JPH0586083A - Bisphosphonic acid derivative - Google Patents

Abstract

PURPOSE:To provide a new bisphosphonic acid derivative having bone resorption suppressing action and low side effect and useful as an agent for the treatment of bone diseases such as osteoporosis. CONSTITUTION:The compound of formula I [X is O or alkylidene of formula II (R<1> and R<2> are H, substituted amino, 1-6C alkyl, etc., which may be substituted with halogen, etc., or halogen); R<3> is H, 1-8C alkyl, etc.; (m) and (n) are 0 or positive integer; m+n is 2-5] and its pharmacologically permissible salt, e.g. 4-methylidenepiperidinomethylene bisphosphonic acid. The derivative of formula I can be produced e.g. by reacting a compound of formula III with a compound of formula (R<3>O)2PHO and treating the resultant compound of formula IV in an acidic medium (preferably an aqueous solution of acetic acid, etc.).

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a bisphosphonic acid derivative and a bone resorption inhibitor containing the same as an active ingredient.

[0002]

As a bisphosphonic acid derivative, a piperidinoalkane bisphosphonic acid derivative is disclosed in JP-A-53-59.
No. 674 is disclosed. However, although this patent publication explains that this compound can be used as a herbicide, it does not suggest that it can be used as a medicine.

By the way, osteoporosis has become a major problem as the population ages. Until now, therapeutic methods such as increasing the calcium concentration in the living body by administering calcium or the like have been used. However, these are not fundamental therapeutic agents for osteoporosis, and the discovery of new therapeutic agents for osteoporosis is desired. Then, JP-A-1-308290
The publication discloses cycloalkylaminomethylene bisphosphonic acid, which is one type of bisphosphonic acid, and it is explained that this compound has a bone resorption inhibiting action and is effective for osteoporosis. However, this bisphosphonic acid has a strong local stimulating action, and has a drawback that it exhibits side effects such as skin swelling when subcutaneously injected, for example.

[0004]

SUMMARY OF THE INVENTION It is, therefore, a first object of the present invention to provide a novel compound which has a bone resorption inhibitory effect and has few side effects and is effective as a therapeutic agent for bone diseases, for example, a therapeutic agent for osteoporosis. A second object of the present invention is to provide a bone resorption inhibitor containing the novel compound as an active ingredient.

[0005]

The first object of the present invention is to:
General formula (I)

[Chemical 3] [Wherein X is an oxygen atom or a formula

[Chemical 4] Is an alkylidene group represented by and when X is an alkylidene group, R ¹ and R ² are (i) hydrogen, (ii) C
_1-6 alkyl group, _C2-6 alkenyl group, _C2-6 alkynyl group, _C1-6 alkyl-carbonyl group, C
_2-6 alkenyl-carbonyl group, _C2-6 alkynyl-carbonyl group (these groups may be substituted with at least one selected from a substituted amino group, a halogen atom and a carboxyl group) or (iii) a halogen atom And may be the same or different, R ³ is hydrogen, C
_1-8 alkyl group or _C7-15 aralkyl group,
m and n are 0 or a positive integer, and (m + n) is 2 to 5], or a bisphosphonic acid derivative or a pharmaceutically acceptable salt thereof. The second object of the present invention has been achieved by a bone resorption inhibitor containing a bisphosphonic acid derivative of general formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient.

First, the bisphosphonic acid derivative of the general formula (I) of the present invention will be described. The bisphosphonic acid derivative of the general formula (I) has a chemical structure remarkably different from the above-mentioned known bisphosphonic acid in that it has an exo double bond (oxo group or alkylidene group) in the molecule. X in the general formula (I) is an oxygen atom or an alkylidene group represented by the above formula. That is, the compound represented by the above general formula (I) has the following general formula (Ia)

[Chemical 5] And the following general formula (Ib)

[Chemical 6] And a bisphosphonic acid derivative represented by The bisphosphonic acid derivatives represented by the general formulas (Ia) and (Ib) will be sequentially described below.

Bisphosphonic acid derivative represented by the general formula (Ia) The bisphosphonic acid derivative represented by the general formula (Ia) is one in which one carbon atom of a nitrogen-containing heterocycle is bonded to an oxo group. R ³ in the general formula (Ia) is hydrogen, a C _1-8 alkyl group or a C _7-15 aralkyl group. C here
_{Examples of the 1-8} alkyl group include linear or branched alkyl groups such as a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group, a heptyl group, and an octyl group. _{Examples of the} C _7-15 aralkyl group include benzyl group, phenylethyl group, methylbenzyl group and naphthylmethyl group. The general formula (Ia)
In the above, there are four R ^{3 s} , and these may be the same or different groups. However, in consideration of the convenience of synthesis and the like, four R ^{3 s} are the same groups. preferable.

Further, m and n are 0 or a positive integer, and (m + n) is 2-5. The reason is (m +
This is because when n) is 1 or less, it is a 3-membered ring or less, and when (m + n) is 6 or more, it is an 8-membered ring or more, both of which are difficult to synthesize.

Specific examples of the bisphosphonic acid derivative of the present invention represented by the general formula (Ia) include bisphosphonic acid derivatives in which m, n and R ³ in the formula are the numbers or groups shown in Table 1 below. However, the present invention is not limited to these exemplified compounds.

[0010]

[Table 1]

Bisphosphonic acid derivative represented by the general formula (Ib) The bisphosphonic acid derivative represented by the general formula (Ib) is one in which one carbon atom of a nitrogen-containing heterocycle is bonded to an alkylidene group. In the general formula (Ib), the formula

[Chemical 7] R ¹ and R constituting the alkylidene group represented by
^2, (i) _{hydrogen, (ii) C} 1~ ₆ alkyl _{group, C 2 to 6 alkenyl, C 2 to 6} alkynyl _{group, C 1 to 6} alkyl - carbonyl _{group, C 2 to 6} alkenyl - carbonyl group,
A _C2-6 alkynyl-carbonyl group (these groups may be substituted with at least one selected from a substituted amino group, a halogen atom and a carboxyl group) or (i
ii) It is a halogen atom.

As the C _1-6 alkyl group, a methyl group, an ethyl group, an n-propyl group, an iso-propyl group,
n-butyl group, branched butyl group, n-pentyl group,
Examples include branched pentyl groups, n-hexyl groups, and branched hexyl groups. Further, the C _2-6 alkenyl group is a linear or branched alkenyl group having one or more double bonds, and examples of such an alkenyl group include a vinyl group, an allyl group, a 1-methylvinyl group, and 2 -Methyl vinyl group, 1-ethyl vinyl group, 2-ethyl vinyl group, 2,
Examples thereof include a 2-dimethylvinyl group, a 3-methylallyl group, a 2-vinylvinyl group, and a 2-butylvinyl group. C
_{The 2-6} alkynyl group is a linear or branched alkynyl group having one or more triple bonds, and such alkynyl group includes ethynyl group, 1-propynyl group, 1-
A butynyl group, a 1-heptynyl group, a 1-isoheptynyl group, a 2-propynyl group and the like can be mentioned. Also, C
_{The 1-6} alkyl-carbonyl group is a _C1-6 alkyl group having a carbonyl group bonded _thereto , and the _C2-6 alkenyl-carbonyl group is a _C2-6 alkenyl group having a carbonyl group bonded _thereto . , _{C 2 to 6} alkynyl - carbonyl groups are those bonded carbonyl group to the _{C 2 to 6} alkynyl group.

These alkyl groups, alkenyl groups, alkynyl groups, alkyl-carbonyl groups, alkenyl-carbonyl groups and alkynyl-carbonyl groups [hereinafter (ii)
May be collectively referred to as a group of groups] may be substituted with at least one selected from a substituted amino group, a halogen atom and a carboxyl group. Examples of the substituted amino group which can be substituted on the group (ii) include dialkylamino groups such as dimethylamino group, diethylamino group and dipropylamino group, and dialkanolamino groups such as dimethanolamino group and diethanolamino group. And so on. Examples of the halogen atom which can be substituted on the group (ii) include fluorine, bromine, iodine and chlorine. Further, R ¹ and / or R ² may be the above-mentioned halogen atom.
Note that R ¹ and R ² described above may be the same or different.

R ³ in the general formula (Ib) is hydrogen, a C _1-8 alkyl group or a C _7-15 aralkyl group, like the bisphosphonic acid derivative of the general formula (Ia). Specific examples of the C _1-8 alkyl group and the C _7-15 aralkyl group are as described above. In the general formula (Ib), four R ^{3 s} are present, and these R ^{3 s} may be the same or different. However, in consideration of the convenience of synthesis, the four R ^{3 s} are It is preferable that they are the same group.

Further, m and n are 0 or a positive integer, and (m + n) is 2 to 5 for the same reason as the above-mentioned bisphosphonic acid derivative of the formula (Ia).

Specific examples of the bisphosphonic acid derivative of the present invention represented by the general formula (Ib) include R ¹ , R ² and
Examples include bisphosphonic acid derivatives in which m, n and R ³ are groups or numbers shown in Tables 2 to 6 below.
The present invention is not limited to these exemplified compounds.

[0017]

[Table 2]

[0018]

[Table 3]

[0019]

[Table 4]

[0020]

[Table 5]

[0021]

[Table 6]

The bisphosphonic acid derivative of the present invention is represented by the general formula (I) in addition to the bisphosphonic acid derivative of the general formula (I) containing the compound of the general formula (Ia) and the compound of the general formula (Ib). Also included are pharmaceutically acceptable salts of bisphosphonic acid derivatives. As these salts, inorganic salts such as sodium salt, potassium salt, magnesium salt, calcium salt and glycine, alanine, phenylalanine,
Examples thereof include salts with amino acids such as lysulin.

Next, a method for producing each bisphosphonic acid derivative of the general formulas (Ia) and (Ib) contained in the bisphosphonic acid derivative of the general formula (I) will be described. First, the production method of the bisphosphonic acid derivative of the general formula (Ia) will be described. The bisphosphonic acid derivative can be produced, for example, by the following production method A or production method B.

Production Method A [Production Method of Bisphosphonic Acid Derivative of General Formula (Ia) in which R ³ is a C _1-8 Alkyl Group or C _7-15 Aralkyl Group] This bisphosphonic acid derivative has the general formula (II)

[Chemical 8] (In the formula, m and n are 0 or a positive integer, and (m
+ N) is 2 to 5) and a compound of the general formula (I
II) (R ³ O) ₂ PHO (III) (wherein R ³ is a C _1-8 alkyl group or a C _7-15 aralkyl group) is reacted to give a compound of the general formula (IV)

[Chemical 9] (Wherein R ³ , m and n are represented by the general formulas (II) and (III))
(The same definition as in 1) is obtained, and then the compound is preferably treated in an acidic medium such as an aqueous acetic acid solution, trifluoroacetic acid, or a dilute aqueous hydrochloric acid solution.

Process B [General formula (I in which R ³ is hydrogen
a) Production Method of Bisphosphonic Acid Derivative] This bisphosphonic acid derivative is obtained by subjecting the bisphosphonic acid derivative of the general formula (Ia) (R ³ = C _1-8 alkyl group or C _7-15 aralkyl group) obtained by the production method A to hydrochloric acid. , An aqueous solution of caustic soda, a mixed solution of hydrogen bromide and acetic acid, (CH ₃ ) ₃ SiI and the like.

On the other hand, the bisphosphonic acid derivative of the general formula (Ib) can be produced, for example, by the following production method 1, production method 2 or production method 3. -Production Method 1 [Production Method of Bisphosphonic Acid Derivative of General Formula (Ib) in which R ³ is a C _1-8 Alkyl Group or C _7-15 Aralkyl Group] This bisphosphonic acid derivative has the general formula (V)

[Chemical 10] (In the formula, R ¹ and R ² are (i) hydrogen, (ii) C _1-6 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group, C _1-6 alkyl-carbonyl group, C 1 _2-6 alkenyl - carbonyl group, C _{2 to 6} alkynyl - carbonyl group (which may be substituted with at least one of these groups selected from a substituted amino group, a halogen atom and a carboxyl group) or (iii) a halogen atom Which may be the same or different, m and n are 0 or a positive integer, and (m + n) is 2 to 5), and a compound represented by the general formula (VI) (R ³ O) ₂ PHO (VI) (wherein R ³ is a C _1-8 alkyl group or a C _7-15 aralkyl group) and a compound of the general formula (VII) HC (OR ⁴ ) ₃ (VII) among the compounds R ⁴ is represented by a is) _{C 1 to 3} alkyl group Obtained by reacting. Where R
_Examples of the C _1-3 alkyl group of ⁴ include a methyl group, an ethyl group, and a linear or branched propyl group.

In this production method 1, it is preferable to use the compound of the general formula (VI) in an amount of 2 to 50 times and the compound of the general formula (VII) in an amount of 1 to 3 times the amount of the compound of the general formula (V). The reaction temperature is preferably 100 to 200 ° C., and the reaction time is preferably 5 to 100 hours. Moreover, you may use the inorganic acid salt or organic acid salt instead of the compound of General formula (V). In this case, in addition to the compound of the general formula (VI) and the compound of the general formula (VII), 1.2
It is also preferred to use ~ 3.5 times the amount of organic base.

Production Method 2 [Production Method of Bisphosphonic Acid Derivative of General Formula (Ib) wherein R ³ is C _1-8 Alkyl Group or C _7-15 Aralkyl Group] This bisphosphonic acid derivative was obtained by the above Production Method A. The following general formula (Ia)

[Chemical 11] (In the formula, R ³ is a C _1-8 alkyl group or a C _7-15 aralkyl group, m and n are 0 or a positive integer, and (m + n) is 2-5). The acid derivative has the general formula (VIII)

[Chemical formula 12] (In the formula, R ¹ and R ² are (i) hydrogen, (ii) C _1-6 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group, C _1-6 alkyl-carbonyl group, C 1 _2-6 alkenyl - carbonyl group, C _{2 to 6} alkynyl - carbonyl group (which may be substituted with at least one of these groups selected from a substituted amino group, a halogen atom and a carboxyl group) or (iii) a halogen atom And may be the same or different).

Production method 3 [General formula (I in which R ³ is hydrogen
b) Method for Producing Bisphosphonic Acid Derivative] This bisphosphonic acid derivative can be produced by the general formula (I
b) obtained by treating the bisphosphonic acid derivative (R ³ = C _1-8 alkyl group or C _7-15 aralkyl group) with hydrochloric acid, caustic soda aqueous solution, hydrogen bromide-acetic acid mixed solution, (CH ₃ ) ₃ SiI, or the like. Be done.

Since the bisphosphonic acid derivative of the general formula (I) thus obtained strongly suppresses bone resorption and has no local stimulating action, it is a bone resorption inhibitor, for example, a therapeutic agent for bone diseases such as an osteoporosis therapeutic agent. Is effectively used as.

Although the bisphosphonic acid derivative of the present invention may be used alone as a bone resorption inhibitor, it can be used in various dosage forms by utilizing a known formulation method. For example, it can be used for oral preparations such as tablets, granules, powders, capsules and syrups, and parenteral preparations such as injections and suppositories. The dose varies depending on the patient's symptoms, age, body weight, therapeutic effect, administration method, and administration period, but usually, in the case of oral administration, it is preferable to administer a dose of 2 to 1000 mg per day for an adult.

[0032]

EXAMPLES Examples of the present invention will be described below. Example 1 (Production method 1) 4-methylidene piperidino methylene bisphosphonic acid ethyl ester (R ¹ = R ² = H, R ³ = -C ₂ H ₅ , m =
Preparation of n = 2) 4-methylidene piperidine hydrochloride 13.7 g (100 mmol), triethylamine 20.2 g (200 mmol), HC (OC ₂ H ₅ ) ₃ 35.6 g (240 mmol) and ethyl phosphite. Ester 85.6 g (620
The mixture of (mmol) is stirred at 140 ° C. for 6 hours. 250 ml of ether was added to the reaction solution, washed with 100 ml of 0.5N-caustic soda aqueous solution and 500 ml of water, and then concentrated under reduced pressure. The residue was distilled under reduced pressure to give 23 g (yield 58%).
The title compound was obtained.

[0033]

[Equation 1]

Example 2 (Production Method 3) 4-methylidene piperidino methylene bisphosphonic acid (R
Preparation of ¹ = R ² = R ³ = H, m = n = 2) 23 g (59.9 mmol) of 4-methylidene piperidinomethylene bisphosphonic acid ethyl ester obtained in Example 1 was dried with CHCl ₃ After adding to 200 ml and cooling to 0 ° C., 49.1 g of Me ₃ SiI (245.6)
Mmol) is added. After stirring this reaction solution at 0 ° C. for 1 hour, the solvent was distilled off under reduced pressure, and methanol was added to the residue to obtain colorless crude crystals. The crude crystals were recrystallized from methanol-water to give 13.9 g of the title compound as colorless plate crystals (yield 8
6%) was obtained.

[0035]

[Equation 2]

Example 3 (Production Method 1) 4-Hexylidenepiperidinomethylene bisphosphonic acid ethyl ester (R ¹ ═CH ₃ (CH ₂ ) ₄ —, R ² ═
_{^{H, R 3 = -C 2 H}} 5, m = n = 2) of the production of 4-f xylylene Den piperidine hydrochloride 6.0 g (28.8
Mmol), Et ₃ N 6.6 g (65.4 mmol),
A mixture of 10.8 g (72.9 mmol) CH (OEt) ₃ and 25.8 g (186.9 mmol) ethyl phosphite is stirred at 140 ° C. for 10 hours. Chloroform (450 ml) was added to the reaction mixture, the mixture was washed with 0.5N-caustic soda aqueous solution (300 ml) and water (1500 ml), and the solvent was evaporated under reduced pressure to give a residue, which was purified by silica gel chromatography to give the title compound as an oil. 3 g (yield 7
1%) was obtained.

[0037]

[Equation 3]

Example 4 (Production method 3) 4-hexylidenepiperidinomethylenebisphosphonic acid (R ¹ ═CH ₃ (CH ₂ ) ₄ —, R ² ═R ³ ═H, m =
Preparation of n = 2) 4-hexylidenepiperidinomethylene bisphosphonic acid ethyl ester obtained in Example 3 9 g (20 mmol)
Is added to 70 ml of dry carbon tetrachloride and, after cooling to 2 ° C., 16.4 g (82 mmol) of Me ₃ SiI is added. The reaction solution was stirred at 2 ° C. for 1 hour, the solvent was distilled off under reduced pressure, and methanol was added to the residue for recrystallization to obtain 6.6 g (yield 97%) of the title compound as colorless scale crystals. ..

[0039]

[Equation 4]

Example 5 (Production method 2) 4-Ethylidene piperidino methylene bisphosphonic acid ethyl ester (R ¹ = -CH ₃ , R ² = H, R ³ = -C ₂
Production of H ₅ , m = n = 2) 7.5 g of ethyltriphenylphosphonium bromide
To a solution of (20 mmol) in THF (50 ml) was added 12.5 ml (20 mmol) of 1.6M BuLi-hexane solution under ice cooling, and then 5.8 g (15 g of 15-oxopiperidinomethylene bisphosphonic acid ethyl ester). Mmol) is added dropwise. After stirring at room temperature for 24 hours, 100 ml of hexane was added to the reaction solution, washed with water and dried, and then the solvent was distilled off to obtain an oily residue. The residue was purified by silica gel chromatography to give 3.5 g (yield 58.7%) of the title compound.

[0041]

[Equation 5]

Example 6 (Production method 3) 4-ethylidene piperidino methylene bisphosphonic acid (R
_{^{1 = -CH 3, R 2 =}} R 3 = H, m = n = 2) obtained in Production Example 5 4-ethylidene-piperidinoethoxy methylene bisphosphonic acid ethyl ester 0.9g of (2.2 mmol) Add carbon tetrachloride (10 ml) solution to Me ₃ Si at 0 ° C.
I (1.8 g, 9.0 mmol) was added, the mixture was stirred at room temperature for 1 hr, and the reaction mixture was concentrated under reduced pressure. The residue was recrystallized from methanol to obtain 0.55 g (yield 88.2%) of the title compound.

[0043]

[Equation 6]

Example 7 (Production Method 1) 4-Propylidenepiperidinomethylene bisphosphonic acid ethyl ester (R ¹ = R ³ = -C ₂ H ₅ , R ² = H, m
= N = 2) Example 1 except that 2.6 g (16.2 mmol) of 4-propylidene piperidine hydrochloride was used instead of 13.7 g (100 mmol) of 4-methylidene piperidine hydrochloride.
In the same manner as in 6.2, 6.2 g (yield 93%) of the title compound was obtained.

[0045]

[Equation 7]

Example 8 (Production method 3) Preparation of 4-propylidene piperidinomethylene bisphosphonic acid (R ¹ = -C ₂ H ₅ , R ² = R ³ = H, m = n = 2) 4-methylidene The same procedure as in Example 2 was repeated except that 3.7 g (9 mmol) of 4-propylidenepiperidinomethylene bisphosphonic acid ethyl ester obtained in Example 7 was used in place of piperidinomethylene bisphosphonic acid ethyl ester. The title compound (0.7 g, yield 25%) was obtained.

[0047]

[Equation 8]

Example 9 (Production Method 1) 4-Butylidenepiperidinomethylene bisphosphonic acid ethyl ester (R ¹ = -C ₃ H ₇ , R ² = H, R ³ = -C)
Preparation of ₂ H ₅ , m = n = 2) 4-Methylidenepiperidine hydrochloride 4-butylidenepiperidine hydrochloride was used in place of 13.7 g (100 mmol).
1.8 g (yield 51%) of the title compound was obtained in the same manner as in Example 1 except that 5 g (8.5 mmol) was used.

[0049]

[Equation 9]

Example 10 (Production method 3) 4-butylidene piperidino methylene bisphosphonic acid (R
^{_{1 = -C 3 H 7, R}} 2 = R 3 = H, m = n = 2) of the production of 4-methylol instead isopropylidene piperidinocarbonyl methylene bisphosphonic acid ethyl ester, 4-butyl obtained in Example 9 0.5 g of the title compound (yield 53%) was obtained in the same manner as in Example 2 except that 1.2 g (2.8 mmol) of redene piperidino methylene bisphosphonic acid ethyl ester was used.

[0051]

[Equation 10]

Example 11 (Production Method 1) 3-Methylidene piperidino methylene bisphosphonic acid ethyl ester (R ¹ = R ² = H, R ³ = -C ₂ H ₅ , m =
Preparation of 1, n = 3) 4-Methylidenepiperidine hydrochloride 1 in place of 13.7 g (100 mmol) of 4-methylidenepiperidine hydrochloride 1
20 g (yield 52%) of the title compound was obtained in the same manner as in Example 1 except that 3.7 g (100 mmol) was used.

[0053]

[Equation 11]

Example 12 (Production method 3) 3-methylidene piperidino methylene bisphosphonic acid (R
¹ = R ² = R ³ = H, m = 1, n = 3) Preparation of 4-methylidene piperidino methylene bisphosphonic acid ethyl ester instead of 3-methylidene piperidino obtained in Example 11. 7.0 g (yield 86%) of the title compound was obtained in the same manner as in Example 2 except that 11.5 g (60 mmol) of methylenebisphosphonic acid ethyl ester was used.

[0055]

[Equation 12]

Example 13 (Production method A) 4-oxopiperidinomethylene bisphosphonic acid ethyl ester (X = oxygen atom, R ³ = -C ₂ H ₅ , m = n =
Preparation of 2) 50 g (0.35 mol) of 1,4-dioxa-8-azaspiro [4.5] -decane, 62 g of CH (OEt) _3.
(0.42 mol) and ethyl phosphite 150
After stirring a mixture of g (1.1 mol) at 140 ° C. for 12 hours, the reaction solution was extracted with chloroform, washed with a 2N-caustic soda aqueous solution, and then the chloroform layer was dried. Then, chloroform was distilled off to obtain 130 g of oily crude 1,4-dioxa-8-azaspiro [4.5] -decane-8-methylenebisphosphonic acid ethyl ester.

[0057]

[Equation 13]

The oily substance was stirred at 110 ° C. in 500 ml of an aqueous acetic acid solution (volume ratio of acetic acid and water = 4: 1),
The residue obtained by removing the acetic acid aqueous solution from the reaction solution was subjected to silica gel column chromatography (2% ethanol-chloroform).
The title compound (95 g, yield 70%) was obtained.

[0059]

[Equation 14]

Example 14 (Production method B) Preparation of 4-oxopiperidinomethylene bisphosphonic acid (X = oxygen atom, R ³ = H, m = n = 2) 4-oxopiperidyi obtained in Example 13 7.7 g of nomethylene bisphosphonic acid ethyl ester and Me ₃ SiI
16.9 g (836 mmol) and carbon tetrachloride 120
After stirring in 0 ml at 0 ° C. for 30 minutes, 50 ml of water and 200 ml of methanol were added to the residue obtained by distilling off the reaction solution under reduced pressure, and the mixture was added to
The mixture was stirred at 30 ° C for 5 hours. The reaction solution was distilled off, and the residue was subjected to silica gel column chromatography (CHCl ₃ : CH ₃
Purification with OH = 9: 1) gave 2.0 g (37% yield) of the title compound.

[0061]

[Equation 15]

Example of Pharmacological Activity Next, the method and results of the antihypercalcemic action of the compound of the present invention in thyroid and parathyroidectomized rats will be described. Wistar male rats 7 weeks old (150
~ 170g) under Nembutal anesthesia, Russel
RG el al, Calcif. Tissue. Res., 6, 183 ~ 196 (197
0) and Muehlbauer RCet al, Mineral Electrolyte
The thyroid and parathyroid glands are surgically removed by the method described in Metab., 5, 296-300 (1981). After feeding for 3 days after the operation, after feeding on a normal diet, blood is collected on the 4th day, the serum calcium level is measured by an atomic absorption method, and the rats whose level is reduced to 5 to 7 mg / dl are selected.

Each of these rats was divided into 5 groups, and the compound of the present invention was dissolved in physiological saline to obtain 5 mg / mouse.
Adjust to ml. This solution is subcutaneously administered at 2 ml / kg once a day before injection of parathyroid hormone (PTH). Saline is administered as a control group. On the next day, 0.2 ml of blood is collected and the serum calcium level is measured in the same manner as above (this value is defined as the 0-day value (a)). At the same time, PT
An osmotic pump (2001 type, Alza) encapsulating H (50 μg / 0.2 ml-physiological saline) was subcutaneously implanted in the back, and 24 hours later, blood was collected from the abdominal aorta and the serum calcium level was measured (this value was measured). 1-day value (b)).

The obtained result was calculated as the serum increased calcium value by the following formula. Serum increase calcium level = PT
H administration 1-day value (b) -PTH administration 0-day value (a) The results obtained in the above test are shown in Table 7.

[0065]

[Table 7]

From the results in Table 7, it is clear that the compounds of Examples 2, 4, 6, 8 and 10 strongly suppress the increase in serum calcium level due to the administration of PTH. Therefore PT
It is clear that the bone resorption effect of H is suppressed. In this pharmacological activity test, no side effect such as skin swelling was observed in any of the individuals subcutaneously administered with the bisphosphonic acid derivative of the present invention.

Example of Toxicity Test LD ₅₀ of the compounds of Examples 2, 4, 6, 8 and 12 is ddy
Strain mice (male), 5 weeks old (22-27 g),
Subcutaneous injection is 100 mg / kg or more.

Formulation Examples Formulation examples of the compound of the present invention are shown. Tablets containing 50 mg of active ingredient per tablet were prepared according to the following formulation. (Component) (mg) Compound of Example 2 50 Crystalline cellulose 50 Carboxymethylcellulose calcium 10 Sodium lauryl sulfate 1 Methylcellulose 3 Calcium stearate 4

According to the following formulation, capsules were prepared by filling capsules with 200 mg of the mixed ingredients containing 50 mg of the active ingredient per tablet. (Component) (mg) Compound of Example 4 50 Lactose 50 Corn starch 40 Crystalline cellulose 50 Calcium stearate 10 The above-mentioned formulation and the two examples are shown, but the formulation is not limited thereto.

[0070]

INDUSTRIAL APPLICABILITY As described above, the novel bisphosphonic acid derivative represented by the general formula (I) of the present invention, which has not been described in the literature, exhibits an excellent bone resorption inhibiting action. Therefore, it is extremely effective as a prophylactic or therapeutic drug for bone diseases caused by bone resorption and the like, for example, osteoporosis, and is particularly useful as a novel drug for osteoporosis.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Satoru Ikegami 14 Minamigawara-cho, Sannomiya-ku, Kyoto-shi, Kyoto Prefecture Central Research Laboratory (Kyoto), Kaken Pharmaceutical Co., Ltd. (72) Yoshiyuki Hiyama, Yamashina-ku, Kyoto Prefecture Central Research Laboratory, Kaken Pharmaceutical Co., Ltd., 14th, Minamikawaramachi, Shinomiya (72) Inventor: Takao Awa, 14th Central Research Laboratory, Minamikawaracho, Sannomiya, Yamashina-Kyoto, Kyoto Prefecture

Claims (2)

[Claims] 1. A compound represented by the general formula (I): [Wherein, X is an oxygen atom or a compound represented by the formula: Is an alkylidene group represented by and when X is an alkylidene group, R ¹ and R ² are (i) hydrogen, (ii) C
_1-6 alkyl group, _C2-6 alkenyl group, _C2-6 alkynyl group, _C1-6 alkyl-carbonyl group, C
_2-6 alkenyl-carbonyl group, _C2-6 alkynyl-carbonyl group (these groups may be substituted with at least one selected from a substituted amino group, a halogen atom and a carboxyl group) or (iii) a halogen atom R ³ is hydrogen, a C _1-8 alkyl group or a C _7-15 aralkyl group, m and n are 0 or a positive integer, and (m + n) is 2 Is a bisphosphonic acid derivative or a pharmaceutically acceptable salt thereof. 2. A bone resorption inhibitor comprising the bisphosphonic acid derivative according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.