JP3099243B2 - Bone resorption inhibitor and naphthalene derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a kitsunenomago or a plant extract containing a naphthalene derivative having a bone resorption inhibiting activity expected to be used as a therapeutic agent for osteoporosis as an active ingredient or containing the naphthalene derivative. And a bone resorption inhibitor.

[0002]

BACKGROUND OF THE INVENTION Osteoporosis is a pathological condition or disease in which the loss of bone has increased to some extent, thereby causing some symptoms or danger. The main symptoms are kyphosis of the spine, lumbar spine and fractures of the vertebral body, femoral neck, lower radius, ribs, upper humerus, etc. The causes are diverse, including endocrine and nutritional disorders. Conventionally, estrogen agents, calcitonin, vitamin D, calcium agents, and the like have been administered as therapeutic agents.

[0003]

However, when the above-mentioned therapeutic agents are administered, the target of administration is limited or the effect is uncertain, so that a sufficient effect has not been obtained.

[0004]

Means for Solving the Problems The present inventors have conducted intensive studies with the aim of developing a more general drug that acts directly on bone and suppresses bone resorption, and as a result, the following general formula (I) It has been found that the naphthalene derivative represented by the formula (1) or a kitsunenomago containing the naphthalene derivative or an extract of the plant directly exerts an excellent effect on inhibiting bone resorption by directly acting on bone, thereby completing the present invention. That is, the present invention relates to (1) general formula

Embedded image [In the formula, A ring and B ring may be substituted, R represents a hydrogen atom, a hydroxyl group or an alkoxy group which may be substituted, and a portion containing a broken line represents a carbon-carbon single bond or a double bond. A bone resorption inhibitor comprising a naphthalene derivative represented by the formula: (2) a bone resorption inhibitor comprising a kitsunenomago or an extract of the plant; (3) a general formula

Embedded image [In the formula, ring B may be substituted, R ′ indicates that ring A is substituted with a halogen atom or an optionally substituted hydrocarbon residue, and a divalent hydrocarbon residue And a portion containing a broken line indicates a carbon-carbon single bond or a double bond], (4) jasticidin G having the following structure:

Embedded image (5) The present invention relates to justicidin H having the following structure.

Embedded image In the above general formulas (I) and (I ′), when the ring A and / or ring B is substituted, the substituent includes:
Examples include a halogen atom, an optionally substituted alkyl group, an aryl group, an alkenyl group, and a hydroxyl group. The number of substitutions is 1-4 each.

Next, each of the above substituents will be described. Examples of the halogen atom include fluorine, chlorine, bromine and iodine, and fluorine or chlorine is preferable. The alkyl group in the alkyl group which may be substituted may be straight-chain, branched or cyclic having 1 to 10 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, cyclopropyl, cyclobutyl,
Examples thereof include cyclopentyl, cyclohexyl, and cycloheptyl, among which those having 1 to 5 carbon atoms are preferable. Examples of the substituent which the alkyl group may have include, for example, halogen, nitro, amino (which may have acyl, alkyl, iminomethyl, imino (aryl-substituted) methyl, amidino, amino as a substituent). , Sulfo, cyano, hydroxy, carboxy, hydrazino, imino, amidino, carbamoyl, aryl (halogen, alkyl, alkoxy, alkylamino, amino, carbamoyl, sulfo, alkylsulfonyl, cyano, hydroxy, carboxy, nitro, acyloxy, aralkyloxy, May have sulfonyloxy as a substituent.), Heterocycle (nitro, oxo, aryl, alkenylene, halogenoalkyl, alkylsulfonyl, alkyl, alkoxy, alkylamino, amino, halogen, carbamoyl, hydroxy, cyano, carboxy) ,
It may have sulfo as a substituent. ).

The aryl group in the optionally substituted aryl group includes, for example, phenyl, naphthyl, biphenyl, anthryl, indenyl and the like. Examples of the substituent which the aryl group may have include, for example, halogen, nitro, cyano, amino (which may have an alkyl, alkenyl, cycloalkyl, and aryl as a substituent), sulfonyl, hydroxy, and sulfoxy. , Sulfamoyl, alkyl (which may have amino, halogen, hydroxy, cyano as a substituent), alkoxy, aralkyloxy, alkylsulfonamide, methylenedioxy, alkylsulfonyl, alkylsulfonylamino and the like. Further, a condensed ring (eg, tetrahydronaphthyl, indanyl, acenaphthyl, etc.) may be formed with cycloalkyl.

The alkenyl group in the alkenyl group which may be substituted may be any of linear, branched and cyclic having 2 to 10 carbon atoms, for example, allyl, vinyl, crotyl, 2-pentene- 1-yl, 3-pentene
1-yl, 2-hexen-1-yl, 3-hexen-1-
Yl, 2-cyclohexenyl, 2-cyclopentenyl, 2
-Methyl-2-propen-1-yl, 3-methyl-2-
Buten-1-yl and the like.
Are preferred. Examples of the substituent which the alkenyl may have include, for example, alkyl having 1 to 6 carbon atoms (which may have the same group as the substituent which the alkyl group may have). Halogen, nitro, amino (acyl, iminomethylene, amidino, alkyl, aryl may be substituted), sulfo, cyano, hydroxy, carboxyalkyloxycarbonyl, carbamoyl, alkylthio, allylthio, alkylsulfinyl, aryl Examples include groups such as sulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, aryl, and acyl. The alkenyl or alkenylene includes isomers related to double bonds (E, Z forms).

[0008] Examples of the halogen in the above description of the substituent include chlorine, bromine, fluorine and iodine. Alkyl in the description of the above substituents has 1 to 1 carbon atoms
10, further preferably 1 to 6, especially 1 to 4, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n
-Pentyl, isopentyl, n-hexyl, isohexyl,
Heptyl, octyl, nonyl, decyl and the like can be mentioned. The cycloalkyl as the above substituent has 3 to 4 carbon atoms.
6 are preferred, for example cyclopropyl,
Cyclobutyl, cyclopentyl, cyclohexyl and the like can be mentioned. The alkoxy as the substituent is preferably an alkoxy having 1 to 4 carbon atoms, and examples thereof include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy and the like. Examples of the aryl as the substituent include phenyl,
Naphthyl and the like. Examples of the heterocyclic ring as the substituent include 2-pyridyl, 3-pyridyl, imidazolyl, thiazolyl, pyrrolidinyl, pyrido [2,3-d] pyrimidyl and the like. As the acyl as the substituent, those having 1 to 6 carbon atoms are preferable, and examples thereof include formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, and hexanoyl. Examples of the aralkyl as the substituent include benzyl, phenethyl, phenylpropyl and the like. Examples of the alkenyl or alkenylene as the substituent include those similar to the aforementioned alkenyl or methylene.

Specific examples of the substituted alkyl include, for example, trifluoromethyl, trifluoroethyl, difluoromethyl, trichloromethyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, methoxyethyl, ethoxyethyl, 1-methoxy Ethyl, 2-methoxyethyl, 2,2-dimethoxyethyl, 2,2-diethoxyethyl and the like can be mentioned. Specific examples of the substituted aryl group include, for example, 4-chlorophenyl, 4-fluorophenyl, 2,4-dichlorophenyl, p-tolyl, 4-methoxyphenyl, 4- (N, N-dimethylamino) phenyl and the like. Can be Specific examples of the substituted alkenyl include, for example, 2,2-dichlorovinyl, 3-hydroxy-2
-Propen-1-yl, 2-methoxyvinyl and the like.

The hydroxyl group which may be substituted includes, in addition to a hydroxyl group and an appropriate substituent for the hydroxyl group, particularly those having a substituent used for a hydroxyl group, such as alkoxy, alkenyloxy, aralkyloxy and acyloxy. Aryloxy. Examples of the alkoxy include alkoxy having 1 to 10 carbon atoms (e.g., methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, isopentoxy, neopentoxy, hexyloxy , Heptyloxy, nonyloxy, cyclobutoxy, cyclopentoxy, cyclohexyloxy, etc.) are preferred.
Examples of the alkenyloxy include those having 2 to 10 carbon atoms such as allyloxy, crotyloxy, 2-pentenyloxy, 3-hexenyloxy, 2-cyclopentenylmethoxy, and 2-cyclohexenylmethoxy. And phenyl-C _1-4 alkyloxy (eg, benzyloxy, phenethyloxy, etc.). As the acyloxy, an alkanoyloxy having 2 to 4 carbon atoms (eg, acetyloxy, propionyloxy, n-butyryloxy, isobutyryloxy, etc.) is preferable. Examples of the aryloxy include phenoxy, 4-chlorophenoxy and the like.

The above alkoxy, alkenyloxy,
In aralkyloxy, acyloxy, aryloxy, each of the alkyl, alkenyl, acyl, and aryl groups may have a substituent, and examples of the substituent include halogen (eg, fluorine, chlorine, bromine, iodine, etc.). , Hydroxyl group, alkoxy having 1 to 6 carbon atoms (eg, methoxy, ethoxy, n-propoxy, isopropoxy, butoxy, pentyloxy, hexyloxy, etc.), and the number of substituents is preferably 1 to 3. Specific examples thereof include, for example, trifluoromethoxy, 2,2,2-trifluoroethoxy, difluoromethoxy, 2-methoxyethoxy, 4-chlorobenzyloxy, 2- (3,4-dimethoxyphenyl) ethoxy and the like. .

When the ring A and / or the ring B are substituted, the substituent is preferably an optionally substituted hydroxyl group among the above-mentioned substituents. The above general formula
In the formula (I ′), the substituent on the ring A represented by R ′ includes:
Examples include a halogen atom, an optionally substituted alkyl group, an aryl group and an alkenyl group. The number of substitution is 1 to 4, and the description of each substituent is the same as described above. Furthermore, in any of the above cases, when there are two or more substituents, these may form a ring with a divalent hydrocarbon residue. Specific examples of such a case, the two substituents _{connected, - (CH 2) P -} , - (CH
CHCH) _m -or -O (CH ₂ ) _n O- (wherein P, m and n each represent an integer) to form a ring together with two adjacent carbon atoms of the benzene ring. The case where a 5, 6 and 7-membered ring is formed is mentioned.

