KR20000011023A - Polyhydroxy phenol derivative and preventive and therapeutic agent of bone and cartilage disease - Google Patents

Abstract

PURPOSE: The invention relates to new polyhydroxy phenol derivatives, their salts and drug compositions containing them which are developed to be used in prevention and treatment of diseases accompanying alteration of cartilage and necrosis. The purpose of the invention is to provide improved treating methods and new effective preventive and therapeutic drugs. CONSTITUTION: The invention relates to new polyhydroxy phenol derivatives, their salts and drug compositions containing them which are developed to be used in prevention and treatment of diseases accompanying alteration of cartilage and necrosis such as bone-absorbent disease, deformative arthralgia, rheumatoid arthritis, etc.

Description

Polyhydroxyphenol derivative and the agent for preventing and treating bone and cartilage diseases containing the same

Japan is entering an aging society, which has never been before, and the increase of bone-absorbing bone diseases such as osteoporosis has become a big social problem. Bone-absorbing bone disease refers to a bone disease caused by abnormal hyperactivity of bone absorption, and various kinds of malignant hypercalcemia caused by myeloma or lymphoma, osteofetosis caused by local bone resorption, and old age and menopause. Osteoporosis caused by the cause. The increase in the number of people who lie only on the basis of the fracture of the elderly on the background of such bone-absorbing bone disease has led to a huge increase in medical expenses. Currently, vitamin D preparations, calcitonin preparations, or ibriflavone preparations are being used for the treatment. In addition, deformable arthrosis, femoral head necrosis, and rheumatoid arthritis are a group of diseases in which articular cartilage and cartilage lower bones degeneration and necrosis due to various causes such as mechanical stress, aging, and inflammation, resulting in cartilage and bone defects. These cartilage defects significantly affect the deterioration of quality of daily life by deformation or pain in the joints. Although treatment with hyaluronic acid, anti-inflammatory agents, analgesics, etc. is given to such a disease group, the agent which effectively prevents or repairs a cartilage defect is not found now.

Accordingly, an object of the present invention is to provide a new prophylactic and therapeutic drug that is aimed at improving the current treatment and furthermore effective.

The inventors have previously found that a strong bone resorption control agent is contained in hops and that the active body is an α acid and an isoα acid represented by the following formula (XIII) (see Japanese Patent Application Laid-Open No. 7-330594). ).

In said formula, R <_1> represents 2-methylpropyl group, 2-propyl group, or 2-butyl group.

However, it is pointed out that since the bone absorption inhibitory active material of the general formula (XIII) is a natural material, problems such as a method of obtaining such as a yield tend to depend on climatic conditions and the like are likely to occur. In view of the possibility that a strong active substance comparable to the bone absorption inhibitory active substance of Formula XIII may be obtained among these peripheral compounds, many compounds were synthesized by attempting structural conversion based on the active substance of Formula XIII. Activity was measured. As a result, a strong activity was found in the polyhydroxyphenol derivatives represented by the following formulas (I) to (XII) and the present invention was completed.

<Start of invention>

The present invention relates to an acylfluoroglucinol derivative which is a compound represented by the following formula (I) or a salt thereof.

In the above formula, R ₁ represents a branched or straight chain alkyl group having 1 to 15 carbon atoms, a substituted or unsubstituted benzyl group, or a substituted or unsubstituted aryl group,

R ₂ represents a hydrogen atom, a branched or straight chain alkyl group having 1 to 15 carbon atoms, a branched or straight chain alkenyl group having 2 to 15 carbon atoms, or a substituted or unsubstituted benzyl group,

R ₃ is a hydrogen atom, a branched or straight chain alkyl group having 1 to 15 carbon atoms, a branched or straight chain alkenyl group having 2 to 15 carbon atoms, a substituted or unsubstituted benzyl group, a hydroxyl group, a branched chain having 1 to 15 carbon atoms Or a straight alkoxy group, a branched or straight chain alkenyloxy group having 2 to 15 carbon atoms, or a substituted or unsubstituted benzyloxy group,

R ₄ represents a hydrogen atom, a branched or straight chain alkyl group having 1 to 15 carbon atoms, a branched or straight chain alkenyl group having 2 to 15 carbon atoms, a substituted or unsubstituted benzyl group, or a hydroxyl group,

R ₅ and R ₆ each independently represent a hydrogen atom, a branched or straight chain alkyl group having 1 to 15 carbon atoms, a branched or straight chain alkenyl group having 2 to 15 carbon atoms, or a substituted or unsubstituted benzyl group,

Provided that when R ₄ is a hydroxyl group, R ₅ and R ₆ are each a hydrogen atom and R ₁ is a 2-propyl group or a 2-butyl group, then R ₂ and R ₃ are hydrogen atoms or 3-methyl-2-butenyl groups And R ₄ is a hydroxyl group, R ₅ and R ₆ are each a hydrogen atom and R ₁ is a 2-methylpropyl group, R ₂ and R ₃ are each a hydrogen atom, 3-methyl-2-butenyl group or 3-methyl- The case of n-butyl group is excluded.

More specifically, the present invention relates to an acylfluoroglucinol derivative which is a compound represented by the following general formula (II) or a salt thereof, and an acylhydroxyhydroquinone derivative which is a compound represented by the following general formula (III) or a salt thereof.

In the formula, R ₁ represents a 2-methylpropyl group or a 2,6-dimethylheptyl group,

R ₂ and R ₃ each independently represent a hydrogen atom, 3-methyl-2-butenyl group, 3,7-dimethyl-2,6-octadienyl group or a substituted or unsubstituted benzyl group,

However, the case where R ₁ is a 2-methylpropyl group and R ₂ or R ₃ are each independently a hydrogen atom or a 3-methyl-2-butenyl group is excluded.

In the above formula, R ₁ represents a branched or straight chain alkyl group having 1 to 15 carbon atoms, a substituted or unsubstituted benzyl group, or a substituted or unsubstituted aryl group,

R ₂ and R ₄ each independently represent a hydrogen atom, a branched or straight chain alkenyl group having 1 to 15 carbon atoms, or a substituted or unsubstituted benzyl group,

R ₅ , R ₆ and R ₇ each independently represent a hydrogen atom, a branched or linear alkyl group or alkenyl group having 1 to 15 carbon atoms, or a substituted or unsubstituted benzyl group.

Moreover, this invention relates to the acylhydroxycyclohexadienone derivative which is a compound represented by following formula (IV), or its salt.

In the above formula, R ₁ represents a branched or straight chain alkyl group having 1 to 15 carbon atoms, a substituted or unsubstituted benzyl group, or a substituted or unsubstituted aryl group,

R ₂ represents a hydrogen atom, a branched or straight chain alkyl group having 1 to 15 carbon atoms, a branched or straight chain alkenyl group having 2 to 15 carbon atoms, or a substituted or unsubstituted benzyl group,

R ₃ represents a branched or straight chain alkyl group having 1 to 15 carbon atoms, a branched or straight chain alkenyl group having 2 to 15 carbon atoms, or a substituted or unsubstituted benzyl group,

R ₈ represents a hydroxyl group, a branched or straight chain alkyl group having 1 to 15 carbon atoms, a branched or straight chain alkenyl group having 2 to 15 carbon atoms, or a substituted or unsubstituted benzyl group,

Provided that when R ₁ is a methyl group and R ₈ is a hydroxyl group, R ₂ and R ₃ are each a 3-methyl-2-butenyl group, and when R ₁ is a 2-propyl group or 2-methylpropyl group, R ₂ And when two or three groups of R ₃ and R ₈ are each a 3-methyl-2-butenyl group and the remaining group is a hydrogen atom or a hydroxyl group.

More specifically, the present invention relates to an acyldihydroxycyclohexadienone derivative which is a compound represented by the following formula (V) or a salt thereof, and an acyltrihydroxycyclohexadienone derivative which is a compound represented by the following formula (VI) or a salt thereof will be.

In the formula, R ₁ represents a 2-methylpropyl group or a 2,6-dimethylheptyl group,

R ₂ represents a hydrogen atom, 3-methyl-2-butenyl group, 3,7-dimethyl-2,6-octadienyl group or a substituted or unsubstituted benzyl group,

R ₃ represents a 3-methyl-2-butenyl group, 3,7-dimethyl-2,6-octadienyl group or a substituted or unsubstituted benzyl group,

However, the case where R ₁ is a 2-methylpropyl group or 2-propyl group, R ₂ is a hydrogen atom or 3-methyl-2-butenyl group, and R ₃ is a 3-methyl-2-butenyl group is excluded.

In the above formula, R ₁ represents a 2-methylpropyl group or a substituted or unsubstituted aryl group,

R ₂ and R ₃ represent a 3-methyl-2-butenyl group or a substituted or unsubstituted benzyl group,

However, the case where R ₁ is a 2-methylpropyl group and R ₂ and R ₃ are a 3-methyl-2-butenyl group is excluded.

Moreover, this invention relates to the pharmaceutical composition which consists of one or more types of the compound represented by following formula (VII) or its pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier.

In the above formula, R ₁ represents a branched or straight chain alkyl group having 1 to 15 carbon atoms, a substituted or unsubstituted benzyl group, or a substituted or unsubstituted aryl group,

R ₂ represents a hydrogen atom, a branched or straight chain alkyl group having 1 to 15 carbon atoms, a branched or straight chain alkenyl group having 2 to 15 carbon atoms, or a substituted or unsubstituted benzyl group,

R ₃ is a hydrogen atom, a branched or straight chain alkyl group having 1 to 15 carbon atoms, a branched or straight chain alkenyl group having 2 to 15 carbon atoms, a substituted or unsubstituted benzyl group, a hydroxyl group, a branched chain having 1 to 15 carbon atoms Or a straight alkoxy group, a branched or straight chain alkenyloxy group having 2 to 15 carbon atoms, or a substituted or unsubstituted benzyloxy group,

R ₄ represents a hydrogen atom, a branched or straight chain alkyl group having 1 to 15 carbon atoms, a branched or straight chain alkenyl group having 2 to 15 carbon atoms, a substituted or unsubstituted benzyl group, or a hydroxyl group,

R ₅ and R ₆ each independently represent a hydrogen atom, a branched or straight chain alkyl group having 1 to 15 carbon atoms, a branched or straight chain alkenyl group having 2 to 15 carbon atoms, or a substituted or unsubstituted benzyl group.

Specifically, the present invention relates to an acylfluoroglucinol derivative or a pharmaceutically acceptable salt thereof, which is a compound represented by formula (VII), and an acylhydroxyhydroquinone derivative or a pharmaceutically acceptable salt thereof, which is represented by formula (VII). It relates to a pharmaceutical composition comprising at least one kind and a pharmaceutically acceptable carrier.

In the formula, R ₁ represents a 2-methylpropyl group or a 2,6-dimethylheptyl group,

R ₂ or R ₃ each independently represent a hydrogen atom, 3-methyl-2-butenyl group, 3,7-dimethyl-2,6-octadienyl group or a substituted or unsubstituted benzyl group.

In the above formula, R ₁ represents a branched or straight chain alkyl group having 1 to 15 carbon atoms, a substituted or unsubstituted benzyl group, or a substituted or unsubstituted aryl group,

R ₂ or R ₄ each independently represent a hydrogen atom, a branched or straight chain alkyl group or alkenyl group having 1 to 15 carbon atoms, or a substituted or unsubstituted benzyl group,

R ₅ , R ₆ or R ₇ each independently represent a hydrogen atom, a branched or straight chain alkyl or alkenyl group having 1 to 15 carbon atoms, or a substituted or unsubstituted benzyl group.

Moreover, this invention relates to the pharmaceutical composition which consists of at least 1 sort (s) of the acyldihydroxycyclohexadienone derivative which is a compound represented by following formula (VII), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

In the above formula, R ₁ represents a branched or straight chain alkyl group having 1 to 15 carbon atoms, a substituted or unsubstituted benzyl group, or a substituted or unsubstituted aryl group,

R ₂ represents a hydrogen atom, a branched or straight chain alkyl group having 1 to 15 carbon atoms, a branched or straight chain alkenyl group having 2 to 15 carbon atoms, or a substituted or unsubstituted benzyl group,

R ₃ represents a branched or straight chain alkyl group having 1 to 15 carbon atoms, a branched or straight chain alkenyl group having 2 to 15 carbon atoms, or a substituted or unsubstituted benzyl group,

R ₈ represents a hydroxyl group, a branched or straight chain alkyl group having 1 to 15 carbon atoms, a branched or straight chain alkenyl group having 2 to 15 carbon atoms, or a substituted or unsubstituted benzyl group.

More specifically, the present invention relates to an acyldihydroxycyclohexadienone derivative or a pharmaceutically acceptable salt thereof, and a acyltrihydroxycyclohexadienone compound represented by the following formula? A pharmaceutical composition comprising at least one derivative or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

In the formula, R ₁ represents a 2-methylpropyl group or a 2,6-dimethylheptyl group,

R ₂ represents a hydrogen atom, 3-methyl-2-butenyl group, 3,7-dimethyl-2,6-octadienyl group, or a substituted or unsubstituted benzyl group,

R ₃ represents a 3-methyl-2-butenyl group, a 3,7-dimethyl-2,6-octadienyl group, or a substituted or unsubstituted benzyl group.

In the above formula, R ₁ represents a 2-methylpropyl group or a substituted or unsubstituted aryl group,

R ₂ and R ₃ represent a 3-methyl-2-butenyl group or a substituted or unsubstituted benzyl group.

The present invention also relates to a method for preventing or treating bone and cartilage diseases, comprising administering at least one of the compounds represented by the above formulas (I), (IV), (V) or (V) in an amount useful for treating or preventing bone and cartilage diseases. It is about. In addition, the present invention relates to the use for the preparation of a pharmaceutical composition for the prevention or treatment of bone and cartilage diseases of one or more compounds of the compounds represented by the formula (I), (IV), (VII) or (VII).

The pharmaceutical composition of the present invention has a bone resorption inhibitory activity and is useful as an agent for preventing or treating diseases of bone or cartilage.

<Embodiment of the invention>

The alkyl group in the compound of the present invention is a branched or straight chain having 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, and includes methyl, n-propyl, isopropyl, n-butyl, sec-butyl, An isobutyl group, various pentyl groups, various hexyl groups, various heptyl groups, etc. can be illustrated. Specific examples of the alkyl group of the substituent R ₁ include a 2-propyl group, 2-methylpropyl group, 2,6-dimethylheptyl group, 2,6,10-trimethyl undecanyl group, and the like.

The alkenyl group is a branched or straight chain having 2 to 15 carbon atoms, preferably 2 to 10 carbon atoms, and having one or two or more unsaturated carbon-carbon bonds. For example, a vinyl group, an allyl group, butenyl group, a pentenyl group, an octadienyl group, etc. are mentioned, Preferably 3-methyl-2- butenyl group, 3,7- dimethyl- 2, 6- octadienyl group is mentioned. , 3,7,11-trimethyl-2,6,10-dodecatrienyl group and the like can be exemplified.

As an aryl group, in addition to having a 6-membered aromatic ring, heterocyclic aromatic substituents, such as a pyridine ring, a pyrimidine ring, a pyrrole ring, an imidazole ring, and a thiophene ring, are mentioned. Preferably, a phenyl group, a naphthyl group, etc. are mentioned. Especially preferably, a phenyl group can be illustrated.

The aryl group and benzyl group may be substituted with various substituents as long as they do not impair the physiological activity of the compound of the present invention. Examples of such substituents include halogen atoms such as chlorine, fluorine and bromine, hydroxyl groups, alkoxy groups having 1 to 15 carbon atoms, alkenyloxy groups having 2 to 15 carbon atoms, acyl groups such as acetyl groups and propionyl groups, and the like.

In addition, as a preferable specific example of the compound represented by general formula (I) of this invention,

(2,4,6-trihydroxyphenyl) (2,6-dimethylheptyl) ketone (compound number: 6),

{3- (3-methyl-2-butenyl) -2,4,6-trihydroxyphenyl} (2,6-dimethylheptyl) ketone (Compound No. 23),

{3,5-bisbenzyl-2,4,6-trihydroxyphenyl} (2-methylpropyl) ketone (Compound No. 34),

{3,5-bis (3,7-dimethyl-2,6-octadienyl) -2,4,6-trihydroxyphenyl} (2-methylpropyl) ketone (compound number: 19),

{3- (3-methyl-2-butenyl) -2,4,6-trihydroxyphenyl} (2-methylpropyl) ketone (Compound No. 26),

{3,6-bis (3-methyl-2-butenyl) -2,4,5-trihydroxyphenyl} (2-methylpropyl) ketone (Compound No. 25),

{6- (3-methyl-2-butenyl) -2,4,5-trihydroxyphenyl} (2-methylpropyl) ketone mono (3-methyl-2-butenyl) ether (compound number: 27 ),

(2,4,5-trihydroxyphenyl} (2-methylpropyl) ketone mono (3-methyl-2-butenyl) ether (compound number: 28),

{3,5-bis (3-methyl-2-butenyl) -2,4,6-trihydroxyphenyl} (phenylmethyl) ketone (compound number: 39),

{3- (3-methyl-2-butenyl) -2,4,6-trihydroxyphenyl} (phenylmethyl) ketone (Compound No. 42),

{3,5-bis (3,7-dimethyl-2,6-octadienyl) -2,4,6-trihydroxyphenyl} (phenylmethyl) ketone (compound number: 43),

{3- (3,7-dimethyl-2,6-octadienyl) -2,4,6-trihydroxyphenyl} (phenylmethyl) ketone (compound number: 46),

{2-hydroxy-6-methyl-4- (3-methyl-2-butenyloxy) phenyl} (2-methylpropyl) ketone (Compound No. 48),

{2,4-dihydroxy-6-methyl-3- (3-methyl-2-butenyl) phenyl} (2-methylpropyl) ketone (compound number: 49),

{4,6-dihydroxy-2-methyl-3- (3-methyl-2-butenyl) phenyl} (3-methylpropyl) ketone (Compound No.:50),

{3,5-bis (3-methyl-2-butenyl) -2-hydroxy-6-methyl-4- (3-methyl-2-butenyloxy) phenyl} (2-methylpropyl) ketone (compound Number: 51),

{2-hydroxy-4- (3-methyl-2-butenyloxy) phenyl} (2-methylpropyl) ketone (Compound No. 53),

{2,4-dihydroxy-3- (3-methyl-2-butenyl) phenyl} (2-methylpropyl) ketone (Compound No. 54),

{2,4-dihydroxy-5- (3-methyl-2-butenyl) phenyl} (2-methylpropyl) ketone (compound number: 55), etc. are mentioned.

Moreover, as a preferable thing of the compound represented by general formula (IV) of this invention,

2,2-bis (3,7-dimethyl-2,6-octadienyl) -3,5-dihydroxy-6- (3-methyl-1-oxobutyl) cyclohexa-3,5-dienone (Compound number: 21),

3,5-dihydroxy-6- (3-methyl-1-oxobutyl) -2,2,4-tris (3,7-dimethyl-2,6-octadienyl) cyclohexa-3,5- Dienone (compound number: 20),

2,2-bisbenzyl-3,5-dihydroxy-6- (3-methyl-1-oxobutyl) cyclohexa-3,5-dienone (Compound No. 35),

3,5-dihydroxy-6- (3-methyl-1-oxobutyl) -2,2,4-trisbenzylcyclohexa-3,5-dienone (Compound No. 36),

2,2-bis (3-methyl-2-butenyl) -3,5-dihydroxy-6- (3,7-dimethyl-1-oxooctyl) cyclohexa-3,5-dienone (compound number : 24),

3,5-dihydroxy-6- (3,7-dimethyl-1-oxooctyl) -2,2,4-tris (3-methyl-2-butenyl) cyclohexa-3,5-dienone ( Compound number: 22),

2,4-bis (3-methyl-1-butenyl) -6- (benzoyl) -2,3,5-trihydroxycyclohexa-3,5-dienone (Compound No. 32),

2,4-dimethyl-6- (3-methyl-1-oxobutyl) -2,3,5-trihydroxycyclohexa-3,5-dienone (Compound No. 31),

2,4-bisbenzyl-6- (3-methyl-1-oxobutyl) -2,3,5-trihydroxycyclohexa-3,5-dienone (Compound No. 33),

3,5-dihydroxy-6- (phenylacetyl) -2,2,4-tris (3-methyl-2-butenyl) cyclohexa-3,5-dienone (Compound No. 40),

3,5-dihydroxy-6- (phenylacetyl) -2,2-bis (3-methyl-2-butenyl) cyclohexa-3,5-dienone (Compound No. 41),

3,5-Dihydroxy-6- (phenylacetyl) -2,2,4-tris (3,7-dimethyl-2,6-octadienyl) cyclohexa-3,5-dienone (Compound No .: 44),

3,5-dihydroxy-6- (phenylacetyl) 2,2-bis (3,7-dimethyl-2,6-octadienyl) cyclohexa-3,5-dienone (Compound No. 45), etc. Can be mentioned.

The compound of the present invention may form a salt with an inorganic base such as an alkali metal oxide or an organic base such as an organic amine. Moreover, you may form solvate with solvents, such as water.

Meanwhile, among the compounds represented by Formula (I), R ₁ is a 2-propyl group, 2-methylpropyl group, or 2-butyl group, and R ₂ and R ₃ are 3-methyl-2-butenyl groups, and the compound represented by Formula XIII is It is a substance known to be contained in hops as a precursor of alpha acid represented by the bone resorption active substance of (refer to R. Stevens, Chemical Reviews, 1967, 19.).

In addition, of the compounds represented by the above formula (I) or (IV), R ₁ is 2-propyl group, 2-methylpropyl group or 2-butyl group, and R ₂ and R ₃ are 3-methyl-2-butenyl group or 3- Compounds that are methylbutyl groups were measured for antimicrobial activity as hop-related compounds (see S. Mizobuchi and Y. Sato, Agric. Biol. Chem., 49, 399 (1985)).

However, the formulas I to? It is not yet known that a series of compounds represented by any of them exhibit potent bone resorption inhibitory activity and were first discovered by the present inventors.

Therefore, the present invention is the above formula (Ⅶ)? It relates to a pharmaceutical composition containing, as an active ingredient, at least one kind of the compound represented by any of the above or a pharmaceutically acceptable salt thereof. The pharmaceutical composition of the present invention may contain various pharmaceutically acceptable carriers.

The pharmaceutical composition of the present invention has a bone resorption inhibitory activity and is useful as an agent for preventing or treating diseases of bone or cartilage.

The bone and cartilage diseases of the present invention include bone absorptive bone diseases such as malignant hypercalcemia, osteopenia or osteoporosis, and degenerative arthrosis occurring in the knees, shoulders, hips, etc., cartilage degeneration and necrosis such as femoral head necrosis and joint rheumatism. Disease and the like.

The polyhydroxyphenol derivatives represented by the formulas (I) to (VI) of the present invention and the compounds which are the pharmaceutical compositions of the present invention represented by the formulas (VII) to (?) Can be prepared by the route of the reaction scheme shown in Table 1 below.

The manufacturing method shown in Table 1 is demonstrated concretely.

<1st process>

This process is the acylation under Friedel-Crafts reaction conditions for polyhydroxybenzyl. The polyhydroxybenzenes (a) and (b) used in this process can be easily obtained as commercially available products, and (c) can be prepared from piclinic acid by the method such as Ohara (Onotera Junichi, Ohara Hay). Separately, see Japanese Chemical Society, 1973, 1808). As the acylating agent (RCOX) used in this step, acetyl chloride, acetyl bromide, acetyl anhydride, butyryl chloride, butyryl bromide, butyryl anhydride, isobutyryl chloride, isobutyryl bromide, iso anhydride Butyryl, 2-butyryl chloride, 2-butyryl bromide, 2-butyryl anhydride, isovaleryl chloride, isovaleryl bromide, anhydrous isovaleryl, 3,7-dimethyloctanoyl chloride, 3,7-dimethyloctanoyl bromide, anhydrous 3,7-dimethyloctanoyl, phenyl acetyl chloride, phenyl acetyl bromide, anhydrous phenyl acetyl, benzoyl chloride, benzoyl bromide, benzoyl anhydride, etc. are mentioned. Acid catalysts used in the reaction include Friedel-Crafts such as aluminum bromide, aluminum chloride, antimony chloride, iron chloride, titanium chloride, tin chloride, bismuth chloride, zinc chloride, boron fluoride, hydrogen fluoride, sulfuric acid, and polyphosphoric acid. Although reagents generally used for reaction are mentioned, aluminum chloride is used suitably. The acid catalyst is used in 1 to 3 molar equivalents. The reaction takes place in a solvent. Examples of the solvent used may include nitromethane, nitrobenzene, carbon disulfide, dichloromethane, carbon tetrachloride, 1,2-dichloroethane, and the like. Nitrobenzene or a mixture of nitrobenzene and carbon disulfide is suitable in view of solubility. The reaction temperature is at 0 ° C to 150 ° C, but proceeds sufficiently at room temperature. Compounds (D), (E) and (F) prepared in the above steps are used in the following steps.

<Second process>

This step introduces an alkyl group or an alkenyl group into acylated polyhydroxybenzenes (D), (E) or (F). The reaction conditions in this step can be carried out under basic conditions or under acidic conditions.

(Iii) reaction under basic conditions

Under these conditions, bases are reacted with acylated polyhydroxybenzenes (D), (E) or (F) to form salts, followed by alkylating or alkenylating agents. Examples of the base used may include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal alkoxides such as sodium methoxy, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium t-butoxide and potassium t-butoxide. Alkali metal hydrides, such as sodium hydride, potassium hydride, and lithium hydride, alkyllithium compounds, such as methyllithium, n-butyllithium, and phenyl lithium, or an aryl lithium compound are used. The reaction takes place in a solvent, water or alcohols such as methanol, ethanol, t-butanol, ethers such as ethyl ether, isopropyl ether, tetrahydrofuran, 1,4-dioxane, dimethyl sulfoxide, N, N Aromatics, such as -dimethylformamide, N-methylpyrrolidone, etc., or benzene, toluene, are mentioned. Such a solvent is selected according to the nature of the base used. Preferred alkylating agents include methyl iodide, bromoethane, 1- or 2-bromopropane, 1- or 2-chloropropane, 1- or 2-bromobutane, 2-methyl-1-bromopropane, 1-bro Morphane, 1-chloropentane, 3-methyl-1-bromobutane, 1-bromooctane, 1-chlorooctane, benzylbromide, benzyl chloride, bromomethylthiophene and the like. As the alkenylating agent, allyl bromide, allyl chloride, 1-bromo-2-butene, 1-chloro-2-butene, 3-methyl-1-bromo-2-butene, 3-methyl-1-chloro- 2-butene, 3,7-dimethyl-1-bromo-2,6-octadiene, 3,7-dimethyl-1-chloro-2,6-octadiene, etc. are mentioned.

(Ii) reaction under acidic conditions

Under these conditions, it can be carried out under the general Friedel-Crafts conditions used in the first step, preferably ethyl ether, 1,4-dioxane or boron fluoride ether (BF3-Et2) or It is preferable to use methylene chloride or the like (see E. Collins and PVRShannon, J. Chem. Soc., Perkin Trans. 1, 1973, 419.). In this case, as the alkylating agent, saturated alcohols such as methanol, ethanol, butanol, 3-methylbutanol, pentanol, and decanol or allyl alcohol, 2-butenol, 3-methyl-2-butenol, 3,7-dimethyl-2 And allyl alcohols such as 6-octadienol.

As described above, in the compound (d), the acylfluoroglucinol derivative and acylhydroxycyclohexadienone derivative of the present invention are obtained by the present step, and the acylhydroxyhydroquinone derivative of the present invention, and further, the compound (f) in the compound (e). In the acyldihydroxycyclohexadienone derivative of the present invention is obtained.

<Third process>

The present invention is to introduce the alkyl derivative (I-4) by reducing the double bond of the allyl derivative (I-3) prepared in the second step. In this step, a general double bond reduction method is applied, and a method by catalytic hydrogenation is suitable. Platinum oxide, palladium-carbon, rhodium-carbon, etc. are used as a catalyst. As the solvent, alcohols such as methanol and ethanol, esters such as ethyl acetate and butyl acetate, and the like are suitable. Although reaction temperature can be performed at 0 degreeC-100 degreeC, operation at room temperature is suitable.

Bone uptake inhibition activity of the polyhydroxyphenol derivatives prepared as described above was assayed by a pit formation assay method. As a result, it showed an excellent bone absorption inhibition rate at a concentration of 1 × 10 ^-5 M (see Example 26, Table 2 and Table 2).

The dosage at the time of clinical administration is also attributable to the administration method, the condition of the disease, the condition of the patient, and the like, but is usually in the range of 0.1 g to 2 g (about 1.5 mg to 30 mg / kg / day) per adult as a compound of the present invention. to be. As the method of administration, intravenous, intramuscular, oral, or rectal administration is possible, and in the case of intravenous administration, in addition to the usual intravenous injection, instillation of infusion of vein is possible. Formulations containing a compound of the present invention are prepared by conventional methods using conventional excipients, additives.

As an injectable preparation, it can be set as an injectable powder preparation, for example. In this case, one or more suitable water-soluble excipients such as mannitol, sucrose, lactose, maltose, glucose, and fructose may be added, dissolved in water, dispensed into vials or ampoules, lyophilized and sealed to form a formulation. You can As an oral preparation, it can be made into an enteric preparation other than the usual tablet, capsule, granule, fine granule, and powder.

In the case of an enteric preparation, mannitol, sucrose, lactose, maltose, starch, lubricants such as silicic anhydride and calcium phosphate, binders such as carboxymethyl cellulose, methyl cellulose, gelatin, gum arabic, and disintegrating agents such as calcium carboxymethyl cellulose Additives are added as necessary to make tablets, granules, fines, etc., and then cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcelluloseacetylsuccinate, polyvinyl alcohol phthalate, styrene, maleic anhydride copolymer, styrene · At least one of an enteric base such as maleic acid copolymer, methyl methacrylate and methacrylic acid copolymer, methyl methacrylate and methacrylic acid copolymer and, if necessary, add a colorant such as titanium oxide and coat it to make a formulation. In addition to the enteric granules prepared herein The granules can be filled into capsules to make capsules. In addition, it is also possible to coat the capsule prepared by a conventional method with the above-mentioned enteric base to make enteric, or to make an enteric capsule using the enteric base alone or a capsule made by mixing gelatin therein.

For suppositories, homogeneous mixtures of lipophilic bases such as semi-synthetic bases mixed with fatty acid monoglycerides and fatty acid diglycerides in various proportions with cacao oil or fatty acid triglycerides, and warmed and dissolved hydrophilic bases such as polyethylene glycol or glycerogelatin are added. Can be mixed into molds and molded into suppositories.

The polyhydroxyphenol derivative provided by the present invention has a potent bone absorption inhibitory activity and is useful as an agent for preventing and treating bone and cartilage diseases.

The present invention relates to a bone absorptive bone disease such as malignant hypercalcemia, osteopathy or osteoporosis and cartilage degeneration and necrosis such as osteoarthritis, femoral head necrosis, and rheumatoid arthritis occurring in the knee, shoulder, and hip joints. The present invention relates to novel polyhydroxyphenol derivatives, salts thereof, and pharmaceutical compositions containing the same, which have been developed for use in the prophylaxis and treatment thereof.

Hereinafter, the present invention will be described in more detail by reference examples, examples and test examples, but the present invention is not limited to these examples.

Reference Example 1

Synthesis of (2-propyl) (2,4,6-trihydroxyphenyl) ketone (4)

12.61 g (100.0 mmol) of 1,3,5-trihydroxybenzene (1) was suspended in a mixture of 35 ml of nitrobenzene and 45 ml of carbon disulfide in a vessel with a calcium chloride tube and stirred. To this was added 40.0 g (300 mmol, 3.00 eq) of granular aluminum chloride in small portions at room temperature. After stirring for 1 hour, a solution of 10.66 g (100.0 mmol, 1.000 equiv) of nitrobenzene (10.0 mL) in isobutyryl chloride was slowly added dropwise. After about 5 hours, the reaction solution was poured into cold 2M hydrochloric acid (500 mL) to decompose the aluminum salt and extract with ether. The organic layer was distilled off ether under reduced pressure after washing with water. A large amount of water was added to the residue and distilled off under reduced pressure to remove nitrobenzene by steam distillation. The residue was taken up in ether, washed with saturated brine, dried over sodium sulfate and the solvent was distilled off under reduced pressure to give 21.7 g of crude product. Recrystallization with petroleum ether-methylene chloride (1: 1) afforded 17.1 g (yield 87.2%) of the target compound (4) as light yellow powder crystals.

1 HNMR δ (TMS): 1.10 (6H, d, J = 7.0 Hz), 3.92 (1H, sept, J = 7.0 Hz), 5.83 (2H, s), 9.93 (1H, bs), 12.1 (2H, bs) .

Reference Example 2

Synthesis of (2-methylpropyl) (2,4,6-trihydroxyphenyl) ketone (5)

The reaction conditions shown in Reference Example 1 were used as they were, except that 12.06 g (100.0 mmol) of isovaleryl chloride was used. The obtained crude product was recrystallized with petroleum ether to obtain 16.7 g (yield 76.9%) of the target product (5) as light colored fine powder crystals.

1 HNMR δ (TMS): 0.95 (6H, d, J = 6.6 Hz), 2.21 (1H, sept, J = 6.6), 2.90 (2H, d, J = 6.6 Hz), 5.86 (2H, s), 9.86 ( 1H, s), 12.01 (2H, s).

<Example 1>

Synthesis of (2,6-dimethylpropyl) (2,4,6-trihydroxyphenyl) ketone (6)

A mixture of 27 ml of nitrobenzene and 23 ml of carbon disulfide was added to 6.613 g (52.4 mmol) of 1,3,5-trihydroxybenzene (1) under a nitrogen atmosphere. 21 g (157.2 mmol, 3 equivalents) of granular aluminum chloride was added thereto under ice cooling, followed by stirring for 2 hours. 10.87 g (57.0 mmol, 1.09 equiv) of nitrobenzene (8 mL) solution of 3,7-dimethyl-octanoyl chloride was added dropwise thereto, and stirring was continued at room temperature for 21 hours. 5 ml of concentrated hydrochloric acid was added to 200 ml of ice, and the reaction mixture was poured into the adjusted cold dilute hydrochloric acid solution, and it stirred, and extracted with ether. The organic layer was washed with saturated brine, dried over sodium sulfate, and then a large amount of water was added to the residue from which the solvent was distilled off under reduced pressure, and nitrobenzene was removed by steam distillation. The residue was extracted with ether, washed with saturated brine, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The crude product was subjected to silica gel column chromatography (100 g of Wacogel C-200, hexane: ethyl acetate = 7: 3). 9.25 g of (2,4,6-trihydroxyphenyl) (2,6-dimethylheptyl) ketone (6) was obtained as an oil.

1 HNMR δ (TMS): 0.85 (6H, d, J = 6.2 Hz), 0.96 (3H, d, J = 6.6 Hz), 1.4 (7H, m), 2.10 (1H, m), 3.00 (2H, m) , 6.02 (2H, s),

MS (FAB) m / z 281 (M + l) &lt; + &gt;.

<Example 2>

Synthesis of (2-methylpropyl) (2,4,5-trihydroxyphenyl) ketone (7)

12.61 g (100.0 mmol) of hydroxyhydroquinone (2) was suspended in 110 mL of nitrobenzene and stirred at room temperature in a vessel with a calcium chloride tube. To this was added 40.0 g (300 mmol, 3.00 equiv) of granular aluminum chloride in small portions. After continuing stirring for 1 hour, 12.06 g (100.0 mmol, 1.000 equiv) of isovaleryl chloride was slowly added dropwise. After 10 hours of dropping, the reaction mixture became a reddish purple amorphous solid, which was mechanically broken into fine pieces. This was put in 500 ml of cold 2M hydrochloric acid, stirred for 30 minutes, and then extracted with ether. The ether layer was distilled off the solvent after washing with water and a large amount of water was added to remove nitrobenzene by steam distillation. The residue was dissolved in ether, washed with saturated brine, dried over sodium sulfate, and the crude product obtained by distilling off the ether under reduced pressure was recrystallized from hexane-petroleum ether (2: 1) to give reddish purple fine crystals. (Yield 86.6%) was obtained.

1 HNMR δ (TMS): 0.96 (6H, d, J = 6.6 Hz), 2.18 (1H, sept, J = 6.6 Hz) 2.69 (2H, d, J = 6.9 Hz), 6.50 (1H, s), 7.17 ( 1H, s), 8.6 (2H, bs), 10.1 (1H, bs).

Reference Example 3

Synthesis of (2-propyl) (2,3,4,6-tetrahydroxyphenyl) ketone (8)

1.00 g (7.04 mmol) of 1,2,3,5-tetrahydroxybenzene (3) was dissolved in 20 ml of nitrobenzene and stirred in a vessel with a calcium chloride tube. 2.82 g (21.1 mmol, 3.00 equivalent) of granular aluminum chloride was added in small portions, and it stirred. After 1 hour, a solution of 0.750 g (7.04 mmol, 1.00 equiv) of nitrobenzene (5.0 mL) wasobutyryl chloride was added dropwise. After 10 hours, the reaction solution was poured into 100 ml of cold 2M hydrochloric acid, stirred for 30 minutes, and extracted with ether. The ether layer was washed with water, ether was distilled off, and a large amount of water was added to remove nitrobenzene by steam distillation. The residue was extracted with ether, washed with saturated brine and dried over sodium sulfate. 1.38 g of the crude product obtained by distilling off the solvent under reduced pressure was subjected to column chromatography purification (SiO ₂ , Wacogel C-300 20 g, hexane: ether = 1: 1) as a yellow powdery crystal, 441 mg of the target product (8) (yield). 65.9%).

1 HNMR δ (TMS): 1.10 (6H, d, J = 6.7 Hz), 3.95 (1H, sept, J = 6.7 Hz), 5.90 (1H, s), 8.62 (bs).

Reference Example 4

Synthesis of (2-methylpropyl) (2,3,4,6-tetrahydroxyphenyl) ketone (9)

Under argon atmosphere, 4.28 g (30.14 mmol) of 1,2,3,5-tetrahydroxybenzene (3) was dissolved in 70 ml of nitrobenzene by stirring. After cooling with water, 16.1 g (120.56 mmol, 4.00 eq) of granular aluminum chloride was added thereto and stirred. 3.67 ml (30.1 mmol, 1.00 equiv) of isovaleryl chloride were dripped little by little. After 5 hours, the reaction solution was poured into 100 ml of cold 2M hydrochloric acid, stirred for 20 minutes, and extracted with ether. The organic layer was washed with water, ether was distilled off, and nitrobenzene was distilled off by steam distillation with a large amount of water. The residue was ether extracted, washed with saturated brine and dried over sodium sulfate. After concentration under reduced pressure, purification was performed by silica gel chromatography (Wakogel C-200 300 g hexane: ethyl acetate = 2: 1) to obtain 1.85 g (yield 27.2%) of the title compound (9) as yellow powdery crystals.

1 H-NMR δ (TMS): 0.97 (6H, d, J = 6.6 Hz), 2.25 (1H, m), 2.96 (2H, d, J = 7.0 Hz), 6.02 (1H, s), 6.9 (1H, brs), 8.5 (1H, brs), 9.79 (1H, brs), 11.76 (1H, brs)

LR-MS (EI, 70V, 300μA) 226 (M +), 211, 193, 169 (base), 69

Reference Example 5

Synthesis of (2,3,4,6-tetrahydroxyphenyl) phenylketone (10)

Under argon atmosphere, 0.935 mL (9.15 mmol, 1.00 equiv) of benzonitrile was added while suspending 1.30 g (9.15 mmol) of 1,2,3,5-tetrahydroxyphenol (3) and 13 mL of ether. 0.624 g (4.57 mmol, 0.50 equiv) of zinc chloride was added while cooling with ice water, and the mixture was stirred at room temperature for 6 hours while venting with hydrogen chloride gas. The aeration of the gas was stopped and left at 4 ° C. for 13 hours, after which the ether layer was removed by decantation from the resulting tar phase precipitate. 39 mL of water was added to this precipitate, stirring in an ice bath, and it heated and refluxed for 2 hours. Filtration was carried out while maintaining a high temperature to obtain reddish brown crystals which precipitated from the filtrate, and redissolved in ether to filter insolubles.

1 H-NMR δ (TMS): 6.03 (1H, s), 7.33-7.66 (6H, m), 8.0-11.0 (3H, br)

13C-NMR δ (TMS): 95.3, 104.3, 125.0, 127.5, 128.2, 130.7, 141.8, 149.5, 153.5, 155.8, 198.9

LR-MS (EI, 70V, 300μA) 246 (M +, Base), 168, 140, 105, 77, 69

Reference Example 6

Synthesis of methyl (2,3,4,6-tetrahydroxyphenyl) ketone (11)

2.00 g (14.08 mmol) of 1,2,3,5-tetrahydroxyphenol (3) and 20 ml of ether were added and suspended in an argon atmosphere, and 1.00 g (24.3 mmol, 1.73 equiv) of acetonitrile was added. 0.70 g (5.14 mmol, 0.36 eq) of zinc chloride was added while ice-cold with ice-cold water, and it stirred at room temperature for 4 hours, ventilating hydrogen chloride gas. The aeration of the gas was stopped and left at 4 ° C. for 13 hours, after which the ether layer was removed by decantation from the resulting tar phase precipitate. 60 mL of water was added to this precipitation, stirring in an ice bath, and it heated and refluxed for 4 hours. A small amount of activated carbon was added to the filtrate while maintaining a high temperature to obtain yellow crystals that precipitated out of the filtrate. After re-dissolving in ether, the insolubles were filtered and the filtrate was concentrated to give 0.82 g (yield 31.8%) of the target substance (11) as yellow flat crystals.

1 H-NMR (90 MHz, d ₆ -DMSO) δ (TMS): 2.61 (3H, s), 5.93 (1H, s), 7.0 (1H, brs), 9.5 (1H, brs), 11.76 (1H, s)

LR-MS (EI, 70V, 300μA) 184 (M +), 169 (base), 69

<Example 3>

{3,5-bis (3-methyl-2-butenyl) -2,4,6-trihydroxyphenyl} (2-propyl) ketone (12), 2,2, -bis (3-methyl-2 -Butenyl) -3,5-dihydroxy-6- (2-methyl-1-oxopropyl) cyclohexa-3,5-dienone (13), {3- (3-methyl-2-butenyl Synthesis of) -2,4,6-trihydroxyphenyl} (2-propyl) ketone (14)

Under nitrogen atmosphere, 600 mg (15.0 mmol, 3.00 equiv) of 60% sodium hydride oil was washed with dry hexane to remove paraffin. 20 ml of dimethyl sulfoxide was added, and it stirred at room temperature. A solution of 981 mg (5.00 mmol) of dimethylsulfoxide (5.0 mL) of (2-propyl) (2,4,6-trihydroxyphenyl) ketone (4) was added in 15 minutes and stirring was continued for another 30 minutes. Thus, a solution of 1.43 g (10.0 mmol, 2.00 equiv) of dimethylsulfoxide (5.0 mL) of 1-bromo-3-methyl-2-butene was added dropwise over 30 minutes. After stirring for 14 hours at room temperature, the reaction mixture was poured into 50 ml of cold 2M hydrochloric acid and extracted with ether. The ether layer was washed with saturated brine, dried over sodium sulfate, and the solvent was distilled off to obtain 1.580 g of crude product as a red oil. Subsequently, thin layer chromatography was used as an index in the order of extraction by silica gel column chromatography (65 g of Wacogel C-200, benzene: ethyl acetate = 9: 1), (a) 239 mg of brown viscous oil, and (b) orange viscous. It was divided into three parts: 342 mg of an oil and (206) 206 mg of a yellow crystalline substance. (a) was purified again by column chromatography (15 g of Wacogel C-300, petroleum ether: ether = 9: 1) to obtain {3,5-bis (3-methyl-2-butenyl)-as yellow crystals. 58 mg of 2,4,6-trihydroxyphenyl} (2-propyl) ketone (12) was obtained.

1 HNMR δ (TMS): 1.16 (6H, d, J = 6.6 Hz), 1.78 (6H, s), 1.83 (6H, s), 3.38 (4H, bd), 3.99 (1H, sept, J = 6.6 Hz) , 5.22 (2H, m), 6.29 (1H, s), 10.14 (2H, s).

(b) was also repeated column chromatography (wacogel C-300 18 g, petroleum ether: ether = 7: 3) as yellow viscous product 2,2-bis (3-methyl-2-butenyl) -3 197 mg of, 5-dihydroxy-6- (2-methyl-1-oxopropyl) cyclohexa-3,5-dienone (13) was obtained.

1 HNMR δ (TMS): 1.17 (6H, d, J = 6.8 Hz), 1.58 (12H, bs), 2.62 (4H, bd), 3.98 (1H, sept, J = 6.8 Hz), 4.85 (2H, m) , 5.96 (1 H, s).

(3-) 3- (3-methyl-2-butenyl) -2,4,6 as yellow crystals by column chromatography (c) 15 g of Wacogel C-300, petroleum ether: ether = 2: 1. 110 mg of -trihydroxyphenyl} (2-propyl) ketone (14) were obtained.

1 HNMR δ (TMS): 1.13 (6H, d, J = 6.6 Hz), 1.66 (3H, s), 1.76 (3H, s), 3.20 (2H, bd), 5.21 (1H, m), 6.02 (1H, s).

<Example 4>

{3,5-bis (3-methyl-2-butenyl) -2,4,6-trihydroxyphenyl} (2-propyl) ketone (12), 2,2, -bis (3-methyl-2 Synthesis of -butenyl) -3,5-dihydroxy-6- (2-methyl-1-oxopropyl) cyclohexa-3,5-dienone (13)

981 mg (5.00 mmol) of (2,4,6-trihydroxyphenyl) (2-propyl) ketone (4) was dissolved in 10.0 mL of dioxane under a nitrogen atmosphere, and cooled with ice water at about 10 ° C. and stirred. Into this, 554 ml (639 mg, 4.50 mmol, 0.900 equiv) of boron trifluoride ether complex was added using a microsyringe. After stirring again for 15 minutes, a solution of 3-methyl-2-butenol 861 mg dioxane (9 ml) was slowly added dropwise. After 4 hours, the reaction solution was poured into 100 ml of ether, and the ether layer was washed sequentially with saturated sodium bicarbonate water and brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure to obtain 1.76 g of a crude product as a red viscous oil. Separation by silica gel column chromatography (50 g of Wacogel C-300, petroleum ether: ether = 9: 1, 7: 3, 5: 5, sequentially extracted with 200 ml each), {3- (3-methyl-2 -Butenyl) -2,4,6-trihydroxyphenyl} (2-propyl) ketone (23) 417 mg and 2,2-bis (3-methyl-2-butenyl) -3,5-dihydrate 338 mg of oxy-6- (2-methyl-1-oxopropyl) cyclohexa-3,5-dieenone (13) was isolated, respectively.

Example 5

{3,5-bis (3-methyl-2-butenyl) -2,4,6-trihydroxyphenyl} (2-methylpropyl) ketone (15), 3,5-dihydroxy-6- ( 3-methyl-1-oxobutyl) -2,2,4-tris (3-methyl-2-butenyl) cyclohexa-3,5-dienone (16), 2,2-bis (3-methyl- Synthesis of 2-butenyl) -3,5-dihydroxy-6- (3-methyl-1-oxobutyl) cyclohexa-3,5-dienone (17)

Under nitrogen atmosphere, 441 mg (11.1 mmol, 2.06 equiv) of 60% sodium hydride was washed with dry hexane to remove paraffin. 6.0 ml of dry methanol was added and stirred under ice cooling. Then, a solution of 1.135 g (5.400 mmol) of methanol (6.0 mL) in (2-methylpropyl) (2,4,6-trihydroxyphenyl) ketone (5) was added dropwise. A solution of 1.205 g (11.52 mmol, 2.130 equiv) of methanol (5.0 mL) in 1-chloro-3-methyl-2-butene was slowly added dropwise. After stirring under ice-cooling for 1.5 hours, 50 ml of saturated ammonium chloride water was added to extract the mixture. The ether layer was washed with saturated brine, dried over sodium sulfate, and the solvent was removed under reduced pressure to obtain 1.752 g of a red viscous oil as a crude product. This was subjected to silica gel column chromatography (40 g of Wacogel C-300, 200 ml each of petroleum ether: ether = 19: 1, 18: 2, 17: 3, 16: 4). {3,5-bis (3-methyl-2-butenyl) -2,4,6-trihydroxyphenyl} (2-methylpropyl) ketone (15) in the order in which thin layer chromatography was run off to the surface; 160 mg was obtained as pale yellow micro needle crystals.

1 HNMR δ (TMS): 0.96 (6H, d, J = 6.6 Hz), 1.78 (6H, s), 1.83 (6H, s), 2.26 (1H, sept, J = 6.6 Hz), 2.94 (2H, d, J = 6.6 Hz), 3.37 (4H, d, J = 6.2 Hz), 5.22 (2H, m), 6.26 (1H, bs), 10.12 (2H, bs).

Subsequently, 3,5-dihydroxy-6- (3-methyl-1-oxobutyl) -2,2,4-tris (3-methyl-2-butenyl) cyclohexa-3,5-dienone ( 16) 549 mg was isolated as yellow crystals.

1 HNMR δ (TMS): 0.96 (6H, d, J = 6.6 Hz), 1.56 (15H, s), 1.78 (3H, s), 2.11 (1H, sept, J = 6.6 Hz), 2.60 (4H, m) , 2.92 (2H, d, J = 6.9 Hz), 3.19 (2H, d, J = 7.3 Hz), 4.79 (2H, m), 5.11 (1H, m).

Then, 259 mg of 2-bis (3-methyl-2-butenyl) -3,5-dihydroxy-6- (3-methyl-1-oxobutyl) cyclohexa-3,5-dienone (17) Was obtained as a yellow viscous oil.

1 HNMR δ (TMS): 0.99 (6H, d, J = 6.6 Hz), 1.57 (12H, bs), 2.16 (1H, sept, J = 6.6 Hz), 2.62 (4H, m), 2.95 (2H, d, J = 6.9 Hz), 4.84 (2H, m), 5.65 (1H, s).

<Example 6>

{3,5-bis (3-methyl-2-butenyl) -2,4,6-trihydroxyphenyl} (2-methylpropyl) ketone (15), 3,5-dihydroxy-6- ( 3-methyl-1-oxobutyl) -2,2,4-tris (3-methyl-2-butenyl) cyclohexa-3,5-dienone (16), 2,2-bis (3-methyl- Synthesis of 2-butenyl) -3,5-dihydroxy-6- (3-methyl-1-oxobutyl) cyclohexa-3,5-dienone (17)

Under nitrogen atmosphere, 2.244 g (20.00 mmol, 2.000 equiv) of potassium t-butoxide was dissolved in 20.0 mL of dry methanol and stirred under ice-cooling. To this was added dropwise a solution of 2.102 g (10.00 mmol) of (2-methylpropyl) (2,4,6-trihydroxyphenyl) ketone (5) in methanol (10.0 mL) and again 1-bromo-3-methyl-. 2.861 g (20.00 mmol, 2.000 equiv) of methanol (15.0 mL) solution of 2-butene was added slowly. After stirring for 1 hour under ice-cooling and 2 hours at room temperature, the mixture was extracted with ether. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was distilled off under reduced pressure to yield 2.932 g of a crude product as a red viscous oil. This was subjected to silica gel column chromatography (100 g of Wacogel C-300, 400 ml of petroleum ether: ether = 9: 1, 8: 2, 7: 3, 6: 4, respectively) in order. 137 mg, 3, of {3,5-bis (3-methyl-2-butenyl) -2,4,6-trihydroxyphenyl} (2-methylpropyl) ketone (15) using thin layer chromatography as an index 5-dihydroxy-6- (3-methyl-1-oxobutyl) -2,2,4-tris (3-methyl-2-butenyl) cyclohexa-3,5-dienone (16) 153 mg And 2,2-bis (3-methyl-2-butenyl) -3,5-dihydroxy-6- (3-methyl-1-oxobutyl) cyclohexa-3,5-dienone (17) 235 Isolation of the mg was confirmed.

<Example 7>

2,2-bis (3-methyl-2-butenyl) -3,5-dihydroxy-6- (3-methyl-1-oxobutyl) cyclohexa-3,5-dienone (17), { Synthesis of 3- (3-methyl-2-butenyl) -2,4,6-trihydroxyphenyl}-(2-methylpropyl) ketone (18)

Under nitrogen atmosphere, 1.47 g (7.00 mmol) of (2-methylpropyl) (2,4,6-trihydroxyphenyl) ketone (5) was dissolved in 14.0 mL of dry dioxane and stirred in ice water (10 ° C.). To this was added 690 ml (795 mg, 5.60 mmol, 0.80 equiv) of boron trifluoride ether complex using a microsyringe. Then a solution of 1.21 g (14.0 mmol, 2.00 equiv) of dioxane (10.0 mL) of 3-methyl-2-butenol was added dropwise at about 0.5 hour. After stirring for 14 hours at room temperature, 140 ml of ether was added, and the organic layer was washed with saturated sodium bicarbonate water and saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure to obtain 2.93 g of a crude product as a red viscous oil. This was subjected to silica gel column chromatography (100 g of Wacogel C-300, 200 mL each of petroleum ether: ether = 9: 1, 8: 2, 7: 3, 6: 4, 5: 5). Using thin layer chromatography as an indicator, 427 mg of oil was collected and silica gel column chromatography was repeated (17 g of Wacogel C-300, effluent with petroleum ether: ether = 8: 2), and 2,2-bis (3- 311 mg of methyl-2-butenyl) -3,5-dihydroxy-6- (3-methyl-1-oxopropyl) cyclohexa-3,5-dienone (17) was isolated.

Subsequently, silica gel column chromatography was repeated for 613 mg of the oily substance that was distilled off (21 g of Wacogel C-300, effluent with petroleum ether: ether = 7: 3), and {3- (3-methyl-2-butenyl 459 mg of) -2,4,6-trihydroxyphenyl}-(2-methylpropyl) ketone (18) was obtained as pale yellow crystals.

1 HNMR δ (TMS): 0.96 (6H, d, J = 6.6 Hz), 1.71 (3H, s), 1.77 (3H, s), 2.23 (1H, sept, J = 6.6 Hz), 2.95 (2H, d, J = 6.3 Hz), 3.31 (2H, bd), 5.22 (1H, m), 5.95 (1H, m).

<Example 8>

{3,5-bis (3,7-dimethyl-2,6-octadienyl) -2,4,6-trihydroxyphenyl} (2-methylpropyl) ketone (19), 3,5-dihydrate Hydroxy-6- (3-methyl-1-oxobutyl) -2,2,4-tris (3,7-dimethyl-2,6-octadienyl) cyclohexa-3,5-dienone (20), 2,2, -bis (3,7-dimethyl-2,6-octadienyl) -3,5-dihydroxy-6- (2-methyl-1-oxobutyl) cyclohexa-3,5-die Synthesis of Paddy Fields (21)

Under a nitrogen atmosphere, 400 mg (10.0 mmol, 2.00 equiv) of 60% sodium hydride oily dispersion was removed by washing with dry hexane. Under ice-cooling, 10.0 mL of dry methanol was added to form a sodium methoxide solution. To this was added dropwise a solution of 1.051 g (5.000 mmol) of methanol (5.0 mL) of (2,4,6-trihydroxyphenyl) (2-methylpropyl) ketone (5). A methanol (8.0 mL) solution of 1.727 g (10.0 mmol, 2.000 equiv) of 1-chloro-3,7-dimethyl-2,6-octadiene was added dropwise to 0.5 hour, and stirring was continued at room temperature for 1 hour. 40 ml of saturated ammonium chloride water was added thereto, and it extracted with ether. After washing with saturated brine and drying over sodium sulfate, the solvent was distilled off under reduced pressure to give 2.527 g of crude product as a red viscous oil. This was subjected to silica gel column chromatography (95 g of Wacogel C-300, hexane: ether = 9: 1, 8: 2, 7: 3, 6: 4. 5: 5, 300 mL each). Thin layer chromatography for each fraction as an indicator

(a) 663 mg of an orange oil,

(b) orange colored oil, 196 mg,

(c) Orange viscous oil was classified as 218 mg.

(a) was further subjected to silica gel column chromatography (wacogel C-300 27 g, hexane: ether = 29: 1, 28: 2, and 27: 3 each 150 mL of the effluent). 128 mg of {3,5-bis (3,7-dimethyl-2,6-octadienyl) -2,4,6-trihydroxyphenyl} (2-methylpropyl) ketone (19) as an orange oil Got it.

1 HNMR δ (TMS): 0.96 (6H, d, J = 6.6 Hz), 1.60 (9H, s), 1.67 (9H, s), 2.07 (9H, m), 2.95 (2H, d, J = 7.2 Hz) , 3.39 (4H, d, J = 9.0 Hz), 5.08 (2H, m), 5.34 (2H, m).

in (b) 3,5-dihydroxy-6- (3-methyl-1-oxobutyl) -2,2,4-tris (3,7-dimethyl-2,6-octadienyl) cyclohexa- 3,5-Dienone (20) was isolated.

1 HNMR δ (TMS): 0.98 (6H, d, J = 6.6 Hz), 1.56 (12H, s), 1.64 (6H, s), 1.91 (12H, bs), 2.24 (1H, m), 2.65 (4H, m), 2.94 (2H, d, J = 6.8 Hz), 3.45 (2H, d, J = 8.0 Hz), 4.95 (6H, m).

in (c) 2,2-bis (3,7-dimethyl-2,6-octadienyl) -3,5-dihydroxy-6- (2-methyl-1-oxobutyl) cyclohexa-3, 5-Dienone (21) was isolated.

1 HNMR δ (TMS): 0.97 (6H, d, J = 6.6 Hz), 1.59 (bs), and 1.67 (bs) (total 18H), 1.99 (9H, m), 2.58 (4H, m), 2.96 (2H , d, J = 6.8 Hz), 4.99 (4H, m), 5.94 (1H, s).

Example 9

3,5-dihydroxy-6- (3,7-dimethyl-1-oxooctyl) -2,2,4-tris (3-methyl-2-butenyl) cyclohexa-3,5-dienone ( 22), Synthesis of {3- (3-methyl-2-butenyl) -2,4,6-trihydroxyphenyl} (2,6-dimethylheptyl) ketone (23)

0.432 g (6.16 mmol, 2.00 equiv) of potassium oxide was added 1 ml of dry methanol under ice-cooling, followed by stirring for 15 minutes. A solution of 0.864 g (3.08 mmol) of (2,4,6-trihydroxyphenyl) (2,6-dimethylheptyl) ketone (6) in methanol (4 mL) was added dropwise and stirred for 30 minutes under ice-cooling. 728 mL (6.47 mmol, 2.10 equiv) of 1-chloro-3-methyl-2-butene was added dropwise and stirred at room temperature for 3.5 hours. 20 ml of saturated ammonia chloride solution was added, extraction was performed with ether, washed with saturated brine, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The crude product was subjected to silica gel column chromatography (wacogel C-300 50 g, hexane: ether = 7: 3). 3,5-dihydroxy-6- (3,7-dimethyl-1-oxooctyl) -2,2,4-tris (3-methyl-2-butenyl) cyclohexa-3,5-dienone ( 22) 0.181 g was obtained as an oil.

1 HNMR δ (TMS): 0.86 (6H, d, J = 6.3 Hz), 0.94 (3H, d, J = 6.6 Hz), 1.25 (7H, m), 1.57 (12H, s), 2.00 (1H, m) , 2.67 (4H, d, J = 6.9 Hz), 3.00 (2H, m), 4.84 (2H, t, J = 6.9 Hz).

MS (EI 38) m / z 416 (M) &lt; + &gt;

Again, {3- (3-methyl-2-butenyl) -2,4,6-trihydroxyphenyl} (2,6-dimethylheptyl) ketone (23) 0.311 by distillation with hexane: ether = 6: 4 g was obtained as an oil.

1 HNMR δ (TMS): 0.84 (6H, d, J = 6.3 Hz), 0.92 (3H, d, J = 7.3 Hz), 1.23 (7H, m), 1.76 (bs), 1.81 (bs), (total 6 H), 2.10 (1H, m), 2.80 (2H, m), 3.13 (2H, m), 3.34 (2H, d, J = 7.3 Hz), 5.24 (1H, m), 5.90 (1H, m)

MS (EI) m / z 348 (M) &lt; + &gt;

<Example 10>

2,2-bis (3-methyl-2-butenyl) -3,5-dihydroxy-6- (3,7-dimethyl-1-oxooctyl) cyclohexa-3,5-dienone (24) Synthesis of

0.619 g (8.82 mmol, 2 equiv) of potassium methoxide was added 5 ml of dry methanol under ice-cooling, followed by stirring for 15 minutes. A solution of 1.536 g (4.41 mmol) of 2,4,6-trihydroxyphenyl} (2,6-dimethylheptyl) ketone (6) in methanol (5 mL) was added dropwise and stirred for 30 minutes under ice-cooling. 1.093 ml (9.702 mmol, 2.20 equiv) of 1-chloro-3-methyl-2-butene was added dropwise and stirred at room temperature for 4 hours. 80 ml of saturated ammonium chloride solution was added, extracted with ether, washed with saturated brine, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The crude product was subjected to silica gel column chromatography (80 g of Wacogel C-300, hexanes: ether = 99: 1, 97: 3, 95: 5). 2,2-bis (3-methyl-2-butenyl) -3,5-dihydroxy-6- (3,7-dimethyl-1-oxooctyl) cyclohexa-3,5-dienone (24) 0.305 g was obtained as an oil.

1 HNMR δ (TMS): 0.86 (6H, d, J = 5.9 Hz), 0.93 (3H, d, J = 6.2 Hz), 1.26 (7H, m), 1.57 (bs), 1.79 (bs), (Total 1 8 H), 2.00 (1H, m), 2.58 (4H, m), 2.97 (2H, m), 3.19 (2H, bd), 4.81 (2H, bt), 5.15 (1H, bt).

MS (EI) m / z 484 (M) &lt; + &gt;

<Example 11>

{3,6-bis (3-methyl-2-butenyl) -2,4,5-trihydroxyphenyl} (2-methylpropyl) ketone (25), {3- (3-methyl-2-part Synthesis of Tenyl) -2,4,5-trihydroxyphenyl} (2-methylpropyl) ketone (26)

Under a nitrogen atmosphere, a solution of 2.102 g (10.0 mmol) of dioxane (20.0 mL) of (2,4,5-trihydroxyphenyl) (2-methylpropyl) ketone (7) was stirred under ice-cooling. 1230 mL (1.420 g, 10.00 mmol, 1.000 equiv) of boron trifluoride ether complex was added followed by the slow addition of a solution of 2.584 g (30.0 mmol) of dioxane (16.0 mL) of 3-methyl-2-butenol. After stirring for 3 hours under ice cooling, the mixture was left at room temperature for 14 hours. 200 ml of ether was added and the organic layer was washed with saturated sodium bicarbonate water and brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure to obtain 4.018 g of the crude product as a dark red oil. Silica gel column chromatography (80 g of Wacogel C-300, hexane: ether = 9: 1, 8: 2, 7: 3, 6: 4, 5: 5 each 300 ml of the distillate) was performed to obtain {3,6-bis. 249 mg of (3-methyl-2-butenyl) -2,4,5-trihydroxyphenyl} (2-methylpropyl) ketone (25) was obtained as yellow fine needle crystals.

1 HNMR δ (TMS): 0.96 (6H, d, J = 6.6 Hz), 1.74 (bs), 1.80 (bs) (total 12H), 2.25 (1H, sept, J = 6.6 Hz), 2.82 (2H, d, J = 7.0 Hz), 3.41 (2H, d, J = 7.0 Hz), 3.48 (2H, d, J = 7.0 Hz), 5.03 (1H, s), 5.03 (1H, m), 5.29 (1H, m) , 6.30 (1 H, s).

231 mg of {3- (3-methyl-2-butenyl) -2,4,5-trihydroxyphenyl} (2-methylpropyl) ketone (26) was isolated as a more polar component.

1 HNMR δ (TMS): 0.98 (6H, d, J = 6.5 Hz), 1.74 (3H, s), 1.82 (3H, s), 2.25 (1H, sept, J = 6.5 Hz), 2.69 (2H, d, J = 6.8 Hz), 3.43 (2H, d, J = 7.0 Hz), 5.30 (1H, m), 7.12 (1H, s).

<Example 12>

{6- (3-methyl-2-butenyl) -2,4,5-trihydroxyphenyl} (2-methylpropyl) ketone mono (3-methyl-2-butenyl) ether (27), ( Synthesis of 2,4,5-trihydroxyphenyl) (2-methylpropyl) ketone mono (3-methyl-2-butenyl) ether (28)

Under a nitrogen atmosphere, 400 mg (10.0 mmol, 2.00 equiv) of 60% sodium hydride oily dispersion was removed by washing with dry hexane. Under ice-cooling, 10.0 mL of dry methanol was added to form a sodium methoxide solution. A solution of 1.051 g (5.000 mmol) of methanol (6.0 mL) of (2,4,5-trihydroxyphenyl) (2-methylpropyl) ketone (7) was added. A solution of 1.046 g (10.0 mmol, 2.000 equiv) of methanol (8.0 mL) in 1-chloro-3-methyl-2-butene was then slowly added. After stirring for 2 hours at room temperature, 200 ml of ether was added, neutralized with 100 ml of saturated ammonium chloride solution, washed with saturated brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure to obtain 1.730 g of a crude product as a red viscous oil. Separation operation by silica gel column chromatography (50 g of Wacogel C-300, 200 ml of petroleum ether: ether = 9: 1, 8: 2, 7: 3, 6: 4 each), followed by {6- 68 mg of (3-methyl-2-butenyl) -2,4,5-trihydroxyphenyl} (2-methylpropyl) ketone mono (3-methyl-2-butenyl) ether (27) yellow fine Obtained as a needle crystal.

1 HNMR δ (TMS): 0.89 (6 H, d, J = 6.4 Hz), 1.74 (s), 1.73 (s) (total 12H), 2.22 (1H, sept, J = 6.4 Hz), 2.79 (2H, d , J = 6.6 Hz), 3.56 (2H, d, J = 5.6 Hz), 4.58 (2H, d, J = 6.9 Hz), 5.17 (1H, m), 5.44 (1H, m), 5.44 (1H, s ), 6.37 (1 H, s).

64 mg of (2,4,5-trihydroxyphenyl} (2-methylpropyl) ketone mono (3-methyl-2-butenyl) ether (28) was obtained as yellow needles from a higher polar portion.

1 HNMR δ (TMS): 0.99 (6H, d, J = 6.6 Hz), 1.74 (3H, s), 1.79 (3H, s), 2.75 (1H, m), 2.71 (2H, d, J = 6.6 Hz) , 4.60 (2H, doublet, J = 6.8 Hz), 5.46 (1H, m), 6.44 (1H, s), 7.22 (1H, s).

Example 13

2,4-bis (3-methyl-2-butenyl) -6- (2-methyl-1-oxopropyl) -2,3,5-trihydroxycyclohexa-3,5-dienone (29) Synthesis of

Under nitrogen atmosphere, 125 mg (3.12 mmol, 3.00 equiv) of a 60% sodium hydride oily dispersion was washed with hexane to remove the oil, and sodium hydride was suspended in 2.0 ml of dimethyl sulfoxide under ice-cooling. A solution of 221 mg (1.04 mmol) of dimethylsulfoxide (1.5 mL) of (1,2,3,5-tetrahydroxyphenyl) (2-propyl) ketone (8) was added dropwise. After stirring for 30 minutes, a solution of 327 mg (2.29 mmol, 2.20 equiv) of dimethylsulfoxide (1.0 mL) in 1-bromo-3-methyl-2-butene was slowly added dropwise. After stirring for 1 hour at room temperature, 100 ml of ether was added and neutralized with saturated ammonium chloride water. The ether layer was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure to obtain 318 mg of crude product as an orange amorphous solid. Purification by silica gel column chromatography (wacogel C-300 10 g, hexane: ether = 7: 3) gave 2,4-bis (3-methyl-2-butenyl) -6- as a yellow viscous oil. 90 mg of (2-methyl-1-oxopropyl) -2,3,5-trihydroxycyclohexa-3,5-dienone (29) was isolated.

1 HNMR δ (TMS): 1.13 (6H, d, J = 6.9 Hz), 1.52 (s), 1.67 (s), 1.73 (s) (12H total), 2.51 (2H, d, J = 7.2 Hz), 3.09 (2H, d, J = 7.2 Hz), 3.71 (1H, sept, J = 7.2 Hz), 5.00 (1H, m), 5.14 (1H, m).

<Example 14>

Synthesis of 2,4-bis (3-methyl-2-butenyl) -6- (1-oxoethyl) -2,3,5-trihydroxycyclohexa-3,5-dienone (30)

Under an argon stream, 200 mg (4.89 mmol, 3.00 equiv) of 60% sodium hydride fraction was washed with hexane to remove the oil. 8.0 ml of dry dimethyl sulfoxide under water cooling was added thereto, and 300 mg (1.63 mmol) of 2-methylpropyl- (2,3,4,6-tetrahydroxyphenyl) ketone (9) was added and stirred for 40 minutes. . 0.367 mL (3.26 mmol, 2.00 equiv) of 1-chloro-3-methyl-2-butene was added dropwise and stirred for 4 hours. 4 ml of 2 M hydrochloric acid was added, extraction was performed with ethyl acetate, and the organic layer was washed with saturated brine and dried over sodium sulfate. After concentration under reduced pressure, silica gel chromatography (100 g of Wacogel C-200, benzene: ethyl acetate: acetic acid = 8: 1: 0.1) gave 242.6 mg (yield 46.5%) of the title compound (30) as yellow powdery crystals.

1 H-NMR (90 MHz, CDCl ₃ ) δ (TMS): 1.53-1.73 (12H, m), 2.51 (5H, m), 3.08 (2H, d, J = 7.5), 5.07 (2H, m), 18.65 ( 1H, s)

LR-MS (EI, 70V, 300 μA) 320 (M +) 252, 196 (base), 69

<Example 15>

Synthesis of 2,4-dimethyl-6- (3-methyl-1-oxobutyl) -2,3,5-trihydroxycyclohexa-3,5-dienone (31)

Under argon stream, 372 mg (9.30 mmol, 3.00 equiv) of 60% sodium hydride oily product was washed with hexane to remove the oil. 7.0 ml of dry dimethyl sulfoxide was added under water cooling, and 700 mg (3.10 mmol) of 2-methylpropyl- (2,3,4,6-tetrahydroxyphenyl) ketone (9) was added thereto and stirred for 30 minutes. . 0.579 ml (9.30 mmol, equivalent) of methyl iodide was added dropwise and stirred for 4 hours. 3 ml of 2 M hydrochloric acid and 1 ml of 10% sodium thiosulfate were added and extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over sodium sulfate. After concentration under reduced pressure, 224 mg (yield 28.4%) of the title compound (31) as yellow powdery crystals were obtained by silica gel chromatography (75 g of Wacogel C-200, carbon tetrachloride: ethyl acetate: acetic acid = 400: 200: 5).

1 H-NMR (90 MHz, CDCl ₃ ) δ (TMS): 0.97 (3H, d, J = 6.6), 1.01 (3H, d, J = 6.6), 1.58 (3H, s), 1.86 (3H, s), 2.15 (1H, m), 2.82 (2H, d, J = 7.0), 4.45 (1H, brs), 7.42 (1H, brs), 18.92 (1H, s)

13C-NMR (90 MHz, CDCl ₃ ) δ (TMS): 6.9, 22.5, 22.8, 26.7, 30.4, 46.8, 75.7, 104.9, 105.2, 168.9, 191.1, 196.4, 201.3

LR-MS (EI, 70V, 300 μA) 254 (M +), 237, 211 (base), 180, 151, 57

<Example 16>

Synthesis of 2,4-bis (3-methyl-2-butenyl) -6-benzoyl-2,3,5-trihydroxycyclohexa-3,5-dienone (32)

Under an argon stream, 440 mg (11.0 mmol, 3.01 equiv) of 60% sodium hydride fraction was washed with hexane to remove the oil. 18.0 ml of dry dimethyl sulfoxide under water cooling was added thereto, and while stirring, 900 mg (3.66 mmol) of phenyl- (2,3,4,6-tetrahydroxyphenyl) -ketone (10) was added and stirred for 30 minutes. 0.830 mL (7.32 mmol, 2.00 equiv) of 1-chloro-3-methyl-2-butene was added dropwise and stirred for 2 hours. 15 ml of saturated ammonium chloride solution and 2 ml of 2M hydrochloric acid were added, extracted with ether, the organic layer was washed with saturated brine and dried over sodium sulfate. After concentration under reduced pressure, 716 mg (yield 51.3%) of the title compound (32) as yellow powdery crystals were obtained by silica gel chromatography (200 g of Wacogel C-200, hexane: ethyl acetate = 4: 1).

1 H-NMR (90 MHz, CDCl ₃ ) δ (TMS): 1.57-1.74 (12H, m), 2.63 (2H, d, J = 7.5), 3.10 (2H, d, J = 7.5), 4.5 (1H, brs ), 5.14 (2H, m), 7.23-7.7 (6H, m), 18.65 (1H, s)

13C-NMR (90 MHz, CDCl ₃ ) δ (TMS): 17.8 18.1, 21.3, 25.7, 25.9, 42.0, 79.1, 105.2, 109.4, 116.1, 121.1, 127.9, 128.1, 131.5, 132.7, 136.9, 137.9, 168.8, 190.6 , 193.5, 195.2

LR-MS (EI, 70V, 300 μA) 382 (M +), 314, 258, 229, 217, 180, 151, 105 (base), 77, 69

<Example 17>

Synthesis of 2,4-bisbenzyl-6- (3-methyl-1-oxobutyl) -2,3,5-trihydroxycyclohexa-3,5-dienone (33)

Under argon stream, 212 mg (5.31 mmol, 2.40 equiv) of 60% sodium hydride fraction was washed with hexane to remove the oil. 11.0 ml of dry dimethyl sulfoxide under water cooling was added, followed by stirring for 40 minutes by addition of 500 mg (2.21 mmol) of 2-methylpropyl- (2,3,4,6-tetrahydroxyphenyl) -ketone (9). It was. 0.525 mL (4.42 mmol, 2.00 equiv) of benzyl bromide was added dropwise, and stirred for 4 hours. 10 ml of saturated ammonium chloride water was added, extracted with ether, and the organic layer was washed with saturated brine and dried over sodium sulfate. After concentration under reduced pressure, 207 mg (yield 23.1%) of the title compound (33) as yellow powdery crystals were obtained by silica gel chromatography (100 g of Wacogel C-200, hexane: ethyl acetate = 3: 2).

1 H-NMR (90 MHz, CDCl ₃ ) δ (TMS): 0.94 (6H, d, J = 6.2), 2.25 (1H, m), 2-3 (2H, br), 2.66 (2H, m), 3.04 ( 2H, s), 3.62 (2H, s), 7.1-7.4 (10H, m), 18.3 (1H, brs)

13C-NMR (90 MHz, CDCl ₃ ) δ (TMS): 22.7, 22.9, 25.7, 27.8, 47.2, 50.5, 606, 105.6, 107.6, 125.9, 127.5, 128.0, 128.3, 128.8, 130.4, 133.5, 140.7, 171.5, 189.2, 195.5, 200.3

LR-MS (EI, 70V, 300μA) 406 (M +), 322, 315 (base), 287, 259, 237, 209, 197, 181, 167, 91

Example 18

{3,5-bisbenzyl-2,4,6-trihydroxyphenyl} (2-methylpropyl) ketone (34), 2,2-bisbenzyl-6- (2-methyl-1-oxobutyl)- 3,5-dihydroxycyclohexa-3,5-dienone (35), 2,2,4-trisbenzyl-6- (3-methyl-1-oxobutyl) -3,5-dihydroxycyclo Synthesis of Hexa-3,5-dienone (36)

2-methylpropyl- (2,4,6-trihydroxyphenyl) ketone (5) 1.05 while dissolving 738 mg (10.0 mmol, 2.00 equiv) of potassium methoxide under argon stream in 25.0 mL of dry methanol under ice cooling and stirring g (5.00 mmol) was added and stirred for 1 hour. 1.19 mL (10.0 mmol, 2.00 equiv) of benzyl bromide was added dropwise, and the mixture was stirred for 4 hours under ice-cooling. 10 ml of saturated ammonium chloride water was added, methanol was distilled off under reduced pressure, extracted with ether, the organic layer was washed with saturated brine and dried over sodium sulfate. Concentrated under reduced pressure, fractionated by silica gel chromatography (150 g of Wacogel C-200, hexane: diethyl ether = 19: 1 to 9: 1 to 4: 1), and elution order 2,2-bisbenzyl-6- (2-methyl-1-oxobutyl) -3,5-dihydroxycyclohexa-3,5-dienone (35), 2,2,4-trisbenzyl-6- (3-methyl-1-oxo Butyl) -3,5-dihydroxycyclohexa-3,5-dienone (36), {3.5-bisbenzyl-2,4,6-trihydroxyphenyl)} (2-methylpropyl) ketone (34 ), 54.9 mg (yield 2.8%), 507 mg (yield 21.1%), and 150 mg (yield 7.7%) were obtained as yellow powdery crystals, respectively.

2,2-bisbenzyl-6- (3-methyl-1-oxobutyl) -3,5-dihydroxycyclohexa-3,5-dienone (35)

1 H-NMR (90 MHz, CDCl ₃ ) δ (TMS): 0.93 (6H, d, J = 6.6), 2.23 (1H, m), 2.91 (2H, d, J = 6.6), 3.99 (4H, s), 4.98, 5.53, 5.98 (total 1H, s, brs, s), 6.90-7.47 (10H, m), 9.86, 10.4, 18.82 (total 2H, brs, brs, s)

LR-MS (EI, 70 V, 300 μA) 390 (M +), 330 (base), 177, 91

2,2,4-trisbenzyl-6- (3-methyl-1-oxobutyl) -3,5-dihydroxycyclohexa-3,5-dienone (36)

1 H-NMR (90 MHz, CDCl ₃ ) δ (TMS): 0.78-1.04 (6H, m), 2.2 (1H, m), 2.73-3.58 (8H, m), 5.6, 6.2 (1H total, each brs), 6.85-7.25 (15H, m), 18.68, 18.87 (1H total, each s)

LR-MS (EI, 70V, 300μA) 480 (M +), 389, 305, 91 (base)

3,5-bisbenzyl-2,4,6-trihydroxyphenyl) (2-methylpropyl) ketone (34)

1 H-NMR (90 MHz, CDCl ₃ ) δ (TMS): 0.79-1.01 (6H, m), 1.5-2.4 (1H, m), 2.59-2.93 (4H, m), 3.43-3.27 (4H, m), 6.93-7.25 (10H, m), 18.2-18.93 (1H, m)

LR-MS (EI, 70V, 300μA) 390 (M +), 299 (base), 91

Example 19

Synthesis of {3,5-bis (3-methylbutyl) -2,4,6-trihydroxyphenyl} (2-methylpropyl) ketone (37)

1.50 g (4.34 mmol) of {3,5-bis (3-methyl-2-butenyl) -2,4,6-trihydroxyphenyl} (2-methylpropyl) ketone (15) were added to 22.0 ml of ethanol. The solution was dissolved and 924 mg (0.217 mmol, 5% equivalent) of 5% palladium activated carbon (water content-50%) was added thereto, followed by vigorous stirring for 2 hours at room temperature under atmospheric hydrogen. The reaction solution was filtered, concentrated under reduced pressure, and the resulting brown oil was subjected to silica gel chromatography (100 g of Wacogel C-200, hexane: ethyl acetate = 10: 1) to give 1.32 g of the target product (37) as a colorless oil (yield 86.6%). )

1 H-NMR (400 MHz, CDCl ₃ ) δ (TMS): 0.97 (18H, d, J = 6.9), 1.37 (4H, m), 1.64 (2H, m), 2.27 (1H, m), 2.54 (4H, m), 2.96 (2H, d, J = 6.8), 4.58 (1H, s), 5.31 (1H, s), 9.69 (1H, brs).

13C-NMR (400 MHz, CDCl ₃ ) δ (TMS): 20.7, 22.5, 22.9, 25.2, 28.3, 38.2, 53.1, 105.1, 106.2, 157.5, 158.2, 206.1

LR-MS (EI, 70V, 300 μA) 350 (M +), 293 (base), 279, 275

Reference Example 7

Synthesis of (phenylmethyl) (2,4,6-trihydroxyphenyl) ketone (38)

12.61 g (100.0 mmol) of chloroglucinol were added to a mixed solution of 45 mL of nitrobenzene and 45 mL of carbon disulfide, and 40.0 g (300 mmol, 3.00 equiv) of aluminum chloride were added in small portions under water-cooled stirring, and the calcium chloride tube was attached. Stirred. Subsequently, 15.46 g (100.0 mmol, 1.000 equiv) of phenylacetyl chloride were slowly added dropwise, and stirring was continued at room temperature for 2 hours. When the generation of acidic gas began to occur, it was put into dilute hydrochloric acid (prepared with 100 ml of concentrated hydrochloric acid and 400 ml of cold water), stirred and extracted with ether. The ether layer was washed with saturated brine and then distilled off under reduced pressure. The mixture was distilled off under reduced pressure while adding water little by little, and nitrobenzene was distilled off by steam distillation. The residue was extracted again with ether, washed with saturated brine and dried over sodium sulfate. The solvent was distilled off to obtain 26.02 g of a red viscous oil. A small amount of methylene chloride was added and left in the refrigerator to crystallize to obtain 19.62 g of (phenylmethyl) (2,4,6-trihydroxyphenyl) ketone (38) as pale yellow powdery crystals.

(38) 1 H-NMR (CDCl ₃ ): 4.42 (2H, s), 5.93 (2H, s), 7.19-7.34 (5H, m)

Example 20

{3,5-bis (3-methyl-2-butenyl) -2,4,6-trihydroxyphenyl} (phenylmethyl) ketone (39), 3,5-dihydroxy-6- (phenylacetyl ) -2,2,4-tris (3-methyl-2-butenyl) cyclohexa-3,5-dienone (40), 3,5-dihydroxy-6- (phenylacetyl) -2,2 -Bis (3-methyl-2-butenyl) -cyclohexa-3,5-dienone (41) and {3- (3-methyl-2-butenyl) -2,4,6-trihydroxyphenyl } Synthesis of (phenylmethyl) ketone (42)

733 mg of sodium methoxide 324 mg (6.00 mmol, 2.00 equiv) in a dry methanol (6.0 mL) solution under nitrogen atmosphere under ice-cooling stirring (phenylmethyl) (2,4,6-trihydroxyphenyl) ketone (38) 3.00 mmol) of dry methanol (3.0 mL) solution was added. Again a solution of 627 mg (6.00 mmol, 2.00 equiv) of methanol (4.0 mL) of 1-chloro-3-methyl-2-butene was slowly added. Stirring was continued for 3 hours. Methanol was distilled off under reduced pressure at room temperature and ether was added. The ether layer was washed with saturated brine, dried over sodium sulfate and the solvent was distilled off to obtain 1.027 g of crude product. This was subjected to silica gel column chromatography (46 g Wacogel C-300, hexane: ether = 19: 1 to 1: 1). 13 mg of {3,5-bis (3-methyl-2-butenyl) 2,4,6-trihydroxyphenyl} (phenylmethyl) ketone (39) in the order of distillation as yellow viscous oil, 98 mg of 5-dihydroxy-6- (phenylacetyl) -2,2,4-tris (3-methyl-2-butenyl) cyclohexa-3,5-dienone (40) as a yellow viscous oily substance 136 mg of 3,5-dihydroxy-6- (phenylacetyl) -2,2-bis (3-methyl-2-butenyl) -cyclohexa-3,5-dienone (41) as a yellow solid , 165 mg of {3- (3-methyl-2-butenyl) -2,4,6-trihydroxyphenyl} (phenylmethyl) ketone (42) were obtained as yellow crystals.

(39) 1 H-NMR (CDCl ₃ ): 1.79 (6H, d, J = 1.2), 1.84 (6H, s), 3.37 (2H, d, J = 7.3), 4.41 (2H, s), 5.22 (1H , m), 7.29 (5H, m)

(40) 1H-NMR (CDCl ₃ ): (major isomer) 1.54 (6H, s), 1.56 (6H, s), 1.77 (6H, s), 2.53 (2H, d, J = 7.8), 2.64 (2H , d, J = 7.3), 3.17 (2H, d, J = 7.3), 4.74 (2H, m), 5.12 (1H, m), 7.29 (5H, m);

(Minor isomer) 1.54 (6H, s), 1.56 (6H, s), 1.77 (6H, s), 2.67 (2H, d, J = 7.3), 3.21 (2H, d, J = 7.3), 4.74 (2H , m), 5.12 (1H, m), 7.29 (5H, m)

(41) 1 H-NMR (CDCl ₃ ): 1.52 (3H, s), 1.55 (3H, s), 1.56 (6H, s), 2.73 (4H, m), 4.41 (2H, s), 4.80 (1H, m)

(42) 1 H-NMR (CDCl ₃ ): 1.68 (3H, s), 1.76 (3H, s), 3.26 (2H, d, J = 7.0), 4.41 (2H, s), 6.00 (1H, s), 7.18-7.33 (5H, m)

Example 21

{3,5-bis (3,7-dimethyl-2,6-octadienyl) -2,4,6-trihydroxyphenyl} (phenylmethyl) ketone (43), 3,5-dihydroxy- 6- (phenylacetyl) -2,2,4-tris (3,7-dimethyl-2,6-octadienyl) cyclohexa-3,5-dienone (44), 3,5-dihydroxy- 6- (phenylacetyl) -2,2-bis (3,7-dimethyl-2,6-octadienyl) cyclohexa-3,5-dienone (45) and {3- (3,7-dimethyl- Synthesis of 2,6-octadienyl) -2,4,6-trihydroxyphenyl} (phenylmethyl) ketone (46)

To a solution of 324 mg (6.00 mmol, 2.00 equiv) of dry methanol (6.0 mL) in sodium methanol under nitrogen atmosphere (phenyl methyl) (2,4,6-trihydroxyphenyl) ketone (38) 733 mg (at room temperature) 3.00 mmol) of dry methanol (3.0 mL) solution was added. Again a solution of 1.036 g (6.00 mmol, 2.00 equiv) of methanol (5.0 mL) in 1-chloro-3,7-dimethyl-2,6-octadiene was slowly added. Stirring was continued for 3 hours at room temperature and 1 hour at 60 ° C. Methanol was distilled off under reduced pressure at room temperature and ether was added. The ether layer was washed with saturated brine, dried over sodium sulfate and the solvent was distilled off to give 1.567 g of crude product. This was subjected to silica gel column chromatography (50 g of Wacogel C-300, hexane: ether = 19: 1 to 6: 1). 132 mg of {3,5-bis (3,7-dimethyl-2,6-octadienyl) -2,4,6-trihydroxyphenyl} (phenylmethyl) ketone (43) in orange in sequence As an oil, 3,5-dihydroxy-6- (phenylacetyl) -2,2,4-tris (3,7-dimethyl-2,6-octadienyl) cyclohexa-3,5-dienone (44) 166 mg as a yellow viscous oil, 3,5-dihydroxy-6- (phenylacetyl) -2,2-bis (3,7-dimethyl-2,6-octadienyl) cyclohexa- 203 mg of 3,5-dienone (45) was used as an orange viscous oily product, and {3- (3,7-dimethyl-2,6-octadienyl) -2,4,6-trihydroxyphenyl} (phenyl 222 mg of methyl) ketone (46) were obtained as yellow crystals.

(43) 1 H-NMR (CDCl ₃ ): 1.59 (6H, s), 1.69 (12H, s), 1.97 (8H, m), 4.23 (2H, s), 5.05 (4H, m), 7.29 (5H, M)

(44) 1H-NMR (CDCl ₃ ): 1.54 (15H, s), 1.60 (3H, s), 1.64 (3H, s), 1.65 (3H, s), 1.69 (3H, s), 1.75-2.20 ( 4H, m), 3.20 (2H, d), 4.39 (2H, s), 4.79 (2H, m), 4.98 (2H, m), 5.04 (1H, m), 5.24 (1H, m), 7.29 (5H , m)

(45) 1H-NMR (CDCl ₃ ): 1.55 (9H, s), 1.65 (3H, s), 1.88 (8H, m), 2.63 (4H, m), 4.40 (2H, s), 4.85 (2H, m), 4.94 (2H, m), 7.28 (5H, m)

(46) 1 H-NMR (CDCl ₃ ): 1.57 (3H, s), 1.65 (3H, s), 1.77 (3H, s), 2.00 (4H, m), 3.29 (2H, d, J = 6.8), 4.41 (2H, s), 5.09 (1H, m), 5.24 (1H, M), 7.25 (5H, m)

Reference Example 8

Synthesis of (2,4-dihydroxy-6-methylphenyl) (2-methylpropyl) ketone (47)

160 ml of benzene was added to 14.20 g (100.0 mmol) of orcinol monohydrate, followed by heat distillation. This was done twice by dehydration operation. 45 ml of nitrobenzene and 45 ml of carbon disulfide were added thereto, and a small amount of 26.7 g (200 mmol, 2.00 equivalents) of aluminum chloride was added thereto under water cooling stirring, and a calcium chloride tube was attached and stirred. Subsequently, 12.1 g (100 mmol, 1.00 equiv) of isovaleryl chloride was slowly added dropwise, and stirring was continued at room temperature for 14 hours. After confirming that acid gas was generated, it was put into dilute hydrochloric acid (prepared with 100 ml of concentrated hydrochloric acid and 400 ml of cold water), stirred and extracted with ether. The ether layer was washed with saturated brine and then distilled off under reduced pressure. The mixture was distilled off under reduced pressure while adding water little by little, and nitrobenzene was distilled off by steam distillation. The residue was extracted with ether, washed with saturated brine and dried over sodium sulfate. The solvent was distilled off to obtain 18.53 g of a dark brown viscous oil. The crude product was separated by silica gel column chromatography (220 g of Wacogel C-200, hexane: ethyl acetate = 9: 1) to give (2,4-dihydroxy-6-methylphenyl) (2-methylpropyl) ketone (47 ) 5.681 g.

(47) 1 H-NMR (CDCl ₃ ): 0.97 (6H, d, J = 6.5), 2.25 (3H, s), 2.27 (1H, m), 2.78 (2H, d, J = 6.6), 6.23 (1H , s), 6.26 (1H, s)

<Example 22>

{2-hydroxy-6-methyl-4- (3-methyl-2-butenyloxy) phenyl} (2-methylpropyl) ketone (48), {2,4-dihydroxy-6-methyl-3 -(3-methyl-2-butenyl) phenyl} (2-methylpropyl) ketone (49) and {4,6-dihydroxy-2-methyl-3- (3-methyl-2-butenyl) pentyl } Synthesis of (3-methylpropyl) ketone (50)

300 mg (7.50 mmol, 1.50 equiv) of 60% sodium hydride was washed with paraffin under petroleum ether under a nitrogen atmosphere, and 7.5 ml of dry methanol was added thereto. Then a solution of 1.04 g (5.00 mmol) of methanol (5.0 mL) of (2,4-dihydroxy-6-methylpropyl) (2-methylpropyl) ketone (47) was added under ice-cooled stirring. Then, a solution of 784 mg (7.50 mmol, 1.50 equiv) of methanol (5.0 mL) in 1-chloro-3-methyl-2-butene was slowly added dropwise. Stirring was continued for 2 hours while returning to room temperature. Ether was added thereto, and the ether layer was washed with saturated ammonium chloride solution, saturated brine and dried over sodium sulfate. The solvent was distilled off to obtain 1.296 g of a dark red oil. A small amount of hexane was added and left in the refrigerator to recover 277 mg of the starting material as colorless needles. Part of the filtrate was separated by silica gel column chromatography (49 g of Wacogel C-300, hexane: acetic acid ether = 29: 1 to 7: 3), followed by {2-hydroxy-6-methyl-4- 108 mg of (3-methyl-2-butenyloxy) phenyl} (2-methylpropyl) ketone (48) was used as a yellow oil, {2,4-dihydroxy-6-methyl-3- (3-methyl 78 mg of -2-butenyl) phenyl} (2-methylpropyl) ketone (49) were colorless fine crystals, and then 260 mg of the tan oil, which was distilled off, was again subjected to column chromatography (6.0 g of Wacogel C-300, hexane: Purified with ethyl acetate = 19: 1), 162 mg of {4,6-dihydroxy-2-methyl-3- (3-methyl-2-butenyl) phenyl} (3-methylpropyl) ketone (50) was obtained. Obtained as a yellow viscous oil.

(48) 1 H-NMR (CDCl ₃ ): 0.97 (6H, d, J = 6.6), 1.74 (3H, s), 1.79 (3H, s), 2.22 (1H, m), 2.55 (3H, s), 2.78 (2H, d, J = 6.8), 4.51 (2H, d, J = 6.8), 5.46 (1H, m), 6.30 (1H, s)

(49) 1 H-NMR (CDCl ₃ ): 0.96 (6H, d, J = 6.4), 1.74 (3H, s), 1.80 (3H, s), 2.28 (1H, m), 2.51 (3H, s), 2.77 (2H, d, J = 6.6), 3.40 (2H, d, J = 6.7), 5.27 (1H, m), 6.20 (1H, s)

(50) 1 H-NMR (CDCl ₃ ): 0.92 (6H, d, J = 6.6), 1.73 (3H, s), 1.79 (3H, s), 2.28 (1H, m), 2.41 (3H, s), 2.74 (2H, d, J = 6.6), 3.31 (2H, d, J = 6.6), 5.07 (1H, m), 6.26 (1H, s)

<Example 23>

{3,5-bis (3-methyl-2-butenyl) -2-hydroxy-6-methyl-4- (3-methyl-2-butenyloxy) phenyl} (2-methylpropyl) ketone (51 ) And {2,4-dihydroxy-6-methyl-3- (3-methyl-2-butenyl) phenyl} (2-methylpropyl) ketone (49)

1.02 g (5.00 mmol) of (2,4-dihydroxy-6-methylphenyl) (2-methylpropyl) ketone (47) in a dry 1,4-dioxane (10.0 mL) solution at 10 ° C. under a nitrogen atmosphere 710 mg (5.00 mmol, 1.00 equiv) of boron trifluoride ether complex was added. Subsequently, a solution of 861 mg (10.0 mmol, 2.00 eq) of dioxane (5.0 mL) in 3-methyl-2-butenol was slowly added dropwise, and stirring was continued for 5 hours while returning to room temperature. Ether was added to the reaction mixture, and the ether layer was washed with saturated sodium bicarbonate water and brine, and dried over sodium sulfate. The solvent was distilled off to give 2.072 g of an orange oil. The crude product was separated by silica gel column chromatography (Wakogel C-300 65 g, hexane: ethyl acetate = 19: 1 to 7: 3), followed by {3,5-bis (3-methyl-2- 246 mg of butenyl) -2-hydroxy-6-methyl-4- (3-methyl-2-butenyloxy) phenyl} (2-methylpropyl) ketone (51) was obtained as a pale yellow viscous oil. 95 mg of 4-dihydroxy-6-methyl-3- (3-methyl-2-butenyl) phenyl} (2-methylpropyl) ketone (49) were obtained as pale yellow fine acicular crystals.

(51) 1 H-NMR (CDCl ₃ ): 0.92 (6H, d, J = 6.4), 1.74 (18H, m), 2.18 (1H, m), 2.38 (3H, s), 2.73 (2H, d, J = 7.2), 3.31 (2H, d, J = 8.4), 3.41 (2H, d, J = 8.6), 3.94 (2H, d, J = 6.8), 5.06 (2H, m), 5.37 (2H, m)

Reference Example 9

Synthesis of (2,4-dihydroxyphenyl) (2-methylpropyl) ketone (52)

5.506 g (50.00 mmol) of resorcinol was added to 45 mL of nitrobenzene, and 13.3 g (100 mmol, 2.00 equiv) of aluminum chloride was added in small portions under water-cooled stirring, and the calcium chloride tube was attached and stirred. Then, 6.03 g (50.0 mmol, 1.00 equiv) of isovaleryl chloride was slowly added dropwise, stirring was continued at room temperature for 1 hour, and then the mixture was heated and stirred at 90 ° C for 6 hours. When the generation of acidic gas stopped, it was put into dilute hydrochloric acid (prepared with 40 ml of concentrated hydrochloric acid and 160 ml of cold water), stirred and extracted with ether. The ether layer was washed with saturated brine and then distilled off under reduced pressure. The mixture was distilled off under reduced pressure while adding water little by little, and nitrobenzene was distilled off by steam distillation. The residue was extracted again with ether, washed with saturated brine and dried over sodium sulfate. The solvent was distilled off and 8.952 g of red viscous oil was obtained. This was purified by silica gel column chromatography (200 g of Wacogel C-200, hexane: ether = 8: 2 to 7: 3) to give (2,4-dihydroxyphenyl) (2-methylpropyl) ketone (52) 4.37 g was obtained as pale yellow crystals.

<Example 24>

{2-hydroxy-4- (3-methyl-2-butenyloxy) phenyl} (2-methylpropyl) ketone (53) and {2,4-dihydroxy-3- (3-methyl-2- Synthesis of Butenyl) phenyl} (2-methylpropyl) ketone (54)

486 mg (2.50 mmol) of (2,4-dihydroxyphenyl) (2-methylpropyl) ketone (52) and 784 mg (7.50 mmol, 3.00 equiv) of 1-chloro-3-methyl-2-butene were added to a nitrogen atmosphere. Dissolved in 7.0 ml of dry methanol.

To this was slowly added dropwise a solution of 405 mg (7.50 mmol, 3.00 equiv) of methanol (7.5 mL) in sodium methoxide under room temperature stirring. After stirring at room temperature for 3 hours and at 50 ° C for 1 hour, methanol was distilled off under reduced pressure at room temperature and ether was added thereto. The ether layer was washed with saturated ammonium chloride solution, saturated brine and dried over sodium sulfate. The solvent was distilled off and 661 mg of red oils were obtained. The crude product was separated by silica gel column chromatography (20 g of Wacogel C-300, hexane: ether = 50: 1 to 4: 1), followed by {2-hydroxy-4- (3-methyl-2- 139 mg of butenyloxy) phenyl} (2-methylpropyl) ketone (53) was obtained as colorless oil. {2,4-dihydroxy-3- (3-methyl-2-butenyl) phenyl} (2- 41 mg of methylpropyl) ketone (54) were obtained as colorless crystals.

(53) 1 H-NMR (CDCl ₃ ): 1.00 (6H, d, J = 6.4), 1.75 (3H, s), 1.79 (3H, s), 2.26 (1H, m), 2.75 (2H, d, J = 6.6), 4.53 (2H, d, J = 6.8), 5.46 (1H, m), 6.42 (1H, d, J = 2.4), 6.43 (1H, dd, J = 9.6, 2.4), 7.64 (1H, d, J = 9.6)

(54) 1 H-NMR (CDCl ₃ ): 1.00 (6H, d, J = 6.4), 1.76 (3H, s), 1.83 (3H, s), 2.26 (1H, m), 2.75 (2H, d, J = 7.0), 3.44 (2H, d, J = 7.0), 5.27 (1H, m), 6.36 (1H, d, J = 8.8), 7.55 (1H, d, J = 8.8)

<Example 25>

Synthesis of {2,4-dihydroxy-5- (3-methyl-2-butenyl) phenyl} (2-methylpropyl) ketone (55)

Boron trifluoride ether at 10 ° C. under a nitrogen atmosphere in a dry 1,4-dioxane (5.0 mL) solution of 486 mg (2.50 mmol) of (2,4-dihydroxyphenyl) (2-methylpropyl) ketone (52) 355 mg (2.50 mmol, 1.00 equiv) of the complex was added. Subsequently, a solution of 431 mg (5.00 mmol, 2.00 equiv) of dimethyl acid (2.0 mL) in 3-methyl-2-butenol was slowly added dropwise to return to room temperature, and the stirring was continued for 22 hours and again at 50 ° C for 3 hours. Ether was added to the reaction mixture, and the ether layer was washed with saturated sodium bicarbonate water, brine and dried over sodium sulfate.

The solvent was distilled off to obtain 864 mg of a colorless oil. The crude product was separated by silica gel column chromatography (Wakogel C-300 25 g, hexane: ether = 19: 1 to 4: 1) to give {2,4-dihydroxy-5- (3-methyl-2- 136 mg of butenyl) phenyl} (2-methylpropyl) ketone (55) was obtained.

(55) 1 H-NMR (CDCl ₃ ): 1.01 (6H, d, J = 6.6), 1.79 (6H, s), 2.26 (1H, m), 2.75 (2H, d, J = 6.6), 3.30 (2H , d, J = 8.3), 5.30 (1H, m), 6.36 (1H, s), 7.45 (1H, s)

Example 26

(1) Preparation of Cells

11-12 days old ICR mice (purchased from Charles River) were euthanized with ether anesthesia and immediately sterilized in 70% ethanol. Using ethanol sterilized ophthalmic scissors and tweezers, the mice's femurs and tibias were extracted and α-MEM medium containing 5% FBS (purchased from Irvine Scientific), 100 U / ml penicillin, 100 μg / ml streptomycin ( Incised using scissors in a flow laboratories), and again, the supernatant obtained by pipetting was collected, washed with culture medium, and suspended in 5% FBS and α-MEM culture medium to osteoclasts containing osteoclasts. I made it. The bone cell suspension supernatant after standing for 3 minutes was taken and passed through a mesh (Cell strainer, 70 µm, purchased from Falcon). Cell concentrations were prepared at 1 × 10 ⁷ / ml and used in groove formation assays.

(2) Assay by Pit Formation Assay

The ivory piece was cut to a thickness of 150 mu m using a precision low speed cutter (purchased from Buehler), and then a 6 mm diameter circular hole was drilled using a single hole punch. The ivory flakes were soaked in 70% ethanol and sonicated twice for 5 minutes and washed three times in sterile PBS and twice in medium. This ivory piece was placed in a 96-hole culture plate (purchased from Falcon) and 100 μl of the culture solution containing the compound of the present invention prepared at a concentration of 2 × 10 ⁻⁵ M (final drug concentration 1 × 10 ⁻⁵ M). Was added to each hole, and 100 µl of the culture solution containing the prepared osteocytes 1 × 10 ⁷ / ml was placed in each hole and incubated in a 37 ° C., 10% CO ₂ incubator for 3 days. After incubation, the cells of ivory flakes were removed with a rubber spatula in 2 N sodium hydroxide solution, and after washing with water and methanol, the absorbing grooves were stained with Coomassie Brilliant Blue, and then, under the microscope, Counted Naturally, the number of grooves in the osteoblasts was varied depending on the percentage of various cells in the osteocytic suspension or the animal lot used. However, in the same experiment, good results were confirmed. The inhibition of bone resorption was calculated by setting the number of absorption grooves without drug addition to 0% and the number of absorption grooves to zero in the presence of rPTH (1 × 10 ⁻⁸ M) in the culture.

This test was done as experiment 1-10. The results are shown in Tables 2 and 3. As is clear from these results, the compound of the present invention shows a significant inhibition of bone resorption and is useful as a compound having an effect of inhibiting bone resorption.

In addition, "(-)" of the additive drug number column of Table 2 and Table 3 represents a control without drug addition, and the number of numbers represents the number of the compound.

Added drug number Drug concentration (m) Absorption groove number (mean ± standard error) % Inhibition Experiment 1 (-) 0 80.1 ± 5.6 0 13 10 ^-5 M 16.8 ± 3.6 79.0 14 10 ^-5 M 26.0 ± 2.6 67.5 15 10 ^-5 M 8.3 ± 2.4 89.6 16 10 ^-5 M 0 100.0 Experiment 2 (-) 0 201.8 ± 10.9 0 25 10 ^-5 M 0 100.0 26 10 ^-5 M 29.3 ± 4.8 85.5 27 10 ^-5 M 38.8 ± 6.6 80.8 28 10 ^-5 M 61.3 ± 5.5 69.6 33 10 ^-5 M 9.8 ± 1.8 95.1 Experiment 3 (-) 0 98.9 ± 9.3 0 29 10 ^-5 M 20.3 ± 2.1 79.5 30 10 ^-5 M 21.4 ± 3.9 78.2 32 10 ^-5 M 33.9 ± 4.1 65.7 Experiment 4 (-) 0 162.6 ± 17.8 0 24 10 ^-5 M 39.3 ± 13.9 75.8 37 10 ^-5 M 14.4 ± 4.9 91.1 Experiment 5 (-) 0 187.7 ± 21.0 0 6 10 ^-5 M 63.4 ± 12.4 61.4 19 10 ^-5 M 55.3 ± 6.1 70.5 20 10 ^-5 M 3.0 ± 1.3 98.4 21 10 ^-5 M 3.5 ± 1.4 98.1 22 10 ^-5 M 3.5 ± 1.1 98.1

Added drug number Drug concentration (m) Absorption groove number (mean ± standard error) % Inhibition Experiment 6 (-) 0 201.8 ± 20.2 0 34 10 ^-5 M 8.2 ± 1.9 95.9 36 10 ^-5 M 3.8 ± 0.9 98.1 47 10 ^-5 M 179.8 ± 23.8 10.9 48 10 ^-5 M 85.2 ± 7.5 57.8 49 10 ^-5 M 44.3 ± 5.4 78.0 50 10 ^-5 M 40.1 ± 7.0 80.1 51 10 ^-5 M 102.7 ± 6.2 42.8 Experiment 7 (-) 0 179.6 ± 34.4 0 39 10 ^-5 M 49.2 ± 9.4 72.6 Experiment 8 (-) 0 125.3 ± 12.2 0 38 10 ^-5 M 55.8 ± 7.7 57.9 40 10 ^-5 M 4.9 ± 3.8 96.1 41 10 ^-5 M 3.2 ± 0.7 97.4 42 10 ^-5 M 31.7 ± 3.6 74.7 Experiment 9 (-) 0 224.8 ± 20.0 0 43 10 ^-5 M 11.3 ± 2.5 95.0 44 10 ^-5 M 7.7 ± 2.0 96.6 45 10 ^-5 M 8.2 ± 1.8 96.4 46 10 ^-5 M 125.3 ± 12.6 44.3 Experiment 10 (-) 0 171.2 ± 16.6 0 52 10 ^-5 M 94.3 ± 13.8 44.9 53 10 ^-5 M 55.1 ± 11.1 67.8 54 10 ^-5 M 66.5 ± 9.7 61.2 55 10 ^-5 M 15.8 ± 3.3 90.8

Claims (21)

A compound of formula (I) or a salt thereof <Formula I> In the above formula, R ₁ represents a branched or straight chain alkyl group having 1 to 15 carbon atoms (excluding methyl group), a substituted or unsubstituted benzyl group, or a substituted or unsubstituted aryl group, R ₂ represents a hydrogen atom, a branched or straight chain alkyl group having 1 to 15 carbon atoms, a branched or straight chain alkenyl group having 2 to 15 carbon atoms, or a substituted or unsubstituted benzyl group, R ₃ is a hydrogen atom, a branched or straight chain alkyl group having 1 to 15 carbon atoms, a branched or straight chain alkenyl group having 2 to 15 carbon atoms, a substituted or unsubstituted benzyl group, a hydroxyl group, a branched chain having 1 to 15 carbon atoms Or a straight alkoxy group, a branched or straight chain alkenyloxy group having 2 to 15 carbon atoms, or a substituted or unsubstituted benzyloxy group, R ₄ represents a hydrogen atom, a branched or straight chain alkyl group having 1 to 15 carbon atoms, a branched or straight chain alkenyl group having 2 to 15 carbon atoms, a substituted or unsubstituted benzyl group, or a hydroxyl group, R ₅ and R ₆ each independently represent a hydrogen atom, a branched or straight chain alkyl group having 1 to 15 carbon atoms, a branched or straight chain alkenyl group having 2 to 15 carbon atoms, or a substituted or unsubstituted benzyl group, Provided that when R ₁ is a branched or straight chain alkyl group having 1 to 15 carbon atoms, R ₄ is a hydroxyl group, and R ₅ and R ₆ are a hydrogen atom or a branched or straight chain alkyl group having 1 to 15 carbon atoms, _{When 2} and R ₃ are a hydrogen atom, 3-methyl-2-butenyl group or a branched or straight chain alkoxy group having 1 to 15 carbon atoms, R ₁ is a branched or straight chain alkyl group having 1 to 15 carbon atoms or a substitution or An unsubstituted aryl group, R ₄ and R ₅ are hydrogen atoms, when R ₆ is a hydrogen atom or a branched or straight chain alkyl group having 1 to 15 carbon atoms, when R ₂ is a hydrogen atom, and R ₁ is The case where R ₂ and R ₃ are a hydrogen atom, 3-methyl-2-butenyl group, or 3-methyl-n-butyl group when it is a 2-methylpropyl group is excluded. The compound or a salt thereof according to claim 1, wherein R ₁ is 2-methylpropyl group, 2,6-dimethylbutyl group, benzyl group or phenyl group. The compound or a salt thereof according to claim 1 or 2, wherein R ₂ or R ₃ is a hydrogen atom, 3-methyl-2-butenyl group, 3,7-dimethyl-2,6-octadienyl group or benzyl group. A compound according to claim 1 or a salt thereof. <Formula II> In the formula, R ₁ represents a 2-methylpropyl group or a 2,6-dimethylheptyl group, R ₂ and R ₃ each independently represent a hydrogen atom, a 3-methyl-2-butenyl group, a 3,7-dimethyl-2,6-octadienyl group, or a substituted or unsubstituted benzyl group, However, the case where R ₁ is a 2-methylpropyl group and R ₂ or R ₃ are each independently a hydrogen atom or a 3-methyl-2-butenyl group is excluded. A compound according to claim 1 or a salt thereof. <Formula III> In the above formula, R ₁ represents a branched or straight chain alkyl group having 1 to 15 carbon atoms (excluding methyl group), a substituted or unsubstituted benzyl group, or a substituted or unsubstituted aryl group, R ₂ and R ₄ each independently represent a hydrogen atom, a branched or straight chain alkyl or alkenyl group having 1 to 15 carbon atoms, or a substituted or unsubstituted benzyl group, R ₅ , R ₆ and R ₇ each independently represent a hydrogen atom, a branched or linear alkyl or alkenyl group having 1 to 15 carbon atoms, or a substituted or unsubstituted benzyl group. The compound of claim 1, 4 or 5, wherein the compound is {3,5-bisbenzyl-2,4,6-trihydroxyphenyl} (2-methylpropyl) ketone, {3,5-bis (3,7-dimethyl-2,6-octadienyl) -2,4,6-trihydroxyphenyl} (2-methylpropyl) ketone, {3- (3-methyl-2-butenyl) -2,4,5-trihydroxyphenyl} (2-methylpropyl) ketone, {3,6-bis (3-methyl-2-butenyl) -2,4,5-trihydroxyphenyl} (2-methylpropyl) ketone, {6- (3-methyl-2-butenyl) -2,4,5-trihydroxyphenyl} (2-methylpropyl) ketone mono (3-methyl-2-butenyl) ether, (2,4,5-trihydroxyphenyl} (2-methylpropyl) ketone mono (3-methyl-2-butenyl) ether, {3,5-bis (3-methyl-2-butenyl) -2,4,6-trihydroxyphenyl} (phenylmethyl) ketone, {3- (3-methyl-2-butenyl) -2,4,6-trihydroxyphenyl} (phenylmethyl) ketone, {3,5-bis (3,7-dimethyl-2,6-octadienyl) -2,4,6-trihydroxyphenyl} (phenylmethyl) ketone, {3- (3,7-dimethyl-2,6-octadienyl) -2,4,6-trihydroxyphenyl} (phenylmethyl) ketone, {2-hydroxy-6-methyl-4- (3-methyl-2-butenyloxy) phenyl} (2-methylpropyl) ketone, {2,4-hydroxy-6-methyl-3- (3-methyl-2-butenyl) phenyl} (2-methylpropyl) ketone, {4,6-dihydroxy-2-methyl-3- (3-methyl-2-butenyl) phenyl} (3-methylpropyl) ketone, {3,5-bis (3-methyl-2-butenyl) -2-hydroxy-6-methyl-4- (3-methyl-2-butenyloxy) phenyl} (2-methylpropyl) ketone, {2-hydroxy-4- (3-methyl-2-butenyloxy) phenyl} (2-methylpropyl) ketone, {2,4-dihydroxy-3- (3-methyl-2-butenyl) phenyl} (2-methylpropyl) ketone, and A compound or a salt thereof, which is any one selected from the group consisting of {2,4-dihydroxy-5- (3-methyl-2-butenyl) phenyl} (2-methylpropyl) ketone. A compound of formula IV: or a salt thereof. <Formula IV> In the above formula, R ₁ represents a branched or straight chain alkyl group having 1 to 15 carbon atoms, a substituted or unsubstituted benzyl group, or a substituted or unsubstituted aryl group, R ₂ represents a hydrogen atom, a branched or straight chain alkyl group having 1 to 15 carbon atoms, a branched or straight chain alkenyl group having 2 to 15 carbon atoms, or a substituted or unsubstituted benzyl group, R ₃ represents a branched or straight chain alkyl group having 1 to 15 carbon atoms, a branched or straight chain alkenyl group having 2 to 15 carbon atoms, or a substituted or unsubstituted benzyl group, R ₈ represents a hydroxyl group, a branched or straight chain alkyl group having 1 to 15 carbon atoms, a branched or straight chain alkenyl group having 2 to 15 carbon atoms, or a substituted or unsubstituted benzyl group, Provided that when R ₁ is a methyl group and R ₈ is a hydroxyl group, R ₂ and R ₃ are each a 3-methyl-2-butenyl group, and when R ₁ is a 2-propyl group or 2-methylpropyl group, R ₂ And when two or three groups of R ₃ and R ₈ are each a 3-methyl-2-butenyl group and the remaining group is a hydrogen atom or a hydroxyl group. The compound or a salt thereof according to claim 7, wherein R ₁ is a 2-methylpropyl group, a 2,6-dimethylheptyl group, or a phenyl group. The compound or a salt thereof according to claim 7 or 8, wherein R ₂ or R ₃ is 3-methyl-2-butenyl group, 3,7-dimethyl-2,6-octadienyl group or benzyl group. The compound of formula V or a salt thereof according to claim 7. <Formula Ⅴ> In the formula, R ₁ represents a 2-methylpropyl group or a 2,6-dimethylheptyl group, R ₂ represents a hydrogen atom, 3-methyl-2-butenyl group, 3,7-dimethyl-2,6-octadienyl group, or a substituted or unsubstituted benzyl group, R ₃ represents a 3-methyl-2-butenyl group, a 3,7-dimethyl-2,6-octadienyl group, or a substituted or unsubstituted benzyl group, However, the case where R ₁ is a 2-methylpropyl group or 2-propyl group, R ₂ is a hydrogen atom or 3-methyl-2-butenyl group, and R ₃ is a 3-methyl-2-butenyl group is excluded. 8. A compound of formula VI or a salt thereof according to claim 7. <Formula VI> In the above formula, R ₁ represents a 2-methylpropyl group or a substituted or unsubstituted aryl group, R ₂ and R ₃ each represent a 3-methyl-2-butenyl group or a substituted or unsubstituted benzyl group, Provided that R ₁ is a 2-methylpropyl group and R ₂ and R ₃ are each a 3-methyl-2-butenyl group. The compound of claim 7, wherein the compound is 2,2-bis (3,7-dimethyl-2,6-octadienyl) -3,5-dihydroxy-6- (3-methyl-1-oxobutyl) cyclohexa-3,5-dienone , 3,5-dihydroxy-6- (3-methyl-1-oxobutyl) -2,2,4-tris (3,7-dimethyl-2,6-octadienyl) cyclohexa-3,5- Dinon, 2,2-bisbenzyl-3,5-dihydroxy-6- (3-methyl-1-oxobutyl) cyclohexa-3,5-dienone, 3,5-dihydroxy-6- (3-methyl-1-oxobutyl) -2,2,4-trisbenzylcyclohexa-3,5-dienone, 2,2-bis (3-methyl-2-butenyl) -3,5-dihydroxy-6- (3,7-dimethyl-1-oxooctyl) cyclohexa-3,5-dienone, 3,5-dihydroxy-6- (3,7-dimethyl-1-oxooctyl) -2,2,4-tris (3-methyl-2-butenyl) cyclohexa-3,5-dienone, 2,4-bis (3-methyl-2-butenyl) -6- (benzoyl) -2,3,5-trihydroxycyclohexa-3,5-dienone, 2,4-dimethyl-6- (3-methyl-1-oxobutyl) -2,3,5-trihydroxycyclohexa-3,5-dienone, 2,4-bisbenzyl-6- (3-methyl-1-oxobutyl) -2,3,5-trihydroxycyclohexa-3,5-dienone, 3,5-dihydroxy-6- (phenylacetyl) -2,2,4-tris (3-methyl-2-butenyl) cyclohexa-3,5-dienone, 3,5-dihydroxy-6- (phenylacetyl) -2,2-bis (3-methyl-2-butenyl) cyclohexa-3,5-dienone, 3,5-dihydroxy-6- (phenylacetyl) -2,2,4-tris (3,7-dimethyl-2,6-octadienyl) cyclohexa-3,5-dienone and Selected from the group consisting of 3,5-dihydroxy-6- (phenylacetyl) -2,2-bis (3,7-dimethyl-2,6-octadienyl) cyclohexa-3,5-dienone A compound or a salt thereof, which is a compound of any one of. A pharmaceutical composition comprising one or more of the compounds according to any one of claims 1 to 12 and a pharmaceutically acceptable carrier. The pharmaceutical composition according to claim 13, which is an agent for preventing and treating bone and cartilage diseases. A method for preventing or treating bone and cartilage diseases, comprising administering at least one compound of any one of claims 1 to 12 in an amount effective for treating or preventing bone and cartilage diseases. Use of at least one compound of the compound according to any one of claims 1 to 12 for the manufacture of a pharmaceutical composition for the prevention or treatment of bone and cartilage diseases. A pharmaceutical composition comprising at least one compound of the formula (I) or salts thereof and a pharmaceutically acceptable carrier. <Formula I> In the above formula, R ₁ represents a branched or straight chain alkyl group having 1 to 15 carbon atoms (excluding methyl group), a substituted or unsubstituted benzyl group, or a substituted or unsubstituted aryl group, R ₂ represents a hydrogen atom, a branched or straight chain alkyl group having 1 to 15 carbon atoms, a branched or straight chain alkenyl group having 2 to 15 carbon atoms, or a substituted or unsubstituted benzyl group, R ₃ is a hydrogen atom, a branched or straight chain alkyl group having 1 to 15 carbon atoms, a branched or straight chain alkenyl group having 2 to 15 carbon atoms, a substituted or unsubstituted benzyl group, a hydroxyl group, a branched chain having 1 to 15 carbon atoms Or a straight alkoxy group, a branched or straight chain alkenyloxy group having 2 to 15 carbon atoms, or a substituted or unsubstituted benzyloxy group, R ₄ represents a hydrogen atom, a branched or straight chain alkyl group having 1 to 15 carbon atoms, a branched or straight chain alkenyl group having 2 to 15 carbon atoms, a substituted or unsubstituted benzyl group, or a hydroxyl group, R ₅ and R ₆ each independently represent a hydrogen atom, a branched or straight chain alkyl group having 1 to 15 carbon atoms, a branched or straight chain alkenyl group having 2 to 15 carbon atoms, or a substituted or unsubstituted benzyl group, Provided that when R ₁ is a branched or straight alkyl group having 1 to 15 carbon atoms, R ₄ is a hydroxyl group, and R ₅ and R ₆ are each hydrogen atoms, R ₂ and R ₃ are each a hydrogen atom or 3-methyl; When it is a 2-butenyl group, when R <_1> is a C1-C15 branched or linear alkyl group, when R <_4> , R <_5> and R <_6> are each hydrogen atoms, R <_2> is a hydrogen atom, and R _{When 1} is a 2-methylpropyl group, the case where R <_2> and R <_3> is a hydrogen atom, 3-methyl- 2-butenyl group, or 3-methyl- n-butyl group, respectively is excluded. A pharmaceutical composition useful as an agent for preventing and treating bone and cartilage diseases, comprising at least one compound of the formula (VII) or a salt thereof and a pharmaceutically acceptable carrier. <Formula Ⅶ> In the above formula, R ₁ represents a branched or straight chain alkyl group having 1 to 15 carbon atoms, a substituted or unsubstituted benzyl group, or a substituted or unsubstituted aryl group, R ₂ represents a hydrogen atom, a branched or straight chain alkyl group having 1 to 15 carbon atoms, a branched or straight chain alkenyl group having 2 to 15 carbon atoms, or a substituted or unsubstituted benzyl group, R ₃ is a hydrogen atom, a branched or straight chain alkyl group having 1 to 15 carbon atoms, a branched or straight chain alkenyl group having 2 to 15 carbon atoms, a substituted or unsubstituted benzyl group, a hydroxyl group, a branched chain having 1 to 15 carbon atoms Or a straight alkoxy group, a branched or straight chain alkenyloxy group having 2 to 15 carbon atoms, or a substituted or unsubstituted benzyl group, R ₄ represents a hydrogen atom, a branched or straight chain alkyl group having 1 to 15 carbon atoms, a branched or straight chain alkenyl group having 2 to 15 carbon atoms, a substituted or unsubstituted benzyl group, or a hydroxyl group, R ₅ and R ₆ each independently represent a hydrogen atom, a branched or straight chain alkyl group having 1 to 15 carbon atoms, a branched or straight chain alkenyl group having 2 to 15 carbon atoms, or a substituted or unsubstituted benzyl group. A pharmaceutical composition comprising at least one compound of the formula (VII) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. <Formula Ⅹ> In the above formula, R ₁ represents a branched or straight chain alkyl group having 1 to 15 carbon atoms, a substituted or unsubstituted benzyl group, or a substituted or unsubstituted aryl group, R ₂ represents a hydrogen atom, a branched or straight chain alkyl group having 1 to 15 carbon atoms, a branched or straight chain alkenyl group having 2 to 15 carbon atoms, or a substituted or unsubstituted benzyl group, R ₃ represents a branched or straight chain alkyl group having 1 to 15 carbon atoms, a branched or straight chain alkenyl group having 2 to 15 carbon atoms, or a substituted or unsubstituted benzyl group, R ₈ represents a hydroxyl group, a branched or straight chain alkyl group having 1 to 15 carbon atoms, a branched or straight chain alkenyl group having 2 to 15 carbon atoms, or a substituted or unsubstituted benzyl group, Provided that when R ₁ is a methyl group and R ₈ is a hydroxyl group, R ₂ and R ₃ are 3-methyl-2-butenyl groups, and when R ₁ is a 2-propyl group or 2-methylpropyl group, R ₂ , Except when two or three groups of R ₃ and R ₈ are each a 3-methyl-2-butenyl group and the remaining group is a hydrogen atom or a hydroxyl group. A method for preventing or treating bone and cartilage diseases, comprising administering the pharmaceutical composition according to claim 17 or 18 or 19 in an amount effective for treating or preventing bone and cartilage diseases. Use of at least one compound of the compound according to claim 17, 18 or 19 for the manufacture of a pharmaceutical composition for the prevention or treatment of bone and cartilage diseases.