JPH03130216A - Bone resorption inhibitory agent - Google Patents

Abstract

PURPOSE:To provide a preventive, therapeutic agent having high bone resorption-inhibitory effect, capable of improving bone metabolism through directly acting on the bone, thus to be used for preventing and curing osteoporosis, containing a specific benzene derivative. CONSTITUTION:The objective inhibitory agent containing a compound of formula I {R<1> is H, alkyl alkenyl or OH; R<2> and R<3> are each H or alkyl or, when adjacent to each other, (CH2)n ((n) is 1 or 2) through mutually linking; A is H or of formula II [R<4> is H, alkyl, OH or carboxyl; R<5> and R<6> are each H or OH or O(CH2)mO ((m) is 1 or 2) through mutually linking adjacent R<4> and R<5> or R<4> and R<6>]; X is CH2 or CO} [e.g. 6-(3,4,5-trimethoxybenzyl)-1,3-benzodioxol-5-ol]. The dose of the present compound, in the case of oral administration, is 1-500 (pref. <10-150)mg/day per adult.

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Field of Application) The present invention relates to a preventive and therapeutic agent for osteoporosis containing a benzene derivative having bone resorption inhibitory activity as an active ingredient.

(Prior Art) Osteoporosis is a pathological condition or disease in which the quantitative loss of bone exceeds a certain level, causing some symptoms or dangers. The main symptoms are vertebral kyphosis, fractures of the lumbar spine, vertebral body, femoral neck, lower end of the radius, ribs, upper end of the humerus, etc. The causes are diverse, including endocrine and nutritional disorders. Conventionally, therapeutic agents such as estrogen agents, calcitonin, vitamin D, and calcium agents have been administered.

(Problems to be Solved by the Invention) However, when administering the above-mentioned therapeutic agents, the subjects to be administered may be limited or the effects may be uncertain, so that sufficient effects are not obtained.

(Means for Solving the Problems) As a result of intensive research aimed at developing a more general drug that directly acts on bones to suppress bone resorption, the present inventors found that the following general formula (I We have completed the present invention by discovering that the benzene derivative represented by ) acts directly on bones and exhibits an excellent bone resorption inhibitory effect.

That is, the present invention provides the following formula: different hydrogen or an optionally substituted alkyl group, or when R20 and R''0 are adjacent, R2 and R3 are connected to each other and the formula -(OH2)n-C where n is 1 or 2 A is hydrogen or a group represented by the formula (R4 is hydrogen, an optionally substituted alkyl group, an optionally substituted hydroxyl group, or an esterified or amidated group). a carboxyl group which may be substituted, Rs and R6 are the same or different and represent hydrogen or an optionally substituted hydroxyl group, or adjacent R4 and R6 or R4 and R6 are connected to each other to form a formula -〇- (OH2)n
o C In the formula, m represents 1 or 2], and X represents -CH2- or -CO-. ) is shown. The present invention relates to a bone resorption inhibiting composition containing a benzene derivative represented by the following.

The alkyl group of the optionally substituted alkyl group represented by R1 may be linear, branched, or cyclic having 1 to 10 carbon atoms (for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, 5ec-butyl, t
ert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl,
Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

The alkenyl group of the optionally substituted alkenyl group represented by R1 includes linear, branched, and carbon atoms having 2 to 10 carbon atoms;
It may be cyclic, for example allyl (all'/l)
, vinyl, crotyl, 2-penten-1-yl, 3-penten-1-yl, 2-hexen-1-yl, 3-hexen-1-yl, 2-cyclohexenyl, 2-cyclopentenyl, 2- Methyl-2-propen-1-yl, 3-
Examples include methyl-2-buten-1-yl.

The optionally substituted hydroxyl group represented by R1 is:
Examples include alkoxy, alkenyloxy, aralkyloxy, acyloxy, and aryloxy having a hydroxyl group and a suitable substituent on the hydroxyl group, especially one used as a protecting group for the hydroxyl group. The alkoxy includes alkoxy having 1 to 10 carbon atoms (e.g., methoxy, I-oxy, propoxy, isopropoxy, butoxy, isobutoxy, 5ec-butoxy, tert-butoxy, pentoxy, isopentoxy, neopentoxy, hexyloxy, heptyloxy) , nonyloxy, cyclobutoxy, cyclopentoxy, cyclohexyloxy, etc.) are preferred. Examples of the alkenyloxy include those having 1 to 10 carbon atoms, such as allyloxy, crotyloxy, 2-pentenyloxy, 3-hexyloxy, 2-cyclopentenylmethoxy, and 2-cyclohexenylmethoxy; ,
Examples include phenyl-C1-4 alkyloxy (eg, benzyloxy, phenethyloxy, etc.).

The acyloxy includes alkanoyloxy having 2 to 4 carbon atoms (e.g., acetyloxy, propionyloxy, n
-butyryloxy, 1so-butyryloxy, etc.) are preferred. Examples of the aryloxy include those having 6 to 10 carbon atoms such as phenoxy and naphthyloxy.

The alkyl group of the optionally substituted alkyl group represented by R2 and R3 may be linear, branched, or cyclic having 1 to 10 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, and isobutyl. , 5eC-
Butyl, tert-butyl, pentyl, isopentyl,
Examples include neopentyl, hexyl, heptyl, octyl, nonyl, decyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclohebutyl.

When 20 and R"O are adjacent to each other, R2 and R5 are connected to form a group represented by -(CHt)n-C, where n represents 1 or 2. te-) But it's okay,
In such a case, R20 and R30 together form a 5- or 6-membered ring.

Examples of the alkyl group and the optionally substituted hydroxyl group of the optionally substituted alkyl group represented by R4 include those described for R1 above.

The optionally esterified carboxyl group represented by R4 is -C0OR? In formula C, R7 represents an optionally substituted alkyl group, aralkyl group, aromatic group or heterocyclic group.

The optionally amidated carboxyl group represented by R4 is 10 ON (R8) (几9) [In the formula, R8
and R9 are the same or different and each represents an optionally substituted alkyl group, aralkyl group, dialkoxyphosphoryl group, aromatic group or heterocyclic group,
Alternatively, they may be linked to each other to form a ring together with a nitrogen atom].

Examples of the optionally substituted hydroxyl group represented by R5 and R6 include those described for R1 above.

When R4 represents an optionally substituted hydroxyl group, adjacent R4 and R6 or R4 and R6 are connected to each other to form the formula -
〇-(OH2)mo-(wherein, m may be 1 or 2).

Examples of the alkyl group of the optionally substituted alkyl group represented by R1 include those having 1 to 6 carbon atoms as described above for R1. The aralkyl group of the optionally substituted aralkyl group represented by R7 is phenyl-01
Examples of the aromatic group in which -4 alkyl (eg, benzyl, phenethyl, 3-phenylpropyl, etc.) may be substituted include, for example, C6-147 aryl such as phenyl, naphthyl, and anthryl.

Examples of the optionally substituted heterocyclic group represented by R7 include a 5- to 7-membered heterocyclic group containing one sulfur atom, nitrogen atom, or oxygen atom, and a 5- to 7-membered heterocyclic group containing 2 to 4 nitrogen atoms. 5- to 6-membered heterocyclic groups containing 1 to 2 nitrogen atoms and 1 sulfur or oxygen atom, and these heterocyclic groups contain 2 or less nitrogen atoms. may be fused with a 6-membered ring containing a benzene ring or a 5-membered ring containing one sulfur atom.

Specific examples of the above heterocyclic groups include 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxasilyl, isoxasilyl, pyrid[2゜3 -d] pyrimidyl, benzopyranyl, 1,8-naphthyridyl, 1,5-naphthyridyl,
1.6-naphthyridyl, 1,7-naphthyridyl, quinolyl, cheno(2,3-b)pyridyl, tetrazolinohethiadiazolyl, oxadiazolyl, triazinyl, triazolyl, thienyl, pyrrolyl, pyrrolinyl, furyl,
Examples include pyrrolidinyl, benzothienyl, indolyl, imidazolidinyl, piperidyl, piperidino, piperazinyl, morpholinyl, and morpholino.

Examples of the optionally substituted alkyl group, aralkyl group, aromatic group or heterocyclic group represented by R8 and R9 include those shown by R7.

The optionally substituted dialkoxyphosphoryl group represented by R8 and R9 includes dimethoxyphosphoryl,
Examples include jetoxyphosphoryl and ethylenedioxyphosphoryl.

R8 and R9 may also be connected to each other through a carbon chain that may contain an oxygen atom, a sulfur atom, or a nitrogen atom to form a 5- to 7-membered ring, and such a ring may be formed by forming a 5- to 7-membered ring. represents a 5- to 7-membered ring formed with Examples of these rings include morpholine, piperidine, thiomorpholine, homopiperidine, piperidine, pyrrolidine, thiazolidine, azepine, and the like.

Examples of the substituent on the optionally substituted alkyl represented by R1 include halogen (e.g., fluorine,
chlorine, bromine, iodine, etc.), hydroxyl group, alkoxy having 1 to G carbon atoms (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentyloxy, hexyloxy, etc.), and the number of substituents is 1 to Three is preferred.

Specific examples of alkyl substituted for R1 include hatrifluoromethyl, trifluoroethyl, difluoromethyl, trichloromethyl, hydroxymethyl,
-Hydroxyethyl, 2-hydroxyethyl, 1-methoxyethyl, 2-methoxyethyl, 1-ethoxyethyl, 2-ethoxyethyl, 2,2-dimethoxyethyl, 2
, 2-jethoxyethyl and the like.

Examples of the substituent in the optionally substituted alkenyl represented by R1 include halogen (e.g., fluorine, chlorine, bromine, iodine, etc.), hydroxyl group, alkoxy having 1 to 6 carbon atoms (e.g., methoxy, ethoxy, propoxy , isopropoxy, butoxy, pentyloxy, hexyloxy, etc.), and the number of substituents is preferably 1 to 3.

Specific examples of alkenyl substituted for R1 include:
For example, 2,2-dichlorovinyl, 3-hydroxy-2-
Examples include propen-1-yl and 2-methoxyvinyl.

Substituents for the optionally substituted hydroxyl group represented by R1 include, for example, halogen (e.g., fluorine, chlorine, bromine, iodine, etc.), hydroxyl group, alkoxy having 1 to 6 carbon atoms (e.g., methoxy, nidoxy, propoxy , isopropoxy, butoxy, pentyloxy, hexyloxy, etc.), and the number of substituents is preferably 1 to 3.

Specific examples of the hydroxyl group substituted for R1 include trifluoromethoxy, 2,2,2-trifluoroethoxy, difluoromethoxy, 2-methoxyethoxy,
Examples include 4-chlorobenzyloxy, 2-C3,4-dimethoxyphenyl)ethoxy, and 4-chlorophenoxy.

Examples of substituents on the optionally substituted alkyl represented by R2 or R1 include halogen (e.g., fluorine, chlorine, bromine, iodine, etc.), hydroxyl group, and carbon atoms of 1 to 6.
alkoxy (e.g., methoxy, ethoxy, propoxy,
isopropoxy, butoxy, pentyloxy, hexyloxy, etc.), and the number of substituents is preferably 1 to 3.

Specific examples of alkyl substituted for R2 or R3 include trifluoromethyl, 2゜2, 2-)
Lifluoroethyl, difluoromethyl, trichloromethyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-methoxyethyl, 2-methoxyethyl, 1-ethoxyethyl, 2-ethoxyethyl, 2,
Examples include 2-dimethoxyethyl and 2,2-jethoxyethyl.

Examples of substituents on the optionally substituted alkyl represented by R4 include halogen (e.g., fluorine,
chlorine, bromine, iodine, etc.), hydroxyl group, alkoxy having 1 to 6 carbon atoms (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentyloxy, hexyloxy, etc.), dialkoxyphosphoryl (dimethoxyphosphoryl, jetoxyphosphoryl, ethylenedioxyphosphoryl, etc.), and the number of substituents is preferably 1 to 3.

Specific examples of alkyl substituted for R4 include trifluoromethyl, 2,2,2-trifluoroethyl, difluoromethyl, trichloromethyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-methoxyethyl. , 2-methoxyethyl, 1-ethoxyethyl, 2-ethoxyethyl, 2,2-dimethoxyethyl, 2,2-jethoxyethyl, dimethoxyphosphorylmethyl, jetoxyphosphorylmethyl, 2-jethoxyphosphorylethyl, etc. .

Substituents for the optionally substituted hydroxyl group represented by R4, R6, or R6 include, for example, halogen (e.g., fluorine, chlorine, bromine, iodine, etc.), hydroxyl group, alkoxy having 1 to B carbon atoms (e.g., methoxy , ethoxy, propoxy, isopropoxy, butoxy, pentyloxy,
hexyloxy, etc.), and the number of substituents is from 1 to
Three is preferred.

Specific examples of substituted hydroxyl groups for R'*R' and R6 include trifluoromethoxy, 2.2
．． 2-trifluoroethoxy, difluoromethoxy, 2
-methoxyethoxy, 4-chlorobenzyloxy, 2-
Examples include (3,4-dimethoxyphenyl)ethoxy.

Examples of substituents in the optionally substituted alkyl group represented by R7 include halogen (e.g., fluorine, chlorine, bromine, iodine, etc.), hydroxyl group, alkoxy having 1 to 6 carbon atoms (e.g., methoxy, ethoxy, propoxy , isopropoxy, butoxy, pentyloxy, hexyloxy, etc.), dialkoxyphosphoryl group, phosphono group, etc., and the number of substituents is preferably 1 to 3.

Specific examples of substituted alkyl groups for R7 include:
For example, trifluoromethyl, 2,2,2-trifluoroethyl, difluoromethyl, 2-methoxyethyl, 2-
Examples include hydroxyethyl, 3-methoxyfurovir, 3-jethoxyphosphorylpropyl, and the like.

Examples of the substituent in the optionally substituted aralkyl group represented by R7 include halogen (e.g., fluorine,
chlorine, bromine, iodine, etc.), hydroxyl group, alkoxy having 1 to 6 carbon atoms (e.g., methoxy, nidoxy, propoxy, isopropoxy, butoxy, pentyloxy, hexyloxy, etc.), dialkoxyphosphoryl group, phosphono group, etc. , the number of substituents is preferably 1 to 3.

Specific examples of aralkyl groups substituted for R7 include 4-fluorobenzyl, 2-(3-trifluoromethylphenyl)ethyl, 2,4-difluorobenzyl, 4-(2-methoxyphenyl)butyl, 4- Examples include jetoxyphosphorylbenzyl.

The optionally substituted aromatic group represented by R7 (substituents here include, for example, halogen (e.g., fluorine, chlorine, bromine, iodine, etc.), alkyl, haloalkyl,
Hydroxyl group, alkoxy having 1 to 6 carbon atoms, acyl having 1 to 10 carbon atoms, alkyl having 1 to 6 carbon atoms, or 1 to 10 carbon atoms
amino optionally substituted with acyl (e.g., dimethylamino, diethylamino, dipropylamino, acetylamino, propionylamino, benzoylamino, etc.),
Carbamoyl optionally substituted with alkyl having 1 to 6 carbon atoms (e.g., dimethylcarbamoyl, ethoxycarbamoyl, dipropylcarbamoyl, etc.), alkoxycarbonyl having 1 to 6 carbon atoms (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, etc.) ), a mono- or dialkoxyphosphoryl group, a mono- or dialkoxyphosphorylalkyl group, a phosphono group, the above-mentioned heterocyclic group, etc., and the number of substituents is preferably 1 to 3. R1
Specific examples of aromatic groups substituted with , for example, 4-chlorophenyl, 4-cyclohexylphenyl,
5,6,7.8-tetrahydro-2-naphthyl, 3-trifluoromethylphenyl, 4-hydroxyphenyl,
3,4.5-trimethoxyphenyl, 6-medoxy2
-naphthyl, 4-(4-chlorobenzyloxy)phenyl, 3゜4-methylenedioxyphenyl, 4-(2,2
゜2-Trifluoroethoxy)phenyl, 4-propionylphenyl, 4-cyclohexanecarbonylphenyl, 4-dimethylaminophenyl, 4-benzoylaminophenyl, 4-jethoxycarbamoylphenyl, 4-
tert-butoxycarbonylphenyl, 4-jethoxyphosphorylphenyl, 4-jethoxyphosphorylmethylphenyl, 4-(2-jethoxyphosphorylethyl)
phenyl, 2-jethoxyphosphorylmethylphenyl,
Examples include 3-jethoxyphosphorylmethylphenyl and 4-dipropoxyphosphorylphenyl.

Examples of substituents in the optionally substituted heterocyclic group represented by R7 include halogen (e.g., fluorine, chlorine, bromine, iodine, etc.), alkyl, haloalkyl, hydroxyl group, alkoxy having 1 to 6 carbon atoms, and Amino optionally substituted with acyl having 1 to 10 carbon atoms, alkyl having 1 to 6 carbon atoms, or acyl having 1 to 10 carbon atoms (e.g., dimethylamino, diethylamino, dipropylamino, acetylamino, propionylamino, benzoylamino, etc.) ), carbamoyl optionally substituted with alkyl having 1 to 6 carbon atoms (e.g. dimethylcarbamoyl, ethoxycarbamoyl,
dipropylcarbamoyl, etc.), alkoxycarbonyl having 1 to 6 carbon atoms (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, etc.), mono- or dialkoxyphosphoryl group, mono- or dialkoxyphosphorylalkyl group, phosphono group, the above-mentioned heterocycle The number of substituents is preferably 1 to 3. Specific examples of substituted heterocyclic groups for R1 include, for example, 5-
Chloro-2-pyridyl, 3-methoxy-2-pyridyl,
5-methyl-2-benzothiazolyl, 5-methyl-4-
Phenyl-2-thiazolyl, 3-phenyl-5-isoxasilyl, 4-(4-chlorophenyl)-5-methyl-2-oxasilyl, 3-phenyl-1,2,4-thiadiazol-5-yl, 5- Methyl-1,3,4-thiadiazol-2-yl, 5-acetylamino-2-pyrimidyl, 3-methyl-2-thienyl, 4,5-dimethyl-2-furanyl, 4-methyl-2-morpholinyl, etc. can give.

A substituent in the optionally substituted alkyl group represented by R8 or R9 above, a substituent in the optionally substituted aralkyl group, a substituent in the optionally substituted aromatic group, and an optionally substituted aromatic group. As substituents in the heterocyclic group, those marked with R7 (
In addition, dialkoxyphosphoryl groups (eg, dimethoxyphosphoryl, jetoxyphosphoryl, ethylenedioxyphosphoryl, etc.) can be mentioned. Specific examples thereof include, in addition to those indicated by R7, 2-jethoxyphosphorylethyl, 3-dimethoxyphosphorylpropyl, 4-jethoxyphosphorylphenyl, 4-dimethoxyphosphorylmethylphenyl, and the like.

Among the above compounds (I), for example, the following compounds are known in the literature.

・3,4-methylenedioxyphenol: Be11S
19. s s.

・3,4-methylenedioxytoluene: Be1lstein 19(1), 614°・
5-allyl-1,3-benzodioxole (safrole): Be1lstein 19.39°・1,3
-Benzodioxole: Be1lstein 19. 20° Also, among compounds (1), for example, compounds of the formula [wherein I/ is a C1-4 alkyl group, R'*R
5 and R6 have the same meanings as above. The compound represented by ] is a new compound and has favorable effects.

Further, the above compound (I) can be produced, for example, in the following manner. That is, method A (1-1) (1-2) [wherein,
R2 and RS have the same meanings as above, 1Q each represents an optionally substituted alkyl, aralkyl or alkenyl group, and X represents a leaving group] Method G (1-3) [In the formula, represents] D method El.

R2゜ RX.

R4゜(1-5) R6 and R6 are the above (I-4) [wherein, 几+, Rj, R3, 几4. R5 and 几6 have the same meanings as above. ] (1-6) (1-7) [In the formula, 几1. R2, R1, R5, 几6. Rγ and X have the same meanings as above] F method G method Rt+ ([-7) (1B) [wherein, R1
, R", R51R"l R", 几8. and 9 and X have the same meanings as above] F method Cl-9) (1-10> EL6 and X
ζ has the same meaning as above] (1-10'') (l-11) [In the formula, R1, R2, R'', R5, R''h5 and x have the same meaning as above, and 几11 is each replaced The optionally substituted alkyl, alkenyl and aralkyl groups represented by RIG and R11 in the formula are the same as those exemplified for R1 and RT above. The leaving groups represented by X include halogen (e.g.
Examples of the halogen represented by Y include chlorine, bromine, and iodine.

Each manufacturing method will be explained in detail below.

Method A In this method, the phenol derivative (1-1) is treated with a base (e.g., sodium hydride, potassium hydride, sodium amide, triethylamine, N-methylmorpholine, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, etc.). (I-2) is produced by reacting with RIG-X (II) in the presence of. This reaction is carried out using an appropriate solvent (eg, tetrahydrofuran, dioxane, ether, toluene, xylene, benzene, 1,2-dichloroethane, 1.
2.2-tetrachloroethane, N,N-dimethylformamide, dimethyl sulfoxide, etc.) at -20°C ~
It is carried out at 100°C, preferably 0°C to 80°C.

(RIG-X) is preferably used in excess of (1-1). The reaction time is usually 0.5 to 30 hours, preferably 1 to 10 hours.

Method B In this method, compound (I-3) is reacted with a benzyl alcohol derivative (ill) in the presence of an acid (e.g., hydrochloric acid, sulfuric acid, nitric acid, acetic acid, oxalic acid, etc.) to produce (I-4). .

This reaction can be carried out using an appropriate solvent (e.g., tetrahydrofuran, dioxane, ether, toluene, xylene, benzene,
2-dichloroethane, 1,1,2,2-tetrachloroethane, methanol, ethanol, propatool, isopropanol, N,N-dimethylformamide, dimethyl sulfoxide, etc.) at -20°C to 200°C, preferably 10 The temperature is between 150°C and 150°C. (The amount of lH used is preferably in excess of (1-3). The reaction time is usually 0.5 to 50 hours, preferably 1 to 50 hours.
It is 15 hours.

Method C In this method, a benzophenone derivative (1- 5).

The reaction of ([-3) and (IV) in this method is carried out in the same manner as the usual Friedel-Crafts reaction. The synthesis means may follow any known method, for example, the method described in Shin Jikken Kagaku Koza 14, Synthesis and Reaction of Organic Compounds (II) (Maruzen, 1977), for example, using benzene as the solvent. , aromatic hydrocarbons such as toluene and xylene, chloroform, dichloromethane, 1,2-dichloroethane, 1,1,2.2-
Examples include halogenated hydrocarbons such as tetrachloroethane, ethers such as diethyl ether and tetrahydrofuran, nitrobenzene, nitromethane, and mixed solvents of carbon disulfide, aluminum, and the like. Examples of Lewis acids include hydrogen fluoride, sulfuric acid, phosphoric acid, phosphoric anhydride, aluminum chloride, tin tetrachloride, and zinc chloride. The amount of Lewis acid used is 1 to 10 per mole of compound (1-3).
A molar level is preferable. The reaction temperature is approximately -2 in both cases.
0°C to about 200°C1 preferably about 0°C to about 100°C
°C, and the reaction time is usually 0.5 to 100 hours, preferably about 1 to 30 hours.

Method D In this method, the ester derivative (r-6) of the compounds (+-4) and (1-5) produced in Methods B and C is subjected to a hydrolysis reaction to form a carboxylic acid derivative (I-7). Manufacture.

This hydrolysis reaction is carried out in a solvent in the presence of an acid or a base according to a conventional method. As the solvent, for example, alcohols such as methanol and ethanol, ethers such as tetrahydrofuran and dioxane, and mixed solvents of water with N,N-dimethylformamide, dimethyl sulfoxide, acetone, etc. can be used as appropriate. Examples of bases that can be used include potassium carbonate, sulfur carbonate, sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, and lithium hydroxide.

As the acid, for example, hydrochloric acid, sulfuric acid, acetic acid, hydrobromic acid, etc. are used. The acid or base is preferably used in excess (base: 1.2 to 6 equivalents, acid: 2 to 50 equivalents) relative to compound (1-6). This reaction is usually carried out at -20°C to 15°C.
It is carried out at 0°C, preferably about -10°C to 100°C. The reaction time is usually 10 minutes to 10 hours, preferably 0.
5 to 5 hours.

In the nature of method E, the carboxylic acid derivative CI-7) is amidated to produce the compound CI-8). Carboxylic acid derivative ([-7
) and the amine derivative (■) can be carried out by a method known per se, for example, by directly condensing CI-7) and the amine derivative (V) with dicyclohexylcarbodiimide or the like; ), such as acid anhydrides, acid halides (acid chlorides, acid bromides),
A method of appropriately reacting an imidazolide or a mixed acid anhydride (eg, an anhydride with methyl carbonate, an anhydride with ethyl carbonate, an anhydride with isobutyl carbonate, etc.) with (V) is used. The simplest method among these is (I-7)
This method uses acid halides or mixed acid anhydrides. When using an acid halide, the reaction is usually carried out with a base (e.g. triethylamine, N-methylmorpholine, sodium bicarbonate, potassium bicarbonate, The amount of (V) (7) used is 1 to 1.2 mol per 1 mol of (1-7). . When using mixed acid anhydrides,
First, ([-7) and a chlorocarbonate (e.g., methyl chlorocarbonate, ethyl chlorocarbonate, isobutyl chlorocarbonate, etc.) are combined with a base (e.g., triethylamine, N-methylmorpholine, sodium bicarbonate, potassium bicarbonate, sodium carbonate, carbonate, etc.). -1 in an appropriate solvent (e.g., chloroform, dichloromethane, ethyl acetate, tetrahydrofuran, water, or a mixture thereof) in the presence of potassium (e.g., potassium).
It is preferable to react at 0°C to +30°C, and (V)
The amount used is 1 to 1.2 mol per 1 mol of (I-7). The reaction time is usually 10 minutes to 5 hours.

In the nature of method F, the benzyl ether CI-9 of compounds (1-4) and (1-5) produced by method B and method G is subjected to a debenzylation reaction to obtain a phenol derivative ([-10). Manufacture. This benzyl group removal reaction is advantageously carried out by catalytic hydrogenation. This reaction uses palladium black, palladium-
In the presence of a catalyst such as carbon, Raney nickel, or platinum oxide, in an appropriate solvent (e.g., methanol, ethanol/propanol, isopropanol, ethyl acetate, dioxane,
tetrahydrofuran, N,N-dimethylformamide, etc.) under a hydrogen stream (1 atm to 150 atm, preferably 1 to 150 atm)
50 atm). Reaction temperature is -20°C to 150°C
°C1 is preferably 0°C to 80°C. The reaction time is usually 0.5 to 20 hours, preferably 1 to 10 hours.

G method The nature is carried out in the same way as method A.

Target product (l-2) obtained by the above A to G production methods,
(1-4), ([-5>, ((-7), (I-8), (
1-10), ((-11) can be isolated and purified by known means such as solvent extraction, liquid conversion, dissolution, filtration, crystallization, recrystallization, chromatography, etc. If these target products obtained are in free form, they can be converted into the following salts according to conventional methods, if necessary.If the target products are obtained as salts, they can also be converted into free forms according to conventional methods. can.

Examples of the pharmacologically acceptable salts of the compound (1) of the present invention include hydrochloride, bromate, iodate, phosphate, nitrate, sulfate, acetate, and citrate. It will be done.

Regarding the toxicity of compound ([), for example, Example N
No mortality was observed even when the compound synthesized in step 19 was orally administered to mice at a rate of 300 my/kg.

As described above, compound (I) in the present invention has excellent bone resorption inhibitory action and low toxicity.

Therefore, the compound (I) of the present invention can be used for the prevention or treatment of osteoporosis in mammals (eg, mice, rats, rabbits, dogs, cats, cows, pigs, humans, etc.).

When administering the present compound (1) (including the case where it forms the above-mentioned pharmacologically acceptable salt) to humans, the administration method may be either oral or parenteral route. Compositions for oral administration include solid or liquid dosage forms, in particular tablets (including sugar-coated tablets and film-coated tablets), gunpowders, granules, powders, capsules (including soft capsules), and syrups. Agents, emulsions, suspensions, etc. Such compositions are produced by methods known per se and contain carriers or excipients commonly used in the pharmaceutical field. For example, carriers and excipients for tablets include lactose, starch, sucrose, and magnesium stearate.

Compositions for parenteral administration include, for example, injections,
Injections include subcutaneous injections, subcutaneous injections, intramuscular injections, and other dosage forms. Such injections are prepared by a method known per se, that is, by suspending or emulsifying the compound in a sterile aqueous or oily liquid commonly used for injections.Aqueous liquids for injection include physiological saline, etc. Examples of oil-based liquids include sesame oil and soybean oil, which may be used in combination with appropriate suspending agents such as sodium carboxymethyl cellulose and nonionic surfactants, if necessary. As the agent, benzyl benzoate, benzyl alcohol, etc. may be used in combination.The prepared injection solution is usually filled into a suitable ampoule.

When the present compound (1) or a salt thereof is used as a preventive treatment for osteoporosis, the daily dose for an adult is 1 to 500 mg, preferably 10 to 150 mg when administered orally.
It is y.

(Effects of the Invention) The composition of the present invention has a strong bone resorption inhibitory effect and directly acts on bones to improve bone metabolism.

In addition, compound (1) and its salts have low toxicity and are therefore extremely useful as preventive and therapeutic agents for osteoporosis.

Next, the method and results for measuring the bone resorption inhibitory effect of compound (I) will be shown.

[Bone resorption inhibitory effect]

Bone resorption is measured using Royce's method [Journal of
Clinical Investigation (J, C11n,
Invest, ) 44.103-116 ($19
According to 5)). That is, sprag at day 19 of pregnancy.
50 μOi of 4sca (calcium isotope, Cac12 solution) was injected subcutaneously into one UE-Dawley rat.The next day, the abdomen was opened, the fetal rat was removed aseptically, and the left and right forearm bones (radius) of the fetal rat were examined under a dissecting microscope. , ulna) were separated from the trunk, and connective tissue and cartilage were removed as much as possible to prepare a preculture sample. 0.6 mA' for each piece of bone
BGJb medium (Fitton-Jackson
modification(GIBCO Labora
tories (USA)] bovine serum albumin, 2 mg
After culturing at 37°C for 24 hours in the above medium containing 10 μg/ml of the compound, the culture was continued for two more days, and the radioactivity of 45Ca in the medium and The radioactivity of 450a in the bone was measured, and 450a was released from the bone into the medium according to the following formula.
The ratio (%) of 50a was determined.

Ratio of 4 5 Ca released from bone into medium (%
) Bone obtained from a fetus from the same litter was treated in the same manner without adding any compound.
Those cultured for one day were used as the control group. The standard deviation above the mean value of the values obtained from five bones in each group was determined, and the ratio (%) of this value to the value of the control group was determined and shown in Table 1.

Example 1 3,4-methylenedioxyphenol (27,6fI)
was dissolved in 2N NaOH (110ml) and dimethyl sulfate (25.2g) was added dropwise at 40-45°C. Further, 2 N NaOH (55m(1) and dimethyl sulfate (12,6y) were added, and after stirring at the same temperature for 3 hours, the reaction solution was extracted with ether. The ether layer was washed with water,
After drying (Mf 804), it was distilled under reduced pressure to give 5-methoxy-1,3-benzodioxole (25,8f, 8
4.7%). Colorless oil.

Bp, 74-75℃/0.5 mmHp, NM
R(δppm1n CDC1x): 3.72(3
H,s), 5.88 (2H,s).

6.30 (IH, da, J=2 and 9Hz), 6.4
7 (IH, a.

J-2Hz), 6.68 (IH,d, J=9
Hz).

Example 2 5-nitoxy-1,3-benzodioxole was obtained in the same manner as in Example 1. Colorless oil. Yield 80%. NMR (
δppm in CDCl4): 1.35 (3
H.

t, J=7Hz), 3.92 (2H, q, J=7Hz)
, 5.91 (2H, s), 6.29 (IH, dcl,
J=3and9Hz), 6.47(IH,a,J=
3Hz), 6.69 (IH, a, J=9Hz).

Example 3 6-nitoxy 1,4-benzodioxane was obtained in the same manner as in Example 1. Colorless oil. Yield 78%. Nun(δ
ppm in CDCl3): 1.37 (3H
,t.

J=7Hz), 3.93 (2H, q, J=7Hz), 4
．． 23 (4H.

s), 6.40 (IH, da, J=3 and 9Hz),
6.47 (Hi.

d, J=3Hz), 6.77 (IH, d, J
=9Liz).

Example 4 3.4-methylenedioxyphenol (9,71, K2
COx (14,59), isopropyl bromide (12,9
1) and N,N-dimethylformamide (80rr+
After stirring the mixture (1) at 70°C for 22 hours, the reaction solution was poured into water (200m#) and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium bicarbonate solution and then with water, dried (RQ 804), and then distilled under reduced pressure to give 5-isopropoxy-1,3-benzodioxole (
9.2F, 73%) was obtained.

Colorless oil. Bp, 93-94℃/1 mmHp,
NMR (δppm in CI)C1i): 1.27
(6H, d, J=7Hz).

415 (1H, m), 5.86 (2H, S), 6.30
(IH, da.

J = 2 and 7Hz), 6.46 (IH, d, J = 2H
z), 6.65 (IH, d, J=9 Hz).

Example 5 5-butoxy-1,3-benzodioquinol was obtained in the same manner as in Example 4. Colorless oil. Yield 89%. Bp, 1
12-120°C/1.5 mmHy.

NMR (δppm in CD013): 0.9
5 (3H, t, J=7Hz), 1.24-1.86
(4H, m), 3.87 (2H, t, J=7Hz),
5.92 (2H, s), 6.29 (IH, dcl,
, T=2and9Hz), 6.47(IH,d,J=
2Hz), 6.69 (IH, d.

J=9Hz).

Example 6 3.4-methylene diphenol (1,38y),
3,4.5-)rimethoxybenzyl alcohol (1,9
8g), formic acid (10mA!) and acetic acid (5ml)
The mixture was heated under reflux for 2 hours.

The reaction solution was concentrated under reduced pressure, and the residue was neutralized with saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate.

The ethyl acetate layer was washed with a saturated aqueous sodium bicarbonate solution and then with water, dried (My 804 ), and the solvent was distilled off under reduced pressure to give 6-(3,4,5-)rimethoxybenzyl)-
1,3-benzodioxol-5-ol (0,28g
, 8.8%). Recrystallized from ethyl acetate-hexane. Colorless plate crystals. Mp136-137°CO Calculated value as Cl7Hu+Os: C,64,14;H
, 5, 70 analysis value: 0. 63.84
;H, 5,71 Examples 7 to 13 Compounds shown in Table 2 were obtained in the same manner.

Example 14 5-methoxy-1,3-benzodioxole (1,52
f) and 3,4-dimethoxybenzoyl chloride (
4,01 was dissolved in dichloromethane (20mj'), and anhydrous 5nC14 (3,,1!) was added dropwise on ice-cooling. The mixture was stirred for 1 hour at room temperature and then diluted with 1.2 NHCI (2
0 mJ) was added dropwise under ice-cooling. The organic layer was separated, washed with water, and then dried (My 804). The solvent was distilled off under reduced pressure, and 2,3',4'-)rimethoxy4-5-methylenedioxybenzophenone (2.6 g) was obtained.

82.0%). Recrystallized from ethanol.

Colorless prismatic crystal. Mp138-139°COCl7Ih
Calculated value as 806: C, 64,55; Il, 5.
10 analysis value: C, 64, 67; H, 5
, 08 Examples 15-46 The compounds shown in Table 3 were obtained in the same manner as in Example 14.

Example 47 Methyl 4-(2-ethoxy-4,5-methylenedioxybenzoyl)benzoate (4,59 M) was dissolved in methanol (45
md), 2NK and OH (21mj?) were added, and the mixture was stirred under reflux for 1 hour. The reaction solution was mixed with water (200ml
l) and extracted with ether.

The aqueous layer was acidified with concentrated hydrochloric acid and extracted with ethyl acetate.

The ethyl acetate layer was washed with water and then dried (RQ 804) L.
The solvent was distilled off under reduced pressure, and 4-(2-ethoxy-4,5-methylenedioxybenzoyl)benzoic acid C4,281°9
8%). Recrystallized from ethanol. Pale yellow prismatic crystal. Mp220-221°C.

Calculated value as c+rHuoe: C, 64, 97:H,
4,49 analysis value: C, 65, 12;
H,4,50 Example 48 4'-benzyloxy-2-ethoxy-4,5-methylenedioxybenzophenone (6 g) was dissolved in ethyl acetate (25
0r+1) and 5% Pd10 (50% wet,
1y) was added and subjected to catalytic reduction at room temperature and pressure. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the portion eluted with ethyl acetate-hexane (1:2) was purified with 4-(2-ethoxy-4,5-methylenedioxybenzoyl)phenol (
2ri.

44%). Recrystallized from ethyl acetate. Pale yellow needles. Calculated value as Mp 182-183°C0c+eHuo5: C, 67,13; H, 4,93 minutes
Analysis value: C, 67, 15; H, 4, 97 Example 49 4-(2-ethoxy-4,5-methylenedioxybenzoyl)phenol (0,7y), isopropylbromide (0,45M, potassium carbonate (0,51y) and N, N
- Dimethylformamide (5 ml) mixture at 70°C
I stirred it for an hour. The reaction solution was poured into water (50 ml'I) and extracted with ethyl acetate.

The ethyl acetate layer was washed with water and then dried (Mg 804 ) L/
, the solvent was distilled off under reduced pressure, and 2-ethoxy-4'-isopropoxy-4,5-methylenedioxybenzophenone (0
, 54f, 1li8%) was obtained. Recrystallized from isopropyl ether. Colorless plate crystals. Calculated value as Mp8G-87C0 C+9H2oOs: C,69,50;
H, 6, 14 analysis value -0, 69, 41
;H,6,16 Example 50 Same as Example 49 (4'-butoxy-2-ethoxy-4,5-methylenedioxybenzophenone was obtained.

Yield 57%. Recrystallized from isopropyl ether-hexane. Colorless prismatic crystal. Mpfi 3-64°C0 C20I (calculated value as 2205: C, 70, 16;
H, [i, 48 analysis value: C, 70, 1
8; H, 6,50 Example 51 4-(2-ethoxy-4,5-methylenedioxybenzoyl)benzoic acid (1,269) was dissolved in tetrahydrofuran (
Oxalyl chloride (0.61g) dissolved in 20m6)
was added and stirred at room temperature for 3.5 hours.

The reaction solution was concentrated under reduced pressure and the residue was dissolved in tetrahydrofuran (8 ml!). Meanwhile, diethyl aminophosphonate (2.45!L) was mixed with tetrahydrofuran (40ml).
) and water-cooled oily sodium hydride (60%,
0.321 was added and stirred for 30 minutes. The above solution was added to this mixture at 0°C and stirred for 30 minutes under water cooling. The reaction mixture was poured into water (250ml) and extracted with ethyl acetate.

The ethyl acetate layer was washed with INFICI, water, saturated aqueous sodium bicarbonate solution, and water in that order, and then dried (M, 9804).
The solvent was then distilled off under reduced pressure to obtain N-(jethoxyphosphoryl)-4-(2-ethoxy-4,5-methylenedioxybenzoyl)benzoic acid amide (1,31), 73%). Recrystallized from ethanol.

Pale yellow needles. Mp168-169°c0Ct+H2*
Calculated value as N0BF: C, 5G, 13; H, 5, 38; N, 3.12 Analysis value: C, 5640: H, 5, 32; N, 3.00 Example 52 4-(2-ethoxy -4,5-methylenedioxybenzoyl)benzoic acid (0,94y) in tetrahydrofuran (
Oxalyl chloride (0,469
) and N,N-dimethylformamide (1 drop) were added and stirred at room temperature for 3.5 hours.

The reaction solution was concentrated under reduced pressure and the residue was dissolved in tetrahydrofuran (6 m(1)).
Oml! ) and stirred at room temperature for 30 minutes. The reaction mixture was poured into water (200m6) and extracted with ethyl acetate. The ethyl acetate layer was washed with 1N HCl, water, a saturated aqueous sodium bicarbonate solution, and water in that order, and then dried (My
804) Shi, the solvent was distilled off under reduced pressure, and N-(jetoxyphosphorylphenyl)-4-(2-ethoxy-4,5
-methylenedioxybenzoyl)benzoic acid amide (1,
36y, 87%) was obtained. Recrystallized from ethanol-hexane. Pale yellow needles. Mp190-191°C0C
Calculated value as 27C0C27H2: C, 61,71; H, 5,37; N, 2.67 Analysis value: C, 61,74; H, 5,34; N, 2.55 Example 53 Example 52 In the same manner, N-(jethoxyphosphorylmethylphenyl)-4-(2-ethoxy-4,5-methylenedioxybenzoyl)benzoic acid amide was obtained. Recrystallization from ethanol-hexane yielded 45%. Pale yellow needles. Mp166-168°C.

Calculated value as CuHsoNOaP: C, Ei 2.33; H, 5,60; N, 2.60 Analysis value: 0.62.11; H, 5,64; N, 2.4
8 Example 54 In the same manner as in Example 14, 2,3.4',5-tetraethoxy-4,5-methylenedioxybenzophenone was obtained. Recrystallized from ethanol, melting point 137-138°C.

Examples 55-62 In the same manner as in Example 52, the compounds shown in Table 4 were obtained.

Formulation Example 1 Composition in 1 tablet (1 compound (compound obtained in Example 12) 50m7 (
2 Cornstarch 30mg (3 Lactose 1i3.4m
1i' (4 hydroxypropyl cellulose 6
mg (5 water (0.03mN)
Total 200 mf Among the above compositions, (1), (2), (3) and (
After mixing 4), adding water and kneading, 40°
c. Vacuum-dried for 16 hours, crushed in a mortar, and passed through a 16-mallow sieve to form granules. (6) was added to the granules and mixed, and tablets of 200 mg each were produced using a rotary tablet press (manufactured by Kikusui Seisakusho).

Formulation Example 2 1 Compound (compound obtained in Example 24) 50 mg2
Cornstarch 30mFI 3) Lactose 11 3.4
mg4 Hydroxycellulose 6mg5)
Water (0.03m1)
6) Magnesium stearate 0.6m77)
Cellulose acetate phthalate 10m
Total g: 210mg Among the above compositions, (1), (2), (3), (4
), (5) and (6) were used to produce tablets in the same manner as in Formulation Example 1. These tablets were coated with the acetone solution of (7) using a bar coater (manufactured by Freund) to produce enteric-coated tablets each having a weight of 210 mda.

Formulation Example 3 Composition in capsule (1) Compound C (compound obtained in Example 48) 30t
ng (2) Cornstarch 40mg (3) Lactose 74m
g(4) Hydroxypropylcellulose
Gmg(5) Water
(0.02 mg) Total 150 mg Among the above compositions, (1), (2), (3) and (
4), mix it (add water and knead it), then mix at 40°
The mixture was vacuum dried for 116 hours, crushed in a mortar, and passed through a 16-mesh sieve to form granules. The granules were filled into gelatin No. 3 capsules using a capsule filling machine (manufactured by Xanaci, Italy) to produce capsules.

Formulation Example 4 (1) Compound (compound obtained in Example 53) 5
mg(2) Sodium salicylate 50rB(3
) Sodium chloride 180mg (4) Sodium metabisulfite 20mg (5
) Methyl-paraben 36mg (6) Propyl-paraben 4mg (7) Distilled water for injection (2ml
l) Among the above compositions, (2), (3), (4)
, (5) and (6) are dissolved in about half of the above amount of distilled water at 80° C. with stirring. The resulting solution is cooled to 40°C and the compound of the invention is dissolved in the solvent. Next, distilled water for injection is added to the solution to adjust the final volume, and the solution is sterilized by sterile filtration using a suitable filter paper to prepare an injection.

(The following is a blank space) Table From this table, it is clear that compound (1) has an excellent bone resorption inhibitory effect.

Note 1) Note 2) NM, R (δppm in CI) C1x): 3
．． 60 (3H.

s), 5.99 (2H, s), 6.55 (1H, s),
6J2 (IH, s), 7.22 (2H, d, J=9Hz
), 7.79 (2H, a, J=9Hz) NM几(δ1)pm in CD013): 0.
96 (EiH.

a, J-6Hz), 4.22 (IH, m), 5.99 (
2H.

s), 6.49 (IH, S), 6.99 (IH, s)
, 7.22 (2H, d, J=9Hz), 7.76 (2
H, a, J = 9Hz) (margin below)

Claims (1)

[Claims] (1) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, R^1 is hydrogen, an optionally substituted alkyl group, an optionally substituted alkenyl group, or an optionally substituted hydroxyl group. , R^2 and R^3 are the same or different and represent hydrogen or an optionally substituted alkyl group, or when R^2O and R^3O are adjacent, R
^2 and R^3 are connected to each other to form the formula -(CH_2)n- [
In the formula, n indicates 1 or 2], and A is hydrogen or the formula ▲ Numerical formula, chemical formula, table, etc. ▼ (R^4 is hydrogen, even if substituted R^5 and R^6 are the same or different and represent hydrogen or a hydroxyl group which may be substituted. or adjacent R^4 and R^5 or R^4 and R^6 are connected to each other to form the formula -O
Indicates that a group represented by (CH_2)mO- [in the formula, m represents 1 or 2] is formed, and X represents -CH_2- or -CO-. ) is shown. ] A bone resorption inhibiting composition containing a benzene derivative represented by: