JPH02184A - Azolaminomethylene bisphosphonic acid derivative and medicine - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I [A represents formulae II-IV (R represents H, halogen, lower alkyl or phenyl; n is 1 or 2); X represents O, S or imino; R<1> to R<4> represent H or lower alkyl]. EXAMPLE:[(5-Methyl-2-oxazolyl)amino]methylene bis(phosphonic acid). USE:A bone resorption inhibitor useful as an anti-inflammatory agent and antirheumatic agent. PREPARATION:A 2-amino-azole expressed by formula V, a lower alkyl orthoformate expressed by formula VI and a phosphorous acid ester expressed by formula VII are subjected to reaction preferably at 150 deg.C for 10-60min.

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Field of Application) The present invention relates to azole aminomethylene bisphosphonic acid derivatives useful as pharmaceuticals such as anti-inflammatory agents and anti-rheumatic agents.

(Prior art) Azole bisphosphonic acid derivatives include 5- to 6-membered heterocyclic thioalkyl bisphosphonic acid containing an unsubstituted nitrogen atom and sulfur atom (Japanese Unexamined Patent Publication No. 59-42395) and azole alkyl bisphosphonic acid (Japanese Unexamined Patent Publication No. 59-42395). Showa 61-4319
Publication No. 7) has been reported.

The present invention relates to azole aminomethylene bisphosphonic acid having a chemical structural feature in that an azole ring is bonded to a methylene group via an imino group.

(Means for Solving the Problems) That is, the present invention is an azole aminomethylene bisphosphonic acid represented by the following formula (1), a lower alkyl ester thereof, or a nontoxic salt thereof.

(n means 1 or 2), X is an oxygen atom, a sulfur atom or an imino group, R'R2,
R3 and R4 each represent a hydrogen atom or a lower alkyl group. ) In the explanation of (1) above, A together with the heteroatoms N and X forms a 5-membered heterocycle (azole) which may have a substituent. Examples of the heterocycle include thiazole, oxazole, imidazole, thiadiazole, oxadiazole, triazole, benzothiazole, and benzoxazole. These heterocycles may have a halogen atom or a lower alkyl group as a substituent. The halogen atom may be a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom, and the lower alkyl group may be a linear or branched hydrocarbon group having 1 to 5 carbon atoms. It is. Typical lower alkyl groups include methyl, ethyl, propyl, and isopropyl. The lower alkyl group of n l-R4 is the same as described above.

The salt of compound (1) is a salt with a non-toxic base. Suitable salts include inorganic base salts such as sodium salts and potassium salts, and organic base salts such as ammonium salts and triethylamine salts.

(Manufacturing method) The compound of the present invention can be manufactured by the method shown by the following reaction formula.

(First manufacturing method) (In the formula, R5R11, R?, Ra and R9 represent a lower alkyl group, and Y represents a halogen atom. The same applies hereinafter.) (First manufacturing method) This method produces 2-aminoazole (n) , orthoformic acid lower alkyl ester (III), and phosphite ester (IV) in corresponding amounts for each reaction are mixed and reacted under heating. A reaction solvent is not particularly required. The reaction is usually carried out at 100° to 200°C, preferably around 150°C for 10
Do this for ~60 minutes.

In order to isolate and purify the reaction product thus obtained, for example, the reaction mixture may be packed into a silica gel column and eluted with a methanol-chloroform mixed solvent.

In this reaction, the formula minoether intermediate is produced by further reacting with phosphite (IV) by 2-aminoazole (■) and orthoformic acid lower alkyl ester ([[). The desired compound can be obtained.

The thus obtained bisphosphonic acid ester can be hydrolyzed, if desired, to lead to the corresponding bisphosphonic acid. This hydrolysis involves treating the bisphosphonic ester with a strong acid or trimethylsilyl halide in a water-free solvent. Usually, commercially available hydrobromide and acetic acid as is or diluted as appropriate; solvents such as chloroform, benzene, toluene, etc. saturated with hydrogen halide gas; solvents such as carbon tetrachloride, dimethylformamide, chloroform, toluene, etc. A material in which trimedelsilane iodide is dissolved is used. The temperature for hydrolysis may be between cooling and heating; for example,
When treated with trimethylsilyl halide under cooling below -10° C., a partially hydrolyzed target compound is produced. This hydrolysis can also be carried out by heating and leaving in concentrated hydrochloric acid.

