JPS62270593A - Diphosphonic acid compound - Google Patents

Abstract

NEW MATERIAL:A compound shown by formula I {R<1>-A- is group shown by formula II-IV [R<1> is (substituted) aryl, heterocyclic or (substituted) lower alkyl; X is O or S]; R<2> is H or lower alkyl; R<1>-A- is group shown by formula II or IV when R<1> is unsubstituted lower alkyl} and a salt thereof. EXAMPLE:Tris(tertiary butylamine salt) of [N-(phenyl) thiocarbamoylmethylene]bis(phosphonic acid). USE:A remedy for bone disease such as osteroporosis Paget, osteolysis, malignant hypercalcemia, rheumatoid rheumatism, etc. PREPARATION:A compound (salt) shown by formula V is reacted with a compound shown by formula R<1>-NCN or an equivalent or a salt thereof.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to a novel diphosphonic acid compound having bone resorption inhibitory activity, and is used in the medical field.

[Prior Art] U.S. Pat. No. 390 discloses that certain alkyl ester derivatives of target compounds described below have insecticidal effects.
6062, and West German Patent Publication No. 2741513 describes that certain acylaminoalkylidene diphosphonic acid compounds are useful as abrasives in toothpaste. It is not known at all that the compound described in 1. also has bone resorption inhibitory activity.

Furthermore, as a certain type of diphosphonic acid compound having anti-inflammatory and anti-rheumatic effects, a compound described in Japanese Patent Application Laid-Open No. 5142395 is known.

Furthermore, as a certain type of diphosphonic acid compound useful for the treatment of bone diseases, those described in JP-A-61-43197 are known.

=11- [Means for Solving the Problems] The diphosphonic acid compound, which is the object compound of the present invention, is novel and is represented by the following general formula [I].

[wherein, R''A- is represented by the formula a lower alkyl group optionally substituted with a good aryl group or heterocyclic group, or a heterocyclic group optionally having acyl, a group represented by (X means O or S, respectively), R2 is hydrogen or When R1 is an unsubstituted lower alkyl group, R1-A- is a group represented by the formula (wherein R1 and X each have the same meanings as before). T] or a salt thereof can be produced by a production method as shown in the reaction formula below.

Production method 1 H 聚迭迭ヱC=0 Production method 3 Production method 4 =15= [In the formula, R3, R4, R5 and R6 each mean a protected hydroxy group, and R1, R2, A and X are each having the same meaning as before] In the foregoing and following description of this specification, preferred examples of the various definitions falling within the scope of this invention are explained in detail below.

"Lower", unless otherwise specified, shall mean groups having 1 to 6 carbon atoms.

Suitable "aryl groups" include phenyl, naphthyl,
Examples include tolyl, mesityl, cumenyl, etc., preferably phenylnaphthyl, and phenyl substituted with a lower alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, etc.

Suitable heterocyclic groups include saturated or unsaturated bicyclic groups or heteropolycyclic groups containing at least one petro atom such as a nitrogen atom, an oxygen atom or a sulfur atom.

Preferred examples of "heterocyclic group" in this sense include pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridyl N-oxyto, dihydropyridyl, tetrahydropyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazinyl, triazolyl, tetrazolyl,
Unsaturated 3-8 containing 1-4 nitrogen atoms such as tetrazolyl
member, more preferably a 5- to 6-membered heterocyclic group; for example, indolyl, isoindolyl, intridinyl,
Unsaturated fused heterocyclic groups containing 1 to 5 nitrogen atoms such as benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl; 1 to 2 oxygen atoms and nitrogen atoms such as oxazolyl, isoxasilyl, oxadiazolyl, etc. an unsaturated 3- to 8-membered heteromonocyclic group containing 1 to 3 atoms; a saturated 3- to 8-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as morpholino and cytononyl; Unsaturated fused heterocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as benzoxasilyl, benzoxadiazolyl, etc.: 1 to 2 sulfur atoms and nitrogen atoms, such as thiazolyl, inthiazolyl, thiadiazolyl, etc. An unsaturated 3- to 8-membered heteromonocyclic group containing 1 to 3 sulfur atoms; for example, an unsaturated 3- to 8-membered heteromonocyclic group containing 1 to 2 sulfur atoms such as λ-chenyl; for example, hendithiazolyl, benzothiadiazolyl Unsaturated fused heterocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, such as; Unsaturated 3- to 8-membered heteromonocyclic groups containing 1 oxygen atom, such as furyl: Sulfur, such as benzochenyl Unsaturated fused heterocyclic group containing 1 to 2 atoms; Examples include unsaturated fused heterocyclic groups containing 1 to 2 oxygen atoms such as benzofuryl.

The above-mentioned "aryl group" and "heterocyclic group" include the aforementioned lower alkyl group; lower alkoxy group [e.g. methoxy,
・oxy, propoxy, isopropoxy, propoxy, pentyloxy, hexyloxy, etc.]; lower alkylthio group [e.g., methylthio, ethylthio, propylthio, isopropylthio, butylthio, pentylthio, hexylthio, etc.]: halo(lower) alkyl group, preferably is a thing,
Di- or trihalo(lower) alkyl group [e.g. chloromethyl, bromomethyl, fluoromethyl, dichloromethyl, difluoromethyl, trifluoromethyl, 2-chloroethyl, 2-bromoethyl, 3-chloropropyl, etc.], lower alkanoyl group [e.g. formyl, acetyl, propionyl, hexanoyl, pivaloyl, etc.], lower alkoxycarbonyl groups [e.g., methoxycarbonyl, ethoxycarbonyl, tertiary butoxycarbonyl, tertiary pentyloxycarbonyl, hexyloxycarbonyl, etc.]
, Al(lower)alkoxycarbonyl group [e.g. benzyloxycarbonyl etc.], Lower alkylsulfonyl group [
For example, mesyl, ethylsulfonyl, etc.], arylsulfonyl groups [for example, phenylsulfonyl, tosyl, etc., etc., acyl groups; lower alkanoylamino groups [for example, formylamino, acetylamino, propylamino, etc.,
Substituents 1 selected from the group consisting of acylamino groups such as lower alkylsulfonylamino groups [e.g. mesylamino, ethylsulfonylamino, propylsulfonylamino, etc.]; and halogens [e.g. fluoro, chloro, bromo, iodo, etc.] or more, preferably 1 to 3,
More preferably, one or two may be substituted.

Preferred examples of such "aryl groups or heterocyclic groups optionally substituted with a substituent selected from the group consisting of lower alkoxy, lower alkylthio, halo(lower) alkyl, acyl, acylamino, and halogen" Examples include phenyl group, naphthyl group, such as hatryl, ethylphenyl, propylphenyl, cumenyl,
Mono- or di- or tri(lower) alkylphenyl groups such as butylphenyl, xylyl, mesityl, e.g. methoxyphenyl, ethoxyphenyl, propoxyphenyl,
Mono- or di- or l-(lower) alkoxyphenyl groups such as impropoxyphenyl, butoxyphenyl, neopentyloxyphenyl, dimethoxyphenyl, such as methylthiophenyl, ethylthiophenyl, propylthiophenyl, isopropylthiophenyl, butylthiophenyl, Dimethylthiophenyl-terminated mono- or di- or tri(lower) alkylthiophenyl groups, such as fluorophenyl, chlorophenyl, bromophenyl, iodophenyl, dichlorophenyl, (fluoro)chlorophenyl, short phenyl, difluorophenyl, trifluorophenyl, trichlorophenyl, etc. mono- or halo- or trihalophenyl groups, such as chloromethylphenyl, dichloromethylphenyl, trifluoromethylphenyl, di(trifluoromethyl)phenyl, mono- or di- or tri[halo(lower) alkylphenyl groups, such as formylaminophenyl, Acetylaminophenyl, Provinylaminophenyl, Cy(acetylamino)
mono- or di- or tri(lower)alkanoylaminophenyl groups such as phenyl, e.g. mesylaminophenyl,
Mono-, di-, or triacylaminophenyl groups such as mono-, di-, or tri-(lower) alkylsulfonylaminophenyl groups such as ethylsulfonylaminophenyl, propylsulfonylaminophenyl, di(mesylamino) phenyl, etc.; Trifluoromethylphenyl, (fluoro)trifluoromethylphenyl, di(
Halogen- and halo(lower)alkyl-substituted phenyl groups such as (chloro)chloromethylphenyl, e.g. ha(methoxy)
Lower alkoxy and halo(lower) alkyl substituted phenyl groups such as trifluoromethylphenyl, (ethoxy)trifluoromethylphenyl, di(methoxy)chloromethylphenyl, pyridyl groups such as methylpyridyl, ethylpyridyl, propylpyridyl, dimethylpyridyl, etc. mono- or di- or tri(lower) alkylpyridyl group,
imidazolyl groups, such as imidazolyl groups substituted with acyl groups such as lower alkoxycarbonyl-substituted imidazolyl groups such as tertiary butoxycarbonylimidazolyl;
Examples include chenyl group, quinolyl group, benzo[b]chenyl group, benzothiazolyl group, such as chlorobenzothiazolyl, fluorobenzthiazolyl-stopped mono- or di- or trihalobenzothiazolyl group, among which further Preferred examples include phenyl group, naphthyl group, mono(01-C4) alkylphenyl group, and mono(01-C4) alkylphenyl group.
4) Alkoxyphenyl group, mono(C1-C4) alkylthiophenyl group, mono- or dihalophenyl group, mono[halo(01-C)alkylpyridyl group, mono(01-C4)
C4) Alkanoylaminophenyl group, mono(01-C
4) Alkylsulfonylaminophenyl group, halogen and halo(01-C4)alkyl-substituted phenyl group, C-
C alkoxy and halo(C1-C4) alkyl-substituted phenyl group, pyridyl group, mono(01-C4) alkylpyridyl group, imidazolyl group, (C1-C4) alkoxycarbonylimidazolyl group, chenyl group, quinolyl group,
Examples include benzo[b]chenyl group, benzothiazolyl group, and monohalobenzothiazolyl group, and the most preferred ones are phenyl group, tolyl group, naphthyl group, methoxyphenyl group, methylthiophenyl group, chlorophenyl group, fluorophenyl group, and dichlorophenyl group. group, trifluoromethylphenyl group, acetylaminophenyl group, mesylaminophenyl group, (chloro)trifluoromethylphenyl group, (methoxy)trifluoromethylphenyl group,
They are a pyridyl group, a methylpyridyl group, an imidazolyl group, a tertiary butoxycarbonylimidazolyl group, a chenyl group, a quinolyl group, a benzo[b]chenyl group, a benzothiazolyl group, and a chlorobenzothiazolyl group.

Suitable "lower alkyl groups" include methyl, ethyl,
Straight chain or branched chain alkyl groups such as propyl, isopropyl, butyl, isobutyl, tertiary pentylhexyl, etc. are mentioned, and among them, 01-=24-C4 alkyl groups are more preferred. The most preferred are methyl and butyl groups.

The preferred lower alkyl group for R1 may be substituted with the above-mentioned heterocyclic group which may be substituted with the above-mentioned acyl.

Suitable "protected hydroxy groups" include, for example, methoxy, propoxy, impropoxy, butoxy, secondary butoxy, isopropoxy, tertiary butoxy, pentyloxy, neopentyloxy, Lower alkoxy groups such as hexyloxy, optionally substituted alkyl (
Examples include mono-, di-, or triphenyl (lower) alkoxy groups that may be substituted with a nitro group such as benzyloxy, 4-nitrobenzyloxy, benzhydryloxy, i-lythyloxy, etc. Among these, preferable examples include lower alkoxy groups, and more preferable ones include hydroxy groups protected with commonly used protecting groups such as
Mention may be made of 1 to C4 alkoxy groups, the most preferred being ethoxy and isopropoxy groups.

Suitable pharmaceutically acceptable salts of the target compound [II are conventional non-toxic salts, such as alkali metal salts such as thorium salts, potassium salts, alkaline earth metal salts such as calcium salts, magnesium salts, or ammonium salts. Inorganic base salts such as methylamine salts, ethylamine salts, propylamine salts, isopropylamine salts, butylamine salts, tertiary butylamine salts, dimethylamine salts, diethylamine salts, trimethylamine salts, triethylamine salts, pyridine salts, picoline organic base salts such as organic amine salts such as dicyclohexylamine salts, N,N'-dibenzylethylenediamine salts, e.g. formates, acetates, trifluoroacetates, maleates, tartrates, methanesulfonates; , organic acid addition salts such as benzenesulfonate, toluenesulfonate, inorganic acid addition salts such as hydrochloride, hydrobromide, sulfate, phosphate, etc., such as arginine salt, aspartate, glutamate, etc. Examples include salts with amino acids.

Regarding this point, I would like to add that compounds [■8] to [1c]
are included within the scope of compound [II, therefore, for suitable salts of these compounds [Ia] to [Ic], reference may be made to the salts exemplified for the target compound [II].

The method for producing the object compound [II] of the present invention will be explained in detail below.

Production method 1 The target compound [■8] or a salt thereof can be produced by reacting compound [1[] or a salt thereof with compound [II['l or an equivalent thereof or a salt thereof.

For suitable salts of compound [11F, compound [II
Refer to the salts with bases exemplified above.

For suitable salts of compound [1[1], compound [I
Reference may be made to the acid addition salts exemplified for I.

A preferred example of the equivalent of compound [111] is 3-(2-pyridyl)-3゜4-dihydro-2H-, which is produced by subjecting 2-pyridyl thiocyane 1 to intermolecular condensation. Examples include intermolecular condensation compounds of [I[[ ] such as and lido[1,2-a]-1,3°5-triazine-2,4-dione.

This reaction is usually carried out in a solvent such as dioxane, tetrahydrofuran, benzene, chloroform, methylene chloride, N,N-dimethylformamide, but it can also be carried out in any other solvent that does not adversely affect the reaction. be able to.

Furthermore, this reaction can be carried out with alkali metals such as thorium and potassium, alkaline earth metals such as magnesium and calcium, hydrides or hydroxides of these metals, such as sodium methoxide, sodium ethoxide, potassium tertiary It can be carried out in the presence of a base such as an alkali metal alkoxide such as butoxide.

The reaction temperature is not particularly limited, and the reaction is usually carried out under cooling or heating.

Production method 2 Target compound [Ib] or a salt thereof is obtained by reacting compound [IV] or a reactive derivative thereof at an amino group or a salt thereof with compound [V] or a reactive derivative thereof at a carboxyl group or a salt thereof. It can be manufactured by

Suitable reactive derivatives at the amino group of compound [■] include Ship's base type imino or its enamine type tautomer, which is produced by the reaction of compound [IV] with a carbonyl compound such as an aldehyde, a ketone, etc.; Silyl derivatives produced by the reaction of compound [IV] with bis(trimethylsilyl)acetamide, mono(trimethylsilyl)acetamide, bis(trimethylsilyl)urea, etc.; derivatives produced by the reaction of compound [IV] with phosphorus trichloride or phosgene, etc. can be mentioned.

For suitable salts of compound [IV] and its reactive derivatives, reference may be made to the salts exemplified for compound [1].

Suitable reactive derivatives of the carboxyl group of compound [V] include acid halides, acid anhydrides, activated amides, activated esters, and the like.

Suitable examples of reactive derivatives include acid chlorides; acid azides; substituted phosphoric acids such as dialkyl phosphoric acid, phenyl phosphoric acid, diphenyl phosphoric acid, dibenzyl phosphoric acid, halogenated phosphoric acid, dialkyl phosphorous acid, sulfurous acid, thiosulfuric acid, sulfuric acid. , sulfonic acids such as methanesulfonic acid, such as acetic acid, propionic acid, butyric acid, isoacetic acid, pivalic acid, pentanoic acid,
Mixed acid anhydrides with acids such as aliphatic carboxylic acids such as isopentanoic acid, 2-ethyl acetic acid, trichloroacetic acid or aromatic carboxylic acids such as benzoic acid: symmetrical acid anhydrides; imidazole, 4-substituted imidazole, dimethyl activated amides with pyrazoles, triazoles or tetrazoles; or e.g. cyanomethyl esters, methoxymethyl esters, dimethyliminomethyl [(cn3)2=c
u-]ester, vinyl ester, propargyl ester, p-nitrophenyl ester, 2,4-dinitrophenyl ester, )-lichlorophenyl ester, pentachlorophenyl ester, mesyl phenyl ester, phenyl asophenyl ester, buenyl thio ester, p - Activated esters such as nitrophenyl thioester, p-cresyl thioester ruthioester, pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolyl thioester, or for example N.

N-dimethylhydroxylamine, 1-hydroxy-2
-(IH)-pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide, 1-hydroxy-IH
Examples include esters with N-hydroxy compounds such as -benzotriazole. These reactive derivatives can be arbitrarily selected from them depending on the type of compound [V] used.

For suitable salts of compound [V] and its reactive derivatives, reference may be made to the salts exemplified for compound [I].

The reaction is usually carried out using water, alcohols such as methanol and ethanol, acetone, dioxane, acetonitrile, chloroform, methylene chloride, chloride, ethylene, tetrahydrofuran, ethyl acetate, N.I. The reaction is carried out in a conventional solvent such as N-dimethylformamide or pyridine, but the reaction can be carried out in any other organic solvent as long as it does not adversely affect the reaction. These customary solvents may also be used as a mixture with water.

In this reaction, when compound [V] is used in the form of a free acid or its salt, N,N'-dicyclohexylcarbodiimide=N-cyclohexyl-N'-morbolinoethylcarbodiimide; N-cyclohexyl -N'
-(4-diethylaminocyclohexyl)carbodiimide, N,N'-diethylcarbodiimiddlecarbodiimide;N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide: N.

N'-carbonylbis(2-methylimidazole);
Pentamethyleneketene-N-cyclohexylimine; diphenylketene-N-cyclohexylimine; ethoxyacetylene; 1-alkoxy-1-chloroethylene; trialkyl phosphite; ethyl polyphosphate; isopropyl polyphosphate; phosphorus oxychloride (posboryl chloride): Trichloride groove; thionyl chloride: oxalyl chloride; lower alkyl haloformate such as ethyl chloroformate, isopropyl chloroformate; triphenylphosphine; 2-ethyl-7-hydroxybenzisoxazolium salt; 2-ethyl-5 −(m
-sulfophenyl)inoxacillium hydroxide inner salt; 1-(1)-chlorohenzenesulfonyloxy)-6-10 rhoIH-benzotriazole, N,N-
Preferably, the reaction is carried out in the presence of a conventional condensing agent, such as the so-called Vilsmeier reagent prepared by the reaction of dimethylformamide with thionyl chloride, phosgene, trichloromethyl chloroformate, phosphorous oxychloride, and the like.

The reaction can also be performed with alkali metal bicarbonates, tri(lower)alkylamines, pyridine, di(lower)alkylaminopyridines, N-(lower)alkylmorpholines, N,N-di(lower)alkylbenzylamines, etc. It may be carried out in the presence of an inorganic base or an organic base. Liquid bases can also be used as solvents.

Although the reaction temperature is not particularly limited, the reaction is usually carried out under cooling or heating.

1 Thief 1 Target compound [Ic] or a salt thereof is obtained by reacting compound [IV] or a reactive derivative thereof at an amino group or a salt thereof with compound [VI] or a reactive derivative thereof at a sulfo group or a salt thereof. It can be manufactured by

For suitable salts of compound [Vf] and its reactive derivatives, reference may be made to the salts exemplified for compound [1].

This reaction can be carried out in substantially the same manner as Production Method 2, and therefore the reaction method and reaction conditions such as base, reactive derivative, condensing agent, solvent, reaction temperature, etc. ”, please refer to the explanation.

Production method 4 The target compound [1] or a salt thereof can be produced by subjecting the compound [■] or a salt thereof to an elimination reaction of the hydroxy protecting group.

This reaction is carried out by conventional methods such as hydrolysis, reduction, etc.

For suitable salts of compound [■], refer to the salts exemplified for compound [1].

Hydrolysis is preferably carried out in the presence of a base, an acid including a Lewis acid, or a halosilane compound.

Suitable bases include, for example, alkali metals such as sodium and potassium, alkaline earth metals such as magnesium and calcium, hydroxides or carbonates or bicarbonates of these metals, trialkylamines such as trimethylamine, triethylamine, etc. , picoline, 1.5-
Diazabicyclo[4,3,0]non-5-ene, 1.4
Inorganic and organic bases such as -diazabicyclo[2,2,2]octane, 1,8-diazabicyclo[5,4,O]undec-7-ene, and the like.

Suitable acids include, for example, formic acid, acetic acid, propionic acid,
Examples include organic acids such as trichloroacetic acid and trifluoroacetic acid, and inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen chloride, and hydrogen bromide.

Desorption using a Lewis acid such as a trihaloacetic acid such as trichloroacetic acid, trifluoroacetic acid, etc. is preferably carried out in the presence of a cation scavenger, such as anisophenol.

Suitable halosilane compounds include, for example, halotri(lower)alkylsilanes such as iodotrimethylsilane and bromotrimethylsilane.

The reaction is usually carried out in water, alcohols such as methanol and ethanol, methylene chloride, chloroform, tetrachloromethane, tetrahydrofuran, and mixtures thereof, but the reaction may also be carried out in any other solvent that does not adversely affect the reaction. It can be performed. If a liquid base, acid or halosilane compound is also used as a solvent, -36= can be obtained.

The reaction temperature is not particularly limited, and the reaction is usually carried out under cooling or heating.

Reduction methods that can be applied to the elimination reaction include chemical reduction and catalytic reduction.

Suitable reducing agents used for chemical reduction include, for example, tin,
Metals such as zinc and iron or metal compounds such as chromium chloride and chromium acetate, and formic acid, acetic acid, propionic acid,
It is a combination with an organic or inorganic acid such as trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid, or hydrobromic acid.

Suitable catalysts used for catalytic reduction are platinum catalysts such as platinum plates, platinum sponges, platinum black, colloidal platinum, platinum oxide, platinum wires, platinum catalysts such as palladium sponges, palladium black, palladium oxide, palladium-hypochloride, colloids. palladium,
Palladium catalysts such as palladium-barium sulfate, palladium-barium carbonate, nickel catalysts such as reduced nickel, nickel oxide, Raney nickel, cobalt catalysts such as reduced cobalt, Raney cobalt, iron catalysts such as reduced iron, Raney iron, etc. Conventional catalysts such as reduced copper, Raney copper, Ullmann saw copper catalysts, etc.

The reduction is usually carried out in conventional solvents that do not adversely affect the reaction, such as water, methanol, ethanol, propatool, N,N-dimethylformamide, or mixtures thereof. Furthermore, when the acids used for chemical reduction are liquid, they can also be used as a solvent. Furthermore, suitable solvents used in the catalytic reduction include, in addition to the above-mentioned solvents, conventional solvents such as diethyl ether, dioxane, tetrahydrofuran, etc., or mixtures thereof.

The reaction temperature of this reaction is not particularly limited, and the reaction is usually carried out under cooling or heating.

Several of the raw material compounds [■] are new compounds,
These compounds or salts thereof can be produced by the production method shown in the following reaction formula.

Production method A [■] or a salt thereof H [■a] or a salt thereof Jl (and [IX] or a reactive derivative at its amino group or a salt thereof ■ C=0 [■b] or a salt thereof Production method C [■Co or a reactive derivative thereof at an amine group or a salt thereof [■C] or a salt thereof production method D [■d] or a salt thereof [■e] or a salt thereof [wherein R means a lower alkyl group] , R1, R2, R
3, R4, R5, R6, A and X each have the same meaning as before].