The alkoxy group in the optionally substituted alkoxy group represented by R in the above general formula (I) includes alkoxy having 1 to 10 carbon atoms (eg, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, isopentoxy, neopentoxy, hexyloxy,
Heptyloxy, nonyloxy, cyclobutoxy, cyclopentoxy, cyclohexyloxy, etc.), and alkoxy having 1 to 6 carbon atoms is preferable. Examples of the substituent which the alkoxy may have include, for example, halogen (eg, fluorine, chlorine, bromine, iodine, etc.), hydroxyl group, alkoxy having 1 to 6 carbon atoms (eg, methoxy, ethoxy, n-propoxy, iso- (Propoxy, butoxy, pentyloxy, hexyloxy, etc.)
And the like, and the number of substituents is preferably 1 to 3. Specific examples of the substituted alkoxy include, for example, trifluoromethoxy, 2,2,2-trifluoroethoxy, difluoromethoxy, 2-methoxyethoxy and the like.
Among the compounds represented by the above general formula (I), the following compounds are referred to as kitsunenomago (Justicia procumbens L. var.
It is a lignan component contained in cantha Honda). Fox nomad is an annual plant of the family Acanthaceae,
It is a weed distributed in warm regions from Japan to Taiwan. In the private sector, foliage is used as a blood purifying agent, and fresh leaves are used externally for muscle pain. On the other hand, the foliage of the fox nomad is called the "shrine bed" and has been used in Chinese medicine for severe lumbar spinal pain and fever from ancient times.

The lignan component of the kitsunenomago represented by the above general formula (I) has already included justicinidine A (I-1), justicinidine B (I-2), justicinidine F (I-3), and defylin (I-6). However, the present inventors have found that a new compound, justicidin G (I-I-
4) and justicidin H (I-5) were found. All of these are allylnaphthalide lactones.
de lactone) compound.

Embedded image

Embedded image The known lignan component of the fox nomad is obtained by a known method or a method equivalent thereto, for example, Planta Medica (Planta Medica).
Medica), 36 , 200 (1979), Tetra Headlon
Letters (Tetrahedron Letters), 1967 , 351
7, Tetraheadron Letters, 1965 , 4167, Pharmaceutical Magazine, 81 , 1596 (1961), etc., using foxgrass or other plants as raw materials.

[0015] The new components, justicidin G (I-4) and justicidin H (I-5), are produced by extracting and purifying from the foliage or whole plant of Kittenomago. Thin layer chromatography (TLC) and high performance liquid chromatography (HPLC) are used as appropriate as means for tracking lignan production in the process of extraction and production. TLC conditions - (1) plate;. Silica gel 60F ₂₅₄ (Merck, West Germany), developing solvent; diethyl ether, the detection method; UV lamp (254 nm) (2) plates; TLC plate RP-8 F ₂₅₄ s (Merck Developing solvent: acetonitrile-water (7: 3), detection method: UV lamp (2
HPLC condition-column; ERC-ODS-1161
(6 × 100 mm), mobile phase; acetonitrile-water (35: 6)
5), column temperature; 40 degrees, flow rate; 1 ml / min, detection wavelength;
254 nm. For example, dry powder of the whole foxgrass is extracted with alkyl halides such as dichloromethane and chloroform, ethers such as diethyl ether and dioxane, ketones such as acetone, esters such as ethyl acetate, and alcohols such as methanol and ethanol. I do. The amount of the extraction solvent is usually 3 to 20 times (w /
w). The extraction temperature may be any range from room temperature to the boiling point of the solvent used. In the case of a solvent that is miscible with water, the efficiency of the extraction operation can be increased by appropriately using a mixed solvent. The extract is filtered and separated from the residue, and then concentrated to produce an extract. The extract thus obtained is subjected to column chromatography with a stationary phase usually 100 to 300 times (w / w) the amount of silica gel such as silica gel 60 (manufactured by Merck), first with dichloromethane or chloroform and then with chloroform. Elute with acetone. The lignan component in the eluate can be detected by TLC. Justicidin A and B which are main components
Is collected and concentrated, and the concentrated residue is used as a stationary phase, usually in an amount of 100 to 300 times (w / w) the amount of reversed phase silica gel such as YMC-ODS (manufactured by Yamamura Chemical Laboratory). Column chromatography, eluting with 40-60% aqueous methanol, followed by TLC and HPLC to give a fraction containing justicidin B and then justicidin A, and concentrated to give a powdery residue. When both are recrystallized from dichloromethane-diethyl ether, most of justistin A and B are both obtained as colorless plate crystals. By repeating the above column chromatography while tracking by TLC and HPLC for all the fractions and the recrystallized mother liquor obtained in the above operation process, justicidin F, diffirin and new substances justicin G and H were obtained. can get. It should be noted that it is naturally presumed that preparations containing the above-mentioned justicidins and difficillin, a herbal medicine of kitsunenomago, which has been used for many years, and a kit containing kitsunenomago itself or various extracts produced therefrom can also be used as a useful bone resorption inhibitor. Is about to be done.

The compounds are described in Journal of Organic Chemistry (J. Org. Chem.), 36 , 3450 (19).
71), Chemical and Pharmaceutical Buretin (Chem. Pharm. Bull.), 25 , 1803 (197)
7) and 37 , 68 (1989), Chemical Communication (Chem. Commun.), 1968 , 653 and 19
80, 354, Journal of Chemical Sosaeti
[J. Chem. Soc. (C)], 1971 , 2091 and 19
66 , 1775, and the like, and a method analogous thereto, but preferably produced using the following synthesis method.

Embedded image

Embedded image

Embedded image [The rings A and B in the above formula have the same meaning as described above] Step 4 Step of producing phenol derivative The individual steps are described in detail below.

Step 1 In this step, the cinnamic alcohol derivative (II) and the phenylpropiolic acid derivative (III) are condensed to form the ester derivative (I
V) is manufactured. The esterification reaction can be carried out by a method known per se, for example, a method of directly reacting (III) with a cinnamon alcohol derivative (II) in the presence of an acid to perform esterification, a reactive derivative of (III), For example, acid anhydrides, acid halides (acid chlorides, acid bromides), imidazolides or mixed acid anhydrides (e.g., anhydrides with methyl carbonate, anhydrides with ethyl carbonate, anhydrides with isobutyl carbonate), etc. A method of appropriately reacting with II) or a method of directly condensing (II) and (III) with dicyclohexylcarbodiimide or the like is used. When an acid halide is used, the reaction is usually carried out in a solvent (eg, chloroform, dichloromethane, ethyl acetate, tetrahydrofuran, water or a mixture thereof) in a base (eg, triethylamine, N-methylmorpholine, sodium hydrogen carbonate, potassium hydrogen carbonate, -10 ° C to +50 in the presence of sodium carbonate, potassium carbonate, etc.)
C., and the amount of (II) used is 1 to 1 mol per mol of (III).
1.2 moles. When using a mixed acid anhydride,
(III) and chlorocarbonate (e.g., methyl chlorocarbonate, ethyl chlorocarbonate, isobutyl chlorocarbonate)
(E.g., triethylamine, N-methylmorpholine, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, etc.) in the presence of an appropriate solvent (e.g., chloroform, dichloromethane, ethyl acetate, tetrahydrofuran,
-10 ° C. to +30
C., and the reaction is carried out at (° C.).
It is 1 to 1.2 mol per mol. When directly condensing with dicyclohexylcarbodiimide or the like, the reaction is usually carried out in a solvent (e.g., acetonitrile, chloroform, dichloromethane, ethyl acetate, tetrahydrofuran, pyridine or a mixture thereof) in a base (e.g., triethylamine,
N-methylmorpholine, 4-dimethylaminopyridine,
The reaction is performed at −10 ° C. to + 100 ° C. in the presence of N, N-dimethylaniline, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium carbonate, potassium carbonate, etc. or an acid (eg, paratoluenesulfonic acid, benzenesulfonic acid, etc.). , (II)
Is used in an amount of 1 to 1.2 mol per 1 mol of (III),
The amount of the acid or salt to be used is 0.01 to 1 mol of (III).
0.3 mol.

Step 2 In this step, a dihydronaphthalene derivative (I ″) is produced by heat-cyclizing the ester derivative (IV). This reaction is usually carried out in a solvent (eg, chloroform, dichloromethane, 1,2
-Dichloroethane, 1,1,2,2-tetrachloroethane,
Ethyl acetate, tetrahydrofuran, benzene, toluene, xylene, N, N-dimethylformamide, dimethylsulfoxide, acetic anhydride or a mixture thereof).
C. to 200.degree. The reaction time is 1 to 50 hours.

Step 3 In this step, a naphthalene derivative (I '') is produced by aromatizing the dihydronaphthalene derivative (I '').
This reaction is a method using a halogenating agent such as N-halogenosuccinimide (eg, N-bromosuccinimide, N-chlorosuccinimide, N-iodosuccinimide), bromine, chlorine, iodine, a dehydrogenation reaction using a noble metal catalyst, quinone,
Alternatively, it is advantageously performed with selenium dioxide or the like. When N-halogenosuccinimide is used, the reaction is usually carried out in an inert solvent (eg, chloroform, dichloromethane, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane, carbon tetrachloride or a mixture thereof). 50 ° C to 150 ° C in the presence of a radical reaction initiator such as benzoyl peroxide
Done in The reaction time is 1 to 50 hours, and the amount of N-halogenosuccinimide used is 1.0 to 1.5 mol, preferably 1.0 to 1.2 mol, per 1 mol of compound (I ''). . The amount of the radical initiator such as benzoyl peroxide to be used is 0.01 to 0.3 mol, preferably 0.05 to 0.2 mol, per 1 mol of compound (I ''). Bromine, chlorine,
When using iodine or the like, this reaction is usually performed in an inert solvent (e.g.,
Chloroform, dichloromethane, 1,2-dichloroethane,
1,1,2,2-tetrachloroethane, carbon tetrachloride or a mixture thereof), and the amount of bromine, chlorine or iodine used is 1.0 to 1.0 with respect to 1 mol of the compound (I '').
It is 5 moles, preferably 1.0-1.2 moles. The reaction temperature is 0 to 120 ° C, preferably 20 to 80 ° C, and the reaction time is 30 minutes to 10 hours. Palladium (Pd) or platinum (Pt) is mainly used as a noble metal catalyst for the dehydrogenation reaction,
As quinones, chloranil, tetrachloro-o-benzoquinone, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone and the like are used.

Step 4 In this method, the compound (I ") or (I"")
A phenol derivative is produced by removing a hydroxyl group substituent from a compound in which the ring and / or ring B substituent is a substituted hydroxyl group. For the conversion from the alkyloxy derivative to the phenol derivative, it is preferable to use boron tribromide or boron trichloride. This reaction was carried out using carbon tetrachloride, chloroform, dichloromethane, 1,2-dichloroethane,
In an inert solvent such as 1,2,2-tetrachloroethane,
The reaction is performed at 50 to 40 ° C, preferably -20 to 30 ° C. It is preferable to use boron tribromide or boron trichloride in an excessive amount based on (I ") or (I"").

The naphthalene derivative thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like. Next, the production method of compound (I) will be specifically described with reference to Reference Examples and Examples, but these examples do not limit the scope of the present invention.

[0022]

REFERENCE EXAMPLES AND EXAMPLES Reference Example 1 3,4-Dimethoxycinnamic alcohol (2.14 g), 4-ethoxyphenylpropiolic acid (2.09 g), p-toluenesulfonic acid (pTsOH.H ₂ O) (0.11 g) ) To pyridine
(28 ml), a solution of N , N -dicyclohexylcarbodiimide (DCC) (2.50 g) in pyridine (9 ml) was added, and the mixture was stirred at room temperature for 3 hours. Acetic acid (12 ml) was added, and 0 ° C
After stirring for 2 hours, the insoluble material is removed by filtration and
(30 ml). Water (100 ml) was added to the filtrate, acidified with concentrated hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, a saturated aqueous solution of sodium hydrogen carbonate and water in that order, and dried (MgSO ₄ ). The solvent was distilled off, and the residue was subjected to silica gel column chromatography.
From the fraction eluted with hexane (1: 5, v / v), 3,4-dimethoxycinnamyl ester of 4-ethoxyphenylpropiolic acid (2.20 g, 54.6%) was obtained. NMR (δ ppm
in CDCl ₃ ): 1.40 (3H, t, J = 7Hz), 3.86 (3H, s), 3.88 (3H
H, s), 4.04 (2H, q, J = 7Hz), 4.85 (2H, d, J = 6Hz), 6.19 (1H,
dt, J = 16 and 6Hz), 6.67 (1H, d, J = 16Hz), 6.85 (2H, d, J = 9
Hz), 6.84-6.97 (3H, m), 7.52 (2H, d, J = 9Hz)

Reference Examples 2 to 32 [Tables 1 and 2] The compounds of Reference Examples 2 to 32 were obtained in the same manner as in Reference Example 1.

Reference Example 33 Phenylpropiolic acid (2.05 g) was dissolved in tetrahydrofuran (10 ml), and oxalyl chloride (2.13) was dissolved.
g) and N, N-dimethylformamide (DMF, 1 drop) were added, and the mixture was stirred at room temperature for 1.5 hours. Concentrate under reduced pressure and dissolve the remaining oil in benzene (50 ml). 3,4-Dimethoxycinnamic alcohol (2.72) was added to the benzene solution.
g) and pyridine (1.3 ml) were added and heated under reflux for 40 minutes. The reaction mixture was allowed to cool, washed with water, 2N HCl, saturated aqueous sodium hydrogen carbonate and water in that order, and dried (MgS
O ₄ ). The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography. From a portion eluted with ethyl acetate-hexane (1: 6, v / v), phenylpropiolic acid 3,4-dimethoxycinnamyl ester ( 3.13g,
(69.4%) of an oil. NMR (δ ppm in CDCl
₃ ): 3.88 (3H, s), 3.90 (3H, s), 4.88 (2H, d, J = 6Hz), 6.19
(1H, dt, J = 16 and 6Hz), 6.67 (1H, d, J = 16Hz), 6.86-7.00
(3H, m), 7.33-7.75 (5H, m)

Reference Examples 34 to 38 [Table 2] The compounds of Reference Examples 34 to 38 were obtained in the same manner as in Reference Example 1.

Example 1 320 L of dichloromethane was added to 40 kg of powder obtained by pulverizing a dried product of whole plant of Foxgamma, extracted at room temperature for 1 day, and filtered. 320 L of dichloromethane was added to the residue again, and the mixture was extracted at room temperature for 1 day, and then filtered. The filtrates were combined, and dichloromethane was distilled off to obtain 1176 g of an extract. Add 10 liters of 60% acetone to this extract,
After the suspension, the mixture was refluxed for 2 hours. After cooling, the suspension was filtered and the filtrate was concentrated to give 176 g of a brown syrup. This product is converted to silica gel (Silica gel 60; Merck,
(West Germany) Chromatography by column (6.5 × 107 cm), eluting with dichloromethane, while confirming by TLC and HPLC, gave 90 g of a fraction containing justicidin and diffiline. This fraction was subjected to reverse phase silica gel (Y
MC-ODS; Yamamura Chemical Laboratory) column (8 × 107c)
m) Chromatography, elution with a 60% acetonitrile aqueous solution, fractionation of justicidin B
31.6 g of (Fr.1) and 58.4 g of a fraction (Fr.2) containing jascidin A as a main component were obtained. Silica gel and reversed-phase silica gel column chromatography were repeated for each fraction, and 2.42 g of justicidin B from Fr.
8.66 g of jasticidin A was obtained from Fr. Next, unnecessary fractions obtained in the process of producing jausticidin A and B were searched by TLC and HPLC, fractions containing lignan substances were combined, and silica gel and reverse phase silica gel column chromatography were repeated three times. 2.64 g of justicidin C, 127 m of justicidin D
g, justicidin G 26mg, justicidin H 11
0 mg and diffiline 134 mg were obtained. Jausticidin G: recrystallized from ethanol to give colorless plate-like crystals. Mp 283-285 ° C. Elemental analysis _{(C 22 H 18 O 8)} :. Calcd C, 64.39; H, 4.42 Found C, 62.24; H, 4.51 UV absorption maximum (ethanol) 228, 259, 307, 353nm infrared absorption Spectrum (KBr) 3300, 1770, 1620, 159
5, 1500, 1260, 1210 cm ^-1 . Justicidin H: recrystallized from ethanol to give pale yellow plate-like crystals. Mp 287-290 ° C. Elemental analysis _{(C 21 H 16 O 7)} : Calculated: C, 66.31; H, 4.24 Found: C, 66.50; H, 4.25 UV absorption maximum (ethanol) 223, 256, 308, 350nm . Infrared absorption spectrum (KBr) 3300, 1730, 1620, 159
2, 1502, 1260, 1220cm ^-1 .

Example 2 4-ethoxyphenylpropiolic acid 3,4-dimethoxycinnamyl ester (2.13 g) in acetic anhydride (40 ml)
The solution was heated under reflux for 14 hours. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography. 1- (4-ethoxyphenyl) -3,4-dihydro-3-hydroxymethyl-6,7-dimethoxynaphthalene-2-carboxylic acid lactone from the part eluted with ethyl acetate-hexane (1: 2, v / v) (0.97 g, 45.5
%). Recrystallization from ethyl acetate gave colorless prism crystals. 190-191 ° C. Elemental analysis C ₂₂ H ₂₂ O ₅ Calculated: C, 72.12; H, 6.05 Found: C, 71.74; H, 6.00

Examples 3 to 34 The compounds of Tables 3 to 5 were obtained in the same manner as in Example 2.

Example 35 1- (4-ethoxyphenyl) -3,4-dihydro-3-
Hydroxymethyl-6,7-dimethoxynaphthalene-2
-Carboxylic acid lactone (0.77 g), N -bromosuccinimide (NBS) (0.45 g), benzoyl peroxide (benzoyl peroxide)
A solution of the peroxide (0.061 g) in carbon tetrachloride (100 ml) was heated under reflux for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography. Lactone 1- (4-ethoxyphenyl) -3-hydroxymethyl-6,7-dimethoxynaphthalene-2-carboxylate was obtained from the portion eluted with ethyl acetate-hexane (1: 2, v / v). Recrystallization from ethyl acetate gave colorless prisms (0.24 g, 31.2%). 218-219 ° C. Elemental analysis C ₂₂ H ₂₀ O ₅ Calculated: C, 72.51; H, 5.53 Found: C, 72.40; H, 5.60

Examples 36 to 66, 72 to 76 [Tables 6 to 8]
6,72-76 compounds were obtained.

Examples 67 to 71 [Table 5] The compounds of Examples 67 to 71 were obtained in the same manner as in Example 2.

