JPH0725810A - Indanone derivative - Google Patents

Abstract

PURPOSE:To provide a new indanone derivative having an action to enhance the contents of calcium and phosphorus in human osteoblasts and useful as an osteogenesis-stimulating agent. CONSTITUTION:An indanone derivative of formula I [R<1> is (substituted)phenyl; R<2> is (substituted) 1-10C hydrocarbon; R<3> is OH, group of formula II (R<4> to R<6> are 1-7C hydrocarbon), -OR<7> (R<7> forms an acetal bond together with the O atom bonded to R<7>); the steric configuration of the double bond related with R<1> is E-configuration or Z-configuration], e.g. 2-(4-methoxycarbonylbenzylidene)-3-(4-phenoxybutyl)-1-indanone. The indanone derivative of formula III is also new, and useful as an intermediate for synthesizing the compound of formula I. The compound of formula I, e.g. a compound of formula IV (R<3> is OH), is obtained by reacting 1,3-indanedione with a Grignard reagent, subjecting the produced new compound of formula V to a TMS reaction, reacting the reaction product with an aldehyde of formula: R<1>CHO, and finally reacting the reaction product with tetrabutylammonium fluoride.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a novel physiologically active indanone derivative. More specifically, it relates to an indanone derivative having an excellent bone formation promoting action.

[0002]

2. Description of the Related Art Normally, it is said that bone metabolism in a healthy person is established by a well-balanced repetition of bone resorption by osteoclasts and bone formation by osteoblasts. , It is considered to be a disease such as osteoporosis and osteomalacia.

As therapeutic agents for such bone diseases, active vitamin D ₃ preparations, calcitonin preparations, diphosphone preparations, estrogen preparations, calcium preparations and the like are often used. It is reported that many of these preparations exert their effects mainly by suppressing bone resorption. In contrast,
At present, few compounds have been known to have a clear effect of promoting bone formation.

Since it is expected that senile osteoporosis with decreased bone turnover will increase from postmenopausal osteoporosis with activated osteoblasts, it will act on osteoblasts and activate bone turnover. There is a strong need for substances that promote bone formation by doing so.

Koshihara et al., The Japanese Biochemical Society (1988 abstract)
Prostaglandin D in p767) ₂Of human osteoblasts
I found that it has a calcification effect. This is Prostag
Rundin D₂Was disassembled¹²Δ-Prostaglandin J₂
Was suggested to have acted. In addition, the present inventors
No. 1-13036, 4-hydroxy-2-siku
Clarification that lopentenones have osteogenesis promoting action
did. The present inventors have also published European Patent Publication No. 338796.
And in International Publication No. WO 91/05766 2-
Substituted-4-hydroxy-2-cyclopentenones are bone-shaped
It is disclosed that it has a growth promoting action.

[0006]

An object of the present invention is to provide a novel indanone derivative having an osteogenesis promoting action.

[0007]

Means for Solving the Problems As a result of intensive studies, the present inventors were able to obtain an indanone derivative having a similar osteogenesis promoting action in addition to the above prostaglandin compound, and completed the present invention. did. The present invention will be described in more detail below.

That is, the present invention provides the following formula [I]:

[0009]

[Chemical 4]

[In the formula, R ¹ represents a substituted or unsubstituted phenyl group; R ² is a substituted or unsubstituted C 1-10 carbon atom.
Represents a hydrocarbon group; R ³ is a hydroxyl group,

[0011]

[Chemical 5]

(Here, R ⁴ , R ⁵ and R ⁶ are the same or different and each represents a hydrocarbon group having 1 to 7 carbon atoms.)
Or —OR ⁷ (wherein R ⁷ represents a group that forms an acetal bond together with the oxygen atom to which R ⁷ is bonded). The configuration about the double bond involving the carbon atom to which R ¹ is bonded is E configuration or Z
Arrangement. ] It is an indanone derivative represented by.

Furthermore, the present invention provides the following formula [II]

[0014]

[Chemical 6]

[In the formula, R ² and R ³ are the same as defined in the above formula [I]. ] The indanone derivative represented by these is also included.

In the above formula [I], when R ¹ is a substituted phenyl group, the substituent on the phenyl group may be one or more of the following substituents.

(I) halogen atom; (ii) substituted or
Unsubstituted hydrocarbon group having 1 to 10 carbon atoms; (iii) -CO
OR⁸Group (R⁸Is a hydrogen atom or a hydrocarbon having 1 to 6 carbon atoms
Carboxyl group or alkoxycarl represented by
Bonyl group; (iv) -NR⁹R ^Ten(R⁹, R^TenIs the same
Differently, a hydrogen atom or a hydrocarbon having 1 to 6 carbon atoms
Represents a group. ) An amino group represented by the formula; (v) -OR¹¹(R
¹¹Is an alkoxy represented by a hydrocarbon group having 1 to 6 carbon atoms)
Group; (vi) trifluoromethyl group, cyano group, tetrazo
Ryryl group, nitro group, hydroxy group, etc.
Wear.

As an example of the halogen atom of (i), chlorine,
Examples thereof include bromine and fluorine atoms. Examples of the hydrocarbon group having 1 to 10 carbon atoms represented by (ii) include, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl,
Isopentyl, neopentyl, t-pentyl, hexyl, heptyl, octyl, 3,7-dimethyloctyl,
Alkyl groups such as nonyl and decyl; 2-propenyl, 2-
Butenyl, 3-butenyl, 2-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 5-hexenyl, 2-methyl-2-propenyl (methallyl), 3,7
-Dimethyl-6-octenyl (citronenyl), 3,7
Examples include alkenyl groups having 3 to 10 carbon atoms such as dimethyl-2,6-octadienyl (geranyl) group. Of these, an alkyl group having 1 to 4 carbon atoms is preferable.

Further, those having a substituent such as the above-mentioned substituents (i), (iii), (iv), (v) and (vi) and an oxo group on these hydrocarbon groups are also included. Can be mentioned.

When R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ shown in the above (iii), (iv) and (v) represent a hydrocarbon group having 1 to 6 carbon atoms, for example, methyl and ethyl. , Propyl,
Isopropyl, butyl, isobutyl, sec-butyl, t-
Butyl, pentyl, isopentyl, neopentyl, t-
Examples thereof include alkyl groups such as pentyl and hexyl groups, cycloalkyl groups such as cyclopropyl, cyclopentyl and cyclohexyl groups, and phenyl groups. Of these, an alkyl group having 1 to 4 carbon atoms is preferable, and a methyl group is particularly preferable.

In the above formula [I] or formula [II], R
^{When 2} represents a hydrocarbon group having 1 to 10 carbon atoms, the following groups can be mentioned.

Methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, isopentyl, neopentyl, t-pentyl,
Alkyl groups such as hexyl, heptyl, octyl, 3,7-dimethyloctyl, nonyl, decyl; 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 4
-Pentenyl, 2-hexenyl, 3-hexenyl, 5-
Alkenyl having 3 to 10 carbon atoms such as hexenyl, 2-methyl-2-propenyl (methallyl), 3,7-dimethyl-6-octenyl (citronenyl), 3,7-dimethyl-2,6-octadienyl (geranyl) group A group etc. can be mentioned. Particularly, an alkyl group having 1 to 6 carbon atoms is preferable.

Furthermore, R ² is substituted and has 1 to 10 carbon atoms.
Examples of the substituent in the case of the hydrocarbon group are the substituents represented by the above-mentioned (i), (iii), (iv), (v) and (vi), an oxo group and the like. . For example, a phenoxy group can be mentioned as a preferable one.

In the above formula [I] or formula [II], R
^{Based on 3} :

[0025]

[Chemical 7]

(Here, R ⁴ , R ⁵ and R ⁶ are the same or different and each represents a hydrocarbon group having 1 to 7 carbon atoms.)
In the case where is represented, preferred examples thereof include trimethylsilyloxy, triethylsilyloxy, t-butyldimethylsilyloxy, t-butyldiphenylsilyloxy and tribenzylsilyloxy groups. Of these, trimethylsilyloxy and t-butyldimethylsilyloxy groups are preferable. When R ³ represents —OR ⁷ (wherein R ⁷ represents a group that forms an acetal bond together with the oxygen atom to which R ⁷ is bonded), examples thereof include methoxymethyloxy and 1-ethoxyethyloxy. ,
Examples thereof include 1-methoxy-1-methylethyloxy, 1-ethoxy-1-methylethyloxy, 2-methoxyethoxymethyloxy and tetrahydropyran-2-yloxy groups. These groups can function as a hydroxyl-protecting group.

In the above formula [I] or [II], R ²
And R ³ are different from each other and the carbon atom to which these substituents are bonded is an asymmetric carbon, the steric configuration on the carbon in the compound of the present invention is either R configuration or S configuration. Alternatively, both may be mixed at an arbitrary ratio.

Specific examples of the indanone derivative of the present invention include the following compounds. (1) 3-hydroxy-3-phenoxybutyl-1-indanone (2) 3-hydroxy-3-butyl-1-indanone (3) 3-hydroxy-3-methyl-1-indanone (4) 3-hydroxy- 3-phenoxybutyl-2-
[(E) -4-Methoxycarbonylbenzylidene] -1
-Indanone (5) 3-Hydroxy-3-phenoxybutyl-2-
[(E) -4-Dimethylaminobenzylidene] -1-indanone (6) 3-Hydroxy-3-phenoxybutyl-2-
(E) -Benzylidene-1-indanone (7) 3-Hydroxy-3-phenoxybutyl-2-
[(E) -4-Methoxybenzylidene] -1-indanone (8) 3-Hydroxy-3-methyl-2-[(E) -4
-Methoxycarbonylbenzylidene] -1-indanone (9) 3-hydroxy-3-methyl-2-[(E) -4
-Dimethylaminobenzylidene] -1-indanone (10) 3-hydroxy-3-methyl-2- (E) -benzylidene-1-indanone (11) 3-hydroxy-3-methyl-2-[(E)-
4-Methoxybenzylidene] -1-indanone (12) 3-hydroxy-3-methyl-2-[(Z)-
4-Methoxycarbonylbenzylidene] -1-indanone (13) 3-hydroxy-3-methyl-2-[(Z)-
4-Dimethylaminobenzylidene] -1-indanone (14) 3-hydroxy-3-methyl-2- (Z) -benzylidene-1-indanone (15) 3-hydroxy-3-methyl-2-[(Z)-
4-Methoxybenzylidene] -1-indanone (16) 3-Hydroxy-3-phenoxybutyl-2-
[(Z) -4-Methoxycarbonylbenzylidene] -1
-Indanone (17) 3-Hydroxy-3-phenoxybutyl-2-
[(Z) -4-Dimethylaminobenzylidene] -1-indanone (18) 3-Hydroxy-3-phenoxybutyl-2-
(Z) -Benzylidene-1-indanone (19) 3-Hydroxy-3-phenoxybutyl-2-
[(Z) -4-Methoxybenzylidene] -1-indanone (20) 3- (4-phenoxybutyl) -3-trimethylsilyloxy-1-indanone (21) 2- (4-methoxycarbonylbenzylidene)
Examples thereof include, but are not limited to, 3--3- (4-phenoxybutyl) -3-trimethylsilyloxy-1-indanone.

The indanone derivative of the present invention can be synthesized, for example, by the following route.

[0030]

[Chemical 8]

This synthesis method will be described in more detail in Examples.

[0032]

The present invention will be described in more detail below with reference to examples, but the scope of the present invention is not limited to these examples.

[0033]

Reference Example 1 Synthesis of 2- (4-methoxycarbonylbenzylidene) -1-indanone

[0034]

[Chemical 9]

1-indanone 1 in a 30 mL 2-neck reaction vessel
49 mg (1.12 mmol) was put, it melt | dissolved in 2 mL of dry tetrahydrofuran, and it cooled at -20 degreeC. Zirconium tetra-t-butoxide (0.25 M tetrahydrofuran solution) (9.0 mL, 2.25 mmol) was added little by little, and the mixture was stirred at -20 ° C for 1 hr. 4-methoxycarbonylbenzaldehyde 276 mg (1.68 mmo
2 mL of a dry tetrahydrofuran solution of 1) was added little by little, and the reaction was carried out at −20 ° C. at room temperature for 24 hours.

A saturated ammonium chloride aqueous solution was added in an ice bath, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride solution and saturated brine, and dried over anhydrous magnesium sulfate. After concentration of the solvent, hexane: ethyl acetate (8 /
By recrystallizing from 2), 86 mg of the title compound was obtained.
(Yield 28%) ¹ H-NMR (CDCl ₃ , TMS) δ / ppm 8.12 (d, 2H, J = 8.6 Hz, ArH), 7.
93 (d, 1H, J = 7.3 Hz, ArH), 7.74
(D, 2H, J = 8.6 Hz, ArH), 7.70
(T, 1H, J = 2.0 Hz, = CH-), 7.66
(D, 1H, J = 7.9 Hz, ArH), 7.59 (d
d, 1H, J = 7.3 Hz, 7.6 Hz, ArH),
7.45 (dd, 1H, J = 7.9 Hz, 7.6 Hz,
ArH), 4.09 (d, 2H , -CH 2 -), 3.9
6 (s, 3H, COOMe).

[0037]

[Reference Example 2] Synthesis of 2- (4-dimethylaminobenzylidene) -1-indane

[0038]

[Chemical 10]

1-indanone 4 in a 50 mL 2-neck reaction vessel
46 mg (3.37 mmol) was added, dissolved in 5 mL of dry tetrahydrofuran and cooled to 0 ° C. 27.0 mL (6.75 mmol) of zirconium tetra-t-butoxide (0.25 M tetrahydrofuran solution) was added little by little, and the mixture was stirred at 0 ° C. for 0.5 hours. A solution of 755 mg (5.06 mmol) of 4-dimethylaminobenzaldehyde in 7 mL of dry tetrahydrofuran was added little by little to 0.
The reaction was carried out at 0 ° C for 3.5 hours.

The reaction mixture was poured into a saturated aqueous ammonium chloride solution containing ice, and the deposited precipitate was removed by filtration and washed with methylene chloride. The organic layer was washed with water, dried, and the solvent was concentrated to precipitate crystals. This was recrystallized from methanol to obtain 226 mg of the title compound. (Yield 25%)
Yellowish brown scaly melting point 164.6-165.1 ° C.

¹ H-NMR (CDCl ₃ , TMS) δ /
ppm 7.90 (d, 1H, J = 7.3 Hz, ArH), 7.
53 to 7.66 (m, 5H, ArH), 7.38 to 7.
44 (m, 1H, ArH), 6.75 (d, 2H, J =
8.9 Hz, ArH), 4.01 (d, 2H, J = 1.
_{3Hz, -CH 2 -), 3.06} (s, 6H, NM
e ₂ ). GC-MSD (EI-Mass) m / z = 263
(M ⁺ )

[0042]

Example 1 3-Hydroxy-3- (4-phenoxybutyl) -1-
Indanone synthesis

[0043]

[Chemical 11]

2.31 g (95.0 mmol) of magnesium was placed in a 500-mL three-neck reaction vessel (Ar substitution), and 19.6 g of 4-phenoxybutyl bromide was added to the dropping funnel.
A solution of (85.5 mmol) in 200 mL of dry ether is added. The solution was added dropwise in a small amount so that the magnesium was immersed therein, and the mixture was warmed slightly. Then, the remaining solution was added dropwise until the ether was refluxed moderately. After the dropping, the mixture was refluxed for 1.5 hours to be sufficiently reacted to prepare a Grignard reagent.

1,3-in a 1 L 3-neck reaction vessel (Ar substitution)
Indandione (5.00 g, 34.2 mmol) was added, dry ether (70 mL) and dry tetrahydrofuran (5) were added.
It was dissolved in 0 mL. The mixture was cooled in an ice bath, the Grignard reagent prepared was added via a cannula, and the mixture was stirred at room temperature for 2 hours.
Reacted for hours.

The reaction mixture was sufficiently cooled in an ice bath, water was added thereto, and an aqueous solution of potassium hydrogen sulfate was further added to acidify the solution. The product was extracted with ether, the organic layer was washed with aqueous potassium hydrogen sulfate solution, water, and dried over anhydrous magnesium sulfate. After evaporating the solvent, the desired product was separated and purified by column chromatography and recrystallized from a hexane: ethyl acetate mixed solvent to obtain 6.70 g of the title compound. (Yield 66%) Light green brown granular crystal melting point 88.3-8
8.8 ° C.

¹ H-NMR (CDCl ₃ , TMS) δ /
ppm 7.61 to 7.70 (m, 3H, ArH), 7.45
(Ddd, 1H, J = 7.6Hz, 5.9Hz, 2.3
Hz, ArH), 7.25 (dd, 2H, J = 8.6H)
z, 7.3 Hz, ArH), 6.92 (dt, 1H, J
= 7.3 Hz, 1.0 Hz), 6.84 (dd, 2H,
J = 8.6 Hz, 1.0 Hz), 3.91 (t, 2H,
_{J = 6.6Hz, -OCH 2 -)} , 2.93 (d, 1
H, J = 18.8 Hz, -C (= O) CH-), 2.7
5 (d, 1H, J = 18.8Hz, -C (= O) CH
-), 2.62 (s, 1H, -OH), 2.08 (dd
d, 1H, J = 13.5Hz, 11.9Hz, 4.6H
z, -OCC (H) C-), 1.89 (ddd, 1H,
J = 13.5Hz, 11.9Hz, 4.6Hz, -OC
C (H) C-), 1.67 to 1.82 (m, 2H, -C
H _2- ), 1.51 to 1.66 (m, 1H, -CH
-), 1.23 to 1.49 (m, 1H, -CH-). GC-MSD (EI-Mass) m / z = 296
(M ⁺ )

[0048]

Example 2 Synthesis of 3- (4-phenoxybutyl) -3-trimethylsilyloxy-1-indanone

[0049]

[Chemical 12]

3-hydroxy-3- (4-phenoxybutyl) -1-indanone 3.00 g (10.12 mmo)
l) was dissolved in 30 mL of DMF, 1.72 g (25.3 mmol) of imidazole and 3.21 mL (25.3 mmol) of chlorotrimethylsilane were added in an ice bath, and the mixture was reacted at room temperature for 13 hours. After the reaction, the product was extracted with ethyl acetate, and the organic layer was washed with a saturated sodium hydrogen carbonate aqueous solution and a saturated sodium chloride aqueous solution in that order and dried. After the solvent was distilled off, the residue was purified by column chromatography (developing solution; hexane: ethyl acetate = 8: 2) to obtain 2.23 g of the title compound. (Yield 60%) ¹ H-NMR (CDCl ₃ , TMS) δ / ppm 7.72 (d, 1H, J = 7.6 Hz, ArH), 7.
60 to 7.66 (m, 2H, ArH), 7.42 to 7.
48 (m, 1H, ArH), 7.26 (dd, 2H, J
= 7.9 Hz, 7.3 Hz, ArH), 6.93 (t,
1H, J = 7.3 Hz, ArH), 6.86 (d, 2
H, J = 7.9 Hz, ArH), 3.92 (t, 2H,
_{J = 6.6Hz, -OCH 2 -)} , 2.92 (d, 1
H, J = 18.8 Hz, -C (= O) CH-), 2.8
6 (d, 1H, J = 18.8Hz, -C (= O) CH
-), 2.05 (ddd, 1H, J = 13.2Hz, 1
2.2 Hz, 4.6 Hz, -OCC (H) C-), 1.
86 (ddd, 1H, J = 13.2Hz, 12.2H
z, 4.6 Hz, -OCC (H) C-), 1.66 ~
_{1.79 (m, 2H, -CH 2} -), 1.46~1.5
4 (m, 1H, -CH-), 1.36 to 1.18 (m,
1H, -CH-), -0.06 (s, 9H, SiM
e). GC-MSD (EI-Mass) m / z = 368
(M ⁺ )

[0051]

Example 3 2- (4-Methoxycarbonylbenzylidene) -3-
Synthesis of (4-phenoxybutyl) -3-trimethylsilyloxy-1-indanone

[0052]

[Chemical 13]

413 mg (1.12 mmol) of 3- (4-phenoxybutyl) -3-trimethylsilyloxy-1-indanone was placed in a 30 mL 2-neck reaction vessel, dissolved in 2 mL of dry tetrahydrofuran and cooled to -20 ° C. Zirconium tetra-t-butoxide (0.25M
Tetrahydrofuran solution) 9.0 mL (2.25 mmo
1) was added little by little, and the mixture was stirred at -20 ° C for 1 hour. 4-
Methoxycarbonylbenzaldehyde 276 mg (1.
A solution of 68 mmol) in 2 mL of dry tetrahydrofuran was added little by little, and the mixture was reacted at −20 ° C. at room temperature for 24 hours.

A saturated ammonium chloride aqueous solution was added in an ice bath, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride solution and saturated brine, and dried over anhydrous magnesium sulfate. After the solvent was concentrated, the title compound (307 mg) was obtained by separating and purifying with a column chromatograph. (Yield 5
3%) ¹ H-NMR (CDCl ₃ , TMS) δ / ppm 8.31 (d, 2H, J = 8.6 Hz, ArH), 8.
23 (d, 2H, J = 8.6 Hz, ArH), 8.05
(D, 1H, J = 7.6 Hz, ArH), 7.91
(S, 1H, = CH), 7.85 to 7.87 (m, 2
H, ArH), 7.66 to 7.72 (m, 1H, Ar
H), 7.33 (dd, 2H, J = 8.6Hz, 7.6)
Hz, ArH), 7.02 (t, 1H, J = 7.6H
z, ArH), 6.80 (d, 2H, J = 8.6 Hz,
ArH), 4.10 (s, 3H, COOMe), 3.6
_{7~3.81 (m, 2H, -OCH 2} -), 2.67
(Ddd, 1H, J = 12.9Hz, 12.5Hz,
4.6 Hz, SiOCC (H) C-), 2.40 (dd
d, 1H, J = 12.9Hz, 12.5Hz, 4.6H
z, SiOCC (H) C-), 1.54 to 1.71
(M, 2H, —CH ₂ —), 1.01 to 1.17 (m,
1H, -CH-), 0.89 to 1.01 (m, 1H,-
CH-), -0.07 (s, 9H, SiMe). GC-MSD (EI-Mass) m / z = 514
(M ⁺ )

[0055]

Example 4 Synthesis of 2- (4-methoxycarbonylbenzylidene) -3-hydroxy-3- (4-phenoxybutyl) -1-indanone

[0056]

[Chemical 14]

2- (4-Methoxycarbonylbenzylidene) -3- (4-phenoxybutyl) -3-trimethylsilyloxy-1-indanone 307 mg (0.6 mm
sol) in a Teflon container, and tetrabutylammonium fluoride trihydrate 282 mg (0.89
mmol) was added, and the mixture was reacted at room temperature for 3.5 hours. The reaction mixture was poured into saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The organic layer was concentrated to give a yellow solid, which was recrystallized from hexane: ethyl acetate (about 7: 3) to give the title compound 2- (4-methoxycarbonylbenzylidene) -3-hydroxy-3- (4 —Phenoxybutyl) -1-indanone (178 mg, yield 68%) was obtained. Melting point 152.6-152.9 ° C. ¹ H-NMR (CDCl ₃ , TMS) δ / ppm 8.12 (d, 2H, J = 8.6 Hz, ArH), 8.
07 (d, 2H, J = 8.6 Hz, ArH), 7.87
(D, 1H, J = 7.6 Hz, ArH), 7.73-
7.76 (m, 3H, ArH), 6.66 (d, 2H,
J = 7.3 Hz, ArH), 3.95 (s, 3H, CO
OMe), 3.63 (ddd, 1H, J = 18.3H
z, 7.8 Hz, 6.3 Hz, -OCH-), 3.58
(Ddd, 1H, J = 18.3 Hz, 7.8 Hz, 6.
6Hz, -OCH-), 2.57 (s, 1H, OH),
2.42 (ddd, 1H, J = 12.5Hz, 12.2
Hz, 4.6 Hz, -OCCH), 2.20 (ddd,
1H, J = 13.2Hz, 12.2Hz, 5.0Hz,
-OCCH), 1.40 to 1.56 (m, 2H, -CH
_2- ), 0.79 to 1.03 (m, 2H, -CH
₂ ―).

[0058]

Example 5 Synthesis of 2- (4-dimethylaminobenzylidene) -3-hydroxy-3- (4-phenoxybutyl) -1-indanone

[0059]

[Chemical 15]

2- (4) obtained by the same method as in Example 3
-Dimethylaminobenzylidene) -3- (4-phenoxybutyl) -3-trimethylsilyloxy-1-indanone 305 mg (0.61 mmol) in THF was placed in a Teflon container, and tetrabutylammonium fluoride trihydrate 282 mg (10 0.89 mmol) and added
The reaction was carried out at 0 ° C for 2 hours. The reaction solution was poured into water and extracted with dichloromethane. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The organic layer was concentrated, and 107 mg of the title compound was obtained by using a silica gel column chromatograph (developing solution: toluene-ethyl acetate). (41%) Further recrystallization from ethanol gave 65 mg of reddish brown granular crystals. (25%) Melting point 170.2 to 170.5 ° C. ¹ H-NMR (CDCl ₃ , TMS) δ / ppm 8.05 (d, 2H, J = 9.2 Hz, ArH), 7.
84 (d, 1H, J = 7.6Hz, ArH), 7.64
~ 7.74 (m, 3H, ArH), 7.46-7.52
(M, 1H, ArH), 7.19 (dd, 2H, J =
7.6 Hz, 7.3 Hz, ArH), 6.87 (td,
1H, J = 7.3 Hz, 1.0 Hz, ArH), 6.7
2 (d, 2H, J = 9.2 Hz, ArH), 6.69
(Dd, 2H, J = 7.6Hz, 1.0Hz, Ar
H), 3.66 (dd, 1H, J = 6.6 Hz, 6.6)
Hz, -OCH-), 3.64 (dd, 1H, J = 6.
6Hz, 6.6Hz, -OCH-), 3.07 (s, 6
_{H, NMe 2), 2.55~2.66 (} m, 1H, -O
CCH-), 2.36 (s, 1H, OH), 2.20 ~
2.31 (m, 1H, -OCCH-), 1.49-1.
_{59 (m, 2H, -CH 2} -), 0.94~1.06
(M, 1H, -CH-), 0.78-0.92 (m, 1
H, -CH-).

[0061]

[Example 6] Measurement of osteogenic action Human-derived osteoblast cell line containing α-ME containing 10% fetal bovine serum
After culturing in M and becoming confluent (passage number 1
8) A compound at a constant concentration was added in the presence of 2 mM α-glycerophosphate, and the culture was continued for 14 days. After washing the cell layer with physiological saline, calcium (Ca) and phosphorus (P) were extracted with 2N hydrochloric acid and quantified. For details of the method for obtaining a human-derived osteoblast cell line, its culture conditions, and the method for measuring Ca and P, see The Journal of Pharmacology and Experi.
mental Therapeutics, 258 , (3), 1991, p1
121 description. As a result, as shown in Table 1,
It was revealed that the compounds of the present invention promote calcification of human osteoblasts.

[0062]

[Table 1]

[0063]

INDUSTRIAL APPLICABILITY The indanone derivative of the present invention has an action of increasing the contents of calcium and phosphorus in human osteoblasts. Therefore, the present compound is a useful compound as an osteogenesis promoter and can be used for the treatment or prevention of osteoporosis, osteomalacia and the like.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Tomohiro Ohta 4-3-2 Asahigaoka, Hino-shi, Tokyo Inside Teijin Ltd. Tokyo Research Center (72) Inventor Atsio Uri 4-3.2 Asahigaoka, Hino-shi, Tokyo No. Teijin Limited Tokyo Research Center

Claims (4)

[Claims] 1. The following formula [I]: [Wherein R ¹ represents a substituted or unsubstituted phenyl group; R 1
² represents a substituted or unsubstituted hydrocarbon group having 1 to 10 carbon atoms; R ³ is a hydroxyl group; (Wherein R ^4, R ^5, R ⁶ are identical or respectively represent. A hydrocarbon group having 1 to 7 carbon atoms) groups represented by or -OR ⁷ (wherein R ^7, is binding R ⁷ Represents a group which forms an acetal bond together with the oxygen atom). The configuration for the double bond involving the carbon atom to which R ¹ is attached is the E or Z configuration. ] The indanone derivative represented by. 2. When R ¹ is a substituted phenyl group, the substituent on the phenyl group is -COOR ⁸ (wherein R ⁸ represents a hydrogen atom or a hydrocarbon group having 1 to 6 carbon atoms) or-.
The indanone derivative according to claim 1, which is NR ⁹ R ¹⁰ (wherein R ⁹ and R ¹⁰ are the same or different and each represents a hydrogen atom or a hydrocarbon group having 1 to 6 carbon atoms). 3. The following formula [II]: [In the formula, R ² and R ³ are the same as defined in the above formula [I]. ] The indanone derivative represented by. 4. R ³ is a phenoxybutyl group, R ³
Is an hydroxyl group, The indanone derivative according to claim 3.