp 125-126.5).

1H NMR (CDCl3) δ 1.6-1.9 (m, 1H), 1.9-2.1 (m, 1H), 2.1-2.3 (m, 2H), 2.7-3.3 (m, 8H), (d, 1H), 7.1- 7.4 (m, 7H), 7.5-7.7 (m, 2H).

Example 54

3-(3,6-Dihydro-4-hydroxy-6-oxo-2-phenyl-5-[(2-phenylethyl)thio]-2H-pyran-2-yl)propionic acid (±)

The title compound was prepared as described in General Method 4, using 0.95 mmol of 3-(3,6-dihydro-4-hydroxy-6-oxo-2-phenyl-2H-pyran-2-yl)propionic acid (±) , 5 mL of absolute EtOH, 1.1 mmol of phenethyl-p-toluenethiosulfonate in 5 mL of absolute EtOH and 2.3 mmol of triethylamine in 5 mL of absolute ethanol. The reaction was refluxed for 2 hours. The product was purified by flash chromatography using CH2Cl2/McOH/MeCO2H (95/5/0.05) to give a solid which was recrystallized from ethyl acetate (mp 150.5-152).

1H NMR (CDCl3) δ 2.1-2.9 (m, 8H), 3.15 (ABq, 2H), 6.9 (d, 2H), 7.1-7.4 (m, 8H).

Example 55

4-(3,6-Dihydro-4-hydroxy-6-oxo-2-phenyl-5-[(2-phenylethyl)thio]-2H-pyran-2-yl)butyric acid (±)

The title compound was prepared as described in General Method 4, using 1.8 mmol of 4-(3,6-dihydro-4-hydroxy-6-oxo-2-phenyl-2H-pyran-2-yl)-butyric acid (± ), 5 mL of absolute EtOH, 2.1 mmol of phenethyl-p-toluenethiosulfonate in 5 mL of absolute EtOH and 4.3 mmol of triethylamine in 5 mL of absolute ethanol. The reaction was refluxed for 3 hours. The product was purified by flash chromatography using CH2Cl2/MeOH/MeCO2H (95/5/0.05) to give an amorphous solid.

1H NMR (CDCl3) δ 1.4-1.6 (m, 1H), 1.6-1.8 (m, 1H), 1.9-2.1 (m, 2H), 2.2-2.4 (m, 3H), 2.4-2.5 (m, 1H) , 2.6-2.8 (m, 2H), 3.15 (ABq, 2H), 6.9 (d, 2H), 7.1-7.5 (m, 8H).

Example 56

5-(3,6-Dihydro-4-hydroxy-6-oxo-2-phenyl-5-[(2-phenylethyl)thio]-2H-pyran-2-yl)pentanoic acid (±)

The title compound was prepared as described in General Method 4, using 1.8 mmol of 5-(3,6-dihydro-4-hydroxy-6-oxo-2-phenyl-2H-pyran-2-yl)pentanoic acid (±) , 10 mL of absolute EtOH, 2.2 mmol of phenethyl-p-toluenethiosulfonate in 10 mL of absolute EtOH and 4.3 mmol of triethylamine in 10 mL of absolute ethanol. The reaction was refluxed for 3 hours. The product was purified by flash chromatography using CH2Cl2/MeOH/MeCO2H (95/5/0.05) to give a solid (mp 113-119.5°C).

1H NMR (CDCl3) δ 0.8-1.1 (m, 1H), 1.1-1.3 (m, 1H), 1.3-1.5 (m, 2H), 1.8-2.0 (m, 2H), 2.1 (t, 2H), 2.2 (t, 2H), 2.5-2.8 (m, 2H), 3.2 (ABq, 2H), 6.9 (d, 2H), 7.1-7.4 (m, 8H), 11.5 (broad s, 1H), 11.9 (broad s , 1H).

Example 57

5,6-Dihydro-4-hydroxy-6-phenyl-3-[(2-phenylethyl)thio]-6-pyridin-4-yl-2H-pyran-2-one (±)

The title compound was prepared as described in General Method 4, using 0.47 mmol of 5,6-dihydro-4-hydroxy-6-phenyl-6-pyridin-4-yl-2H-pyran-2-one (±), 0.56 mmol of phenethyl-p-toluenethiosulfonate in 5 mL of absolute EtOH, 2 mmol of NaHCO3 and 0.65 mmol of triethylamine in 5 mL of absolute ethanol. The reaction was stirred overnight at room temperature. The solid product was dissolved in ethyl acetate (melting point 203-205°C).

1H NMR (CDCl3) δ 2.1 (t, 2H), 2.5 (t, 2H), 3.7 (ABq, 2H), 6.9 (d, 2H), 7.1-7.6 (m, 10H), 8.6 (d, 2H ).

Example 58

5,6-Dihydro-4-hydroxy-6-[(methylphenylamino)methyl]-6-phenyl-3-[(2-phenyl-ethyl)thio]-2H-pyran-2-one (±)

The title compound was prepared as described in General Method 4, using 0.55 mmol of 5,6-dihydro-4-hydroxy-6-[(methylphenylamino)methyl]-6-phenyl-4-yl-2H-pyran-2-one (+), 0.61 mmol of phenethyl-p-toluenethiosulfonate in 5 mL of absolute EtOH and 2.2 mmol of NaHCO3 and 0.61 mmol of triethylamine in 5 mL of absolute ethanol. The reaction is stirred overnight at room temperature, then 2 hours at 50°C. The solid product was purified by flash chromatography using CH2Cl2/MeOH (99/1) to give a solid (mp 48-57°C).

1H NMR (CDCl3) δ 2.2-2.3 (m, 1H), 2.3-2.5 (m, 1H), 2.6-2.8 (m, 2H), 3.08 (s, 3H), 3.15 (d, 1H), 3.35 (d , 1H), 3.7 (ABq, 2H), 6.7-6.9 (m, 3H), 7.1-7.6 (m, 12H).

Example 59

4-(3,6-Dihydro-4-hydroxy-6-oxo-2-phenyl-5-[(2-phenylethyl)thio]-2H-pyran-2-yl)butyramide (±)

0.75 mmol of 4-(3,6-dihydro-4-hydroxy-6-oxo-2-phenyl-2H-pyran-2-yl)butyric acid (+), 1.5 mmol of 4-methylmorpholine was added to a 50 mL reaction flask and 7.5 mL of CH2Cl2. The reaction was cooled to 0°C and 1.5 mmol of methyl chloroformate in 3.5 mL of CH2Cl2 was added. The reaction was stirred for 2 hours at 0°C. Ammonia was blown through the reaction mixture for 10-15 minutes, and the reaction was left for 30 minutes with stirring at 0°C, and then for 1.5 hours at room temperature. The reaction was poured into ethyl acetate and 1M HCl, the aqueous layer was extracted twice with ethyl acetate, dried over MgSO4 and concentrated. The crude reaction mixture was purified by flash chromatography using CH2Cl2/MeOH/MeCO2H (98/2/0.05) to give 4-(3,6-dihydro-4-hydroxy-6-oxo-2-phenyl-2H-pyran) -2-yl)-butyramide (±) in solid form (melting point 51-54°C).

1H NMR (DMSO-d6) δ 1.0-1.2 (m, 1H), 1.3-1.6 (m, 1H), 1.8-2.0 (m, 4H), 2.9 (ABq, 2H), 4.8 (s, 1H), 6.6 (s, 1H), 7.2 (s, 1H), 7.2-7.5 (m, 5H), 11.4 (broad s, 1H).

The title compound was prepared as described in General Method 4, using 0.42 mmol of 4-(3,6-dihydro-4-hydroxy-6-oxo-2-phenyl-2H-pyran-2-yl)butyramide (+) in 5 mL absolute EtOH, 0.58 mmol benzyl-p-toluenethiosulfonate in 5 mL absolute EtOH, 1.67 mmol NaHCOs and 0.42 mmol triethylamine in 5 mL absolute ethanol. The reaction is stirred overnight at room temperature. The product was purified by flash chromatography using CH2Cl2/MeOH (90/10) to give the desired solid (mp 47.5-53°C).

1H NMR (DMSO-d6) δ 1.0-1.3 (m, 1H), 1.3-1.6 (m, 1H), 1.7-2.1 (m, 4H), 3.1 (s, 2H), 3.5 (ABq, 2H), 6.7 (s, 1H), 7.0-7.5 (m, 11H), 11.4 (s, 1H).

Example 60

5-(3,6-Dihydro-4-hydroxy-6-oxo-2-phenyl-5-[(2-phenylethyl)thio]-2H-pyran-2-yl)pentanamide (±)

1.2 mmol of 5-(3,6-dihydro-4-hydroxy-6-oxo-2-phenyl-2H-pyran-2-yl)pentanoic acid (±), 2.4 mmol of 4-methylmorpholine was added to a 50 mL reaction flask and 10 mL of CH2Cl2- The reaction was cooled to 0°C and 2.4 mmol of methyl chloroformate was added in 3 mL of CH2Cl2- The reaction was stirred for 2 hours at 0°C. Ammonia was blown through the reaction mixture for 10-15 minutes, and the reaction was left for 30 minutes with stirring at 0°C. The reaction was poured into ethyl acetate and 1M HCl, the aqueous layer was extracted twice with ethyl acetate, dried over MgSO4 and concentrated. The crude reaction mixture was purified by flash chromatography using CH2Cl2 to give 5-(3,6-dihydro-4-hydroxy-6-oxo-2-phenyl-2H-pyran-2-yl)pentanamide (±) in solid form (melting point 173-174°C).

1H NMR(DMSO-d6) δ 0.8-1.0(m, 1H), 1.1-1.3 (m, 1H), 1.3-1.5 (m, 2H), 1.8-2.0 (m, 4H), 2.9 (ABq, 2H) , 4.8 (s, 1H), 6.6 (s, 1H), 7.2 (s, 1H), 7.2-7.5 (m, 5H), 11.4 (s, 1H).

The title compound was prepared as described in General Method 4, using 0.60 mmol of 5-(3,6-dihydro-4-hydroxy-6-oxo-2-phenyl-2H-pyran-2-yl)pentanamide (±) in 5 mL absolute EtOH, 0.85 mmol phenethyl-p-toluenethiosulfonate, 2.4 mmol NaHCO3 and 0.60 mmol triethylamine in 5 mL absolute ethanol. The reaction is stirred overnight at room temperature. The product was purified by flash chromatography using CH2Cl2/MeOH (90/10), which was then slurried in ether to give the desired solid (softened at 100-105°C, completely melted at 120°C).

1H NMR (DMSO-d6) δ 1.1-1.3 (m, 1H), 1.3-1.5 (m, 2H), 1.8-2.0 (m, 4H), 2.2 (t, 2H), 2.5-2.6 (m, 2H) , 3.2 (s, 2H), 6.6 (s, 1H), 6.9 (d, 2H), 7.1-7.6 (m, 9H), 11.5 (s, 1H).

Example 61

N-Benzyl-4-(3,6-dihydro-4-hydroxy-6-oxo-2-phenyl-5-[(phenylmethyl)thio]-2H-pyran-2-yl)butyramide (±)

0.75 mmol of 4-(3,6-dihydro-4-hydroxy-6-oxo-2-phenyl-2H-pyran-2-yl) malic acid (±), 1.5 mmol of 4-methylmorpholine was added to a 50 mL reaction flask and 7.5 mL of CH2Cl2- The reaction was cooled to 0°C and 1.5 mmol of methyl chloroformate in 3.5 mL of CH2Cl2 was added. The reaction was stirred for 2 hours at 0°C. Benzylamine (1.6 mmol) in CH2Cl2 (5 mL) was added, and the reaction was left for 30 minutes with stirring at 0°C, and then for 1.5 hours at room temperature. The reaction was poured into ethyl acetate and 1M HCl, the aqueous layer was extracted twice with ethyl acetate, dried over MgSO4 and concentrated. The crude reaction mixture was purified by flash chromatography using CH2Cl2/MeOH (99/1).

The resulting carbamate (200 mg) was hydrolyzed by the action of 0.1 M HCl (20 mL) in p-dioxane (4 mL) for 1 hour at room temperature, whereby N-benzyl-4-(3,6-dihydro-4- hydroxy-6-oxo-2-phenyl-2H-pyran-2-yl)butyramide (+/-).

The title compound was prepared as described in General Method 4, using 0.33 mmol of N-Benzyl-4-(3,6-dihydro-4-hydroxy-6-oxo-2-phenyl-2H-pyran-2-yl)butyramide (±), 5 mL absolute EtOH, 0.47 mmol benzyl-p-toluenethiosulfonate, 1.33 mmol NaHCO3 and 0.33 mmol triethylamine in 5 mL absolute ethanol. The reaction is stirred overnight at room temperature. The product was purified by flash chromatography using CH2Cl2/MeOH (95/5) to give the desired solid (melting point 48-52°C).

1H NMR (DMSO-d6) δ 1.1-1.3 (m, 1H), 1.4-1.6 (m, 1H), 1.8-1.9 (m, 2H), 2.0-2.2 (m, 2H), 3.1 (s, 2H) , 3.6 (ABq, 2H), 4.2 (d, 2H), 7.0 (m, 2H), 7. l -7.5 (m, 13H), 8.3

(t, 1H), 11.4 (broad s, 1H).

Example 62

N-Benzyl-5-(3,6-Dihydro-4-hydroxy-6-oxo-2-phenyl-5-[(2-phenylethyl)thio]-2H-pyran-2-yl)pentanamide (±)

0.83 mmol of 5-(3,6-Dihydro-4-hydroxy-6-oxo-2-phenyl-2H-pyran-2-yl)pentanoic acid (±), 1.65 mmol of 4 -methylmorpholine and 10 mL of CH2Cl2. The reaction was cooled to 0°C and 1.65 mmol of methyl chloroformate in 5 mL of CH2Cl2 was added. The reaction was stirred for 2 hours at 0°C. Benzylamine (1.7 mmol) in CH2Cl2 (5 mL) was added, and the reaction was left for 2 hours with stirring at 0°C, and then for 1.5 hours at room temperature. The reaction was poured into ethyl acetate and 1M HCl, the aqueous layer was extracted twice with ethyl acetate, dried over MgSO4 and concentrated. The crude reaction mixture was used without further purification.

The resulting carbamate (200 mg) was hydrolyzed by the action of 0.1 M HCl (20 mL) in p-dioxane (4 mL) for 8 hours at room temperature, whereby N-benzyl-5-(3,6-Dihydro-4- hydroxy-6-oxo-2-phenyl-2H-pyran-2-yl)pentanamide (+/-).

1H NMR (DMSO-d6) δ 0.8-1.0 (m, 1H), 1.1-1.3 )m, 2H), 2.9 (ABq, 2H), 4.2 (ABq, 2H), 4.85 (s, 1H), 7.1-7.5 (m, 10H), 8.2 (sheet t, 1H), 11.4 (s, 1H).

The title compound was prepared as described in General Method 4, using 0.58 mmol of N-benzyl-5-(3,6-Dihydro-4-hydroxy-6-oxo-2-phenyl-2H-pyran-2-yl)pentanamide (±) in 5 mL absolute EtOH, 0.82 mmol benzyl-p-toluenethiosulfonate, 2.34 mmol NaHCO3 and 0.82 mmol triethylamine in 5 mL absolute ethanol. The reaction is stirred overnight at room temperature. The product was purified by flash chromatography using CH2Cl2/MeOH (99/1) to give the desired solid (mp 47-49°C).

1H NMR (DMSO-d6) δ 1.0-1.2 (m, 1H), 1.3-1.5 (m, 1H), 1.5.1-7 (m, 2H), 1.8-2.0 (m, 2H), 2.0-2.2 ( m, 2H), 2.9 (ABq, 2H), 3.5 (d, 1H), 3.7 (d, 1H), 4.4 (m, 2H), 5.7 (broad t, 1H), 6.8-6.9 (m, 2H), 7.0-7.5 (m, 13H).

Example 63

N-Benzyl-4-(3,6-dihydro-4-hydroxy-6-oxo-2-phenyl-5-[(phenylmethyl)thio]-2H-pyran-2-yl)-N-methylbutyramide (±)

The title compound was prepared as described in General Method 4, using 0.33 mmol of N-Benzyl-4-(3,6-dihydro-4-hydroxy-6-oxo-2-phenyl-2H-pyran-2-yl)- N-methyl-butyramide (±), 0.92 mmol of benzyl-p-toluenethiosulfonate in 5 mL of absolute EtOH, 2.63 mmol of NaHCO3 and 0.92 mmol of triethylamine in 5 mL of absolute ethanol. The reaction was heated for 2 hours at 50°C. The solid product was purified by flash chromatography using CH2Cl2/MeOH (99/1-98/2) to give a solid (mp 47-49°C).

1H NMR (DMSO-d6) 1.5-1.8 (m, 1H), 1.9-2.1 (m, 2H), 2.3 (ABq, 2H), 2.84/2.91 (s/s, 3H), 2.98-3.02 (m, 2H ), 3.5 (dd, 1H), 3.7 (dd, 1H), 4.46/4.55 (s/s, 2H), 6.8-6.9 (m, 2H), 7.0-7.5 (m, 13H).

General method 5

The desired compounds were prepared by adding the appropriate acid chloride (1.05 equiv) to a solution of 5,6-dihydro-2H-pyran-2-one (1.0 equiv), triethylamine (0.5 equiv) and THF at 5°C. The suspension was stirred overnight at room temperature and diluted with ethyl acetate and water. The organic phase was washed with ice-cooled 1M HCl, sodium chloride solution, dried over MgSO4 and concentrated. The residue was dissolved in toluene, catalytic DMAP was added and heated at 80-85°C for 4 to 8 hours. The solution was cooled to room temperature and diluted with water. The organic phase was washed with ice-cooled 1M HCl, sodium chloride solution, dried (MgSO4), and concentrated. The product was chromatographed on silica gel, eluted with 5:1 hexane/ethyl acetate, resulting in a 3-acylated intermediate. This material was dissolved in glacial acetic acid, sodium cyanoborohydride (2 eq.) was added and stirred at room temperature for 2 hours. The reaction mixture was diluted with water, acidified conc. HCl and extracted with ethyl acetate. The extract was washed with sodium chloride solution, dried (MgSO4), and concentrated, whereby the desired compound was obtained.

Example 64

5,6-Dihydro-4-hydroxy-6,6-diphenyl-3-(2-phenylethyl)-2H-pyran-2-one

The title compound was prepared as described in General Method 5, using 2.0 mmol of 5,6-dihydro-4-hydroxy-6,6-diphenyl-2H-pyran-2-one, 2.1 mmol of phenacetyl chloride, 2.1 mmol of triethylamine and 10 mL of THF, followed by 10 mL of THF and catalytic DMAP. Chromatography of the residue yielded 1.5 mmol of the 3-acyl compound. The reduction of that acyl derivative was completed with 3 mmol of sodium cyanohydride. The product was dissolved in ether (melting point 158-159°C).

1H NMR (DMSO-d6) δ 2.31 (m, 4H), 3.37 (m, 2H), 6.93 (d, 1H), 7.07-7.17 (m, 3H), 7.24-7.28 (m, 2H), 7.35 (m , 8H).

Alternatively, the title compound can be prepared as follows. A suspension of 0.25 g (6.2 mmol) of sodium hydride in 5 mL of dry THF was cooled to 0°C in a stream of nitrogen, and a solution of 1.40 g (6.0 mmol) of ethyl 2-(2-phenylethyl)acetoacetate in THF (2 mL) was added ). The solution was stirred for ten minutes at 0°C, 4.3 mL of 1.4 M n-butyllithium was added, and it was stirred for the next fifteen minutes. A solution of 0.55 g (3.0 mmol) of benzophenone in THF (3 mL) was added all at once and the reaction mixture was stirred at room temperature for two hours. Water (75 mL) was added and the mixture was stirred overnight at room temperature. The solution was washed with ether. The aqueous layer was acidified to pH 2 with 6 M HCl and extracted with ethyl acetate, the extract was washed with sodium chloride solution, dried over magnesium sulfate and concentrated. The residue was triturated in ether/hexane 1:1, and the solid was filtered and dried to give the title compound.

Example 65

5,6-Dihydro-4-hydroxy-6-(3-methylbutyl)-6-phenyl-3-(2-phenylethyl)-2H-pyran-2-one (+/-)

The title compound was prepared as described in General Method 5, using 2.0 mmol of 5,6-dihydro-4-hydroxy-6-(methylbutyl)-6-phenyl-2H-pyran-2-one, 2.1 mmol of phenylacetyl chloride, 2.1 mmol triethylamine and 10 mL THF, followed by 10 mL THF and catalytic DMAP. Chromatography of the residue yielded 1.0 mmol of the acyl compound as an intermediate. The reduction of this intermediate product was carried out with 2 mmol of sodium cyanohydride. The product is obtained as a solid (melting point 125-126°C).

1H NMR (DMSO-d6) δ 0.76 (m, 7H), 1.12 (m, 1H), 1.38 (m, 1H), 1.87 (m, 2H), 2.27-2.46 (m, 4H), 2.97 (q, 2H ), 6.98-7.38 (m, 10H).

Example 66

5,6-Dihydro-4-hydroxy-6,6-diphenyl-3-(3-phenylpropyl)-2H-pyran-2-one

The title compound was prepared as described in General Method 5, using 2.5 mmol of 5,6-dihydro-4-hydroxy-6,6-diphenyl-2H-pyran-2-one, 2.7 mmol of phenylacetyl chloride, 2.8 mmol of triethylamine and 20 mL of THF, followed by 20 mL of THF and catalytic DMAP. Chromatography of the residue yielded 1.0 mmol of the 3-acyl compound. The reduction of that acyl derivative was completed with 3 mmol of sodium cyanohydride. The product was dissolved in ether (melting point 61-63°C).

1H NMR (DMSO-d6) δ 1.35 (m, 2H), 2.05 (t, 2H), 2.14 (t, 2H), 3.42 (term s, 2H), 6.92 (m, 2H), 7.17-7.40 (m, 13H).

Example 67

5,6-Dihydro-4-hydroxy-6-phenyl-3,6-bis(2-phenylethyl)-2H-pyran-2-one (+/-)

The title compound was prepared as described in General Method 5, using 3.0 mmol of 5,6-dihydro-4-hydroxy-6-phenyl-6-(2-phenylethyl)-2H-pyran-2-one, 3.2 mmol of hydrocinnamoyl- chloride, 3.2 mmol of triethylamine and 30 mL of THF, followed by 30 mL of THF and catalytic DMAP. Chromatography of the residue yielded 1.5 mmol of the acyl compound as an intermediate. The reduction of this intermediate product was carried out with 3 mmol of sodium cyanohydride. The product was dissolved in ether/hexane (1:5) (melting point 68-70°C).

1H NMR (DMSO-d6) δ 2.20 (m, 2H), 2.35 (m, 2H), 2.42-2.59 (m, 4H plus DMSO), 3.06 (q, 2H), 7.00 (dd, 2H), 7.07-7.43 (m, 13H).

General method 6

The desired compounds were prepared by adding piperidine (1.05 equiv) to a cold (ice bath) solution of 3-bromo-5,6-dihydro-4-hydroxy-2H-pyran-2-one (1.0 mmol, prepared by General Method 3) and the required thiol ( 1.05 mmol), and dichloromethane (20 mL). The mixture was stirred at room temperature from 8 to 48 hours. Water was added, the organic phase was separated and dried over MgSO4, and concentrated.

Example 68

4-Hydroxy-3-(2-isopropylphenylthio)-5,6-dihydro-6,6-diphenyl-2H-pyran-2-one

The title compound was prepared as described in General Method 6, using 1.0 mmol of 3-bromo-5,6-dihydro-4-hydroxy-6,6-diphenyl-2H-pyran-2-one (prepared in Example AAA), 1.05 mmol of 2-isopropylbenzothiol and 1.05 mmol of piperidine in 20 mL of dichloromethane. The product was slurried in ether to obtain a solid (melting point 216-217°C).

1H NMR (DMSO-d6) δ 1.17 (d, J=6.8 Hz, 6H), 3.20 (m, 1H), 3.77 (broad s, 2H), 5.64 (d, 1H), 6.45 (t, 1H), 6.92 (t, 1H), 7.12 (d, 1H), 7.32-7.48 (m, 10H).

Example 69

5,6-Dihydro-4-hydroxy-6,6-diphenyl-3-phenylthio-2H-pyran-2-one

The title compound was prepared as described in General Method 6, using 0.96 mmol of 3-bromo-5,6-dihydro-4-hydroxy-6,6-diphenyl-2H-pyran-2-one (prepared in Example AAA), 1.0 mmol of benzenethiol and 1.0 mmol of piperidine in 20 mL of dichloromethane. The product was dissolved in ether/hexane (1:1) and a solid was obtained (melting point 78-80°C).

1H NMR (DMSO-d6) δ 3.37 (shirox, 2H), 6.35 (m, 2H), 6.93 (m, 3H), 7.29-7.49 (m, 10H).

Example 70

5,6-Dihydro-4-hydroxy-3-(3-methylphenylthio)-6,6-diphenyl-2H-pyran-2-one

The title compound was prepared as described in General Method 6, using 1.3 mmol of 3-bromo-5,6-dihydro-4-hydroxy-6,6-diphenyl-2H-pyran-2-one (prepared in Example AAA), 1.4 mmol of 3-methylbenzenethiol and 1.4 mmol of piperidine in 25 mL of dichloromethane. The product was dissolved in ether/hexane (1:1), and the resulting solid was dissolved in 2M NaOH, washed with water, acidified to pH 2 and extracted with ethyl acetate. The extract was washed with water, dried over MgSO4 and concentrated to give a solid (melting point 56-60°C).

1H NMR (DMSO-d6) δ 2.07 (s, 3H), 3.77 (s, 2H), 6.06 (m, 1H), 6.45 (s, 1H), 6.78 (m, 2H), 7.25-7.47 (m, 10H ).

Example 71

5,6-Dihydro-4-hydroxy-6-phenyl-6-(2-phenylethyl)-3-phenylthio-2H-pyran-2-one (+/-)

The title compound was prepared as described in General Method 6, using 1.50 mmol of 3-bromo-5,6-dihydro-4-hydroxy-6-phenyl-6-(2-phenylethyl)-2H-pyran-2-one ( prepared in Example BBB), 1.60 mmol of benzenethiol and 1.60 mmol of piperidine in 30 mL of dichloromethane. The product is slurried in ether/hexane (1:1), whereby a solid is formed. The crude product was chromatographed on silica gel, eluted first with chloroform and then with 5% methanol in chloroform, whereby the title compound was obtained (melting point 58-60°C).

1H NMR (DMSO-d6) δ 2.22-2.39 (m, 3H), 2.62 (m, 1H), 3.46 (q, 2H), 6.48 (m, 2H), 6.98 (m, 3H), 7.15 (m, 3H ), 7.25 (m, 2H), 7.46 (m, 5H).

Example 72

5,6-Dihydro-4-hydroxy-3-(2-isopropylthio)-6-phenyl-6-(2-phenylethyl)-2H-pyran-2-one (+/-)

The title compound was prepared as described in General Method 6, using 1.50 mmol of 3-bromo-5,6-dihydro-4-hydroxy-6-phenyl-6-(2-phenylethyl)-2H-pyran-2- he (prepared in Example BBB), 1.60 mmol of 2-isopropylbenzenethiol and 1.60 mmol of piperidine in 30 mL of dichloromethane. The product was slurried in ether/hexane (1:1), whereby a solid was obtained. The crude product was chromatographed on silica gel, eluting first with chloroform and then with 5% methanol in chloroform, whereby the title compound was obtained (melting point 66-67°C).

1H NMR (DMSO-d6) δ 1.16 (t, 6H), 2.21-2.35 (m, 3H), 2.60 (m, 1H), 3.21 (m, 1H), 3.42 (q, 2H), 5.88 (d, 1H) ), 6.56 (t, 1H), 6.94 (t, 1H), 7.13 (m, 4H), 7.25 (m, 2H), 7.45 (m, 5H).

Example 73

5,6-Dihydro-4-hydroxy-3-(3-methylphenylthio)-6-phenyl-6-(2-phenylethyl)-2H-pyran-2-one (+/-)

The title compound was prepared as described in General Method 6, using 2.0 mmol of 3-bromo-5,6-dihydro-4-hydroxy-6-phenyl-6-(2-phenylethyl)-2H-pyran-2-one ( prepared in Example BBB), 2.2 mmol of 3-methylbenzenethiol and 2.2 mmol of piperidine in 30 mL of dichloromethane. The product was dissolved in ether/hexane (1:1). The crude product was chromatographed on silica gel, eluting first with chloroform and then with 5% methanol in chloroform, whereby the title compound was obtained (melting point 68-80°C).

1H NMR (DMSO-d6) δ 2.06 (s, 3H), 2.18-2.36 (m, 3H), 2.6 (m, 1H), 3.38 (2H + H2O), 6.26 (d, 1H), 6.46 (s, 1H ), 6.75 (m, 1H), 6.83 (t, 1H), 7.15 (m, 3H), 7.24 (m, 2H), 7.45 (m, 5H).

Example 74

5-[3,6-Dihydro-4-hydroxy-5-(2-isopropylthio)-6-osco-2-phenyl-2H-pyran-2-one (+/-)

The title compound was prepared as described in General Method 6, using 1.1 mmol of 5-[5-bromo-3,6-dihydro-4-hydroxy-6-osco-2-phenyl-2H-pyran-2-yl]- pentanoic acid (prepared in Example DDD), 1.3 mmol of 2-isopropylbenzenethiol and 1.3 mmol of piperidine in 20 mL of dichloromethane. The crude product was chromatographed on silica gel, eluting first with 5% methanol in chloroform and then with 9:1:0.5 chloroform/methanol/acetic acid to give the title compound (mp 145-146°C).

1H NMR (DMSO-d6) δ 1.07-1.19 (t plus m, 7H), 1.25 (m, 1H), 1.43 (m, 2H), 1.91 (m, 2H), 2.15 (t, 2H), 3.19 (m , 1H), 3.41 (2H + H2O), 5.81 (d, 1H), 6.54 (t, 1H), 6.93 (t, 1H), 7.12 (d, 1H), 7.29-7.44 (m, 5H).

Example 75

5,6-Dihydro-4-hydroxy-6-(3-methylbutyl)-6-phenyl-3-(2-isopropyl-phenylthio)-2H-pyran-2-one (+/-)

The title compound was prepared as described in General Method 6, using 2.0 mmol of 3-bromo-5,6-dihydro-4-hydroxy-6-(3-methylbutyl)-6-phenyl-2H-pyran-2-one ( prepared in Example CCC), 2.2 mmol of 2-isopropylbenzenethiol and 2.2 mmol of piperidine in 30 mL of dichloromethane. The crude product was chromatographed on silica gel, eluting first with chloroform and then with 5% methanol in chloroform, whereby the title compound was obtained (melting point 64-65°C).

1H NMR (DMSO-d6) δ 0.80 (m, 6H), 0.95 (m, 1H), 1.17 (t, 7H), 1.42 (m, 1H), 1.93 (m, 2H), 3.20 (m, 1H), 3.45 (2H + H2), 5.84 (d, 1H), 6.55 (t, 1H), 6.93 (t, 1H), 7.12 (d, 1H), 7.40 (m, 5H).

Example 76

5,6-Dihydro-4-hydroxy-6-(3-methylbutyl)-6-phenyl-3-phenylthio-2H-pyran-2-one (+/-)

The title compound was prepared as described in General Method 6, using 1.5 mmol of 3-bromo-5,6-dihydro-4-hydroxy-6-(3-methylbutyl)-2-phenyl-2H-pyran-2-one ( prepared in Example CCC), 1.6 mmol of benzenethiol and 1.6 mmol of piperidine in 20 mL of dichloromethane. The crude product was chromatographed on silica gel, first eluting with chloroform and then with 5% methanol in chloroform, whereby the title compound was obtained (melting point 154-155°C).

1H NMR (DMSO-d6) δ 0.80 (m, 6H), 0.97 (m, 1H), 1.16(m, 2H), 1.42 (m, 1H), 1.91 (m, 2H), 3.40 (2H + H2O), 6.45 (m, 2H), 6.93 (m, 3H), 7.37 (m, 5H).

Example 77

Methyl 2-[[5,6-dihydro-4-hydroxy-6-(3-methylbutyl)-2-oxo-6-phenyl-2H-pyran-3-yl]thio]benzoate

The title compound was prepared as described in General Method 6, using 1.9 mmol of 3-bromo-5,6-dihydro-4-hydroxy-6-(3-methylbutyl)-6-phenyl-2H-pyran-2-one ( prepared in Example CCC), 2.2 mmol of methyl thiosalicylate and 2.1 mmol of piperidine in 30 mL of dichloromethane. The crude product was chromatographed on silica gel, eluted first with chloroform and then with 5% methanol in chloroform, whereby the title compound was obtained (melting point 115-116°C).

1H NMR (DMSO-d6) δ 0.80 (m, 6H), 1.0 (m, 1H), 1.17 (m, 1H), 1.43 (m, 1H), 1.96 (m, 2H), 3.40 (2H + H2O), 3.81 (s, 3H), 6.02 (broad d, 1H), 6.88 (t, 1H), 7.05 (t, 1H), 7.42 (m, 5H), 7.80 (dd, 1H).

Example 78

2-[[5,6-Dihydro-4-hydroxy-6-(3-methylbutyl)-2-oxo-6-phenyl-2H-pyran-3-yl]thio]benzoic acid (+/-)

A solution of 0.3 mmol of the compound, which was prepared in Example 77, in 15 mL of 1 M sodium hydroxide was stirred for 3 hours at room temperature. The solution was washed with ether and acidified to pH 2.0 with 6 M hydrochloric acid. The solution was extracted with ethyl acetate, and the extract was washed with sodium chloride solution, dried over magnesium sulfate, and concentrated to give the title compound (melting point 99-101°C).

1H NMR (DMSO-d6) δ 0.80 (m, 6H), 0.95 (m, 1H), 1.15 (m, 1H), 1.43 (m, 1H), 1.91 (m, 2H), 3.4 (2H + H2O), 6.05 (d, 1H), 6.85 (broad t, 1H), 7.03 (t, 1H), 7.42 (m, 5H), 7.79 (dd, 1H).

Example 79

5,6-Dihydro-3-(2-sec-butylphenylthio)-4-hydroxy-6,6-diphenyl-2H-pyran-2-one (+/-)

The title compound was prepared as described in General Method 6, using 1.6 mmol of 3-bromo-5,6-dihydro-4-hydroxy-6,6-diphenyl-2H-pyran-2-one (prepared in Example AAA), 1.7 mmol of 2-sec-butylbenzenethiol and 1.7 mmol of piperidine in 25 mL of dichloromethane. The product was chromatographed on silica gel, eluted first with chloroform and then with 5% methanol in chloroform, whereby the title compound was obtained (melting point 161-162°C).

1H NMR (DMSO-d6) δ 0.81 (t, 3H), 1.15 (d, 3H), 1.43-1.64 (m, 2H), 2.98 (m, 1H), 3.77 (s, 2H), 5.65 (dd, 1H ), 6.47 (t, 1H), 6.92 (t, 1H), 7.07 (d, 1H), 7.34-7.48 (m, 10H), 12.4 (broad s, 1H).

Example 80

5,6-Dihydro-4-hydroxy-3-(2-methoxyphenylthio)-6,6-diphenyl-2H-pyran-2-one

The title compound was prepared as described in General Method 6, using 1.5 mmol of 3-bromo-5,6-dihydro-4-hydroxy-6,6-diphenyl-2H-pyran-2-one (prepared in Example AAA), 1.6 mmol of 2-methoxybenzenethiol and 1.6 mmol of piperidine in 25 mL of dichloromethane. The product was chromatographed on silica gel, eluted first with chloroform and then with 5% methanol in chloroform, whereby the title compound was obtained (melting point 170-172°C).

1H NMR (DMSO-d6) δ 3.76 (broad, 5H), 5.44 (dd, 1H), 6.26 (t, 1H), 6.85 (m, 1H), 6.91 (t, 1H), 7.34-7.50 (m, 10H ).

Example 81

5,6-Dihydro-3-(2-sec-butylphenylthio)-4-hydroxy-6-phenyl-6-(2-phenylethyl)-2H-pyran-2-one (+/-)

The title compound was prepared as described in General Method 6, using 2.0 mmol of 3-bromo-5,6-dihydro-4-hydroxy-6-phenyl-6-(2-phenylethyl)-2H-pyran-2-one ( prepared in Example BBB), 2.1 mmol of 2-sec-butylbenzenethiol and 2.1 mmol of piperidine in 25 mL of dichloromethane. The product was chromatographed on silica gel, eluted first with chloroform and then with 5% methanol in chloroform, whereby the title compound was obtained (melting point 67-68°C).

1H NMR (DMSO-d6) δ 0.82 (q, 3H), 1.09 (t, 3H), 1.46-1.61 (m, 2H), 2.26 (m, 2H), 2.35 (m, 1H), 2.62 (m, 1H ), 2.98 (m, 1H), 3.47 (q, 2H), 5.90 (t, 1H), 6.56 (t, 1H), 6.94 (t, 1H), 7.07-7.18 (m, 4H), 7.25 (m, 2H), 7.45 (m, 5H).

Example 82

5,6-Dihydro-4-hydroxy-3-(4-methyl-2-isopropylphenylthio)-6,6-diphenyl-2H-pyran-2-one

The title compound was prepared as described in General Method 6, using 2.0 mmol of 3-bromo-5,6-dihydro-4-hydroxy-6,6-diphenyl-2H-pyran-2-one (prepared in Example AAA), 2.1 mmol of 4-methyl-2-isopropylbenzenethiol and 2.1 mmol of piperidine in 30 mL of dichloromethane. The product was chromatographed on silica gel, eluted first with chloroform and then with 5% methanol in chloroform, whereby the title compound was obtained (melting point 185-186°C).

1H NMR (DMSO-d6) δ 1.17 (d, J=10 Hz, 6H), 2.15 (s, 3H), 3.17 (m, 1H), 3.76 (broad s, 2H), 5.56 (d, 1H), 6.29 (d, 1H), 6.94 (s, 1H), 7.32-7.47 (m, 10H).

Example 83

5,6-Dihydro-4-hydroxy-3-(3-methoxyphenylthio)-6,6-diphenyl-2H-pyran-2-one

The title compound was prepared as described in General Method 6, using 1.8 mmol of 3-bromo-5,6-dihydro-4-hydroxy-6,6-diphenyl-2H-pyran-2-one (prepared in Example AAA), 2.0 mmol of 3-methoxybenzenethiol and 2.0 mmol of piperidine in 25 mL of dichloromethane. The product was chromatographed on silica gel, eluted first with chloroform and then with 5% methanol in chloroform, whereby the title compound was obtained (melting point 61-62°C).

1H NMR (DMSO-d6) δ 3.63 (s, 3H), 3.76 (s, 2H), 5.64 (broad d, 1H), 6.42 (s, 1H), 6.54 (d, 1H), 6.74 (t, 1H) , 7.32-7.47 (m, 10H).

Example 84

5,6-Dihydro-4-hydroxy-3-(5-methyl-2-isopropylphenylthio)-6,6-diphenyl-2H-pyran-2-one

The title compound was prepared as described in General Method 6, using 2.0 mmol of 3-bromo-5,6-dihydro-4-hydroxy-6,6-diphenyl-2H-pyran-2-one (prepared in Example AAA), 2.1 mmol of 5-methyl-2-isopropylbenzenethiol and 2.1 mmol of piperidine in 25 mL of dichloromethane. The product was chromatographed on silica gel, eluted first with chloroform and then with 5% methanol in chloroform, whereby the title compound was obtained (melting point 183-184°C).

1H NMR (DMSO-d6) δ 1.15 (d, 6H), 1.85 (s, 3H), 3.22 (m, 1H), 3.80 (broad s, 2H), 5.88 (broad s, 1H), 6.77 (d, 1H ), 7.03 (d, 1H), 7.32-7.47 (m, 10H).

Example 85

5,6-Dihydro-4-hydroxy-3-(5-methyl-2-isopropylphenylthio)-6-phenyl-6-(2-phenylethyl)-2H-pyran-2-one (+/-)

The title compound was prepared as described in General Method 6, using 2.0 mmol of 3-bromo-5,6-dihydro-4-hydroxy-6-phenyl-6-(2-phenylethyl)-2H-pyran-2-one ( prepared in Example BBB), 2.1 mmol of 5-methyl-2-isopropylbenzenethiol and 2.1 mmol of piperidine in 25 mL of dichloromethane. The product was chromatographed on silica gel, eluted first with chloroform and then with 5% methanol in chloroform (melting point 66-67°C).

1H NMR (DMSO-d6) δ 1.16 (d, 6H), 1.87 (m, 6H), 2.26 (m. 3H), 2.57 (m, 1H), 3.23 (m, 1H), 3.43 (q, 2H), 6.01 (broad s, 1H), 6.78 (d, 1H), 7.03-7.27 (m, 6H), 7.37-7.47 (m, 5H).

Example 86

5,6-Dihydro-3-(4-chloro-2-isopropylphenylthio)-4-hydroxy-6,6-diphenyl-2H-pyran-2-one

The title compound was prepared as described in General Method 6, using 2.0 mmol of 3-bromo-5,6-dihydro-4-hydroxy-6,6-diphenyl-2H-pyran-2-one (prepared in Example AAA), 2.1 mmol of 4-chloro-2-isopropylbenzenethiol and 2.1 mmol of piperidine in 30 mL of dichloromethane. The product was chromatographed on silica gel, eluted first with chloroform and then with 5% methanol in chloroform (melting point 95-96°C).

1H NMR (DMSO-d6) δ 1.16 (d, 6H), 3.23 (m, 1H), 3.73 (broad s, 2H), 5.60 (d, 1H), 6.45 (d, 1H), 7.14 (d, 1H) , 7.32-7.48 (m, 10H).

Example 87

5,6-Dihydro-4-hydroxy-3-(4-methyl-2-isopropylphenylthio)-6-phenyl-6-(2-phenylethyl)-2H-pyran-2-one (+/-)

The title compound was prepared as described in General Method 6, using 2.0 mmol of 3-bromo-5,6-dihydro-4-hydroxy-6-phenyl-6-(2-phenylethyl)-2H-pyran-2-one ( prepared in Example BBB), 2.1 mmol of 4-methyl-2-isopropylbenzenethiol and 2.1 mmol of piperidine in 30 mL of dichloromethane. The product was chromatographed on silica gel, eluted first with chloroform and then with 5% methanol in chloroform (melting point 75-76°C).

1H NMR (DMSO-d6) δ 1.15 (m, 6H), 2.16 (s, 3H), 2.19-2.36 (m, 3H), 2.62 (m, 1H), 3.21 (m, 1H), 3.44 (q, 2H ), 5.82 (d, 1H), 6.40 (dd, 1H), 6.95 (d, 1H), 7.10-7.18 (m, 3H), 7.25 (m, 2H), 7.44 (m, 5H).

Example 88

Methyl 2-[[5,6-dihydro-4-hydroxy-2-oxo-6-(2-phenylethyl)-6-phenyl-2H-pyran-3-yl]thio]benzoate (+/-)

The title compound was prepared as described in General Method 6, using 1.9 mmol of 3-bromo-5,6-dihydro-4-hydroxy-6-phenyl-6-(2-phenylethyl)-2H-pyran-2-one ( prepared in Example BBB), 2.2 mmol of methyl thiosalicylate and 2.1 mmol of piperidine in 30 mL of dichloromethane. The crude product was chromatographed on silica gel, first eluting with chloroform and then with 5% methanol in chloroform, whereby the title compound was obtained (melting point 91-92°C).

1H NMR (DMSO-d6) δ 2.25 (m, 2H), 2.38 (m, 1H), 2.62 (m, 1H), 3.44 (q, 2H), 3.82 (s, 3H), 6.06 (broad d, 1H) , 6.90 (t, 1H), 7.05-7.52 (m, 11H), 7.81 (dd, 1H).

General method 7

The desired compounds were prepared by adding p-toluenesulfonate reagent (prepared in General Method 2), 5,6-dihydro-2H-pyran-2-one, ethanol and Et3N to a reaction vessel. The mixture was then heated from 4 to 48 hours at 40°C. After that, the mixture was diluted with water, acidified conc. HCl, and the product was extracted with diethyl ether, CH2Cl2 or ethyl acetate. The organic layers were combined and dried over Na2SO4.

Example 89

5,6-Dihydro-4-hydroxy-6-phenyl-6-(2-phenylethyl)-3-[(2-trifluoromethylphenyl)-methylthio]-2H-pyran-2-one (+/-)

The title compound was prepared as described in General Method 7, using: 5,6-dihydro-4-hydroxy-6-phenyl-6-(2-phenylethyl)-2H-pyran-2-one (0.250 g, 0.850 mmol ), (2-trifluoromethyl)benzyl-p-toluenethiosulfonate (0.350 g, 1.02 mmol), Et3N (0.280 mL, 2.00 mmol), NaHCO3 (0.50 g, 0.68 mmol), absolute ethanol (3.0 mL). The mixture was heated for 16 h at 40°C, then diluted with diethyl ether (100 mL) and washed with water. The solvent was removed in vacuo and the residue was purified by column chromatography (SiO2, 100% CH2Cl2 to 2% methanol in CH2Cl2) to give a solid (0.316 g, mp 59-62°C).

1H NMR (400 MHz, DMSO-d6) δ 7.603-7.581 (m, 1H), 7.432-7.026 (m, 13H), 3.780 (d, 1H, J=14 Hz), 3.69 (d, 1H, J=14 Hz), 3.310 (d, 1H, J=17.5 Hz), 3.220 (d, 1H, J=17.5 Hz), 2.567-2.505 (m, 1H), 2.253-2.157 (m, 3H).

Example 90

5,6-Dihydro-4-hydroxy-3-[(2,5-dimethylphenyl)methylthio]-6-phenyl-6-(2-phenyl-ethyl)-2H-pyran-2-one (+/-)

The title compound was prepared as described in General Method 7, using: 5,6-dihydro-4-hydroxy-6-phenyl-6-(2-phenylethyl)-2H-pyran-2-one (0.312 g, 1.02 mmol ), 2,5-dimethylbenzyl-p-toluenethiosulfonate (0.250 g, 0.850 mmol), Et3N (0.230 mL, 1.60 mmol), NaHCO3 (0.071 g, 0.85 mmol) and absolute ethanol (3.0 mL). The mixture was heated for 16 h at 40°C, then diluted with diethyl ether (100 mL) and washed with water. The solvent was removed in vacuo, and the residue was purified by column chromatography (SiO2, 100% CH2Cl2 to 2% methanol in CH2Cl2), whereby cruline (0.116 g, melting point 54-56°C) was obtained, which was dried in vacuum.

1H NMR (400 MHz, DMSO-d6) δ 11.498 (broad s, 1H), 7.405-7.380 (m, 4H), 7.327-7.285 (m, 1H), 7.258-7.221 (m, 2H), 7.168-7.128 ( m, 1H), 7.090 (d, 2H, J=7.5 Hz), 6.970 (d, 1H, J=8 Hz), 6.890 (d, 1H, J=8 H/.), 6.821 (s, 1H), 3.600 (d, 1H,J=11 Hz), 3.505 (d, 1H,J=11 Hz), 3.250 (d, 1H, J=17 Hz), 3.176 (d, 1H, J=17 Hz), 2.619-2.564 (m, 1H), 2.235-2.168 (m, 9H).

Example 91

5,6-Dihydro-4-hydroxy-3-(naphthalen-1-ylmethylthio)-6-phenyl-6-(2-phenylethyl)-2H-pyran-2-one (+/-)

The title compound was prepared as described in General Method 7, using: 5,6-dihydro-4-hydroxy-6-phenyl-6-(2-phenylethyl)-2H-pyran-2-one (0.20 g, 0.68 mmol ), (1-naphthalen-1-ylmethyl)-p-toluenethiosulfonate (0.27 g, 0.82 mmol), Et3N (0.18 mL, 1.3 mmol), NaHCO3 (0.68 mmol) and absolute ethanol (3.0 mL). The mixture was heated for 16 h at 40°C, then diluted with diethyl ether (100 mL) and washed with water. The solvent was removed in vacuo and the residue was purified by column chromatography (SiO2, 100% CH2Cl2 to 1% methanol in CH2Cl2) to give a solid (0.158 g, mp 58-60°C).

1H NMR (400 MHz, DMSO-d6) δ 11.533 (broad s, 1H), 8.177 (d, 1H, J=8 Hz), 7.886 (dd, 1H, J=2 Hz), J=7 Hz), 7.761 (d, 1H, J=8 Hz), 7.501-7.05 (m, 14H), 4.120 (d, 1H, J=12 Hz), 3.995 (d, 1H, J=12 Hz), 3.274 (d, 1H, J=18 Hz), 3.194 (d, 1H, J=18 Hz), 2.636-2.581 (m, 1H), 2.288-2.169 (m, 3H).

Example 92

3-(Biphen-2-ylmethylthio)-5,6-dihydro-4-hydroxy-6-phenyl-6-(2-phenylethyl)-2H-pyran-2-one (+/-)

The title compound was prepared as described in General Method 7, using: 5,6-dihydro-4-hydroxy-6-phenyl-6-(2-phenylethyl)-2H-pyran-2-one (0.250 g, 0.85 mmol ), (biphen-2-ylmethyl)-p-toluenethiosulfonate (0.360 g, 1.02 mmol), Et3N (0.14 mL, 1.0 mmol), NaHCO3 (0.85 mmol), absolute ethanol (5.0 mL). The mixture was heated for 16 h at 40°C, then diluted with diethyl ether (100 mL) and washed with water. The solvent was removed in vacuo and the residue was purified by column chromatography (SiO2, 100% CH2Cl2 to 1% methanol in CH2Cl2) to give a solid (0.317 g, mp 58-60°C).

1H NMR (400 MHz, DMSO-d6) δ 11.569 (broad s, 1H), 7.429-7.066 (m, 19H), 3.528 (d, 1H, J=12 Hz), 3.477 (d, 1H, 1=12 Hz) ), 3.280 (dd, 1H, J=17 Hz), 3.183 (d, 1H, J=17 Hz), 2.607-2.502 (m, 1H), 2.246-2.144 (m, 3H).

Example 93

3-(2-Chlorophenylmethylthio)-5,6-dihydro-4-hydroxy-6-phenyl-6-(2-phenylethyl)-2H-pyran-2-one (+/-)

The title compound was prepared as described in General Method 7, using: 5,6-dihydro-4-hydroxy-6-phenyl-6-(2-phenylethyl)-2H-pyran-2-one (0.250 g, 0.85 mmol ), (2-chlorobenzyl)-p-toluenethiosulfonate (0.320 g, 1.02 mmol), Et3N (0.14 mL and absolute ethanol (5.0 mL). The mixture was heated for 16 h at 40°C, then diluted with diethyl ether (100 mL ), and washed with water. The solvent was removed in vacuo, and the residue was purified by column chromatography (SiO2, 100% CH2Cl2 to 2% methanol in CH2Cl2) to give a solid (0.317 g, mp 53-55°C).

1H NMR (400 MHz, DMSO-d6) δ 11.551 (broad s, 1H), 7.435-7.005 (m, 13H), 6.800 (dd, 1H, J=1.5 Hz, J=7.5 Hz), 3.750 (d, 1H , J= 13 Hz), 3.620 (d, 1H, J=13 Hz), 3.251 (d, 1H, J=17 Hz), 3.171 (d, 1H, J=17 Hz), 2.595-2.542 (m, 1H ), 2.233-2.125 (m, 3H).

Example 94

3-(2-Chlorophenylmethylthio)-5,6-dihydro-4-hydroxy-6-(3-methylbutyl)-6-phenyl-2H-pyran-2-one (+/-)

The title compound was prepared as described in General Method 7, using: 5,6-dihydro-4-hydroxy-6-phenyl-6-(3-methylbutyl)-2H-pyran-2-one (0.250 g, 0.85 mmol ), (2-chlorobenzyl)-p-toluenethiosulfonate (0.390 g, 1.24 mmol), Et3N (0.17 mL, 1.24 mmol), NaHCO3 (0.5 mmol) and absolute ethanol (5.0 mL). The mixture was heated for 16 h at 40°C, then diluted with diethyl ether (100 mL) and washed with water. The solvent was removed in vacuo and the residue was purified by column chromatography (SiO2, 100% CH2Cl2 to 2% methanol in CH2Cl2) to give a thick oil (0.36 g) which was dried in vacuo.

1H NMR (400 MHz, DMSO-d6) δ 7.388-7.267 (m, 6H), 7.181, (td, 1H, J= 1.5 Hz, J=7.5 Hz), 7.052 (t, 1H, J-7.5 Hz), 6.800 (dd, 1H, J=1.5 Hz, J=7.5 Hz), 3.718 (d, 1H, J= 13 Hz), 3.596 (d, 1H, J=13 Hz), 3.112 (s, 2H), 1.921- 1.797 (m, 2H), 1.402-1.320 (m, 1H), 1.156-1.065 (m, 1H), 0.844-0.739 (m, 7H).

Example 95

3-(Biphen-2-ylmethylthio)-5,6-dihydro-4-hydroxy-6-(3-methylbutyl)-6-phenyl-2H-pyran-2-one (+/-)

The title compound was prepared as described in General Method 7, using: 5,6-dihydro-4-hydroxy-6-phenyl-6-(3-methylbutyl)-2H-pyran-2-one (0.250 g, 0.96 mmol ), (2-methylbiphenyl)-p-toluenethiosulfonate (0.439 g, 1.24 mmol), Et3N (0.17 mL, 1.24 mmol), absolute ethanol (3.0 mL) and NaHCO3 (0.5 g). The mixture was heated for 16 h at 40°C, then diluted with diethyl ether (100 mL) and washed with water. The solvent was removed in vacuo and the residue was purified by column chromatography (SiO2, 100% CH2Cl2 to 2%; methanol in CH2Cl2) to give a solid (0.33 g, m.p. 49-51) which was dried in vacuo.

1H NMR (400 MHz, DMSO-d6) δ 7.425-7.153 (m, 13H), 7.74 (dd, 1H, J= 1 Hz, J=7 Hz), 3.480 (dd, 2H, 1=12 Hz, J= 17 Hz), 3.149 (dd, 2H, J=17 Hz, J=22 Hz), 1.921-1.821 (m, 2H), 1.402-1.336 (m, 1H), 1.161-1.071 (m, 1H), 0.847- 0.707 (m, 7H).

Example 96

5,6-Dihydro-3-(2,5-dimethylphenylmethylthio)-4-hydroxy-6-(3-methylbutyl)-6-phenyl-2H-pyran-2-one (+/-)

The title compound was prepared as described in General Method 7, using: 5,6-dihydro-4-hydroxy-6-phenyl-6-(3-methylbutyl)-2H-pyran-2-one (0.250 g, 0.96 mmol ), (2,5-dimethylbenzyl)-p-toluenethiosulfonate (0.380 g, 1.24 mmol), Et3N (0.17 mL, 1.24 mmol), absolute ethanol (3.0 mL) and NaHCO3 (0.5 g). The mixture was heated for 16 h at 40°C, then diluted with diethyl ether (100 mL) and washed with water. The solvent was removed in vacuo and the residue was purified by column chromatography (SiO2, 100% CH2Cl2 to 2% methanol in CH2Cl2) to give a thick oil (0.286 g).

1H NMR (400 MH/., DMSO-d6) δ 11.433 (broad s, 1H), 7.380-7.251 (m, 5H), 6.973 (d, 1H, J=7.5 H/,), 6.905.(d, 1H , J=7.5 Hz), 6.187(s, 1H), 3.584 (d, 1H, J=l 1.5 Hz), 3.481 (d, 1H, J= 11.5 Hz), 3.133 (s, 2H), 2.209 (s, 3H), 2.184 (s, 3H), 1.933-1.858 (m, 2H), 1.421-1.355 (m, 1H), 1.177-1.986 (m, 1H), 0.870-0.751 (m, 7H).

Example 97

5,6-Dihydro-4-hydroxy-3-(3-methoxyphenylmethylthio)-6-phenyl-6-(2-phenylethyl)-2H-pyran-2-one (+/-)

The title compound was prepared as described in General Method 7, using: 5,6-dihydro-4-hydroxy-6-phenyl-6-(2-phenylethyl)-2H-pyran-2-one (0.250 g, 0.85 mmol ), (3-methoxybenzyl)-p-toluenethiosulfonate (0.340 g, 1.11 mmol), Et3N (0.25 mL, 1.81 mmol), absolute ethanol (3.0 mL) and NaHCO3 (0.5 g). The mixture was heated for 16 h at 40°C, then diluted with diethyl ether (100 mL) and washed with water. The solvent was removed in vacuo and the residue was purified by column chromatography (SiO2, 100% CH2Cl2 to 2% methanol in CH2Cl2) to give a thick oil (0.286 g).

1H NMR (400 MHz, DMSO-d6) δ 7.411-7.376 (m, 4H), 7.361-7.280 (m, 1H), 7.235 (t, 2H, J=7 Hz), 7.146 (t, 1H, J=7 Hz), 7.078-7.019 (m, 3H), 6.769 (d, 1H, J=2 Hz), 6.762-6.698 (m, 1H), 6.555 (d, 1H, J=7 Hz), 3.694 (s, 3H ), 3.670 (d, 1H, J=17 Hz), 3.585 (d, 1H, J=13 Hz), 3.220 (d, 1H, J=17 Hz), 3.158 (d, 1H, J=17 Hz), 2.590-2.525 (m, 1H), 2.219-2.141 (m, 3H).

Example 98

3-(Biphen-2-ylmethylthio)-5,6-dihydro-4-hydroxy-6,6-diphenyl-2H-pyran-2-one

The title compound was prepared as described in General Method 7, using: 5,6-dihydro-4-hydroxy-6,6-diphenyl-2H-pyran-2-one (0.250 g, 0.94 mmol), (2-methylbiphenyl )-p-toluenethiosulfonate (0.389 g, 1.1 mmol), Et3N (0.26 mL, 1.9 mmol), absolute ethanol (3.0 mL) and NaHCO3 (0.5 g). The mixture was heated for 16 h at 40°C, then diluted with diethyl ether (100 mL) and washed with water. The solvent was removed in vacuo and the residue was purified by column chromatography (SiO2, 100% CH2Cl2 to 2% methanol in CH2Cl2) to give a thick oil (0.286 g).

1H NMR (400 MHz, DMSO-d6) δ 11.770 (broad s, 1H), 7.434-7.148 (m, 18H), 6.9659 (d, 1H, J=7 Hz), 3.595 (s, 2H), 3.407 (s , 2H).

Example 99

3-(3-Chlorophenylmethylthio)-5,6-dihydro-4-hydroxy-6-phenyl-6-(2-phenylethyl)-2H-pyran-2-one (+/-)

The title compound was prepared as described in General Method 7, using: 5,6-dihydro-4-hydroxy-6-phenyl-6-(2-phenylethyl)-2H-pyran-2-one (0.250 g, 0.85 mmol ), [(3-chlorophen-1-yl)methyl]-p-toluenethiosulfonate (0.340 g, 1.11 mmol), Et3N (0.25 mL, 1.81 mmol), absolute ethanol (3.0 mL) and NaHCO3 (0.5 g). The mixture was heated for 16 h at 40°C, then diluted with diethyl ether (100 mL) and washed with water. The solvent was removed in vacuo and the residue was purified by column chromatography (SiO2, 100% CH2Cl2 to 2% methanol in CH2Cl2) to give a thick oil (0.155 g).

1H NMR (400 MHz, DMSO-d6) δ 7.420-7.060 (m, 13H), 6.848 (d, 1H, J=7 Hz), 3.688 (d, 1H, J=13 Hz), 3.597 (d, 1H, J=13 Hz), 3.219 (d, 1H, J=17 Hz), 3.153 (d, 1H, J=17 Hz), 2.592-2.526 (m, 1H), 2.241-2.120 (m, 3H).

Example 100

5,6-Dihydro-4-hydroxy-6-(2-phenylethyl)-6-phenyl-3-[((3-trifluoromethyl)phenyl)-methylthio]-2H-pyran-2-one (+/-)

The title compound was prepared as described in General Method 7, using: 5,6-dihydro-4-hydroxy-6-phenyl-6-(2-phenylethyl)-2H-pyran-2-one (0.250 g, 0.85 mmol ), [(3-trifluoromethylphen-1-yl))methyl]-p-toluenethiosulfonate (0.340 g, 1.11 mmol), Et3N (0.25 mL, 1.81 mmol), absolute ethanol (3.0 mL) and NaHCO3 (0.5 g). The mixture was heated for 16 h at 40°C, then diluted with diethyl ether (100 mL) and washed with water. The solvent was removed in vacuo and the residue was purified by column chromatography (SiO2, 100% CH2Cl2 to 2% methanol in CH2Cl2) to give a thick oil (0.273 g).

1H NMR (400 MHz, DMSO-d6) δ 11.60 (broad s, 1H), 7.523-7.481 (m, 2H), 7.392-7.124 (m, 9H), 7.064 (d, 2H, J=8 Hz), 3.794 (d, 1H, J=13 Hz), 3.703 (d, 1H, J=13 Hz), 3.162 (s, 2H), 2.583-2.525 (m, 1H), 2.233-2.124 (m, 3H).

Example 101

5,6-Dihydro-4-hydroxy-3-(3-methylphenylmethylthio)-6-phenyl-6-(2-phenylethyl)-2H-pyran-2-one (+/-)

The title compound was prepared as described in General Method 7, using: 5,6-dihydro-4-hydroxy-6-phenyl-6-(2-phenylethyl)-2H-pyran-2-one (0.380 g, 0.85 mmol ), -[(3-methylphen-1-yl))methyl]-p-toluenethiosulfonate (0.298 g, 1.02 mmol), Et3N (0.25 mL, 1.81 mmol), absolute ethanol (3.0 mL) and NaHCO3 (0.5 g). The mixture was heated for 16 h at 40°C, then diluted with diethyl ether (100 mL) and washed with water. The solvent was removed in vacuo and the residue was purified by column chromatography (SiO2, 100% CH2Cl2 to 2% methanol in CH2Cl2) to give a thick oil (0.242 g).

1H NMR (400 MHz, DMSO-d6) δ 11.427 (broad s, 1H), 7.423-7.374 (m, 4H), 7.330-7.288 (m, 1H), 7.238 (t, 2H, J=7 Hz), 7.145 (t, 2H, J=8 Hz), 7.086-7.007 (m, 2H), 6.952 (d, 2H, J=6 Hz), 6.790 (d, 1H, J=7 Hz), 3.630 (d, 1H, J=12.5 Hz), 3.544 (d, 1H, J=12.5 Hz), 3.277 (d, 1H, J=17.5 Hz), 3.153 (d, 1H, J=17.5 Hz), 2.567 (broad t, 1H, J =12 Hz), 2.244-2.132 (m, 3H).

Example 102

3-[4-Hydroxy-2-oxo-6-(2-phenylethyl)-6-phenyl-5,6-dihydro-2H-pyran-3-ylthio-methyl]benzonitrile (+/-)

The title compound was prepared as described in General Method 7, using: 5,6-dihydro-4-hydroxy-6-phenyl-6-(2-phenylethyl)-2H-pyran-2-one (0.250 g, 0.85 mmol ), [(3-cyanophen-1-yl))methyl]-p-toluenethiosulfonate (0.309 g, 1.02 mmol), Et3N (0.25 mL, 1.81 mmol), absolute ethanol (5.0 mL) and NaHCO3 (0.5 g). The mixture was heated for 16 h at 40°C, then diluted with diethyl ether (100 mL) and washed with water. The solvent was removed in vacuo and the residue was purified by column chromatography (SiO2, 100% CH2Cl2 to 2% methanol in CH2Cl2) to give a solid (0.242 g, mp 58-60°C).

1H NMR (400 MHz, DMSO-d6) δ 11.572 (broad s, 1H), 7.585 (d, 1H, J=7 Hz), 7.499 (s, 1H), 7.426-7.078 (m, 10H), 7.066 (d , 2H, J=7 Hz), 3.736 (d, 1H, J=13.5 Hz), 3.637 (d, 1H, J=13.5 Hz), 3.185 (AB 2H, JAB= 17.5 Hz), 2.570-2.511 (m, 1H), 2.207-1.074 (m, 3H).

Example 103

3-(2-Chlorophenylmethylthio)-5,6-dihydro-4-hydroxy-6,6-diphenyl-2H-pyran-2-one

The title compound was prepared as described in General Method 7, using: 5,6-dihydro-4-hydroxy-6,6-diphenyl-2H-pyran-2-one (0.250 g, 0.94 mmol), [(2- chlorphen-1-yl))methyl]-p-toluenethiosulfonate (0.304 g, 1.10 mmol), Et3N (0.26 mL, 1.9 mmol), absolute ethanol (5.0 mL) and NaHCO3 (0.5 g). The mixture was heated for 16 h at 40°C, then diluted with diethyl ether (100 mL) and washed with water. The solvent was removed in vacuo, and the residue was purified by column chromatography (SiO2, 100% CH2Cl2 to 2% methanol in CH2Cl2) to give a solid (0.123 g, melting point 153-155°C).

1H NMR (400 MHz, DMSO-d6) δ 7.415-7.271 (m, 11H), 7.187 (td, 1H, J=1.3Hz, J=7 Hz), 7.047 (td, 1H, J=1.3Hz, J =7 Hz), 6.658 (dd, 1H, J=1.3Hz, J=7 Hz), 3.610 (s, 2H), 3.582 (s, 2H).

Example 104

5,6-Dihydro-4-hydroxy-6-(3-methylbutyl)-6-phenyl-3-[(trifluoromethylphenyl)-methylthio]-2H-pyran-2-one (+/-)

The title compound was prepared as described in General Method 7, using: 5,6-dihydro-4-hydroxy-6-phenyl-6-(3-methylbutyl)-2H-pyran-2-one (0.250 g, 0.94 mmol ), (3-trifluoromethylbenzyl)-p-toluenethiosulfonate (0.43 g, 1.24 mmol), Et3N (0.17 mL, 1.24 mmol), absolute ethanol (5.0 mL), and NaHCO3 (0.5 g). The mixture was heated for 16 h at 40°C, then diluted with diethyl ether (100 mL) and washed with water. The solvent was removed in vacuo and the residue was purified by column chromatography (SiO2, 100% CH2Cl2 to 2% methanol in CH2Cl2) to give a thick oil (0.364 g).

1H NMR (400 MHz, DMSO-d6) δ 7.523-7.503 (m, 2H), 7.318-7.232 (m, 6H), 7.188 (d, 1H, J=7.5 Hz), 3.781 (d, 1H, J=13 Hz), 3.689 (d, 1H, J=13 Hz), 3.076 (AB, 2H, JAB=14 Hz), 1.869-1.783 (m, 2H), 1.380-1.314 (m, 1H), 1.41-1.040 (m , 1H), 0.828-0.727 (m, 7H).

Example 105

5,6-Dihydro-4-hydroxy-3-(methoxyphenylmethylthio)-6-(3-methylbutyl)-6-phenyl-2H-pyran-2-one (+/-)

The title compound was prepared as described in General Method 7, using: 5,6-dihydro-4-hydroxy-6-phenyl-6-(3-methylbutyl)-2H-pyran-2-one (0.250 g, 0.94 mmol ), (3-methoxybenzyl)-p-toluenethiosulfonate (0.385 g, 1.24 mmol), Et3N (0.17 mL, 1.24 mmol), absolute ethanol (3.0 mL) and NaHCO3 (0.5 g). The mixture was heated for 16 h at 40°C, then diluted with diethyl ether (100 mL) and washed with water. The solvent was removed in vacuo and the residue was purified by column chromatography (SiO2, 100% CH2Cl2 to 1.5% methanol in CH2Cl2) to give a thick oil (0.364 g).

1H NMR (400 MHz, DMSO-d6) δ 7.365-7.243 (m, 5H), 7.071 (t, 1H, J=8 Hz), 7.754-6.715 (m, 2H), 6.562 (d, 1H, J=7.5 Hz), 3.699 (s, 3H), 3.651 (d, 1H, 3=12 Hz), 3.567 (d, 1H, J=12 H/), 3.098 (s, 2H), 1.869-1.819 (m, 2H) , 1.387-1.321 (m, 1H), 1.125-1.066 (m, 1H), 0.809-0.702 (m, 7H).

Example 106

5,6-Dihydro-4-hydroxy-3-(3-methylphenylmethylthio)-6-(3-methylbutyl)-6-phenyl-2H-pyran-2-one (+/-)

The title compound was prepared as described in General Method 7, using: 5,6-dihydro-4-hydroxy-6-phenyl-6-(3-methylbutyl)-2H-pyran-2-one (0.250 g, 0.94 mmol ), [(3-methylphen-1-yl)methyl]-p-toluenethiosulfonate (0.36 g, 1.24 mmol), Et3N (0.17 mL, 1.24 mmol), absolute ethanol (3.0 mL) and NaHCO3 (0.5 g). The mixture was heated for 16 h at 40°C, then diluted with diethyl ether (100 mL) and washed with water. The solvent was removed in vacuo and the residue was purified by column chromatography (SiO2, 100% CH2Cl2 to 1.5% methanol in CH2Cl2) to give a thick oil (0.290 g).

1H NMR (400 MHz, DMSO-d6) δ 7.384-7.262 (m, 5H), 7.054 (t, 1H, J=7.5 Hz), 6.979 (d, 1H, J=7.5 Hz), 6.937 (s, 1H) , 6.782 (d, 1H, J=7.5 Hz), 3.609 (d, 1H, J=12.5 Hz), 3.524 (d, 1H, J=12.5 Hz), 3.108 (s, 2H), 2.226 (s, 3H) , 1.902-1.803 (m, 2H), 1.398-1.332 (m, 1H), 1.149-1.059 (m, 1H), 0.849-0.709 (m, 7H).

Example 107

3-(Benzo[1,3]dioscol-5-ylmethylthio)-5,6-dihydro-4-hydroxy-6-phenyl-6-(2-phenylethyl)-2H-pyran-2-one (+/-)

The title compound was prepared as described in General Method 7, using: 5,6-dihydro-4-hydroxy-6-phenyl-6-(2-phenylethyl)-2H-pyran-2-one (0.250 g, 0.85 mmol ), benzo[1,3]dioxol-5-ylmethyl-p-toluenethiosulfonate (0.36 g, 1.02 mmol), Et3N (0.25 mL, 1.81 mmol), absolute ethanol (3.0 mL) and NaHCO3 (0.5 g). The mixture was heated for 16 h at 40°C, then diluted with diethyl ether (100 mL) and washed with water. The solvent was removed in vacuo and the residue was purified by column chromatography (SiO2, 100% CH2Cl2 to 1.5% methanol in CH2Cl2) to give a solid (0.290 g, mp 53-5 °C).

1H NMR (400 MHz, DMSO-d6) δ 11.404 (broad s, 1H), 7.499-7.249 (m, 5H), 7.239-7.216 (m, 2H), 7.168-7.124 (m, 1H), 7.077 (d, 2H, J=7 Hz), 6.683 (d, 1H, J=1.5 Hz), 6.607 (d, 2H, J=8 Hz), 6.390 (dd, 1H, J=1.5 Hz, J=8 Hz), 5.942 (d, 2H, J=2 Hz),

3.600 (d, 1H, J=13 Hz), 3.509 (d, 1H, J=13 Hz), 3.195 (AB, 2H, JAB=17 Hz), 2.595-2.511 (m, 1H), 2.244-2.094 (m , 3H).

General method 8

The desired compounds were prepared by adding 5,6-dihydro-2H-pyran-2-one and dry dichloromethane to a reaction vessel, followed by the addition of acid chloride and Et3N. The mixture was left with stirring for 15 minutes, and was diluted with diethyl ether. The mixture was then washed with saturated NaHCO3 solution (2x), and the organic layer was dried over MgSO4. The solvent was then removed in vacuo, the residue redissolved in CH 3 CN and Et 3 N and acetone-cyanohydrin were added. The mixture was left for 18 h with stirring, and then it was diluted with ether. The mixture was then washed with 1.0 M HCl, dried over Na2SO4, and the solvent was removed in vacuo. The residue was dissolved in glacial acetic acid and NaBH3CN was added. The reaction was left for 30 minutes, and then sodium chloride solution was added. The mixture was then extracted with ethyl acetate, the organic layers were combined, dried over MgSO4, and the solvent was removed in vacuo.

Example 108

5,6-Dihydro-4-hydroxy-6,6-diphenyl-3-phenylmethyl-2H-pyran-2-one

The title compound was prepared as described in General Method 8, using: 5,6-dihydro-4-hydroxy-6,6-diphenyl-2H-pyran-2-one (0.250 g, 0.940 mmol), Et3N (0.13 mL , 0.94 mmol), benzoyl chloride (0.109 mL, 0.94 mmol), CH2Cl2 (2.0 mL), acetonitrile (5 mL), acetone-cyanohydrin (0.01 mL, 0.09 mmol), Et3N (0.27 mL, 1.9 mmol), ice acetic acid (10.0 mL) sodium cyanoborohydride (0.133 g, 2.11 mmol). Purification of the residue by column chromatography (SiO2, 4/1 hexane/ethyl acetate to 3/1 hexane/ethyl acetate) gives a solid (0.105 g, melting point 63-65°C).

1H NMR (400 MHz, DMSO-d6) δ 11.136 (s, 1H), 7.501-7.280 (m, 11H), 6.997-6.932 (m, 2H), 6.566 (d, 2H, J=7 Hz), 3.530 ( s, 2H), 3.432 (s, 2H).

Example 109

5,6-Dihydro-4-hydroxy-6-phenyl-6-(2-phenylethyl)-3-phenylmethyl-2H-pyran-2-one (+/-)

The title compound was prepared as described in General Method 8, using: 5,6-dihydro-4-hydroxy-6-phenyl-6-(2-phenylethyl)-2H-pyran-2-one (0.250 g, 0.850 mmol ), Et3N (0.26 mL, 1.94 mmol), benzoyl chloride (0.109 mL, 0.94 mmol), CH2Cl2 (2.0 mL), acetonitrile (5.0 mL), acetone-cyanohydrin (0.04 mL, 0.43 mmol), Et3N (0.26 mL, 1.9 mmol), glacial acetic acid (10.0 mL) sodium cyanoborohydride (0.151 g, 2.4 mmol). Purification of the residue by column chromatography (SiO2, 100% CH2Cl2 to 2% methanol in CH2Cl2) gave a thick oil (0.384 g).

1H NMR (400 MHz, DMSO-d6) δ 10.922 (broad s, 1H), 7.395-7.315 (m, 5H), 7.297-7.126 (m, 3H), 7.084-7.028 (m, 5H), 6.775-6.611 ( m, 2H), 3.423 (s, 2H), 3.248 (d, 1H, J=17 Hz), 3.175 (d, 1H, J= 17Hz), 2.619-2.551 (m, 1H), 2.292-2.227 (m, 3H).

Example 110

5,6-Dihydro-4-hydroxy-3-[(2-methylphenyl)methyl]-6-phenyl-6-(2-phenylethyl)-2H-pyran-2-one (+/-)

The title compound was prepared as described in General Method 8, using: 5,6-dihydro-4-hydroxy-6-phenyl-6-(2-phenylethyl)-2H-pyran-2-one (0.250 g, 0.850 mmol ), Et3N (0.12 mL, 0.85 mmol), 3-methylbenzoyl chloride (0.11 mL, 0.85 mmol), CH2Cl2 (5.0 mL), acetonitrile (4.0 mL), acetone-cyanohydrin (0.04 mL, 0.43 mmol), Et3N (0.24 mL, 1.7 mmol), glacial acetic acid (10.0 mL), sodium cyanoborohydride (0.151 g, 2.4 mmol). Purification of the residue by column chromatography (SiO2, 100% CH2Cl2 to 2% methanol in CH2Cl2) gives a solid (0.195 g, melting point 109-111°C).

1H NMR (400 MHz, DMSO-d6) δ 10.886 (broad s, 1H), 7.457-7.359 (m, 5H), 7.242 (t, 2H, J= 7 Hz), 7.169-7.130 (m, 1H), 7.097 (d, 2H, J=7.5 Hz), 7.001 (d, 1H, J=7.5 Hz), 6.937 (t, 1H, J=7.5 Hz), 6.695 (t, 1H, J=17 Hz), 6.215 (d , 1H, J=7.5 Hz), 3.292 (d, 1H, J=17 Hz), 3.169 (d, 1H, J=17 Hz), 2.643-2.584 (m, 1H), 2.50-2.475 (2H + solvent) , 2.296-2.182 (m, 3H), 2.125 (s, 3H).

Example 111

5,6-Dihydro-4-hydroxy-3-[(3-methylphenyl)methyl]-6-phenyl-6-(2-phenylethyl)-2H-pyran-2-one (+/-)

The title compound was prepared as described in General Method 8, using: 5,6-dihydro-4-hydroxy-6-phenyl-6-(2-phenylethyl)-2H-pyran-2-one (0.250 g, 0.850 mmol ), Et3N (0.12 mL, 0.85 mmol), 3-methylbenzoyl chloride (0.12 mL, 0.89 mmol), CH2Cl2 (3.0 mL), acetonitrile (5.0 mL), acetone-cyanohydrin (0.037 mL, 0.40 mmol), Et3N (0.24 mL, 1.8 mmol), glacial acetic acid (5.0 mL), sodium cyanoborohydride (0.16 g, 2.6 mmol). Purification of the residue by column chromatography (SiO2, 100% CH2Cl2 to 2% methanol in CH2Cl2) gives a solid (0.250 g, melting point 53-55°C).

1H NMR (400 MHz, DMSO-d6) δ 10.884 (broad s, 1H), 7.418-7.310 (m, 5H), 7.231 (t, 2H, J= 7.5 Hz), 7.148-7.122 (m, 1H), 7.071 (d, 2H, J=7 Hz), 6.929 (t, 1H, J=7.5 Hz), 6.843 (d, 1H, J=7.5 Hz), 6.587 (d, 1H, J=7.5 Hz), 6.545 (s , 1H), 3.398 (AB, 2H, JAB=15.5 Hz), 3.248 (d, 1H, J=17 Hz), 3.125 (d, 1H, J=17 Hz), 2.607-2.511 (m, 1H), 2.338 -2.159 (m, 3H), 2.094 (s, 3H).

Example 112

5,6-Dihydro-4-hydroxy-3-[(3-methylphenyl)methyl]-6,6-diphenyl-2H-pyran-2-one

The title compound was prepared as described in General Method 8, using: 5,6-dihydro-4-hydroxy-6,6-diphenyl-2H-pyran-2-one (0.300 g, 1.13 mmol), Et3N (0.16 mL , 1.13 mmol), 3-methylbenzoyl chloride (0.15 mL, 1.13 mmol), CH2Cl2 (4.0 mL), acetonitrile (4.0 mL), acetone-cyanohydrin (0.05 mL, 0.58 mmol), Et3N (0.32 mL, 2.3 mmol), glacial acetic acid (4.0 mL) sodium cyanoborohydride (0.28 g, 4.5 mmol). Purification of the residue by column chromatography (SiO2, 100% CH2Cl2 to 1% methanol in CH2Cl2) gives a solid (0.223 g, melting point 57-59°C).

1H NMR (400 MHz, DMSO-d6) δ 11.112 (broad s, 1H), 7.414-7.270 (m, 10H), 6.875-6.812 (m, 2H), 6.429-6.392 (m, 2H), 3.527 (s, 2H), 3.409 (s, 2H), 2.060 (s, 3H).

Example 113

5,6-Dihydro-4-hydroxy-3-[(2-methylphenyl)methyl]-6,6-diphenyl-2H-pyran-2-one

The title compound was prepared as described in General Method 8, using: 5,6-dihydro-4-hydroxy-6,6-diphenyl-2H-pyran-2-one (0.300 g, 1.13 mmol), Et3N (0.16 m L, 1.15 mmol), 2-methylbenzoyl chloride (0.15 mL, 1.13 mmol), CH2Cl2 (4.0 mL), acetonitrile (4.0 mL), acetone-cyanohydrin (0.05 mL, 0.58 mmol), Et3N (0.32 mL, 2.3 mmol) , glacial acetic acid (4.0 mL) sodium cyanoborohydride (0.28 g, 4.5 mmol). Purification of the residue by column chromatography (SiO2, 100% CH2Cl2 to 1% methanol in CH2Cl2) gives a solid (0.135 g, melting point 169-171°C).

1H NMR (400 MHz, DMSO-d6) δ 11.102 (broad s, 1H), 7.444-7.260 (m, 10H), 6.981 (d, 1H, J=7.5 Hz), 6.900 (t, 1H, J=7.5 Hz) ), 6.577 (t, 1H, J=7 Hz), 5.897 (d, 1H, J=7.5 Hz), 3.557 (s, 2H), 3.341 (s, 2H), 2.115 (s, 3H).

Example 114

5,6-Dihydro-4-hydroxy-6-phenyl-6-(2-phenylethyl)-3-[(2-trifluoromethylphenyl)-methyl]-2H-pyran-2-one

The title compound was prepared as described in General Method 8, using: 5,6-dihydro-4-hydroxy-6-phenyl-6-(2-phenylethyl)-2H-pyran-2-one (0.300g, 1.02 mmol ), Et3N (0.15 mL, 1.1 mmol), 2-trifluoromethylbenzoyl chloride (0.21 mL, 1.02 mmol), CH2Cl2 (4.0 mL), acetonitrile (4.0 mL), acetone-cyanohydrin (0.04 mL, 0.47 mmol), Et3N (0.29 mL, 2.1 mmol), glacial acetic acid (3.0 mL), sodium cyanoborohydride (0.20 g, 3.1 mmol). Purification of the residue by column chromatography (SiO2, 100% CH2Cl2 to 1% methanol in CH2Cl2) gave an oil (0.102 g).

1H NMR (400 MHz, DMSO-d6) δ 11.21 (broad s, 1H), 7.584 (d, 1H, J=8 Hz), 7.457-7.030 (m, 12H), 6.179 (d, 1H, J=7.5 Hz) ), 3.594 (s, 2H), 3.362 (d, 1H, J=17 Hz), 3.249 (d, 1H, J=17 Hz), 2.686-2.603 (m, 1H), 2.374-2.182 (m, 3H) .

Example 115

5,6-Dihydro-4-hydroxy-3-[(2-isopropylphenyl)methyl]-6,6-diphenyl-2H-pyran-2-one

The title compound was prepared as described in General Method 8, using: 5,6-dihydro-4-hydroxy-6,6-diphenyl-2H-pyran-2-one (0.300 g, 1.15 mmol), Et3N (0.17 mL , 1.2 mmol), 2-isopropylbenzoyl chloride (1.02 mmol), CH2Cl2 (4.0 mL), acetonitrile (4.0 mL), acetone-cyanohydrin (0.05 mL, 0.5 mmol), Et3N (0.35 mL, 2.5 mmol), glacial acetic acid (5.0 mL) of sodium cyanoborohydride (0.50 g, 8.5 mmol). Purification of the residue by column chromatography (SiO2, 100% CH2Cl2 to 1% methanol in CH2Cl2) gave a solid (0.128 g, melting point 224-226°C).

1H NMR (400 MHz, DMSO-d6) δ 11.180 (broad s, 1H), 7.446-7.235 (m, 10H), 7.109 (d, 1H, J=7.5 Hz), 6.970 (t, 1H, J=7.5 Hz ), 6.515 (t, 1H, J=7.5 Hz), 5.841 (d, 1H, J=7.5 Hz), 3.560 (s, 2H), 3.463 (s, 2H), 1.174-1.094(m, 7H).

Example 116

5,6-Dihydro-4-hydroxy-6-(3-methylbutyl)-3-[(3-methylphenyl)methyl]-6-phenyl-2H-pyran-2-one (+/-)

The title compound was prepared as described in General Method 8, using: 5,6-dihydro-4-hydroxy-6-phenyl-6-(3-methylbutyl)-2H-pyran-2-one (0.300 g, 1.15 mmol ), Et3N (0.17 mL, 1.2 mmol), 3-methylbenzoyl chloride (0.15 mL, 1.15 mmol), CH2Cl2 (4.0 mL), acetonitrile (4.0 mL), acetone-cyanohydrin (0.05 mL, 0.5 mmol), Et3N (0.35 mL, 2.5 mmol), glacial acetic acid (4.0 mL), sodium cyanoborohydride (0.51 g, 8.1 mmol). Purification of the residue by column chromatography (SiO2, 100% CH2Cl2 to 0.5% methanol in CH2Cl2) gives a solid (0.252 g, mp 53-55°C).

1H NMR (400 MHz, DMSO-d6) δ 7.376-7.244 (m, 5H), 6.915 (t, 1H, J=7.5 Hz), 6.831 (d, 1H, J=7.5 Hz), 6.549 (d, 1H, J=7.5 Hz), 6.509 (s, 1H), 3.369 (AB, 2H, JAB=14.4 Hz), 3.112 (AB, 2H, JAB=17.5 Hz), 2.088 (s, 3H), 1.962 (m, 2H) , 1.416-1.333 (m, 1H), 1.152-1.061 (m, 1H), 0.898-0.726 (m, 7H).

Example 117

5,6-Dihydro-4-hydroxy-6-(3-methylbutyl)-6-phenyl-3-phenylmethyl-2H-pyran-2-one (+/-)

The title compound was prepared as described in General Method 8, using: 5,6-dihydro-4-hydroxy-6-(3-methylbutyl)-6-phenyl-2H-pyran-2-one (0.300 g, 1.15 mmol ), Et3N (0.17 mL, 1.2 mmol), benzoyl chloride (0.13 mL, 1.15 mmol), CH2Cl2 (4.0 mL), acetonitrile (4.0 mL), acetone-cyanohydrin (0.05 mL, 0.5 mmol), Et3N (0.35 mL, 2.5 mmol), glacial acetic acid (4.0 mL), sodium cyanoborohydride (0.51 g, 8.1 mmol). Purification of the residue by column chromatography (SiO2, 100% CH2Cl2 to 1% methanol in CH2Cl2) gives a solid (0.215 g, melting point 46-48°C).

1H NMR (400 MHz, DMSO-d6) δ 10.864 (broad s, 1H), 7.375-7.248 (m, 7H), 7.026-7.000 (m, 2H), 6.737-6.713 (m, 1H), 3.393-3.332 ( 2H, solvent covered), 3.110 (AB, 2H, JAB=17 Hz), 1.933-1.870 (m, 2H), 1.402-1.353 (m, 1H), 1.132-1.084 (m, 1H), 0.891-0.710 (m , 7H).

Example 118

5,6-Dihydro-4-hydroxy-6-(3-methylbutyl)-3-[(2-methylphenyl)methyl]-6-phenyl-2H-pyran-2-one (+/-)

The title compound was prepared as described in General Method 8, using: 5,6-dihydro-4-hydroxy-6-(3-methylbutyl)-6-phenyl-2H-pyran-2-one (0.300 g, 1.15 mmol ), Et3N (0.17 mL, 1.2 mmol), 2-methylbenzoyl chloride (0.15 mL, 1.15 mmol), CH2Cl2 (4.0 mL), acetonitrile (4.0 mL), acetone-cyanohydrin (0.05 mL, 0.5 mmol), Et3N (0.35 mL, 2.5 mmol), glacial acetic acid (4.0 mL), sodium cyanoborohydride (0.51 g, 8.1 mmol). Purification of the residue by column chromatography (SiO2, 100% CH2Cl2 to 1% methanol in CH2Cl2) gives a solid (0.215 g, melting point 46-48°C).

1H NMR (400 MHz, DMSO-d6) δ 10.829 (broad s, 1H), 7.395-7.303 (m, 5H), 6.994 (d, 1H, J=7 Hz), 6.927 (t, 1H, J=7 Hz ), 6.674 (t, 1H, J=7 Hz), 6.149 (d, 1H, J=7 Hz), 3.305 (AB, 2H, JAB=17 Hz), 3.158 (AB, 2H, JAB=17.5 Hz), 2.115 (s, 3H), 1.988-1.854 (m, 2H), 1.439-1.356 (m, 1H), 1.177-1.087 (m, 1H), 0.943-0.852 (m, 1H), 0.792-0.767 (m, 6H) ).

Example 119

5,6-Dihydro-4-hydroxy-3-[(3-methoxyphenyl)methyl]-6-phenyl-6-(2-phenylethyl)-2H-pyran-2-one (+/-)

The title compound was prepared as described in General Method 8, using: 5,6-dihydro-4-hydroxy-6-phenyl-6-(2-phenylethyl)-2H-pyran-2-one (0.300 g, 1.02 mmol ), Et3N (0.15 mL, 1.1 mmol), 2-methoxybenzoyl chloride (0.17 mL, 1.02 mmol), CH2Cl2 (4.0 mL), acetonitrile (4.0 mL), acetone-cyanohydrin (0.05 mL, 0.5 mmol), Et3N ( 0.35 mL, 2.5 mmol), glacial acetic acid (5.0 mL), sodium cyanoborohydride (0.47 g, 7.5 mmol). Purification of the residue by column chromatography (SiO2, 100% CH2Cl2 to 1% methanol in CH2Cl2) gives a solid (0.227 g, melting point 62-64°C).

1H NMR (400 MHz, DMSO-d6) δ 10.823 (broad s, 1H), 7.436-7.362 (m, 5H), 7.265 (t, 2H), 7.176-7.098 (m, 3H), 7.022 (td, 1H, J=l Hz, J=8 Hz),), 6.815 (d, 1H, J=7.5 Hz), 6.400 (td, 1H, J=1 Hz, J=7.5 Hz), 5.952 (dd, 1H, J= 1 Hz, J=7 Hz), 3.716 (s, 3H), 3.391-3.169 (m, 4H), 2.650-2.582 (m, 1H), 2.354-2.182 (m, 3H).

Example 120

5,6-Dihydro-4-hydroxy-3-[(naphthalen-1-yl)methyl]-6,6-diphenyl-2H-pyran-2-one

The title compound was prepared as described in General Method 8, using: 5,6-dihydro-4-hydroxy-6,6-diphenyl-2H-pyran-2-one (0.300 g, 1.13 mmol), Et3N (0.160 mL , 1.15 mmol), 1-naphthoyl chloride (1.13 mmol), CH2Cl2 (6.0 mL), acetonitrile (4.0 mL), acetone-cyanohydrin (0.05 mL, 0.5 mmol), Et3N (0.35 mL, 2.5 mmol), glacial acetic acid (6.0 mL) of sodium cyanoborohydride (0.50 g, 7.9 mmol). Purification of the residue by column chromatography (SiO2, 100% CH2Cl2 to 1.5% methanol in CH2Cl2) gives a solid (0.120 g, melting point 203-205°C with decomposition).

1H NMR (400 MHz, DMSO-d6) δ 11.223 (broad s, 1H), 8.057 (d, 1H, J=7 Hz), 7.855-7.821 (m, 1H), 7.603 (d, 1H, J=8 Hz) ), 7.514-7.302 (m, 12H), 6.866 (dd, 1H, J=6.5 Hz, J=8 Hz), 5.975 (d, 1H, J=7 Hz), 3.874 (s, 2H), 3.621 (s , 2H).

Example 121

5,6-Dihydro-4-hydroxy-3-[(2-isopropylphenyl)methyl]-6-(3-methylbutyl)-6-phenyl-2H-pyran-2-one (+/-)

The title compound was prepared as described in General Method 8, using: 5,6-dihydro-4-hydroxy-6-(3-methylbutyl)-6-phenyl-2H-pyran-2-one (0.300 g, 1.15 mmol ), Et3N (0.17 mL, 1.2 mmol), 2-isopropylbenzoyl chloride (1.15 mmol), CH2Cl2 (4.0 mL), acetonitrile (4.0 mL), acetone-cyanohydrin (0.05 mL, 0.5 mmol), Et3N (0.35 mL, 2.5 mmol), glacial acetic acid (5.0 mL) sodium cyanoborohydride (0.50 g, 8.1 mmol). Purification of the residue by column chromatography (SiO2, 100% CH2Cl2) gives a solid (0.118 g, melting point 124-126°C).

1H NMR (400 MHz, DMSO-d6) δ 10.855 (broad s, 1H), 7.395-7.306 (m, 5H), 7.115 (dd, 1H, J=1 Hz, J=7.5 Hz), 6.991 (t, 1H , J=7 Hz), 6.622 (td, 1H, J=1 Hz, J=7 Hz), 6.123 (d, 1H, J=7 Hz), 3.422 (s, 2H), 3.210-3.102 (m, 3H ), 1.975-1.871 (m, 2H), 1.437-1.371 (m, 1H), 1.142-1.084 (m, 7H), 0.938-0.807 (m, 1H), 0.791-0.766 (m, 6H).

Example 122

5,6-Dihydro-4-hydroxy-3-[(2-isopropylphenyl)methyl]-6-phenyl-6-(2-phenylethyl)-2H-pyran-2-one (+/-)

The title compound was prepared as described in General Method 8, using: 5,6-dihydro-4-hydroxy-6-phenyl-6-(2-phenylethyl)-2H-pyran-2-one (0.300 g, 1.02 mmol ), Et3N (0.17 mL, 1.2 mmol), 2-isopropylbenzoyl chloride (1.02 mmol), CH2Cl2 (4.0 mL), acetonitrile (4.0 mL), acetone-cyanohydrin (0.05 mL, 0.5 mmol), Et3N (0.35 mL, 2.5 mmol), glacial acetic acid (4.0 mL) sodium cyanoborohydride (0.45 g, 7.1 mmol). Purification of the residue by column chromatography (SiO2, 100% CH2Cl2) gives a solid (0.130 g, melting point 73-74°C).

1H NMR (400 MHz, DMSO-d6) δ 7.424-7.328 (m, 6H), 7.259-7.222 (m, 2H), 7.157-7.082 (m, 3H), 6.996 (t, 1H, J=7HZ), 6.638 (td, 1H, J=1.5 Hz, J=8 Hz), 6.195 (d, 1H, J=7 Hz), 3.440 (s, 2H), 3.268-3.133 (m, 2H), 2.630-2.528 (m , 1H), 2.332-2.147 (m, 3H), 2.332-2.147 (m, 7H).

Example 123

3-[(2-Chlorophenyl)methyl]-5,6-dihydro-4-hydroxy-6-(3-methylbutyl)-6-phenyl-2H-pyran-2-one (+/-)

The title compound was prepared as described in General Method 8, using: 5,6-dihydro-4-hydroxy-6-(3-methylbutyl)-6-phenyl-2H-pyran-2-one (0.300 g, 1.15 mmol ), Et3N (0.17 mL, 1.2 mmol), 2-chlorobenzoyl chloride (0.15 mL, 1.15 mmol), CH2Cl2 (4.0 mL), acetonitrile (4.0 mL), acetone-cyanohydrin (0.05 mL, 0.5 mmol), Et3N ( 0.35 mL, 2.5 mmol), glacial acetic acid (4.0 mL), sodium cyanoborohydride (0.720 g, 11.5 mmol). Purification of the residue by column chromatography (SiO2, 100% CH2Cl2) gave a solid (0.165 g, melting point 51-53°C).

1H NMR (400 MHz, DMSO-d6) δ 11.061 (broad s, 1H), 7.425-7.275 (m, 6H), 7.072 (td, 1H, J=1.5 Hz, J=7.5 Hz), 6.774 (td, 1H , J=1.2 Hz, J=7.5 Hz), 6.059 (dd, 1H, J=1.2 Hz, J=7.5 Hz), 3.428 (AB, 2H, JAB=16.5 Hz), 3.91 (AB, 2H, JAB=17 Hz), 1.964-1.884 (m, 2H), 1.450-1.384 (m, 1H), 1.163-1.118 (m, 1H), 0.951 (m, 1H), 0.802-0.776 (m, 6H).

Example 124

3-[(2-Chlorophenyl)methyl]-5,6-dihydro-4-hydroxy-6,6-di-phenyl-2H-pyran-2-one (+/-)

The title compound was prepared as described in General Method 8, using: 5,6-dihydro-4-hydroxy-6,6-diphenyl-2H-pyran-2-one (0.300 g, 1.13 mmol), Et3N (0.17 mL , 1.2 mmol), 2-chlorobenzoyl chloride (0.14 mL, 1.15 mmol), CH2Cl2 (4.0 mL), acetonitrile (4.0 mL), acetone-cyanohydrin (0.05 mL, 0.5 mmol), Et3N (0.35 mL, 2.5 mmol), glacial acetic acid (4.0 mL) sodium cyanoborohydride (0.50 g, 7.9 mmol). Purification of the residue by column chromatography (SiO2, 100% CH2Cl2 to 0.5% MeOH in CH2Cl2) gives a solid (0.130 g, melting point 185-187°C).

1H NMR (400 MHz, DMSO-d6) δ 11.351 (broad s, 1H), 7.464-7.282 (m, 11H), 7.054 (t, 1H, J=7 Hz), 6.679 (td, 1H, J=1 Hz , J=7.5 Hz), 5.797 (d, 1H, J=7. Hz), 3.586 (s, 2H), 3.472 (s, 2H).

Example 125

6-Cyclopentylmethyl-5,6-dihydro-4-hydroxy-6-phenyl-3-phenylmethyl-2H-pyran-2-one (+/-)

The title compound was prepared as described in General Method 8, using: 6-cyclopentylmethyl-5,6-dihydro-4-hydroxy-6-phenyl-2H-pyran-2-one (0.300 g, 1.10 mmol), Et3N ( 0.17 mL, 1.2 mmol), benzoyl chloride (0.13 mL, 1.15 mmol), CH2Cl2 (4.0 mL), acetonitrile (4.0 mL), acetone-cyanohydrin (0.05 mL, 0.5 mmol), Et3N (0.35 mL, 2.5 mmol), glacial acetic acid (4.0 mL) sodium cyanoborohydride (0.50 g, 7.9 mmol). Purification of the residue by column chromatography (SiO2, 100% CH2Cl2) gave a solid (0.188 g, 53-55°C).

1H NMR (400 MHz, DMSO-d6) δ 10.849 (broad s, 1H), 7.371-7.284 (m, 5H), 7.040-7.004 (m, 3H), 6.747-6.724 (m, 2H), 3.395 (s, 2H), 3.117 (AB, 2H, JAB=17.5 Hz), 2.059-1.950 (m, 2H), 1.652-1.578 (m, 2H), 1.561-1.289 (m, 5H), 1.021-0.844 (m, 2H) .

Example 126

5,6-Dihydro-4-hydroxy-6-pentyl-6-phenyl-3-phenylmethyl-2H-pyran-2-one (+/-)

The title compound was prepared as described in General Method 8, using: 5,6-dihydro-4-hydroxy-6-n-pentyl-6-phenyl-2H-pyran-2-one (0.300 g, 1.15 mmol), Et3N (0.17 mL, 1.2 mmol), benzoyl chloride (0.13 mL, 1.15 mmol), CH2Cl2 (4.0 mL), acetonitrile (4.0 mL), acetone-cyanohydrin (0.05 mL, 0.5 mmol), Et3N (0.35 mL, 2.5 mmol ), glacial acetic acid (4.0 mL) sodium cyanoborohydride (0.50 g, 7.9 mmol). Purification of the residue by column chromatography (SiO2, 100% CH2Cl2) yields an oil (0.215 g).

1H NMR (400 MHz, DMSO-d6) δ 10.850 (broad s, 1H), 7.367-7.287 (m, 5H), 7.018-7.002 (m, 3H), 6.724-6.700 (m, 2H), 3.380 (AB, 2H, JAB=14 Hz), 3.096 (AB, 2H, JAB=17 Hz), 1.950-1.820 (m, 2H), 1.230-1.100 (m, 5H), 1.080-0.920 (m, 1H), 0.775 (t , 3H, J=7 Hz).

Example 127

3-[(3-Chloromethylphenyl)methyl]-5,6-dihydro-4-hydroxy-6,6-diphenyl-2H-pyran-2-one

The title compound was prepared as described in General Method 8, using: 5,6-dihydro-4-hydroxy-6,6-diphenyl-2H-pyran-2-one (0.300 g, 1.13 mmol), Et3N (0.17 mL , 1.2 mmol), 3-(chloromethyl)benzoyl chloride (0.13 mL, 1.13 mmol), CH2Cl2 (5.0 mL), acetonitrile (5.0 mL), acetone-cyanohydrin (0.05 mL, 0.5 mmol), Et3N (0.35 mL, 2.5 mmol), glacial acetic acid (6.0 mL) sodium cyanoborohydride (0.50 g, 7.9 mmol). Purification of the residue by column chromatography (SiO2, 4/1 hexane/ethyl acetate to 3/2 hexane/ethyl acetate) gave a solid (0.118 g, melting point 135-137°C).

1H NMR (400 MHz, DMSO-d6) δ 11.211 (s, 1H), 7.418-7.280 (m, 10H), 7.088 (d, 1H, 7.5 Hz), 6.975 (t, 1H, J=7.5 Hz), 6.689 (s, 1H), 6.513 (d, 1H, J=7.5 Hz), 4.498 (s, 2H), 3.540 (s, 2H), 3.447 (s, 2H).

Example 128

5,6-Dihydro-3-(benzoylcarbonyl)-4-hydroxy-6,6-diphenyl-2H-pyran-2-one

The desired compound was prepared by adding 5,6-dihydro-4-hydroxy-6,6-diphenyl-2H-pyran-2-one (0.500 g, 1.88 mmol) and dry dichloromethane (10.0 mL) to a reaction vessel, after which it was added benzoyl chloride (0.22 mL, 1.88 mmol) and Et3N (0.28 mL, 2.0 mmol). The mixture was left with stirring for 15 minutes, and was diluted with diethyl ether. The mixture was then washed with saturated NaHCO3 solution (2x) and the organic layer was dried over MgSO4. The solvent was removed in vacuo, the residue was dissolved in CH3CN, and Et3N (0.56 mL, 4.0 mmol) and acetone-cyanohydrin were added. The mixture was left with stirring for 18 hours, and was diluted with diethyl ether. The mixture was then washed with 1.0 M HCl, dried over Na2SO4, and the solvent was removed in vacuo. Purification of the residue by column chromatography (SiO2, 3/2 hexane/ethyl acetate) gave a solid (0.357 g, melting point 66-68°C).

1H NMR (400 MHz, CDCl3) δ 7.495-7.208 (m, 15H), 3.558 (s, 2H).

Example 129

5,6-Dihydro-4-hydroxy-6,6-diphenyl-3-phenylmethylthio-2H-pyran-2-one

The title compound was prepared according to General Method 4, yielding an oil.

1H NMR (400 MHz, CDCl3) δ 7.3-7.14 (m, 5H), 3.8 (s, 2H), 2.54 (s, 2H), 1.5-1.35 (m, 4H), 1.26-1.11 (m, 12H), 0.87-0.80 (t, 6H).

Example 130

5,6-Dihydro-4-hydroxy-6-phenyl-3-[(2-isopropyl-5-methylphenyl)thio]-2(1H)-pyridinone (±)

The title compound was prepared as described in General Method 3, using 95.6 mg of 5,6-dihydro-4-hydroxy-6-phenyl-2(1H)-pyridinone, 180 mg of S-(2-isopropyl-5-methylphenyl toluene) -4-thiosulfonate (prepared according to Ranasinghe and Fuchs, Synthetic Communications 18: 227, (1988)) and 0.08 mL of triethylamine in 5 mL of absolute ethanol. The solution was stirred overnight at room temperature. Purification by "flash" chromatography using CH2Cl2/isopropanol (99/1 to 95/5) as eluent, a solid was obtained (melting point 184-186°C).

1H NMR (CDCl3) δ 1.28 (d, 3H), 1.29 (d, 3H), 2.23 (s, 3H), 2.98 (d, 2H), 3.52 (qn, 1H), 4.85 (t, 1H), 5.63 ( s, 1H), 6.78 (s, 1H), 6.96 (m, 1H), 7.14 (d, 1H), 7.35-7.44 (m, 5H), 7.55 (s, 1H).

Example 131

4-Hydroxy-3-[(1-isopropyl-4,4-dimethyl-4.5-dihydro-1H-imidazol-2-yl)thio]-6-phenyl-5,6-dihydro-2H-pyran-2-one

The desired compound was prepared by adding 4-hydroxy-6,6-diphenyl-2H-pyran-2-one (0.250 g, 0.85 mmol) and dry t-butanol (4.5 mL) to a reaction vessel, followed by the addition of N-bromosuccinimide ( 0.151 g, 0.850 mmol). The mixture was left with stirring for 1 hour in a dark place, and the solvent was removed under vacuum, and the obtained mixture was washed with water. The organic layer was then dried over Na2SO4, and the solvent was removed in vacuo. The resulting residue was redissolved in dichloromethane (6.0 mL) and 1-isopropylimidazolidin-2-thione (0.184 g, 1.28 mmol) was added first, which was prepared according to the method described by A. F. McKay et al., J. Am. Chem. Soc. 1956, 78, 1618), and then piperidine (0.084 mL, 0.85 mmol). The mixture was left with stirring for 14 hours in a dark place, and was diluted with an additional amount of CH2Cl2, and the mixture was then washed with water. The organic layer was dried over Na2SO4, and the solvent was removed in vacuo. The obtained solid was purified by column chromatography (SiO2, 1/1 CH2Cl2/ethyl acetate to 14/4/1 CH2Cl2/ethyl acetate/methanol) which was then redissolved in CH2Cl2, filtered through sinter, and the solvent was removed in vacuo. whereby the title compound was obtained (0.234 g, m.p. 160-162 °C with decomposition).

1H NMR (400 MHz, DMSO-d6) δ 7.732 (s, 1H), 7.420-7.336 (m, 4H), 7.277-7.212 (m, 3H), 7.137 (t, 1H, J=7 Hz), 7.080- 7.60 (m, 2H), 3.970-3.904 (m, 1H), 3.842 (t, 2H, J=10 Hz), 3.602-3.517 (m, 2H), 2.925 (AB, 2H, JAB=16 Hz), 2.617 -2.540 (m, 1H), 2.315-2.240 (m, 1H), 2.160-2.025 (m, 2H), 1.206-1.180 (m, 6H).

Example 132

4-Hydroxy-3-[(1-isopropyl-1,4,5,6-tetrahydro-pyridin-2-yl)thio]-6-phenyl-5,6-dihydro-2H-pyran-2-one

The title compound was prepared as described in Example 41 using: 5,6-dihydro-4-hydroxy-6-phenyl-6-(2-phenylethyl)-2H-pyran-2-one (0.250 g, 0.850 mmol), t-butanol (3.5 mL), n-bromosuccinimide (0.151 g, 0.85 mmol), CH2Cl2 (6.0 mL), 1-isopropyltetrahydropyrimidin-2-thione (0.270 g, 1.70 mmol), which was prepared according to the method described by A. F. McKay et al. al., J. Am. Chem. Soc. 1956, 78, 1618) and piperidine (0.084 mL, 0.85 mmol). Purification of the residue by column chromatography (SiO2, 1/1 CH2Cl2/ethyl-acetate to 2/14/1 ethyl-acetate/CH2Cl2/methanol) gave a solid which was re-dissolved in CH2Cl2, filtered through sinter, and the solvent was removed in vacuo , whereby the title compound was obtained (0.356 g, melting point 103-105°C).

1H NMR (400 MHz, DMSO-d6) δ 7.440-7.371 (m, 4H), 7.296 (t, 1H, J=7 Hz), 7.233 (t, 2H, J=7 Hz), 7.139 (t, 1H, J=7 Hz), 7.077 (d, 2H, J=7 Hz), 6.515 (broad s, 1H), 4.365-4.300 (m, 1H), 3.335-3.308 (m, 2H), 3.024-2.924 (m, 4H), 2.624-2.548 (m, 1H), 2.341-2.265 (m, 1H), 2.156-2.061 (m, 2H), 1.763-1.737 (m, 2H), 1.201-1.180 (m, 6H).

Example 133

6-(2-Benzo[1,3]dioxo-5-yl-ethyl)-5,6-dihydro-4-hydroxy-6-phenyl-3-[(2-iso-propyl-5-methylphenyl)thio] -2H-pyran-2-one (+/-)

The title compound was prepared as described in General Method 3, using: 400 mg of 6-(2-benzo[1,3]dioxo-5-yl-ethyl)-5,6-dihydro-4-hydroxy-6-phenyl -2H-pyran-2-one, 41.5 mg of S-(2-isopropyl-5-methylphenyl) toluene-4-thiosulfonate and 0.17 mL of triethylamine in 20 mL of absolute ethanol. The solution was stirred overnight at room temperature. Purification of the residue by flash chromatography using hexane/isopropanol (90/10 to 50/50) as eluent gave a solid (mp 83-85°C).

1H NMR (CDCl3) δ 1.21 (d, 3H), 1.25 (d, 3H), 1.93 (s, 3H), 2.20-2.40 (m, 3H), 2.60-2.75 (m, 1H), 3.30 (dd, 2H) ), 3.42 (q, 1H), 5.89 (m, 2H), 6.11 (s, 1H), 6.52 (d, 1H), 6.56 (s, 1H), 6.69 (d, 1H), 6.87 (d, 1H) , 7.07 (d, 1H), 7.30-7.50 (m, 5H), 7.64 (broad s, 1H).

Determination of HIV protease inhibition

Starting substances

DTT buffer: 1.0 mM dithiothreitol (DTT) was prepared fresh every day in 0.1% polyethylene glycol (Mr 8000), 80 mM NaOAc, 160 mM NaCl, 1.0 mM EDTA and titrated to pH 4.7 with HCl.

HIV-1 Protease: Enzyme was obtained from Bachem Bioscience Inc. Undiluted enzyme was thawed at -80°C and diluted 50-fold with DTT buffer. The solution was always kept at 0°C in ice water and used in the experiment within 20 min after thawing.

Enzyme substrate: Substrate III obtained from Bachem Bioscience Inc. is the undecapeptide H-His-Lys-Ala-Arg-Val-Leu-p-Nitrophenylalanine-Glu-Ala-Norleucine-Ser-NH2 purity >97%). A stock solution of 200 μM in DTT buffer is prepared and stored on ice. A fresh substrate solution is prepared daily.

Test compound: 10 mM inhibitor (I) in dimethyl sulfoxide (DMSO) is diluted to a concentration of 200 μM in DTT buffer. A 10 mM stock solution with 2% DMSO in DTT buffer was made from the 200 mM stock solution. Two inhibitor solutions are used to prepare final solutions of [I] = 100, 50, 20, 10, 5, 2, 1, 0.5 and 0 μM with 2% DMSO in DTT buffer in each reaction well. (total inhibitor volume 50 μl).

Determination procedure

20 μL of substrate (final concentration 40 μM), 50 μL of inhibitor (in such a concentration that the final dilution leads to the desired tested concentration) and 20 μL of DTT buffer are added to each reaction well. Reaction plates (96 wells) are incubated at 37°C for at least 5 minutes.

10 μL of the diluted protease solution is added to the well of the reaction plate with constant shaking. After shaking for 10 seconds, the plates are transferred to a cell heating block at 37°C. (the final reaction volume is 100 (μL).

The reaction is incubated for 5 minutes at 37°C. The reaction is stopped by placing the reaction plate on a shaker and adding 20 μL of trifluoroacetic acid (TFA) and shaking for 10 seconds. The intensity of proteolysis is determined by separating the undegraded substrate and the two degradation products using reverse-phase high-pressure liquid chromatography, and by measuring the absorbance at 220 nm, so that the relative areas of the signals corresponding to individual components are determined. The relative signal areas are used to calculate the % conversion of substrates to products as a function of the concentration of the applied inhibitor. Data are presented as % of the control (ratio of % conversion in the presence and absence of the inhibitor x 100) in relation to the concentration of the inhibitor, and are tested according to the equation: y= 100/1+(X/IC50)A where ICso is the concentration of the inhibitor at 50 % inhibition, and A slope of the inhibition curve. The results are shown in Table I.

[image]

Anti-HIV-1 activity

By applying general methods according to Pauwels et al., (J. Virol. Methods, 16, 171-185, 1987) and according to Mann et al. (AIDS Research and Human Retroviruses, 253-255, 1989 (anti-viral assays for acute infections by HIV-1 were performed on the H9 cell line). Cultures were pooled in 1 mL RPM1 1640 medium/10% fetal calf serum which was contained 105 infectious doses of HIV1iiib for an effective multiplicity of infection of 0.01. Two hours after virus absorption, the cells were washed once and plated in 96-well microtiter plates at a density of 104 cells per well. Test compounds were added to obtain the desired drug concentration and 0.1% DMSO in a final volume of 200 μL. Comparative uninfected cultures were used for XTT cytotoxicity assays at 7 days post-infection. Cultures were tested for the degree of viral replication by reverse transcriptase at 4 and 7 days post-infection.

[image]

Combinations of protease inhibitors with other anti-AIDS treatments, such as (but not limited to) reverse transcriptase inhibitors AZT or ddC, can achieve synergistic effects. J.C. Craig et al., Antiviral Chem. Chemother., 38: 348-352 (1994); DM Lambert et al., Antiviral Res., 21: 327-342 (1993); A. M. Caliendo el al., Clin. Infect. Dis., 18/4: 516-524 (1994).

The compounds of this invention show antibacterial activity when tested by the microtitration dilution method, as described in Heifetz et al., Antimicr. Agents. & Chemoth. 6: 124 (1974) which is incorporated herein by reference.

Using the above comparative method, the following minimum inhibitory concentrations (MICs in μg/mL) were obtained for representative compounds from the invention against clinically relevant gram-positive pathogens that have become highly resistant to conventional therapy in recent years.

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It is obvious to an expert that other combinations, which are not specifically mentioned in this report, were also considered in comparison. Such other combinations are considered to be within the scope and spirit of the invention. Thus, it should not be understood that the invention is limited by the description of the specific parts described so far, but is limited only by the stated patent claim.

Claims (25)

1. A compound or pharmaceutically compatible salt of the formula [image] indicated that X represents OR 5 , NHR 5 , CH 2 OR 5 , CO 2 R 6 or SR 5 , wherein R 5 represents R 6 , or COR6, and R6 can independently be H, a straight chain alkyl group containing 1 to 6 carbon atoms, a branched or cyclic alkyl group containing 3 to 7 carbon atoms, an alkylcycloalkyl group containing from 5 to 9 carbon atoms, benzyl, phenyl or heterocyclyl ; Z represents O or S; Y represents O, S, C(R 6 ) 2 , NF or NR 6 ; R1 and R1' are each [CH2]n1-[W1]n2-[Ar]n2-[CH2]n3-[W2]n4-R7; R2 is independently one of the possible R1 groups, with the restriction that if W1 represents a heteroatom n1 is an integer from 1 to 4; R3 is independently one of the possible R1 groups, with the restriction that if W1 represents a heteroatom n1 is an integer from 1 to 4; R2 and R3 can together form an unsubstituted or substituted three-, four-, five-, six- or seven-membered ring, wherein the substituents represent one or more R7 groups mentioned below; R4 is [CH2]n2-[W3]n2-[CH2]n3-[W4]n4-[Ar]n2-[CH2]n3-[W2]n4-R7; n1, n2, n3, n4 and n5 each represent an integer from 0 to 4, 0 to 1, 0 to 4, 0 to 1, and 0 to 2; W1, W2, and W4 each independently represent O, OCONR7, S(O)n5, CO, C(=NR7)NR7, CR7=CR7, C≡C, NR7, CS, C=N-R7, C=NOR7, NR7SO2, SO2NR7, C=C(R7)2, CR7N(R7)2, CR7OR7, C(R7)2, NCO2R7, NR7CO2, CO2, NCON(R7)2, NR7CONR7, NCOR7, NR7CO or CONR7: W3 represents one of the W1 groups with the restriction that if n1 in R4 is zero, then W3 represents -CO,-CR7=CR7, -C≡C, -CS, -C=N-R7, -C=NOR7, -CR7N( R7)2, -C=C(R7)2, -CR7OR7, -C(R7)2, -CO2, -CONR7; R7 is independently H, Ar, a straight-chain or branched alkyl or alkenyl group containing 1 to 6 carbon atoms, or two R7 groups can together form a ring of 3 to 7 atoms, or a corresponding substituted derivative in which one or more substituents represent CO2R6, COR6 , CON(R6)2, NR6CON(R6)2, NR6COR6, OR6, S(O)n5R6, N(R6)2, Cl, Br, F, CF3 Ar, OAr or S(O)n5Ar; Ar independently represents phenyl, naphthyl, a five- or six-membered heterocyclic ring containing 1 to 4 heteroatoms, a cycloalkyl containing 3 to 6 atoms, a fused ring system containing 8-10 atoms or a corresponding substituted derivative, wherein the substituents can be F, Cl , Br, CN, NO2 (CH2)n6R6, (CH2)n6C(Me)=CH2, (CH2)n6N(R6)2, (CH2)n6NR6CON(R6)2, (CH2)n6NR6COR6, (CH2)n6OR6, ( CH2)n6OCOR6, (CH2)n6OCON(R6)2, (CH2)n6CO2R6, (CH2)n6CON(R6)2, (CH2)n6COR6, CF3, (CH2)n6S(O)n5R6, OCH2O or O(CH2)20 ; you n6 is independently an integer from 0 to 3. 2. The compound of the formula from claim 1, characterized in that X represents OH, NH2 or SH; Z represents O; Y represents C(R6)2, S, NF or NR6, and; R1 and R1' are H. 3. A compound of the formula from claim 1, characterized in that X represents OH or NH2; Z represents O; Y represents O, and; R 2 and R 3 are not H; you W3 represents one of the following groups: CO, CR7=CR7; C≡C, CS, C=N-R7, C=NOR7, C=C(R7)2, CR7OR7, C(R7)2, -CO2. and CONR7. 4. A compound of the formula from claim 3, characterized in that [image] 5. A compound of the formula from claim 3, characterized in that [image] 6. A compound of the formula from claim 3, characterized in that W3 represents one of the following groups: CR-7=CR7, -C≡C-, and C(R7)2. 7. Compound of the formula from patent claim 6, characterized in that it is selected from the following group of compounds: 5,6-Dihydro-4-hydroxy-6-phenyl-6-(2-phenylethyl)-3-[[3-(phenylmethoxy)phenyl]methyl]-2H-pyran-2-one; 5,6-Dihydro-4-hydroxy-6-(3-methylbutyl)-3-[5-methyl-1-(phenylmethyl)hexyl]-6-phenyl-2H-pyran-2-one; 3-[1-(Cyclohexylthio)-5-methylhexyl]-5,6-dihydro-4-hydroxy-6-(3-methylbutyl)-6-lenyl-2H-pyran-2-one; 3-[2-(Cyclohexyl-1-[(3-methylbutyl)amino]ethyl]-5,6-dihydro-4-hydroxy-6-(3-methylbutyl)-6-phenyl-2H-pyran-2-one ; 5,6-Dihydro-4-hydroxy-3-[(2-isopropyl-5-methylphenyl)methyl]-6-(2-phenylethyl)-6-phenyl-2H-pyran-2-one; 5,6-Dihydro-4-hydroxy-3-[(3-hydroxymethyl-2-isopropyl-5-methylphenyl)methyl]-6,6-diphenyl-2H-pyran-2-one; 5,6-Dihydro-4-hydroxy-3-[[4-(hydroxymethyl)phenyl]methyl]-6-pentyl-6-phenyl-2H-pyran-2-one; 5,6-Dihydro-4-hydroxy-3-[(3-hydroxyphenyl)methyl]-6-(2-phenylethyl)-6-phenyl-2H-pyran-2-one; 5,6-Dihydro-4-hydroxy-6-pentyl-6-phenyl-3-[[4-(pyridin-3-ylmethoxy)phenyl]methyl]-2H-pyran-2-one; 5,6-Dihydro-4-hydroxy-3-[[(2-isopropyl-3-[2-(morpholin-4-yl)ethoxy]phenyl]methyl]-6-(2-phenylethyl)-6-phenyl- 2H-pyran-2-one; 5,6-Dihydro-4-hydroxy-3-(3-methyl-1-phenyl-but-2-enyl)-6,6-diphenyl-2H-pyran-2-one; 5,6-Dihydro-4-hydroxy-6-(3-methylbutyl)-3-(3-methyl-1-propyl-but-2-enyl)-6-phenyl-2H-pyran-2-one; 5,6-Dihydro-4-hydroxy-3-[[2-(hydroxymethyl)phenyl]methyl]-6-(2-phenylethyl)-6-phenyl-2H-pyran-2-one; 5,6-Dihydro-4-hydroxy-6-(2-phenylethyl)-6-phenyl-3-(2-phenyl-[1,3]dithiolan-2-yl)-2H-pyran-2-one; 4-Hydroxy-3-[methoxy(phenyl)methyl]-6-phenyl-6-(2-phenylethyl)-3-(phenylpropylamino)-5,6-dihydro-2H-pyran-2-one; 3-[Cyclopentyl(cyclopentyloxy)methyl]-4-hydroxy-6-(2-phenylethyl)-6-propyl-5,6-dihydro-2H-pyran-2-one; 3-(1-Cyclopentyloxy-3-methylbutyl]-4-hydroxy-6-(3-methylbutyl)-6-phenyl-5,6-dihydro-2H-pyran-2-one; and 6-Cyclopentyl-3-[cyclopentyl(isopropoxy)methyl]-4-hydroxy-6-methylbutyl-5,6-dihydro-2H-pyran-2-one. 8. A compound of the formula from claim 3, characterized in that R4 represents -[Ar] [CH2]n3 [W2]n4 R7 with the restriction that Ar is not C3-C5 spirocyclyl. 9. Compound of the formula from patent claim 8, characterized in that it is selected from the following group of compounds: 6-Butyl-3-(3,5-dimethylphenyl)-5,6-dihydro-4-hydroxy-6-phenyl-2H-pyran-2-one; 3-[4-[(Phenylmethoxy)methyl]-1-tert-butyl-1H-imidazol-2-yl]-5,6-dihydro-4-hydroxy-6-(2-phenylethyl)-6-phenyl-2H -pyran-2-one; you 3-(1-tert-Butyl-4-methyl-1H-pyrrol-2-yl]-5,6-dihydro-4-hydroxy-6,6-diphenyl-2H-pyran-2-one. 10. A compound of the formula from claim 1, characterized in that X represents OR5, NHR5, or SR5, Z represents O; Y represents O; R 5 is COR 6 or R 5 ; you R6 represents a straight-chain alkyl group containing 1 to 6 carbon atoms, a branched or cyclic alkyl group containing 3 to 7 carbon atoms, nonnyl or phenyl. 11. A compound of the formula from patent claim 10, characterized in that it is selected from the following group of compounds: N-[3-[Cyclopropyl[4-(acetoxy)-5,6-dihydro-2-oxo-6-phenyl-6-(2-phenylethyl)-2H-pyran-3-yl]methyl]phenyl]benzenesulfonamide; 5-[Cyclopropyl]-3-[(phenylsulfonyl)amino]phenyl]methyl]-3,6-dihydro-6-oxo-2,2-diphenyl-2H-pyran-4-yl propanoate; 3,5-Dihydro-6-oxo-2-(2-phenylethyl)-5-(1-phenylpropyl)-2-propyl-2H-pyran-4-yl 2,2-dimethyl-ylbutanoate; 5-[Cyclopropyl[3-[(ethylsulfonyl)amino]phenyl]methyl]-3,6-dihydro-6-oxo-2-(2-phenylethyl)-2-propyl-2H-pyran-4-yl benzeneacetate. 12. A pharmaceutical composition for the treatment of an infection or disease caused by a particular strain of bacteria, containing a sufficient amount of the compound of claim 1 necessary to ensure the antibacterial effect of a dose of the compound ranging from about 1 to about 50 mg/kg per day, together with a pharmaceutically acceptable excipient. 13. A pharmaceutical composition for the treatment of an infection or disease caused by a retrovirus, containing a sufficient amount of the compound of claim 1 to provide an antiviral effect of a dose of the compound, ranging from about 1 required to about 50 mg/kg per day, together with a pharmaceutically effective auxiliary means. 14. A pharmaceutical composition for the treatment of an infection or disease caused by a retrovirus, containing a sufficient amount of the compound of claim 2 to provide an antiviral effect of a dose of the compound, ranging from about 1 required to about 50 mg/kg per day, together with a pharmaceutically effective auxiliary means. 15. A pharmaceutical composition for the treatment of an infection or disease caused by a retrovirus, containing a sufficient amount of the compound of claim 4 necessary to ensure the antiviral effect of a dose of the compound, ranging from about 1 to about 50 mg/kg per day, together with a pharmaceutically effective auxiliary means. 16. A method of treating an infection or disease caused by a retrovirus, characterized by the fact that it includes the administration of the preparation from patent claim 1 to a person in need of such treatment. 17. A method of treating infections or diseases caused by a retrovirus, characterized by the fact that it comprises the administration of the preparation from claim 1 in combination with an HIV reverse transcriptase inhibitor to a person in need of such treatment. 18. A method of treating infections or diseases caused by a retrovirus, characterized by the fact that it includes the administration of the preparation from claim 1 in combination with AZT to a person in need of such treatment. 19. The method of treatment of infections or diseases caused by reatrovirus, characterized in that it comprises the administration of the preparation from patent claim 1 in combination with ddC to a person who needs such treatment. 20. A method of treating infections or diseases caused by a retrovirus, characterized by the fact that it comprises administering the preparation from patent claim 2 to a person who needs such treatment. 21. A method of treating infections or diseases caused by a retrovirus, indicated by the fact that it comprises administering the preparation from claim 2 in combination with an inhibitor of reverse transcriptase of the HIV virus to a person who needs such treatment. 22. A method of treating infections or diseases caused by a retrovirus, characterized by the fact that it comprises administering the preparation from patent claim 3 to a person who needs such treatment. 23. A method of treating infections or diseases caused by a retrovirus, characterized in that it comprises administering the preparation from patent claim 4 to a person in need of such treatment. 24. A method of treating infections or diseases caused by a retrovirus, characterized in that it comprises administering the preparation from claim 4 in combination with an HIV reverse transcriptase inhibitor to a person in need of such treatment. 25. A method of treating infections or diseases caused by a retrovirus, characterized by the fact that it comprises administering the preparation from patent claim 7 to a person who needs such treatment.