Example 77 1- (4-Chlorophenyl) -3-hydroxymethyl-
6,7-Dimethoxynaphthalene-2-carboxylic acid lactone (1.06 g) was dissolved in dichloromethane (100 ml), and boron tribromide (3.53N dichloromethane solution) was dissolved.
(3.40 ml) was added at room temperature. After stirring at room temperature for 2 hours, the reaction solution was poured into ice water (500 ml) and extracted with ethyl acetate. The organic layer was washed with water and dried (MgSO ₄ ). The solvent was distilled off, and the precipitated crystals were collected with isopropyl ether-hexane, washed and recrystallized from ethanol-chloroform to give 1- (4-chlorophenyl) -6,7-.
Dihydroxy-3-hydroxymethylnaphthalene-2-
The carboxylic acid lactone (0.51 g, 52%) was obtained as pale orange prism crystals. Melting point> 300 ° C Elemental analysis: C ₁₈ H ₁₁ O ₄ Cl Calculated: C, 66.17; H, 3.39 Found: C, 66.08; H, 3.33

[Table 1]

[Table 2] Note 1) NMR (δ ppm in CDCl ₃ ): 1.32 (6H, d, J = 6 Hz),
3.86 (3H, s), 3.88 (3H, s), 4.57 (1H, m), 4.85 (2H, d, J = 6H
z), 6.18 (1H, double d, J = 16 and 6Hz), 6.66 (1H, d, J = 16
Hz), 6.97 (1H, d, J = 9Hz), 6.82 (2H, d, J = 9Hz), 6.83 (1H, d
ouble d, J = 9 and 2Hz), 6.94 (1H, d, J = 2Hz), 7.50 (2H, d,
J = 9Hz). Note 2) NMR (δppm in CDCl ₃ ): 3.90 (12H, m), 4.87 (2
H, d, J = 7Hz), 6.21 (1H, double t, J = 16 and 6Hz), 6.70 (1
(H, d, J = 16Hz), 6.8-7.0 (4H, m), 7.10 (1H, d, J = 2Hz), 7.27
(1H, double d, J = 8and 2Hz). Note 3) NMR (δppm in CDCl ₃ ): 1.43 (6H, t, J = 7Hz),
3.87 (3H, s), 3.88 (3H, s), 4.06 (2H, q, J = 7Hz), 4.10 (2H, s
q, J = 7Hz), 4.85 (2H, d, J = 6Hz), 6.18 (1H, doublet, J = 16 a
nd 6Hz), 6.66 (1H, d, J = 16Hz), 6.79 (2H, d, J = 9Hz), 6.89
(1H, d, J = 2Hz), 6.90 (1H, double d, J = 9 and 2Hz), 7.06
(1H, d, J = 2 Hz), 7.18 (1 H, doubled, J = 9 and 2 Hz) .Note 4) NMR (δ ppm in CDCl ₃ ): 3.87 (3H, s), 3.88 (3
H, s), 4.25 (4H, s), 4.85 (2H, d, J = 6Hz), 6.19 (1H, double
t, J = 16 and 6Hz), 6.66 (1H, d, J = 15Hz), 6.77-7.13 (6H,
m). Note 5) NMR (δppm in CDCl ₃ ): 2.08 (2H, m), 2.90 (4
H, t, J = 7Hz), 4.88 (2H, double d, J = 7a
nd 1Hz), 6.27 (1H, double)
t, J = 16 and 7 Hz), 6.72 (1H,
d, J = 16 Hz), 7.16-7.19 (2H,
m), 7.30 (1H, s), 7.36 (2H,
d, J = 9 Hz), 7.53 (2H, d, J = 9H)
z).

[Table 3]

[Table 4]

[Table 5]

[Table 6]

[Table 7]

[Table 8] Next, the measurement method and results of the bone resorption inhibiting effect of compound (I) will be described.

[Bone resorption inhibitory action] The bone resorption inhibitory action was measured by the method of Royce [Journal of Clinical Investigation (J. Clin. In
vest.) 44 , 103-116 (1965)]. That is, one Sprague-Dawley rat on the 19th day of pregnancy
50 μC of ⁴⁵ Ca (calcium isotope, CaCl ₂ solution)
Inject subcutaneously, open the abdomen the next day, take out the fetal rat aseptically, dissect the left and right forearms (radius, ulna) of the fetal rat from the trunk under a dissecting microscope, and remove the connective tissue and cartilage as much as possible. A culture sample was used. Each bone was sliced into 0.6 ml of BGJ _b medium (Fitton-Jackson modificat
ion, [GIBCO Labora-tories (USA)] in bovine serum albumin (containing 2 mg / ml) at 37 ° C. for 24 hours, and then the compound was added at 10 μg / ml and 1 μg / ml. After further culturing for 2 days, the radioactivity of ⁴⁵ Ca in the medium and the radioactivity of ⁴⁵ Ca in the bone were measured, and ⁴⁵ C released from the bone into the medium according to the following formula.
The ratio (%) of a was determined.

(Equation 1) A group obtained by culturing bone obtained from a fetus of the same litter in the same manner without adding any compound for 2 days was used as a control group. The average value ± standard deviation of the values obtained from 5 bones in each group was determined, and the ratio (%) of this value to the value of the control group was determined, and the results are shown in [Table 9] and [Table 10].

[Table 9]

[0034]

[Table 10] As is clear from Table 9 and Table 10, compound (I) has a strong bone resorption inhibitory action.

The pharmacologically acceptable salts of compound (I) include, for example, alkali metal salts such as sodium salt, potassium salt and the like, which are produced by a usual method. The compound (I) in the present invention has an excellent inhibitory action on bone resorption. Therefore, compound (I) is a mammal (eg, mouse, rat, rabbit, dog, cat, cow, pig, human, etc.)
And used as a bone resorption inhibitor. When the present compound is administered to a human, the method of administration may be either oral or parenteral. Compositions for oral administration include solid or liquid dosage forms, specifically tablets
(Including sugar-coated tablets and film-coated tablets), pills, granules,
Powders, capsules (including soft capsules), syrups, emulsions, suspensions and the like. Such a composition contains a carrier or excipient which is produced by a method known per se and usually used in the field of pharmaceuticals. For example, carriers for tablets, excipients such as lactose, starch, sucrose,
And magnesium stearate. Compositions for parenteral administration include, for example, injections, suppositories and the like, and the injections include dosage forms such as subcutaneous injections, intradermal injections, and intramuscular injections. Such injections are prepared by a method known per se, that is, by suspending or emulsifying Compound (I) in a sterile aqueous or oily liquid usually used for injections. Aqueous solutions for injection include physiological saline and isotonic solutions, and may be used in combination with a suitable suspending agent, if necessary, such as sodium carboxymethyl cellulose or a nonionic surfactant. As the oily liquid, sesame oil, soybean oil and the like can be mentioned, and as a solubilizer, benzyl benzoate, benzyl alcohol and the like may be used in combination. The prepared injection is usually filled in a suitable ampoule. When compound (I) or a salt thereof is used as a bone resorption inhibitor, the daily dose for adults is estimated to be 1 to 500 mg, preferably 10 to 150 mg, for oral administration.

[0036] Of the above composition, (1), (2), (3) and (4) were mixed, water was added thereto, kneaded, dried at 40 ° C. under vacuum for 16 hours, crushed in a mortar, Granules were passed through a 16 mesh sieve. (6) was added to the granules and mixed, and a tablet of 200 mg per tablet was produced using a rotary tableting machine (manufactured by Kikusui Seisakusho).

[0037] Tablets were produced in the same manner as in Preparation Example 1 using (1), (2), (3), (4), (5) and (6) among the above compositions. This tablet
The acetone solution of (7) was film-coated with a Harcoater (Freund, West Germany) to produce enteric coated tablets of 210 mg per tablet.

[0038] Of the above composition, (1), (2), (3) and (4) were mixed, water was added to the mixture, kneaded, then vacuum dried at 40 ° C. for 16 hours, crushed in a mortar, and 16 mesh To obtain granules. The granules were filled into gelatin No. 3 capsules using a capsule filling machine (manufactured by Xanasea, Italy) to produce capsules.

[0039] Among the above compositions, (2), (3), (4), (5) and (6) are dissolved in about half of the above distilled water at 80 ° C. with stirring. The obtained solution is cooled to 40 ° C., and the compound of the present invention is dissolved in the solution. Next, distilled water for injection is added to the solution to adjust the final volume, and the solution is sterilized by sterile filtration using an appropriate filter paper to prepare an injection.

[0040]

The drug of the present invention has a strong bone resorption inhibiting action and acts directly on bone to improve bone metabolism. Therefore, the drug is expected to be used as a bone resorption inhibitor as a preventive or therapeutic drug for osteoporosis.

──────────────────────────────────────────────────の Continuation of the front page (51) Int.Cl. ⁷ Identification code FI C07D 407/04 C07D 407/04 (56) References Reference table Hei 4-503510 (JP, A) Chem. Pharm. Bull. , 34 (5), p. 2056-2060 (1986) (58) Fields investigated (Int. Cl. ⁷ , DB name) A61K 31/365 A61K 35/78 C07D 307/92 C07D 407/04 CA (STN) REGISTRY (STN)

Claims (6)

(57) [Claims] 1. A compound of the general formula [In the formula, A ring and B ring may be substituted, R represents a hydrogen atom, a hydroxyl group or an alkoxy group which may be substituted, and a portion containing a broken line represents a carbon-carbon single bond or a double bond. ] A bone resorption inhibitor comprising a naphthalene derivative represented by the following formula: 2. A bone resorption inhibitor comprising a kitsunenomago or an extract of said plant. 3. A compound of the general formula [In the formula, ring B may be substituted, R ′ indicates that ring A is substituted with a halogen atom or an optionally substituted hydrocarbon residue, and a divalent hydrocarbon residue And a portion containing a broken line indicates a carbon-carbon single bond or a double bond], provided that the compound has the following structure: except for. ). 4. A compound of the general formula [In the formula, ring B may be substituted, R ′ indicates that ring A is substituted with an optionally substituted hydrocarbon residue, and a ring is formed with a divalent hydrocarbon residue. And the portion containing a broken line indicates a carbon-carbon single bond or a double bond]. 5. Justicidin G having the following structure: 6. Justicidin H having the following structure: