WO1998052899A1 - Polyhydroxybenzene derivatives and preventive/remedy for bone and cartilage diseases - Google Patents

Abstract

Compounds having potent activities of inhibiting bone resorption and being useful as preventives/remedies for bone and cartilage diseases and medicinal compositions containing the same. The compounds refer to polyhydroxyphenols represented by general formula (I) to (III) and quinone analogues thereof.

Description

 Specification

Polyhydroxybenzene derivatives and bones composed of them · Prevention and treatment of cartilage diseases

Technical field

 The present invention relates to bone resorbable bone diseases such as malignant hypercalcemia, bone pageet disease or osteoporosis, and osteoarthritis occurring in knees, shoulders, hip joints, etc., cartilage metamorphosis such as osteonecrosis of the femur, rheumatoid arthritis, etc. Novel polyhydroxybenzene derivative, salt or solvate thereof, developed for the purpose of preventing and treating diseases associated with the following, and a pharmaceutical composition containing one or more of them as an active ingredient About things. Background art

 Japan is entering an unprecedented aging society, and the increase in bone resorbable bone diseases such as osteoporosis has become a major social problem. Bone resorbable bone disease refers to a bone disease caused by abnormally enhanced bone resorption, such as myeloma, lymphoma, or hypercalcemia caused by bone marrow. There are osteoporosis caused by various factors such as Graves' disease, aging and closing. The increase in the number of bedridden people due to the fracture of the elderly due to bone resorbable bone disease has led to a huge increase in medical expenses. However, at present, vitamin D preparation and calcitonin preparation dipriflavone preparation have been used for treatment, but they have not been a fundamental treatment method and are limited to symptomatic treatment.

Osteoarthritis, femoral head necrosis, and rheumatoid arthritis are a group of diseases in which articular cartilage and subchondral bone are degenerated or necrotic due to various factors such as mechanical stress, aging, and inflammation, and cartilage • bone loss. is there. These cartilage defects can significantly affect the quality of daily life due to joint deformation and pain. Despite the treatment of these disease groups with hyaluronic acid, anti-inflammatory drugs, and analgesics, there is currently no drug that can effectively prevent or repair cartilage defects. The present inventors have previously reported that hops contain a potent bone resorption inhibitor and that the active body is known to have the structure of humulone (R. Stevens,

Chem., Rev., (19669)) and its homologues (see Japanese Patent Application Laid-Open No. Hei 7-330594). However, it has been pointed out that humulones, which are natural bone resorption inhibiting active substances, are natural substances, so that the yield is easily affected by climatic conditions and other factors, and it is pointed out that there is a problem in obtaining them.

 The present inventors have previously filed an application for finding out that polyhydroxybenzene derivatives have strong activity (Japanese Patent Application No. 8-154710).

 Therefore, an object of the present invention is to provide a new effective prophylactic / therapeutic agent, particularly a prophylactic / therapeutic agent for bone / cartilage disease, with the aim of improving the current treatment method. Disclosure of the invention

 The present inventor tried structural transformation based on the structure of the humulone in order to find a powerful active substance comparable to the above humulone among the compounds around the humulone, synthesized many compounds, and measured the activity. did. As a result, the inventors have found potent activity in novel polyhydroxybenzene derivatives represented by the following general formulas (I) to (III) and completed the present invention. BEST MODE FOR CARRYING OUT THE INVENTION

 That is, the present invention provides a novel polyhydroxybenzene derivative in which a benzene ring is substituted with two or more hydroxyl groups or derivatives thereof (for example, an alkoxy group), and one or more of these polyhydroxybenzene derivatives. The present invention relates to a pharmaceutical composition for preventing and treating bone and cartilage diseases comprising two or more types.

 Specifically, the present invention provides the following general formula (I)

(Wherein RR ² and R ³ are each independently a hydrogen atom, a linear or branched substituted or unsubstituted alkyl group having 1 to 15 carbon atoms, Represents a linear or branched, substituted or unsubstituted alkenyl group, substituted or unsubstituted benzyl group, or aryl group;

RR ⁽ⁱ is each independently a hydrogen atom, a linear or branched substituted or unsubstituted alkyl group having 1 to 15 carbon atoms, a linear or branched chain having 2 to 15 carbon atoms. Represents a substituted or unsubstituted alkenyl group, or a substituted or unsubstituted benzyl group.)

Or a salt or solvate thereof, an acylpyrogallol derivative.

 Further, the present invention provides the following general formula (II)

(In the formula, R ′, R ² and R ⁴ are each independently a hydrogen atom, a halogen atom, a linear or branched substituted or unsubstituted alkyl group having 1 to 15 carbon atoms, A linear or branched substituted or unsubstituted alkenyl group having 2 to 15 carbon atoms, a substituted or unsubstituted benzyl group, or a linear or branched substituted or unsubstituted 3 to 15 carbon atom group; Represents a substituted 1-oxoalkyl group, a linear or branched substituted or unsubstituted 1-oxoalkenyl group having 3 to 15 carbon atoms, or a substituted or unsubstituted 1-oxoaralkyl group. ,

R ³ is a hydroxyl group, a linear or branched substituted or unsubstituted alkyl group having 1 to 15 carbon atoms, a linear or branched substituted or unsubstituted alkyl group having 1 to 15 carbon atoms. Substituted alkyloxy group, linear or branched substituted or unsubstituted alkenyl group having 2 to 15 carbon atoms, linear or branched substituted or unsubstituted having 2 to 15 carbon atoms Represents an alkenyloxy group, a substituted or unsubstituted benzyl group, or a substituted or unsubstituted benzyloxy group,

R ⁵ and R ⁶ each independently represent a hydrogen atom, a linear or branched chain having 1 to 15 carbon atoms. Substituted or unsubstituted alkyl group, linear or branched, substituted or unsubstituted alkenyl group having 2 to 15 carbon atoms, substituted or unsubstituted benzyl group, linear group having 3 to 15 carbon atoms Or a branched or substituted substituted or unsubstituted 1-oxoalkyl group, a linear or branched substituted or unsubstituted 1-oxoalkenyl group having 3 to 15 carbon atoms, or a substituted or unsubstituted group Represents a 1-oxoaralkyl group.

Provided that R ⁴ is a straight-chain or branched unsubstituted 1-oxoalkyl group having 3 to 15 carbon atoms, or a straight-chain or branched unsubstituted 1-oxo alkyl group having 3 to 15 carbon atoms. When a one-year-old oxoalkenyl group or an unsubstituted 1-oxoaralkyl group and R ³ is a hydroxyl group, R ¹ and R ² are simultaneously a hydrogen atom and have 1 to 15 carbon atoms. A straight-chain or branched unsubstituted alkyl group, a straight-chain or branched-chain unsubstituted alkenyl group having 2 to 15 carbon atoms, or a substituted or unsubstituted Except when it is a benzyl group. )

And a resorcinol derivative which is a salt or solvate thereof.

 Further, the present invention provides a compound represented by the following general formula (III)

(Wherein RR ² and R \ R ⁵ each independently represent a hydrogen atom, a linear or branched substituted or unsubstituted alkyl group having 1 to 15 carbon atoms, and a carbon atom having 2 to 15 carbon atoms. Linear or branched, substituted or unsubstituted alkenyl group, substituted or unsubstituted benzyl group, linear or branched, substituted or unsubstituted 1-oxoalkyl having 3 to 15 carbon atoms A linear or branched, substituted or unsubstituted 1-oxoalkenyl group having 3 to 15 carbon atoms, or a substituted or unsubstituted 1-oxoaralkyl group;

3 is a hydroxyl group, a linear or branched substituted or unsubstituted alkyl group having 1 to 15 carbon atoms, a linear or branched substituted or unsubstituted alkyl group having 1 to 15 carbon atoms. Alkyloxy group, linear or branched, substituted or unsubstituted alkenyl having 2 to 15 carbon atoms A substituted or unsubstituted alkenyloxy group, a substituted or unsubstituted benzyl group, or a substituted or unsubstituted benzyloxy group having 2 to 15 carbon atoms.

Provided that R ¹ is a straight-chain or branched unsubstituted 1-oxoalkyl group having 3 to 15 carbon atoms, or a straight-chain or branched unsubstituted 3 to 15 carbon atoms 1 represents a 1-year-old oxoalkenyl group or an unsubstituted 1-oxoaralkyl group, and when R ^{: i} represents a hydroxyl group, R ² represents a hydrogen atom, and has 1 to 15 carbon atoms. Straight-chain or branched unsubstituted alkyl group, straight-chain or branched-chain unsubstituted alkenyl group having 2 to 15 carbon atoms, or substituted or unsubstituted benzyl group Except when. ), A salt thereof, or a solvate thereof, to a hydroxycyclohexane derivative.

 The present invention relates to the prevention and treatment of bone and cartilage diseases comprising one or more of the compounds represented by the above general formulas (I), (II) and (III), and salts or solvates thereof. And a pharmaceutical composition for use.

 In addition, the present invention relates to a compound represented by the general formula (I), (II) or (III), one or more of its salt or solvate thereof, and a pharmaceutically acceptable carrier. The present invention relates to a pharmaceutical composition for preventing and treating bones and cartilage diseases.

 The alkyl group in the general formula (I), (II) or (III) of the present invention has 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 3 to 15 carbon atoms, and more preferably 3 to 15 carbon atoms. And preferably 3 to 10 linear or branched ones, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, sec-butyl group, isobutyl group And various pentyl groups, various hexyl groups, various butyl groups, various octyl groups, various decyl groups, and the like. Examples of the alkyl group of the present invention include a halogen atom such as a chlorine atom and a bromine atom, an oxygen-containing substituent such as a hydroxyl group, an ether group and a carbonyl group, an amino group, a substituted amino group, a cyclic amino group and a urea group. Or a sulfur-containing substituent such as a mercapto group, a sulfido group or a sulfone group.

As the alkenyl group, a linear or branched chain having 2 to 20 carbon atoms, preferably 2 to 15 carbon atoms, more preferably 3 to 20 carbon atoms, and still more preferably 3 to 15 carbon atoms. Thing And having one or more unsaturated carbon-carbon bonds. Examples thereof include a vinyl group, an aryl group, a butenyl group, a pentenyl group, an octagenyl group and the like, preferably a 3-methyl-2-butenyl group, a 3,7-dimethyl-2,6-octagenyl group, 3, 7, 11-trimethyl-2, 6, 10-dodecenyl group and the like can be exemplified. These alkenyl groups include halogen atoms such as chlorine atom and bromine atom, oxygen-containing substituents such as hydroxyl group, ether group and carbonyl group, nitrogen-containing groups such as amino group, substituted amino group, cyclic amino group and urea group. It may be substituted with a substituent or a sulfur-containing substituent such as a mercapto group, a sulfido group or a sulfone group. Examples of the halogen atom include chlorine, fluorine, bromine, and iodine.

 The benzyl group may be substituted with the various substituents described above as long as the physiological activity of the compound of the present invention is not impaired. Examples of these substituents include halogen atoms such as chlorine, fluorine, bromine and iodine, a hydroxyl group, an alkoxy group having 1 to 15 carbon atoms, an alkenyloxy group having 2 to 15 carbon atoms, an acetyl group and a propionyl group. And the like.

 The 1-oxoalkyl group or 1-oxoalkenyl group includes the aforementioned C1 to C15, preferably C1 to C10, more preferably C3 to C15, and still more preferably C3 to C15. An alkyl group having 0 or an alkenyl group having 2 to 20 carbon atoms, preferably 2 to 15 carbon atoms, more preferably 3 to 20 carbon atoms, and still more preferably 3 to 15 carbon atoms, is a carbonyl group (C = 0), and the total number of carbon atoms in the 1-oxoalkyl group is 2 to 16, preferably 3 to 16, more preferably 3 to 11, The —oxoalkenyl group has 3 to 21 carbon atoms, preferably 3 to 16. more preferably 4 to 16 carbon atoms. Alkyl and alkenyl groups bonded to these carbonyl groups include halogen atoms such as chlorine atoms and bromine atoms, hydroxyl groups and ether groups. Oxygen-containing substituents such as carbonyl groups, amino groups, substituted amino groups, and cyclic groups. It may be substituted with a nitrogen-containing substituent such as a amino group or a urine group, or a sulfur-containing substituent such as a mercapto group, a sulfido group or a sulfone group.

The 1-oxoaralkyl group is one in which an aralkyl group is bonded to a carbonyl group, and the aralkyl group has 7 to 25 carbon atoms, preferably 7 to 20 carbon atoms, and more preferably Is 7 to 16, and the total carbon number of the 1-oxoaralkyl group is 8 to 26, preferably 8 to 21, and more preferably 8 to 17. The chain portion of the aralkyl group may be linear or branched. Examples of the aralkyl group include a benzyl group, a phenethyl group, a naphthylmethyl group, a / 3-naphthylmethyl group, and the like. No. These 1-oxoaralkyl groups include a halogen atom such as a chlorine atom and a bromine atom, an oxygen-containing substituent such as a hydroxyl group, an ether group and a carbonyl group, an amino group, a substituted amino group, a cyclic amino group, It may be substituted with a nitrogen-containing substituent such as a urea group or a sulfur-containing substituent such as a mercapto group, a sulfido group or a sulfone group.

 The aryl group may be a single ring or a group having a plurality of rings as long as it has a six-membered aromatic ring, and is not particularly limited, and has 6 to 20 carbon atoms. Preferably those having 6 to 12 are preferred. Further, the ring may have a hetero atom such as an oxygen atom, a nitrogen atom or a sulfur atom. Examples of the aryl group include a phenyl group, a naphthyl group, and a biphenyl group. These aryl groups include halogen atoms such as chlorine atom and bromine atom, oxygen-containing substituents such as hydroxyl group, ether group and carbonyl group, amino group, substituted amino group, cyclic amino group and urea group. It may be substituted with a nitrogen-containing substituent or a sulfur-containing substituent such as a mercapto group, a sulfide group or a sulfone group.

 The benzyl group may be not only an unsubstituted one but also a substituted one.Examples of the benzyl group include a chlorine atom, a halogen atom such as a bromine atom, a hydroxyl group, an ether group and a carbonyl group. Nitrogen-containing substituents such as oxygen-containing substituents, amino groups, aminoamino groups, cyclic amino groups, and urea groups; and sulfur-containing substituents such as mercapto groups, sulfide groups, and sulfone groups. These substituents are preferably substituted on the phenyl ring, but are not limited to the phenyl ring.As the benzyloxy group, the above-mentioned unsubstituted or substituted benzyl group may be an oxygen group. It is bonded to an atom.

The novel polyhydroxybenzene derivative in which the benzene ring is substituted with two or more hydroxyl groups or derivatives thereof (for example, an alkoxy group or the like) according to the present invention can have the various substituents described above. The novel polyhydroxybenzene derivative of the present invention The conductor is preferably a compound represented by the above general formula (I), (II) or (III), a salt thereof or a solvate thereof. More specifically, the compounds of the present invention include the following compounds. Can be mentioned. The numbers in brackets after the compound names in the following examples are the “compound numbers” of the present invention referred to below.

 First, preferred specific examples of the compound represented by the general formula (I) of the present invention include (2-methylpropyl) (3,4,5-trihydroxyphenyl) ketone (1) and (3,5-dihydroxy). Droxy 2- (3-methyl-1-butenyl) 1-4- (3-methyl-2-butenyloxy) phenyl} (2-methylpropyl) ketone (2), {3,5-dihydroxy-1-41 (3-methyl-2-butenyloxy) phenyl} (2-methylpropyl) ketone (3),

 {2- (3-Methyl-2-butenyl) -1,3,4,5-trihydroxyphenyl} (2-methylpropyl) ketone (4)

And the like.

 Preferred examples of the compound represented by the general formula (II) of the present invention include:

 (2,6-dihydroxy-1-4-methylphenyl) (2-methylpropyl) ketone (5),

 {2,6-dihydroxy-14-methyl-3- (3-methyl-12-butenyl) phenyl} (2-methylpropyl) ketone (9),

 {3,5-bis (3-methyl-2-butenyl) —2,6-dihydroxy-14-methylphenyl} (2-methylpropyl) ketone (10),

 (5-Chloro-2,4-dihydroxyphenyl) (2-methylpropyl) ketone (11), '

 {5-Methyl-1-2-Hydroxy-3- (3-Methyl-2-butenyl) -14- (3-Methyl-2-butenyloxy) phenyl} (2-Methylpropyl) Ketone (1

2),

 {5-chloro-2-hydroxy-4- (3-methyl-12-butenyloxy) phenyl} (2-methylpropyl) ketone (13),

{5-chloro-2,4-dihydroxy-1- 3- (3-methyl-2-butenyl) phen Nil} (2-methylpropyl) ketone (14),

 1,3-bis (3-methyl-1-oxobutyl) -1,2,4,6-trihydroxybenzene (15),

 1,3-bis (3-methyl-1-oxobutyl) -5— (3-methyl-2-butenyl) -1,2,4,6-trihydroxybenzene (17),

 {3-(2-(1-piperidino) ethyl) 1, 2, 4, 6-trihydroxyphenyl} (2 -methylpropyl) ketone (2 3),

 {3,5-bis (2- (1-piperidino) ethyl) -1,2,4,6-trihydroxyphenyl} (2-methylpropyl) ketone (24),

 {3-(3-(N, N-dimethylamino) propyl) 1, 2, 4, 6-trihydroxyphenyl} (2-methylpropyl) ketone (25),

 2- (3-methyl-2-butenyl) -1-1,3,5-trihydroxybenzene (22), and

 1,3,5—trihydroxy 2,4,6—tris (3-methyl-2-butenyl) benzene (18)

And the like.

 Preferred specific examples of the general formula (III) of the present invention include:

5-Hydroxy-3-methyl-6 _ (3-methyl-1-oxoxotyl) 1,2,2,4-tris (3-methyl-1-butenyl) cyclohexa 3,5-genone (7), 2,2-bis (3-methyl-2-butenyl) —5-hydroxy-3-methyl-6- (3-methyl-1-1-oxobutyl) cyclohexa 3,5-genone (8),

2,2-bis (3-methyl-2-butenyl) -1,4,6-bis (3-methyl-1-oxobutyl) -1,3,5-dihydroxycyclohexa 3,5-genone (16),

3-hydroxy-5- (3-methyl-2-butenyloxy) -1,2,4,1-tris (3-methyl-2-butenyl) cyclohexa-1,5-genone (20),

3,5-dihydroxy-1,2,2,4,6-tetrakis (3-methyl-2-butenyl) cyclohexa 3,5-genone (19), and

3,5-dihydroxy-1,2,2,4-tris (3-methyl-2-butenyl) cyclo mouth hex-1,5-genone (21) And the like.

 The polyhydroxybenzene derivative represented by the general formulas (I) to (III) of the present invention can be produced by the following method.

 The alkoxylated or alkenylated compound of the present invention can be carried out by a reaction of condensing the corresponding hydroxybenzene derivative with an alkylating agent or alkenylating agent under basic or acidic conditions.

 In the reaction under basic conditions, a base is allowed to act on a polyhydroxybenzene derivative, and then an alkylating agent or an alkenylating agent is actuated. Bases used in this reaction include alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, and lithium hydroxide, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, and sodium t-butoxide. Alkali metal alkoxides such as potassium t-butoxide, sodium hydride, potassium hydride, alkali metal hydrides such as lithium hydride, methyllithium, ethyllithium, n-butyllithium, t-butyllithium, Examples thereof include alkyllithium compounds such as enyllithium or aryllithium compounds, or tertiary amines such as triethylamine, triisopropylamine, diazabicyclononene, diazabicycloundecene, and dimeteraminoviridine.These bases are used, if necessary, under an atmosphere of an inert gas such as nitrogen or argon.

 The reaction is carried out in a solvent such as water, methanol, ethanol, alcohols such as n-propanol, isopropanol and t-butyl alcohol, ethyl ether, isopropyl ether, tetrahydrofuran, and 1,4-dioxane. And ethers such as dimethoxetane, N, N-dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone, and aromatics such as benzene and toluene. These solvents are appropriately used depending on the base used.

Examples of the alkylating agent include methyl iodide, promoethane, 1-promopropane, 2-bromopropane, 1-clopropane, 2-clopropane, bromobutane 1-bromo-13-methylbutane, various bromooctanes, and various chroma ports. Octane, 1-chloro-3,7-dimethyloctane, benzyl chloride, bromomethylthiophene Benzene, 1-chloro-2-piberidinoethane, 1-chloro-3-dimethylaminopropane bread and the like. Examples of the alkenylating agent are arylpromide, aryl chloride, 1-promo 2-butene, 1-promo 3 —methyl-2-butene, 1-chloro-1 3 —methyl-2-butene, 1-chloro-7,7 —Dimethyl-1,2,6-octane.

 On the other hand, acid catalysts used for reactions under acidic conditions include aluminum bromide, aluminum chloride, antimony chloride, iron chloride, titanium chloride, tin chloride, bismuth chloride, zinc chloride, boron fluoride, and boron fluoride ether. Examples include complexes, Lewis acids such as hydrogen fluoride, sulfuric acid, hydrochloric acid, polyphosphoric acid, trifluoroacetic acid, and trifluoromethanesulfonic acid, and strong Brenstead acid. The reaction is carried out in a solvent such as nitromethane, nitrobenzene, carbon disulfide, methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane, ethyl ether, 1,4-dioxane, Tetrahydrofuran and the like can be mentioned. The reaction is appropriately selected under various combinations of these acid catalysts and solvents, and the reaction is carried out in 1,4-dioxane using a boron fluoride ether complex. It is suitable for the convenience of the reaction. As the alkylating or alkenylating agent at this time, saturated alcohols such as ethanol, butyl alcohol, 3-methylbutyl alcohol, benzyl alcohol, and decanol, aryl alcohol, 2-butenol, and 3-methyl = 2 —Butenol, 3,7-dimethyl-2,6-—unsaturated alcohols such as kagegenol.

 The compound having a 1-oxoalkyl group or a 1-year-old oxoalkyl group on the benzene ring of the compound of the present invention can be produced by a conventional Friedel-Crafts reaction acylation method. Further, the compound of the present invention having an alkyl group on the benzene ring can be produced by a usual Friedel-Crafts reaction alkylation method.

 The compound represented by the general formula (III) of the present invention is an enol-type alkyl or alkenyl derivative of the compound represented by the general formula (II).

Further, the compound of the present invention can be converted into a salt of an alkali metal or the like, if necessary. Further, the compound of the present invention may be used as a solvate of a reaction solvent or, if necessary, another solvent. For example, it can be obtained as a hydrate. ^_ It has not yet been known that a series of compounds represented by any of the general formulas (I) to (III) of the present invention exhibit a potent bone resorption inhibitory activity, and was first clarified by the present inventors. .

 That is, the present invention provides a bone / cartilage comprising one or more novel polyhydroxybenzene derivatives in which a benzene ring is substituted with two or more hydroxyl groups or derivatives thereof (for example, an alkoxy group). The present invention relates to a pharmaceutical composition for preventing and treating diseases.

 Specifically, the present invention provides the following general formula (IV):

(Wherein RR ² and R ³ are each independently a hydrogen atom, a linear or branched substituted or unsubstituted alkyl group having 1 to 15 carbon atoms, Represents a linear or branched substituted or unsubstituted alkenyl group, a substituted or unsubstituted benzyl group, or an aryl group;

R \ R ^5, R ⁶ are each independently a hydrogen atom, a linear or branched, substituted or unsubstituted alkyl group of from 1 1 to 5 carbon atoms, 2 to 1 to 5 of the straight Or a branched or unsubstituted alkenyl group or a substituted or unsubstituted benzyl group. )

And a salt or a solvate thereof, which is one or more of acylpyrogallol derivatives, and a pharmaceutical composition for preventing and treating bone and cartilage diseases.

Further, the present invention provides the following general formula (V):

(In the formula, R ′, R ² , and R ⁴ each independently represent a hydrogen atom, a halogen atom, a linear or branched substituted or unsubstituted alkyl group having 1 to 15 carbon atoms, Straight-chain or branched-chain substituted or unsubstituted alkenyl group, substituted or unsubstituted benzyl group having 3 to 15 carbon atoms, straight-chain or branched-chain substituted or unsubstituted 1 represents an oxoalkyl group, a linear or branched substituted or unsubstituted 1-oxoalkenyl group having 3 to 15 carbon atoms, or a substituted or unsubstituted 1-oxoaralkyl group;

R ³ is a hydroxyl group, a linear or branched substituted or unsubstituted alkyl group having 1 to 15 carbon atoms, a linear or branched substituted or unsubstituted alkyl group having 1 to 15 carbon atoms. Substituted alkyloxy group, linear or branched, substituted or unsubstituted alkenyl group having 2 to 15 carbon atoms, linear or branched substituted or unsubstituted, having 2 to 15 carbon atoms Represents an alkenyloxy group, a substituted or unsubstituted benzyl group, or a substituted or unsubstituted benzyloxy group,

RR ⁶ is each independently a hydrogen atom, a linear or branched substituted or unsubstituted alkyl group having 1 to 15 carbon atoms, a linear or branched alkyl group having 2 to 15 carbon atoms. Substituted or unsubstituted alkenyl group, substituted or unsubstituted benzyl group, linear or branched substituted or unsubstituted 1-oxoalkyl group having 3 to 15 carbon atoms, and 3 to 15 carbon atoms Represents a linear or branched, substituted or unsubstituted 1-oxoalkenyl group or a substituted or unsubstituted 1-oxoaralkyl group. )

And a salt or a solvate thereof, which is a resorcinol derivative or a resorcinol derivative, and relates to a pharmaceutical composition for preventing and treating bone and cartilage diseases. Further, the present invention provides the following general formula (VI):

(Wherein, R ′, R ² , and RR ⁵ each independently represent a hydrogen atom, a linear or branched substituted or unsubstituted alkyl group having 1 to 15 carbon atoms, and a carbon atom having 2 to 1 carbon atoms. 5 linear or branched substituted or unsubstituted alkenyl group, substituted or unsubstituted benzyl group, 3 to 15 linear or branched substituted or unsubstituted 1 A oxoalkyl group, a linear or branched, substituted or unsubstituted 1-oxoalkenyl group having 3 to 15 carbon atoms, or a substituted or unsubstituted 1-oxoaralkyl group;

R ³ is a hydroxyl group, a linear or branched substituted or unsubstituted alkyl group having 1 to 15 carbon atoms, a linear or branched substituted or unsubstituted alkyl group having 1 to 15 carbon atoms An alkyloxy group, a linear or branched substituted or unsubstituted alkenyl group having 2 to 15 carbon atoms, a linear or branched substituted or unsubstituted having 2 to 15 carbon atoms Represents an alkenyloxy group, a substituted or unsubstituted benzyl group, or a substituted or unsubstituted benzyloxy group. )

And a salt thereof, or a solvate thereof, comprising one or more of hydroxycyclohexane derivatives, and a pharmaceutical composition for preventing and treating bone and cartilage diseases.

 Preferably, the present invention comprises one or more of a compound represented by the above general formula (I), (II) or (III), a salt thereof, or a hydroxycyclohexane derivative which is a solvate thereof. The present invention relates to a pharmaceutical composition for preventing and treating bone and cartilage diseases.

 The pharmaceutical composition of the present invention can also contain various pharmaceutically acceptable carriers. The present invention relates to a compound represented by formula (IV), (V) or (VI): The present invention also relates to a pharmaceutical composition comprising one or more salts or solvates thereof and a pharmaceutically acceptable carrier.

Preferably, the present invention is represented by the general formula (I), (II) or (III). The present invention also relates to a pharmaceutical composition comprising one or more of a compound, a salt thereof, or a solvate thereof, and a pharmaceutically acceptable carrier.

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

 Further, the present invention provides a method for administering a therapeutically effective amount of the compound represented by the general formula (IV), (V) or (VI), a salt thereof, or a solvate thereof to a patient having an osteochondral disease. Bone and cartilage diseases. More preferably, the present invention provides a therapeutically effective amount of a compound represented by the above general formula (I), (II) or (III), a salt thereof or a solvate thereof for a patient with bone / cartilage disease. The invention relates to a method for treating a bone / cartilage disease comprising administering.

 Further, the present invention provides a use of the compound represented by the general formula (IV), (V) or (VI), a salt thereof or a solvate thereof for producing a prophylactic / therapeutic agent for bone / cartilage disease. About. More preferably, the present invention relates to the use of the compound represented by the general formula (I), (II) or (III), a salt thereof or a solvate thereof for producing a preventive / therapeutic agent for bone / cartilage disease. .

 The bone and cartilage diseases of the present invention include, for example, malignant hypercalcemia, bone Petiet's disease or osteoporosis, and bone resorbable diseases, osteoarthritis occurring in knees, shoulders, hip joints, etc., necrosis of the femoral head, rheumatoid arthritis, etc. Cartilage degeneration and diseases associated with necrosis.

The bone resorption inhibiting activity of the polyhydroxybenzene derivative represented by the general formula (IV), (V) or (VI) of the present invention was assayed by a pitformation assay method. As a result, the general formula of the present invention (IV), showed poly hydroxycarboxylic benzene derivative 1 X 1 0- ⁵ M concentration with a high bone resorption inhibition rate represented by (V) or (VI).

The dosage in the clinic depends on the administration method, disease state and patient condition, but usually ranges from 0.1 to 2 g (about 1. SSO ZK gZ) per adult per day as the compound of the present invention. The method of administration is intravenous, intramuscular, oral, or rectal. In the case of intravenous administration, normal intravenous injection or intravenous drip infusion is possible. Preparations containing the compound of the present invention are produced by conventional methods using ordinary excipients and additives. The preparation for injection can be, for example, a powder preparation for injection. In that case, add an appropriate aqueous excipient, such as one or more of mannitol, sucrose, lactose, maltose, glucose, and fructoses, dissolve in water, and dispense into vials or ampoules. It can be lyophilized and sealed to form a formulation. Oral preparations include ordinary tablets, capsules, granules, fine granules and powders, as well as enteric preparations.

 In the case of enteric preparations, use lubricants such as mannitol, sucrose, lactose, maltose, starch, citric anhydride, calcium phosphate, and disintegrants such as carboxymethylcellulose, gelatin, and gum arabic. Tablets, granules, fine granules, etc. may be added by adding excipients as needed, and then cellulose acetate phthalate, hydroxypropyl methylcellulose acetyl succinate, polyvinyl alcohol phthalate, steel One or more of enteric bases such as len maleic acid copolymer, methyl methacrylate-methacrylic acid copolymer, and methyl methacrylate-methacrylic acid copolymer, and if necessary, oxidation. In addition to adding a coloring agent such as titanium and coating to form a preparation, the capsules are filled with the enteric granules or fine granules produced here. It can be a flop cell Le agent. In addition, the capsules produced by the usual method can be coated with the enteric agent described above as an enteric solvent, or enteric coated using the enteric agent alone or a capsule prepared by mixing gelatin with the enteric agent can be used. Capsules can also be made.

 For suppositories, lipophilic base, semi-synthetic base in which fatty acid monoglyceride and fatty acid diglyceride are mixed in various proportions with fatty acid triglyceride and fatty acid triglyceride, hydrophilic groups such as polyethylene glycol and glycerogelatin A suppository can be made by adding a solution prepared by heating and dissolving the mixture, mixing uniformly, putting into a mold and molding. Example

Hereinafter, the present invention will be described in more detail with reference to Reference Examples, Examples, and Test Examples, but the present invention is not limited thereto. Example Synthesis of (2-methylpropyl) (3,4,5-trihydroxyphenyl) ketone (1)

 (1) Under a nitrogen atmosphere, 6.60 g (165 minol, -3.30 equivalents) of 60% sodium hydride was washed away with petroleum ether. Add 100 mL of dimethylformamide (DMF) to the mixture, and add 9.22 g (50. Oramol) of DMF to the mixture under ice-cooling and stirring.

(25. OmL) solution was added. When foaming was completed, 13.9 g (165 ol) of methoxymethyl chloride was slowly dropped. After stirring for 4 hours, 150 raL of saturated ammonium chloride water was added, and the mixture was extracted with ether. The ether layer was washed with a saturated saline solution and dried over sodium sulfate. The solvent was distilled off under reduced pressure to obtain 14.97 g of methyl 3,4,5-tris (methoxymethyl) benzoate as an orange oily substance.

1H- negation _{R (CDC1 3): 3.51 (} 6H, s), 3.61 (3H, s), 3.88 (3H, s),

 5.21 (2H, s), 5.24 (4H, s), 7.53 (2H, s).

 (2) 1.20 g (31.6 ramol) of lithium aluminum hydride was suspended in dry tetrahydrofuran (THF) 40. OraL under a nitrogen atmosphere. A solution of 9.49 g (30. Oramol) of THF (30. OmL) in THF (30. OmL) was added dropwise over 20 minutes while stirring under ice-cooling with stirring. Lasted one hour. Thereafter, 1.2 mL of water, 1.2 raL of 15% sodium hydroxide water, and 3.6 mL of water were sequentially added, followed by stirring for 1 hour. Ether was added and white precipitate was filtered off, and the ether layer was dried over sodium sulfate. The solvent was distilled off to obtain 8.35 g of 3,4,5-tris (methoxymethyl) benzyl alcohol as a colorless oil.

(3) Pyridinium chromochloride (PCC) 9.70 g (45. Omraol, 1.55 equiv.), Sodium acetate 750 rag (9. OraraoK 0.31 equiv.), And molecular sieves 3 A appropriate amount under nitrogen atmosphere Was added to dry methylene chloride 40. OraL and stirred at room temperature. A solution of 8.34 g (28.9 mmol) of 3,4,5-tris (methoxymethyl) benzyl alcohol in methylene chloride (20. OmL) was added dropwise thereto over 40 minutes, and stirring was continued for 1 hour. 300 mL of ether was added to the reaction mixture, which was filtered, and the ether layer was distilled under reduced pressure to obtain a red oily substance. This was dissolved again in ether and passed through a short column of silica gel. The solvent was distilled off under reduced pressure to obtain 3,4,5-tris (methoxymethyl) benzaldehyde 7.53 g as an orange oil. (4) 3,4,5-Tris (methoxymethyl) benzaldehyde 7.52 g (26.3 mmol) in THF (60. OmL) solution under a nitrogen atmosphere under ice-cooled stirring, 2 M 2-methylpropyl Pyrmagnesium bromide in ether solution 16. OmL (32. OmraoK Ί. Eq.) Was added slowly. After that, 20m of saturated ammonium chloride water was added and extracted with ether. The ether layer was washed with saturated saline, dried over sodium sulfate, and the solvent was distilled off. As a orange oil, 3-methyl-1- (3,4,5-tris (methoxymethyl) phenyl} butane 8.44 g of knol were obtained.

 1H—band R (CDCls): 0.95 (6H, d, 1 = 6.2), 1.60 (2H, m),

 3.50 (6H, s), 3.61 (3H, s), 4.60 (1H, m),

 5.12 (2H, s), 5.19 (4H, s), 6.83 (2H, s)

 (5) PCC 7.92 g (36.8 mraoK 1.50 equivalents), sodium acetate 906rag (11.4 mmol, 0.47 equivalents), molecular sieves 3 A appropriate amount, and 3-methyl-one {3,4,5-tris ( (Methoxymethyl) phenyl} Butanol (8.44 g, 24.5raraol) and the same operation as (3) above, (2-Methylpropyl) {3,4,5-tris (methoxymethyl) phenyl } Ketone 7.58g was obtained.

 (6) Dissolve 7.57 g of (2-methylpropyl) {3,4,5-tris (methoxymethyl) phenyl} ketone in methanol lOOraL, add 2 M hydrochloric acid 2. Add OmL and at 50 ° C After heating for 3 hours, methanol and water were distilled off at room temperature under reduced pressure. The residue was purified by silica gel column chromatography (co-gel C—300 70 g, hexane: ethyl acetate = 2: 1) (2-methylpropyl) (3,4,5-trihydroxyphenyl) ketone (1) 2.70 g was obtained as gray crystals.

 Compound (1) 1H—band R (DMS0): 0.96 (6H, d, J = 6.4), 2.23 (1H, m),

 2.70 (2H, d, J = 6.6), 7.12 (2H, s). Example 2

{3,5-dihydroxy-2- (3-methyl-1-butenyl) -4-1 (3-methyl-2-butenyloxy) phenyl} (2-methylpropyl) ketone (2) and 3, Synthesis of 5-dihydroxy 4- (3-methyl-2-butenyloxy) phenyl} (2-methylpropyl) ketone (3) Paraffin was washed away with petroleum ether from 441 mg of 60% sodium hydride (1.16 equivalents to 2.06 equivalents) under a nitrogen atmosphere, and 6. OmL of dry methanol was added. Then, a solution of 631 mg (3.OO mmol) of (2—methylpropyl) (3,4,5—trihydroxyphenyl) kedon (1) in methanol (3.OmL) was added with stirring under ice-cooling. Further, a solution of 660 mg (6.30 mmol, 2.10 equivalents) of 1-chloro-3-methyl-2-butene in methanol (6. Ora L) was slowly added dropwise. Stirring was continued for 2 hours while returning to room temperature. An ether was added thereto, and the ether layer was washed with saturated aqueous ammonium chloride and saturated saline, and dried over sodium sulfate. The solvent was distilled off to obtain a dark red oil (1.020 g).

 This was separated by silica gel column chromatography (Co-gel C-300, 47 g, hexane: ether = 9: 1 to 1: 1), and {3,5-dihydroxy1-2— ( 3—Methyl—2—butenyl) 1 4— (3—Methyl-2—butenyloxy) phenyl} (2—methylpropyl) ketone (2) 61,6 mg as a viscous oil, 3,5—dihydroxy 4— 56 mg of (3-methyl-2-butenyloxy) phenyl} (2-methylpropyl) ketone (3) were obtained as white crystals.

Compound (2) 1H-NMR (CDC1 3): 0.95 (6H, d, J = 6.4), 1.64 (6H, s),

 1.74 (6H, s), 2.20 (1H, m), 2.66 (2H, d, J = 6.6),

 3.44 (2H, d, J-5.8), 4.56 (2H, d, J = 7.5), 5.16 (1H, m), 5.51 (1H, m), 6.68 (1H, s)

 Compound (3) 1H-NMR (CDC 13): 0.97 (6H, d, J = 6.6), 1.68 (3H, s),

 1.78 (3H, s), 2.27 (1H, m), 2.76 (2H, d, J-6.8),

 4.67 (2H, d, J-7.5), 5.52 (1H, in), 7.21 (2H, s) Example 3

 Synthesis of {2 — (3 —methyl-2-butenyl) 1-3, 4, 5 — trihydroxyphenyl} (2 —methylpropyl) ketone (4)

(2—Methylpropyl) (3,4,5—Trihydroxyphenyl) Ketone (1) Drying of 529rag (2.52mraol) 1,4 Dioxane (5. OraL) solution in a nitrogen atmosphere at 10 ° C added 321 rag of boron trifluoride etherate (2.26 rarao to 0.901 equivalent). Then 433 mg (5.03 mmol, 2.00 eq.) Of 3-methyl-2-butenol A solution of xane (5.0fflL) was slowly added dropwise, and the mixture was stirred for 14 hours while returning to room temperature. -Ether was added to the reaction mixture, and the ether layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over sodium sulfate. The solvent was distilled off to obtain 1.118 g of a dark red oily substance. The crude product was separated by silica gel column chromatography (ヮ -gel C-300 48 g, hexane: ether = 9: 1 to 1: 1), and {2- (3-methyl-2-butenyl)- 58 rag of 3,4,5-trihydroxyphenyl} (2-methylpropyl) ketone (4) was obtained as orange crystals.

 Compound (4) 1H-NMR (CDCla): 0.91 (6H, d, J-6.4), 1.68 (3H, s),

 1.73 (3H, s), 2.16 (1H, m), 2.63 (3H, d, J = 6.8),

 3.49 (2H, d, J = 6.4), 5.16 (1H, m), 6.73 (1H, s) Example 4

 Of (2,6-dihydroxy-4-methylphenyl) (2-methylpropyl) ketone (5) and (2,4-dihydroxy-6-methylphenyl) (2-methylpropyl) ketone (6) Synthesis

 150 raL of benzene was added to 14.20 g (100. Oramol) of orcin monohydrate, and the mixture was heated and distilled. Dehydration operation was performed twice. To this, 45 mL of nitrobenzene and 45 mL of carbon disulfide were added, and 26.7 g (200 mmol, 2.00 equivalents) of aluminum chloride was added little by little under water cooling and stirring, and a calcium chloride tube was attached and stirred. Then, 12.lg (lOOmraol, 1.00 equivalent) of isovaleryl chloride was slowly added dropwise, and stirring was continued at room temperature for 14 hours. After confirming that the generation of acid gas had stopped, the mixture was poured into dilute hydrochloric acid (prepared from 100 mL of concentrated hydrochloric acid and 400 raL of cold water), stirred, and extracted with ether. The ether layer was washed with saturated saline and then distilled off under reduced pressure. The mixture was distilled under reduced pressure while adding water little by little, and ditrobenzene was distilled off by steam distillation. The residue was extracted with ether, washed with saturated saline, and dried over sodium sulfate. The solvent was distilled off to obtain 18.53 g of a brown viscous oily substance.

The crude product was separated by silica gel column chromatography (Co-gel C—200 220 g, hexane: ethyl acetate = 9: 1), and was separated in the order of effluent (2,6-dihydroxy-4-methylphenyl) (2- 0.908 g of (methylpropyl) ketone (5) and (2,4-dihydroxy-16-methylphenyl) (2-methylpropyl) ketone (6) 5.68 got lg.

 Compound (5) 1H—Maraudal R (CDC1: 0.98 (6H, d, J = 6.6), 2.28 (1H, m),

 2.33 (3H, s), 2.98 (2H, d, J = 6.6), 6.22 (2H, s)

 Compound (6) 1H-NMR (CDCls): 0.97 (6H, d, J-6.5), 2.25 (3H, s),

 2.27 (1H, ra), 2.78 (2H, d, J = 6.6), 6.23 (1H, s),

 6.26 (1H, s) Example 5

 5 —Hydroxy-1 3 —Methyl-6 — (3—Methyl-1 1-year-old oxobutyl) 1,2,2,4-Tris (3—Methyl-2-butenyl) cyclohexa 1,3,5 —Genone (7) ,

 5—Hydroxy-1 3—Methyl-6— (3—Methyl-1 oxobutyl) 1,2,2-Bis (3—Methyl-12—butenyl) cyclohexa 3,5—Genon (8), and

 {2,6-Dihydroxy-4-methyl-3- (3-methyl-2-butenyl) phenyl} Synthesis of (2-methylpropyl) ketone (9)

 After 240 mg (6.00 mmol, 2.00 equivalents) of 60% sodium hydride was washed off the paraffin with a petroleum ether under a nitrogen atmosphere, 6. OmL of dry methanol was added. Then, a solution of 625 mg (3. OOraraol) of (2,6-dihydroxy-14-methylphenyl) (2-methylpropyl) ketone (5) in methanol (4. OmL) was added thereto under ice-cooling and stirring. Further, a solution of 627 mg (6.00 mmol, 2.00 equivalents) of 1-chloro-3-methyl-2-butene in methanol (4. OraL) was slowly added dropwise. Stirring was continued for 3 hours while returning to room temperature. Ether was added thereto, and the ether layer was washed with saturated aqueous ammonium chloride and saturated saline, and dried over sodium sulfate. The solvent was distilled off to obtain 931 mg of a red oily substance.

The crude product was separated by silica gel column chromatography (ヮ -gel C-300 44 g, hexane: ether = 19: 1 to 4: 1), and the 5-hydroxy-3-methyl-6 — (3—Methyl—1—oxobutyl) —2,2,4—Tris (3-monomethyl—2—butenyl) cyclohexa—3,5—Genone (7) 245 mg as a pale yellow oil —Hydroxy 3 —Methyl-6— (3 —Methyl— 1 year old Tyl) — 2,2-bis (3-methyl-2-butenyl) cyclohexa-3,5-dienone (8) 149 rag as pale yellow oil and (2,6-dihydroxy-4) 160 mg of monomethyl-3- (3-methyl-2-butenyl) phenyl} (2-methylpropyl) ketone (9) was obtained as yellow needle crystals.

 (7) 1H-NMR (CDCls): 0

.95 (6H, d, J = 6.4), 1.54 (12H, s),

 1.68 (3H, s), 1.73 (3H, s), 1.95 (3H, s), 2.28 (1H, m),

2.41-2.78 (4H, m), 2.94 (2H, d, 1 = 6.8),

3.05 (2H, d, J = 6.4), 4.62 (2H, m), 4.90 (1H, ra) Compound (8) 1H-NMR (CDC1 3): 0.95 (6H, d, J = 6.6), 1.56 (12H , s),

 2.01 (3H, s), 2.29 (1H, m), 2.92 (2H, d, J = 6.8),

3.01 (2H, d, J = 7.0), 4.67 (2H, m), 6.24 (1H, s) Compound (9) 1H—Maraudal R (CDCla): 0.97 (6H, d, J = 6.6), 1.71 (3H , d, J = l.3),

 1.80 (3H, s), 2.22 (3H, s), 2.27 (1H, ra),

 2.99 (2H, d, J = 6.8), 3.29 (2H, d, J = 6.6),

 5.09 (1H, ID), 6.19 (1H, s) Example 6

 {3,5-bis (3-methyl-2-butenyl) -1,2,6-dihydroxy-14-methylphenyl} (2-methylpropyl) ketone (10), and

 Synthesis of {2,6-dihydroxy-1-methyl-3- (3-methyl-2-butenyl) phenyl} (2-methylpropyl) ketone (9)

(2,6-dihydroxy-1-4-methylphenyl) (2-methylpropyl) ketone (5) 521 mg (2.50 ramol) of dry 1,4-dioxane (5.0 mL) solution in a nitrogen atmosphere under a nitrogen atmosphere. At CC, 355 mg (2.50 ramol, 1.00 equivalent) of boron trifluoride etherate was added. Then, a solution of 431 mg (5.00 ramol, 2.00 eq) of 3-methyl-2-butenol in dioxane (2.0 mL) was slowly added dropwise, and stirring was continued for 14 hours while returning to room temperature. Ether was added to the reaction mixture, and the ether layer was washed with saturated aqueous sodium hydrogen carbonate and saturated saline, and dried over sodium sulfate. Evaporation of the solvent gave 874 mg of an orange oil. The crude product was separated by silica gel column chromatography (co-gel C-300 24 g, hexane: ether = 19: 1 to 7: 3), and {3,5-bis ( 3-Methyl-2-butenyl) 1,2,6-dihydroxy-1 4-methylphenyl} (2-methylpropyl) ketone (10) 222rag as a yellow oil, followed by {2,6-dihydroxy-1 4-Methyl-1- (3-methyl-2-butenyl) phenyl} (2-methylpropyl) ketone (9) 235rag was obtained as yellow crystals.

 Compound (10) 1H-NMR (CDC1: 0.96 (6H, d,] = 6.6), 1.72 (6H, s),

 1.82 (6H, s), 2.22 (1H, m), 2.24 (3H, s),

 2.99 (2H, d, J = 6.8), 3.34 (4H, d, J = 6.8),

 5.08 (2H, m) Example 7

 Synthesis of (5-chloro-2,4-dihydroxyphenyl) (2-methylpropyl) ketone (11)

 (4) Add 7.23 g (50.Ommol) of monochlororesorcinol to a mixed solution of 40 mL of benzene and 40 raL of carbon disulfide, add 13.3 g of aluminum chloride (100 equivalents of 100 mmOK) with water cooling and stirring, and add a little by little to the calcium chloride tube. And stirred. Then, 6.03 g (50.0 ramol, 1.00 equivalent) of isovaleryl chloride was slowly added dropwise, and stirring was continued at room temperature for 14 hours. When the generation of acid gas stopped, the solution was poured into dilute hydrochloric acid (prepared from concentrated hydrochloric acid 50raL and cold water 200raL), stirred and extracted with ether. The ether layer was washed with saturated saline and then distilled off under reduced pressure. The mixture was distilled under reduced pressure while adding water little by little, and the nitrobenzene was distilled off by steam distillation. The residue was extracted with ether, washed with saturated saline, and dried over sodium sulfate. The solvent was distilled off to obtain 7.14 g of a dark gray solid. The crystals were recrystallized from hexanechloroform to obtain 2.864 g of (5-chloro-2,4-dihydroxyphenyl) (2-methylpropyl) ketone (11) as gray needles.

Compound (1 1) 1H-negation _{R (CDC1 3): 1.00 (} 6H, d, J = 6.4), 2.26 (1H, m),

2.73 (2H, d, J = 6.8), 6.54 (1H, s), 7.68 (1H, s) Example 8 {5 —Chloro 1 —Hydroxy 3 — (3 —Methyl-2 —Butenyl) 1-4 1 (3 —Methyl — 2 —Butenyloxy) phenyl} (2 —Methylpropyl) ketone (1 2)

 {5 —Cl 2 —Hydroxy 41- (3-Methyl-2-butenyloxy) phenyl) (2-Methylpropyl) ketone (13), and

 {5 — Synthesis of 2,4-dihydroxy 3 — (3 —methyl-2-butenyl) phenyl} (2 —methylpropyl) ketone (14)

 After washing paraffin with 240 rag of 60% sodium hydride (6.0 equivalents, 2.00 equivalents) with a petroleum ether under a nitrogen atmosphere, 5. OraL of dry methanol was added. Then, a solution of 686 mg (3. OOramol) of 686 mg (3. OOramol) in methanol (4. OraL) was added to the mixture under ice-cooling and stirring. In addition, a solution of 627 mg (6. OOmmoK 2.00 equivalents) of 1-methyl-3-3-methyl-2-butene in methanol (3. OmL) was slowly added dropwise. Stirring was continued for 14 hours while returning to room temperature. Ether was added thereto, and the ether layer was washed with saturated ammonium chloride water and saturated saline, and dried over sodium sulfate. The solvent was distilled off to obtain 907 mg of a dark red viscous oil. The crude product was separated by silica gel column chromatography (Co-gel C-300, 45 g, hexane: ether = 29: 1-7-7: 3) and, in the order of effluent, {5—chloro-2-hydroxy-3— (3—Methyl—2—butenyl) —4— (3—Methyl—2—Butenyloxy) phenyl} (2—Methylpropyl) ketone (1 2) 92rag, {5—Chloro 1—Hydroxy One 4 — (3-Methyl-2-butenyloxy) phenyl} (2-Methylpropyl) ketone (13) 80 mg and {5 — Black mouth 1, 4 — Dihydro mouth — 3 — (3 —Methyl-2-butenyl) phenyl} (2-methylpropyl) ketone (14) 58 rag was obtained.

 Compound (12) 1H-NMR (CDC1: 1.01 (6H, d, 1 = 6.6), 1.68 (3H, s),

 1.72 (3H, s), 1.78 (6H, s), 2.28 (1H, in),

 2.77 (2H, d, J-6.8), 3.41 (2H, d, 1 = 6.8),

 4.51 (2H, d, J = 7.3), 5.18 (1H, in), 5.58 (1H, m), 7.64 (1H, s)

Compound (13) 1H-NMR (CDCla): 1.01 (6H, d, J = 6.6), 1.75 (3H, s), 1.79 (3H, s), 2.28 (1H, m), 2.75 (2H, d, J = 6.6),

 4.61 (2H, d, J = 6.6), 5.48 (1H, m), 6.45 (1H, s), 7.69 (1H, s).

 (14) 1H-NMR (CDCls): 1.00 (6H, d, J = 6.4), 1.71 (3H, s),

 1.80 (3H, s), 2.27 (1H, ra), 2.74 (2H, d, J = 6.8), 3.42 (2H, d, J = 7.3), 5.24 (1H, m), 7.61 (1H, s) Example 9

 Synthesis of 2,4-bis (3-methyl-1-oxobutyl) 1,3,5-trihydroxybenzene (15)

 1,3,5— Trihydroxybenzene 25.2g (200mraol) is added to a mixed solution of nitrobenzene lOOraL and carbon disulfide lOOraL, and 53.3g (400mmoK 2.00 equivalent) of aluminum chloride is added little by little under water cooling and stirring. And stirred. Then, 24.lg (200 mmol, 1.00 equivalent) of isovaleryl chloride was slowly added dropwise, and stirring was continued at room temperature for 4 hours. When the generation of acid gas stopped, the mixture was poured into dilute hydrochloric acid (prepared from 200 mL of concentrated hydrochloric acid and 800 mL of cold water), and extracted with ether after stirring. The ether layer was washed with saturated saline and then distilled off under reduced pressure. The mixture was distilled under reduced pressure while adding water little by little, and the nitrobenzene was distilled off by water vapor distillation. The residue was extracted with ether, washed with saturated saline, and dried over sodium sulfate. The solvent was distilled off to obtain a gray solid. Upon standing, 11.5 g of (2-methylpropyl) (2,4,6-trihydroxyphenyl) ketone was crystallized. The filtrate was subjected to silica gel column chromatography (ヮ cogel C-200, hexane: ether = 4: 1 to 2: 3) in the order of effluent to give (2-methylpropyl) (2,4,6-triethyl). 5.0 g of (hydroxyphenyl) ketone and 21.4 g of 2,4-bis (3-methyl-1-oxobutyl) -1,1,3,5-trihydroxybenzenene (15) were obtained.

Compound (1 5) 1H-NMR ( CDC1 3): 0.92 (12H, d, J = 6.6), 2.15 (2H, m),

2.90 (4Η, d, J = 6.6), 5.89 (1H, s) Example 10 2,2—bis (3-methyl-2-butenyl) —4,6_bis (3—methyl-1-one-oxobutyl) -1,3,5—dihydroxycyclohexa 3,5—genon (16), and ,

 Synthesis of 2,4—bis (3-methyl-1-oxobutyl) —6— (3—methyl—2—butenyl) —1,3,5—trihydroxybenzene (17)

 Under a nitrogen atmosphere, a solution of 864 mg (16. Ommol, 2.12 equivalents) of sodium methoxide in a dry methanol (16.0 IDL) solution was stirred under ice-cooling with 2,4-bis (3-methyl-1-oxo). A solution of 2.226 g (7.562 inmol) of methanol (10. OfflL) in 1,3,5—trihydroxybenzene (15) was added. In addition, 1.673 g (16. OOrarao and 2.12 equivalents) of 1-chloro-3-methyl-2-butene was slowly added dropwise. Stirring was continued for 3 hours while returning to room temperature. The methanol was distilled off under reduced pressure at room temperature. Ether was added to this, and the ether layer was washed with saturated aqueous ammonium chloride and saturated saline, and dried over sodium sulfate. The solvent was distilled off to obtain 2.874 g of a brown oily substance.

 The crude product was separated by silica gel column chromatography (Co-gel C-300, 85 g, hexane: ether = 19: 1) and, in the order of effluent, 2,2-bis (3-methyl-1-2-butenyl) 4, 6-bis (3-methyl-1-oxoxotyl) -3,5-dihydroxycyclinehexa-3,5-genone (16) 450mg as a pale yellow oil, 2,4-bis (3 —Methyl-1 1-year-old oxobutyl) -6— (3-Methyl-12-butenyl) -11,3,5—Trihydroxybenzene (17) (453 mg) was obtained as an orange oil.

 Compound (16) 1H-NMR (CDC): 0.99 (12H, d, J = 6, 6), 1.55 (12H, s),

 2.18 (2H, m), 2.60-2.79 (4H, m), 2.95 (2H, d, J = 7.0), 2.99 (2H, d, J = 6.9), 4.77 ( 2H, m)

 Compound (17) 1H—Maraudal R (CDC): 0.98 (12H, d, J = 6.6),

 1.82 (3H, d, 1.3), 1.87 (3H, s), 2.26 (2H, m), 2.97 (4H, d, J = 6.8), 3.40 (2H, d, 1 = 7. 1),

5. 23 (1H, in). Example 1 1 1,3,5—trihydroxy-1,2,4,6—tris (3-methyl-1-butenyl) benzene (18),

 3,5—dihydroxy 2,2,4,6—tetrakis (3—methyl-2-butenyl) cyclohexa 3,5—genone (19),

 3-hydroxy-5- (3-methyl-2-butenyloxy) -1,2,4-tris (3-methyl-2-butenyl) cyclohexa-1,5-genone (20),

3,5—Dihydroxy-2,2,4—Synthesis of tris (3—methyl-2-butenyl) cyclohexa-1,3,5—genone (2 1)

 Under a nitrogen atmosphere, a solution of 14.18 g (262.5 mmol, 3.500 equivalents) of sodium methoxide in dry methanol UOOraL) was stirred under ice-cooling while stirring with 1,3,5—trihydroxybenzen 9.458 g (75.OOmmol). Of methanol (30. OmL) was added. In addition, 23.53 g (225. Oramo and 3.000 equivalents) of 1-cloth—3-methyl-2-butene was slowly added dropwise. Stirring was continued for 3 hours while returning to room temperature. The methanol was distilled off under reduced pressure at room temperature. Ether was added to this, and the ether layer was washed with saturated aqueous ammonium chloride and saturated saline, and dried over sodium sulfate. The solvent was distilled off to obtain 22.164 g of an orange viscous oil.

 The crude product was separated by silica gel column chromatography (Co-gel C—200, 350 g, hexane: ether = 19: 1 to 7: 3), and the 1,3,5—trihydrofuran in the order of effluent. Xy 2,4,6—tris (3-methyl-2-butenyl) benzene (18) 2.27 g as an orange viscous oil 3,5—dihydroxy 2,2,4,6—tetrax (3-Methyl-1-butenyl) cyclohexa-3,5-genone (1.9) 1.73 g as an orange viscous oil, 3-hydroxy-5- (3-methyl-2-butenyloxy) ) 1,2,2,4-Tris (3-methyl-2-butenyl) cyclohexa-1,5-genone (20) 540 mg as an orange oil, 3,5-dihydroxy-1,2,2 4 — Tris (3 — methyl-2 — butenyl) cyclohexa 3,5 — Genone (21) 6.85 g of red oil It was obtained as a thing.

Compound (1 8) 1H-NMR ( CDC1 3): 1. 76 (9H, s), 1. 82 (9H, s),

 3.36 (6H, d,] = 7.1), 5.23 (3H, m), 5.39 (3H, bs) Compound (1 9) 1H—Marine R (CDCla): 1.62 (6H , s), 1.64 (6H, s),

1.75 (3H, d, 1.3), 1.78 (3H, d, J = l.3), 1.79 (3H, s), 1.81 (3H, s),

 2.51 (2H, dd, J = 13.7, 7.1),

 2.61 (2H, dd, J = 13.7, 8.1), 3.19 (2H, d, J = 7.3),

3.34 (2H, d, J = 7.0), 4.86 (2H, m), 5.16 (1H, in),

5.24 (1H, m)

 Compound (20) 1H-NMR (CDC 1.0: 1.55 (6H, s), 1.60 (6H, d, J = 0.7),

 1.72 (3H, s), 1.75 (3H, s), 1.78 (3H, s),

 1.81 (3H, s), 2.40 (4H, d, J-7.8),

 3.34 (2H, d, 1 = 7.1), 4.42 (2H, d, 1 = 6.9),

 4.83 (2H, m), 5.25 (1H, ra), 5.46 (1H, m),

 6.04 (1H, s)

 Compound (2 1) 1H— 丽 R (CDC): 1.58 (6H, s), 1.62 (6H, s),

 1.80 (6H, s), 2.55 (4H, d, J = 7.0), 3.15-3.38 (2H, ra), 4.86 (2H, ra), 5.16 (1H, m), 5.97 (1H, s) Example 1 Two

 3-hydroxy-1-5- (3-methyl-12-butenyloxy) -12,2,4-tris (3-methyl-12-butenyl) cyclohexa 3,5-genone (20),

3,5-dihydroxy-1,2,2,4-tris (3-methyl-2-butenyl) cyclohexa-1,5-genone (21), and

 Synthesis of 2- (3-Methyl-2-butenyl) —1,3,5—trihydroxybenzene (22)

Under a nitrogen atmosphere, a solution of 8.78 g (3.00 equivalents of 120ramoK) of potassium methoxide in dry methanol (200 mL) was stirred under ice-cooling with 1,0,3,5-trihydroxybenzene 5.00 g (40. Oramol) of methanol (40. Oramol). 30. OmL) solution was added. Further, 12.4 g (3.00 equivalents of 120 mmoK) of 3-methyl-2-butene was slowly added dropwise. Stirring was continued for 3 hours while returning to room temperature. The methanol was distilled off under reduced pressure at room temperature. Ether was added thereto, and the ether layer was washed with saturated aqueous ammonium chloride and saturated saline, and dried over sodium sulfate. The solvent was distilled off to obtain 12.93 g of an orange viscous oil. The crude product was separated by silica gel column chromatography (Co-gel C—200 350 g, hexane: ether = 9: 1 to 3: 1) and, in the order of effluent, 3-hydroxy-5_ (3-methyl- 2—Butenyloxy) 1,2,2,4—Tris (3—methyl-2—butenyl) cyclohexa-1,5—Genone (20) as an orange oil, 3,5—Dihydroxy 2,2, 4—Tris (3-methyl-2-butenyl) cyclohexa-1,3,5-genone (21) as a red oil and 2— (3—Methyl-2-butenyl) 1-1,3, 5 — Trihydroxybenzene (22) was obtained as an orange oil.

 Compound (2 2) 1H—Maraudal R (CDCla): 1.70 (6H, d, J = 8.4), 3.24 (2H, d, J-7.0), 5.24 (1H, m), 5.96 (2H, s) Example 13

 [3 — {2-(1 —piperidino) ethyl} — 2, 4, 6 — trihydroxyphenyl] (2 —methylpropyl) ketone (2 3) and

 Synthesis of [3,5—Bis {2— (1-piperidino) ethyl} -12,4,6—trihydroxyphenyl] (2-methylpropyl) ketone (24)

In a nitrogen atmosphere, a solution of 1.08 g (20. OmmoK 4.00 equivalents) of sodium methoxide in a dry methanol (20. OmL) solution was stirred at room temperature at room temperature to give (2-methylpropyl) (2,4,6-trihydroxyphenyl). A solution of 1.05 g (5. OOramol) of ketone in dry methanol (5. OmL) was added. In addition, a solution of 1.84 g (10. Ommo 1, 2.00 equivalents) of methanol (1. OmL) in 1 (2-chloroethyl) piperidine hydrochloride was slowly added. After heating at 60 ° C for 3 hours, methanol was distilled off under reduced pressure, and 30. OmL of methylene chloride was added to the residue, followed by stirring. The insoluble material was removed by filtration, and the solvent was distilled off under reduced pressure to obtain 2.16 g of an orange solid. This was separated by silica gel column chromatography (Co-gel C-300, 50 g, methylene chloride: methanol = 100: 1 to 100: 10), and [3— (2— (1— Piperidino) ethyl} —2,4,6—trihydroxyphenyl] (2—methylpropyl) ketone (23) 399 mg as a yellow solid, then [3,5—bis {2— (1-piperidino) Ethyl} —2,4,6—trihydroxyphenyl] (2-methylpyrrol) ketone (24) 11 mg was isolated as a yellow solid. Compound (23) 1H-NMR (CDC1: 0.96 (6H, d, J = 6.6), 1.45 (2H, ra),

 1.60 (2H, m), 1.71 (4H, m), 2.23 (1H, ra),

 2.50-2.95 (8H, m), 2.92 (2H, d, J-6.8), 5.89 (1H, s) 13C-NMR: 24.1, 26.6, 27.0, 27.3, 29.3, 45.0, 57.2,

 95.5, 105.0, 112.0, 155.8, 157.8, 161.8, 205.6.

Compound (2 4) 1H-NMR ( CDC1 3): 0.95 (6H, d, J = 6.6), 1.40 (2H, ra),

 1.49 (4H, m), 1.60 (2H, ra), 1.84 (5H, m),

 2. (1H, ra) 2.42 (3H, m), 2.82 (4H, ra),

 2.96 (2H, m), 2.98 (2H, d, J = 6.8), 3.32 (2H, m),

3.49 (6H, m), 3.87 (1H, m)

 Synthesis of {3- (N, N-dimethylamino) propyl-l, 2,4,6-trihydroxyphenyl} (2-methylpropyl) ketone (25)

 Under a nitrogen atmosphere, a solution of sodium methoxide 540rag (10. OmioK 4.00 equivalents) in dry methanol (10. OmL) was stirred at room temperature with (2-methylpropyl) (2, 4, 6-trihydroxyphenyl) ketone ( 5) A solution of 526 mg (2.50 raraol) in dry methanol (5. Ora L) was added. In addition, a solution of 3- (dimethylamino) -1-propane hydrochloride 79 Orag (5. OOmmoK 2.00 eq.) In methanol (5. OmL) was slowly added. After heating at 60 ° C for 3 hours, methanol was distilled off under reduced pressure, and the residue was mixed with 20.OmL of methylene chloride and stirred. The insoluble matter was removed by filtration, and the solvent was distilled off under reduced pressure to obtain 786 mg of a yellow solid. This was separated by silica gel column chromatography (ヮ -gel C-300 25 g, methylene chloride: methanol = 100: 1 to 100: 6), and the target compound, {3- (N, N-dimethylamino) propyl- 8 mg of 2,4,6-trihydroxyphenyl} (2-methylpropyl) ketone (25) n was isolated as a yellow solid.

 Compound (25) lH-NMR (DMSO): 0.93 (6H, d, J-6.6), 1.89 (1H, m),

 2.07 (1H, ra), 2.20 (1H, m), 2.48 (3H, s),

2.52 (3H, s), 2.50-2.80 (4H, ra), 2.93 (2H, d, J = 6.6), 5.77 (1H, s). Experimental example 1

Bone resorption inhibitory activity test

 (1) Preparation of cells

 After 11- to 12-day-old ICR mice (Charles River Corp.) were euthanized by ether anesthesia and immediately immersed in 70% ethanol for disinfection. The femur and tibia of the mouse were removed and a-MEM medium containing 5% FBS (Irvin Scientific), 1 OOU / mL penicillin, lO OmgZmL streptomycin (Flow Laboratories) was used. In a tree (F1ow Laboratories), cut into small pieces with scissors, collect the supernatant obtained by pipetting, wash with medium, and add 5% FBS, The cells were suspended in a MEM culture solution to obtain bone cells containing osteoclasts. After leaving still for 3 minutes, the supernatant of the bone cell suspension of bone cells was taken and passed through a mesh (Cell strainer, 70 μ μ, manufactured by Falcon). The cell concentration was adjusted to 1 × 10 ′ ZmL and used for the bone resorption pit formation inhibition activity test.

 (2) Assay by bone resorption pit formation inhibitory activity test

Ivory pieces were cut to a thickness of 150 am using a precision low-speed cutting machine (manufactured by Bueh 1er) and punched out using a single-hole punch into a disc with a diameter of 6 and hidden. . The ivory pieces were immersed in 70% ethanol, subjected to ultrasonic washing twice for 5 minutes each, and washed three times with sterile PBS and twice with a medium. The ivory piece 9 6-well culture plates (file Rukon (F Alcon) Co., Ltd.) put 2 X 1 0- ^S培溶liquid 1 in which the invention compounds prepared is entered the concentration of M 0 0 a L each well in addition,培溶solution 1 containing osteocytes 1 X 1 0 Vm L prepared in the al 0 0 L was placed in each well (final drug ^{concentration, 1 X 1 0- 5 M)} , 3 7. C. The cells were cultured in a 10% CO ₂ incubator for 3 days. After culturing, the cells on the ivory pieces are removed with a rubber spatula in 2 M sodium hydroxide solution, washed with water and methanol, and then the resorption pits are stained with Coomassie-Priantl Table-1. Was counted.

培溶solution to r P TH (1 X 1 0 - 8 M) 0% absorption窩数drug additive-free in the presence, where the absorption窩数is zero as 1 0 0% bone resorption inhibition rate Was calculated. As a result, the compound of the present invention had a remarkable effect on inhibiting bone resorption. The results are shown in Table 1,

table 1

Added drug game,

 Raku W V) i'yo | »

 '! ¾ 乂 ί¾ W ^ t l \ [[-ν / ο)

 1 1) U1 1 test JVl ο Ζ. ± 1 U »4 D 1.

 1 2 1 0 Μ 1 1 U. 3 ± l d, 1 ο ./

(1) 0 1 8 7, 7 ± 2 1. Test result 3 10 Μ 1 47.9 ± 15.4 ά \. L test 4 10 " ⁵ Μ 47.1 ± 4.97 4.9

2 1 6 l ei— ⁵ Μ 1.8 ± 0.7 9 99.0

 1 7 10 0 Μ 0.6 ± 0.3 ± 9 9 .7

 Actual (-) 0 2 0 1 .8 ± 20 .2 0

Experiment 5 1 0 — ⁵ Μ 10 2 .6 ± 1 1 .5 49.2

 3 1 5 1 0 Μ 1.6 ± 0.7 0.7 9 9. 2

(I) 0 2 7 5.6 ± 2 3.90

7 1 0 — ⁶ Μ 6 2 .1 ± 4.4 77.5 Actual 8 1 0 — 5 7 ⁵ 7.6 ± 8.4 79.1

9 1 0 -.... .. 5 Μ 3 5 ± 0 8 9 8 7 Experiment 1 0 1 0 Μ 7 7 1 ± 9 5 7 2 0

1 1 1 0 — ⁵ Μ 2 2 0. 4 ± 2 2, 4 2 0. 0

4 1 4 1 0 — ⁵ Μ 1 2 6 .1 ± 2 1 .0 ⁵ 4 .2

2 0 10 0 1 .4 ± 0 .5 9 9 .5

 2 1 1 0 Μ 1 25.5 .5 ± 2 3 .3 54.5

 2 2 1 U Μ υ, ± ώ 4. Ί U. 1 Sou (1) 0 2 17.5 ± 1 4. 0 0

 Test 1 2 1 0 Μ 10 7 .3 ± 1 6 .8 5 0 .7

5 1 3 1 0 -.. ... 5 Μ 1 0 7 8 ± 1 4 1 5 0 4 real (one) 0 1 7 9 6 ± 3 4 4 0

 Test 1 8 1 0 "Μ 28.5 ± 8. 1 8 4. 1

6 1 9 1 0 — ⁵ Μ 28.8 ± 5.18.4 0 Actual (1) 0 1 25.3 ± 1 2 .2 0

2 3 1 0 — ⁵ Μ 4 2 .8 ± 1 0 .5 ⁶ 5.8

 7 2 5 1 0 Μ 1 1 3 .0 ± 1 3 .7 1 9 .9

Claims

Scope of Claim General formula (I) (wherein R ', R2, and R3 each independently represent a hydrogen atom, a linear or branched substituent having 1 to 15 carbon atoms, or R 4 represents an unsubstituted alkyl group, a linear or branched substituted or unsubstituted alkenyl group having 2 to 15 carbon atoms, a substituted or unsubstituted benzyl group, or an aryl group; R ′ ′ and R 6 are each independently a hydrogen atom, a linear or branched substituted or unsubstituted alkyl group having 1 to 15 carbon atoms, a linear chain having 2 to 15 carbon atoms. Or a branched chain unsubstituted or unsubstituted alkenyl group or a substituted or unsubstituted benzyl group.) Or a salt thereof or a solvate thereof. 2. A compound according to claim 1 or a salt thereof, which is a 2-methylpropyl group 3. A compound according to claim 1, wherein R 1 or R 3 is a hydrogen atom or a 3-methyl-2-butenyl group. Range The compound according to paragraph 1 or 2, or a salt thereof 4. The claim according to claim 1, 2, or 3, wherein RR s or R 6 is a hydrogen atom or a 3-methyl-2-butenyl group. Or a salt thereof 5. The compound is (2—methylpropyl) (3,4,5—trihydroxyphenyl) ketone, {3,5—dihydroxy-1 2— (3—methyl-2-butenyl) 1 4 1 (3—methyl-2-butenyloxy) phenyl} (2—methylpropyl) ketone, {3,5—dihydroxy-1-4 -— (3—methyl1-2—butenyloxy) phenyl} (2 —Methylpropyl) ketone, and one selected from the group consisting of {2— (3-methyl-1-2-butenyl) -1,3,4,5—trihydroxyphenyl} (2-methylpropyl) ketone The compound according to any one of claims 1 to 4 Or a salt thereof 6. General formula (II) (wherein RR 2 and R are each independently a hydrogen atom, a halogen atom, a linear or branched substituent having 1 to 15 carbon atoms, Unsubstituted alkyl group, straight-chain or branched-chain substituted or unsubstituted alkenyl group having 2 to 15 carbon atoms, substituted or unsubstituted benzyl group, straight-chain or 3 to 15 carbon atoms A branched or substituted 1-oxoalkyl group, a linear or branched, substituted or unsubstituted 1-oxoalkenyl group having 3 to 15 carbon atoms, or a substituted or unsubstituted 1 represents an oxoaralkyl group; R 3 represents a hydroxyl group, a linear or branched substituted or unsubstituted alkyl group having 1 to 15 carbon atoms, a linear or branched alkyl group having 1 to 15 carbon atoms; Branched or unsubstituted alkyloxy group, linear or branched, substituted or unsubstituted alkenyl group having 2 to 20 carbon atoms, carbon RR 6 represents a linear or branched, substituted or unsubstituted alkenyloxy group, a substituted or unsubstituted benzyl group, or a substituted or unsubstituted benzyloxy group of the formulas 2 to 20; Each independently represents a hydrogen atom, a linear or branched substituted or unsubstituted alkyl group having 1 to 15 carbon atoms, a linear or branched substituted or unsubstituted alkyl group having 2 to 15 carbon atoms, or Unsubstituted alkenyl group, substituted or unsubstituted benzyl group, C3-C15 linear or branched substituted or unsubstituted 1-oxoalkyl group, C3-C15 linear Or a branched or unsubstituted 1-oxoalkenyl group or a substituted or unsubstituted 1-oxoaralkyl group. Provided that R 4 is a straight-chain or branched unsubstituted 1-oxoalkyl group having 3 to 15 carbon atoms, or a straight-chain or branched unsubstituted C 3 to 15 carbon atom When R 1 and R 2 are a oxoalkenyl group or an unsubstituted 1-oxoaralkyl group, and R 3 is a hydroxyl group, R ′ and R 2 are simultaneously a hydrogen atom and have 1 to 15 carbon atoms. A straight-chain or branched unsubstituted alkyl group, a straight-chain or branched-chain unsubstituted alkenyl group having 2 to 15 carbon atoms, or a substituted or unsubstituted benzyl group Or a salt thereof, or a solvate thereof. 7. The compound according to claim 6, wherein R 1 is a 3-methyl-1-oxobutyl group or a 3-methyl-2-butenyl group, or a salt thereof. 8. The compound according to claim 6, wherein R 2 or R 4 is a hydrogen atom, a 3-methyl-1-oxobutyl group, or a 3-methyl-2-butenyl group, or a salt thereof. 9. The compound according to claim 6, 7, or 8, wherein R 3 is a hydroxyl group or a methyl group, or a salt thereof. 10. The compound according to any one of claims 6 to 9, wherein R 5 or R β is a hydrogen atom, or a salt thereof. 1 1. The compound is (2,6-dihydroxy-4-methylphenyl) (2-methylpropyl) ketone, {2,6-dihydroxy-1-4-methyl-3- (3-methyl-1-butenyl) phen (2-methylpropyl) ketone, {3,5-bis (3-methyl-2-butenyl) -1,2,6-dihydroxy-1-4-methylphenyl} (2-methylpropyl) ketone, (5—chloro-2,4-dihydroxyphenyl) (2—methylpropyl) ketone, {5—chloro-2—hydroxy-1 3— (3—methyl—2—butenyl) —4- (3-methyl-2-—) (Butenyloxy) phenyl} (2-methylpropyl) ketone, {5-chloro-2-hydroxy-1- 4— (3-methyl-2-butenyloxy) phenyl} (2-methylpropyl) ketone {5— Black mouth one, two four hydroxy 3 — (3 — Methyl 1 — butenyl) phenyl} (2 — Methylpropyl) ketone, 1, 3 — Bis (3 — Methyl 1 — Oxoptyl) — 2, 4, 6 — Trihydroxybenzene, 1 , 3—Bis (3—Methyl-1 oxobutyl) —5— (3—Methyl-1—Butenyl) -1,2,4,6—Trihydroxybenzene, {3,5—Bis (2— (1 —piperidino) ethyl) 1, 2, 4, 6 — trihydroxyphenyl} (2 —methylpropyl) ketone, {3 1 — (2 — (1 —piperidino) ethyl) 1, 2, 4, 6 — Trihydroxyphenyl} (2-methylpropyl) ketone, {3- (3- (N, N-dimethylamino) propyl) -1,2,4,6 — Trihydroxyphenyl} (2 —Methylpropyl) ketone, 2 — (3 —Methyl-2-butenyl) -1,3,5 —Trihydro Claims 6 to 10 which are any one selected from the group consisting of xylene, and 1,3,5—trihydroxy2,4,6—tris (3-methyl-2-butenyl) benzene Item 7. The compound according to any one of the items above, or a salt thereof. 1 2. General formula (III) (wherein, RRRR5 is each independently a hydrogen atom, a linear or branched substituted or unsubstituted alkyl group having 1 to 15 carbon atoms, To 20 linear or branched, substituted or unsubstituted alkenyl groups, substituted or unsubstituted benzyl groups, and linear or branched, substituted or unsubstituted, 2 to 16 carbon atoms A 1-oxoalkyl group, a linear or branched, substituted or unsubstituted 1-oxoalkenyl group having 3 to 21 carbon atoms, or a substituted or unsubstituted 1-oxoaralkyl group, R 3 is a hydroxyl group, a linear or branched substituted or unsubstituted alkyl group having 1 to 15 carbon atoms, a linear or branched substituted or unsubstituted alkyl group having 1 to 15 carbon atoms An alkyloxy group, a linear or branched substituted or unsubstituted alkenyl group having 2 to 20 carbon atoms, a linear or branched Represents a branched or unsubstituted alkenyloxy group, a substituted or unsubstituted benzyl group, or a substituted or unsubstituted benzyloxy group, provided that R ′ is a straight or branched chain having 2 to 16 carbon atoms. A branched unsubstituted 1-oxoalkyl group, a straight-chain or branched unsubstituted 1-year-old oxoalkenyl group having 3 to 21 carbon atoms, or an unsubstituted 1-oxo group When R represents a aralkyl group and R 3 represents a hydroxyl group, R 2 represents a hydrogen atom, a linear or branched unsubstituted alkyl group having 1 to 15 carbon atoms, and a carbon number of 1 to 15 carbon atoms. A linear or branched unsubstituted alkenyl group or a substituted or unsubstituted benzyl group of 2 to 15), or a salt thereof, or a solvent thereof. Japanese food. 13. The compound according to claim 12, wherein R 1 or R 2 is a hydrogen atom, a 3-methyl-1-oxobutyl group, or a 3-methyl-2-butenyl group, or a salt thereof. 14. The compound according to claim 12 or 13, wherein R 3 is a hydroxyl group or a methyl group, or a salt thereof. 15. The compound according to claim 12, 13, or 14, or a salt thereof, wherein R 4 is a 3-methyl-2-butenyl group. 16. The compound according to any one of claims 12 to 15, or a salt thereof, wherein R6 is a hydrogen atom or a 3-methyl-2-butenyl group. 1 7. The compound is 5-hydroxy-13-methyl-6_ (3-methyl_1 1-year-old oxobutyl) -1,2,4-tris (3-methyl-12-butenyl) cyclohexa-3 , 5-Genon, 2,2-bis (3-methyl-2-butenyl) -1-5-hydroxy-13-methyl-6- (3-methyl-11-oxobutyl) cyclohexa 3,5-Genon, 2 , 2-bis (3-methyl-1-butenyl) -1,4,6-bis (3-methyl-11-oxobutyl) -1,3,5-dihydroxycyclohexa 3,5-genonone, 3-hydroxy-5 — (3-methyl-2-butenyloxy) — 2,2,4-tris (3-methyl-2-butenyl) cyclohexa 3,5-genone, 3,5-dihydroxy-1,2,2,4, 6-tetrakis (3-methyl-2-butenyl) cyclohexa-1,3-genon, and 3,12-dihydroxy-1,2,2,4-tris (3-methyl-1-butenyl) cyclohexa-hexa 3,5—genon Item 7. The compound according to any one of items 6 or a salt thereof. 18. An amount effective for prevention or treatment of one or more of the compound, salt or solvate thereof according to any one of claims 1 to 17 or a solvate thereof, and A pharmaceutical composition comprising a pharmaceutically acceptable carrier. 19. The pharmaceutical composition according to claim 18, which is an agent for preventing and treating bone and cartilage diseases, 20. The general formula (IV;), wherein RRR 3 is independently hydrogen. An atom, a linear or branched substituted or unsubstituted alkyl group having 1 to 15 carbon atoms, a linear or branched substituted or unsubstituted alkenyl group having 2 to 15 carbon atoms, Represents a substituted or unsubstituted benzyl group or aryl group, and RR ′ and R 6 each independently represent a hydrogen atom, a linear or branched C 1 to C 15 substituted or Represents an unsubstituted alkyl group, a linear or branched substituted or unsubstituted alkenyl group having 2 to 15 carbon atoms, or a substituted or unsubstituted benzyl group. V), (wherein RR 2 and R 4 are each independently a hydrogen atom, a halogen atom, a linear or branched substituted or unsubstituted alkyl group having 1 to 15 carbon atoms, C2-C15 linear or branched substituted or unsubstituted alkenyl group, substituted or unsubstituted benzyl group, C3-C15 linear or branched substituted or An unsubstituted 1-oxoalkyl group, a linear or branched, substituted or unsubstituted 1-oxoalkenyl group having 3 to 15 carbon atoms, or a substituted or unsubstituted 1-oxoaralkyl group; R 3 represents a hydroxyl group, a linear or branched substituted or unsubstituted alkyl group having 1 to 15 carbon atoms, a linear or branched substituted group having 1 to 15 carbon atoms. Or an unsubstituted alkyloxy group, a linear or branched substituted or unsubstituted alkenyl group having 2 to 15 carbon atoms, a linear or branched substituted or unsubstituted alkenyl group having 2 to 15 carbon atoms, or Represents an unsubstituted alkenyloxy group, a substituted or unsubstituted benzyl group, or a substituted or unsubstituted benzyloxy group, 6> R fi are each independently a hydrogen atom, a linear or branched substituted or unsubstituted alkyl group having 1 to 15 carbon atoms, a linear or branched alkyl group having 2 to 15 carbon atoms. Chain-substituted or unsubstituted alkenyl group, substituted or unsubstituted benzyl group, straight-chain or branched-chain substituted or unsubstituted 1-oxoalkyl group having 3 to 15 carbon atoms, 3 to 1 carbon atoms 5 represents a linear or branched, substituted or unsubstituted 1-oxoalkenyl group or a substituted or unsubstituted 1-oxoaralkyl group. Or a compound represented by the general formula (VI), wherein R ', R2, R4, and R5 each independently represent a hydrogen atom, a linear or branched substituted or unsubstituted carbon atom having 1 to 15 carbon atoms. An alkyl group, a linear or branched substituted or unsubstituted alkenyl group having 2 to 15 carbon atoms, a substituted or unsubstituted benzyl group, a linear or branched chain having 3 to 15 carbon atoms Substituted or unsubstituted 1-oxoalkyl group, linear or branched substituted or unsubstituted 1-year-old oxoalkenyl group having 3 to 15 carbon atoms, or substituted or unsubstituted 1-oxoalkyl group Represents an oxoaralkyl group, and R 3 is a hydroxyl group, a linear or branched substituted or unsubstituted alkyl group having 1 to 15 carbon atoms, a linear or branched alkyl group having 1 to 15 carbon atoms. A substituted or unsubstituted alkyloxy group having 2 to 15 carbon atoms, a linear or branched substituted or unsubstituted alkenyl group having 2 to 15 carbon atoms, 15 represents a linear or branched, substituted or unsubstituted alkenyloxy group, substituted or unsubstituted benzyl group, or substituted or unsubstituted benzyloxy group. Or a bone / cartilage disease prevention / treatment agent comprising a solvate thereof. 21. A method for treating bone and cartilage disease, comprising administering to a patient an effective amount of the preventive and therapeutic agent for bone and cartilage disease according to claim 20. 2 2.—General formulas (IV) and (wherein R ′ and R \ R3 each independently represent a hydrogen atom, a straight-chain or branched-chain substituted or unsubstituted group having 1 to 15 carbon atoms. Represents a linear or branched, substituted or unsubstituted alkenyl group having 2 to 15 carbon atoms, a substituted or unsubstituted benzyl group, or an aryl group, wherein RR 5 and R β are Each independently represents a hydrogen atom, a linear or branched substituted or unsubstituted alkyl group having 1 to 15 carbon atoms, or a linear or branched substituted group having 2 to 15 carbon atoms. Or an unsubstituted alkenyl group or a substituted or unsubstituted benzyl group.), General Formula (V), wherein RR 2 and R 4 each independently represent a hydrogen atom, a halogen atom, a carbon atom A linear or branched, substituted or unsubstituted alkyl group having 1 to 15 carbon atoms, a linear or branched, substituted or unsubstituted alkenyl group having 2 to 15 carbon atoms, Is an unsubstituted benzyl group, a linear or branched substituted or unsubstituted 1-oxoalkyl group having 3 to 15 carbon atoms, a linear or branched substituted group having 3 to 15 carbon atoms Or an unsubstituted 1-oxoalkenyl group or a substituted or unsubstituted 1-oxoaralkyl group; R 3 is a hydroxyl group, a linear or branched substituted or unsubstituted 1 to 15 carbon atom group; A substituted alkyl group, a linear or branched substituted or unsubstituted alkyloxy group having 1 to 15 carbon atoms, a linear or branched substituted or unsubstituted alkyl group having 2 to 15 carbon atoms. Represents a substituted alkenyl group, a linear or branched substituted or unsubstituted alkenyloxy group having 2 to 15 carbon atoms, a substituted or unsubstituted benzyl group, or a substituted or unsubstituted benzyloxy group. , R s and R 6 are each independently a hydrogen atom, a linear or branched configuration having 1 to 15 carbon atoms. Or an unsubstituted alkyl group, a linear or branched, substituted or unsubstituted alkenyl group having 2 to 15 carbon atoms, a substituted or unsubstituted benzyl group, a linear group having 3 to 15 carbon atoms, or A branched or unsubstituted 1-oxoalkyl group, a linear or branched, substituted or unsubstituted 1-oxoalkenyl group having 3 to 15 carbon atoms, or a substituted or unsubstituted Or a 1-oxoaralkyl group.) Or a compound represented by the general formula (VI), wherein RR 2 and RR 5 are each independently a hydrogen atom, a linear or branched chain having 1 to 15 carbon atoms. Substituted or unsubstituted alkyl group, straight-chain or branched-chain substituted or unsubstituted alkenyl group having 2 to 15 carbon atoms, substituted or unsubstituted benzyl group, straight-chain having 3 to 15 carbon atoms A linear or branched substituted or unsubstituted 1-oxoalkyl group; a linear or branched C3-C15 substituted or unsubstituted alkyl group; Represents an unsubstituted 1-year-old oxoalkenyl group or a substituted or unsubstituted 1-oxoaralkyl group; Substituted or unsubstituted alkyl group, linear or branched substituted or unsubstituted alkyloxy group having 1 to 15 carbon atoms, linear or branched substituted or unsubstituted alkyl group having 2 to 15 carbon atoms Or an unsubstituted alkenyl group, a linear or branched substituted or unsubstituted alkenyloxy group having 2 to 15 carbon atoms, a substituted or unsubstituted benzyl group, or a substituted or unsubstituted benzyloxy group Represents a group. ) Use of a compound represented by the formula, a salt thereof, or a solvate thereof for the manufacture of a prophylactic / therapeutic agent for bone / cartilage disease. WO 98/52899 Request for amendment 麵 ~ / ~ 6 [October 19, 1998 (19.1.10.98) Accepted by the International Bureau: Claims 6, 11, 1 and 12 at the time of filing are amended Was filed; claim 19 originally filed was withdrawn; other claims remained unchanged. (Page 11)]

1. General formula (I)

(In the formula, R ′ and RR ^{: 1} each independently represent a hydrogen atom, a linear or branched substituted or unsubstituted alkyl group having 1 to 15 carbon atoms, and a carbon atom having 2 to 15 carbon atoms. A linear or branched substituted or unsubstituted alkenyl group, a substituted or unsubstituted benzyl group, or an aryl group;

R \ R \ ^Rβ each independently represents a hydrogen atom, a linear or branched substituted or unsubstituted alkyl group having 1 to 15 carbon atoms, a linear or branched alkyl group having 2 to 15 carbon atoms, It represents a branched or unsubstituted alkenyl group or a substituted or unsubstituted benzyl group. )

Or a salt thereof, or a solvate thereof.

2. The compound according to claim 1, wherein R ² is a 2-methylpropyl group, or a salt thereof.

3. The compound according to claim 1, wherein R ′ or R ³ is a hydrogen atom or a 3-methyl-2-butenyl group, or a salt thereof.

4. R \ R ⁵ or R ^fi or a hydrogen atom 3 - first the claims is a-methyl-2-butenyl, 2, or The compound according to item 3, or a salt thereof.

 5. The compound is

 (2-Methylpropyl) (3,4,5-trihydroxyphenyl) ketone, (3,5-Dihydroxy-1-2- (3-methyl-2-butenyl) 1-41- (3-methyl-2-butenyloxy) Phenyl} (2-methylpropyl) ketone,

 {3,5-Dihydroxy 4- (3-methyl-2-butenyloxy) phenyl} (2-methylpropyl) ketone,

 {2-(3-Methyl-2-butenyl) 1, 3, 4, 5 — Trihydroxypropyl}

-44- Amended paper (Article 19 of the Convention) (2-Methylpropyl) ketone

The compound according to any one of claims 1 to 4, which is any one selected from the group consisting of: or a salt thereof.

6. (after correction) General formula (II)

(Wherein, RR ² and R each independently represent a hydrogen atom, a halogen atom, a linear or branched substituted or unsubstituted alkyl group having 1 to 15 carbon atoms, and a carbon atom having 2 to 15 carbon atoms. A straight-chain or branched-chain substituted or unsubstituted alkenyl group, a substituted or unsubstituted benzyl group, a straight-chain or branched-chain substituted or unsubstituted monooxoalkyl having 3 to 15 carbon atoms A linear or branched, substituted or unsubstituted 1-oxoalkenyl group having 3 to 15 carbon atoms, or a substituted or unsubstituted 1-oxoaralkyl group,

R ^: 'is a hydroxyl group, a linear or branched substituted or unsubstituted alkyl group having 1 to 15 carbon atoms, a linear or branched substituted or unsubstituted alkyl group having 1 to 15 carbon atoms or An unsubstituted alkyloxy group, a linear or branched substituted or unsubstituted alkenyl group having 2 to 20 carbon atoms, a linear or branched substituted or unsubstituted alkyl group having 2 to 20 carbon atoms. Represents a substituted alkenyloxy group, a substituted or unsubstituted benzyl group, or a substituted or unsubstituted benzyloxy group,

R \ R ⁸ are each independently a hydrogen atom, a linear or branched匱換or unsubstituted alkyl group having 1 to 5 carbon atoms, a linear or branched from 2 to 1 to 5 carbon atoms A branched or unsubstituted alkenyl group, a substituted or unsubstituted benzyl group, a linear or branched, substituted or unsubstituted 1-oxoalkyl group having 3 to 15 carbon atoms, and a carbon number of 3 to 15 15 represents a linear or branched, substituted or unsubstituted 1-oxoalkenyl group or a substituted or unsubstituted 1-oxoaralkyl group.

Provided that R ⁴ is a straight-chain or branched unsubstituted 1-oxoalkyl group having 3 to 15 carbon atoms, or a straight-chain or branched unsubstituted 1-oxo alkyl group having 3 to 15 carbon atoms. One year old

-45- Amended paper (Article 19 of the Convention) When it is a alkenyl group or an unsubstituted 1-oxoaralkyl group and R ³ is a hydroxyl group, R ′ and R ² are simultaneously a hydrogen atom and a straight-chain alkyl group having 1 to 15 carbon atoms. Or a branched unsubstituted alkyl group, a linear or branched unsubstituted alkenyl group having 2 to 15 carbon atoms, or a substituted or unsubstituted benzyl group. Remove. Further, when R ³ is a hydroxyl group, R ⁴ , R "'and R ^e are hydrogen atoms, and R' is an unsubstituted l-oxoalkyl group, and R ² is an unsubstituted 1-oxoalkyl group And when R 3 is a hydroxyl group and R ² , RR and R ¹⁵ are hydrogen atoms, except that R ′ is an unsubstituted alkenyl group.)

Or a salt thereof, or a solvate thereof.

7. The compound or a salt thereof according to claim 6, wherein R ¹ is a 3-methyl-1-oxobutyl group or a 3-methyl-2-butenyl group.

8. The compound according to claim 6 or 7, wherein R ² or R is a hydrogen atom, a 3-methyl-1-oxobutyl group, or a 3-methyl-21-butenyl group, or a salt thereof.

9. The compound according to claim 6, 7 or 8, wherein R ³ is a hydroxyl group or a methyl group, or a salt thereof.

1 0. R "'or R ⁶ The compound according to any one of claims sixth to item 9 the range of a hydrogen atom, or a salt thereof.

 1 1. (after correction)

 (2,6-dihydroxy-1-41-methylphenyl) (2-methylpropyl) ketone,

{2,6-dihydroxy-1-4-methyl-3- (3-methyl-2-butenyl) phenyl} (2-methylpropyl) ketone,

 {3,5-bis (3-methyl-1-butenyl) -12,6-dihydroxy-14-methylphenyl} (2-methylpropyl) ketone,

 (5-chloro-1,4-dihydroxyphenyl) (2-methylpropyl) ketone,

{5-chloro-2-3-hydroxy (3-methyl-2-butenyl) -14- (3-methyl-2-butenyloxy) phenyl} (2-methylpropyl) ketone,

{5-chloro-2-4-hydroxy (3-methyl-1-butenyloxy) phenyl} (2-methylpropyl) ketone

 {5—Chloro-1,2—dihydroxy—3— (3-Methyl-1-butenyl)

-46- Amended paper (Article 19 of the Convention) Nyl} (2-Methylpropyl) Ketone, -1,3—Bis (3—Methyl-1 oxobutyl) —5— (3—Methyl-2-butenyl) -1,2,4,6—Trihydro Roxybenzene,

 {3, 5 —bis (2 — (1 —piperidino) ethyl) 1, 2, 4, 6 — trihydroxyphenyl} (2 -methylpropyl) ketone,

 {3 1-(2 — (1 —piperidino) ethyl) 1, 2,4,6 — trihydroxyphenyl} (2 —methylpropyl) ketone,

 {3-(3 — (N, N—dimethylamino) propyl) — 2, 4, 6 — trihydroxyphenyl} (2 —methylpropyl) ketone, and

 1,3,5—trihydroxy 2,4,6—tris (3-methyl-1-butenyl) benzene

The compound according to any one of claims 6 to 10, which is any one selected from the group consisting of: or a salt thereof.

 1 2. (after correction) General formula (I I I)

(Wherein, RRRR ⁵ are each independently a hydrogen atom, a linear or branched substituted or unsubstituted alkyl group of from 1 1 to 5 carbon atoms, straight-chain carbon number of 2-2 0 The Is a branched or substituted or unsubstituted alkenyl group, a substituted or unsubstituted benzyl group, a linear or branched, substituted or unsubstituted 1-oxoalkyl group having 2 to 16 carbon atoms, Represents a 3 to 21 linear or branched substituted or unsubstituted 1-year-old oxoalkenyl group or a substituted or unsubstituted 1-oxoaralkyl group;

R ³ is a hydroxyl group, a linear or branched substituted or unsubstituted alkyl group having 1 to 15 carbon atoms, a linear or branched substituted or unsubstituted alkyl group having 1 to 15 carbon atoms An alkyloxy group, a substituted or unsubstituted linear or branched alkenyl group having 2 to 20 carbon atoms, a substituted or unsubstituted linear or branched chain having 2 to 20 carbon atoms Alkenyoki of

-47- Amended paper (Article 19 of the Convention) Represents a benzyl group, a substituted or unsubstituted benzyl group, or a substituted or unsubstituted benzyloxy group.

Provided that R ¹ is a linear or branched unsubstituted 1-oxoalkyl group having 2 to 16 carbon atoms, a linear or branched unsubstituted 3 to 21 carbon atoms. 1 When a 1-year-old oxoalkenyl group or an unsubstituted 1-oxoaralkyl group is represented and R ³ represents a hydroxyl group, R ² represents a hydrogen atom and a straight-chain having 1 to 15 carbon atoms. An unsubstituted or branched unsubstituted alkyl group, a linear or branched unsubstituted alkenyl group having 2 to 15 carbon atoms, or a substituted or unsubstituted benzyl group. In addition, when R ³ is a hydroxyl group and R ² is a hydrogen atom or an unsubstituted 1-oxoalkyl group, the case where R ¹ is a hydrogen atom, an unsubstituted alkyl group or an unsubstituted alkenyl group. Exclude <. )

Or a salt thereof, or a solvate thereof.

13. The compound according to claim 12, wherein R ′ or R ² is a hydrogen atom, a 3-methyl-1-oxobutyl group, or a 3-methyl-2-butenyl group, or a salt thereof.

14. The compound according to claim 12, wherein R ³ is a hydroxyl group or a methyl group, or a salt thereof.

15. The compound according to claim 12, 13, or 14, or a salt thereof, wherein R ⁴ is a 3-methyl-2-butenyl group.

1 6. R ⁵ is A compound according to any one of a hydrogen atom or a 3-methyl-2-butenyl group a is Claims first 2 to 1 5 wherein, or a salt thereof.

 1 7. The compound is

 5-Hydroxy-1-3-methyl-6- (3-methyl-1-oxobutyl) 1,2,4-Tris (3-methyl-1-butenyl) cyclohexa 3,5-genon, 2,2- Bis (3-methyl-2-butenyl) -5-hydroxy-1-3-methyl-6- (3-methyl-1-1-oxobutyl) cyclohexa-3,5-genone, 2,2-bis (3-methyl- 2-butenyl) —4,6-bis (3-methyl-1-oxobutyl) -1,3,5-dihydroxycyclohexa 3,5-genonone, 3-hydroxy-5— (3-methyl-2-butenyloxy) 2,2,4-tris (3-methyl-2-butenyl) cyclohexa-1,3-genone,

-48- Amended paper (Article 19 of the Convention) 3,5-dihydroxy-1,2,2,4,6-tetrakis (3-methyl-1-butenyl) cyclohexa 3,5-genone, and

 3,5-dihydroxy-1,2,4, tris (3-methyl-2-butenyl) cyclo mouth hexer 3,5—genone

The compound according to any one of claims 12 to 16, which is one selected from the group consisting of: or a salt thereof.

 1 8. One or more of the compound, salt or solvate thereof according to any one of claims 1 to 17 and an amount effective for the prevention and treatment of bone and cartilage diseases, and A pharmaceutical composition comprising a pharmaceutically acceptable carrier.

1 9. (Delete)

20. The general formula (IV;),

(Wherein, R ', RR ³ are each independently a hydrogen atom, a linear or branched, substituted or unsubstituted alkyl group having a carbon number of 1-1 5, linear from 2 to 1 to 5 carbon atoms A chain or branched chain substituted or unsubstituted alkenyl group, substituted or unsubstituted benzyl group, or aryl group;

R ⁴ , R ⁵ , and R ^fl each independently represent a hydrogen atom, a linear or branched substituted or unsubstituted alkyl group having 1 to 15 carbon atoms, and a linear chain having 2 to 15 carbon atoms. Represents a substituted or unsubstituted substituted or unsubstituted alkenyl group or a substituted or unsubstituted benzyl group. ),

 General formula (V),

-49- Amended paper (Article 19 of the Convention)

(Wherein, R ', RR ⁴ each independently represent a hydrogen atom, a halogen atom, a linear or branched, substituted or unsubstituted alkyl group having 1 to 5 carbon atoms, 2 to 1 5 carbon atoms Linear or branched substituted or unsubstituted alkenyl group, substituted or unsubstituted benzyl group, linear or branched substituted or unsubstituted 1-oxoalkyl group having 3 to 15 carbon atoms A linear or branched, substituted or unsubstituted 1-oxoalkenyl group having 3 to 15 carbon atoms, or a substituted or unsubstituted 1-oxoaralkyl group;

R ³ is a hydroxyl group, a linear or branched substituted or unsubstituted alkyl group having 1 to 15 carbon atoms, a linear or branched substituted or unsubstituted alkyl group having 1 to 15 carbon atoms. Substituted alkyloxy group, linear or branched, substituted or unsubstituted alkenyl group having 2 to 15 carbon atoms, linear or branched substituted or unsubstituted, having 2 to 15 carbon atoms Represents an alkenyloxy group, a substituted or unsubstituted benzyl group, or a substituted or unsubstituted benzyloxy group,

R ⁵ and R ^fi are each independently a hydrogen atom, a linear or branched substituted or unsubstituted alkyl group having 1 to 15 carbon atoms, a linear or branched alkyl group having 2 to 15 carbon atoms. A branched or unsubstituted alkenyl group, a substituted or unsubstituted benzyl group, a linear or branched, substituted or unsubstituted 1-oxoalkyl group having 3 to 15 carbon atoms, and a carbon number of 3 to 15 It represents 15 straight-chain or branched substituted or unsubstituted 1-oxoalkenyl groups or substituted or unsubstituted 1-oxoaralkyl groups. )

Or the general formula (V I)

-50- Amended paper (Article 19 of the Convention)

(In the formula, R ′ and RRR ″ are each independently a hydrogen atom, a linear or branched substituted or unsubstituted alkyl group having 1 to 15 carbon atoms, Straight-chain or branched-chain substituted or unsubstituted alkenyl group, substituted or unsubstituted benzyl group, straight-chain or branched-chain substituted or unsubstituted 1-year-old oxoalkyl having 3 to 15 carbon atoms A linear or branched, substituted or unsubstituted 1-year-old oxoalkenyl group having 3 to 15 carbon atoms, or a substituted or unsubstituted 1-oxoaralkyl group;

R ³ is a hydroxyl group, a linear or branched substituted or unsubstituted alkyl group having 1 to 15 carbon atoms, a linear or branched substituted or unsubstituted alkyl group having 1 to 15 carbon atoms An alkyloxy group, a linear or branched, substituted or unsubstituted alkenyl group having 2 to 15 carbon atoms, a linear or branched, substituted or unsubstituted group, having 2 to 15 carbon atoms Represents an alkenyloxy group, a substituted or unsubstituted benzyl group, or a substituted or unsubstituted benzyloxy group. )

A preventive or therapeutic agent for bone and cartilage diseases comprising a compound represented by the formula: or a salt thereof or a solvate thereof.

 21. A method for treating bone and cartilage disease, comprising administering to a patient an effective amount of the preventive and therapeutic agent for bone and cartilage disease according to claim 20.

 2 2. General formula (IV),

-51-Amended paper (Article 19 of the Convention) (Wherein, R ', RR ³ are each independently a hydrogen atom, a linear or branched, substituted or unsubstituted alkyl group having 1 to 5 carbon atoms, straight of 2-1 5 carbon atoms A chain or branched chain substituted or unsubstituted alkenyl group, substituted or unsubstituted benzyl group, or aryl group;

^R \ R ^r \ R ⁶ are each independently a hydrogen atom, a linear or branched, substituted or unsubstituted alkyl group having 1 to 5 carbon atoms, the number 2-1 5 straight Or a branched or unsubstituted alkenyl group or a substituted or unsubstituted benzyl group. ),

 General formula (V;),

(In the formula, R ′, R ² , and R ⁴ are each independently a hydrogen atom, a halogen atom, a linear or branched substituted or unsubstituted alkyl group having 1 to 15 carbon atoms, Straight- or branched-chain substituted or unsubstituted alkenyl group, substituted or unsubstituted benzyl group having 3 to 15 carbon atoms, linear or branched-chain substituted or unsubstituted 3 to 15 carbon atoms 1-oxoalkyl group, straight-chain or branched-chain substituted or unsubstituted 1-oxoalkenyl having 3 to 15 carbon atoms

-52- Amended paper (Article 19 of the Convention) Represents a group or a substituted or unsubstituted 1-oxoaralkyl group;

 Is a hydroxyl group, a linear or branched substituted or unsubstituted alkyl group having 1 to 15 carbon atoms, a linear or branched substituted or unsubstituted alkyl group having 1 to 15 carbon atoms. Alkyloxy group, linear or branched, substituted or unsubstituted alkenyl group having 2 to 15 carbon atoms, linear or branched, substituted or unsubstituted alkenyl group having 2 to 15 carbon atoms A benzyl group, a substituted or unsubstituted benzyl group, or a substituted or unsubstituted benzyloxy group;

RR ⁶ is each independently a hydrogen atom, a linear or branched substituted or unsubstituted alkyl group having 1 to 15 carbon atoms, a linear or branched alkyl group having 2 to 15 carbon atoms. Substituted or unsubstituted alkenyl group, substituted or unsubstituted benzyl group, linear or branched substituted or unsubstituted 1-oxoalkyl group having 3 to 15 carbon atoms, and 3 to 15 carbon atoms Represents a linear or branched, substituted or unsubstituted 1-oxoalkenyl group or a substituted or unsubstituted 1-oxoaralkyl group. )

Or the general formula (V I)

(Wherein, R ′, R ² , and R \ R ⁵ each independently represent a hydrogen atom, a linear or branched substituted or unsubstituted alkyl group having 1 to 15 carbon atoms, Straight-chain or branched-chain substituted or unsubstituted alkenyl group, substituted or unsubstituted benzyl group having 3 to 15 carbon atoms, straight-chain or branched-chain substituted or unsubstituted 1 monooxoalkyl group; represents a linear or branched, substituted or unsubstituted 1-year-old oxoalkenyl group having 3 to 15 carbon atoms, or a substituted or unsubstituted 1-oxoaralkyl group;

R ³ is a hydroxyl group, a linear or branched substituted or unsubstituted C 1 -C 15

-53- Amended paper (Article 19 of the Convention) Alkyl group, linear or branched substituted or unsubstituted alkyloxy group having 1 to 15 carbon atoms, linear or branched substituted or unsubstituted alkenyl having 2 to 15 carbon atoms A linear or branched alkenyloxy group having 2 to 15 carbon atoms, a substituted or unsubstituted benzyl group, or a substituted or unsubstituted benzyloxy group. )

Use of a compound represented by the formula, a salt thereof, or a solvate thereof for the manufacture of a prophylactic / therapeutic agent for bone / cartilage disease.

-54- Amended paper (Article 19 of the Convention)