JPH10324657A - Polyhydroxybenzene derivatives and prophylactic / therapeutic agents comprising bone and cartilage diseases comprising them - Google Patents

Abstract

(57) [Summary] The present invention provides a compound useful as a prophylactic / therapeutic agent for bone / cartilage disease and a pharmaceutical composition containing the same. The present invention relates to, for example, polyhydroxyphenol derivatives represented by the following formula (I) and quinone analogs thereof. Embedded image (Wherein, R ¹ , R ² , and R ³ each independently represent 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) A substituted or unsubstituted alkenyl group, a substituted or unsubstituted benzyl group, or an aryl group, wherein R ⁴ , R ⁵ , and R ⁶ each independently represent a hydrogen atom, a carbon atom of 1; To 15 linear or branched, substituted or unsubstituted alkyl groups, 2 to 15 carbon atoms, linear or branched, substituted or unsubstituted alkenyl groups, or substituted or unsubstituted (The benzyl group is represented.) The polyhydroxyphenol derivative and the quinone analog thereof of the present invention have a strong inhibitory activity on bone resorption, and are useful as an agent for preventing or treating bone and cartilage diseases.

Description

DETAILED DESCRIPTION OF THE INVENTION [0001] The present invention relates to malignant hypercalcemia
Osteoporosis, bone page disease or osteoporosis
Disease, osteoarthritis of the knee, shoulder, hip joint, etc.
Diseases associated with cartilage degeneration / necrosis such as femoral necrosis and rheumatoid arthritis
Novel Polyhide Developed for Prevention and Treatment of Cancer
Droxybenzene derivatives, their salts or solvates, and
And one or more of them as active ingredients
A pharmaceutical composition comprising: [0002] [Prior Art] Japan is entering an aging society like never before
A company with a large increase in bone resorbable bone diseases such as osteoporosis
Has become a meeting problem. Bone resorption bone disease is
Bone disease caused by hyperactivity, such as myeloma or
Malignant hypercalcemia caused by lymphoma, etc.
Bone Page disease caused by ectopic bone resorption, aging and closure
Osteoporosis caused by various factors such as
is there. Fracture of the elderly due to such bone resorbable bone disease
Increase in the number of bedridden people
Has led to a significant increase. However at present
Made of vitamin D, calcitonin and ipriflavone
Drug is used for treatment, but it has become a fundamental treatment
It is just symptomatic treatment. Also, osteoarthritis, large
Necrosis of the femoral head, rheumatoid arthritis, mechanical stress, aging,
Articular cartilage and subchondral bone are altered by various factors such as inflammation
Group of diseases that cause sexual or necrosis or cause cartilage or bone defects
You. These cartilage defects are usually caused by joint deformation and pain.
Significantly affects the quality of life. These disease groups
Treatment with hyaluronic acid, anti-inflammatory drugs, analgesics, etc.
Although it has been applied, it is effective to prevent or repair cartilage defects
No remedy is currently found. [0003] The inventors have previously reported that strong bones
Wherein the anti-absorption agent is included, and the active body is
Humron (R. Steve) whose structure is already known
ns, Chem. Rev .. , (1969)) and
And their homologs (Japanese Patent Laid-Open No. 7-33)
0594). However, with natural bone resorption inhibiting active substances
Some humulons are natural substances, so the yield is climatic.
There is a problem in how to obtain it because it is easily affected by conditions, etc.
It is pointed out that it is easy to operate. Also, we have previously described
Strong activity of polyhydroxybenzene derivative
And filed an application (Japanese Patent Application No. 8-154710).
issue). [0004] SUMMARY OF THE INVENTION Therefore, the present invention
The challenge is to improve current therapies and make them more effective
New prophylactic / therapeutic agents, especially those for bone and cartilage diseases
It is to provide. [0005] Means for Solving the Problems The present inventors have proposed humulones.
Some of the compounds around it are as powerful as the above humulones
Based on the structure of the above humulones to find active substances
Try structural transformation, synthesize many compounds, measure activity
Was. As a result, the following general formulas (I) to (III) are used.
Activity of new polyhydroxybenzene derivatives
And completed the present invention. That is, the present invention
Two or more hydroxyl groups or derivatives thereof (for example, a
Novel polyhydroxybenze substituted with alkoxy group)
Derivatives and their polyhydroxybenzene derivatives
Prediction of bone / cartilage disease containing one or more types of body
The present invention relates to a pharmaceutical composition for prevention and treatment. Specifically, the present invention
Is represented by the following general formula (I) [0006] Embedded image (Where R¹, R^Two, R^ThreeIs independently hydrogen
Atom, linear or branched substitution having 1 to 15 carbon atoms or
Unsubstituted alkyl group, linear or branched having 2 to 15 carbon atoms
Chain-like substituted or unsubstituted alkenyl group, substituted or unsubstituted
Represents a benzyl group or an aryl group;^Four, R^Five,
R⁶Are each independently a hydrogen atom, a straight-chain or
Is a branched or unsubstituted alkyl group having 2 to 2 carbon atoms
15 straight-chain or branched-chain substituted or unsubstituted alkenyl
Represents a benzyl group or a substituted or unsubstituted benzyl group.
You. ), A salt thereof or a solvate thereof.
Acylpyrogallol derivatives. In addition, the present invention
Is represented by the following general formula (II) [0008] Embedded image (Where R¹, R^Two, R^Four, R^Five, R⁶Are each
Independently a hydrogen atom, a halogen atom, a straight chain having 1 to 15 carbon atoms
Or branched substituted or unsubstituted alkyl group, carbon number
2 to 15 linear or branched substituted or unsubstituted al
Kenyl group, substituted or unsubstituted benzyl group, having 3 to 1 carbon atoms
5 straight-chain or branched-chain substituted or unsubstituted 1-oxo
Alkyl group, straight-chain or branched-chain configuration having 3 to 15 carbon atoms
A substituted or unsubstituted 1-oxoalkenyl group, or a substituted or unsubstituted
Represents an unsubstituted 1-oxoaralkyl group;^ThreeIs water
Acid group, linear or branched substitution having 1 to 15 carbon atoms or
Unsubstituted alkyl group, linear or branched having 1 to 15 carbon atoms
Chain-like substituted or unsubstituted alkyloxy group, having 2 to 2 carbon atoms
15 straight-chain or branched-chain substituted or unsubstituted alkenyl
A straight-chain or branched-chain substituent having 2 to 15 carbon atoms, or
Unsubstituted alkenyloxy group, substituted or unsubstituted ben
A jyl group or a substituted or unsubstituted benzyloxy group
Express. However, R^FourIs a straight chain having 3 to 15 carbon atoms
Or a branched unsubstituted 1-oxoalkyl group, carbon number
3 to 15 linear or branched unsubstituted 1-oxo
Soalkenyl group or unsubstituted 1-oxoaralkyl
And R^ThreeIs a hydroxyl group,¹When
R^TwoAre simultaneously a hydrogen atom, a straight-chain or straight-chain having 1 to 15 carbon atoms.
Is a branched unsubstituted alkyl group having 2 to 15 carbon atoms
A linear or branched unsubstituted alkenyl group, or
Excludes the case of a substituted or unsubstituted benzyl group. )
Or a salt thereof or a solvate thereof,
It relates to a lucinol derivative. Further, the present invention provides the following:
General formula (III) [0011] Embedded image (Where R¹, R^Two, R^Four, R^FiveAre each independently
Hydrogen atom, linear or branched configuration having 1 to 15 carbon atoms
Substituted or unsubstituted alkyl group, straight chain having 2 to 15 carbon atoms
Or a branched, substituted or unsubstituted alkenyl group,
Is an unsubstituted benzyl group, a straight or branched chain having 3 to 15 carbon atoms.
A branched or unsubstituted 1-oxoalkyl group, carbon
Straight-chain or branched-chain substituted or unsubstituted
1-oxoalkenyl group or substituted or unsubstituted 1-
An oxoaralkyl group;^ThreeIs a hydroxyl group, carbon number 1
To 15 linear or branched substituted or unsubstituted alkyl
Alkyl groups, straight-chain or branched-chain substituents having 1 to 15 carbon atoms.
Or an unsubstituted alkyloxy group, a straight chain having 2 to 15 carbon atoms
Or branched or unsubstituted or substituted alkenyl group, carbon
A straight-chain or branched-chain substituted or unsubstituted a
Alkenyloxy group, substituted or unsubstituted benzyl group, or
Represents a substituted or unsubstituted benzyloxy group. However, R¹Is a straight chain having 3 to 15 carbon atoms
Or a branched unsubstituted 1-oxoalkyl group, carbon number
3 to 15 linear or branched unsubstituted 1-oxo
Soalkenyl group or unsubstituted 1-oxoaralkyl
Represents a group, and R^ThreeRepresents a hydroxyl group,^Two
Is hydrogen atom, linear or branched having 1 to 15 carbon atoms
An unsubstituted alkyl group having 2 to 15 carbon atoms
Is a branched unsubstituted alkenyl group, or a substituted or unsubstituted
Except when it is a substituted benzyl group. )
Product, its salt, or its solvate, hydroxycycline
It relates to a rohexane derivative. The present invention relates to the above-mentioned general formulas (I), (II) and
Is a compound represented by formula (III), a salt thereof or a solvate thereof:
Prediction of bone and cartilage diseases containing one or more
The present invention relates to a pharmaceutical composition for prevention and treatment. In addition, the present invention
A compound represented by the general formula (I), (II) or (III)
Compound, a salt thereof, or a solvate thereof,
And bone and cartilage diseases consisting of a pharmaceutically acceptable carrier
The present invention relates to a pharmaceutical composition for prevention and treatment. In the present invention, the above general formula (I), (II) or
The alkyl group in (III) has 1 to 1 carbon atoms.
5, preferably a linear or branched C1-C10
For example, methyl group, ethyl group, n-propyl
Group, isopropyl group, n-butyl group, sec-butyl
Group, isobutyl group, various pentyl groups, various hexyl groups,
Various heptyl groups, various octyl groups, various decyl groups, etc.
Examples can be given. These alkyl groups of the present invention
Represents a halogen atom such as a chlorine atom or a bromine atom, a hydroxyl group,
Oxygen-containing substituents such as ether group and carbonyl group, amino
Group, substituted amino group, cyclic amino group, urea group, etc.
Substituent, or mercapto group, sulfide group, sulfone
It may be substituted with a sulfur-containing substituent such as a group. The alkenyl group includes 2 to 15 carbon atoms;
Preferably a linear or branched one having 2 to 15 carbon atoms
And having one or more unsaturated carbon-carbon bonds
Have For example, vinyl group, allyl group, butene
And a benzyl group, a pentenyl group and an octadienyl group.
And preferably a 3-methyl-2-butenyl group, 3,7-
Dimethyl-2,6-octadienyl group, 3,7,11-
Examples include trimethyl-2,6,10-dodecatrienyl group
Can be shown. These alkenyl groups are
Atom, halogen atom such as bromine atom, hydroxyl group, ether
Group, oxygen-containing substituent such as carbonyl group, amino group, substitution
Amino group, cyclic amino group, nitrogen-containing substituents such as urea group,
Or a mercapto group, a sulfide group, a sulfone group, etc.
It may be substituted with a sulfur-containing substituent. With halogen atoms
In addition, mention chlorine, fluorine, bromine, iodine, etc.
Can be done. The benzyl group has an effect on the physiological activity of the compound of the present invention.
Unless impaired, it is substituted with the various substituents described above.
You may. These substituents include chlorine, fluorine, and odor.
Halogen atom such as iodine and iodine, hydroxyl group, carbon number 1 to 1
5 alkoxy groups, alkenyloxy having 2 to 15 carbon atoms
Group, acyl group such as acetyl group or propionyl group, etc.
Examples can be given. 1-oxoalkyl group or 1-oxoal
As the kenyl group, the above-mentioned carbon number of 1 to 15, preferably
Is an alkyl group having 1 to 10 carbon atoms, or 2-1
5, preferably an alkenyl group having 2 to 15 carbon atoms
A compound bonded to a carbonyl group (C = O).
The measured carbon number is 2 to 2 carbon atoms in a 1-oxoalkyl group.
16, preferably 3 to 15, more preferably 3 to 11
In the 1-oxoalkenyl group, the number of carbon atoms is 3 to 16,
Preferably it is 3-15, more preferably 3-11.
Alkyl or alkenyl bonded to these carbonyl groups
Is a halogen atom such as a chlorine atom or a bromine atom,
Oxygen-containing substituents such as
Including amino groups, substituted amino groups, cyclic amino groups, urea groups, etc.
Nitrogen substituent, or mercapto group, sulfide group, sulf
It may be substituted with a sulfur-containing substituent such as a phon group. 1
-As an oxoaralkyl group,
And an aralkyl group having 7 carbon atoms.
~ 25, preferably 7-20, more preferably 7-16
And the total carbon of the 1-oxoaralkyl group
The number is 8 to 26 carbon atoms, preferably 8 to 21 carbon atoms, more preferably
Or 8-17. The chain portion of this aralkyl group is
It may be straight-chain or branched, and may have an aralkyl group
For example, benzyl group, phenethyl group, α-naph
A tylmethyl group, a β-naphthylmethyl group, and the like.
You. These 1-oxoaralkyl groups are chlorine atom, odor
Halogen atoms such as elemental atoms, hydroxyl groups, ether groups,
Oxygen-containing substituents such as bonyl group, amino group, substituted amino
Group, a cyclic amino group, a nitrogen-containing substituent such as a urea group, or
Sulfur-containing such as mercapto group, sulfide group and sulfone group
It may be substituted with a substituent. The aryl group has a six-membered aromatic ring.
Have multiple rings, even if they are monocyclic
May be used, and is not particularly limited, but has 6 to 6 carbon atoms.
20, preferably 6 to 12. Also, the ring
Heterogeneous atom such as oxygen atom, nitrogen atom or sulfur atom in
May be provided. Examples of the aryl group include
Examples include phenyl, naphthyl, and biphenyl groups.
I can do it. Also, these aryl groups are chlorine
Atom, halogen atom such as bromine atom, hydroxyl group, ether
Group, oxygen-containing substituent such as carbonyl group, amino group, substitution
Amino group, cyclic amino group, nitrogen-containing substituents such as urea group,
Or a mercapto group, a sulfide group, a sulfone group, etc.
It may be substituted with a sulfur-containing substituent. As the benzyl group, only unsubstituted
And may have a substituent, a benzyl group
Is a halogen atom such as a chlorine atom or a bromine atom.
Oxygen containing atoms, hydroxyl groups, ether groups, carbonyl groups, etc.
Substituent, amino group, substituted amino group, cyclic amino group, urea
Nitrogen-containing substituents such as a group, a mercapto group, a sulfide group,
Examples include sulfur-containing substituents such as sulfone groups.
When these substituents are substituted on the phenyl ring,
Although preferred, it is not limited to a phenyl ring. Be
As the benzyloxy group, the above-mentioned unsubstituted or substituted benzene
A zyl group is bonded to an oxygen atom. The benzene ring of the present invention has two or more hydroxyl groups or
Is a new group substituted by a derivative (for example, an alkoxy group).
Typical polyhydroxybenzene derivatives are the various types described above.
It can have a substituent. New in the present invention
The preferred polyhydroxybenzene derivative is preferably
A compound represented by the general formula (I), (II) or (III)
Or a salt or solvate thereof, wherein the compound of the present invention is
More specifically, the following compounds can be mentioned.
You. The parentheses after the compound names in the following examples
Are the `` compound numbers '' of the present invention, which are referred to below.
You. First, the compound represented by the general formula (I) of the present invention
Preferred specific examples of the compound include (2-methylpropyl
) (3,4,5-trihydroxyphenyl) ketone
(1), {3,5-dihydroxy-2- (3-methyl-
2-butenyl) -4- (3-methyl-2-butenyloxy
C) phenyl} (2-methylpropyl) ketone (2),
{3,5-dihydroxy-4- (3-methyl-2-bute
Nyloxy) phenyl} (2-methylpropyl) ketone
(3), {2- (3-methyl-2-butenyl) -3,
4,5-trihydroxyphenyl} (2-methylpropyl
G) ketones (4) and the like. The compound of the present invention represented by the general formula (II)
What is indicated as preferred is (2,6-dihi)
Droxy-4-methylphenyl) (2-methylprop
L) ketone (5), {2,6-dihydroxy-4-methyl
3- (3-methyl-2-butenyl) phenyl} (2
-Methylpropyl) ketone (9), {3,5-bis (3
-Methyl-2-butenyl) -2,6-dihydroxy-4
-Methylphenyl} (2-methylpropyl) ketone (1
0), (5-chloro-2,4-dihydroxyphenyl)
(2-Methylpropyl) ketone (11), @ 5-chloro
-2-hydroxy-3- (3-methyl-2-butenyl)
-4- (3-methyl-2-butenyloxy) phenyl}
(2-methylpropyl) ketone (12), 5-5-chloro
-2-hydroxy-4- (3-methyl-2-butenylo
Xy) phenyl} (2-methylpropyl) ketone (1
3), {5-chloro-2,4-dihydroxy-3- (3
-Methyl-2-butenyl) phenyl} (2-methylpro
Pill) ketone (14), 1,3-bis (3-methyl-1
-Oxobutyl) -2,4,6-trihydroxybenze
(15), 1,3-bis (3-methyl-1-oxob)
Tyl) -5- (3-methyl-2-butenyl) -2,4,
6-trihydroxybenzene (17), {3,5-bis
(2- (1-piperidino) ethyl) -2,4,6-tri
Hydroxyphenyl} (2-methylpropyl) ketone
(24), {3- (2- (1-piperidino) ethyl)-
2,4,6-trihydroxyphenyl} (2-methyl
Ropyl) ketone (23), {3- (3- (N, N-dimethyl)
Ruamino) propyl) -2,4,6-trihydroxyp
Enyl} (2-methylpropyl) ketone (25), 2-
(3-methyl-2-butenyl) -1,3,5-trihydr
Roxybenzene (22) and 1,3,5-trihydride
Roxy-2,4,6-tris (3-methyl-2-buteni
G) benzene (18) and the like. Further, the compound represented by the general formula (III) of the present invention
A more preferred specific example is 5-hydroxy-3-methyi.
Ru-6- (3-methyl-1-oxobutyl) -2,2,
4-tris (3-methyl-2-butenyl) cyclohexa
-3,5-dienone (7), 2,2-bis (3-methyl
-2-butenyl) -5-hydroxy-3-methyl-6-
(3-methyl-1-oxobutyl) cyclohexa-3,
5-dienone (8), 2,2-bis (3-methyl-2-
Butenyl) -4,6-bis (3-methyl-1-oxob)
Tyl) -3,5-dihydroxycyclohexa-3,5-
Dienone (16), 3-hydroxy-5- (3-methyl
-2-butenyloxy) -2,2,4-tris (3-meth
Tyl-2-butenyl) cyclohexa-3,5-dienone
(20) 3,5-dihydroxy-2,2,4,6-te
Thrakis (3-methyl-2-butenyl) cyclohexa-
3,5-dienone (19) and 3,5-dihydroxy
C-2,2,4-tris (3-methyl-2-butenyl)
Cyclohexa-3,5-dienone (21) and the like.
You. The compounds represented by the general formulas (I) to (III) of the present invention
The polyhydroxybenzene derivative used is prepared by the following method.
Can be manufactured. The alkoxy or alkenyl oxy of the present invention
The converted compound is derived from the corresponding hydroxybenzene derivative.
The product is treated under basic or acidic conditions with an alkylating agent or
It can be carried out by a reaction of condensation with a nilating agent. salt
The reaction under basic conditions is a polyhydroxybenzene derivative
After the action of a base, alkylating or alkenylating
The agent works. The base used in this reaction
Sodium hydroxide, potassium hydroxide, lithium hydroxide
Alkali metal hydroxides such as sodium, sodium methoxy
, Potassium methoxide, sodium ethoxide, potassium
Um ethoxide, sodium t-butoxide, potassium t
-Alkali metal alkoxides such as butoxide, hydrogenated
Alkali such as trim, potassium hydride, lithium hydride
Metal hydride, methyllithium, ethyllithium, n-
Butyllithium, t-butyllithium, phenyllithium
Alkyllithium compounds such as aluminum or aryllithium
Compound or triethylamine, triisopropylamine
Min, diazabicyclononene, diazabicyclo undece
And tertiary amines such as dimethylaminopyridine
I can do it. These bases can be nitrogen or
Used under an atmosphere of an inert gas such as gon. The reaction is carried out in a solvent, and the solvent is water.
, Methanol, ethanol, n-propanol, iso-
Alcohols such as propanol and t-butyl alcohol
, Ethyl ether, isopropyl ether, tetrahi
Drofuran, 1,4-dioxane, dimethoxyethane, etc.
Ethers, N, N-dimethylformamide, dimethyl
Sulfoxide, N-methylpyrrolidone, etc., benzene,
And aromatics such as ruene. These solutions
A suitable medium is appropriately used depending on the base used.
It is. Alkylating agents include methyl iodide and bromo
Ethane, 1-bromoepropane, 2-bromopropane,
1-chloropropane, 2-chloropropane, bromobuta
, 1-bromo-3-methylbutane, various bromoocta
, Various chlorooctanes, 1-chloro-3, 7-dimethyl
Luoctane, benzyl chloride, bromomethylthiophene
1-chloro-2-piperidinoethane, 1-chloro-
3-dimethylaminopropane and the like can be mentioned.
Allyl bromide, allyl chloride
, 1-bromo-2-butene, 1-bromo-3-methyl
-2-butene, 1-chloro-3-methyl-2-butene,
1-chloro-3,7-dimethyl-2,6-octadiene
And the like. On the other hand, the acid used for the reaction under acidic conditions
As the catalyst, aluminum bromide, aluminum chloride,
Antimony chloride, iron chloride, titanium chloride, tin chloride, chloride
Bismuth, zinc chloride, boron fluoride, boron fluoride
Ter complex, hydrogen fluoride, sulfuric acid, hydrochloric acid, polyphosphoric acid, tri
Lewis acids such as fluoroacetic acid and trifluoromethanesulfonic acid
And strong Bronsted acids. The reaction is soluble
The reaction is performed in a medium, and as a solvent in this case, nitromethane,
Nitrobenzene, carbon disulfide, methylene chloride, chloropho
Lum, carbon tetrachloride, 1,2-dichloroethane, ethyl
-Ter, 1,4-dioxane, tetrahydrofuran, etc.
Can be mentioned. Various of these acid catalysts and solvents
The reaction is carried out by selecting as appropriate under the combination of
Performed in 1,4-dioxane using a urethane ether complex
This is preferable in terms of good yield and simple reaction.
The alkylating or alkenylating agent used at this time is
Tanol, butyl alcohol, 3-methylbutyl alcohol
-Saturated alcohols such as alcohol, benzyl alcohol and decanol
-Allyl alcohol, 2-butenol, 3-methyl
= 2-butenol, 3,7-dimethyl-2,6-octane
Unsaturated alcohols such as tadienol may be mentioned.
come. The compound of the present invention has one benzene ring on the benzene ring.
Having an -oxoalkyl group or a 1-oxoalkenyl group
The compound is acylated by the usual Friedel-Crafts reaction.
It can be manufactured by a method. Furthermore, the present invention
Compounds having an alkyl group on the benzene ring of the compound,
According to the usual alkylation method of the Friedel-Crafts reaction
Can be manufactured. The compound represented by the general formula (III) of the present invention
Are enol forms of the compounds of general formula (II)
It is an alkyl or alkenyl derivative. In addition, the present invention
Compounds should be salts such as alkali metals if necessary
Can also. Further, the compound of the present invention may be used in a reaction solvent or an essential solvent.
Solvates of solvents as needed, for example, as hydrates
You can also get. Any of the general formulas (I) to (III) of the present invention
A series of compounds indicated by these compounds have potent bone resorption inhibitory activity.
Is not yet known and has been initiated by the present inventors.
It was revealed. That is, the present invention relates to a method in which two benzene rings are used.
More than one hydroxyl group or a derivative thereof (eg, an alkoxy group
) Substituted polyhydroxybenzene derivatives
Prevention of bone and cartilage diseases comprising one or more
It relates to a pharmaceutical composition for treatment. Specifically, the present invention
General formula (IV) [0032] Embedded image (Where R¹, R^Two, R^ThreeIs independently hydrogen
Atom, linear or branched substitution having 1 to 15 carbon atoms or
Unsubstituted alkyl group, linear or branched having 2 to 15 carbon atoms
Chain-like substituted or unsubstituted alkenyl group, substituted or unsubstituted
Represents a benzyl group or an aryl group;^Four, R^Five,
R⁶Are each independently a hydrogen atom, a straight-chain or
Is a branched or unsubstituted alkyl group having 2 to 2 carbon atoms
15 straight-chain or branched-chain substituted or unsubstituted alkenyl
Represents a benzyl group or a substituted or unsubstituted benzyl group.
You. ), A salt thereof or a solvate thereof.
Containing one or more acylpyrogallol derivatives
Pharmaceutical composition for the prevention and treatment of bone and cartilage diseases
I do. Further, the present invention provides the following general formula (V): [0034] Embedded image (Where R¹, R^Two, R^Four, R^Five, R⁶Are each
Independently a hydrogen atom, a halogen atom, a straight chain having 1 to 15 carbon atoms
Or branched substituted or unsubstituted alkyl group, carbon number
2 to 15 linear or branched substituted or unsubstituted al
Kenyl group, substituted or unsubstituted benzyl group, having 3 to 1 carbon atoms
5 straight-chain or branched-chain substituted or unsubstituted 1-oxo
Alkyl group, straight-chain or branched-chain configuration having 3 to 15 carbon atoms
A substituted or unsubstituted 1-oxoalkenyl group, or a substituted or unsubstituted
Represents an unsubstituted 1-oxoaralkyl group;^ThreeIs water
Acid group, linear or branched substitution having 1 to 15 carbon atoms or
Unsubstituted alkyl group, linear or branched having 1 to 15 carbon atoms
Chain-like substituted or unsubstituted alkyloxy group, having 2 to 2 carbon atoms
15 straight-chain or branched-chain substituted or unsubstituted alkenyl
A straight-chain or branched-chain substituent having 2 to 15 carbon atoms, or
Unsubstituted alkenyloxy group, substituted or unsubstituted ben
A jyl group or a substituted or unsubstituted benzyloxy group
Express. Where R^FourIs a straight chain having 3 to 15 carbon atoms
Or a branched unsubstituted 1-oxoalkyl group, carbon number
3 to 15 linear or branched unsubstituted 1-oxo
Soalkenyl group or unsubstituted 1-oxoaralkyl
And R^ThreeIs a hydroxyl group,¹When
R^TwoAre simultaneously a hydrogen atom, a straight-chain or straight-chain having 1 to 15 carbon atoms.
Is a branched unsubstituted alkyl group having 2 to 15 carbon atoms
A linear or branched unsubstituted alkenyl group, or
Excludes the case of a substituted or unsubstituted benzyl group. )
Or a salt thereof or a solvate thereof,
Bone comprising one or more lucinol derivatives
-It relates to a pharmaceutical composition for the prevention and treatment of cartilage diseases. Further
The present invention provides a compound represented by the following general formula (VI) [0037] Embedded image (Wherein R¹, R^Two, R^Four, R^FiveAre each independently
Hydrogen atom, linear or branched configuration having 1 to 15 carbon atoms
Substituted or unsubstituted alkyl group, straight chain having 2 to 15 carbon atoms
Or a branched, substituted or unsubstituted alkenyl group,
Is an unsubstituted benzyl group, a straight or branched chain having 3 to 15 carbon atoms.
A branched or unsubstituted 1-oxoalkyl group, carbon
Straight-chain or branched-chain substituted or unsubstituted
1-oxoalkenyl group or substituted or unsubstituted 1-
An oxoaralkyl group;^ThreeIs a hydroxyl group, carbon number 1
To 15 linear or branched substituted or unsubstituted alkyl
Alkyl groups, straight-chain or branched-chain substituents having 1 to 15 carbon atoms.
Or an unsubstituted alkyloxy group, a straight chain having 2 to 15 carbon atoms
Or branched or unsubstituted or substituted alkenyl group, carbon
A straight-chain or branched-chain substituted or unsubstituted a
Alkenyloxy group, substituted or unsubstituted benzyl group, or
Represents a substituted or unsubstituted benzyloxy group. Where R¹Is a straight chain having 3 to 15 carbon atoms
Or a branched unsubstituted 1-oxoalkyl group, carbon number
3 to 15 linear or branched unsubstituted 1-oxo
Soalkenyl group or unsubstituted 1-oxoaralkyl
Represents a group, and R^ThreeRepresents a hydroxyl group,^Two
Is hydrogen atom, linear or branched having 1 to 15 carbon atoms
An unsubstituted alkyl group having 2 to 15 carbon atoms
Is a branched unsubstituted alkenyl group, or a substituted or unsubstituted
Except when it is a substituted benzyl group. )
Product, its salt, or its solvate, hydroxycycline
Bone containing one or more rohexane derivatives
-It relates to a pharmaceutical composition for the prevention and treatment of cartilage diseases. Further, the pharmaceutical composition of the present invention is pharmaceutically acceptable.
May be included, the present invention, the above-mentioned,
A compound represented by the general formula (I), (II) or (III)
Product, its salt or its solvate,
And a pharmaceutical composition comprising a pharmaceutically acceptable carrier.
It is also a thing. The pharmaceutical composition of the present invention has a bone resorption inhibitory activity.
It is useful as an agent for preventing or treating bone or cartilage diseases.
You. The bone and cartilage diseases of the present invention include malignant hypercalcemia
Disease, bone resorption disease such as bone Behcet's disease or osteoporosis,
Osteoarthritis of the knee, shoulder, hip, etc., femur
Diseases associated with cartilage degeneration and necrosis such as head necrosis and rheumatoid arthritis
Which means The above-mentioned general formula (I), (II) or
Of the polyhydroxybenzene derivative represented by (III)
The bone resorption inhibitory activity was determined by using a pit for
Test by the method of the migration assay)
did. As a result, the general formulas (I) and (II) of the present invention
Or a polyhydroxybenzene derivative represented by (III)
Body 1X10^-FiveAt a concentration of M, a high bone resorption inhibition rate was exhibited. The dosage in the clinic depends on the administration method and the state of the disease.
Depending on the situation and the patient's condition, the compound of the present invention is usually used.
0.1-2 g per day for adults (about 1.5-30 / Kg
/ Day). Administration methods include intravenous and intramuscular
Intravenous, oral and rectal administration is possible
Is capable of intravenous infusion as well as normal intravenous injection. Departure
Formulations containing the above compounds use conventional excipients and additives.
And is manufactured by conventional methods. As an injection preparation,
For example, it can be a powder formulation for injection. In that case
Suitable aqueous excipients such as mannitol, sucrose, milk
One kind of sugar, maltose, glucose, fructose and the like or
Add two or more and dissolve in water, and place in a vial or ampoule
After dispensing, it can be lyophilized and sealed to form a preparation.
Oral preparations include ordinary tablets, capsules, granules,
Not only fine granules and powders but also enteric-coated preparations
come. In the case of an enteric preparation, mannitol
, Sucrose, lactose, maltose, starch, anhydrous silica
Lubricants such as acid and calcium phosphate,
Additives for disintegrants such as lulose, gelatin, gum arabic
As needed to make tablets, granules, fine granules, etc.
And cellulose acetate tophthalate, hydroxypro
Pilmethylcellulose acetyl succinate, polyvinyl alcohol
Rualcohol phthalate, styrene-maleic acid copolymer
Body, methyl methacrylate-methacrylic acid copolymer,
Enteric properties of methyl acrylate-methacrylic acid copolymer
One or more bases and, if necessary, titanium oxide
A colorant such as
Or enteric coated granules or fine granules prepared here
Into capsules. Also usually
The capsule prepared by the method described in 1) is coated with the enteric agent described above.
As the enteric agent, or the enteric agent alone or
Enteric coated using capsules made by mixing gelatin
It is also possible to make the capsule into an acidic capsule. For suppositories, cocoa butter, fatty acid trigs
Fatty acid monoglyceride, fatty acid diglyceride to lyceride
Lipophilic base, semi-synthetic base,
Hydrophilic base such as ethylene glycol and glycerogelatin
Is heated and dissolved, and mixed evenly.
It can be shaped into suppositories. [0045] EXAMPLES Hereinafter, the present invention will be described with reference examples, examples, and tests.
The present invention will be described in more detail with reference to examples.
It is not something to be done. Embodiment 1 (2-methylpropyl) (3,4,5-trihydroxy
Synthesis of phenyl) ketone (1) (1) 60% sodium hydride 6.60 g (1
65 mmol, 3.30 equiv.) Of paraffin was washed with petroleum ether.
Shed. Add 100 mL of dimethylformamide (DMF)
And add 9.22 g of gallic acid methyl ester (5
0.0mmol) in DMF (25.0 mL) was added. Foaming is complete
13.9g of methoxymethyl chloride (165mmo
l) was slowly added dropwise. After stirring for 4 hours,
150 mL of ammonium water was added, and the mixture was extracted with ether. D
The ter layer is washed with saturated saline and dried over sodium sulfate
did. The solvent was distilled off under reduced pressure to give 3, 4, 5-
14.97 g of methyl tris (methoxymethyl) benzoate was obtained.
Was. 1H-NMR (CDCl_Three): 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) Lithium aluminum hydride 1.20
g (31.6 mmol) in a dry atmosphere under a nitrogen atmosphere.
(THF) in 40.0 mL. 3, under ice-cooled stirring
Methyl 4,5-tris (methoxymethyl) benzoate 9.49
g (30.0 mmol) in THF (30.0 mL) in 20 minutes
Stirring was continued for another hour. Then 1.2 mL of water, 15%
1.2 mL of aqueous sodium hydroxide and 3.6 mL of water are sequentially added,
Stir for 1 hour. Add 100 mL of ether and filter the white precipitate.
Separately, the ether layer was dried over sodium sulfate. solvent
And 3,4,5-tris (Methoxy
8.35 g of (cimethyl) benzyl alcohol were obtained. (3) Pyridinium chromochloride (P
CC) 9.70 g (45.0 mmol, 1.55 equivalents), sodium acetate 7
50 mg (9.0 mmol, 0.31 equivalent) and molecular sieve
Bus 3A appropriate amount dry methylene chloride 40.0mL under nitrogen atmosphere
And stirred at room temperature. This is followed by 3, 4, 5-tris (me
8.34 g (28.9 mmol) of toxicmethyl) benzyl alcohol
Of methylene chloride (20.0 mL) was added dropwise over 40 minutes.
Stirring was continued for 1 hour. Add 300 mL of ether to the reaction mixture.
After filtration, the ether layer was distilled under reduced pressure to obtain a red oily substance.
Obtained. This is dissolved again in ether, and short silica gel
Passed through the system. Evaporate the solvent under reduced pressure to give an orange oil
3,4,5-tris (methoxymethyl) benzaldehyde
7.53 g of the product was obtained. (4) 3,4,5-tris (methoxymeth
Butyl) benzaldehyde 7.52 g (26.3 mmol) in THF (6
0.0 mL) 2M 2-M
Ether solution of methyl propyl magnesium bromide 1
6.0 mL (32.0 mmol, 1.22 eq) was added slowly. That
Then add 20m of saturated ammonium chloride solution and extract with ether
did. The ether layer was washed with a saturated saline solution, and sodium sulfate was used.
After drying on the above, the solvent was distilled off to give 3-methyl orange oil.
-1- {3,4,5-tris (methoxymethyl) phenyi
8.44 g of rubutanol was obtained. 1H-NMR (CDCl_Three): 0.95 (6H, d, J = 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) 7.92 g (36.8 mmol, 1.50 g) of PCC
Equivalent), 906 mg of sodium acetate (11.4 mmol, 0.47 equivalent)
Amount), molecular sieves 3A appropriate amount, and 3-meth
Ru-1- {3,4,5-tris (methoxymethyl) fe
Using 8.44 g (24.5 mmol) of n-dibutanol
(2-methylpropyl) by the same operation as (3)
{3,4,5-tris (methoxymethyl) phenyl} ke
7.58 g of ton was obtained. (6) (2-methylpropyl) ｛3,
4,5-tris (methoxymethyl) phenyl diketone 7.
57 g was dissolved in 100 mL of methanol, and 2.0 mL of 2M hydrochloric acid was added thereto to give 5
After heating at 0 ° C for 3 hours, methanol and
The water was distilled off. The residue was purified by silica gel column chromatography (wa
Cogel C-300 70 g, hexane: ethyl acetate = 2:
1) Purification by (2-methylpropyl) (3, 4, 5)
-Trihydroxyphenyl) ketone (1) 2.70 g gray
Obtained as crystals. Compound (1) 1H-NMR (DMSO): 0.96 (6H, d, J = 6.4),
2.23 (1H, m), 2.70 (2H, d, J = 6.6), 7.12 (2H, s). Embodiment 2 {3,5-dihydroxy-2- (3-methyl-2-bute)
Nyl) -4- (3-methyl-2-butenyloxy) fe
Nil @ (2-methylpropyl) ketone (2), and
3,5-dihydroxy-4- (3-methyl-2-buteni
(Loxy) phenyl} (2-methylpropyl) ketone
Synthesis of (3) 441 mg (11.1 mmol, 2.06 equivalents) of 60% sodium hydride
Paraffin was washed away with petroleum ether under nitrogen atmosphere
Thereafter, 6.0 mL of dry methanol was added. Then (2-meth
Propyl) (3,4,5-trihydroxyphenyl)
631 mg (3.00 mmol) of ketone (1) in methanol (3.0 mL)
The solution was added under ice cooling and stirring. Further, 1-chloro-3-me
660 mg (6.30 mmol, 2.10 equivalents) of chill-2-butene meta
A nor (6.0 mL) solution was slowly added dropwise. Return to room temperature
Stirring was continued for 2 hours while stirring. Add ether to this and add
The aqueous layer with saturated aqueous ammonium chloride and saturated saline,
Dried over sodium acid. Evaporate solvent to dark red oil
1.020 g of the product were obtained. This is applied to silica gel column chromatography (wa
47 g of Kogel C-300, hexane: ether = 9: 1
~ 1: 1), and in order of effluent,
Hydroxy-2- (3-methyl-2-butenyl) -4-
(3-methyl-2-butenyloxy) phenyl} (2-
61 mg of methylpropyl) ketone (2) as a viscous oil
3,5-dihydroxy-4- (3-methyl-2-bu
(Tenyloxy) phenyl} (2-methylpropyl) keto
56 mg of compound (3) were obtained as white crystals. Compound (2) 1H-NMR (CDCl_Three): 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 (CDCl3): 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, m), 7.21
 (2H, s) Embodiment 3 {2- (3-methyl-2-butenyl) -3,4,5-to
Lihydroxyphenyl (2-methylpropyl) ketone
Synthesis of (4) (2-methylpropyl) (3,4,5-trihydroxy
Phenyl) ketone (1) 529 mg (2.52 mmol) dry 1,
In a dioxane (5.0 mL) solution under a nitrogen atmosphere, 10
321 mg of boron trifluoride etherate complex (2.26 mmol, 0.9
01 eq.). Then 3-methyl-2-buteno-
433 mg (5.03 mmol, 2.00 equivalents) of dioxane (5.0 mL)
The solution was slowly added dropwise and stirred for 14 hours while returning to room temperature.
Continued. Ether was added to the reaction mixture, and the ether layer was saturated.
Washed with aqueous sodium bicarbonate solution and saturated saline solution, sodium sulfate
Dried over lium. The solvent was distilled off and a dark red oily substance 1.11
8 g were obtained. The crude product is separated by silica gel column chromatography (wa
48 g of Kogel C-300, hexane: ether = 9: 1 to 1
1: 1), and separated by {2- (3-methyl-2-buteni)
) -3,4,5-trihydroxyphenyl} (2-meth
58 mg of tylpropyl) ketone (4) as orange crystals
Was. Compound (4) 1H-NMR (CDCl_Three): 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) Embodiment 4 (2,6-dihydroxy-4-methylphenyl) (2-
Methylpropyl) ketone (5) and (2,4-dihi)
Droxy-6-methylphenyl) (2-methylprop
L) Synthesis of ketone (6) 150 mL of benzene in 14.20 g (100.0 mmol) of orcin monohydrate
, And heat distillation was performed. Dehydration operation was performed twice.
Add 45 mL of nitrobenzene and 45 mL of carbon disulfide to this and cool with water
26.7 g of aluminum chloride (200 mmol, 2.00 equivalents) with stirring
Was added little by little, and a calcium chloride tube was attached and stirred. About
With 12.1 g (100 mmol, 1.00 equivalent) of isovaleryl chloride
The mixture was slowly added dropwise, and stirring was continued at room temperature for 14 hours. Acid moth
After confirming that the generation of sulfuric acid has stopped,
(Prepared from 100 mL of acid and 400 mL of cold water).
-Tell extracted. After washing the ether layer with saturated saline,
Distilled off under reduced pressure. Decompress while adding water little by little to this
The nitrobenzene was distilled off by steam distillation.
The residue was extracted with ether and washed with a saturated saline solution.
And dried over um. Distill off the solvent and dark brown viscous oil 18.5
3 g were obtained. The crude product was subjected to silica gel column chromatography (wa
Cogel C-200 220 g, hexane: ethyl acetate = 9:
(2) 6-dihydroxy-
4-methylphenyl) (2-methylpropyl) ketone
(5) 0.908 g and (2,4-dihydroxy-6-me
Tylphenyl) (2-methylpropyl) ketone (6) 5.
681 g were obtained. Compound (5) 1H-NMR (CDCl_Three): 0.98 (6H, d, J = 6.6),
2.28 (1H, m), 2.33 (3H, s), 2.98 (2H, d, J = 6.6), 6.2
2 (2H, s) Compound (6) 1H-NMR (CDCl_Three): 0.97 (6H, d, J = 6.5),
2.25 (3H, s), 2.27 (1H, m), 2.78 (2H, d, J = 6.6), 6.
23 (1H, s), 6.26 (1H, s) Embodiment 5 5-hydroxy-3-methyl-6- (3-methyl-1-
Oxobutyl) -2,2,4-tris (3-methyl-2
-Butenyl) cyclohexa-3,5-dienone (7),
5-hydroxy-3-methyl-6- (3-methyl-1-
Oxobutyl) -2,2-bis (3-methyl-2-bute
Nyl) cyclohexa-3,5-dienone (8), and
{2,6-dihydroxy-4-methyl-3- (3-methyl
2-butenyl) phenyl} (2-methylpropyl)
Synthesis of ketone (9) 240 mg of 60% sodium hydride (6.00 mmol, 2.00 equivalents)
Paraffin was washed away with petroleum ether under nitrogen atmosphere
Thereafter, 6.0 mL of dry methanol was added. Then (2,6-
Dihydroxy-4-methylphenyl) (2-methylpro
Pill) ketone (5) 625 mg (3.00 mmol) of methanol
(4.0 mL) solution was added under ice-cooled stirring. 1-black
627 mg of b-3-methyl-2-butene (6.00 mmol, 2.00 equivalents)
Volume) in methanol (4.0 mL) was slowly added dropwise.
Stirring was continued for 3 hours while returning to room temperature. Add ether to this
Add ether layer to saturated aqueous ammonium chloride, saturated saline
And dried over sodium sulfate. Distill off the solvent
931 mg of a red oil was obtained. The crude product was subjected to silica gel column chromatography (wa
Kogel C-300 44 g, hexane: ether = 19:
1-4:
Xy-3-methyl-6- (3-methyl-1-oxobuty)
) -2,2,4-tris (3-methyl-2-buteni)
B) 245 mg of cyclohexa-3,5-dienone (7)
5-hydroxy-3-methyl-6- as a yellow oil
(3-methyl-1-oxobutyl) -2,2-bis (3
-Methyl-2-butenyl) cyclohexa-3,5-die
Non (8) 149 mg as pale yellow oil and $ 2,
6-dihydroxy-4-methyl-3- (3-methyl-2
-Butenyl) phenyl} (2-methylpropyl) ketone
(9) 160 mg was obtained as yellow needle crystals. Compound (7) 1H-NMR (CDCl_Three): 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,
J = 6.8), 3.05 (2H, d, J = 6.4), 4.62 (2H, m), 4.90 (1
H, m) Compound (8) 1H-NMR (CDCl_Three): 0.95 (6H, d, J = 6.6),
1.56 (12H, s), 2.01 (3H, s), 2.29 (1H, m), 2.92 (2
H, d, J = 6.8), 3.01 (2H, d, J = 7.0), 4.67 (2H, m), 6.
24 (1H, s) Compound (9) 1H-NMR (CDCl_Three): 0.97 (6H, d, J = 6.6),
1.71 (3H, d, J = 1.3), 1.80 (3H, s), 2.22 (3H, s), 2.
27 (1H, m), 2.99 (2H, d, J = 6.8), 3.29 (2H, d, J = 6.
6), 5.09 (1H, m), 6.19 (1H, s) Embodiment 6 {3,5-bis (3-methyl-2-butenyl) -2,6
-Dihydroxy-4-methylphenyl} (2-methylp
Ropyl) ketone (10) and {2,6-dihydroxy
Ci-4-methyl-3- (3-methyl-2-butenyl) phenyl
Synthesis of phenyl} (2-methylpropyl) ketone (9) (2,6-dihydroxy-4-methylphenyl) (2-
Drying of 521 mg (2.50 mmol) of methyl propyl) ketone (5)
In a dry 1,4-dioxane (5.0 mL) solution under a nitrogen atmosphere
355mg (2.50mmo) boron trifluoride ether complex at 10 ° C
l, 1.00 eq). Then 3-methyl-2-bu
431 mg (5.00 mmol, 2.00 equivalents) of dioxane
(2.0 mL) while slowly dropping the solution to room temperature.
Stirring was continued for hours. Ether was added to the reaction mixture,
The ter layer is washed with saturated aqueous sodium hydrogen carbonate and saturated saline.
Purified and dried over sodium sulfate. Evaporate the solvent and turn orange
874 mg of an oil were obtained. The crude product is purified by silica gel column chromatography.
Mat (Wako-Gel C-300 24 g, hexane: ether =
19: 1 to 7: 3), and separated in the order of outflow.
{3,5-bis (3-methyl-2-butenyl) -2,6
-Dihydroxy-4-methylphenyl} (2-methylp
Ropyl) ketone (10) 222 mg as a yellow oil
In this case, 2,6-dihydroxy-4-methyl-3- (3-
Methyl-2-butenyl) phenyl {(2-methylpropyl
235 mg of ketone (9) was obtained as yellow crystals. Compound (10) 1H-NMR (CDCl_Three): 0.96 (6H, d, J = 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) Embodiment 7 (5-chloro-2,4-dihydroxyphenyl) (2-
Synthesis of methyl propyl) ketone (11) 7.23 g (50.0 mmol) of 4-chlororesorcinol was
Add water mixture and mix with 40mL of carbon dioxide and 40mL of carbon disulfide
Add 13.3 g (100 mmol, 2.00 equivalents) of aluminum chloride
The mixture was added in portions, and a calcium chloride tube was attached and stirred. Incidentally
6.03 g (50.0 mmol, 1.00 equivalent) of sovaleryl chloride
The mixture was dropped dropwise, and stirring was continued at room temperature for 14 hours. Acid gas
When generation of water stops, dilute hydrochloric acid (concentrated hydrochloric acid 50 mL and cold water 20
0 mL), stir and extract with ether.
Was. The ether layer was washed with saturated saline and distilled off under reduced pressure.
did. Distill under reduced pressure while adding water little by little to this.
Nitrobenzene was distilled off by gas distillation. Remove the residue
Tel extraction, washing with saturated saline, and drying over sodium sulfate
did. The solvent was distilled off to obtain 7.14 g of a dark gray solid. Hex
Recrystallized from chloroform as gray needles
(5-chloro-2,4-dihydroxyphenyl) (2-
2.864 g of methylpropyl) ketone (11) was obtained. Compound (11) 1H-NMR (CDCl_Three): 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) Embodiment 8 {5-chloro-2-hydroxy-3- (3-methyl-2
-Butenyl) -4- (3-methyl-2-butenyloxy
C) phenyl} (2-methylpropyl) ketone (1
2), {5-chloro-2-hydroxy-4- (3-methyl)
2-butenyloxy) phenyl} (2-methylpro
Pill) ketone (13) and {5-chloro-2,4-
Dihydroxy-3- (3-methyl-2-butenyl) fe
Synthesis of nil @ (2-methylpropyl) ketone (14) 240 mg of 60% sodium hydride (6.00 mmol, 2.00 equivalents)
Paraffin was washed away with petroleum ether under nitrogen atmosphere
Thereafter, 5.0 mL of dry methanol was added. Then (5-black
B-2,4-dihydroxyphenyl) (2-methylpro
Pill) ketone (11), 686 mg (3.00 mmol) of methanol
(4.0 mL) solution was added under ice-cooled stirring. 1-black
627 mg of b-3-methyl-2-butene (6.00 mmol, 2.00 equivalents)
Volume) in methanol (3.0 mL) was slowly added dropwise.
Stirring was continued for 14 hours while returning to room temperature. This is ether
And the ether layer was washed with saturated aqueous ammonium chloride and saturated saline.
Washed with water and dried over sodium sulfate. Distill off the solvent
This gave 907 mg of a dark red viscous oil. The crude product was subjected to silica gel column chromatography (wa
Cogel C-300 45 g, hexane: ether = 29: 1
75-chloro-
2-hydroxy-3- (3-methyl-2-butenyl)-
4- (3-methyl-2-butenyloxy) phenyl}
92 mg of (2-methylpropyl) ketone (12)
Loro-2-hydroxy-4- (3-methyl-2-buteni
(Loxy) phenyl} (2-methylpropyl) ketone
(13) 80 mg and {5-chloro-2,4-dihydro
Xy-3- (3-methyl-2-butenyl) phenyl}
58 mg of (2-methylpropyl) ketone (14) were obtained. Compound (12) 1H-NMR (CDCl_Three): 1.01 (6H, d, J = 6.
6), 1.68 (3H, s), 1.72 (3H, s), 1.78 (6H, s), 2.28
(1H, m), 2.77 (2H, d, J = 6.8), 3.41 (2H, d, J = 6.8),
4.51 (2H, d, J = 7.3), 5.18 (1H, m), 5.58 (1H, m), 7.
64 (1H, s) Compound (13) 1H-NMR (CDCl_Three): 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). Compound (14) 1H-NMR (CDCl_Three): 1.00 (6H, d, J = 6.
4), 1.71 (3H, s), 1.80 (3H, s), 2.27 (1H, m), 2.74
(2H, d, J = 6.8), 3.42 (2H, d, J = 7.3), 5.24 (1H, m),
7.61 (1H, s) Embodiment 9 2,4-bis (3-methyl-1-oxobutyl) 1,
Synthesis of 3,5-trihydroxybenzene (15) 25.2 g (200 mmol) of 1,3,5-trihydroxybenzene
Into a mixed solution of 100 mL of nitrobenzene and 100 mL of carbon disulfide
53.3 g of aluminum chloride (400 mmol, 2.
(00 eq.) Little by little and add a calcium chloride tube and stir.
Was. Then 24.1 g of isovaleryl chloride (200 mmol, 1.00
Eq.) Was slowly added dropwise, and stirring was continued at room temperature for 4 hours.
When the generation of acid gas stops, dilute hydrochloric acid (concentrated hydrochloric acid 200m
L and 800 mL of cold water).
Extracted. The ether layer was washed with saturated saline and then
Evaporated. Distilling under reduced pressure while adding water little by little to this
Then, nitrobenzene was distilled off by steam distillation. Residual
The product was extracted with ether and washed with saturated saline solution, sodium sulfate
Dried on. The solvent was distilled off to obtain a gray solid. put
(2-Methylpropyl) (2,4,6-tri
11.5 g of (hydroxyphenyl) ketone crystallized out. Filtrate section
The silica gel column chromatography (Wakogel C-200,
Xan: ether = 4: 1 to 2: 3)
In order, (2-methylpropyl) (2,4,6-trihydrid
Roxyphenyl) ketone 5.0 g and 2,4-bis (3
-Methyl-1-oxobutyl) 1,3,5-trihydro
21.4 g of xylene (15) was obtained. Compound (15) 1H-NMR (CDCl_Three): 0.92 (12H, d, J = 6.
6), 2.15 (2H, m), 2.90 (4H, d, J = 6.6), 5.89 (1H, s) Embodiment 10 2,2-bis (3-methyl-2-butenyl) -4,6-
Bis (3-methyl-1-oxobutyl) -3,5-dihi
Droxycyclohexa-3,5-dienone (16), and
And 2,4-bis (3-methyl-1-oxobutyl)-
6- (3-methyl-2-butenyl) -1,3,5-tri
Synthesis of hydroxybenzene (17) Under a nitrogen atmosphere, sodium methoxide 864mg (16.0mmo
l, 2.12 eq.) in dry methanol (16.0 mL)
Under stirring, 2,4-bis (3-methyl-1-oxobuty)
) -1,3,5-trihydroxybenzene (15) 2.
A solution of 226 g (7.562 mmol) in methanol (10.0 mL) was added.
Was. Further, 1.673 g of 1-chloro-3-methyl-2-butene
(16.00 mmol, 2.12 equiv) was slowly added dropwise. At room temperature
Stirring was continued for 3 hours while returning. Methanol at room temperature under reduced pressure
Was distilled off. Ether is added to this and the ether layer is saturated with salt.
Washed with aqueous ammonium fluoride and saturated saline, sodium sulfate
Dried on. The solvent was distilled off to obtain 2.874 g of a brown oily substance.
Was. The crude product was subjected to silica gel column chromatography (Wako-Gel).
85 g of C-300, hexane: ether = 19: 1)
2,2-bis (3-methyl-2-
Butenyl) -4,6-bis (3-methyl-1-oxob)
Tyl) -3,5-dihydroxycyclohexa-3,5-
450 mg of dienone (16) as a pale yellow oil
-Bis (3-methyl-1-oxobutyl) -6- (3-
Methyl-2-butenyl) -1,3,5-trihydroxy
453 mg of benzene (17) were obtained as an orange oil. Compound (16) 1H-NMR (CDCl_Three): 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-NMR (CDCl_Three): 0.98 (12H, d, J = 6.
6), 1.82 (3H, d, J = 1.3), 1.87 (3H, s), 2.26 (2H,
m), 2.97 (4H, d, J = 6.8), 3.40 (2H, d, J = 7.1), 5.23
(1H, m). Embodiment 11 1,3,5-trihydroxy-2,4,6-tris (3
-Methyl-2-butenyl) benzene (18), 3,5-
Dihydroxy-2,2,4,6-tetrakis (3-methyl
Ru-2-butenyl) cyclohexa-3,5-dienone
(19), 3-hydroxy-5- (3-methyl-2-bu
Tenenyloxy) -2,2,4-tris (3-methyl-2
-Butenyl) cyclohexa-3,5-dienone (2
0), 3,5-dihydroxy-2,2,4-tris (3
-Methyl-2-butenyl) cyclohexa-3,5-die
Synthesis of non (21) Under a nitrogen atmosphere, sodium methoxide 14.18g (262.5m
mol, 3.500 equivalents) in dry methanol (200 mL) solution
Under cold stirring, 1,3,5-trihydroxybenzene 9.45
8 g (75.00 mmol) of methanol (30.0 mL) solution was added.
Was. Further 23.53 g of 1-chloro-3-methyl-2-butene
(225.0 mmol, 3.000 equivalents) was slowly added dropwise. At room temperature
Stirring was continued for 3 hours while returning. Methanol at room temperature under reduced pressure
Was distilled off. Ether is added to this and the ether layer is saturated with salt.
Washed with aqueous ammonium fluoride and saturated saline, sodium sulfate
Dried on. The solvent is distilled off and orange viscous oil 22.164 g
I got The crude product was subjected to silica gel column chromatography (wa
350 g of Kogel C-200, hexane: ether = 19: 1
~ 7: 3), and in the order of outflow, 1,3,5-to
Rehydroxy-2,4,6-tris (3-methyl-2-
Butenyl) benzene (18) 2.27 g as orange viscous oil
To give 3,5-dihydroxy-2,2,4,6-tetra
Kiss (3-methyl-2-butenyl) cyclohexa-3,
1.73 g of 5-dienone (19) as an orange viscous oil
3-hydroxy-5- (3-methyl-2-butenyloxy)
B) -2,2,4-tris (3-methyl-2-buteni)
) 540 mg of cyclohexa-3,5-dienone (20)
3,5-dihydroxy-2,2,4 as orange oil
-Tris (3-methyl-2-butenyl) cyclohexa-
6.85 g of 3,5-dienone (21) were obtained as a red oil.
Was. Compound (18) 1H-NMR (CDCl_Three): 1.76 (9H, s), 1.82
(9H, s), 3.36 (6H, d, J = 7.1), 5.23 (3H, m), 5.39 (3
H, bs) Compound (19) 1H-NMR (CDCl_Three): 1.62 (6H, s), 1.64
(6H, s), 1.75 (3H, d, J = 1.3), 1.78 (3H, d, J = 1.3),
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,
m), 5.24 (1H, m) Compound (20) 1H-NMR (CDCl_Three): 1.55 (6H, s), 1.60
(6H, d, J = 0.7), 1.72 (3H, s), 1.75 (3H, s), 1.78 (3
H, s), 1.81 (3H, s), 2.40 (4H, d, J = 7.8), 3.34 (2H,
d, J = 7.1), 4.42 (2H, d, J = 6.9), 4.83 (2H, m), 5.25
(1H, m), 5.46 (1H, m), 6.04 (1H, s) Compound (21) 1H-NMR (CDCl_Three): 1.58 (6H, s), 1.62
(6H, s), 1.80 (6H, s), 2.55 (4H, d, J = 7.0), 3.15-3.
38 (2H, m), 4.86 (2H, m), 5.16
(1H, m), 5.97 (1H, s) Embodiment 12 3-hydroxy-5- (3-methyl-2-butenyloxy)
B) -2,2,4-tris (3-methyl-2-buteni)
G) cyclohexa-3,5-dienone (20), 3, 5
-Dihydroxy-2,2,4-tris (3-methyl-2
-Butenyl) cyclohexa-3,5-dienone (2
1) and 2- (3-methyl-2-butenyl) -1,
Synthesis of 3,5-trihydroxybenzene (22) Under a nitrogen atmosphere, potassium methoxide 8.78 g (120 mmol,
(3.00 eq.) In dry methanol (200 mL)
Below, 5.00 g of 1,3,5-trihydroxybenzene (40.
(0 mmol) in methanol (30.0 mL). further
12.4 g of 1-chloro-3-methyl-2-butene (120 mmol,
3.00 equiv.) Was slowly added dropwise. Stir while returning to room temperature
Lasted 3 hours. Methanol was distilled off under reduced pressure at room temperature. This
Ether was added thereto and the ether layer was saturated with ammonium chloride.
The extract was washed with water and saturated saline, and dried over sodium sulfate.
The solvent was distilled off to obtain 12.93 g of an orange viscous oily substance. Crude product
To silica gel column chromatography (Wako-Gel C-200 350
g, separated by hexane: ether = 9: 1 to 3: 1)
And, in the order of effluent, 3-hydroxy-5- (3-methyl
-2-butenyloxy) -2,2,4-tris (3-meth
Tyl-2-butenyl) cyclohexa-3,5-dienone
(20) as an orange oil, 3,5-dihydroxy-
2,2,4-tris (3-methyl-2-butenyl) cycl
Rohexa-3,5-dienone (21) as red oil
And 2- (3-methyl-2-butenyl) -1,
3,5-trihydroxybenzene (22) is an orange oil
As obtained. Compound (22) 1H-NMR (CDCl_Three): 1.70 (6H, d, J = 8.
4), 3.24 (2H, d, J = 7.0), 5.24
(1H, m), 5.96 (2H, s) Embodiment 13 [3- {2- (1-piperidino) ethyl} -2,4,6
-Trihydroxyphenyl] (2-methylpropyl) ke
Ton (23) and [3,5-bis {2- (1-pipe)
(Rizino) ethyl} -2,4,6-trihydroxyphenyl
[2] Synthesis of (2-methylpropyl) ketone (24) Under a nitrogen atmosphere, sodium methoxide 1.08g (20.0mmo
l, 4.00 equiv.) in dry methanol (20.0 mL) solution at room temperature
Under stirring, (2-methylpropyl) (2,4,6-
1.05 g (5.00 mmol) of dryoxyphenyl) ketone
A solution of ethanol (5.0 mL) was added. Furthermore, 1- (2-k
Loloethyl) piperidine hydrochloride 1.84 g (10.0 mmol, 2.00
(Equivalent) in methanol (10.0 mL) was slowly added.
After heating at 60 ° C for 3 hours, methanol is distilled off under reduced pressure.
30.0 mL of methylene chloride was added to the residue and stirred. Filter insoluble matter
The solvent was distilled off under reduced pressure to give 2.16 g of an orange solid.
Obtained. This is a silica gel column chromatography operation (Wako-ge
C-300 50g, methylene chloride: methanol = 100: 1-1
00:10), and [3- 順 に 2-
(1-piperidino) ethyl} -2,4,6-trihydro
[Xyphenyl] (2-methylpropyl) ketone (23)
399 mg as a yellow solid, then [3,5-bis @ 2-
(1-piperidino) ethyl} -2,4,6-trihydro
Xyphenyl] (2-methylpropyl) ketone (24)
111 mg was isolated as a yellow solid. Compound (23) 1H-NMR (CDCl_Three): 0.96 (6H, d, J = 6.6),
 1.45 (2H, m), 1.60 (2H, m), 1.71 (4H, m), 2.23 (1
H, m), 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, 4
5.0, 57.2, 95.5, 105.0, 112.0, 155.8, 157.8, 161.8,
 205.6. Compound (24) 1H-NMR (CDCl_Three): 0.95 (6H, d, J = 6.6),
 1.40 (2H, m), 1.49 (4H, m), 1.60 (2H, m), 1.84 (5
H, m), 2.24 (1H, m) 2.42 (3H, m), 2.82 (4H, m), 2.96
 (2H, m), 2.98 (2H, d, J = 6.8), 3.32 (2H, m), 3.49
(6H, m), 3.87 (1H, m) Embodiment 14 {3- (N, N-dimethylamino) propyl-2,4,6
-Trihydroxyphenyl {(2-methylpropyl) ke
Synthesis of tons (25) Under nitrogen atmosphere, sodium methoxide 540mg (10.0mmo
l, 4.00 equiv.) in dry methanol (10.0 mL) solution at room temperature
(2-Methylpropyl) (2,4,6-trihydrogen under stirring
Roxyphenyl) ketone (5) 526 mg (2.50 mmol) dry
Dry methanol (5.0 mL) solution was added. In addition, 3- (
Lamino) -1-chloropropane hydrochloride 790mg (5.00mmo
l, 2.00 eq) in methanol (5.0 mL)
I got it. After heating at 60 ° C for 3 hours, methanol was collected under reduced pressure.
Then, 20.0 mL of methylene chloride was added to the residue, and the mixture was stirred. Insoluble
The substance was removed by filtration, and the solvent was distilled off under reduced pressure.
6 mg were obtained. This is a silica gel column chromatography operation (wa
Cogel C-300 25 g, methylene chloride: methanol = 10
0: 1 to 100: 6), and the target compound {3- (N, N-di)
Methylamino) propyl-2,4,6-trihydroxy
Phenyl (2-methylpropyl) ketone (25) 128m
g was isolated as a yellow solid. Compound (25) 1H-NMR (DMSO): 0.93 (6H, d, J = 6.6),
1.89 (1H, m), 2.07 (1H, m), 2.20 (1H, m), 2.48 (3H,
 s), 2.52 (3H, s), 2.50-2.80 (4H, m), 2.93 (2H, d,
J = 6.6), 5.77 (1H, s). Experimental Example 1 Bone resorption inhibitory activity test (1) Preparation of cells 11-12 day old ICR mice (Charles River)
Euthanized by ether anesthesia immediately after
It was immersed in 0% ethanol for disinfection. Mouse femur and
Remove the tibia and remove 5% FBS (Ilvin Scientific
(IrvinScientific), 100U
/ ML penicillin, 100mg / mL Streptomyces
-MEM medium containing flow-through (Flow Laboratories (F
low Laboratories) with scissors
The supernatant obtained by slicing and further pipetting is
After collecting and washing with culture solution, 5% FBS, α-MEM culture
The cells were suspended in the solution to obtain osteocytes containing osteoclasts. 3 minutes still
Remove the osteocyte suspension supernatant of the osteocytes after
Rust strainer, 70 μM, Falcon
(Made by the company). Cell concentration 1X10⁷/ ML prepared bone
It was used for the test for inhibiting the formation of resorption pits. (2) Examination by bone resorption pit formation inhibitory activity test
Set Precision low speed cutting machine for ivory pieces to 150μm thickness (Buhler
(Manufactured by Bühler) 6 mm in diameter
Was punched out using a one-hole punch. This ivory
The pieces are immersed in 70% ethanol and ultrasonically washed twice for 5 minutes each.
The treatment was performed and the cells were washed three times with sterile PBS and twice with medium.
This ivory piece was placed in a 96-well culture plate (Falcon (Falcon)).
2x10)^-FiveBook adjusted to M concentration
Add 100 μL of the culture solution containing the compound of the present invention to each well.
Bone cells 1 × 10⁷Medium containing 100 / mL
μL into each well (final drug concentration, 1 × 10^-FiveM), 3
7 ° C, 10% CO_TwoCulture for 3 days in an incubator
Was. After culturing, the cells on the ivory pieces are placed in 2M sodium hydroxide solution.
Remove with rubber spatula and wash with water and methanol
Later, the resorption fossa was stained with Coomassie Brilliant Blue,
The number of absorption pits was counted under a microscope. RPTH in the culture solution
(1X10^-8M) The number of absorption cavities without drug added in the presence of
%, When the number of resorption fossae is zero, 100%
The absorption inhibition rate was calculated. As a result, bone resorption of the compound of the present invention
The effect of suppressing yield was remarkable. Table 1 shows the results. [0071] [Table 1] [0072]

   ────────────────────────────────────────────────── ─── Continuation of front page    (72) Inventor Kazuyuki Doi             1-3-2 Minamidai, Kawagoe-shi, Saitama 2 Japan             Kist Marion Roussel, Inc. Information Technology             Intraoperative (72) Inventor Kazuyuki Kitamura             1-3-2 Minamidai, Kawagoe-shi, Saitama 2 Japan             Kist Marion Roussel, Inc.             Inside the office

Claims (1)

Claims: 1. A compound of the general formula (I) (Wherein, R ¹ , R ² , and R ³ each independently represent 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) A substituted or unsubstituted alkenyl group, a substituted or unsubstituted benzyl group, or an aryl group, wherein R ⁴ , R ⁵ and R ⁶ each independently represent a hydrogen atom, ~ 15
A linear or branched substituted or unsubstituted alkyl group of
Represents a straight-chain or branched-chain substituted or unsubstituted alkenyl group having 2 to 15 carbon atoms, 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) R ¹ or R ³ is a hydrogen atom, or 3-methyl-
The compound according to claim 1, which is a 2-butenyl group,
Or a salt thereof. 4. The compound according to claim 1, 2 or 3, wherein R ⁴ , R ⁵ or R ⁶ is a hydrogen atom or a 3-methyl-2-butenyl group, or a salt thereof. 5. The compound according to claim 1, wherein the compound is (2-methylpropyl) (3,
4,5-trihydroxyphenyl) ketone, {3,5-
Dihydroxy-2- (3-methyl-2-butenyl) -4
-(3-methyl-2-butenyloxy) phenyl} (2
-Methylpropyl) ketone, {3,5-dihydroxy-
4- (3-methyl-2-butenyloxy) phenyl}
(2-methylpropyl) ketone, {2- (3-methyl-
The compound according to any one of claims 1 to 4, wherein the compound is any one selected from the group consisting of 2-butenyl) -3,4,5-trihydroxyphenyl} (2-methylpropyl) ketone.
Or a salt thereof, or a salt thereof. 6. The compound of the general formula (II) (Wherein, R ¹ , R ² , R ⁴ , R ⁵ , and R ⁶ each independently represent 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, a linear or branched substituted or unsubstituted 3 to 15 carbon atoms 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-oxoalkenyl group;
Represents an 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 alkyl group having 1 to 15 carbon atoms; A substituted or 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, having 2 to 15 carbon atoms. Represents a substituted alkenyloxy group, a substituted or unsubstituted benzyl group, or a substituted or unsubstituted benzyloxy 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 an oxoalkenyl group or an unsubstituted 1-oxoaralkyl group and R ³ is a hydroxyl group,
¹ and R ² are simultaneously a hydrogen atom, a linear or branched unsubstituted alkyl group having 1 to 15 carbon atoms, a linear or branched unsubstituted alkenyl group having 2 to 15 carbon atoms Or a substituted or unsubstituted benzyl group is excluded. 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. A compound according to claim 8, wherein R ² or R ⁴ is a hydrogen atom, 3-methyl-1-
The compound according to claim 6 or 7, which is an 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 ⁶ is a hydrogen atom, or a salt thereof. (11) the compound is (2,6-dihydroxy-4);
-Methylphenyl) (2-methylpropyl) ketone,
{2,6-dihydroxy-4-methyl-3- (3-methyl-2-butenyl) phenyl} (2-methylpropyl)
Ketone, {3,5-bis (3-methyl-2-butenyl)
-2,6-dihydroxy-4-methylphenyl} (2-
Methylpropyl) ketone, (5-chloro-2,4-dihydroxyphenyl) (2-methylpropyl) ketone,
{5-chloro-2-hydroxy-3- (3-methyl-2
-Butenyl) -4- (3-methyl-2-butenyloxy) phenyl} (2-methylpropyl) ketone, {5-
Chloro-2-hydroxy-4- (3-methyl-2-butenyloxy) phenyl {(2-methylpropyl) ketone {5-chloro-2,4-dihydroxy-3- (3-methyl-2-butenyl) phenyl} (2-methylpropyl)
Ketone, 1,3-bis (3-methyl-1-oxobutyl) -2,4,6-trihydroxybenzene, 1,3-
Bis (3-methyl-1-oxobutyl) -5- (3-methyl-2-butenyl) -2,4,6-trihydroxybenzene, {3,5-bis (2- (1-piperidino) ethyl)- 2,4,6-trihydroxyphenyl} (2-methylpropyl) ketone, {3- (2- (1-piperidino) ethyl) -2,4,6-trihydroxyphenyl}
(2-methylpropyl) ketone, {3- (3- (N, N-
Dimethylamino) propyl) -2,4,6-trihydroxyphenyl} (2-methylpropyl) ketone, 2-
(3-methyl-2-butenyl) -1,3,5-trihydroxybenzene and 1,3,5-trihydroxy-
The compound according to any one of claims 6 or R10, which is any one selected from the group consisting of 2,4,6-tris (3-methyl-2-butenyl) benzene, or a salt thereof. A compound of the general formula (III) (Wherein R ¹ , R ² , R ⁴ and R ⁵ are each independently a hydrogen atom, a linear or branched substituted or unsubstituted alkyl group having 1 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 substituted or unsubstituted 1-oxoalkenyl group or a substituted or unsubstituted 1-oxoaralkyl group having ³ to 15 carbon atoms, wherein 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 alkyloxy group having 1 to 15 carbon atoms, Linear or branched, substituted or unsubstituted alkenyl group, having 2 to 15 carbon atoms Chain substituted or unsubstituted alkenyloxy group, a substituted or unsubstituted benzyl group, or a substituted or unsubstituted benzyloxy group. However, R ¹ is a 3 to 15 carbon atoms linear or branched A chain-like unsubstituted 1-oxoalkyl group,
Straight or branched unsubstituted 1 having 3 to 15 carbon atoms
-Oxoalkenyl group, or an unsubstituted 1-oxoaralkyl group, and when R ³ represents a hydroxyl group, R ² is a hydrogen atom, a linear or branched chain having 1 to 15 carbon atoms. Is an unsubstituted alkyl group, a linear or branched unsubstituted alkenyl group having 2 to 15 carbon atoms, or a substituted or unsubstituted benzyl group. Or a salt thereof, or a solvate thereof. 13. R1 ^or R ² is a hydrogen atom, 3-methyl-1
The compound according to claim 12, which is -oxobutyl group or 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, wherein R ⁴ is a 3-methyl-2-butenyl group, or a salt thereof. 16. The compound according to claim 12, wherein R ⁵ is a hydrogen atom or a 3-methyl-2-butenyl group, or a salt thereof. (17) the compound is 5-hydroxy-3-methyl-,
6- (3-methyl-1-oxobutyl) -2,2,4-
Tris (3-methyl-2-butenyl) cyclohexa-
3,5-dienone, 2,2-bis (3-methyl-2-butenyl) -5-hydroxy-3-methyl-6- (3-methyl-1-oxobutyl) cyclohexa-3,5-dienone, 2-bis (3-methyl-2-butenyl)-
4,6-bis (3-methyl-1-oxobutyl) -3,
5-dihydroxycyclohexa-3,5-dienone, 3
-Hydroxy-5- (3-methyl-2-butenyloxy) -2,2,4-tris (3-methyl-2-butenyl) cyclohexa-3,5-dienone, 3,5-dihydroxy-2,2,4 , 6-tetrakis (3-methyl-2
-Butenyl) cyclohexa-3,5-dienone and 3,5-dihydroxy-2,2,4-tris (3-
The compound according to any one of claims 12 to 16, which is one selected from the group consisting of methyl-2-butenyl) cyclohexa-3,5-dienone, or a salt thereof. 18. A pharmaceutical composition comprising one or more of the compounds according to any one of claims 1 to 17 as an active ingredient. (19) the pharmaceutical composition according to the above (18), which is an agent for preventing or treating bone and cartilage diseases;