In order to convert diphosphonic acid into a salt, it is treated with a base such as sodium hydroxide, potassium hydroxide, ammonia, etc. by a conventional method.

(Second production method) In this method, first, a mixed solution of phosphorus halide (V) and trialkyl phosphite (VI) is heated at, for example, 40 to 100°C.
Preferably react at 60 to 80°C for 15 to 30 minutes,
Then, formylaminoazole (■) is added to this mixed solution, for example at 40-100°C, preferably at 60-8°C.
Heat at 0°C for several hours. The progress of the reaction can be easily confirmed by TLC (developing system: chloroform-methanol). After the reaction is completed, excess trialkyl phosphite is distilled off. Isolating the reaction product thus obtained,
For purification, for example, the reaction mixture may be purified as it is using a silica gel column, or it may be made into a chloroform solution, washed with water, the solvent may be distilled off, and then purified using a silica gel column. The bisphosphonic acid ester thus obtained can be hydrolyzed to the corresponding bisphosphonic acid, if desired, in the same manner as described in the first production method, and it can also be further converted into a salt.

(Effect of the invention) Compound (1) and its salt provided by the present invention are:
It has a bone resorption inhibitory effect and also has the effect of suppressing hypercalcemia caused by bone resorption. It is also recognized to have excellent anti-inflammatory and antipyretic and analgesic effects.

Next, the hypercalcemia suppressing effects of the compounds of the present invention will be shown together with test methods.

Hypercalcemia suppressive effect Parathyroid hormone
The effect of lowering serum calcium level when the active ingredient of the present invention was administered to hypercalcemic rats was measured by administering one (hereinafter referred to as PTH).

Test method: 30 μg/kg of human l-34PTH was intravenously administered to 5-week-old male Wistar rats that had been fasted for 20 hours. PTH was dissolved in physiological saline containing 0.1% BSA,
mf2/kg was administered. 0.1% BS for normal control group
Only physiological saline containing A was administered in the same manner. PTH administration 4 The animals were given double litters, and blood was collected from the abdominal vena cava using a vacuum blood collection tube.

The blood was immediately centrifuged at 4°C, 3,000 rpm for 10 minutes,
Serum was separated. Ionized calcium (Ca
) 6 degrees immediately Ca + 1 meter (Horiba,
Measured using Cera 250).

The compounds of the present invention were prepared using caustic soda and hydrochloric acid at a concentration of 2 mQ/kg in physiological saline solution at pH 7.4 for subcutaneous administration, and at 5 mQ/kg in distilled aqueous solution at pH 7.4 for oral administration. The animals were adjusted to have the following properties and administered 24 or 72 hours before PTH administration. Physiological saline or distilled water was administered to the normal control group and the control group in the same manner.

The results are expressed as mean ± S, E for each group, and comparisons between groups were tested using one-way analysis of variance. Note that a risk rate of less than 5% was considered significant.

Table 1 shows the results of subcutaneous administration and oral administration.

Table 1 Mean ± S, E, *: P<0.05, **;
P<0.01 The compound of Example 6 was administered 24 hours before PTH administration, and the others were administered 72 hours before PTH administration.The compound of the present invention can be used as a bone resorption inhibitor, as well as an antirheumatic agent and an antiarthritic agent. It can also be used as an anti-inflammatory, antipyretic, and analgesic.

The compound (1) of the present invention and its salts can be used as is or as a pharmaceutical composition mixed with known pharmaceutically acceptable carriers, excipients, and the like. Administration can be by oral administration such as tablets, capsules, powders, granules, gunpowder, injections, etc.
It may be administered parenterally, such as syrup, ointment, or tablets. The dosage varies depending on the subject, route of administration, symptoms, etc., but it is usually 10 mg orally per day for adults.
g, 0.1 to 10 mg parenterally.

(Prescription example) Next, examples of prescriptions for the medicament of the present invention will be given.

Tablet; 5+ng of the compound of Example 10
Lactose 119mg Corn starch 67mg Hydroxypropylcellulose 4mg Carboxymethylcellulose calcium 4mg Magnesium stearate 1mg Total amount 20
0mg 0.5g of the compound of Example 10, 119g of lactose,
) 67 g of corn corn starch was mixed uniformly, 40 mQ of hydroxypropyl cellulose IO% (W/W) aqueous solution was added to the mixture, and the resulting mixture was wet-granulated.

The granules thus obtained were mixed with methylcellulose calcium 4
g and 1 g of magnesium stearate and compress the mixture into 200 mg tablets.

Capsule: Compound of Example 1O 5i+g
Crystalline cellulose 50mg Crystalline lactose 144mg Magnesium stearate 1mg Total amount 200mg I and ooo times the amount of each of the above ingredients were mixed and filled into gelatin capsules to produce 200mg capsules.

(Example) Next, the compound of the present invention and its production method will be explained with reference to Examples.

Example! (Bottom') NHCH (Act:=:: 7.5 g of 2-aminobenzothiazole, 8.6 g of ethyl orthoformate, and 14 g of diethyl phosphite were heated at 150°C for 30 minutes.
The mixture was heated and stirred for 1 minute. The reaction solution was returned to room temperature and purified using a silica gel column (eluted with 2% methanol/chloroform) to obtain 4 g of tetraethyl((2-benzothiazolyl)amino)methylenebis(phosphonate) as a solid.

The physical and chemical properties of this product are as shown.

(i) Mass spectrometry value (FAB Mass) 437
(M+1) (11) Nuclear magnetic resonance spectrum (c D C
13) δI2-1.4 (12H, CH, CH, OX
4).

4.0-4.4 (8H, CH3CH10X4).

5.28 (IH, dt, NHCH).

7.0-7.7 (4H, H of benzothiazole ring) Example 2゜α and NHCH<test amount.

a) 3.3 g of tetraethyl [(2-benzothiazolyl)amino)methylenebis(phosphonate) was dissolved in 30 ml (l) of carbon tetrachloride, and 4.52+n4 trimethylsilane iodide was added dropwise under cooling with ice water. Returned to room temperature for 1 hour. Stirred.

The reaction solution was concentrated, methanol was added, and the mixture was concentrated again. The obtained solid was washed with chloroform.

b) This solid is reduced to 0. Dissolved in IN sodium hydroxide solution. This was purified on a HP-20 resin column (eluted with water) to give trisodium((2-benzothiazolyl)amino)methylenebis(phosphonate) 1 as a hygroscopic solid.
．． 2g was obtained.

The physical and chemical properties of this product are as follows.

(i) Elemental analysis value (CJ7Nt06SPjNaff
-0,511tO) C (%) H (%) N (%
) Theoretical value 24.07 2,02 7.02 Experimental value 24.10 2.46 7.02 (ii)
Mass spectrometry value (F A B Mass) 391 (M
+ 1) (iii) Nuclear magnetic resonance spectrum (D,
0) 63.96 (I H, t, NHCH) 6
．． 9-7.6 (4H, H of benzothiazole ring) Example 3 4.2 g of 2-amino-5-chlorobenzoxazole,
3.7g of ethyl orthoformate, 6.9g of diethyl phosphite
The mixture was heated and stirred at 150°C for 30 minutes. The reaction solution was returned to room temperature and purified in the same manner as in Example 1 to obtain tetraethyl [(2
5 g of -(5-chloro)penzoxatizolyl)aminocomethylenebis(phosphonate) was obtained as a liquid.

The physical and chemical properties of this product are as follows.

(i) Mass spectrometry value (FAB Mass)
455.457(ii) Nuclear magnetic resonance spectrum (C
D CIs) 61.2-1.4 (12H, CH3C
HtOX4).

4.0-4.4 (8H, CH3CHtOX4).

4.82 (IH, t, NHCH).

6.95-7.4 (3H, H of benzoxazole ring)
Example 4゜'a>"1(CH Silane 6
．． 9 m2 was added under cooling with ice water. Processed in the same manner as in Example 2,
Trisodium [(2-(5
2.9 g of -chloro)benzooxacyl)aminocomethylene bis(phosphonate) was obtained.

The physical and chemical properties of this product are as follows.

(i) Elemental analysis value (CsHsNtOsCIPtNa
s ・1.511!0)C(%)I((%)N(
%) Theoretical value 22.06 2. H6,43 experimental value 2
2.0? 2.18 6.18(ii) Mass spectrometry value (FAB Mass) 409 (M-41) (
iii) Nuclear magnetic resonance spectrum (D!0 medium)64.
08 (IH, t, NHCH) 7.0-7.4
(3H, H of benzothiazole ring) Example 5 3 g of 2-aminothiazole 5.3 g of ethyl orthoformate
, 8.2 g of diethyl phosphite was heated and stirred at 150° C. for 1 hour. The reaction solution was returned to room temperature and purified in the same manner as in Example 1 to obtain 3.7 g of tetraethyl[(2-thiazolyl)aminocomethylenebis(phosphonate) as a solid.

The physical and chemical properties of this material are as follows.

(1) Mass spectrometry value (FAB Mass) 387
(M + 1) (11) Nuclear magnetic resonance spectrum (CD
in CI3) 61.2 to 1.3 (12H, CI, CH,
0X4).

4.0-4.4 (8H, CH, CH, 0X4).

5, H (II-1, t, N1-ICH).

6.55, 7.15 (each IH, d, H of thiazole ring)
Example 6 3.7 g of tetraethyl((2-thiazolyl)amino)methylenebis(phosphonate) was dissolved in carbon tetrachloride/4 m(l
5.8+n (2) of trimethylsilane iodide was added under cooling with ice water. Treated and purified as in Example 2a) to give ((2-thiazolyl)amino)methylenebis(phosphonic acid) 1 as a hygroscopic solid. .3g was obtained.

The physical and chemical properties of this product are as follows.

(i) Elemental analysis value CC, H@N, 085P, ・l/
3) f, 0) C (%) H (%) N (%) Theoretical value 17.14 3.10 10.00 Experimental value 17J3 3.10 9.87 (ii)
Mass spectrometry value (F A B Mass) 275 (M
+ I) (iii) Nuclear magnetic resonance spectrum (DX
(in O) 64.0g (l H,t, NHCH)6
．． 90,7.22 (Each IH, d, H of thiazole ring) Example 7 2-amino-1,3,4-thiadiazole 5L 7.3 g of ethyl orthoformate, 13.6 g of diethyl phosphite were added to 15
The mixture was heated and stirred at 0°C for 30 minutes. The reaction solution was returned to room temperature and purified in the same manner as in Example 1 to obtain tetraethyl ((1,3,4
-thiadiazol-2-yl)amino)methylenebis(
phosphonate) was obtained as a solid.

The physical and chemical properties of this product are as follows.

(1) Mass spectrometry value (FAB Mass) 38
8(M+1)(11) Nuclear magnetic resonance spectrum (D
MSO-d, medium) 61.0 to 1.4 (12H, CH, C
H, OX4).

3.9-4.3 (8H, CH, Cl-1tOX4).

5.02 (lH, dt, NHCH).

8.42 (l H, d, NI-ICH) 8.6
8 (IH,s, H of cyanoazole ring) Example 8
3.2 g of ゜tetraethyl ((1,3,4-thiadiazol-2-yl)amino)methylenebis(phosphonate) was dissolved in 60 m of carbon tetrachloride, and 51 g of trimethylsilane iodide was added under cooling with ice water. Example 2a ),
((+,3.4thiadiazol-2-yl)amino)methylenebis(phosphonic acid) 1 as a purified hygroscopic solid
．． 3g was obtained.

The physical and chemical properties of this product are as follows.

(1) Elemental analysis values (c, rl, N, 0, S P
,・l/3H20) C (%) H (%) N (%
) Theoretical value 12.81 2.49 14.94 Experimental value 13.01 2J1 15.21 (ii) Mass spectrometry value (FAB Mass) 276 (M+1) (
iii) Nuclear magnetic resonance spectrum (in DtO) δ4,
24 (I H, t, NHCH) 8.78
(l H, s, 1-1 of the thiaditisol ring) Example 9゜Chem, Ber, vol. 95, p. 2419 (1
2-amino-5 synthesized by the method described in 962)
-Methyloxazole 3.0Cg (30.6mmol)
, 5.44 g of ethyl orthoformate (36,8n+n+ol
), and diethyl phosphite 16.9 g (122 mmol
) is reacted for 2.5 hours on a 145° C. oil bath and then similarly concentrated under reduced pressure (approximately 3011 io+Hg). The residue was subjected to column chromatography twice (first time: silica gel, chloroform-methanol, second time: silica gel, ethyl acetate-
5.29 g (13.8 mmol) of tetraethyl [(5-methyl-2-oxacylyl) aminocomethylene bis(phosphonate)
) was obtained.

(1) Mass spectrometry value (EI), 384 (M),
247 (100).

(II) Nuclear magnetic resonance spectrum (in CDCIs) δ x
, 3(bt, 12H), 2.2(d, 3H),
4. o~4.2(n, 8H), 4.6(bt,
l H), 6.4 (q, I H) Example 10° 1.1 g of tetraethyl [(5-methyl-2-oxacylyl) aminocomethylene bis(phosphonate) was dissolved in 11 nl of carbon tetrachloride, and argon gas, 2.4 g of trimethylsilane iodide was added dropwise under ice water. Return to room temperature 4
After stirring for 5 minutes, it was concentrated. Methanol was added to the reaction residue, and the mixture was concentrated again. When acetonitrile was added to the resulting syrup, it solidified. Washing the solid with hot methanol gives
[0.5 g of (5-methyl-2-oxacylyl)aminocomethylenebis(phosphonic acid) was obtained.

(1) Melting point 250°C (decomposition) (ii) Mass spectrometry value (FAB) 273 (M+1) (
Mountain) Elemental analysis value (CsH+oN to ?P t ・H
to )C(%) H(%) N(%) P(
%) Theoretical value 20.70 4.17 9°66
21.35 Experimental value 20.73 3.62 9.9
8 21.22 Example 11 16
The mixture was heated and stirred at 0°C for 30 minutes. The reaction solution was returned to room temperature and purified using a silica gel column (chloroform-methanol) to obtain 4 g of tetraethyl[(4-phenyl-2-thiazolyl)aminocomethylenebis(phosphonate) as a solid.

(i) Mass spectrometry value (FAB Mass) 4
63 (M + 1) (ii) Nuclear magnetic resonance spectrum (in DMSO-d8) δ: 1.04-1.36 (12
H, CH3CH, OX4).

3.90~4.30 (8H, CH3CHtoX4
).

5.22 (IH, dt, NHCH).

7.12 (l H,s', H of thiazole ring)
.

7.36.7.84.8.36 (H in phenyl ring) The following compound was synthesized in the same manner as in Example 11.

Example 12゜Tetraethyl[(5-methyl-2-thiazolyl)aminocomethylenebis(phosphonate) (1) Pale yellow oil (11) Mass spectrometry value (F A B Mass) 40
1(M+1)(iii) Nuclear magnetic resonance spectrum (in cDc13) δ: 1.2-1.4 (12H, CH
ac Hto X 4).

2.30 (3H, d, CH, JC).

4.0-4.4 (8H, CH3CHtoX4).

4.96 (IH, t, NHCH).

Tetraethyl [(4,5-dimethyl-2-thiazolyl)
Aminocomethylene bis(phosphonate) (i) Pale yellow oil (ii) Mass spectrometry value (F A B Mass)
415 (M + 1) (iii) Nuclear magnetic resonance spectrum (CD C1, middle) δ:l, 2-1.4 (
12H, CH3CH20X4).

4.0-4.4 (8H, CH3CH, 0X4)4.
90 (lH,t, NHCH).

Example 14゜Tetraethyl[(5-methyl-1,3,4-thiazol-2-yl)aminocomethylenebis(phosphonate) (i) Pale yellow oil (ii) Mass spectrometry value (FAB Mass) 40
2(M+1)(iii) Nuclear magnetic resonance spectrum (C
D CI3) δ: 1.2 to 1.5 (12H, CH
3CHtOX4).

2.56 (3H, s, beauty).

e 3.96-4.40 (8H, CH3CH20X4)5.
04 (IH, t, NHCH).

Example 15 5.7 g of 2-amino-4-methylthiazole was dissolved in dichloromethane 57+n+2, and formic acid-acetic acid (5
3) mixture 14- was added dropwise. After returning to room temperature and stirring overnight, the reaction solution was concentrated. The resulting solid was washed with ether to dissolve 4-methylthiazolyl-2-formamide in 6.
I got 6g.

Trimethyl phosphite 8.7mQ, and phosphorus trichloride 0.9m
After reacting the mixed solution of No. 12 at 65 to 70° C. for 15 minutes, 4-methylthiazolyl-2-formamide Ig was added to the reaction solution, and stirring was continued at that temperature for 1 hour. After concentrating the reaction solution, it was purified using a silica gel column (chloroporm-methanol) to obtain 1 g of tetramethyl[(4-methyl-2-thiazolyl)aminocomethylenebis(phosphonate) as a pale yellow oily substance.

The physical and chemical properties of this product are as follows.

(i) Mass spectrometry value (FAB Mass) 345
(M+I) (ii) Nuclear magnetic resonance spectrum (CD
C1, medium) 3.8 to 4.0 (12H, CH30X 4
).

5.14 (IH,t, NHCH).

6.1G, (l H,Q, f) The following compound was synthesized in the same manner as in Example 15.

Example 16゜Tetramethyl [(1,2,4-triazol-3-yl)aminocomethylenebis(phosphonate) (i) Pale yellow oil (ii) Mass spectrometry value (FAB Mass) 31
5(M+1)(:iii) Nuclear magnetic resonance spectrum (DMSO-d, medium) 63.6-3.8 (12H
, CH30X4).

4.78 (IH, dt, NHC current).

7.10 (IH, d, LN/).

7.8 (2H, NHCHH husband) Example using the same method as Example 15! , 3.5.7.9
.

Compounds 11, 12, 13 and 14 can be prepared.

Example 17 4 g of tetraethyl [(4-phenyl-2-thiazolyl) aminocomethylene bis(phosbonate) was dissolved in 4 g of carbon tetrachloride.
Dissolved in 0 m (!, under water cooling, trimethyl iodide 7
g was added dropwise. After 1 hour of returning to room temperature, the reaction solution was concentrated, methanol was added, and condensation was again carried out.

After washing the obtained solid with methanol, 0. It was dissolved with IN aqueous sodium hydroxide solution and the pH was adjusted to 7.

This was purified using an HP-20 resin column (eluted with water),
0.6 g of trisodium [(4-phenyl-2-thiazolyl)aminocomethylenebis(phosphonate)] was obtained.

The physical and chemical properties of this product are as follows.

(i) Elemental analysis value (C+oHsNtOeSPyNa
s' 0.5HtO)C(%) H(%) N(%
) Theoretical value 28.23 2J5 6.59 Experimental value
28.45 2.91 6.64 (11) Mass spectrometry value (F A I3 Mass) 417 (M +
l) (iii) Nuclear magnetic resonance spectrum (D, in 0) δ3.84 (11-1, t, NHC±)6.
84 (l H, s, H of thiazole ring) 7.4 ~
7. 111 (5H, H of phenyl ring) Example 18 After reaction in the same manner as in Example 17, it was purified without converting it into a sodium salt.

(1,2,4-)Riazol-3-yl)aminomethylenebis(phosphonic acid) (1) Elemental analysis value (C, )(,N 4oep t・f)
, 5HtO) C (%) H (%) N (%) Theoretical value 13.48 3.37 20.97 Experimental value 13.87 3.23 20.69 (ii)
Mass spectrometry value (FAB Mass) 259 (
M + t ) (iii) Nuclear magnetic resonance spectrum (
D! 0) δ4.12 (I H,t, NHCH
)8.22 (I I-1,5,H-,11,) Example 19゜600 mg of tetramethyl [(4-methyl-2-thiazolyl) aminomethylene bis(phosphonate) was dissolved in 6 m of concentrated hydrochloric acid.
Q, and heated under reflux for 1.5 hours.

After concentrating the reaction solution, water was added to precipitate crystals, which were collected by filtration to obtain 450 mg of [(4-methyl-2-thiazolyl)aminocomethylenebis(phosphonic acid).

The physical and chemical properties of this product are as follows.

(1) Elemental analysis value (CsH,.N t Oa S P
t) C (%) I1 (%) N (%) Theoretical value 20.84 3.50 9.72 Experimental value 20.57 3.50 9.52 (11) Mass spectrometry value (F A B M ass) 289 (M +
1) (Mountain) Nuclear magnetic resonance spectrum (D t O+
K t in COa) 3.72 (I H, L,
NHCH)6.18 (IH, d, H persons) The following compound was synthesized in the same manner as in Example 19.

Example 20° and NHCH(PO,H,)Ie [(5-methyl-2-thiazolyl)aminocomethylenebis(phosphonic acid) (i) Elemental analysis value (C5III.NtOeSPt.
o, 5uto) C (%) I4 (%) N (%) Theoretical value 20.21 3.73 9.43 Experimental value 20.19 3.65 9.31 (ii)
Mass spectrometry value (F A B M ass) 289 (M
+ 1) (iii) Nuclear magnetic resonance spectrum (1
) in to+KtcO3) δ2.26 (3H, s,
Sentence) e 3.85 (I H, t, NHCH) 6.80
(I H, d, H engineering) Example 21゜:: Is door HCH (PO, H,)! [(4,5-dimethyl-2-thiazolyl)aminocomethylenebis(phosphonic acid) (1) Elemental analysis value (Ca) f ltN to sS P
t) C (%) H (%) N (%) Theoretical value 23.85 4.00 9.27 Experimental value 23.36 3.94 9.07 (11) Mass spectrometry value (FAB Mass) 303 (M+1) (i
ii) Nuclear magnetic resonance spectrum (during D10) Example 2
2゜[(5-methyl-1,3,4-thiadiazol-2-yl)aminocomethylenebis(phosphonic acid) (1) Elemental analysis value (C, I-I QN, OsS P,) C (%)
H (%) N (%) Theoretical value 16.62 3.14 14.53 Experimental value 16.34 3.29. 14.1.3 (1
1) Mass spectrometry value (FAB Mass) 290 (
M + 1) (Mountain) Nuclear magnetic resonance spectrum (D, in 0) δ 2,62 3.60 (3H, s, human) CH.

(IH, t, NHCH)

Claims (1)

[Claims] 1. General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, A is the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ or ▲ Mathematical formula ,Chemical formula,
There are tables, etc. ▼ Groups shown by《However, R is a hydrogen atom, a halogen atom,
a lower alkyl group or a phenyl group, n means 1 or 2], X is an oxygen atom, a sulfur atom or an imino group, R^1, R
^2, R^3 and R^4 each mean a hydrogen atom or a lower alkyl group. ) Azolaminomethylenebisphosphonic acid lower alkyl ester or its non-toxic salt. 2.A is a group represented by ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (in the formula, R is a hydrogen atom or a lower alkyl group, and n is 1
or 2), X is an oxygen atom or a sulfur atom, and R^1, R^2, R^3 and R^4 are a hydrogen atom or a lower alkyl group, respectively.
Compounds described in Section. 3. The compound according to claim 1, which is [(5-methyl-2-oxazolyl)amino]methylenebis(phosphonic acid) or a salt thereof. 4. General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (A in the formula is a formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ or ▲ Numerical formulas, chemical formulas,
There are tables, etc. ▼ Groups shown by《However, R is a hydrogen atom, a halogen atom,
a lower alkyl group or a phenyl group, n means 1 or 2], X is an oxygen atom, a sulfur atom or an imino group, R^1, R
^2, R^3 and R^4 each mean a hydrogen atom or a lower alkyl group. ) A bone resorption inhibitor containing azolaminomethylenebisphosphonic acid, its lower alkyl ester, or its non-toxic salt as an active ingredient. 5. In the general formula of Claim 4, A is a group represented by ▲There are numerical formulas, chemical formulas, tables, etc.▼ (in the formula, R is a hydrogen atom or a lower alkyl group, and n means 1 or 2). , X is an oxygen atom or a sulfur atom, R^1, R^2
, R^3 and R^4 each mean a hydrogen atom or a lower alkyl group, and the bone resorption according to claim 4, wherein the active ingredient is azolaminomethylenebisphosphonic acid, a lower alkyl ester thereof, or a non-toxic salt thereof. Suppressant. 6. The bone resorption inhibitor according to claim 4, which contains [(5-methyl-2-oxazolyl)amino]methylenebis(phosphonic acid) or a salt thereof as an active ingredient.