JP2007530600A - Antiviral agent - Google Patents

Abstract

The present invention provides a method of treating or preventing hepatitis B virus, comprising administering an effective amount of a compound of formula (1) or a pharmaceutically acceptable derivative, salt or prodrug thereof. . In addition, compounds of formula (1) and pharmaceutical compositions thereof are provided. Furthermore, a process for producing the compound of formula (1) is described.
[Chemical 1]

Description

  The present invention relates to the use of naphthopyrans as medicaments for the treatment and / or prevention of hepatitis B, pharmaceutical compositions for use in such therapy and novel naphthopyrans.

  Human hepatitis B virus infection is a major public health problem because of the ability of the virus to cause acute and chronic infections. Chronic hepatitis B virus infection (hereinafter referred to as “HBV”) is a cause of severe liver disease in humans and frequently causes cirrhosis and hepatocellular carcinoma. Currently, there is no fully effective treatment for successful management of chronic HBV infection. Over 250 million chronic HBV carriers worldwide cannot benefit from currently available commercial vaccines.

  Currently available treatments for HBV are only partially effective and can be associated with adverse side effects. In addition, many patients acquire antimicrobial resistance, leading to reduced effectiveness. Thus, there is a need for new effective treatments for HBV.

  According to the present invention, it has been found that the compound of formula (1) is an active agent against hepatitis B virus.

〔式中、
ＸはＯＨ、ＯＲ_９またはハロであり；
ＲおよびＲ_１は、独立してＨ、Ｃ_１−６アルキル、Ｃ_２−６アルケニル、Ｃ_２−６アルキニル、Ｃ_３−６シクロアルキル、アリールから選択されるか、またはそれらが結合している炭素原子と一体となって、飽和または不飽和Ｃ_３−６炭素環式環を形成し；
Ｒ_２およびＲ_３は、独立してＨ、Ｃ_１−６アルキル、Ｃ_２−６アルケニル、Ｃ_２−６アルキニル、Ｃ_３−６シクロアルキルから選択されるか、またはそれらが結合している炭素原子と一体となって二重結合を形成し；
Ｒ_４およびＲ_５は、独立してＨ、Ｃ_１−６アルキル、Ｃ_２−６アルケニル、Ｃ_２−６アルキニル、Ｃ_３−６シクロアルキル、ＯＨ、ＯＲ_９、ハロまたはＮＲ_１０Ｒ_１０から選択されるか、またはそれらが結合している炭素原子と一体となって二重結合を形成し；
Ｒ_６およびＲ_７は、独立してＨ、Ｃ_１−６アルキル、Ｃ_２−６アルケニル、Ｃ_２−６アルキニル、Ｃ_３−６シクロアルキル、ＯＨまたはＯＲ_９から選択され；
Ｒ_８は、独立してＨ、Ｃ_１−６アルキル、Ｃ_２−６アルケニル、Ｃ_２−６アルキニル、Ｃ_３−６シクロアルキル、ＯＨ、ＯＲ_９またはハロから選択され；
Ｒ_９はＣ_１−６アルキル、Ｃ_２−６アルケニル、Ｃ_２−６アルキニル、Ｃ_３−６シクロアルキル、アリール、Ｃ(＝Ｏ)Ｒ_１１またはＳ(Ｏ)_２Ｒ_１２であるか、またはＯＲ_９はアミノ酸残基であり；
各Ｒ_１０は、独立してＨおよびＣ_１−６アルキルから選択され；
Ｒ_１１はＣ_１−２１アルキル、Ｃ_２−２１アルケニル、Ｃ_２−２１アルキニル、Ｃ_３−６シクロアルキル、Ｃ_３−６シクロアルキルＣ_１−６アルキル、アリールまたはアリールＣ_１−６アルキルであり；そして
Ｒ_１２はＣ_１−６アルキル、Ｃ_２−６アルケニル、Ｃ_２−６アルキニルまたはアリールである。〕
の化合物またはその薬学的に許容される誘導体、塩もしくはプロドラッグを投与することを含む方法が提供される。 According to one aspect of the present invention, a method for treating or preventing hepatitis B virus in a subject, wherein the subject has an effective amount of formula (1):

[Where,
X is OH, OR ₉ or halo;
R and R ₁ are independently selected from H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, aryl, or they are attached United with a carbon atom to form a saturated or unsaturated C _3-6 carbocyclic ring;
R ₂ and R ₃ are independently selected from H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, or the carbon to which they are attached. Unite with the atom to form a double bond;
R ₄ and R ₅ are independently selected from H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, OH, OR ₉ , halo or NR ₁₀ R ₁₀ Or together with the carbon atoms to which they are attached form a double bond;
R ₆ and R ₇ are independently selected from H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, OH or OR ₉ ;
R ₈ is independently selected from H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, OH, OR ₉ or halo;
R ₉ is C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, aryl, C (═O) R ₁₁ or S (O) ₂ R ₁₂ , or OR ₉ is an amino acid residue;
Each R ₁₀ is independently selected from H and C _1-6 alkyl;
R ₁₁ is C _1-21 alkyl, C _2-21 alkenyl, C _2-21 alkynyl, C _3-6 cycloalkyl, C _3-6 cycloalkyl C _1-6 alkyl, aryl or aryl C _1-6 alkyl And R ₁₂ is C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl or aryl. ]
Or a pharmaceutically acceptable derivative, salt or prodrug thereof.

  According to a further aspect of the present invention there is provided the use of a compound of formula (1) in the manufacture of a medicament for the treatment or prevention of hepatitis B virus.

  In accordance with yet a further aspect of the present invention, there is provided a method of treating or preventing hepatitis B virus comprising administering an effective amount of a compound of formula (1) and a second therapeutic agent.

In accordance with another aspect of the present invention, a compound of formula (1) wherein R ₅ is OH, OR ₉ or NHR ₁₀ when R and R ₁ are both methyl and R ₄ is OH or OR ₉ Not selected from).

In accordance with another aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of formula (1) and a pharmaceutically acceptable carrier, excipient or adjuvant (wherein R in the compound of formula (1) And when R ₁ is both methyl and R ₄ is OH or OR ₉ , R ₅ is not selected from OH, OR ₉ or NHR ₁₀ ).

  In accordance with the present invention, the compound of formula (1) can exist in the form of a pharmaceutically acceptable derivative, salt or prodrug.

DETAILED DESCRIPTION Throughout this specification and the appended claims, unless the context requires otherwise, the terms “include” and variations thereof such as “include” and “include” It is to be understood that a process or integer or group of steps is meant to be included, but does not exclude all other integers or processes or integers or groups of processes.

  Citation of any prior document in this specification shall not be construed, nor should it be construed as an admission that that prior document forms common general knowledge in Australia.

  The term “halo” or “halogen” as used herein means fluorine (fluoro), chlorine (chloro), bromine (bromo) or iodine (iodo).

The term “alkyl” as used herein alone or in compounds such as NH (alkyl) or N (alkyl) ₂ is suitably 1 to 3, 1 to 6, 1 Means a monovalent linear or branched hydrocarbon group having from 10 to 1 or 21 to 21 carbon atoms. For example, suitable alkyl groups are methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 2-, 3- or 4- Including but not limited to methylpentyl, 2-ethylbutyl, n-hexyl or 2-, 3-, 4- or 5-methylpentyl.

  The term “alkenyl” as used herein means a straight or branched chain hydrocarbon group having one or more double bonds between carbon atoms. Suitable alkenyl groups include, but are not limited to, ethenyl, propenyl, isopropenyl, butenyl, pentenyl and hexenyl.

  The term “alkynyl” as used herein refers to a straight or branched chain hydrocarbon group containing one or more triple bonds. Suitable alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl and hexenyl.

  The term “cycloalkyl” as used herein refers to a cyclic hydrocarbon group. Suitable cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

As used herein, the term “aryl” means a C ₆ -C ₁₀ aromatic hydrocarbon group such as phenyl or naphthyl.

The term “heterocyclyl” when used alone or in the term compound containing a monocyclic, polycyclic, fused or conjugated hydrocarbon residue is preferably C _3-6 , where One or more carbon atoms (and hydrogen atoms attached thereto, if appropriate) are replaced with heteroatoms to provide a non-aromatic residue. Suitable heteroatoms include O, N and S. When two or more carbon atoms are substituted, this can be due to two or more identical or different heteroatoms. Suitable examples of heterocyclic groups may include pyrrolidinyl, pyrrolinyl, piperidyl, piperazinyl, morpholino, indolinyl, imiazolidinyl, pyrazolidinyl, thiomorpholino, dioxanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrrolyl and the like.

Each alkyl, alkenyl, alkynyl, cycloalkyl, aryl or heterocyclyl group, _{C 1} optionally - ₃ alkyl, OH, OC ₁ - ₃ alkyl, _{halo, CN, NO 2, CO 2} H, CO 2 C 1-3 alkyl , CONH _2, CONH _{(C 1-3} alkyl), CON _{(C 1-3 alkyl) 2,} trifluoromethyl, optionally substituted with _NH 2, NH (alkyl) or N _{(alkyl) 2.} For example, the optionally substituted aryl group can be a 4-methylphenyl or 4-hydroxyphenyl group, and the optionally substituted alkyl group is 2-hydroxyethyl, trifluoromethyl, or difluoromethyl. obtain.

The term “amino acid residue” as used herein means an α-amino acid or β-amino acid linked to the naphthopyrandione structure, preferably via the carboxylic acid group of the amino acid. The amino acid may be an L- or D-isomer and may have a naturally occurring side chain or a non-naturally occurring side chain. The amino acid is further substituted at the α-position or β-position with -C ₁ -C ₆ alkyl, -C ₂ -C ₆ alkenyl, -C ₂ -C ₆ alkynyl,-(CH ₂ ) _n COR _a ,-( _{CH 2) n R b, -PO} 3 H, - (CH 2) n heterocyclyl or - (CH _{2) n} aryl (where, _{R a} is _{-OH, -NH 2, -NHC 1 -C} 3 alkyl, - OC ₁ -C a ₃ alkyl or _-C 1 -C ₃ alkyl, and _{R b} is -OH, -SH, _-SC 1 -C ₃ alkyl, _-OC 1 -C ₃ alkyl, _-C 3 -C ₆ cycloalkyl Alkyl, —C ₃ -C ₆ cycloalkenyl, —NH ₂ , —NHC ₁ —C ₃ alkyl or —NHC (C═NH) NH ₂ , n is 0 or an integer from 1 to 6, and each Alkyl, alkenyl, alkynyl, cycloalkoxy , Cycloalkenyl, aryl or heterocyclyl _{groups, -OH, -NH 2, -NHC 1} -C 3 alkyl, _-OC 1 -C ₃ alkyl, -SH, _-SC 1 -C ₃ alkyl, _-CO 2 H, - Optionally substituted with one or more groups selected from CO ₂ C ₁ -C ₃ alkyl, —CONH ₂ or —CONHC ₁ -C ₃ alkyl).

The term “α-amino acid” as used herein has an amino group and a carboxyl group, where the amino group and the carboxyl group are separated by one carbon atom, an α-carbon atom. Means. α-amino acids include naturally occurring and non-naturally occurring L-amino acids and their D-isomers, as well as their derivatives such as salts or functional groups protected with appropriate protecting groups. . The α-amino acid is further substituted at the α-position with —C ₁ -C ₁₀ alkyl, —C ₂ -C ₁₀ alkenyl, —C ₂ -C ₁₀ alkynyl, — (CH ₂ ) _n COR _a , — (CH _2). ) _n R _b , —PO ₃ H, — (CH ₂ ) _n heterocyclyl or — (CH ₂ ) _n aryl (where R _a is —OH, —NH ₂ , —NHC ₁ -C ₃ alkyl, —OC ₁₎ -C ₃ alkyl or _C 1 -C ₃ alkyl, and _{R b} is -OH, -SH, _-SC 1 -C ₃ alkyl, _-OC 1 -C _{3 alkyl,} -C 3 _{-C 12} cycloalkyl, - C ₃ -C ₁₂ cycloalkenyl, —NH ₂ , —NHC ₁ -C ₃ alkyl or —NHC (C═NH) NH ₂ , n is 0 or an integer from 1 to 10, and each alkyl, alkenyl , Alkynyl, cycloal Le, cycloalkenyl, aryl or heterocyclyl _{groups, -OH, -NH 2, -NHC 1} -C 3 alkyl, _-OC 1 -C ₃ alkyl, -SH, _-SC 1 -C ₃ alkyl, _-CO 2 H, -CO ₂ C ₁ -C ₃ alkyl, optionally substituted with a group selected from optionally substituted with one or more groups selected from -CONH ₂ or -CONHC3H6N ₁ -C ₃ alkyl).

The term “β-amino acid” as used herein means an amino acid that differs in that there are α-amino acids and two (2) carbon atoms that separate the carboxyl terminus and the amino terminus. Therefore, β-amino acids with specific side chains can exist as R or S enantiomers at either the α (C2) or β (C3) carbons, for a given side chain, a total of four isomers. Is possible. The side chain may be the same as that of a naturally occurring α-amino acid or may be the side chain of a non-naturally occurring amino acid.

Furthermore, the β-amino acids may have mono-, di-, tri- or tetra-substitution at the C2 and C3 carbon atoms. The mono-substitution can be a C2 or C3 carbon atom. Di-substitution includes two substituents on the C2 carbon atom, two substituents on the C3 carbon atom, or one substituent on each of the C2 and C3 carbon atoms. Tri-substitution includes two substituents on the C2 carbon atom and one substituent on the C3 carbon atom or two substituents on the C3 carbon atom and one substituent on the C2 carbon atom. Tetra-substitution includes two substituents on the C2 carbon atom and two substituents on the C3 carbon atom. Suitable substituents include -C ₁ -C ₆ alkyl, -C ₂ -C ₆ alkenyl, -C ₂ -C ₆ alkynyl,-(CH ₂ ) _n COR _a ,-(CH ₂ ) _n R _b , -PO ₃ H, — (CH ₂ ) _n heterocyclyl or — (CH ₂ ) _n aryl (where R _a is —OH, —NH ₂ , —NHC ₁ -C ₃ alkyl, —OC ₁ -C ₃ alkyl or —C an ₁ -C ₃ alkyl, and _{R b} is -OH, -SH, _-SC 1 -C ₃ alkyl, _-OC 1 -C ₃ alkyl, _-C 3 -C ₆ cycloalkyl, _-C 3 -C ₆ cycloalkyl Alkenyl, —NH ₂ , —NHC ₁ -C ₃ alkyl or —NHC (C═NH) NH ₂ , n is 0 or an integer from 1 to 6, and each alkyl, alkenyl, alkynyl, cycloalkyl, cyclo Alkenyl, aryl Other heterocyclyl _{groups, -OH, -NH 2, -NHC 1} -C 3 alkyl, _-OC 1 -C ₃ alkyl, -SH, _-SC 1 -C _{3 alkyl, -CO 2 H, -CO 2 C} 1 Optionally substituted with one or more groups selected from —C ₃ alkyl, —CONH ₂ or —CONHC ₁ -C ₃ alkyl).

  The term “non-naturally occurring amino acid” as used herein means an amino acid having a side chain that is not present in a naturally occurring L-α-amino acid. Examples of non-naturally occurring amino acids and derivatives are norleucine, 4-aminobutyric acid, 4-amino-3-hydroxy-5-phenylpentanoic acid, 6-aminohexanoic acid, t-butylglycine, norvaline, phenylglycine, ornithine, Including but not limited to the use of sarcosine, 4-amino-3-hydroxy-6-methylheptanoic acid, 2-thienylalanine and / or D-isomers of amino acids.

  It will also be appreciated that compounds of formula (1) may have asymmetric centers and therefore can exist in more than one isomeric form. The invention therefore also provides compounds that are substantially pure at one or more asymmetric centers, eg, greater than about 90% ee, such as about 95% or 97% ee, or greater than 99% ee. As well as mixtures thereof including racemic mixtures. Such isomers can be prepared, for example, by asymmetric synthesis using chiral intermediates or by chiral resolution.

  The term “pharmaceutically acceptable derivative” refers to any pharmaceutically acceptable salt, hydrate or prodrug, or a compound of formula (1) or an antiviral active metabolite or its metabolite upon administration to a subject. It can include all other compounds that can provide residues (directly or indirectly).

  Suitable pharmaceutically acceptable salts include salts of pharmaceutically acceptable inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, carbonic acid, boric acid, sulfamic acid, and hydrobromic acid, or acetic acid, Propionic acid, butyric acid, tartaric acid, maleic acid, hydroxymaleic acid, fumaric acid, malic acid, citric acid, lactic acid, mucoic acid, gluconic acid, benzoic acid, succinic acid, oxalic acid, phenylacetic acid, methanesulfonic acid, toluenesulfonic acid , Pharmaceutically acceptable such as benzenesulfonic acid, salicylic acid, sulfanilic acid, aspartic acid, glutamic acid, edetic acid, stearic acid, palmitic acid, oleic acid, lauric acid, pantothenic acid, tannic acid, ascorbic acid and valeric acid Including but not limited to salts of organic acids.

  Basic salts include sodium, potassium, lithium, calcium, magnesium, zinc, ammonium, alkylammonium such as a salt formed from triethylamine, alkoxyammonium such as a salt formed from ethanolamine and ethylenediamine, choline or arginine, Examples include, but are not limited to, those formed with pharmaceutically acceptable cations such as amino acids such as lysine or histidine.

  Basic nitrogen-containing groups are quaternary with agents such as lower alkyl halides such as methyl, ethyl, propyl and butyl chloride, bromide and iodide; dialkyl sulfates such as dimethyl and diethyl sulfate; and others. Can be

  The term “prodrug” is used in its broadest sense and includes derivatives that convert in vivo to a compound of the invention. Such derivatives will readily occur to those skilled in the art, for example, compounds in which a free hydroxy group has been converted to a group such as an ester, carbonate or carbamate and can be converted back to a hydroxy group in vivo. including. Prodrugs may include modification of one or more functional groups of the compound of formula (1). For example, as in the method described in US Pat. No. 5,672,607, an antiviral naphthopirprodrug having increased water solubility (eg, it is better for compositions for parenteral administration) can be converted to a quinone functional group. Can be prepared by reducing to the corresponding quinol followed by reaction with phosphorus oxychloride to form the corresponding phosphate ester. After in vivo administration of a composition comprising such a soluble antiviral naphthopirprodrug, the prodrug is easily hydrolyzed to the corresponding quinol, which is then oxidized to be active in vivo active parent antiviral naphtho. Re-form pyrandione. Similarly, other types of derivatives can be prepared from the present reduced quinol derivatives of the present antiviral naphthopyrandione; they can also serve as prodrugs for use in therapeutic compositions. For example, other types of esterification (eg, acetylation) may be used to produce anti-antigens such as 7,8,10-triacetoxy-3,3-dimethyl-3H-naphtho [2,1-b] pyran. Viral naphthopyramprodrugs can be produced. Again, after in vivo administration, the prodrug is readily hydrolyzed and oxidized to its parent active antiviral naphthopyran compound.

〔式中、
ＸはＯＨ、ＯＲ_９またはハロであり；
ＲおよびＲ_１は、独立してＨ、Ｃ_１−６アルキル、Ｃ_２−６アルケニル、Ｃ_２−６アルキニル、Ｃ_３−６シクロアルキル、アリールから選択されるか、またはそれらが結合している炭素原子と一体となって、飽和または不飽和Ｃ_３−６炭素環式環を形成し；
Ｒ_２およびＲ_３は、独立してＨ、Ｃ_１−６アルキル、Ｃ_２−６アルケニル、Ｃ_２−６アルキニル、Ｃ_３−６シクロアルキルから選択されるか、またはそれらが結合している炭素原子と一体となって二重結合を形成し；
Ｒ_４およびＲ_５は、独立してＨ、Ｃ_１−６アルキル、Ｃ_２−６アルケニル、Ｃ_２−６アルキニル、Ｃ_３−６シクロアルキル、ＯＨ、ＯＲ_９、ハロまたはＮＲ_１０Ｒ_１０から選択されるか、またはそれらが結合している炭素原子と一体となって二重結合を形成し；
Ｒ_６およびＲ_７は、独立してＨ、Ｃ_１−６アルキル、Ｃ_２−６アルケニル、Ｃ_２−６アルキニル、Ｃ_３−６シクロアルキル、ＯＨまたはＯＲ_９から選択され；
Ｒ_８は、独立してＨ、Ｃ_１−６アルキル、Ｃ_２−６アルケニル、Ｃ_２−６アルキニル、Ｃ_３−６シクロアルキル、ＯＨ、ＯＲ_９またはハロから選択され；
Ｒ_９はＣ_１−６アルキル、Ｃ_２−６アルケニル、Ｃ_２−６アルキニル、Ｃ_３−６シクロアルキル、アリール、Ｃ(＝Ｏ)Ｒ_１１またはＳ(Ｏ)_２Ｒ_１２であるか、またはＯＲ_９はアミノ酸残基であり；
各Ｒ_１０は、独立してＨおよびＣ_１−６アルキルから選択され；
Ｒ_１１はＣ_１−２１アルキル、Ｃ_２−２１アルケニル、Ｃ_２−２１アルキニル、Ｃ_３−６シクロアルキル、Ｃ_３−６シクロアルキルＣ_１−６アルキル、アリールまたはアリールＣ_１−６アルキルであり；そして
Ｒ_１２はＣ_１−６アルキル、Ｃ_２−６アルケニル、Ｃ_２−６アルキニルまたはアリールである。〕
の化合物またはその薬学的に許容される誘導体、塩もしくはプロドラッグを投与することを含む方法が提供される。 In a first aspect, a method of treating or preventing hepatitis B virus in a subject, wherein the subject has an effective amount of formula (1):

[Where,
X is OH, OR ₉ or halo;
R and R ₁ are independently selected from H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, aryl, or they are attached United with a carbon atom to form a saturated or unsaturated C _3-6 carbocyclic ring;
R ₂ and R ₃ are independently selected from H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, or the carbon to which they are attached. Unite with the atom to form a double bond;
R ₄ and R ₅ are independently selected from H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, OH, OR ₉ , halo or NR ₁₀ R ₁₀ Or together with the carbon atoms to which they are attached form a double bond;
R ₆ and R ₇ are independently selected from H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, OH or OR ₉ ;
R ₈ is independently selected from H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, OH, OR ₉ or halo;
R ₉ is C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, aryl, C (═O) R ₁₁ or S (O) ₂ R ₁₂ , or OR ₉ is an amino acid residue;
Each R ₁₀ is independently selected from H and C _1-6 alkyl;
R ₁₁ is C _1-21 alkyl, C _2-21 alkenyl, C _2-21 alkynyl, C _3-6 cycloalkyl, C _3-6 cycloalkyl C _1-6 alkyl, aryl or aryl C _1-6 alkyl And R ₁₂ is C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl or aryl. ]
Or a pharmaceutically acceptable derivative, salt or prodrug thereof.

In other aspects, a compound of formula (1) wherein R ₅ is not selected from OH, OR ₉ or NHR ₉ when R and R ₁ are both methyl and R ₄ is OH or OR ₉ ) Is provided.

In preferred embodiments, one or more of the following definitions applies:
X is OH, OC _1-6 alkyl or halo;
R and R ₁ are independently selected from H or C _1-3 alkyl, or together with the carbon atom to which they are attached, a saturated or unsaturated C _3-6 carbocyclic ring Forming;
R ₂ and R ₃ are each hydrogen;
R ₄ and R ₅ are independently selected from H, OH, OR ₉ or halo or together with the carbon atom to which they are attached form a double bond;
R ₆ and R ₇ are independently selected from H, OH, C _1-6 alkyl, C _1-6 alkoxy;
R ₈ is H, OH, OR ₉ , C _1-6 alkyl or halo;
R ₉ is C (═O) R ₁₁ or S (O) ₂ R ₁₂ ;
R ₁₁ is C _1-21 alkyl;
R ₁₂ is C _1-6 alkyl, phenyl or tosyl.

〔式中、Ｒ、Ｒ_１、Ｒ_２、Ｒ_３、Ｒ_４およびＲ_５は、式(１)について定義の通りである。〕
のものを含む。 Preferred compounds of the invention are those of formula (2):

[Wherein R, R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are as defined for formula (1). ]
Including

Preferred compounds of the invention include the following:
8-hydroxy-3,3-dimethyl-3H-naphtho [2,1-b] pyran-7,10-dione,
8-hydroxy-3,3-dimethyl-1,2-dihydro-3H-naphtho [2,1-b] pyran-7,10-dione,
9-bromo-8-hydroxy-3,3-dimethyl-1,2-dihydro-3H-naphtho [2,1-b] pyran-7,10-dione,
9-bromo-8-hydroxy-3,3-dimethyl-3H-naphtho [2,1-b] pyran-7,10-dione,
9-bromo-3,3-dimethyl-8- (4-methylbenzenesulfonyloxy) -1,2-dihydro-3H-naphtho [2,1-b] pyran-7,10-dione,
9-bromo-3,3-dimethyl-8- (4-methylbenzenesulfonyloxy) -3H-naphtho [2,1-b] pyran-7,10-dione,
8-acetoxy-3,3-dimethyl-3H-naphtho [2,1-b] pyran-7,10-dione,
2,9-dibromo-1,8-dihydroxy-3,3-dimethyl-1,2-dihydro-3H-naphtho [2,1-b] pyran-7,10-dione,
8,9-dichloro-3,3-dimethyl-1,2-dihydro-3H-naphtho [2,1-b] pyran-7,10-dione,
7,8,10-triacetoxy-3,3-dimethyl-3H-naphtho [2,1-b] pyran,
9-bromo-8-hydroxy-3,3-dimethyl-3H-naphtho [2,1-b] pyran-7,10-dione,
9-bromo-8-hydroxy-3,3-dimethyl-3H-naphtho [2,1-b] pyran-7,10-dione,
9-bromo-3,3-dimethyl-8- (4-methylbenzenesulfonyloxy) -1,2-dihydro-3H-naphtho [2,1-b] pyran-7,10-dione,
9-bromo-3,3-dimethyl-8- (4-methylbenzenesulfonyloxy) -3H-naphtho [2,1-b] pyran-7,10-dione,
8-bromo-3,3-dimethyl-9- (4-methylbenzenesulfonyloxy) -3H-naphtho [2,1-b] pyran-7,10-dione,
8-bromo-3,3-dimethyl-9- (4-methylbenzenesulfonyloxy) -1,2-dihydro-3H-naphtho [2,1-b] pyran-7,10-dione,
8,9-dichloro-3,3-dimethyl-1,2-dihydro-3H-naphtho [2,1-b] pyran-7,10-dione,
3,3-dimethyl-7,10-dioxo-7,10-dihydro-3H-benzo [f] chromene-8-olate sodium;
3,3-Dimethyl-7,8-dioxo-7,8-dihydro-3H-benzo [f] chromene-10-olate sodium 8-hydroxy-3-methyl-3-phenyl-3H-benzo [f] chromene -7,10-dione, and 8-hydroxy-3,3-diphenyl-3H-benzo [f] chromene-7,10-dione.

Preferably the compound of formula (1) is:
8-hydroxy-3,3-dimethyl-3H-naphtho [2,1-b] pyran-7,10-dione (compound (1)),
8-hydroxy-3,3-dimethyl-1,2-dihydro-3H-naphtho [2,1-b] pyran-7,10-dione (compound (2))
It is.

〔式中、Ｒ、Ｒ_１、Ｒ_２、Ｒ_３、Ｒ_５、Ｒ_６、Ｒ_７、Ｒ_８、およびＸは式(１)について定義の通りであり、Ｒ_４はＨ、Ｃ_１−６アルキル、Ｃ_２−６アルケニル、Ｃ_２−６アルキニル、Ｃ_３−６シクロアルキル、ハロまたはＮＲ_１０Ｒ_１０から選択されるか、またはＲ_５およびＲ_４とＲ_５が結合している炭素原子間の結合と一体となって二重結合を形成する。〕
のものを含む。 In another embodiment, the compounds of the present invention have the formula (3):

[Wherein R, R ₁ , R ₂ , R ₃ , R ₅ , R ₆ , R ₇ , R ₈ , and X are as defined for formula (1), R ₄ is H, C _1-6 Selected from alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, halo or NR ₁₀ R ₁₀ , or between carbon atoms to which R ₅ and R ₄ and R ₅ are attached A double bond is formed integrally with the bond. ]
Including

Compounds of formula (1) can be prepared using methods described or illustrated herein or known in the art. It will be appreciated that minor modifications to the methods described herein or known in the art may be necessary for the synthesis of certain specific compounds of formula (1). General synthetic methods applicable to the synthesis of this compound are such as Comprehensive Organic Transformations, RC Larock, 1989, VCH Publishers and Advanced Organic Chemistry, J. March, 4th Edition (1992), Wiley InterScience, and references cited therein. Can be seen in the standard reference book. It will also be appreciated that certain reactive groups may need to be protected and deprotected during the synthesis process. Suitable protecting and deprotecting methods for reactive functional groups in the literature, for example Protective Groups in Organic Synthesis, TW Greene & P. Wutz, in ^{John Wiley & Son, 3 rd Edition} , 1999, is known.

The compounds of the present invention can be prepared according to the general method of Scheme 1.

  An appropriately substituted 2,6-dihydroxynaphthalene (3) is reacted with an appropriately substituted enal or enone (4) in the presence of a suitable base for cyclization to give naphthopyranol (5). . The naphthopyranol is then oxidized to the corresponding intermediate orthoquinone (6) with a suitable oxidizing agent, then reduced with a suitable reducing agent and oxidized to the desired naphthopyrandione (7) with a suitable oxidizing agent. Further modification of the substituents on the naphthopyrandione can be performed using chemical methods known to those skilled in the art for the production of the desired substituent or substituents. One skilled in the art can protect and deprotect certain functional groups during the reaction sequence using conventional methods. Such methods are known in the art and include, for example, those described by Greene and Wutz (supra). The reaction sequences described in Examples 1 and 2 illustrate the preparation of compounds (1) and (2) and provide examples of how to use the reaction sequence of Scheme 1. One skilled in the art will recognize that a wide variety of reaction conditions can be utilized to effect the desired conversion, including solvents, bases, oxidants, reducing agents, temperatures and reaction times.

Substituted enones such as (4) are added to substituted 2,6-dihydroxynaphthalene (3) in the opposite orientation of Scheme 1, depending on the exact nature of the reagents and conditions used, and still produce the naphthopyran product. provide. Such a reaction is shown in Scheme 2 and provides naphthopyranol (8). Naphtopyranol (8) can be isomerized to efficiently provide naphthopyranol of general formula (5), which is then subjected to further reaction according to the general method of Scheme 1 to provide compounds of formula (1). obtain.

  Alternative synthetic methods for providing compounds of formula (1) are shown in Schemes 3 and 4. In Scheme (3), an appropriately substituted butyne (9) is reacted with an appropriately substituted hydroxytetralone (10). Group L is any suitable leaving group and includes groups such as bromo, chloro, and hydroxyl. The reaction between tetralone and butyne can be acid or base catalyzed to give naphthopyran (12). In some cases, the reaction can be carried out in one vessel, but the intermediate (11) can be isolated. Intermediate (11) can be conveniently cyclized by heating in the presence of a suitable base such as, for example, diethylaniline. This cyclized product (12) can then be oxidized to give quinone (13), which can then be further modified to give other compounds of formula (1).

  Scheme (4) outlines a reaction sequence similar to that of scheme (3), starting with an appropriately substituted hydroxynaphthalene. This is based on a study reported by Bigi et al., J. Org. Chem., 62, 7024-7027 (1997). The present cyclized naphthopyran (15) can itself be treated with the compound (5) of scheme (1) to give the compound of the invention.

  Many other methods for the preparation of benzopyrans have been reported in the chemical literature and one skilled in the art can adapt these methods to obtain the compounds of the invention, eg, Ishino et al., Syn. Comm ., 31, 439-448 (2001).

Further modifications may include derivatization of double bonds. For example, when R ₄ and R ₅ together with the carbon atom to which they are attached form a double bond, the double bond can be derivatized by addition, oxidation or reduction reactions. An example of such derivatization with potential double bonds is shown in Scheme 5. Reductive acetylation for protection of the quinone moiety of the compound can be followed by epoxidation of the pyran double bond followed by epoxide ring opening and deprotection with an amine and oxidation for quinone regeneration. One skilled in the art can readily determine appropriate reagents and conditions for performing such transformations.

  One skilled in the art can modify such reaction schemes by using different epoxide ring-opening reagents, by using asymmetric epoxidation catalysts, and by changing the nature of the substituents.

  The term “effective amount” as used herein means the amount of a compound that, when administered according to a desired dosing regimen, provides the desired hepatitis B virus treatment or therapeutic activity, or disease prevention. Administration can occur at intervals of minutes, hours, days, weeks, months or years, or continuously over any such period. A therapeutically or therapeutically effective amount, when administered according to a desired dosing regimen, achieves at least part of the desired therapeutic effect, delays the onset of hepatitis B, inhibits progression, or develops or The amount of the compound that stops progression or partially or fully recovers. A prophylactically effective amount is that amount of a compound that, when administered according to a desired dosage regimen, is sufficient to at least partially prevent or delay the onset of a particular disease or condition.

  In yet another aspect of the invention, there is provided the use of a compound of formula (1) in the manufacture of a medicament for treating or preventing hepatitis B virus.

  Suitable dosages can fall within the range of about 0.1 ng / kg body weight to 1 g / kg body weight per administration. The dose is preferably within the range of 1 μg to 1 g / kg body weight per dose, for example within the range of 1 mg to 1 g / kg body weight per dose. In one embodiment, the dosage is in the range of 1 mg to 500 mg / kg body weight per dose. In other embodiments, the dosage is in the range of 1 mg to 250 mg / kg body weight per dose. In yet another preferred embodiment, the dosage is in the range of 1 mg to 100 mg / kg body weight per dose, eg up to 50 mg / kg body weight per dose. In yet another embodiment, the dosage ranges from 1 μg to 1 mg / kg body weight per dose.

  Appropriate dosages and regimens can be determined by the attending physician and can depend on the severity of the condition and the general age, health condition and weight of the subject.

  The active ingredient can be administered in a single dose or in consecutive doses. While it is possible for the active ingredient to be administered alone, it is preferable to present it as a composition, preferably as a pharmaceutical composition.

  According to a further aspect, there is provided a method of treating or preventing hepatitis B virus comprising administering an effective amount of a compound of formula (1) and a second therapeutic agent.

  When administered as a combination, the compound of formula (1) and the second therapeutic agent can be administered simultaneously, separately or sequentially.

  The second therapeutic agent can be a known antiviral or antiretroviral agent or other medicament used for the treatment of viral infections. Representative examples of suitable second therapeutic agents include immunomodulators, immunostimulants and antibiotics. Examples of antiviral agents are acyclovir, val-acyclovir, penciclovir, famciclovir, ganciclovir, foscarnet, ribavirin, interferon-alpha, PEG-interferon-alpha, lamivudine, adefovir, thymosin alpha 1, entecavir, telbivudine, Emtricitabine, elvucitabine, MCC-478, hepavir B, MIV-210, valtorcitabine, HepeX-B, zidovudine, didanocin, zalcitabine, stavudine, lamivudine, abacavir, tenofovir, emtricavivir, Indinavir, nelfinavir, amprenavir, ritonavir, azatanavir, nevirapine, delavirdine, efavirenz, enfurvitide, Includes Ligivir, Combivir, Kaletra, MIV310, mozenavir, SPD754, SPD746, T1249, TMC125, TMC114, VX-175, tipranavir, and other non-nucleoside reverse transcriptase inhibitors and protease inhibitors. Examples of immunomodulators and immunostimulants include interferon alpha, PEG-interferon, thymosin alpha 1, HepeX-B, HBV immunoglobulin, HBV monoclonal antibody, and EngerixB, Havelix, HB-Vax II, infanrix hep B, Includes vaccines such as twinrix. Preferably, the second therapeutic agent is an agent suitable for treating or preventing hepatitis B virus in a subject. Such therapeutic agents include interferon-alpha, PEG-interferon-alpha, lamivudine, adefovir, thymosin alpha 1, entecavir, terbivudine, emtricitabine, elbucitabine, MCC-478, hepavir B, MIV-210, valtrocitabine, and Including, but not limited to, HepeX-B.

  Yet another aspect of the invention relates to a pharmaceutical composition comprising a compound of formula (1) and a pharmaceutically acceptable carrier, diluent or excipient.

  The formulation of such compositions is known to those skilled in the art. The composition may contain pharmaceutically acceptable additives such as carriers, diluents or excipients. These include all conventional solvents, dispersants, extenders, solid carriers, coatings, antifungal and antibacterial agents, skin penetrants, surfactants, isotonic and absorbent agents, etc. as appropriate . It will be appreciated that the compositions of the present invention may also include other additional physiologically active agents.

  The carrier must be pharmaceutically acceptable in the sense of being compatible with the other ingredients of the composition and not injurious to the subject. Composition is oral, enteral, inhalation, nasal, transdermal, topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intrathecal, intravenous and intradermal) Including those suitable for administration. The composition can conveniently be present in unit dosage form and can be prepared by methods known in the pharmaceutical arts. Such methods include the step of bringing into association the active ingredient with the carrier comprising one or more accessory ingredients. In general, the compositions are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and, if necessary, shaping the product.

  Depending on the disease or condition to be treated, it may or may not be desirable for the compound of formula (1) to cross the blood vessel / brain barrier. Therefore, the composition used in the present invention can be formulated as water-soluble or fat-soluble.

  Compositions of the present invention suitable for oral administration are as separate units such as capsules, sachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution in an aqueous or non-aqueous liquid or It can exist as a suspension; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient can also be present as a bolus, electuary or paste.

  A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets are prepared by free-flowing active ingredients such as powders or granules in a suitable machine, optionally with binders (e.g. inert diluents, preservatives, disintegrants (e.g. sodium starch glycolate, cross-linked Polyvinylpyrrolidone, cross-linked sodium carboxymethylcellulose))), a surfactant or a dusting agent. Molded tablets can be made by casting, in a suitable machine, a mixture of the powdered compound moistened with a liquid diluent. The tablets can be coated or scored as desired and, for example, slow or controlled of the active ingredient therein by the use of various ratios of hydroxypropyl methylcellulose to provide the desired release characteristics Can be formulated to provide a controlled release. The tablets can be provided with an enteric coating if desired, providing release in portions of the gastrointestinal tract other than the stomach.

  Compositions suitable for topical administration to the oral cavity include lozenges containing the active ingredient in flavored bases, usually sucrose and acacia or gum tragacanth; gelatin and glycerin, or inert such as sucrose and gum acacia A pastille containing the active ingredient in a base; and a mouthwash containing the active ingredient in a suitable liquid carrier.

  The compounds of formula (1) can be administered intranasally or via inhalation, for example by means of an atomizer, aerosol or nebulizer.

  Compositions suitable for topical administration to the skin comprise the compound dissolved or suspended in any suitable carrier or base and can be in the form of a lotion, gel, cream, paste, ointment, etc. . Suitable carriers include mineral oil, propylene glycol, polyoxyethylene, polyoxypropylene, emulsifying wax, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. Transdermal devices such as patches can also be used to administer the compounds of the present invention.

  A composition for rectal administration can be present as a suppository with a suitable carrier base comprising, for example, cocoa butter, gelatin, glycerin or polyethylene glycol.

  Compositions suitable for vaginal administration can be present as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing, in addition to the active ingredient, carriers known to be suitable in the art.

  Compositions suitable for parenteral administration include aqueous and non-aqueous isotonic sterile injection solutions that may include antioxidants, buffers, bactericides, and solutes that render the composition isotonic with the intended recipient's blood; and Includes aqueous and non-aqueous sterile suspensions that may include suspending and thickening agents. The composition can be present in unit dose or multi-dose sealed containers, such as ampoules and vials, and can be freeze-dried that requires only the addition of a sterile liquid carrier, such as water, just prior to use for injection. Can be stored under (freeze drying) conditions. Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, and tablets of the kind previously described.

  Preferred unit dosage compositions are those containing a daily dosage or unit of active ingredient, a daily sub-dose as described above, or an appropriate dosage thereof.

  In addition to the active ingredients specified above, the compositions of the present invention may include other agents customary in the art for the type of composition, such as those suitable for oral administration as binders, sweeteners Such additional agents as thickeners, flavoring agents, disintegrating agents, coating agents, preservatives, lubricants and / or time delay agents. Suitable sweeteners include sucrose, lactose, glucose, aspartame or saccharin. Suitable disintegrants include corn starch, methylcellulose, polyvinyl pyrrolidone, xanthan gum, bentonite, alginic acid or agar. Suitable flavoring agents include mint oil, winter green oil, cherries, oranges or raspberry flavors. Suitable coating agents include polymers or copolymers of acrylic acid and / or methacrylic acid and / or their esters, waxes, fatty alcohols, zein, shellac or gluten. Suitable preservatives include sodium benzoate, vitamin E, alpha-tocopherol, ascorbic acid, methyl paraben, propyl paraben or sodium bisulfite. Suitable lubricants include magnesium stearate, stearic acid, sodium oleate, sodium chloride or talc. Suitable time delay agents include glyceryl monostearate or glyceryl distearate.

  Those skilled in the art will recognize that the invention described herein is susceptible to variations and modifications other than those specifically described. It is to be understood that the invention includes all such changes and modifications that fall within the spirit and scope. The invention also includes all of the steps, characteristics, compositions and compounds mentioned or shown herein, individually or collectively, and any two or more of the steps or characteristics. Including any and all combinations of

  The invention will now be described with reference to the following examples, which are included for purposes of illustration only and are not intended to limit the generality of the invention as described above.

Example 1
Compound 1: 9-hydroxy-3,3-dimethyl-3H-naphtho [2,1-b] pyran-7,10-dione Step 1: 3,3-dimethyl-3H-naphtho [2,1-b] pyran -8-ol 2,6-dihydroxynaphthalene (50.0 g, 0.312 mol), 3-methyl-2-butenal (30 mL, 26.24 g, 0.312 mol) and pyridine (38 mL, 37.02 g, 0.468 mol) ) Was heated under reflux for 3.5 hours. The mixture was cooled to room temperature, diluted with dichloromethane (500 mL), filtered through a sintered glass funnel (porosity 3), then washed with aqueous hydrochloric acid solution (1M, 2 × 250 mL) and water (1 × 250 mL). The organic layer is extracted with a solution of aqueous sodium hydroxide (2M, 1 × 250 mL and 1 × 125 mL), the combined aqueous extracts are cooled in an ice-salt bath, and a creamy white precipitate is added with an aqueous hydrochloric acid solution (5M). Acidified (pH ~ 2) until formed (with stirring). The solid was stirred with cooling for an additional 10 minutes, collected by filtration, washed with water and dried under high vacuum at 40 ° C. to give the desired crude product as a fluffy white-gray solid (43.9 g, 62% ). The crude product was used in the subsequent reaction without further purification.

Recrystallized from diethyl ether / hexane mp 120-123 °. ^{δ (1 H) (300MHz,} CDCI 3) 1.47, s, 2 × CH 3; 4.77, s, OH; 5.71, d, J 10.2 Hz, H2; 6.97, d, J 10.2 Hz, H1; 7.02, d, J 8.7 Hz, H5; 7.08, s, H7; 7.10, dd, J 8.7, 2.7 Hz, H9; 7.48, d, J 8.7 Hz, H6; 7.85, d, J 8.7 Hz, H10.m / z (ES ⁺ , 100 V) 471 (2M + H + H ₂ O, 100%), 245 (M + H + H ₂ O, 62), 227 (M + H, 63).

Step 2: 3,3-Dimethyl-3H-naphtho [2,1-b] pyran-7,8-dione 3,3-Dimethyl-3H-naphtho [2,1-b] pyran-in acetonitrile (70 mL) To an oxygen-saturated solution of 8-ol (3.0 g, 13 mmol), a catalytic amount of N, N-bis (salicylidene) ethylenediaminocobalt (II) hydrate, ([Co (II) (Salen) ₂ ]) ( 300 mg, 0.91 mmol, 7 mol%) was added and oxygen was bubbled through the mixture until the reaction was deemed complete by TLC (hexane-ethyl acetate 4: 1) or HPLC (generally 4.5 hours). The orange / brown reaction mixture was diluted with ethyl acetate and the entire mixture was filtered through a plug of flash silica (11 × 7 cm) to remove the catalyst. The plug was washed with ethyl acetate until the eluent was almost colorless. The solvent was concentrated in vacuo and the residue was dried under high vacuum to give the desired crude product as an orange solid (2.73 g, 86%). The crude product was used in the subsequent reaction without further purification.

The product was recrystallized from ethyl acetate / hexanes to give red needles; mp 189-193 °. δ ( ¹ H) (300 MHz, CDCI ₃ ) 1.50, s, 2 × CH ₃ ; 5.92, d, J 10.4 Hz, H2; 6.43, d, J 10.4 Hz, H1; 6.71, d, J 10.5 Hz, H9; 6.84, d, J 8.6 Hz, H5; 7.72, d, J 10.5 Hz, H10; 7.97, d, J 8.6 Hz, H6.m / z (ES ⁺ , 30 V) 263 (M + Na, 9%), 242 (M + H + 1, 19), 241 (M + H, 100).

Step 3: 9-hydroxy-3,3-dimethyl-3H-naphtho [2,1-b] pyran-7,10-dione 3,3-dimethyl-3H-naphtho [2,1-b] pyran-7, A solution of 8-dione (4.59 g, 19.1 mmol) in toluene (340 mL) was washed twice with a solution of sodium dithionite (24.9 g, 0.143 mol) in water (250 mL). The yellow organic layer was then added in one portion to an oxygen saturated solution of potassium tert-butoxide (12.19 g, 115 mmol) in tert-butanol (110 mL) and the resulting mixture was stirred at room temperature with oxygen bubbling for an additional 30 minutes. (Note: longer time seems to reduce yield). The resulting dark red solution is acidified with aqueous hydrochloric acid solution (initially 2M then 5M) until the color changes to yellow / orange (pH˜1), then water (˜40 mL) is added to dissolve the formed salt And the layers were separated. The organic phase was washed with water (1 × 85 mL) and then extracted with saturated aqueous sodium bicarbonate solution (5 × 85 mL). The combined aqueous extracts were returned to the separatory funnel and allowed to stand for 1 hour (to separate additional amount of toluene) and the layers were separated again. The combined basic extracts were cooled in an ice-salt bath and carefully acidified with stirring (aqueous hydrochloric acid, 5M, ˜80 mL) dropwise over 30 min until the color turned pale yellowish ( pH ~ 1-2). The resulting precipitate was further cooled with stirring in an ice-salt bath and the solid was collected and washed with water (˜100 mL) to remove colored impurities and recrystallized orange / brown solid (anhydrous ethanol) The desired product was obtained as orange crystals (1.04 g, 21%), mp 208 °. δ ( ¹ H) (300 MHz, CDCI ₃ ) 1.48, s, 2 × CH ₃ ; 5.94, d, J 10.5 Hz, H2; 6.23, s, H9; 7.03, d, J 8.4 Hz, H5; 7.83, d, J 10.5 Hz, H1; 7.99, d, J 8.4 Hz, H6, m / z (ES ⁺ , 100 V) 279 (M + Na, 100%), 257 (M + H, 46), 159 (46), 137 (49), 86 (44), 59 (50).

Example 2
Compound 2: 8-hydroxy-3,3-dimethyl-1,2-dihydro-3H-naphtho [2,1-b] pyran-7,10-dione 8-hydroxy-3,3-dimethyl-3H-naphtho [ A solution of 2,1-b] pyran-7,10-dione (132 mg, 0.52 mmol) and platinum (IV) oxide (15 mg) in ethyl acetate (15 mL) was stirred under a hydrogen atmosphere for 7 hours. The resulting mixture was stirred with air injection for 1 hour and then filtered through a pad of diatomaceous earth. The pad was washed with ethyl acetate, then the filtrate and washings were combined and concentrated in vacuo to give a green solid (128 mg, 96%). Recrystallization from ethyl acetate / hexane using activated carbon gave 8-hydroxy-3,3-dimethyl-1,2-dihydro-3H-naphtho [2,1-b] pyran-7,10-dione. m.p. 183.5-187 °. δ ( ¹ H) (300MHz, CDCI ₃ ) 1.37, s, 2 × CH ₃ ; 1.85, t, J 6.8 Hz, 2 × H2; 3.30, t, J 6.8 Hz, 2 × H1; 6.20, s, H9; 7.03, d, J 8.6 Hz, H5; 7.98, d, J 8.6 Hz, H6. M / z (ES ⁺ , 30 V) 259 (M + H, 77%), 174 (88), 159 (100).

Example 3
Compound 3: 8-Acetoxy-3,3-dimethyl-3H-naphtho [2,1-b] pyran-7,10-dione Concentrated sulfuric acid (1 drop) in 8-hydroxy-3 in acetic anhydride (10 mL), To a stirred orange suspension of 3-dimethyl-3H-naphtho [2,1-b] pyran-7,10-dione (855 mg, 3.34 mmol) is added and the mixture is added to an oil bath (oil bath temperature). 100 ° C). The mixture immediately became homogeneous red-black. After 10 minutes, the mixture was cooled (ice / water bath) and water (50 mL) was added. The product was extracted with ethyl acetate (150 mL), the organic phase was separated, dried (Na ₂ SO ₄ ), filtered through a silica plug, and the plug was washed with ethyl acetate until no color eluted. The filtrate was concentrated in vacuo and the residue was dried overnight under vacuum to give the title compound as a red solid (965 mg, 97%). ¹ H NMR (300MHz, CDCl ₃ ) δ 1.48 (6H, s, 2 × CH ₃ ), 2.37 (3H, s, COCH ₃ ), 5.94 (1H, d, J 10.5 Hz, H2), 6.34 (1H, s , H9), 7.07 (1H, d, J 8.4 Hz, H5), 7.73 (1H, d, J 10.5 Hz, H1), 7.97, (1H, d, J 8.4 Hz, H6).

Example 4
Compound 4: 7,8,10-triacetoxy-3,3-dimethyl-3H-naphtho [2,1-b] pyran Stirring 8-hydroxy-3,3-dimethyl-3H-naphtho [2,1 -B] A solution of pyran-7,10-dione (110 mg, 0.93 mmol) in acetic anhydride (3 mL) and pyridine (4 mL) was heated in an oil bath at 60 <0> C for 15 min. Zinc powder (530 mg) was added in one portion and the mixture became pale yellow. After heating for 15 minutes, the mixture was cooled to room temperature and filtered through a sinter (porosity 4) while washing with ethyl acetate. The filtrate was poured into ice / water (20 mL) and acidified with aqueous hydrochloric acid solution (2.0 M). The organic phase was separated and the aqueous phase was washed with ethyl acetate (3 × 50 mL). The combined organic phases were dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The resulting solid was recrystallized from ethanol to give the title compound as a colorless solid (96 mg, 58%). 1H NMR (300MHz, CDCl ₃ ) δ 1.46 (6H, s, 2 × CH ₃ ), 2.31 (3H, s, COCH3), 2.37 (3H, s, COCH3), 2.43 (3H, s, COCH3), 5.64 ( 1H, d, J 10.1 Hz, H2), 7.11 (1H, s, H9), 7.12 (1H, d, J 9.0 Hz, H6), 7.23 (1H, d, J 10.2 Hz, H1), 7.67 (1H, d, J 9.0 Hz, H5).

臭素(３５４mg、２.２１mmol)の乾燥ジクロロメタン(４mL)溶液を、冷却した(０℃)３滴の氷酢酸を含む８−ヒドロキシ−３,３−ジメチル−１,２−ジヒドロ−３Ｈ−ナフト[２,１−ｂ]ピラン−７,１０−ジオン(５０６mg、１.９６mmol)の乾燥ジクロロメタン(４mL)溶液に滴下した。冷却浴を除き、混合物を室温で２０分撹拌し、次いで真空で濃縮して、９−ブロモ−８−ヒドロキシ−３,３−ジメチル−１,２−ジヒドロ−３Ｈ−ナフト[２,１−ｂ]ピラン−７,１０−ジオンを明オレンジ色粉末として得た(６３５mg、９６％)：ｍ.ｐ. ２１３−２１６℃(実測値：Ｃ、５３.５；Ｈ、４.０。Ｃ_１５Ｈ_１３ＢｒＯ_４はＣ、５３.４；Ｈ、３.９％が必要)。ν_max 3316m, 1660s, 1642s, 1364s, 1286s, 1262s, 1174m, 1114s, 1048s cm^-1. ¹H NMR(300MHz, CDCl₃) δ 1.38(6H, s, 2×CH₃), 1.87(2H, t, J = 6.8 Hz, H2), 3.32(2H, t, J = 6.8 Hz, H1), 7.06(1H, d, J = 8.6 Hz, H5), 8.00(1H, d, J = 8.6 Hz, H6). m/z(ESI⁺)339(M[⁸¹Br]+H), 337(M[⁷⁹Br]+H)。 Example 5
Compound 5: 9-Bromo-8-hydroxy-3,3-dimethyl-3H-naphtho [2,1-b] pyran-7,10-dione

A solution of bromine (354 mg, 2.21 mmol) in dry dichloromethane (4 mL) was cooled (0 ° C.) to 8-hydroxy-3,3-dimethyl-1,2-dihydro-3H-naphtho containing 3 drops of glacial acetic acid [ 2,1-b] pyran-7,10-dione (506 mg, 1.96 mmol) was added dropwise to a dry dichloromethane (4 mL) solution. The cooling bath was removed and the mixture was stirred at room temperature for 20 minutes and then concentrated in vacuo to give 9-bromo-8-hydroxy-3,3-dimethyl-1,2-dihydro-3H-naphtho [2,1-b. Pyran-7,10-dione was obtained as a bright orange powder (635 mg, 96%): mp 213-216 ° C. (found: C, 53.5; H, 4.0. C ₁₅ H ₁₃ BrO ₄ requires C, 53.4; H, 3.9% required). _{ν max 3316m, 1660s, 1642s,} 1364s, 1286s, 1262s, 1174m, 1114s, 1048s cm -1. 1 H NMR (300MHz, CDCl 3) δ 1.38 (6H, s, 2 × CH 3), 1.87 (2H, t , J = 6.8 Hz, H2), 3.32 (2H, t, J = 6.8 Hz, H1), 7.06 (1H, d, J = 8.6 Hz, H5), 8.00 (1H, d, J = 8.6 Hz, H6) ^{. m / z (ESI +)} 339 (M [81 Br] + H), 337 (M [79 Br] + H).

水素化ナトリウム(４２mg、油中８０％分散、１.４０mmol)を乾燥ヘキサンで洗浄し、次いで上清を除去した。残存固体を窒素流下で乾燥させた。８−ヒドロキシ−３,３−ジメチル−３Ｈ−ナフト[２,１−ｂ]ピラン−７,１０−ジオン(３２７mg、１.２８mmol)のテトラヒドロフラン(５mL)溶液を添加し、得られた溶液を室温で１０分撹拌した。これを０℃に冷却し、臭素(２６５mg、１.６６mmol)の乾燥ジクロロメタン(３mL)溶液を添加した。混合物を室温に温め、２０分撹拌し、その後溶媒を真空で濃縮して、褐色残渣を得た。フラッシュクロマトグラフィー(２０−５０％酢酸エチル／ヘキサンと１％氷酢酸)により、９−ブロモ−８−ヒドロキシ−３,３−ジメチル−３Ｈ−ナフト[２,１−ｂ]ピラン−７,１０−ジオンをオレンジ色−褐色固体として得た(４３mg、１０％)。(実測値：Ｍ＋Ｈ、３３４.９９０９、３３６.９８８７。Ｃ_１５Ｈ_１２ＢｒＯ_４ ^＋は３３４.９９１９、３３６.９９００が必要)。¹H NMR(300MHz, CDCl₃) δ 1.49(6H, s, 2×CH₃), 5.99(1H, d, J = 10.2 Hz, H2), 7.05(1H, d, J = 8.4 Hz, H5), 7.75(1H, bs, OH), 7.82(1H, d, J = 10.2 Hz, H1), 8.01(1H, d, J = 8.4 Hz, H6). m/z(ESI⁺)337(M[⁸¹Br]+H), 335(M[⁷⁹Br]+H)。 Example 6
Compound 6: 9-Bromo-8-hydroxy-3,3-dimethyl-3H-naphtho [2,1-b] pyran-7,10-dione Compound 7: 2,9-dibromo-1,8-dihydroxy-3 , 3-Dimethyl-1,2-dihydro-3H-naphtho [2,1-b] pyran-7,10-dione

Sodium hydride (42 mg, 80% dispersion in oil, 1.40 mmol) was washed with dry hexane and then the supernatant was removed. The remaining solid was dried under a stream of nitrogen. A solution of 8-hydroxy-3,3-dimethyl-3H-naphtho [2,1-b] pyran-7,10-dione (327 mg, 1.28 mmol) in tetrahydrofuran (5 mL) was added and the resulting solution was allowed to cool to room temperature. For 10 minutes. This was cooled to 0 ° C. and a solution of bromine (265 mg, 1.66 mmol) in dry dichloromethane (3 mL) was added. The mixture was warmed to room temperature and stirred for 20 minutes, after which the solvent was concentrated in vacuo to give a brown residue. 9-Bromo-8-hydroxy-3,3-dimethyl-3H-naphtho [2,1-b] pyran-7,10- by flash chromatography (20-50% ethyl acetate / hexane and 1% glacial acetic acid). Dione was obtained as an orange-brown solid (43 mg, 10%). _{(Found: M + H, 334.9909,336.9887.C 15 H} 12 BrO 4 + is required 334.9919,336.9900). ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.49 (6H, s, 2 × CH ₃ ), 5.99 (1H, d, J = 10.2 Hz, H2), 7.05 (1H, d, J = 8.4 Hz, H5), 7.75 (1H, bs, OH), 7.82 (1H, d, J = 10.2 Hz, H1), 8.01 (1H, d, J = 8.4 Hz, H6) .m / z (ESI ⁺ ) 337 (M [ ⁸¹ Br ] + H), 335 (M [ ⁷⁹ Br] + H).

Also recovered from the flash chromatography column was crude compound 6 contaminated with pyran ring bromination product (compound 7). This was subjected to preparative HPLC (isocratic 60% A, 40% B), and 2,9-dibromo-1,8-dihydroxy-3,3-dimethyl-1,2-dihydro-3H-naphtho [2 , 1-b] pyran-7,10-dione (3 mg, 0.5%) was obtained, mp 202.5-205 ° (found: M + H, 412.9901, _{414.8981,416.8961. [C 15 H 13 Br} 2 O 5- H 2 O] + is required 412.9024,414.9005,416.8987). ν _max 3475w, 1664m, 1582m, 1370m, 1284s, 1262s, 1184m, 1122m, 1016m cm ^-1 δ ( ¹ H) (300MHz, CDCl ₃ ) 1.59, s, CH ₃ ; 1.66, s, CH ₃ ; 4.42, d , J 3.8 Hz, H2; 4.73, bs, OH; 5.50, d, J 3.8 Hz, H1; 7.22, d, J 8.7 Hz, H5; 8.13, d, J 8.7 Hz, H6.m / z (ES ⁺ , 70 V) 457 (M [ ⁸¹ Br] [ ⁸¹ Br] + Na, 13%), 455 (M [ ⁸¹ Br] [ ⁷⁹ Br] + Na, 31), 453 (M [ ⁷⁹ Br] [ ⁷⁹ Br] + Na, 22), 435 (M [ ⁸¹ Br] [ ⁸¹ Br] + H, 7), 433 (M [ ⁸¹ Br] [ ⁷⁹ Br] + H, 18), 431 (M [ ⁷⁹ Br] [ ⁷⁹ Br] + H, 12), 417 (M [ ⁸¹ Br] [ ⁸¹ Br] -H ₂ O + H, 16), 415 (M [ ⁸¹ Br] [ ⁷⁹ Br] -H ₂ O + H, 36), 413 ( M [ ⁷⁹ Br] [ ⁷⁹ Br] -H ₂ O + H, 20), 336 (M- [ ⁷⁹ Br + H ₂ O] + H, 100), 334 (M- [ ⁸¹ Br + H ₂ O] + H, 100).

ピリジン(０.４０mL、４.９５mmol)を、冷却し(０℃)、撹拌した９−ブロモ−８−ヒドロキシ−３,３−ジメチル−１,２−ジヒドロ−３Ｈ−ナフト[２,１−ｂ]ピラン−７,１０−ジオン(５５０mg、１.６３mmol)の乾燥ジクロロメタン(１０mL)溶液に窒素下添加した。４−メチルベンゼンスルホニルクロライド(３５０mg、１.８４mmol)の乾燥ジクロロメタン(８mL)溶液を滴下し、次いで撹拌を１.５時間、０℃で続けた。ジイソプロピルエチルアミン(２.５mL、１４.４mmol)を添加し、撹拌をさらに３時間続け、その時水性塩酸溶液(２.０Ｍ)を添加した。生成物をジクロロメタンおよび酢酸エチルで抽出し、合わせた抽出物を乾燥させ、濾過し、真空で濃縮して、褐色固体(７９８mg)を得た。これの酢酸エチル／ヘキサンでのトリチュレーションにより、黄色固体(６１０mg)を得て、それは^１Ｈ ＮＭＲ分光学によると、〜１０％の不飽和ピラン(化合物９)を含んだ。 Example 7
Compound 8: 9-Bromo-3,3-dimethyl-8- (4-methylbenzenesulfonyloxy) -1,2-dihydro-3H-naphtho [2,1-b] pyran-7,10-dione Compound 9: 9-Bromo-3,3-dimethyl-8- (4-methylbenzenesulfonyloxy) -3H-naphtho [2,1-b] pyran-7,10-dione

Pyridine (0.40 mL, 4.95 mmol) was cooled (0 ° C.) and stirred 9-bromo-8-hydroxy-3,3-dimethyl-1,2-dihydro-3H-naphtho [2,1-b. Pyran-7,10-dione (550 mg, 1.63 mmol) was added to a dry dichloromethane (10 mL) solution under nitrogen. A solution of 4-methylbenzenesulfonyl chloride (350 mg, 1.84 mmol) in dry dichloromethane (8 mL) was added dropwise and then stirring was continued for 1.5 hours at 0 ° C. Diisopropylethylamine (2.5 mL, 14.4 mmol) was added and stirring continued for another 3 hours, at which time aqueous hydrochloric acid solution (2.0 M) was added. The product was extracted with dichloromethane and ethyl acetate and the combined extracts were dried, filtered and concentrated in vacuo to give a brown solid (798 mg). Trituration of this with ethyl acetate / hexanes gave a yellow solid (610 mg) which, according to ¹ H NMR spectroscopy, contained -10% unsaturated pyran (compound 9).

The yellow solid sample (560 mg) was dissolved in ethyl acetate (30 mL) and platinum (IV) oxide (25 mg) was added. The resulting mixture was stirred under a hydrogen atmosphere for 8.5 hours, after which it was filtered through a pad of Celite® and the filtrate was stirred in air at room temperature overnight. Concentration in vacuo yielded a brown solid that contained ˜5% unsaturated pyran (compound 9) by ¹ H NMR spectroscopy. The hydrogenation was repeated on this solid overnight at room temperature under hydrogen using a solution of platinum (IV) oxide (69 mg) in ethyl acetate (35 mL). The mixture was filtered through a pad of Celite® and the filtrate was concentrated in vacuo to give a brown residue (580 mg). This was dissolved in acetonitrile (45 mL), and a solution of cerium ammonium nitrate (617 mg) in water (20 mL) was added dropwise. The resulting mixture was stirred at room temperature for 2 hours and water (35 mL) was added. The resulting precipitate was collected by filtration, washed with water, hexane, dried under vacuum at 40 ° C. for 2 hours, and 9-bromo-3,3-dimethyl-8- (4-methylbenzenesulfonyloxy) -1 , 2-dihydro-3H-naphtho [2,1-b] pyran-7,10-dione as a brown solid (300 mg, 41%): mp 109-115 ° C. (found: C, 53 _{.6; H, 4.1.C 22 H 19} BrO 6 S is C, 53.8; H, requires 3.9%). _{ν max 1672s, 1580m, 1370s,} 1302s, 1288s, 1222m, 1202m, 1174s, 994s, 718s cm -1. 1 H NMR (300MHz, CDCl 3) δ 1.37 (6H, s, 2 × CH 3), 1.87 (2H , t, J = 6.3 Hz, H2), 2.50 (3H, s, ArCH ₃ ), 3.27 (2H, t, J = 6.3 Hz, H1), 7.11 (1H, d, J = 8.4 Hz, H5), 7.41 (2H, d, J = 7.8 Hz, H3 '), 7.98 (3H, app d, J = ^8.1 Hz, 2 x H2' and H6). M / z (ESI ⁺ ) 493 (M [ ⁸¹ Br] + H), 491 (M [ 79 Br] + H).

ピリジン(０.１５mL、１.８５mmol)を、冷却し(０℃)、撹拌した９−ブロモ−８−ヒドロキシ−３,３−ジメチル−３Ｈ−ナフト[２,１−ｂ]ピラン−７,１０−ジオン(２３５mg、０.７０mmol)の乾燥ジクロロメタン(５mL)溶液に窒素下添加した。４−メチルベンゼンスルホニルクロライド(０.１４８mg、０.７８mmol)の乾燥ジクロロメタン(４mL)溶液を滴下し、撹拌を１時間、０℃で続けた。ジイソプロピルエチルアミン(１.０mL、５.７４mmol)を添加し、撹拌をさらに３時間続け、そのとき水性塩酸溶液(１.０Ｍ)を添加した。生成物をジクロロメタンおよび酢酸エチルで抽出し、合わせた抽出物を乾燥させ、濾過し、真空で濃縮して、褐色固体を得た。フラッシュクロマトグラフィー(酢酸エチル／ヘキサン３：７)により、９−ブロモ−３,３−ジメチル−８−(４−メチルベンゼンスルホニルオキシ)−３Ｈ−ナフト[２,１−ｂ]ピラン−７,１０−ジオンを褐色固体として得た(９７mg、２８％)：ｍ.ｐ. １６７−１６８℃(実測値：Ｍ＋Ｈ、４９０.９９８、４８８.９９９。Ｃ_２２Ｈ_１８ＢｒＯ_６Ｓ^＋は４９０.９９９、４８９.００１が必要)。ν_max 1672s, 1388m, 1288s, 1218m, 1172s, 1112m, 1018m, 1004m, 732s, 706m, 688cm^-1. ¹H NMR(300MHz, CDCl₃) δ 1.49(6H, s, 2×CH₃), 2.50(3H, s, ArCH₃), 6.00(1H, d, J = 10.5 Hz, H2), 7.10(1H, d, J = 8.4 Hz, H5), 7.41(2H, d, J = 8.1 Hz, H3’), 7.69(1H, d, J 10.5 = Hz, H1), 7.98(2H, d, J = 8.1 Hz, H2’), 8.00(1H, d, J = 8.4 Hz, H6). m/z(ESI⁺)491(M[⁸¹Br]+H), 490(M[⁷⁹Br]+H+1)。 Example 8
Compound 9: 9-bromo-3,3-dimethyl-8- (4-methylbenzenesulfonyloxy) -3H-naphtho [2,1-b] pyran-7,10-dione

Pyridine (0.15 mL, 1.85 mmol) was cooled (0 ° C.) and stirred 9-bromo-8-hydroxy-3,3-dimethyl-3H-naphtho [2,1-b] pyran-7,10. -To a solution of dione (235 mg, 0.70 mmol) in dry dichloromethane (5 mL) was added under nitrogen. A solution of 4-methylbenzenesulfonyl chloride (0.148 mg, 0.78 mmol) in dry dichloromethane (4 mL) was added dropwise and stirring was continued for 1 hour at 0 ° C. Diisopropylethylamine (1.0 mL, 5.74 mmol) was added and stirring was continued for another 3 hours, at which time aqueous hydrochloric acid solution (1.0 M) was added. The product was extracted with dichloromethane and ethyl acetate and the combined extracts were dried, filtered and concentrated in vacuo to give a brown solid. 9-Bromo-3,3-dimethyl-8- (4-methylbenzenesulfonyloxy) -3H-naphtho [2,1-b] pyran-7,10 by flash chromatography (ethyl acetate / hexane 3: 7). Dione was obtained as a brown solid (97 mg, 28%): mp 167-168 ° C. (found: M + H, 490.998, 488.999. C ₂₂ H ₁₈ BrO ₆ S ⁺ is 490.999, 489.001 is required). _{ν max 1672s, 1388m, 1288s,} 1218m, 1172s, 1112m, 1018m, 1004m, 732s, 706m, 688cm -1. 1 H NMR (300MHz, CDCl 3) δ 1.49 (6H, s, 2 × CH 3), 2.50 ( 3H, s, ArCH ₃ ), 6.00 (1H, d, J = 10.5 Hz, H2), 7.10 (1H, d, J = 8.4 Hz, H5), 7.41 (2H, d, J = 8.1 Hz, H3 ') , 7.69 (1H, d, J 10.5 = Hz, H1), 7.98 (2H, d, J = 8.1 Hz, H2 '), 8.00 (1H, d, J = 8.4 Hz, H6) .m / z (ESI ^{+ ) 491 (M [81 Br]} + H), 490 (M [79 Br] + H + 1).

２,７−ジヒドロキシナフタレン(３３.２ｇ、２０７mmol)、３−メチル−２−ブテナール(２０.０mL、２０７mmol)およびピリジン(１７.０mL)の混合物を、１１０℃で２０時間、窒素下加熱した。混合物を室温に冷却し、ジエチルエーテル(１５０mL)で希釈した。有機相を分離し、連続的に水性硫酸溶液(５％、１５０mL)、水(１５０mL)、水性炭酸水素ナトリウム溶液(５％、１５０mL)および水(１５０mL)で洗浄した。有機相を乾燥させ、濾過し、真空で濃縮して、３,３−ジメチル−３Ｈ−ナフト[２,１−ｂ]ピラン−９−オール淡黄褐色固体として得た(４３.１ｇ、９２％)：¹H NMR(300MHz, CDCl₃) δ 1.48(6H, s, 2×CH3), 4.99(1H, br s, OH), 5.67(1H, d, J = 10 Hz, H2), 6.84-6.93(3H, m, H1, H5, H8), 7.23(1H, d, J 2.3 = Hz, H10), 7.55(1H, d, J = 8.8 Hz, H6), 7.63(1H, d, J = 8.8 Hz, H7). m/z(FAB, 3NBA/MeOH)227(M+H, 68%)。 Example 9:
Compound 10: 8-Bromo-3,3-dimethyl-9- (4-methylbenzenesulfonyloxy) -3H-naphtho [2,1-b] pyran-7,10-dione Step 1
3,3-Dimethyl-3H-naphtho [2,1-b] pyran-9-ol

A mixture of 2,7-dihydroxynaphthalene (33.2 g, 207 mmol), 3-methyl-2-butenal (20.0 mL, 207 mmol) and pyridine (17.0 mL) was heated at 110 ° C. for 20 hours under nitrogen. The mixture was cooled to room temperature and diluted with diethyl ether (150 mL). The organic phase was separated and washed successively with aqueous sulfuric acid solution (5%, 150 mL), water (150 mL), aqueous sodium bicarbonate solution (5%, 150 mL) and water (150 mL). The organic phase was dried, filtered and concentrated in vacuo to give 3,3-dimethyl-3H-naphtho [2,1-b] pyran-9-ol as a light tan solid (43.1 g, 92% ): ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.48 (6H, s, 2 × CH3), 4.99 (1H, br s, OH), 5.67 (1H, d, J = 10 Hz, H2), 6.84-6.93 (3H, m, H1, H5, H8), 7.23 (1H, d, J 2.3 = Hz, H10), 7.55 (1H, d, J = 8.8 Hz, H6), 7.63 (1H, d, J = 8.8 Hz M / z (FAB, 3NBA / MeOH) 227 (M + H, 68%).

Ｎ,Ｎ’−ビス(サリチリデン)エチレンジアミノコバルト(II)水和物(４.５ｇ、１４mmol)を、撹拌している３,３−ジメチル−３Ｈ−ナフト[２,１−ｂ]ピラン−９−オール(４３.２ｇ、１９０mmol)のアセトニトリル(１.０Ｌ)溶液に添加し、酸素を混合物を通して、ＨＰＬＣで反応進行をモニタリングしながらバブリングした。さらななる量の触媒(４.１ｇ、３.４ｇおよび２.７ｇ)を各々１８.５時間、２４.５時間および４４.５時間に添加した。合計１１２時間後、ＨＰＬＣは出発ナフトールを示さず、混合物をシリカパッド(５×１２cm)を通して濾過し、パッドを酢酸エチルで、さらに赤色のものが溶出しなくなるまで洗浄した。濾液をを真空で濃縮し、得られた残渣を酢酸エチル／ヘキサンから再結晶して、３,３−ジメチル−３Ｈ−ナフト[２,１−ｂ]ピラン−９,１０−ジオンを栗色針状結晶として得た(１４.５ｇ、３２％)：ｍ.ｐ. １０９−１１０℃。¹H NMR(300MHz, CDCl₃) δ 1.46(6H, s, 2×CH3), 6.00(1H, d, J = 10.3 Hz, H2), 6.27(1H, d, J = 10 Hz, H8), 6.98(1H, d, J = 8.2 Hz, H5), 7.09(1H, d, J = 8.2 Hz, H6), 7.32(1H, d, J = 10.3 Hz, H1). m/z(FAB, 3NBA/MeOH)242(M+H+1, 52%)。 Process 2
3,3-Dimethyl-3H-naphtho [2,1-b] pyran-9,10-dione

N, N′-bis (salicylidene) ethylenediaminocobalt (II) hydrate (4.5 g, 14 mmol) was stirred with 3,3-dimethyl-3H-naphtho [2,1-b] pyran-9. -All (43.2 g, 190 mmol) in acetonitrile (1.0 L) was added and oxygen was bubbled through the mixture while monitoring the reaction progress by HPLC. Further quantities of catalyst (4.1 g, 3.4 g and 2.7 g) were added at 18.5 hours, 24.5 hours and 44.5 hours, respectively. After a total of 112 hours, HPLC showed no starting naphthol, the mixture was filtered through a silica pad (5 × 12 cm) and the pad was washed with ethyl acetate until no further red color eluted. The filtrate was concentrated in vacuo, and the resulting residue was recrystallized from ethyl acetate / hexane to give 3,3-dimethyl-3H-naphtho [2,1-b] pyran-9,10-dione as maroon needles. Obtained as crystals (14.5 g, 32%): mp 109-110 ° C. ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.46 (6H, s, 2 × CH3), 6.00 (1H, d, J = 10.3 Hz, H2), 6.27 (1H, d, J = 10 Hz, H8), 6.98 (1H, d, J = 8.2 Hz, H5), 7.09 (1H, d, J = 8.2 Hz, H6), 7.32 (1H, d, J = 10.3 Hz, H1) .m / z (FAB, 3NBA / MeOH ) 242 (M + H + 1, 52%).

３,３−ジメチル−３Ｈ−ナフト[２,１−ｂ]ピラン−９,１０−ジオン(１４.５ｇ、６０.３mmol)のトルエン(８５０mL)溶液を、亜ジチオン酸ナトリウム(８４ｇ)の水(８５０mL)溶液で２回洗浄した。得られた淡黄色溶液を、次いで酸素で飽和されたカリウムｔｅｒｔ−ブトキシド(３７.０ｇ、３３０mmol)のｔｅｒｔ−ブタノール(３７０mL)溶液に添加した。得られた混合物を環境温度で３０分撹拌した。その後水性塩酸溶液(１.０Ｍ、２５０mL)を添加した。有機相を分離し、飽和水性炭酸水素ナトリウム(３×２５０mL)で抽出した。合わせた水性抽出物を冷却し(氷／水浴)、濃塩酸で酸性化した。得られた沈殿を濾過により回収し、水(１.０Ｌ)で洗浄し、２時間、４０℃で真空下乾燥させて、９−ヒドロキシ−３,３−ジメチル−３Ｈ−ナフト[２,１−ｂ]ピラン−７,１０−ジオンをオレンジ色固体として得た(７.１０ｇ、４６％)：¹H NMR(300MHz, CDCl₃) δ 1.47(6H, s, 2×CH3), 5.99(1H, d, J = 10.4 Hz, H2), 6.25(1H, s, H8), 7.11(1H, dd, J = 8.4, 0.6 Hz, H5), 7.47(1H, s, OH), 7.76(dd, J = 10.4, 0.6 Hz, H1), 7.97(1H, d, J = 8.5 Hz, H6. m/z(FAB, 3NBA/MeOH)258(M+H+1, 50%), 257(M+H, 100)。 Process 3
9-hydroxy-3,3-dimethyl-3H-naphtho [2,1-b] pyran-7,10-dione

A solution of 3,3-dimethyl-3H-naphtho [2,1-b] pyran-9,10-dione (14.5 g, 60.3 mmol) in toluene (850 mL) was added sodium dithionite (84 g) in water (84 g). 850 mL) solution was washed twice. The resulting pale yellow solution was then added to a solution of potassium tert-butoxide (37.0 g, 330 mmol) saturated with oxygen in tert-butanol (370 mL). The resulting mixture was stirred at ambient temperature for 30 minutes. Aqueous hydrochloric acid solution (1.0 M, 250 mL) was then added. The organic phase was separated and extracted with saturated aqueous sodium bicarbonate (3 × 250 mL). The combined aqueous extracts were cooled (ice / water bath) and acidified with concentrated hydrochloric acid. The resulting precipitate was collected by filtration, washed with water (1.0 L), dried under vacuum at 40 ° C. for 2 hours, and 9-hydroxy-3,3-dimethyl-3H-naphtho [2,1- b] Pyran-7,10-dione was obtained as an orange solid (7.10 g, 46%): ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.47 (6H, s, 2 × CH 3), 5.99 (1H, d, J = 10.4 Hz, H2), 6.25 (1H, s, H8), 7.11 (1H, dd, J = 8.4, 0.6 Hz, H5), 7.47 (1H, s, OH), 7.76 (dd, J = 10.4, 0.6 Hz, H1), 7.97 (1H, d, J = 8.5 Hz, H6. M / z (FAB, 3NBA / MeOH) 258 (M + H + 1, 50%), 257 (M + H, 100 ).

水素化ナトリウム(１２mg、油中８０％分散、０.４０mmol)を９−ヒドロキシ−３,３−ジメチル−３Ｈ−ナフト[２,１−ｂ]ピラン−７,１０−ジオン(１００mg、０.３９mmol)のテトラヒドロフラン(２mL)溶液に添加し、混合物を室温で１０分撹拌した。懸濁液を０℃に冷却し、臭素(７０mg、０.４４mmol)のジクロロメタン(１mL)溶液を添加した。オレンジ色溶液を室温に温め、次いで２０分撹拌した。水性塩酸溶液(１.０Ｍ)を添加し、生成物をジクロロメタンおよび酢酸エチルで抽出した。合わせた有機相を乾燥させ、濾過し、真空で濃縮して褐色残渣(１２９mg、９９％)を得た。 Process 4
8-Bromo-3,3-dimethyl-9- (4-methylbenzenesulfonyloxy) -3H-naphtho [2,1-b] pyran-7,10-dione

Sodium hydride (12 mg, 80% dispersion in oil, 0.40 mmol) was added to 9-hydroxy-3,3-dimethyl-3H-naphtho [2,1-b] pyran-7,10-dione (100 mg, 0.39 mmol). ) In tetrahydrofuran (2 mL) and the mixture was stirred at room temperature for 10 minutes. The suspension was cooled to 0 ° C. and a solution of bromine (70 mg, 0.44 mmol) in dichloromethane (1 mL) was added. The orange solution was warmed to room temperature and then stirred for 20 minutes. Aqueous hydrochloric acid solution (1.0 M) was added and the product was extracted with dichloromethane and ethyl acetate. The combined organic phases were dried, filtered and concentrated in vacuo to give a brown residue (129 mg, 99%).

Pyridine (25 μL, 0.31 mmol) was cooled (0 ° C.) and stirred with the above 8-bromo-9-hydroxy-3,3-dimethyl-3H-naphtho [2,1-b] pyran-7,10- Dione (25 mg, 0.07 mmol) was added to a dry dichloromethane (1 mL) solution. A solution of 4-methylbenzenesulfonyl chloride (17 mg, 0.09 mmol) in dry dichloromethane (1 mL) was added dropwise and then stirring was continued for 1 hour at 0 ° C. Diisopropylethylamine (115 μL, 0.66 mmol) was added and stirring was continued for another 3 hours, at which time aqueous hydrochloric acid solution (1.0 M) was added and the mixture was extracted with dichloromethane and ethyl acetate. The combined organic phases were dried, filtered and concentrated in vacuo to give 8-bromo-3,3-dimethyl-9- (4-methylbenzenesulfonyloxy) -3H-naphtho [2,1-b] pyran- 7,10-dione was obtained as a brown solid (35 mg, 95%): mp 181.5-184 ° C. (found: C, 54.0; H, 3.5. C ₂₂ H ₁₇ BrO _6. S is C, 54.0; H, 3.5% required). _{ν max 1678m, 1382s, 1294s,} 1285s, 1183m, 1128m, 1062m, 986m, 806s, 682s, 564m cm -1. 1 H NMR (300MHz, CDCl 3) δ 1.49 (6H, s, 2 × CH 3), 2.50 (3H, s, ArCH ₃ ), 5.98 (1H, d, J = 10.5 Hz, H2), 7.09 (1H, d, J = 8.4 Hz, H5), 7.41 (2H, d, J = 8.3 Hz, H3 ' ), 7.70 (1H, d, J = 10.5 Hz, H1), 7.98 (2H, d, J = 8.3 Hz, H2 '), 8.04 (1H, d, J 8.4 Hz, H6) .m / z (ESI ⁺ ) 491 (M [ ⁸¹ Br] + H), (M [ ⁷⁹ Br] + H).

酸化白金(IV)(２５mg)を、８−ブロモ−３,３−ジメチル−９−(４−メチルベンゼンスルホニルオキシ)−３Ｈ−ナフト[２,１−ｂ]ピラン−７,１０−ジオン(１９９mg、０.４１mmol)の酢酸エチル(８mL)溶液に添加し、得られた懸濁液を水素雰囲気下、２８時間撹拌した。反応物をCelite(登録商標)のパッドを通して濾過し、濾過ケーキを酢酸エチルおよびジクロロメタンで洗浄した。濾液および洗液を合わせ、乾燥させ、濾過し、真空で濃縮して、褐色残渣を得て、それをアセトニトリル(２０mL)に溶解し、０℃に冷却した。硝酸セリウムアンモニウム(２００mg、０.３６mmol)の水(６mL)溶液を、次いで添加し、混合物を室温に温め、２時間撹拌し、その後それを水で希釈した。生成物をジクロロメタンで抽出し、抽出物を乾燥させ、濾過し、真空で濃縮して、８−ブロモ−３,３−ジメチル−９−(４−メチルベンゼンスルホニルオキシ)−１,２−ジヒドロ−３Ｈ−ナフト[２,１−ｂ]ピラン−７,１０−ジオンをオレンジ色−褐色固体として得た(１９３mg、９７％)：ｍ.ｐ. １６８−１６９.５℃(実測値：Ｃ、５３.６；Ｈ、３.８。Ｃ_２２Ｈ_１９ＢｒＯ_６ＳはＣ、５３.８；Ｈ、３.９％が必要)。ν_max 1680s, 1668m, 1620m, 1578w, 1566w, 1382s, 1290s cm^-1. ¹H NMR(300MHz, CDCl₃) δ 1.37(6H, s, 2×CH₃), 1.87(2H, t, J = 6.2 Hz, H2), 2.50(3H, s, ArCH₃), 3.27(2H, t, J = 6.2 Hz, H1), 7.10(1H, d, J 8.6 = Hz, H5), 7.41(2H, d, J = 7.7 Hz, H3'), 7.97(2H, d, J = 7.7 Hz, H2'), 8.03(1H, d, J = 8.6 Hz, H6). m/z(ESI⁺)(M[⁸¹Br]+H), 491(M[⁷⁹Br]+H)。 Example 10
Compound 11: 8-Bromo-3,3-dimethyl-9- (4-methylbenzenesulfonyloxy) -1,2-dihydro-3H-naphtho [2,1-b] pyran-7,10-dione

Platinum (IV) oxide (25 mg) was added to 8-bromo-3,3-dimethyl-9- (4-methylbenzenesulfonyloxy) -3H-naphtho [2,1-b] pyran-7,10-dione (199 mg). , 0.41 mmol) in ethyl acetate (8 mL) and the resulting suspension was stirred under a hydrogen atmosphere for 28 hours. The reaction was filtered through a pad of Celite® and the filter cake was washed with ethyl acetate and dichloromethane. The filtrate and washings were combined, dried, filtered, and concentrated in vacuo to give a brown residue that was dissolved in acetonitrile (20 mL) and cooled to 0 ° C. A solution of ceric ammonium nitrate (200 mg, 0.36 mmol) in water (6 mL) was then added and the mixture was allowed to warm to room temperature and stirred for 2 hours, after which it was diluted with water. The product is extracted with dichloromethane, the extract is dried, filtered and concentrated in vacuo to give 8-bromo-3,3-dimethyl-9- (4-methylbenzenesulfonyloxy) -1,2-dihydro- 3H-naphtho [2,1-b] pyran-7,10-dione was obtained as an orange-brown solid (193 mg, 97%): mp 168-169.5 ° C. (found: C, 53 _{.6; H, 3.8.C 22 H 19} BrO 6 S is C, 53.8; H, requires 3.9%). _{ν max 1680s, 1668m, 1620m,} 1578w, 1566w, 1382s, 1290s cm -1. 1 H NMR (300MHz, CDCl 3) δ 1.37 (6H, s, 2 × CH 3), 1.87 (2H, t, J = 6.2 Hz, H2), 2.50 (3H, s, ArCH ₃ ), 3.27 (2H, t, J = 6.2 Hz, H1), 7.10 (1H, d, J 8.6 = Hz, H5), 7.41 (2H, d, J = 7.7 Hz, H3 '), 7.97 (2H, d, J = 7.7 Hz, H2'), 8.03 (1H, d, J = 8.6 Hz, H6). M / z (ESI ⁺ ) (M [ ⁸¹ Br] + H), 491 (M [ 79 Br] + H).

９−ヒドロキシ−３,３−ジメチル−３Ｈ−ナフト[２,１−ｂ]ピラン−７,１０−ジオン(１.２０ｇ、４.６mmol)および酸化白金(IV)(１２５mg)の混合物の酢酸エチル(３０mL)溶液を水素下、３.５時間撹拌した。暗色混合物を撹拌して、空気に３０分曝し、その後Celite(登録商標)のプラグを通して濾過した。濾液の真空での濃縮により、黄色残渣を得て、それをフラッシュクロマトグラフィー(酢酸エチル／ヘキサン７：３と１％氷酢酸)、続く酢酸エチル／ヘキサンからの再結晶に付して、９−ヒドロキシ−３,３−ジメチル−１,２−ジヒドロ−３Ｈ−ナフト[２,１−ｂ]ピラン−７,１０−ジオンを黄色針状結晶として得た(９４８mg、７９％)：ｍ.ｐ. １５５℃(昇華)、＞１７７℃(分解)。ν_max 3328, 3148, 3108, 1656, 1628, 1566cm^-1. ¹H NMR(300MHz, CDCl₃) δ 1.38(6H, s, 2×CH3), 1.89(2H, t, J = 6.5 Hz, H2), 3.29(2H, t, J = 6.5 Hz, H3), 6.25(1H, s, H8), 7.13(1H, d, J = 8.5 Hz, H5), 7.47(1H, s, OH), 7.97(1H, d, J = 8.5 Hz, H6). m/z(FAB, 3NBA/MeOH)261(M+H+2, 11%), 260(M+H+1, 27%), 259(M+H, 51)。 Example 11
Compound 12: 8,9-dichloro-3,3-dimethyl-1,2-dihydro-3H-naphtho [2,1-b] pyran-7,10-dione Step 1
9-hydroxy-3,3-dimethyl-1,2-dihydro-3H-naphtho [2,1-b] pyran-7,10-dione

Ethyl acetate of a mixture of 9-hydroxy-3,3-dimethyl-3H-naphtho [2,1-b] pyran-7,10-dione (1.20 g, 4.6 mmol) and platinum (IV) oxide (125 mg) (30 mL) The solution was stirred under hydrogen for 3.5 hours. The dark mixture was stirred and exposed to air for 30 minutes before being filtered through a plug of Celite®. Concentration of the filtrate in vacuo gave a yellow residue which was subjected to flash chromatography (ethyl acetate / hexane 7: 3 and 1% glacial acetic acid) followed by recrystallization from ethyl acetate / hexane to give 9- Hydroxy-3,3-dimethyl-1,2-dihydro-3H-naphtho [2,1-b] pyran-7,10-dione was obtained as yellow needles (948 mg, 79%): m.p. 155 ° C. (sublimation),> 177 ° C. (decomposition). _{ν max 3328, 3148, 3108,} 1656, 1628, 1566cm -1. 1 H NMR (300MHz, CDCl 3) δ 1.38 (6H, s, 2 × CH3), 1.89 (2H, t, J = 6.5 Hz, H2) , 3.29 (2H, t, J = 6.5 Hz, H3), 6.25 (1H, s, H8), 7.13 (1H, d, J = 8.5 Hz, H5), 7.47 (1H, s, OH), 7.97 (1H , d, J = 8.5 Hz, H6) .m / z (FAB, 3NBA / MeOH) 261 (M + H + 2, 11%), 260 (M + H + 1, 27%), 259 (M + H , 51).

９−ヒドロキシ−３,３−ジメチル−１,２−ジヒドロ−３Ｈ−ナフト[２,１−ｂ]ピラン−７,１０−ジオン(１.１ｇ、４.３mmol)をジクロロメタン(２０mL)および塩化チオニル(１５mL)に溶解した。反応を室温で２４時間撹拌し、揮発物を真空で除去した。残渣を酢酸エチル(３０mL)に溶解し、水(３０mL)で洗浄し、乾燥させ、濾過し、真空で濃縮した。残渣をフラッシュクロマトグラフィー(酢酸エチル／ヘキサン５：９５)、続くエタノールからの再結晶により精製し、９−クロロ−３,３−ジメチル−１,２−ジヒドロ−３Ｈ−ナフト[２,１−ｂ]ピラン−７,１０−ジオンをオレンジ色針状結晶として得た(６３３mg、５３％)：ｍ.ｐ. １４０−２℃(実測値：Ｃ、６４.９；Ｈ,４.８。Ｃ_１５Ｈ_１３ＣｌＯ_３はＣ、６５.１；Ｈ、４.７％が必要)。λ_max(log ε)216, 268, 350 sh, 412 nm(4.35, 4.25, 3.23, 3.44). νmax 3700-3300s br, 3070w, 3000w, 1680s, 1660s, 1620m, 1590m, 1580s cm^-1. ¹H NMR(300MHz, CDCl₃) δ 1.38(6H, s, 2x CH3), 1.88(2H, t, J = 7.0 Hz, H2), 3.29(2H, t, J = 7.0 Hz, H1), 7.12(1H, d, J = 8.5 Hz, H5), 7.12(1H, s, H8), 7.95(1H, d, J = 8.5 Hz, H6). m/z(FAB, 3NBA)280(M[37Cl]+H+1, 14%), 279(M[37Cl]+H, 40), 278(M[35Cl]+H+1, 49), 277(M[35Cl]+H, 100), 276(44), 233(17)。 Process 2
9-chloro-3,3-dimethyl-1,2-dihydro-3H-naphtho [2,1-b] pyran-7,10-dione

9-hydroxy-3,3-dimethyl-1,2-dihydro-3H-naphtho [2,1-b] pyran-7,10-dione (1.1 g, 4.3 mmol) in dichloromethane (20 mL) and thionyl chloride (15 mL). The reaction was stirred at room temperature for 24 hours and the volatiles were removed in vacuo. The residue was dissolved in ethyl acetate (30 mL), washed with water (30 mL), dried, filtered and concentrated in vacuo. The residue was purified by flash chromatography (ethyl acetate / hexane 5:95) followed by recrystallization from ethanol to give 9-chloro-3,3-dimethyl-1,2-dihydro-3H-naphtho [2,1-b. Pyran-7,10-dione was obtained as orange needles (633 mg, 53%): mp 140-2 ° C. (found: C, 64.9; H, 4.8. C ₁₅ H ₁₃ ClO ₃ is C, 65.1; H, 4.7% required). _{λ max (log ε) 216,} 268, 350 sh, 412 nm (4.35, 4.25, 3.23, 3.44). νmax 3700-3300s br, 3070w, 3000w, 1680s, 1660s, 1620m, 1590m, 1580s cm -1. 1 H NMR (300MHz, CDCl ₃ ) δ 1.38 (6H, s, 2x CH3), 1.88 (2H, t, J = 7.0 Hz, H2), 3.29 (2H, t, J = 7.0 Hz, H1), 7.12 (1H, d, J = 8.5 Hz, H5), 7.12 (1H, s, H8), 7.95 (1H, d, J = 8.5 Hz, H6) .m / z (FAB, 3NBA) 280 (M [37Cl] + H + 1, 14%), 279 (M [37Cl] + H, 40), 278 (M [35Cl] + H + 1, 49), 277 (M [35Cl] + H, 100), 276 (44), 233 (17).

塩素ガスを、濃塩酸(５滴)を含む９−クロロ−３,３−ジメチル−１,２−ジヒドロ−３Ｈ−ナフト[２,１−ｂ]ピラン−７,１０−ジオン(６３３mg、２.３mmol)の氷酢酸(５０mL)溶液中、７０℃で５分バブリングした。反応物を５５分、７０℃撹拌し、室温に冷却し、真空で濃縮した。残渣をフラッシュクロマトグラフィー(トルエン／ヘキサン７：３)で精製し、８,９−ジクロロ−３,３−ジメチル−１,２−ジヒドロ−３Ｈ−ナフト[２,１−ｂ]ピラン−７,１０−ジオンをオレンジ色固体として得た(５０８mg、７１％)この物質のサンプルをエタノールから再結晶して、オレンジ色微結晶を得た：ｍ.ｐ. １５８−６０℃(実測値：Ｃ、５７.９；Ｈ、３.７。Ｃ_１５Ｈ_１２Ｃｌ_２Ｏ_３はＣ、５７.９；Ｈ、３.９％が必要)。λmax(log ε)220, 275, 290 sh, 350 sh, 412 nm(4.32, 4.19, 4,01, 3.29, 3.38). νmax 3700-3330m br, 3050m, 2950m, 1700s, 1680m, 1600m, 1580s cm^-1. ¹H NMR(300MHz, CDCl₃) δ 1.38(6H, s, 2×CH3), 1.88(2H, t, J = 7.0 Hz, H2), 3.27(2H, t, J = 7.0 Hz, H1), 7.12(1H, d, J = 8.5 Hz, H5), 8.04(1H, d, J = 8.5 Hz, H6). m/z(FAB, 3NBA)315(M[37Cl2]+H, 16%), 314(M[37Cl35Cl]+H+1, 32), 313(M[37Cl35Cl]+H, 74), 312(M[35Cl2]+H+1, 64), 311(M[35Cl2]+H, 100), 310(42), 309(16)。 Process 3
8,9-Dichloro-3,3-dimethyl-1,2-dihydro-3H-naphtho [2,1-b] pyran-7,10-dione

Chlorine gas was added to 9-chloro-3,3-dimethyl-1,2-dihydro-3H-naphtho [2,1-b] pyran-7,10-dione (633 mg, 2. 3 mmol) in a solution of glacial acetic acid (50 mL) at 70 ° C. for 5 minutes. The reaction was stirred for 55 minutes at 70 ° C., cooled to room temperature and concentrated in vacuo. The residue was purified by flash chromatography (toluene / hexane 7: 3) and 8,9-dichloro-3,3-dimethyl-1,2-dihydro-3H-naphtho [2,1-b] pyran-7,10. Dione was obtained as an orange solid (508 mg, 71%) A sample of this material was recrystallized from ethanol to give orange microcrystals: mp 158-60 ° C. (found: C, 57 _{.9; H, 3.7.C 15 H 12} Cl 2 O 3 is C, 57.9; H, requires 3.9%). . λmax (log ε) 220, 275, 290 sh, 350 sh, 412 nm (4.32, 4.19, 4,01, 3.29, 3.38) νmax 3700-3330m br, 3050m, 2950m, 1700s, 1680m, 1600m, 1580s cm - ^{1. 1 H NMR (300MHz,} CDCl 3) δ 1.38 (6H, s, 2 × CH3), 1.88 (2H, t, J = 7.0 Hz, H2), 3.27 (2H, t, J = 7.0 Hz, H1) , 7.12 (1H, d, J = 8.5 Hz, H5), 8.04 (1H, d, J = 8.5 Hz, H6) .m / z (FAB, 3NBA) 315 (M [37Cl2] + H, 16%), 314 (M [37Cl35Cl] + H + 1, 32), 313 (M [37Cl35Cl] + H, 74), 312 (M [35Cl2] + H + 1, 64), 311 (M [35Cl2] + H, 100 ), 310 (42), 309 (16).

水性水酸化ナトリウム(２.０Ｍ、３.３８mL、６.７５mmol)を、化合物１(１.７３ｇ、６.７５mmol)のメタノール(１０mL)中の撹拌しているオレンジ色懸濁液に滴下した。混合物は均質な赤色になった。３０分後、揮発物を真空で除去し、得られた赤色残渣を水(１５０mL)に溶解し、濾過し(空隙率４焼結物)、４８時間フリーズ・ドライした。化合物１３を赤色固体として得た(１.８０ｇ、９６％)：¹H NMR(300MHz, D⁶DMSO) δ 1.38(6H, s, 2×CH₃), 5.26(1H, s, H9), 5.82(1H, d, J = 10.2 Hz, H2), 6.83(1H, d, J = 8.4 Hz, H6), 7.64(1H, d, J = 8.4 Hz, H5), 8.14(1H, d, J = 10.2 Hz, H1). m/z(ES⁺, 30 V)257(M-Na+H, 100%)；ＨＰＬＣ １００％／４.７４分。
^１Ｈ ＮＭＲはまたＤ_２Ｏで行うことができ、化合物１３は水に１０mg／mLで十分溶解する Example 12
Compound 13: 3,3-dimethyl-7,10-dioxo-7,10-dihydro-3H-benzo [f] chromene-8-olate sodium or 3,3-dimethyl-7,8-dioxo-7,8 -Dihydro-3H-benzo [f] chromene-10-ola-delta sodium

Aqueous sodium hydroxide (2.0 M, 3.38 mL, 6.75 mmol) was added dropwise to a stirring orange suspension of compound 1 (1.73 g, 6.75 mmol) in methanol (10 mL). The mixture became a homogeneous red color. After 30 minutes, the volatiles were removed in vacuo, and the resulting red residue was dissolved in water (150 mL), filtered (sintered with a porosity of 4) and freeze-dried for 48 hours. Compound 13 was obtained as a red solid (1.80 g, 96%): ¹ H NMR (300 MHz, D ⁶ DMSO) δ 1.38 (6H, s, 2 × CH ₃ ), 5.26 (1H, s, H9), 5.82 (1H, d, J = 10.2 Hz, H2), 6.83 (1H, d, J = 8.4 Hz, H6), 7.64 (1H, d, J = 8.4 Hz, H5), 8.14 (1H, d, J = 10.2 Hz, H1). M / z (ES ⁺ , 30 V) 257 (M-Na + H, 100%); HPLC 100% / 4.74 min.
¹ H NMR can also be performed with D ₂ O, and compound 13 dissolves well in water at 10 mg / mL.

HPLC conditions
Performed on a Water 2690 Alliance System using a Waters C18 5 μm Symmetry Column (Part # WAT046980) and a flow rate of 0.7 mL / min. Measured at a column temperature of 30 ° C. and λ = 254 nM.
Buffer:
Buffer A: 100% water buffer B: 100%
Buffer C: 2% aqueous formic acid gradient (linear gradient curve “6”)

２,６−ジヒドロキシナフタレン(７１６mg、４.４７mmol)のトルエン(２００mL)中の撹拌している懸濁液を還流温度(油浴温度１６０℃)まで加熱した。１時間後、混合物は均質となり、ｐ−トルエンスルホン酸水和物(５４mg、０.４０mmol)、続いて２−フェニル−ブト−３−イン−２−オール(５８８mg、４.０２mmol)のトルエン(５０mL)溶液を、還流を維持しながら２０分にわたり添加した。４時間後のＴＬＣ(酢酸エチル／ヘキサン１：４)は、極微量の２,６−ジヒドロキシナフタレンを示した。さらに２時間後、混合物を室温に冷却し、水性水酸化ナトリウム溶液(１０％、４００mL)で洗浄した。有機相を酢酸エチル(１００mL)で希釈し、乾燥させ(Ｎａ_２ＳＯ_４)、濾過し、真空で濃縮して、黒色半固体(８０４mg)を得た。これを酢酸エチル／ヘキサン／ジクロロメタン／メタノール(１mL：４mL：１mL：１mL)に溶解し、フラッシュ(flask)クロマトグラフィーに付し、酢酸エチル／ヘキサン１：４で溶出した。３−メチル−３−フェニル−３Ｈ−ベンゾ[ｆ]クロメン−８−オールを褐色固体として得た(２３０mg、１８)：ＭＳ(ＥＳＩ⁻)ｍ／ｚ ２８７(Ｍ−１)。ＨＰＬＣ ９９.３％／７.５８分。 Example 13
Compound 14: 8-hydroxy-3-methyl-3-phenyl-3H-benzo [f] chromene-7,10-dione Step 1
3-Methyl-3-phenyl-3H-benzo [f] chromen-8-ol

A stirred suspension of 2,6-dihydroxynaphthalene (716 mg, 4.47 mmol) in toluene (200 mL) was heated to reflux temperature (oil bath temperature 160 ° C.). After 1 hour the mixture became homogeneous and p-toluenesulfonic acid hydrate (54 mg, 0.40 mmol) followed by 2-phenyl-but-3-in-2-ol (588 mg, 4.02 mmol) of toluene ( 50 mL) solution was added over 20 minutes while maintaining reflux. TLC after 4 hours (ethyl acetate / hexane 1: 4) showed traces of 2,6-dihydroxynaphthalene. After an additional 2 hours, the mixture was cooled to room temperature and washed with aqueous sodium hydroxide solution (10%, 400 mL). The organic phase was diluted with ethyl acetate (100 mL), dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to give a black semi-solid (804 mg). This was dissolved in ethyl acetate / hexane / dichloromethane / methanol (1 mL: 4 mL: 1 mL: 1 mL), subjected to flash chromatography and eluted with ethyl acetate / hexane 1: 4. 3-Methyl-3-phenyl-3H-benzo [f] chromen-8-ol was obtained as a brown solid (230 mg, 18): MS (ESI ⁻ ) m / z 287 (M−1). HPLC 99.3% / 7.58 min.

Ｃｏ(ＳＡＬＥＮ)_２(２３mg)を、アセトニトリル(３mL)中の３−メチル−３−フェニル−３Ｈ−ベンゾ[ｆ]クロメン−８−オール(２１７mg、０.７５mmol)の撹拌している均質黄色溶液に一度に添加した。酸素を、混合物を通してバブリングし、９０分後混合物をシリカプラグを通して濾過し、プラグを着色物が溶出しなくなるまで酢酸エチルで洗浄した。揮発物を真空で除去して、３−メチル−３−フェニル−３Ｈ−ベンゾ[ｆ]クロメン−７,８−ジオンをオレンジ色固体として得た(２２８mg、１００％)：¹H NMR(300MHz, CDCl₃) δ 1.86(3H, s, CH₃), 6.25(1H, d, J = 10.2 Hz, H2), 6.43(1H, d, J = 10.5 Hz, H9), 6.85(1H, d, J = 10.2 Hz, H1), 6.97(1H, d, J = 8.4 Hz, H6), 7.35(5H, m, ArH), 7.72(1H, d, J = 10.5 Hz, H9), 7.99(1H, d, J = 8.4 Hz, H5)MS(ESI⁺)m/z 303(M+1)。 Process 2
3-Methyl-3-phenyl-3H-benzo [f] chromene-7,8-dione

Co (SALEN) ₂ (23 mg) was stirred into a homogeneous yellow solution of 3-methyl-3-phenyl-3H-benzo [f] chromen-8-ol (217 mg, 0.75 mmol) in acetonitrile (3 mL). At once. Oxygen was bubbled through the mixture and after 90 minutes the mixture was filtered through a silica plug and the plug was washed with ethyl acetate until no color eluted. Volatiles were removed in vacuo to give 3-methyl-3-phenyl-3H-benzo [f] chromene-7,8-dione as an orange solid (228 mg, 100%): ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.86 (3H, s, CH ₃ ), 6.25 (1H, d, J = 10.2 Hz, H2), 6.43 (1H, d, J = 10.5 Hz, H9), 6.85 (1H, d, J = 10.2 Hz, H1), 6.97 (1H, d, J = 8.4 Hz, H6), 7.35 (5H, m, ArH), 7.72 (1H, d, J = 10.5 Hz, H9), 7.99 (1H, d, J = 8.4 Hz, H5) MS (ESI ⁺ ) m / z 303 (M + 1).

水性水酸化ナトリウム溶液(４Ｍ、５mL)を、エタノール(５mL)中の３−メチル−３−フェニル−３Ｈ−ベンゾ[ｆ]クロメン−７,８−ジオン(３２mg、０.１１mmol)のオレンジ色懸濁液に添加し、混合物は均質褐色となった。１時間後、混合物を冷却し(氷／水浴)、ｐＨ〜２.０まで酸性化した(５.０Ｍ水性塩酸溶液)。得られたオレンジ色懸濁液を２０分、冷却浴中で、次いで１０分、室温で撹拌した。沈殿を濾過により回収し、水(３０mL)で洗浄し、次いで一晩真空下で乾燥させて、８−ヒドロキシ−３−メチル−３−フェニル−３Ｈ−ベンゾ[ｆ]クロメン−７,１０−ジオンをオレンジ色固体として得た(２７mg、８２％)：¹H NMR(300MHz, CDCl₃) δ 1.84(3H, s, CH₃), 6.22(1H, s, H9), 6.26(1H, d, J = 10.5 Hz, H2), 7.14(1H, d, J = 8.7 Hz, H6), 7.20-7.45(5H, m, ArH), 8.05(2H, m, H5およびH1)。ＭＳ(ＥＳＩ⁻)ｍ／ｚ ３１７(Ｍ−１)。ＨＰＬＣ １００％／７.１２分。 Process 3
8-Hydroxy-3-methyl-3-phenyl-3H-benzo [f] chromene-7,10-dione

Aqueous sodium hydroxide solution (4M, 5 mL) was added to an orange suspension of 3-methyl-3-phenyl-3H-benzo [f] chromene-7,8-dione (32 mg, 0.11 mmol) in ethanol (5 mL). Upon addition to the turbid liquid, the mixture became a homogeneous brown color. After 1 hour, the mixture was cooled (ice / water bath) and acidified to pH ~ 2.0 (5.0 M aqueous hydrochloric acid solution). The resulting orange suspension was stirred for 20 minutes in a cooling bath and then for 10 minutes at room temperature. The precipitate was collected by filtration, washed with water (30 mL) and then dried under vacuum overnight to give 8-hydroxy-3-methyl-3-phenyl-3H-benzo [f] chromene-7,10-dione. Was obtained as an orange solid (27 mg, 82%): ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.84 (3H, s, CH ₃ ), 6.22 (1H, s, H9), 6.26 (1H, d, J = 10.5 Hz, H2), 7.14 (1H, d, J = 8.7 Hz, H6), 7.20-7.45 (5H, m, ArH), 8.05 (2H, m, H5 and H1). ^{MS (ESI -) m / z} 317 (M-1). HPLC 100% / 7.12 min.

トルエン(２００mL)中の２,６−ジヒドロキシナフタレン(５０２mg、３.１３mmol)の撹拌している懸濁液を、還流温度(油浴温度１３０℃)まで加熱した。１時間後、混合物は均質となり、ｐ−トルエンスルホン酸水和物(５４mg、０.２８mmol)、続いて１,１−ジフェニル−プロプ−２−イン−１−オール(５８８mg、２.８２mmol)のトルエン(４０mL)溶液を、還流を維持しながら３０分にわたり添加した。２日後、混合物を室温に冷却し、水性水酸化ナトリウム溶液(１０％、４００mL)で洗浄した。有機相を酢酸エチル(２００mL)で希釈し、乾燥させ(Ｎａ_２ＳＯ_４)、濾過し、真空で濃縮して、黒色固体を得た。これをクロロホルム／ヘキサン(５mL：５mL)に溶解し、フラッシュクロマトグラフィーに付して、クロロホルム／ヘキサン１：１、次いで非希釈(neat)クロロホルムで溶出した。３,３−ジフェニル−３Ｈ−ベンゾ[ｆ]クロメン−８−オールを褐色固体として得た(２１３mg、１９％)：ＭＳ(ＥＳＩ⁻)ｍ／ｚ ２８７(Ｍ−１)。ＨＰＬＣ ８０.３％／８.８９分。 Example 14
Compound 15: 8-hydroxy-3,3-diphenyl-3H-benzo [f] chromene-7,10-dione Step 1
3,3-diphenyl-3H-benzo [f] chromen-8-ol

A stirred suspension of 2,6-dihydroxynaphthalene (502 mg, 3.13 mmol) in toluene (200 mL) was heated to reflux temperature (oil bath temperature 130 ° C.). After 1 hour, the mixture became homogeneous and p-toluenesulfonic acid hydrate (54 mg, 0.28 mmol) followed by 1,1-diphenyl-prop-2-yn-1-ol (588 mg, 2.82 mmol). Toluene (40 mL) solution was added over 30 minutes while maintaining reflux. After 2 days, the mixture was cooled to room temperature and washed with aqueous sodium hydroxide solution (10%, 400 mL). The organic phase was diluted with ethyl acetate (200 mL), dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to give a black solid. This was dissolved in chloroform / hexane (5 mL: 5 mL), subjected to flash chromatography, eluting with chloroform / hexane 1: 1, then neat chloroform. 3,3-Diphenyl-3H-benzo [f] chromen-8-ol was obtained as a brown solid (213 mg, 19%): MS (ESI ⁻ ) m / z 287 (M−1). HPLC 80.3% / 8.89 min.

Ｃｏ(ＳＡＬＥＮ)_２(２２mg)を、アセトニトリル(３mL)中の３,３−ジフェニル−３Ｈ−ベンゾ[ｆ]クロメン−８−オール(２１３mg、０.６１mmol)の均質黄色溶液に一度に添加した。酸素を混合物を通してバブリングし、３時間後、混合物をシリカプラグを通して濾過し、プラグを着色物が溶出しなくなるまで酢酸エチルで洗浄した。揮発物を真空で除去して、褐色固体を得て、それをジクロロメタンに溶解し、該溶液をフラッシュクロマトグラフィーに付して、非希釈ジクロロメタンで溶出した。３,３−ジフェニル−３Ｈ−ベンゾ[ｆ]クロメン−７,８−ジオンをオレンジ色固体として得た(３２mg、１４％)。ＭＳ(ＥＳＩ^＋)ｍ／ｚ ３６５(Ｍ＋１)。 Process 2
3,3-diphenyl-3H-benzo [f] chromene-7,8-dione

Co (SALEN) ₂ (22 mg) was added in one portion to a homogeneous yellow solution of 3,3-diphenyl-3H-benzo [f] chromen-8-ol (213 mg, 0.61 mmol) in acetonitrile (3 mL). Oxygen was bubbled through the mixture and after 3 hours the mixture was filtered through a silica plug and the plug was washed with ethyl acetate until no color eluted. The volatiles were removed in vacuo to give a brown solid that was dissolved in dichloromethane and the solution was subjected to flash chromatography eluting with undiluted dichloromethane. 3,3-Diphenyl-3H-benzo [f] chromene-7,8-dione was obtained as an orange solid (32 mg, 14%). MS (ESI ^<+> ) m / z 365 (M + l).

水性水酸化ナトリウム溶液(４Ｍ、３mL)を、エタノール(３mL)中の３,３−ジフェニル−３Ｈ−ベンゾ[ｆ]クロメン−７,８−ジオン(２２mg、０.０６mmol)の撹拌しているオレンジ色懸濁液に添加し、混合物は均質な褐色となった。３０分後、混合物を冷却し(氷／水浴)、ｐＨ〜２.０まで酸性化した(５.０Ｍ水性塩酸溶液)。得られたオレンジ色懸濁液を２０分、冷却浴中、次いで１０分、室温で撹拌した。沈殿を濾過により回収し、水(１５mL)で洗浄した。この残渣を酢酸エチル(５mL)に溶解し、シリカプラグを通して濾過し、プラグを酢酸エチル(１５０mL)次いで酢酸エチル／酢酸(３０：１)で溶出して、３×１５mLフラクションを回収した。フラクション１および２を合わせ、真空で濃縮して、８−ヒドロキシ−３,３−ジフェニル−３Ｈ−ベンゾ[ｆ]クロメン−７,１０−ジオンをオレンジ色固体として得た(６mg、２４％)。¹H NMR(300 MHz, CDCl₃) δ 6.23(1H, s, H9), 6.45(1H, d, J = 10.4 Hz, H2), 7.20(1H, d, J = 8.4 Hz, H6), 7.40(10H, m, ArH), 8.00(1H, d, J = 8.4 Hz, H5), 8.16(1H, d, J = 10.4 Hz, H1). MS(ESI⁺)m/z 381(M+1)。ＨＰＬＣ ８６.５％／８.８１分。 Process 3
8-Hydroxy-3,3-diphenyl-3H-benzo [f] chromene-7,10-dione

Aqueous sodium hydroxide solution (4M, 3 mL) was added to a stirred orange of 3,3-diphenyl-3H-benzo [f] chromene-7,8-dione (22 mg, 0.06 mmol) in ethanol (3 mL). Upon addition to the color suspension, the mixture became a homogeneous brown color. After 30 minutes, the mixture was cooled (ice / water bath) and acidified to pH ~ 2.0 (5.0 M aqueous hydrochloric acid solution). The resulting orange suspension was stirred for 20 minutes in a cooling bath and then for 10 minutes at room temperature. The precipitate was collected by filtration and washed with water (15 mL). This residue was dissolved in ethyl acetate (5 mL), filtered through a silica plug, and the plug was eluted with ethyl acetate (150 mL) then ethyl acetate / acetic acid (30: 1) to collect a 3 × 15 mL fraction. Fractions 1 and 2 were combined and concentrated in vacuo to give 8-hydroxy-3,3-diphenyl-3H-benzo [f] chromene-7,10-dione as an orange solid (6 mg, 24%). ¹ H NMR (300 MHz, CDCl ₃ ) δ 6.23 (1H, s, H9), 6.45 (1H, d, J = 10.4 Hz, H2), 7.20 (1H, d, J = 8.4 Hz, H6), 7.40 ( 10H, m, ArH), 8.00 (1H, d, J = 8.4 Hz, H5), 8.16 (1H, d, J = 10.4 Hz, H1). MS (ESI ⁺ ) m / z 381 (M + 1). HPLC 86.5% / 8.81 min.

Antiviral activity Antiviral activity test was performed on 2.215 human hepatoma cells infected with hepatitis B according to the method of Korba and Gerin, Antiviral Research, 19, 55-70 (1992). Briefly, cells were seeded in 96 well plates and cell culture medium containing various concentrations of compounds was added. The medium was changed daily for 9 days and fresh compound-containing medium was added daily. On day 10, the viral DNA in the supernatant was measured and the reduction in the amount of virus in the supernatant was calculated and compared to cells incubated without drug. Six separate experiments were performed for each drug concentration. Effective concentrations of 50% and 90% inhibition of virus replication were determined from dose response curves. The results for several compounds of the invention are shown in Table 1.

  Antiviral activity was also tested on HepG2 hepatoma cells infected with HBV having mutations associated with lamivudine (3TC) resistance. Two cell lines containing the L180M mutation in HBV DNA polymerase and the double L180M / M204V mutation were used. Cells were seeded in 6-well plates and allowed to adhere overnight. The next day, the culture medium was replaced with either medium alone or medium containing the desired concentration of antiviral compound. The medium was changed to fresh medium with or without antiviral compounds on day 3. On day 5, supernatants and cell lysates were analyzed for HBV core protein concentration by non-denaturing Western blot using anti-HBV core antibody.

The results for several compounds are shown in Table 2, where a decrease of more than 50% of the measured concentration of virus core protein compared to the control at compound concentrations above 50 μmolar is shown as +. The 50% core reduction below 50 μmolar is shown as ++ and the 50% core reduction below 10 μmolar compound as ++.

Claims (12)

A method of treating or preventing hepatitis B virus in a subject, wherein the subject has an effective amount of formula (1):

[Where,
X is OH, OR ₉ or halo;
R and R ₁ are independently selected from H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, aryl, or they are attached United with a carbon atom to form a saturated or unsaturated C _3-6 carbocyclic ring;
R ₂ and R ₃ are independently selected from H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, or the carbon to which they are attached. Unite with the atom to form a double bond;
R ₄ and R ₅ are independently selected from H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, OH, OR ₉ , halo or NR ₁₀ R ₁₀ Or together with the carbon atoms to which they are attached form a double bond;
R ₆ and R ₇ are independently selected from H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, OH or OR ₉ ;
R ₈ is independently selected from H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, OH, OR ₉ or halo;
R ₉ is C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, aryl, C (═O) R ₁₁ or S (O) ₂ R ₁₂ , or OR ₉ is an amino acid residue;
Each R ₁₀ is independently selected from H and C _1-6 alkyl;
R ₁₁ is C _1-21 alkyl, C _2-21 alkenyl, C _2-21 alkynyl, C _3-6 cycloalkyl, C _3-6 cycloalkyl C _1-6 alkyl, aryl or aryl C _1-6 alkyl And R ₁₂ is C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl or aryl. ]
Or a pharmaceutically acceptable derivative, salt or prodrug thereof. The compound of formula (1) is represented by formula (2):

R and R ₁ are independently selected from H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, aryl, or they are attached United with a carbon atom to form a saturated or unsaturated C _3-6 carbocyclic ring;
R ₂ and R ₃ are independently selected from H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, or the carbon to which they are attached. Unite with the atom to form a double bond;
R ₄ and R ₅ are independently selected from H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, OH, OR ₉ , halo or NR ₁₀ R ₁₀ Or together with the carbon atoms to which they are attached form a double bond;
R ₉ is C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, aryl, C (═O) R ₁₁ or S (O) ₂ R ₁₂ , or OR ₉ is an amino acid residue;
Each R ₁₀ is independently selected from H and C _1-6 alkyl;
R ₁₁ is C _1-21 alkyl, C _2-21 alkenyl, C _2-21 alkynyl, C _3-6 cycloalkyl, C _3-6 cycloalkyl C _1-6 alkyl, aryl or aryl C _1-6 alkyl And R ₁₂ is C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl or aryl. ]
The method of Claim 1 which is a compound of these. The compound of formula (1) is:
8-hydroxy-3,3-dimethyl-3H-naphtho [2,1-b] pyran-7,10-dione,
8-hydroxy-3,3-dimethyl-1,2-dihydro-3H-naphtho [2,1-b] pyran-7,10-dione,
9-bromo-8-hydroxy-3,3-dimethyl-1,2-dihydro-3H-naphtho [2,1-b] pyran-7,10-dione,
9-bromo-8-hydroxy-3,3-dimethyl-3H-naphtho [2,1-b] pyran-7,10-dione,
9-bromo-3,3-dimethyl-8- (4-methylbenzenesulfonyloxy) -1,2-dihydro-3H-naphtho [2,1-b] pyran-7,10-dione,
9-bromo-3,3-dimethyl-8- (4-methylbenzenesulfonyloxy) -3H-naphtho [2,1-b] pyran-7,10-dione,
8-acetoxy-3,3-dimethyl-3H-naphtho [2,1-b] pyran-7,10-dione,
2,9-dibromo-1,8-dihydroxy-3,3-dimethyl-1,2-dihydro-3H-naphtho [2,1-b] pyran-7,10-dione,
8,9-dichloro-3,3-dimethyl-1,2-dihydro-3H-naphtho [2,1-b] pyran-7,10-dione,
7,8,10-triacetoxy-3,3-dimethyl-3H-naphtho [2,1-b] pyran,
9-bromo-8-hydroxy-3,3-dimethyl-3H-naphtho [2,1-b] pyran-7,10-dione,
9-bromo-8-hydroxy-3,3-dimethyl-3H-naphtho [2,1-b] pyran-7,10-dione,
9-bromo-3,3-dimethyl-8- (4-methylbenzenesulfonyloxy) -1,2-dihydro-3H-naphtho [2,1-b] pyran-7,10-dione,
9-bromo-3,3-dimethyl-8- (4-methylbenzenesulfonyloxy) -3H-naphtho [2,1-b] pyran-7,10-dione,
8-bromo-3,3-dimethyl-9- (4-methylbenzenesulfonyloxy) -3H-naphtho [2,1-b] pyran-7,10-dione,
8-bromo-3,3-dimethyl-9- (4-methylbenzenesulfonyloxy) -1,2-dihydro-3H-naphtho [2,1-b] pyran-7,10-dione,
8,9-dichloro-3,3-dimethyl-1,2-dihydro-3H-naphtho [2,1-b] pyran-7,10-dione,
3,3-dimethyl-7,10-dioxo-7,10-dihydro-3H-benzo [f] chromene-8-olate sodium;
3,3-dimethyl-7,8-dioxo-7,8-dihydro-3H-benzo [f] chromene-10-olate sodium;
8-hydroxy-3-methyl-3-phenyl-3H-benzo [f] chromene-7,10-dione, and 8-hydroxy-3,3-diphenyl-3H-benzo [f] chromene-7,10-dione The compound of claim 1 selected from the group consisting of: The compound of formula (1) is:
8-hydroxy-3,3-dimethyl-3H-naphtho [2,1-b] pyran-7,10-dione,
8-hydroxy-3,3-dimethyl-1,2-dihydro-3H-naphtho [2,1-b] pyran-7,10-dione)
The method of claim 1, wherein the method is selected from the group consisting of: The compound of formula (1) is of formula (3):

[Where,
X is OH, OR ₉ or halo;
R and R ₁ are independently selected from H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, aryl, or they are attached United with a carbon atom to form a saturated or unsaturated C _3-6 carbocyclic ring;
R ₂ and R ₃ are independently selected from H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, or the carbon to which they are attached. Unite with the atom to form a double bond;
R ₄ is selected from H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, halo or NR ₁₀ R ₁₀ , or R ₅ and R ₄ and R Combined with the bond between the carbon atoms to which ₅ is bonded to form a double bond;
R ₅ is selected from H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, OH, OR ₉ , halo or NR ₁₀ R ₁₀ , or R ₄ And together with the bond between the carbon atoms to which R ₄ and R ₅ are bonded, forms a double bond;
R ₆ and R ₇ are independently selected from H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, OH or OR ₉ ;
R ₈ is independently selected from H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, OH, OR ₉ or halo;
R ₉ is C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, aryl, C (═O) R ₁₁ or S (O) ₂ R ₁₂ , or OR ₉ is an amino acid residue;
Each R ₁₀ is independently selected from H and C _1-6 alkyl;
R ₁₁ is C _1-21 alkyl, C _2-21 alkenyl, C _2-21 alkynyl, C _3-6 cycloalkyl, C _3-6 cycloalkyl C _1-6 alkyl, aryl or aryl C _1-6 alkyl And R ₁₂ is C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl or aryl. ]
The method of Claim 1 which is a compound of these.   6. The method according to any one of claims 1 to 5, comprising administering a second therapeutic agent. Formula (1):

[Where,
X is OH, OR ₉ or halo;
R and R ₁ are independently selected from H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, aryl, or they are attached United with a carbon atom to form a saturated or unsaturated C _3-6 carbocyclic ring;
R ₂ and R ₃ are independently selected from H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, or the carbon to which they are attached. Unite with the atom to form a double bond;
R ₄ and R ₅ are independently selected from H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, OH, OR ₉ , halo or NR ₁₀ R ₁₀ Or together with the carbon atoms to which they are attached form a double bond;
R ₉ is C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, aryl, C (═O) R ₁₁ or S (O) ₂ R ₁₂ , or OR ₉ is an amino acid residue;
Each R ₁₀ is independently selected from H and C _1-6 alkyl;
R ₁₁ is C _1-21 alkyl, C _2-21 alkenyl, C _2-21 alkynyl, C _3-6 cycloalkyl, C _3-6 cycloalkyl C _1-6 alkyl, aryl or aryl C _1-6 alkyl And R ₁₂ is C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl or aryl;
However, when R and R ₁ are both methyl, and when R is OH or OR ₉ , R ₅ is not selected from OH, OR ₉ or NHR ₉ . ]
Or a pharmaceutically acceptable derivative, salt or prodrug thereof. The compound of formula (1) is represented by formula (2):

[Where,
R and R ₁ are independently selected from H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, aryl, or they are attached United with a carbon atom to form a saturated or unsaturated C _3-6 carbocyclic ring;
R ₂ and R ₃ are independently selected from H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, or the carbon to which they are attached. Unite with the atom to form a double bond;
R ₄ and R ₅ are independently selected from H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, OH, OR ₉ , halo or NR ₁₀ R ₁₀ Or together with the carbon atoms to which they are attached form a double bond;
R ₆ and R ₇ are independently selected from H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, OH or OR ₉ ;
R ₈ is independently selected from H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, OH, OR ₉ or halo;
R ₉ is C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, aryl, C (═O) R ₁₁ or S (O) ₂ R ₁₂ , or OR ₉ is an amino acid residue;
Each R ₁₀ is independently selected from H and C _1-6 alkyl;
R ₁₁ is C _1-21 alkyl, C _2-21 alkenyl, C _2-21 alkynyl, C _3-6 cycloalkyl, C _3-6 cycloalkyl C _1-6 alkyl, aryl or aryl C _1-6 alkyl And R ₁₂ is C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl or aryl. ]
The compound of Claim 7 which is a compound of these. The compound of formula (1) is:
8-hydroxy-3,3-dimethyl-3H-naphtho [2,1-b] pyran-7,10-dione,
8-hydroxy-3,3-dimethyl-1,2-dihydro-3H-naphtho [2,1-b] pyran-7,10-dione,
9-bromo-8-hydroxy-3,3-dimethyl-1,2-dihydro-3H-naphtho [2,1-b] pyran-7,10-dione,
9-bromo-8-hydroxy-3,3-dimethyl-3H-naphtho [2,1-b] pyran-7,10-dione,
9-bromo-3,3-dimethyl-8- (4-methylbenzenesulfonyloxy) -1,2-dihydro-3H-naphtho [2,1-b] pyran-7,10-dione,
9-bromo-3,3-dimethyl-8- (4-methylbenzenesulfonyloxy) -3H-naphtho [2,1-b] pyran-7,10-dione,
8-acetoxy-3,3-dimethyl-3H-naphtho [2,1-b] pyran-7,10-dione,
2,9-dibromo-1,8-dihydroxy-3,3-dimethyl-1,2-dihydro-3H-naphtho [2,1-b] pyran-7,10-dione,
8,9-dichloro-3,3-dimethyl-1,2-dihydro-3H-naphtho [2,1-b] pyran-7,10-dione,
7,8,10-triacetoxy-3,3-dimethyl-3H-naphtho [2,1-b] pyran,
9-bromo-8-hydroxy-3,3-dimethyl-3H-naphtho [2,1-b] pyran-7,10-dione,
9-bromo-8-hydroxy-3,3-dimethyl-3H-naphtho [2,1-b] pyran-7,10-dione,
9-bromo-3,3-dimethyl-8- (4-methylbenzenesulfonyloxy) -1,2-dihydro-3H-naphtho [2,1-b] pyran-7,10-dione,
9-bromo-3,3-dimethyl-8- (4-methylbenzenesulfonyloxy) -3H-naphtho [2,1-b] pyran-7,10-dione,
8-bromo-3,3-dimethyl-9- (4-methylbenzenesulfonyloxy) -3H-naphtho [2,1-b] pyran-7,10-dione,
8-bromo-3,3-dimethyl-9- (4-methylbenzenesulfonyloxy) -1,2-dihydro-3H-naphtho [2,1-b] pyran-7,10-dione,
8,9-dichloro-3,3-dimethyl-1,2-dihydro-3H-naphtho [2,1-b] pyran-7,10-dione,
3,3-dimethyl-7,10-dioxo-7,10-dihydro-3H-benzo [f] chromene-8-olate sodium;
3,3-dimethyl-7,8-dioxo-7,8-dihydro-3H-benzo [f] chromene-10-olate sodium;
8-hydroxy-3-methyl-3-phenyl-3H-benzo [f] chromene-7,10-dione and 8-hydroxy-3,3-diphenyl-3H-benzo [f] chromene-7,10-dione 8. The compound of claim 7, selected from the group consisting of: The compound of formula (1) is:
8-hydroxy-3,3-dimethyl-3H-naphtho [2,1-b] pyran-7,10-dione,
8-hydroxy-3,3-dimethyl-1,2-dihydro-3H-naphtho [2,1-b] pyran-7,10-dione)
8. The compound of claim 7, selected from the group consisting of: The compound of formula (1) is of formula (3):

[Where,
X is OH, OR ₉ or halo;
R and R ₁ are independently selected from H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, aryl, or they are attached United with a carbon atom to form a saturated or unsaturated C _3-6 carbocyclic ring;
R ₂ and R ₃ are independently selected from H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, or the carbon to which they are attached. Unite with the atom to form a double bond;
R ₄ is selected from H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, halo or NR ₁₀ R ₁₀ , or R ₅ and R ₄ and R Combined with the bond between the carbon atoms to which ₅ is bonded to form a double bond;
R ₅ is selected from H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, OH, OR ₉ , halo or NR ₁₀ R ₁₀ , or R ₄ And together with the bond between the carbon atoms to which R ₄ and R ₅ are bonded, forms a double bond;
R ₆ and R ₇ are independently selected from H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, OH or OR ₉ ;
R ₈ is independently selected from H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, OH, OR ₉ or halo;
R ₉ is C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, aryl, C (═O) R ₁₁ or S (O) ₂ R ₁₂ , or OR ₉ is an amino acid residue;
Each R ₁₀ is independently selected from H and C _1-6 alkyl;
R ₁₁ is C _1-21 alkyl, C _2-21 alkenyl, C _2-21 alkynyl, C _3-6 cycloalkyl, C _3-6 cycloalkyl C _1-6 alkyl, aryl or aryl C _1-6 alkyl And R ₁₂ is C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl or aryl. ]
The compound of Claim 1 which is a compound of these.   A pharmaceutical composition comprising a compound according to any of claims 7 to 11 and a pharmaceutically acceptable carrier, diluent or excipient.