The above method for producing the raw material compound will be explained in detail below.

Type Jb friend Δ Compound [■a] or a salt thereof can be produced by reacting compound [■] or a salt thereof with compound [I [[] or an equivalent thereof or a salt thereof.

For suitable salts of compound [■], refer to the base salts exemplified for compound [1].

This reaction can be carried out in substantially the same manner as Production Method 1, so for the reaction method and reaction conditions such as Example λ, base, solvent, and reaction temperature, please refer to the explanation of Production Method J1]. Just refer to it.

Production method B Compound [■b] or a salt thereof is obtained by reacting compound [IX] or a reactive derivative thereof at an amine group or a salt thereof with compound [V] or a reactive derivative thereof at a carboxyl group or a salt thereof. It can be manufactured by

For suitable salts of compound [IX] and its reactive derivatives, refer to the salts exemplified for compound [I].

This reaction can be carried out in substantially the same manner as Production Method 2, and therefore, the reaction method and reaction conditions such as reactive derivatives, condensing agents, solvents, reaction temperatures, etc., can be found in the explanation of the production method. Please refer to .

Production method C Compound [■C] or a salt thereof can react with compound [IX] or a reactive derivative at its amino group or a salt thereof with compound [VI] or a reactive derivative at its sulfo group or a salt thereof. It can be manufactured by

This reaction can be carried out in substantially the same manner as the chemical reaction, and therefore the reaction scheme and reaction conditions such as base, reactive derivative, condensing agent, solvent, reaction conditions, etc. Please refer to the explanation of method 2.

Production method Compound [■e] or a salt thereof can be produced by reacting compound [■d] or a salt thereof with a lower alkylating agent.

For suitable salts of compound [■d], compound [1]
Please refer to the salts exemplified in .

For suitable salts of compound [■e], compound [11
Please refer to the acid addition salts exemplified in .

Suitable lower alkylating agents include, for example, methyl iodide,
Lower alkyl halides such as propyl iodide and butyl iodide; lower alkyl arenesulfonates such as methyl henzenesulfonate and ethyl toluenesulfonate; ) alkyl, etc.

This reaction can be carried out in the presence of a base as exemplified in Production Method 1.

This reaction is usually carried out in a solvent such as dioxane, tetrahydrofuran, benzene, chloroform, methylene chloride, N,N-dimethylformamide, but it can also be carried out in any other organic solvent that does not adversely affect the reaction. If the lower alkylating agent is a liquid, it can be used as a solvent.

The reaction temperature is not particularly limited, and the reaction is usually carried out under cooling or heating.

Both reactions of production method A and production method can be carried out simultaneously. In this case, compound [I[[] and a lower alkylating agent are added to compound [■] in which R2 is hydrogen, and compound [■]
e] is obtained. This manufacturing method is also included within the scope of this invention.

The compound obtained by the above production method can be crushed, recrystallized,
It can be isolated and purified by conventional methods such as column chromatography, reprecipitation, etc.

Compound [I] and other compounds may contain one or more stereoisomers based on asymmetric return atoms, and such isomers and mixtures thereof are included within the scope of this invention. shall be taken as a thing.

For therapeutic purposes, the compound [I] of this invention and its pharmaceutically acceptable salts may be prepared in a pharmaceutically acceptable form such as an organic or inorganic solid or liquid excipient suitable for oral, parenteral or topical administration. It can be used in the form of pharmaceutical preparations containing one of the above compounds as an active ingredient, mixed with a carrier.

Pharmaceutical formulations may be capsules, tablets, dragees, granules, solutions, suspensions, emulsions, and the like. If desired, these formulations may contain auxiliaries, stabilizers, wetting agents or emulsifiers, buffers and other commonly used additives.

The dose of compound [I] varies depending on the age and condition of the patient, but the average single dose of compound [1] is approximately 0.1 m
L 1 +ng, 10mg, 50mg, 100mg,
250 mg, 500 mg, and 1.000 mg are effective in treating the bone disease.

Generally, 0.1mg/individual to about 1000m per day
Amounts between g/individual may be administered.

[Effects of the Invention] The target compound [■] and its salts have bone resorption inhibitory activity and are useful for treating bone diseases.

In order to demonstrate the usefulness of the target compound [1], compound [I]
The pharmacological test results of several representative compounds are shown below.

Experiment: The calvaria of neonatal Wistar rats 1-2 days old were excised under sterile conditions, washed with Dulbecco's modified Eagle's medium, and divided along the mid-suture line. The calvarial halves were pooled and randomized into different groups. Each half of the calvaria was cultured individually as free-floating bone in multiple volumes of blood containing 2 mQ of Dulbecco's modified Eagle's medium with 10% calf fat serum heat-inactivated for 1 hour at 56°C. hpru
(1-34) (IXIOM) Treatment and Test Compound (1
x 10-7 or I x 10-6 M) The treatment was started from the zero dose. All cultures were carried out at 37°C, 95% air and 5% CO2 at atmospheric pressure for 6 days. Bone resorption was quantified by measuring calcium accumulation in the culture medium after 6 days.

The total lucium concentration in the culture solution was measured by the 0CPC method using a spectrophotometer (Hitachi model U-3200, Tokyo, Japan).

As a comparative test, a similar test was conducted using hPIH (I
'M) It was carried out using a culture solution containing glue and a culture solution containing neither hPTH nor the test compound.

The test results were expressed as inhibition percentage calculated by the following formula.

C,: total lucium concentration in cultures treated with both hPTH and test compound Co: hPT) (and total lucium concentration CP in control culture without both test compounds; culture treated with hPTH only) Total calcium concentration in liquid Test compound (a) [N-(phenyl)thiocarbamoylmethylene]
Tris(tertiary butylamine) salt of bis(phosphonic acid) (b) [N-(4-chlorophenyl)carbamoylmethylene] tris(tertiary butylamine) salt of bis(phosphonic acid) <C) [N-(a -chlorophenyl)thiocarbamoylmethylene cobis(phosphonic acid))-lis(tert-butylamine) salt (d) Disodium salt of [N-(2-benzo[bcochenyl)thiocarbamoylmethylene]bis(phosphonic acid) (e) Disodium salt of [N-(4-1-lifluoromethylphenyl)thiocarbamoylmethylene]bis(phosphonic acid) (f>[N-(3-trifluoromethylphenyl)thiocarbamoylmethylene acid)] Sodium salt (g>[N-(4-chloro-3-trifluoromethylphenyl)thiocarbamoylmethylene (posponic acid) disodium salt (h)[N-(4-methoxy-3-trifluoromethylphenyl) thiocarbamoylmethylene] disodium salt of bis(phosphonic acid) (i) ] Tris(tertiary butylamine) salt of bis(phosphonic acid) (k) [(4-chlorophenyl)sulfonylaminomethylene] disodium salt of bis(phosphonic acid) (1) [N-(3-mesylaminophenyl) As is clear from the above test results, the target compound [1]
and its salts have strong bone resorption inhibitory activity and treat bone diseases characterized by abnormal bone metabolism such as osteoporosis, budget bone disease, osteolysis, malignant hypercalcemia and rheumatoid arthritis. It is useful as a bone metabolism improving agent.

[Example] The present invention will be described in more detail below with reference to Production Examples and Examples.

Production Example 1 A stirred solution of 2-aminobenzo[b-cothiophene (1,11 g) in anhydrous toluene (4,5 mB), carbon disulfide (0,62 g) and triethylamine (0,755 g)
) were added sequentially and stirred at 0 to 5°C in a nitrogen stream for 3 days. The precipitate is collected by filtration and washed with anhydrous toluene (10 mQ). The obtained white powder was dissolved in chloroform (a, smQ), and I. ethylamine (0.76 g) was added.
Cool to 0°C. Ethyl chloroformate (0,84
g) is added dropwise over 20 minutes. After stirring for 1 hour at room temperature, the solution is washed twice with IN hydrochloric acid (5 mQ), then with saturated brine, and dried. The solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography and eluted with n-hexane to obtain benzo[b-cothiophene-2-thiocyanate (118 mg) as an oil.

IR (liquid film) i 2080 cm-1MMR (CDC
l2.8): 7.06 (LH,s), 7.32
-7.41 (2B, m), 7.63-7.73
(2H, m) Preparation Example 2 To a suspension of 60% oily sodium hydride (120 mg) in distilled tetrahydrofuran (4 mA) at room temperature is added methylenebis(phosphonic acid)tetraisopropyl (688 mg) in one portion. After stirring the mixture for several minutes, it was cooled in a water bath and dissolved in phenylisothiocyanate 1- (0.36 ml
) is added. After stirring the reaction mixture at room temperature for 3 hours, methanol (2 mQ) is added to decompose the excess phenyl inthiocyanate. The mixture is concentrated under reduced pressure and the residue is dissolved in a mixture of diethyl ether and IN hydrochloric acid. The separated organic layer was collected, washed with water, and then dried with magnesium sulfate. The solvent was distilled off, and the residue was subjected to silica gel column chromatography and eluted with a mixed solvent of chloroform and methanol (30:1 v/v) to obtain [N-
Tetraisopropyl (phenyl)thiocarbamoy J remethylene]bis(posponate) (0.75 g) is obtained as crystals.

Melting point: 64-66°C IR (methanol): 3300. 1600.
1500. 1400. 1250°1000 am
-' NMR (CDC1a, 8) ' 1.2-1.6 (
24B1m), 4.31 (H(.

t, J=23.5Hz>, 4.65-5.0 (,
4H, m>, 7.2-7.45 (3H, m>,
7.75-7.85 (2H, m), 1.0.2
4 (IH.

brs) The following compounds (Production Examples 3 to 27) are obtained in the same manner as Production Example 2.

Production Example 3 [N-(4-Fluorophenylmethylenecobis(phosphonic acid)tetraisopropyl] Melting point: 173-174°C IR (methanol): 3450. 335
0. 1665 am'''INMR (CDCl
2, δ ); 1.26-1.50 (2
4B, m), 3.62 (IH.t, J=20Hz>
, 4.69-4.97 (4H, m>, 7.0
0 (2H, t, J=8Hz), 7.48 (2H.d
d, J=8 and 5Hz>, 7.56 (LH.s
) [N-(p-)lyl)carbamoylmethylene]bis(phosphonic acid)tetraisopropyl Melting point: 96-98°C IR (methanol): 3300. 166
0 cm-'NMR (CDCl2, δ): 1.
20-4.52 (24H.m), 2.32 (38,
s), 3.53 (11(, tJ=20Hz>,
4.70-4.92 (4.H.m>, 7.12
(2H, d, J=8Hz), 7.42 (2H, d
.

J=8Hz), 8.69 (LH.s) Pear j0 Appearance [N-(4-methoxyphenyl)carbamoylmethylene]bis(posphonate)tetraisopropyl Melting point j 99-100°C IR (methanol)' 3300. 16
60 am-'NMR (CDCl2, δ): 1
．． 31-1.41 (24H.m), 3.53 (1M
,t,J=23Hz), 3.79 (3B,s),
4.71-4.92 (4H.m), 6.86
(2H, d, J=9Hz), 7.44 (2H, d
.

J=9Hz>, 8.65 (IH.s) Production Example 6 [N-(4-chlorophenyl)thiocarbamoylmethylene]bis(phosphonic acid)tetraisobuvir NMR (CDC13,8)' 1.21-1.4
6 (24H1m>, 4.30 (LH, tj=2
2) +z), 4.78 (4H, m>, 7.35 and 7.78 (4H, ABq, J-8,8Hz),
10.25 (LH, br s) Production Example 7 [N-(1-naphthyl)thiocarbamoylmethylenecobis(posphonate)tetraisopropyl IR (liquid film):
3500.3320.2975.2925.1590
゜1380, 1250.1000 cm""'NMR (
CDCIs, S)' 1.37-1.47 (24
H1m), 4.51 (LH, t, J=24Hz), 4
．． 90 (4H, m), 7.48-8.34 (7H,
m), 10.30 (IH, br s) Production Example 8 [N-(3-Tripleomethylphenyl)thiocarbamoylmethylenezbis(posboxylic acid)te)-lysobrovir Melting point: 49-51°C IR (CH2C12): 2980.2930.14
50.1385.1335゜1130, 990 cm-
' NMR (CDC13, l; ) ' 1.25-1.5
7 (2487m), 4.34 (11,t, J=23H
z>, 4. ．． 70-5.00 (4H, m), 7.
50-7.60 (2H, m), 8.04 (IH,
m), 8.16 (1B, s).

10.4 (IH,s) Production Example 9 [N-(4-h Lifluoromethylphenyl)thiocarbamoyl methylene bis(phosphonic acid)tetraisopropyl Melting point: 98-100°C IR (Nunyol): 3250. 3200.
1610. 1320. 1250°1120cm
-1 NMR (CDCIs, δ) 71.31-1.44 (
24H, m>, 4.32 (IH, t, J=23Hz>
, 4.81 (4H, m), 7.66 and 8.0
0 (4)1. ABq, J=8.5Hz>, 1.0
．． 43 (IT(,s) Production Example 10 [N-(3-chlorophenyl)thiocarbamoylmethylene bis(phosphonic acid)te)-lysobrovir Melting point; 61-62°C IR (liquid film): 3450.3300.1595.15
50.1480°1380, 1260.1100.10
00 Cm-INMR (CDC1a, 8)' 1-
21-144 (244m), 4.30(1)(,t,
J-23Hz>, 4.69-4.91 (4H,
m), 7.20-7.37 (28, m>, 7
．． 65 (IH,br d,J=8)1z), 8.
00 (1B, br s), 10.27 (LH
,s) Production Example 11 [N-(2-chlorophenyl)thiocarbamoylmethylenezbis(phosphonic acid)tetraisopropyl IR (liquid film): 3500.3300.1380.1
260°990cm-1 NMR (CDC1s, S)' 1.28-1
．． 43 (24t(1m), 4.26(it(,
t, J-20Hz), 4.76-4.95 (4B
, m>, 7.17-7.36 (2H, m>, 7
．． 76 (18, dd, J=8 and 2Hz>, 8.
45 (18,dd, J=8 and 2Hz).

10.20 (IH,s> Production Example 12 [N-(4-fluorophenyl)thiocarbamoylmethylenezbis(bosphonic acid)tetraisopropyl IR (liquid film): 3480.3300.1510.1
000 cm-INMR (CDCIs, l; )'
1.26-1.53 (24H1m>, 4.326O- (HLt, J-2411z), 4.70-4.94
(4H, m), 7.04-7.13 (2)1.
m>, 7.7t-7,78(2H,m), 10
．． 19 ('ILs) Production Example 13 [N-(p-tolyl)thiocarbamoylmethylenecobis(bosubonic acid)tetraisopropyl IR (liquid film):
3500.3300.1535.1385.1260°1000 cm' NMR (CDC1s, 8)' 1.21-1.43
(24H1m>, 2.35 (3H, s), 4.31
(IH, t, J=20Hz), 4.70-4.94
(4H, m>, 7.20 (2H, d, J=8) 1z
), 7.65 (2)1. d.

J=8Hz>, 10.16 (LH,s) Production Example 14 [N-(2-methoxyphenyl)thiocarbamoylmethylenecobis(phosphonic acid)tetraisopropyl NMR (CDCIs, δ): 1.18-
1.50 (24H, m>, 3.92 (3H, m
), 4.37 (IH, t, J=24Hz),
4.73-4.93 (48, m), 6.94-7.
03 (2H, m), 7.16 (IH, td.

J=8 and 2Hz>, 8.96 (IH, d, J=
8Hz>.

10.45 (LH,s) Production Example 15 [N-(3,4-dichlorophenyl)thiocarpamoylmethelencobis(phosphonic acid)tetraisopropyl Melting point: 90-92°C IR (Nujol): 3300. 3200.
1260. 990 cm-'NMR (CDC),
s, S): 1.32-1.71 (24) 11m>
, 4.29 (1B, t, J=23Hz), 4.67
-4.94 (4B, m), 7.45 (IH, d
, J=9Hz), 7.65 (IH, dd, J=9 and 2Hz>, 8.14 (IH, d, J=2Hz)
, 10.30 (LH,s) Production Example 16 [N-(2-benzo[b-cochenyl)thiocarbamoylmethylene]bis(phosboxylic acid)tetraisopropyl IR (liquid film): 3500.3210.1600.15
80.1380°1260, LIOo, 1000
cm-'NMR (CDC13, δ): 1.23-1
．． 44 (24H, m>, 4.31 (1B, t, J=
22) 1z), 4.66-4.94 (4H, m
), 7.26-7.40 (3H, m>, 7.6
6-7.80 (2H, m), 11.11 (LH, s
) Production Example 17 [N-(2-trifluoromethylphenyl)thiocarbamoylmethylene]bis(phosboxylic acid)tetraisopropyl IR (liquid film) F 3330.2980.1530.1
460.1380°1320, 1260.1170.1
140゜1100 cm-1 NMR (CDCl2.8): 1.20-1.50
(24H, m>, 4.48 (IH, t, J=23H
z), 4.70-5.00 (4H, m),
7.41 (IH, t, J=8Hz), 7. '60
(LH, t, J=8Hz), 7.72 (IH, d,
J=8H2), 7.87 (IH, d, J=8Hz
>, 9.91 (IH, s) Production Example 18 [N-(4-chloro-3-trifluoromethylphenyl)thiocarbamoylmethylene]bis(phosboxylic acid)tetraisopropyl Melting point: 101-102°C IR (Nujia -L): 3150. 3100.
1390. 1320. 1210゜1000cn
n-1 NMR (CDCl2.δ): 1.25-1.46
(24H, m), 4.33 (IH, t, J=22Hz
>, 4.74-4.97 (4H, m), 7.
54 (1, H, d, J = 8 Hz), , 8.05 (I
H, dd, J=8 and 3Hz>, 8.22 (L
H, d, J=3Hz>, 10.41 (LH, s)
Pear"l"l [N-(4-methoxy-3-trifluoromethylphenyl)thiocarbamoylmethylene]bis(bosphonic acid)tetraisopropyl IR (liquid film): 3450.3250.1500.1
260°1140 cm-' NMR (CDC1s, S): 1.34-1.44 (
24H1m), 3.92 (3H,s), 4.32 (
1B, t, J=23Hz>, 4.70-4.94 (4
H, m), 7.02 (LH, d, J=8Hz),
7.93 (LH.

br s), 7.95 (IH, dd, J=8 and 2Hz) Production Example 20 [N-(4-)lifluoromethylphenylrubamoylmethylene]bis(phosphonic acid)tetraisopropyl Melting point: 136-137°C IR (Xia-IL): 3250. 3
200. 1670, 1600. 1540.

1320, 1250, 1120. 950 cm-
1BMR (CDC1s, S)' t. 30-1-
42 (24H, m), 3. 58 (IH.t, J
=22Hz>, 4.73-4.91 (4H, n
n>, 7.57 and 7.66 (each 2H
, d, J-7Hz), 9.05 (1B, s) Production Example 21 Tetraisopropyl (N-methylcarbamoylmethylenesulfonate) Melting point: 96-100°C IR (nudium): 3270, 16
40, 1255. 980 cm-1BMR
(CDCl2, δ) i 1.2-1.5 (24H,
m>, 2:85 (3H.

d,, C4Hz>, 3.48 (IH, t, J=23
Hz>, 4.65-4.95 (4H, m>, 6.8
6 (1B, br) Production Example 22 [N-(n-butyl)thiocarbamoylmethylenecobis(phosphonic acid)tetraisopropyl IR (liquid film):
3500, 3350. 1545, 1385.

1260 cm-1 NMR (C20, δ): 0.95 (3H.t.
J=7Hz>, 1.21-1.54 (26H, m>,
1.59-1.74 (2H, m), 3.64 (
2H, dt.

J=7Hz), 4.23 (IH, t, J=23H
z), 4.65-4.89(4)1. m), 8
．． 56 (1B, br m) jI soup bun [N-(4-methylthiophenyl)thiocarbamoylmethylene]bis(phosphonic acid)tetraisopropyl IR (N9-9): 1480. 1450.
1090. 920°810 cm-1 NMR (CDC13,8>' 1.15-1.5 (
24H1m), 2.47 (IH,s), 4.27 (
IH, t, J=21Hz), 4.5-4.95 (4B
, m), 7.26 (2H, d, J=8.6Hz>
, 7.76 (2H.

d, J4.6Hz), 10.2 (IH, s) jl
Eto [N-(4-mesylaminophenyl)thiocarbamoylmethylene cobis(phosphonic acid)tetraisopropyl Melting point: 141-143°C IR (nu9-r) j 3300. 3100.
1610. 1510. 1420°1380, 133
5.1250.1150°1000 am-' NMR (CDC1a, 8) = 1.33-1.67
(24H9m), 3.02 (31(,s), 4.3
0 (IH, t, J=23)1z), 4.70-4
．． 92 (4H, rn), 7.29 and 7.50 (
each 2H, d.

JJHz), 7.45 (IH,s), 10.
23 (IH,s) Production Example 25 [N-(3-mesylaminophenyl)thiocarbamoylmethylene]bis(bosphonic acid)tetraisopropyl Melting point: 144-145°C IR (liquid film): 3450.3150.1600.1
380.1240°1150 cm-' NMR (CDCl2.δ): 1.34-1.48
(24H, m), 3.06 (3) 1. s), 4.3
1 (1B, t, J=22Hz>, 4.73-4.9
1 (4H, nn), 6.84 (ILbr s),
7.12 (LH,br d.

J=6Hz), 7.32-7.39 (2H, m>,
7.98 (IH.

br s), 10.29 (LH, br s) Production Example 26 [N-(a-acetylaminophenylrubamoylmethylene]bis(phosphonic acid)tetraisopropyl IR (liquid film): 3500, 3300. 169
0, 1515, 1385.

1260, 1100 cm-' NM! ? (CDCl2, δ)' 1.13-165
(24H, m), 2.21 (3H, s), 4.3
4 (IH, t, J=22Hz>, 4.58-4.9
8(4)1. m), 7.55 and 7.76 (28
, d, J=7Hz).

10, 20 (IH.s) Production Example 27 [N-(3-acetylaminophenyl)thiocarbamoylmethylene]bis(phosphonic acid)tetraisopropyl IR (liquid film): 3450, 3300, 169
0. 1610. 1550.

1260, 1110 cm-'NMR'(CDC13=8)' 1.10 1.
62 (24H, m), 2-17 (3H, s), 4.
30 (1B, t, J=22Hz), 4.55-5.
00 (4H.m), 7.30-7.62 (3H,m
), 8.15 (IH.s) pear 33-transformed methylene bis(posphonate) tetraisopropyl (66
8mg) and potassium quint-butoxide (224m
g) c7) Reflux the warm mixture of anhydrous toluene (5 mQ) for 1 hour. The solution was cooled to room temperature and 3-(2-pyridyl)-3.4-dihydro-2H-pyrido[1.2-a-triazine-2.4-dione (2.0 g
) and anhydrous tetrahydrofuran (25 mtr) are added and the mixture is stirred at 60 °C for 30 min. Cool the reaction mixture in an ice-water bath and add IN hydrochloric acid. Separate the organic layer and extract the aqueous layer with ethyl acetate. The organic layers are combined, washed with saturated brine, dried, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography using methanol, methylene chloride and diethyl ether (1:1).
0:30v/v) mixed solvent, [N-(
Tetraisopropyl 2-pyridyl)carbamoylmethylenebis(phosphonate) (1.42 g) is obtained as an oil.

IRC liquid film): 3360. 3250. 169
0 cm-'NMR (CDC13,l; ): 1.
20 1-58 (24H.tn), 2. 30
(1) 1,br s), 3.60 (18,t.J=
20Hz), 4.67-5, 05 (4H.m),
7.06 (LH, dd, J=7 and 5Hz), 7
．． 60-7.77 (18, m), 8.12 (IH
．． d.

J=7Hz>, 8.30 (IH.br d,, C5
Hz>, 9.11 (IH, br s) Production Example 29 2-benzo[b]thiophenecarboxylic acid (356mg>
and 2 synthesized from oxalyl chloride (0,3smQ)
-benzo[b]thiophenecarboxylic acid chloride in a solution of methylene chloride (2 mQ) at 5°C (aminomethylene).
A warm mixture of bis(phosphonate)tetraethyl (606 mg), pyridine (316 mg) and a trace amount of 4-(dimethylamine)pyridine in methylene chloride (8 mQ) is added. After stirring at room temperature for 2 hours while adding ethyl acetate, the reaction mixture is washed successively with water, IN hydrochloric acid, saturated aqueous sodium bicarbonate solution, and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. Diisopropyl ether was added to the residue and filtered to obtain [(2-benzo[b]thiophenecarboxamide)methylene]bis(phosphonic acid)tetraethyl (790 mg) as a white powder, which was recrystallized from a mixed solvent of ethyl acetate and n-hexane. do.

Melting point: 120-121°C IR: 3210. 1640.
1630 cm-'NMR (CDC13, f; )
' 1.30-1.42 (12H1m), 4.09
-4.41 (8H, m), 5.22 (IH, td
, J=20 and 9Hz>,6.63 (18,d,
J=9Hz), 7.38-7.50 (2Lm), 7
．． 85 (LH,s), 7.85-7.92 (2
H, m> In the same manner as Production Example 29, the following (Production Examples 30 to 30)
Compound 33) is obtained.

Production Example 30 Tetraethyl [(2-quinolinecarboxamide)methylene]bis(phosponate) Melting point: 5111-59°C IR (Nujol): 3500. 3400.
1680 am-1HMR (CDC13,8)'
1.10-1.55 (12H1m), 1.04-4
．． 45 (8H, m>, 5.24 (IH, td, J
=20 and 9Hz), 7.65 (IH,t,J=
7H2), 7.32 (IH, t.

J-7Hz>, 7.90 (IH, d, J=7Hz)
, 8.17 (LH, d.

J=7Hz), 8.29 (2H,q, J=10 and 8Hz).

8.25 (1B, d, J=9Hz) Production Example 31 (Pensoylaminomethylene)bis(phosphonic acid)tetraethyl 7l- IR(C)ICl3) + 3430.1665.16
00.1580.1480°1390, 1368 cm
-1 NMR(CDCl2.δ)i 1.31 (6H,t,
J=7)1z), 1.35(6H,t, J=7Hz)
, 4.05-4.35 (8H, m), 5.2
6 (IH, dt, J=10.22Hz), 6.7
7 (IH, d, J=10Hz).

7.40-7.60 (3H, m), 7.81
<2H, d, J=8Hz> Production Example 32 [(4-chlorobenzoylamino)methylene]bis(phosphonic acid)tetraethyl NMR (CDCl2. δ): 1.31
(6H, t, J=7Hz), 1.35 (6H, t,
J=7Hz), 4.22 (4H, qJ=7)1z)
, 4.23(4)1. q, J=7Hz), 5.2
4 (IH, dt, J=10.22Hz).

4.23 (4H, q, J=7Hz>, 5.24 (
LH, dtJ=10°22Hz), 6.82 (IJ
l, d, J=10Hz), 7.44 (2H, d.

J=8Hz), 7.74 (2H, d, J:8Hz)
Production Example 33 [(2-pyridinecarboxamide)methylene]bis(phosphonic acid)tetraethyl IR (liquid film)' 3500.3400.1685 c
m-'NMR (CDCl2.δ): 1.28-1.3
7 (12H, m), 4.15-4.32 (8)1
．． m>, 5.18 (1)1. td, J = 20 and 10 Hz), 7.27-7.51 (H(, m)
, 7.82-7.91 (LH.

td, J=8 and 2Hz>, 8.17 (LH,d
, J=8Hz).

8.54 (IH, d, J40Hz>, 8.58
-8.62 (LH, m> Production Example 34 N of 2-[1-(tert-butoxycarbonyl)imidazol-4-yl]acetic acid (45 mg) and (aminomethylene)bis(phosphonic acid)tetraethyl (91 mg) ,
N-ethyl-N'-(3-
dimethylaminopropyl) carbodiimide hydrochloride (4
2 mg) and stirred at 5°C for 36 hours. The reaction mixture is diluted with chloroform (10 mQ) and washed with cold IN aqueous citric acid (10 mQ). The washings are extracted twice with chloroform (10 mQ), and all the organic layers are combined, dried over sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (10 mQ), washed with water (xomQ), dried over magnesium sulfate, and concentrated under reduced pressure to give [
Tetraethyl [2-(1-(tert-butoxycarbonyl)imidazol-4-yl)acetamido]methylene]bis(phosphonate) (67 mg) is obtained as a colorless oil.

NMR (CDCl2.8)' 1.32 (6H9
t, J=61(z>,133(68,t,J=6)+z
), 1.62 (9H,s), 3.60 (2H,
s).

4.1-4.3 (8H, m), 5.06 (IH,
dt, J: 12Hz.

24Hz>, 7.28 (11(,s), 7.59
(LH, d, J=12Hz>.

8.07 (IH,s) Production Example 35 (aminomethylene)bis(phosphonic acid)tetraethyl (
661 mg) of pyridine (2 mQ) was added with benzenesulfonic acid chloride (0.s5 mA) while stirring at room temperature.
and 4-(dimethylamino)pyridine (50 mg) were added, and the mixture was stirred at the same temperature for 4 hours. The reaction mixture is diluted with ethyl acetate (2 omn) and washed successively with 4 portions of IN hydrochloric acid, water, and saturated aqueous sodium bicarbonate solution. After drying over magnesium sulfate, the solvent is distilled off under reduced pressure. The residue was subjected to silica gel (20 g) column chromatography and eluted with a mixed solvent of chloroform and methanol (20:1 v/v) to obtain (phenylsulfonylamino methylene).
Bis(bosphonate)te[·laethyl (364 mg) is obtained as a yellow oil.

IR(C)ICl3): 3390. 30
00. 1343. 1256°1165 cm-
'NMR (CDCl2.δ); 1.25 (6H, t
, J=7Hz>, 1.28 (6H,t, J=7Hz)
, 3.90-4.20 (8H, m>, 4.23(
IH, t, J=22)1z), 5.68 (IH
, br s), 7.45-7.60 (3H, m
), 7.91 (2H, dd, J=2.8Hz) In the same manner as in Production Example 35, the following compounds (Production Examples 36 to 40) are obtained.

Production Example 36 Tetraethyl (tosylaminomethylene)bis(phosphonic acid) NMR (CDC13,S)' 1.21.45 (
1,2H1m>, 2.42 (3H,s), 3.9-4
．． 4 (9H, m>, 7.3 and 7.75 (4H,
ABq, J=8.4Hz) Production Example 37 [(4-10 Lofenyl)sulfonylaminomethylenecobis(phosphonic acid)tetraethyl Melting point: 130-13
1°C NMR (CDCl2.S)' 1.27 (6H1
t, J = 6Hz), 1.30 (6H, t, J = 6Hz>
, 3.90-4.30 (8H, m>, 5.3
2 (IH, br s), 7.48 (2H, d, J
=8Hz), 7.84 (2H.

d, J=8Hz) Production Example 38 [(3,4-dichlorophenyl)sulfonylaminomethylenecobis(posphonate)tetraethyl Melting point: 104
-106℃ IR (Nujol): 3600. 3400.
3000. 1630. 1200°1160, 10
70 cm-' NMR (CDC13,8)' 1.20-1.40
(12)1. m), 4.00-4.40 (9H, m
>, 7.58 (LH, d, J: 8.5Hz), 7
．． 74 (LH, dd, J=9.0 and 2Hz),
7.99 (IH, d.

J-2Hz) 1”Δη [(2-chenyl)sulfonylaminomethylenecobis(
Tetraethyl phosphonate IR (liquid film): 3070.2960.1255.1
155°1020 cm-' NMR (CDC13,8)' 1.21.5 (12
H1m>, 2.3 (IHlbr), 4.0-4.
35 (9H, m), 7.09 (LH, dd, J
=4Hz and 5Hz>, 7.60 (LH, dd,
J4Hz and 5Hz), 7.66 (IH, ddj
4Hz and 4Hz) Production Example 40 [(8-quinolyl)sulfonylaminomethylene]bis(
Tetraethyl phosphonate NMR (CDCl2.8) j 1.10 (6H,
t, J=7Hz), 1.19(68,t, J=7Hz
), 3.80-4.20 (8H, m), 4.40
(IH, t, J-22Hz), 7.57 (IH, d
d, J=8.4)1z).

7.65 (IH, t, J-8Hz), 8.06 (
IH, d, J = 8Hz).

8.29 (IH, dd, J=8.2Hz>, 8.3
3 (11(, d.

J=8Hz), 9.07 (IH, dd, J=4.2
Hz) Production Example 41 To a suspension of 63.9% oily sodium hydride (44 mg) in distilled tetrahydrofuran (2, OmQ) was added methylenebis(phosphonic acid)tetraisopropyl (344 mg) all at once at 5°C, and the solution was stirred at room temperature for 30 min. Stir for a minute. The mixture was cooled in a water bath and 4-chlorophenylisocyanate (1
54 mg) and stirred at 5° C. for 30 minutes and then at room temperature for 1 hour to obtain a solution containing the sodium salt of [N-(4-chlorophenyl)carbamoylconitancohis(phosboxylate)tetraisopropyl]. Methyl iodide (426 mg) was added to the resulting solution at room temperature, stirred at the same temperature for 5 hours, and then an aqueous solution of ammonium chloride was added. The separated oil is extracted with ethyl acetate, and the extract is washed with saturated brine and dried. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography and eluted with a mixed solvent of n-hexane and ethyl acetate (1: lv/v) to obtain 1-[N-(4-chlorophenyl)carbamoylconitane. Tetraisopropyl-1,1-bis(phosphonate) (399 mg) is obtained as a colorless oil.

IR: 3350. 1695
am-'tJMR(CDCl2.8') 41.20
-1.55 (241 (, stone), 1.70 (3B, t
, 14Hz), 4.68-4.92 (4H, m>
, 7.28 (2H, dj=8Hz), 7.52 (
2H, d, J=8 Hz), 9.29 (IH, s) In the same manner as in Production Example 2, the following compounds (Examples 1 to 31) are obtained.

Example 1 [N-(phenyl)thiocarbamoylmethylene]bis(
Tris (tertiary butylamine salt) of phosphonic acid) Melting point: 140°C NMR (C20,8>: 135 (27H, br
s), 4.05 (it(,t.

J-20Hz), 7.3-7.75 (5H, +n)
Hanhuangki 1 [N-(4-chlorophenyl)carbamoylmethylene]
Tris(tertiary butylamine) salt of bis(phosphonic acid) Melting point i 206-210°C IR (Nujol): 3700-2000.
1660. 1540. 1150°1090, 825
cm-1 NMR (C20,8)' 1.4 (27t(
, br s), 3.23 <1)1. t.

, C20Hz), 7.40 and 7.50 (4H,
ABq.

J=9Hz) Example 3 Tris(tert-butylamine) salt of [N-(phenyl)carbamoylmethylene]via9-s(phosphonic acid) Melting point: 207-209°C IR (nugital): 3700-2000.
1650. 1600. 1150°1130, 106
5.960 cm-'NMR(C20,S)' 1
．． 40 (27H9br s), 3.25 (IHlt
.

, C20Hz>, 7.15-7.6 (5)t, m)
Fire Agriculture 1 [N-(4-fluorophenyl)carbamoylconitan bis(phosphonic acid) tris(tertiary butylamine)
Salt melting point: 209-211°C IR: 3700-2000
(br), 1650 cm-1HMR (C20,
8)' 1.36 (27H1s), 3.23 (L
H, t-9J: 20Hz), 7.14 (2H, t,
J=8Hz>, 7.50 (28°dd, J=8 and 51(z)) Example 5 Tris(tertiary butylamine) of [N-(3,4-dichlorophenyl)carbamoylmethylene]bis(phosphonic acid) Salt 80 = Melting point: 21.6-220℃ IR (Nujol): 3600-2100
(br), 1660 cm-'NMR (C20,
8): 1.35 (27H4), 3.30 (I
H,t.

J-20Hz), 7.38 (1)1. d, d, J-
9 and 2Hz>.

7.50 (ILd, J=9t(z), 7.81 (
LH, d, J = 2 Hz) Example 6 [N-(+)-)lyl)carbamoylmethylene]bis(
Tris (tertiary butylamine) salt of phosphonic acid) Melting point: 221-230°C
br), 1655 am-'NMR (C20, δ
>: 1.36 (27H, s), 2.
32 (3Ls).

3.27 (IH, t, J=20Hz), 7.25 (
2H, d, J = 8Hz>.

7.40 (2H, d, J=8Hz) Example 7 Tris(tertiary butylamine) salt of [N-(4-methoxyphenyl)carbamoin remethylene]bis(phosphonic acid) Melting point: 214-220°C IR (Sujoor): 3700-2300
(br), 1650 cm-'NMR (C20,
δ>: 1.37 (27)1. s), 3.27
(IH, t.

J=20Hz), 3.85 (38,s), 7.0
2 (2H, d.

J=8Hz>, 7.45 (2H, d, C3Hz) Example 8 Melting point of tris(tert-butylamine) salt of 1-[N-(4-chlorophenyl)carbamoyl]ethane-1,1-bis(phosphonic acid) : 237-239℃ IR: 3700-2000 (
br), 1650 cm-1HMR (C20, δ
): 1.36 (27H,s), 1.56 (3
8,t.

J=14Hz), 7.38 (2H,d, J=8Hz
), 7.50 (2Ld, J=8Hz) Tris(tert-butylamine) salt of [N-(4-chlorophenyl)thiocarbamoylmethylene]bis(phosphonic acid) Melting point: 206-208℃ NMR( C20, δ): 1.34 (27Lm>,
4.08 (IH, t.

J=22Hz>, 7.47 and 7.60 (4H,
ABq.

J=8)1z) Example 10 Bis(tert-butylamine) salt of [N-(1-naphthyl)thiocarbamoylmethylene]bis(posonic acid) Melting point: 160'C (decomposition) NMR(C20, δ)= 1.35 (18H, s),
4.24 (LH,t.

J=22Hz>, 7.60-8.23 (78,m)
Example 11 [Disodium salt of N-(3-trifluoromethylphenyl)thiocarhamoylmethylene cobis(phosponic acid) Melting point = 218°C (decomposition) IR (Nujol): 3300. 1600.
14.10. 1170. 1130°1.070.
890 cm' NMR (C20,l; )' 4-21 (IH,t
, J=20Hz), 7-60-7.77 (2H, +
n), 7.82 (IH, m), 8.10 (LH
, s) Example 12 Disodium salt of [N-(4-trifluoromethylphenyl)thiocarbamoylmethylene]bis(phosphonic acid) Melting point: 218°C (decomposition) IR (nudial) 2 3260. 1610. 1
425. 1400. 1335°1170, 1065
cm-' NMR (C20, δ): 4.11 (IH, t, J
=20.7)1z), 7.80 and 7.88 (4
H, ABq, J = 8.8 Hz) Tue] d's[N-(3-chlorophenyl)thiocarbamoylmethylene] bis(phosponic acid) Cina) lithium salt Melting point: 224°C (decomposition) IR (Nujol): 3300. 3200.
2350. 1595. 1400°1255, 12
00.1170.1090 cm-'Example 14 Disodium salt of [N-(2-chlorophenyl)thiocarbamoylmethylene]bis(phosphonic acid) Melting point: 255-257°C (decomposition) IR (nudisil)' 3700-2400
(br), 1590. 1150°1120 cm
-1 84-Example 15 Disodium salt of [N-(4-fluorophenyl)thiocarbamoylmethylenecobis(phosphonic acid) Melting point: 247-249°C (decomposition) IR (Skyl)' 3700-2300 (
br), 1220°1090 cm' NMR (C20,8)' 4. to (LHlt,
J=21Hz),? -21 (2H, tJ=9Hz),
7.58 (2H, dd, J=9 and 5Hz) Fire 1 second 1 second [Disodium salt of N-(p-tolyl)thiocarbamoylmethylenecobis(phosphonic acid) Melting point: 255-25
8℃ (decomposition) IR (X di, -l): 3700-2300
(br,), 1520°1150 cm-' NMR (C20, δ): 2.37 (3H, s),
4.04 (LH,t,.

J: 20Hz>, 7.32 and 7.52 (2H,
dd,, C8) 1z) Fire - Example 17 Disodium salt of [N-(2-methoxyphenylylmethylene]bis(phosphonic acid) Melting point = 227°C (decomposition) IR (Sujol): 3605, 33
50, 1600. 1540, 1400.

1240, 1160. 1050 cm-'NMR
(C20,S)' 3. 90 (3H,s), 4
-09 (LH.t.

J=20Hz), 7.03-7.19 (2H, m)
, 7.37 (1)1. t.

J=8)1z), 8.14 (ILd, J=8)1
z) 11 juice l Disodium salt of [N-(3,4-dichlorophenyl)thiocarbamoylmethylene]bis(phosphonic acid) Melting point j 24B-250°C (decomposition) IR (N9-9): 3700-2300
(br), 1190.

1090 cm-' NMR (C20,S): 4.03 (LH,t,
J=20Hz), 7.53-7, 64 (2H, m>
, 8.03 (1.)1. s＞Fire1-Sal CN-C2-pyridyl)carbamoylmethylene]bis(
Disodium salt of bosonic acid) Melting point: >300℃
(br), 1675 cm-'NMR (
C20, δ): 3.47 (18,t,
J=20Hz), 7.27(LH.tJ=6Hz>
, 7.83 (1.T(,d,J=8Hz), 7.
95 (IH.t.J=8Hz), 8.29 (IH.t.J=8Hz),
d, J = 6Hz) Inuarashi Koei (N-(2-benz[b]chenyl)thiocarbamoylmethylene]bis(posboxylic acid) disodium salt Melting point i >280°C IR (Nujol): 3700-2:to
o (br), 1460, 1410.

1230, 1160 cm-' NMR (C20,8)' 4. 02 (IH,
t. J=20Hz), 7. 35-7, 47 (2H
, m), 7.45 (LH,s), 7.85 (I
H,d.

J: 11Hz), 7.97 (IH, d, J=15H
z＞衷】■('IIdon [N-(2-trifluoromethylphenyl)theocarbamoylmethylene]bis(phosphonic acid) disodium salt Melting point: 212'C (decomposition) IR (nujol): 3250, 24
00. 1530, 1410, 1320.

1150, 1060 cm-' NMR (C20,S)' 4. ta (LH.
t, J=21Hz), 7. 52-7, 60 (IH
, m), 7.65-7.76 (2H, m),
7.83 (LH.d.J=8)1z) Example 22 Disodium salt of [N-(4-chloro-3-trifluoromethylphenyl)thiocarbamoylmethylenesulfonic acid) Melting point: 245°C (decomposed) IR (Nujor>: 3350, 32
00, 1620. 1560. 14g5.

1415, 1320 cm-1 NMR (C20, δ): 4.00 (IHi, J
= 20Hz), 7.68 (LH, d, J = 9Hz),
7.88 (IH.d, J=9Hz>, 8.29(
IH, s) Fruit 1 In-(4-methoxy-3-trifluoromethylphenyl)thiocarbamo, ylmethylene]his(posubonic acid)
Disodium salt Melting point: 249-252℃ (decomposition) IR (Skyl): 3250, 235
0, 1505, 1325. 1280.

1130 cm-' NMR (C20, δ): 4.05 (IH, t,
J-20Hz>, 7.28 (18, d, J=9Hz>
, ? ．． 77 (1) 1, dj=9Hz>, 7
．． 97 (IH.d, J: 2Hz> Example 24 Bis(tertiary butylamine) salt melting point of (N-methylcarbamoylmethylenesulfonic acid); 22
9℃ (decomposition) IR (sujigor): 3600-2000
．． 1645. 1150 cm-'NMR (
C20,l; ) :1. , 36 (18H,s), 2
．． 79 (3H, s).

3, 22 (IH, t, J = 21 Hz) Example 25 Disodium salt of [N-(n-butyl)thiocarbamoylmethylene]bis(phosboxylic acid) Melting point: >250°C IR (sudisil): 3500. 3250.
1560. 1280. 1180°1065 cm
"" NMR (C20,8) ' 0.94 (3H1t, J
=7Hz), 1.33-1.51 (2H, m), 1.
51-1.69 (2H, m), 3.61 (2H
,t.

J=8Hz), 3.91 (1)1. t, , J=2
1 Hz) Example 26 Disodium salt of [N-(4-trifluoromethylphenyl)carbamoylmethylene cobis(phosphonic acid) Melting point: >250°C IR (striped seal): 3700-3000
(br), 2300. 1650°1600, 13
35.1100 am-'NMR(C20,S)'
3.31. <1)1. t, J=20Hz), 7.7
0(4H,s) Example 27 Disodium salt of [N-(4-methylthiophenylmoylmethylene]bis(phosphonic acid) Melting point = 215°C (decomposition) IR (striped seal): 3500, 33
00. 1500, 1390, 11.70.

1065 am-' NMR (C20,l; ): 2.5 (
IH,s), 4.09 <18. t.

J-211+z), 7.4 (2H, d, J=8
．． 6Hz), 7.59 (2H.

dj=8.6Hz> Example 28 Disodium salt of [N-(4-mesylaminophenyl)thiocarbamoylmethylene]bis(phosphonic acid) Melting point = 225°C (decomposition) IR (striped seal): 3200. 235
0, 1510. 1320.

1150 cm-' NMR (C20.8)' 3. 12 (3)1
．． s), 4. 08 (LH, t.

, C20Hz), 7.34 and 7.65 (eac
h 2H, d.

J=9Hz) Example 29 Disodium salt of [N-C3-mesylaminophenylbamoylmethylene]bis(phosphonic acid) Melting point: 212°C (decomposition) IR (striped seal): 3300, 24
00, 1620. 1340, 1160.

1080 cm""' NMR (C20, δ): 3.12 (3)1. s
), 4.80 (IH, t.

J=20Hz>, 7.22-7.25 (LH, br
d, J=6Hz>.

7, 45-7.49 (2H, m>, 7.73
(IH, br s) Example 39 Disodium salt of [N-(4-acetylaminophenylrubamoylmethylene]bis(phosphone*)) Melting point: 218°C (decomposition) IR (striped seal): 3250, 23
50, 1660. 1510, 1400.

1140, 1060 cm-1 NMR (C20,8)' 2. 18 (3H,
s), 4. 80 (IH, t.

J-20) 1z), 7.50 and 7.64 (2H
, d, J = 8 Hz > Huo Isakudon [Disodium salt of N-(3-acetylaminophenyl)thiocarbamoylmethylenecobis(phosphonic acid) Melting point: 209°C (decomposition) IR (striped seal): 3200, 23
50, 1670, 1605, 1550.

=92-1160, 1080 cm-' NMR (C20, δ): 2.16
(311,s), 4.80 (H(,t.

J=20Hz), 7.35-7.57 (2H, m),
7.76 (HLbr s) In the same manner as in Production Example 29, the following compounds (Examples 32 to 37) are obtained.

Example 32 Bis(tert-butylamine) salt of [(2-benzo[b]thiophenecarboxamide)methylene]bis(phosphonic acid) Melting point; 234-238°C IR (sudisil): 3700-2050
(br), 1640 cm-'NMR (C
20,l; )' 1.40 (18H,s), 4.
59 (IH, t.

J=20Hz>, 7.43-7.58 (2H, m>
, 7.95-8.08 (28, m), 8.11 (
1) 1,s) Example 33 [(2-quinolinecarboxamido)methylene]bis(phosphonic acid) tris(tertiary butylamine) salt IR (sudisyl): 3700-2000
(br), 1660 cm-1 NMR (C2
0,l; ) j 1.46 (27H,s), 4.
61 (IH, t.

J=20Hz), 7.76 (IH, t, J=11
Hz>, 7.94 (1,H.

t, J=11)+z>, 8.08 (IH, d, J
=8Hz), 8.20(2H,,tJ=11Hz>
, 8.58 (LH, d, J=8Hz) Example 34 Disodium salt of (benzoylaminomethylene)bis(posphonic acid) Melting point: >260°C NMR (C20,8): 4.66 (LH, t, J
=20Hz), 7.20-7.50 (3H, m>,
7.85 (2H, d, J = 8 Hz) Example 35 Disodium salt of [(4-chlorobenzoylamine)methylene]bis(phosphonic acid) Melting point: >260°C NMR (C20, δ) i 4.65 ( IH,tj=
20Hz), 7.55 (2Ld, J=91(z),
7.83 (2)1. d.
(br), 1670 cm-1BMR (C20,
δ): 4.64 (LH,t,,T=20H2),
7.64-7.71 (LH, m), 8.04
−8.14 (2H, m>, 8.66 (IH, d
J=5Hz) ■4 strokes [(2-(imidazol-4-yl)acetamido)methylene]bis(posphonic acid) Melting point: 247-250°C NMR (C20,l; ): 3-77 (2
H1s), 4.55 (IHlt.

, C21Hz>, 7.24 (LH,s), 8.5
1 (18, s) In the same manner as in Production Example 35, the following compounds (Examples 38 to 43) are obtained.

Example 38 (Phenylsulfonylaminomethylene)bis(phosphonic acid) Melting point: 215-216°C NMR (C20, δ > 3.95 (LH
, t, J=21Hz>, 7.50-7.70 (3
H, m), 7.89 (IH, dd, J=1.8Hz
) Example 39 (l-cylaminomethylene)bis(phosphonic acid) Melting point:
232-233°C NMR (C20, δ) i 3.98 (IH
4, J=21Hz), 7.78 and 7.41
(4H, ABq, J=8.1Hz>Tuesday) α Milk [(4-chlorophenyl)sulfonylaminomethylene]
Disodium salt of bis(phosphonic acid) Melting point: >260
°C NMR (C201): 3.80 (IHL, J=2
0Hz), 7.59 (2H, d, J=8Hz>, 7
．． 88 (2B, d, J = 8 Hz) Example 41 [(3,4-dichlorophenyl)sulfonylaminomethylene cobis(phosphonic acid) Melting point j >250°C IR (Sujimil): 3100. 1345.
1270. 1230°1050 cm-' NMR (C20,8): 3.74 (1)1. t,
J=20Hz), 7.70(IH, d, J=9Hz>
, 7.80 (LH, d, J=9Hz>, 8.09
(IH,s) Example 42 [(2-chenyl)sulfonylaminomethylene]bis(
(Posphonic acid) Melting point: 231°C (decomposition) IR (Sujimeal>: 3540. 1325.
1165 cm-1BMR (C20,8): 3
．． 98 (IH, t, J=21Hz), 7.1-7.
2 (IH, m>, 7.73 (IH, d, J=3.5
Hz), 7.79 (IH.

d, J = 5Hz>
Phosphonic acid) disodium salt Melting point i >260°C NMR (C20, δ): 3.65 (IH, t, J=
19Hz), 7.61 (LH, dJ=3.7Hz),
7.65 (IH, tj=7Hz>.

8.11 (LH, d, J=7Hz), 8.40 (
18, dJ=7Hz>.

8.44 (IH, d, J=7Hz), 8.96 (
1)1. d, J=3Hz) K凰輿M [N-(phenyl)thiocarbamoylmethylenecobis(
Tetraisopropyl phosphonate (0,101g) (7
) Iodotrimethylsilane (0.1 smQ) was added at once to a methylene chloride (4 ml) solution at 5°C, and the mixture was heated for 30 min at room temperature.
After stirring for a minute, extract with water. The extract is washed with methylene chloride, and the solvent is azeotropically distilled off with toluene under reduced pressure. The resulting residue containing [N-(phenyl)thiocarbamoylmethylenecobis(phosboxylic acid) was dissolved in ethanol (2.1 m
fl) and tertiary butylamine (0.11 mQ
) is added. The solvent is distilled off, and the residue is powdered with a mixed solvent of ethanol and diethyl ether. The resulting powder was dissolved in water and lyophilized to give [N-(phenyl)
Tris(tert-butylamine) salt (93 mg) of thiocarbamoyl methylene cobis(posphonic acid) is obtained as a colorless powder.

Melting point = 140°C NMR (C20, f; ) = 1.35 (27H, b
rs), 4-05 (IH9tJ=20Hz>,
7.3-7.75 <5H, m) In the same manner as in Example 44, the following compounds (Examples 45 to 54) are obtained.

Fire 1 - Example μ [N-(4-chlorophenyl)carbamoylmethylene]
Tris(tertiary butylamine) salt of bis(phosphonic acid) Melting point: 206-210°C IR: 3700-2000. 1
660. 1540. 1150°1090, 825
Cm'NMR(C20,8>' 1.4 <27!(
, br s), 3.23 (LHlt.

J=20Hz>, 7.40 and 7.50 (4H,
ABq.

J=9Hz) Tris(tertiary butylamine) salt of [N-(phenyl)carbamoylconitane]his(phosponic acid) Melting point: 207-209°C IR (sujoor): 3700-2000.
1650. 1600. 1150°1130, 106
5.960 cm-'NMR (,C20,8): 1.
40 (27H,br s), 3.25 (lf(,
't.

J=20Hz>, 7.15-7.6 (5H, m)9
91 Example 47 Tris(tertiary butylamine) of [N-(4-fluorophenyl)carbamoylmethylene]bis(phosphonic acid)
Salt melting point: 209-211℃ IR (streak seal): 3700-2000
(br), 1650 cm-1HMR (C20,
8>: 1.36 (27H, s), 3.23 (
IH,t.

J=20Hz>, 7.14 (2H,t, J-8Hz
), 7.50 (2H.

dd, J=8 and 5 Hz) Example 48 Tris(tert-butylamine) salt of [N-(3,4-dichlorophenyl)carbamoylmethylene]bis(phosphonic acid) Melting point: 216-220°C IR ): 3600-2100
(br), 1660 am-1HMR (C20,
δ)': 1.35 (27H, s), 3.30
(LH,t.

J=20Hz), 7.38 (IH, dd, J=9 and 2Hz).

7.50 (LH, d, J=9Hz), 7.81 (
IH, d, J = 2 Hz > Example 49 [N-(p-tolyl)carbamoyl, methylenecobis(
Tris (tertiary butylamine) salt of phosphonic acid Melting point: 221-230°C IR (sujoor): 3700-2000
(br), 1655 cm' NMR (C20
,f; )' 1.36 (27H,s),
2.32 (3H, s).

3.27 (1)1. t, J=20H2), 7.25
(2H, d, J=8Hz).

7.40 (20,d, J=8Hz) Example 50 Tris(tertiary butylamine) of [N-(4-methoxyphenyl)carbamoylmethylene]bis(phosphonic acid)
Salt melting point: 214-220℃ IR (Sujoor>: 3700-2300
(br), 1650 am-1HMR (C20,
δ): 1.37 (27H,s), 3.27 (I
H,t.

, C20)1z), 3.85 (3H,s), 7.
02 (28, d.

J=8)1z), 7.45 (2H,d, J=8Hz
>Example 51 Tris(tertiary butylamine) salt of 1-[N-(4-10 phenyl)carbamoylconitane-1,1-bis(phosphonic acid) Melting point i 237-239°C IR (Nunyol): 3700- 2000
(br), 1650 cm-'NMR (D20.
f;)' 1.36 (27H1s), 1.56
(3H9t.

J-141(z>, 7.38 (2!(, d, J=
8) 1z), 7.50 (2H.

ci, J=suz) Tris(tertiary butylamine) salt of [N-(4-chlorophenyl)thiocarbamoylmethylene]bis(phosphonic acid) Melting point: 206-208°C NMR (D20,8): 1.34 (27H1m>
, 4.08 (IHlt.

J=22Hz), 7.47 and 7.60 (4H,
ABq.

J=8Hz) Example 53 [N-(1-naphthyl)thiocarbamoylmethyleneamine) Salt melting point: 160°C (decomposition)' NMR (D20.8): 1.35 (18
H. s), 4.24 (LH,t-.

J:22Hz), 7.60-8.23 (7H, m>
Fire 11M 1 part (N-methyl rubbermoyl mebrun) bis(tertiary butylamine) salt of bis(posonic acid) Melting point: 229°C (
Disassembly) IR (nu9-ru)' 3600-2000.
1645. 1150 am-'NMR (D
20. 8) '1. 36 (18H,s), 2
, 79 (3H-s).

3, 22 (LH, tJ = 21 Hz>) [N-(3-trifluoromethylphenyl)thiocarbamoylmethylene phosponate] Tetraisopropyl (phosponic acid) was added to a solution of tetraisopropyl (2 g) in methylene chloride (36 mQ) at 0°C. Add iodotrimethylsilane (2.86mρ) and stir at the same temperature for 4 hours.Water (40mQ) is added to the reaction mixture.
The aqueous layer is separated, washed four times with methylene chloride, and then concentrated. Acetonitrile (30mQ)
tertiary butylamine (534 mg) is added. Filter the formed precipitate and Further add tertiary butylamine (534 mg) to liquid a. The generated precipitate is collected by filtration, combined with the previous precipitate, and mixed with Dowex.
) 50wX 8 (H+ type, 5mQ) (Trademark:
The sample was subjected to column chromatography (manufactured by Dow Chemical Company) and eluted with water. The eluate was concentrated and the obtained [N-(3
-1-Lifluoromethylphenyl)thiocarbamoylmethylene cohis (phosponic acid) was dissolved in water (2Qm
Q) Sodium acetate (266mg)
Add. The mixture is stirred at 60°C for 20 minutes and then heated to 100°C without adding ethanol. After cooling the mixture, the formed precipitate was collected by filtration and dried under reduced pressure.
Disodium salt of (3-trifluoromethylphenyl)thiocarbamoylmethylene]bis(posonic acid) (5
44 mg).

Melting point = 218°C (decomposition) IR (Sujoor) j 3300, 16
00, 1410. 1170, 1130.

1070, 890 cm-1 NMR (D20.8)' 4. 21 (IH,
t, J=20Hz>, 7. 60-7, 77 (2H
, m), 7.82 (LH, m>, 8.10
(LH,s) In the same manner as in Example 55, the following compounds (Examples 56 to 74) are obtained.

104-Example 56 [Disodium salt of N-(4-trifluoromethylphenyl)thiocarbamoylmethylene cobis(phosphone m) Melting point = 218°C (decomposition) T. R (streak seal): 3260. 1610
．． 1425, 1400, 1335.

11, 70. 1065 cm"" NMR (D20,8)' 4. 11 (IH,
t-, J=20.7Hz), 7. 80 and 7.88
(4H, ABq.J=8.8Hz>Example 57 [Disodium salt melting point of N-(3-chlorophenyl)thiocarbamoylmethylenecobis(phosponic acid); 224"C (decomposition) IR (x9-x) : 3300. 320
0,2350. 1595, 1400.

1255, 1200, 1170. 1090 cm
-INMR (D20, δ): 4.12 (IH,
t, J: 20Hz>, 7.31-7, 56 (3H
．． m), 7.88 (LH, s) Harm JIL Competition [N-(2-'/Rolophenyl) Theocarbamoylmethylene] Bis(74, Sulfonic Acid) Cina I Lium Salt Melting Point: 255-257°C <Decomposition ) IR (Sujoor)' 3700-2400
(br), 1590. 1150°1120 cm
-' Example 59 Cina(.lium salt of [N-(4-fluorophenyl)thiocarbamoylmethylene]bis(phosphonic acid) Melting point: 247-249''c (decomposition)゛ IR(
Sujoor): 3700-2300 (br
), 1220°1090 cm-' NMR (D20.δ): 4.10 (IH,tj=
21Hz), 7.21 (2H, t, J=9H2),
7.58 (2H, dd, J=9 and 5Hz) Example 60 Disodium salt of [N-(p-1□lyl)thiocarbamoylmethylenecobis(phosphonic acid) Melting point: 255-2
58°C (decomposition) IR (nucle) '3700-2300 (
br, ), 1520°1150 cm"" NMR (D20.δ): 2.37 (3H, s),
4.04 (IH, t.

J=20Hz>, 7.32 and 7.52 (2H,
dd, J-8Hz) Example 61 Disodium salt of [N-(2-methoxyphenyl)thiocarbamoylmethylene]bis(phosboxylic acid) Melting point: 227"C (decomposition) IR (Sujol'): 3605. 3350
．． 1600. 1540. 1,400°1240,
1160.1.050 cm-'NMR (D20.E
)' 3.90 (3H1s), 4.09 (IHl
t.

J=20Hz), 7.03-7.19 (2B, m>
, 7.37 (IH, t.

J-8Hz), 8.1.4 (IH, d, J=8Hz
>Example 62 Disodium salt of [N-(3,4-dichlorophenyl)thiocarbamoylmethylene]bis(phosphonic acid) Melting point: 248-250°C (decomposition) IR (Sujor)' 3700-2300
(br), 1190°1090 cm-' 7-N (D20.l; )' 4.03 (IH1
tJ=20Hz>, 7.53-7.64 (2H, m
), 8.03 (LH,s) Example 63 [N-(2-pyridyl)carbamoylmethylenecobis(
Disodium salt of phosphonic acid) Melting point: >300°C IR (Sujoor): 3700-2100
(br), 1675 cm-'NMR (D20.
l;)' 3.47 (IHlt, J=20Hz)
, 7.27(1)1. t, J=6Hz), 7.83
(IH, d, J=8Hz), 7.95 (1B, t, J
-8Hz), 8.29 (1)1. d, J=6Hz)
Disodium salt of Khoji [N-(2-benzo[b]chenyl)thiocarbamoylmethylene]bis(bosphonic acid) Melting point j >280°C IR (Sujol): 3700-2300
(br), 1460. 1410°1230, 11
60 cm-' NMR, (D20.δ) i 4.02 (1B, t,
J=20Hz>, 7.35-7.47 (2H, m)
, 7.45 (LH,s), 7.85 (LH,d
.

J=11Hz>, 7.97 (IH, d, J=15H
z) 408-Example 65 Disodium salt of [N-(2-trifluoromethylphenyl)thiocarbamoylmethylene]bis(phosphonic acid) Melting point: 212°C (decomposition) IR (nucle): 3250. 2400.
1530. 1410. 1320°1150, 106
0 cm-' NMR (D20,8)' 4.16 (IHlt,
J=21Hz), 7.52-7.60 (LH, m),
7.65-7.76 (2H, m), 7.83 (I
H, d, J = 8 Hz) Example 66 Disodium salt of [N-(4-chloro-3-trifluoromethylphenyl)thiocarbamoylmethylene]his(phosphonic acid) Melting point: 245°C (decomposition) IR (Sujol ): 3350. 3200,
1620. 1560. 1485°1415, 132
0 cm-' NMR (D20.δ): 4.00 (IH, t, J
=20Hz>, 7.68(LH, d, J=9Hz>,
7.88 (IH, d, J=9Hz), 8.29 (
LH,s) Example 67 Disodium salt of [N-(4-me)xy-3-(-lifluoromethylphenyl)thiocarbamoylmethylene (phosphonic acid) Melting point: 249-252''c (decomposition) IR (Suji wool): 3250, 2350.15
05, 1325, 1280.

1130 am-1 NMR (C20, δ): 4.05 (IH, t,
J=20)1z), 7.28(IH,d,J=9Hz
>, 7.77 (IH.d, J=9Hz), 7.9
7 (1u, a, J=2Hz> Example 68 [Disodium salt of N-(n-butyl)thiocarbamoylmethylenecobis(phosboxylic acid)] Melting point: >250°C IR (sujiwor): 3500, 32
50, 1560. 1280, 1180.

1065 cm' IJMR (C20, δ): 0.94 (3H.t
J=7Hz>, 1.33-1. , 51(2)1. m＞
, 1.51-1.69 (2H.m>, 3.61
(2B, t.

J=8Hz), 3.91 (LH.t, J=2].H
z) Example 69 Disodium salt of [N-(4-hlifluoromethylphenyl)carbamoylmethylene]bis(phosboxylic acid) Melting point i >250°C T. R (Sujoor): 3700-3000
(br), 2300, 1650.

1600, 1335. 1100 cm-'NMR
(C20, l; )' 3. 31 (LH.t, J
=20Hz>, 7-70 (4H.s) Example 70 Disodium salt of [N-(4-methylthiophenyl)thiocarbamoylmethylene]bis(phosphonic acid) Melting point: 215"C (decomposition) IR (streak?- ): 3500.33
00, 1500, 1390, 1170.

1065 cm-1 NMR (C20,8)' 2. 5 (LH,s
), 4. 09 (IH, t.

J=21Hz), 7.4 (2H, d, J=8.6H
z), 7.59 (2H.

d, J=8. 6Hz) Disodium salt of [N-(4-mesylaminophenyl)thiocarbamoylmethylene]bis(phosphonic acid) Melting point: 225°C (decomposition) IR (nu9-9): 3200, 235
0. 1510, 1320.

1150 am' NMR (C20,l; ): 3.12 (3H.s
), 4.08 (IH.t.

J=20Hz), 7.34 and 7.65 (eac
h 2H, d.

, C9Hz) Example 72 Disodium salt of [N-(3-mesylaminophenyl)thiocarbamoylmethylene]bis(bosphonic acid) Melting point = 212°C (decomposition) IR (Sudiral'I: 3300, 2
400. 1620. 1340. 11.60
.

1080 cm-1 NMR (C20,8)' 3.12
(3H, s), 4.80 (IH, t.

J=2 (lHz>, 7.22-7.25 (IH.b
r d, J = 6 Hz).

7, 45-7.49 (2H.m), 7.73 (I
H, br s) 112-Example 73 Disodium salt of [N-(4-acetylaminophenyl)thiocarbamoylmethylenecobis(phosboxylic acid)] Melting point: 218°C (decomposition) IR (Sujol): 3250. 23
50, 1660, 1510, 1400.

1140, 1060 cm-1 NMR (C20,8): 2. 18 (3)1.
s), 4. 80 (18.t.

J=20Hz>, 7.50 and 7.64 (2)1
, d. J=8Hz) Example 74 Disodium salt of [N-(3-acetylaminophenyllbamoylmethylene]bis(phosphonic acid) Melting point = 209°C (decomposition) IR (Sujol): 3200, 23
50, 1670. 1605, 1550.

1160, 1080 cm-' NMR (C20,8): 2. 16 (3H.s
), 4-80 (LH.t.

J=20Hz), 7.35-7.57 (2H, m>
, 7.76 (IH.

brs) Example 75 [N-(phenyl)thiocarbamoylmethylene]bis(
tris(tertiary butylamine) salt (phosphonic acid) (9,
07g) to Dowex 50wX 8
(H+ form, 76 mp) was subjected to column chromatography and eluted with water. The eluate is concentrated to obtain a residue containing [N-(phenyl)thiocarbamoylmethylene]bis(phosphonic acid). The obtained residue was dissolved in water and added to a 1M aqueous solution of sodium acetate 11 (34.2 mR),
Stir the mixture for 30 minutes. Ethanol (t6oma
) and then heated to form a precipitate. The mixture is cooled and the formed precipitate is collected by filtration to obtain the disodium salt of [N-(phenyl)thiocarbamoylmethylene]bis(phosponic acid) (6.07 g).

Melting point: 216°C (decomposition) IR (streak seal): 3500. 3300.
1505. 1175. 1145°920 cm' NMR (D20.δ) i 4.10 (IH, t, J
-21Hz>, 7.3-7.75 (5H, m>) Example 76 [(2-benzo[b-cothiophenecarboxamide)methylene]bis(posphonate)tetraethyl (463mg)
To a solution of methylene chloride (2 mQ) at 5°C, add iodo-rimethylsilane (1 mQ) all at once. Mixture 5°
C. for 1 hour, left in the refrigerator for 2 days, and then stirred at room temperature for 1 hour. The reaction mixture is extracted with water, the extract is washed with methylene chloride and diethyl ether, and then concentrated under reduced pressure.

The residue was dissolved in water and tertiary butylamine (183 mg
) and lyophilized to obtain [(2-benzo[b]thiophenecarboxamide)methylene]bis(phosphonic acid).
The bis(tert-butylamine) salt (277 mg) of the following is obtained as a white powder.

Melting point: 234-238'C IR (streak seal) i 3700-2050
(br), 1640 cm-'NMR (D20.
δ): 1.40 (18H,s), 4.59 (
18,t.

J=20Hz), 7.43-7.58 (2H, m>
, 7.95-8.08 (2H, m>, 8.11 (
LH,s) 115 - Example 77 In the same manner as in Example 76, the tris(tert-butylamine) salt of [(2-quinoline lupoxamide) methylene bis(phosphonic acid) is obtained.

IR (line sticker): 3700-2000
(br), 1660 cm-1BMR (D20.
S)' 1.46 (27H9s), 4.61.
(LHLt.

J-20Hz>, 7.76 (LH, tj=11Hz
), 7.94 (IH.

t, J=11Hz), 8.08 (IH, d, J=8
Hz), 8.20 (2H, t, J41Hz), 8.
58 (IH, d, J=8 Hz) Example 78 In the same manner as in Example 76, [(2-pyridinecarboxamide)methylenecobis(phosphonic acid) is obtained.

Melting point: 277°C (decomposition) IR (streak seal): 3150. 1670.
1640. 1615 am-'NMR (DMSO
-d6. δ): 4.60 (IH, td, J=20
and 10Hz>, 7.63-7.70 (IH, m
>, 8.00-8.10 (IH, m>, 8.37
(LH, d, J=10t(z), 8.70 (IH.

After stirring a warm mixture of [(2-pyridinecarboxamido)methylene]bis(phosponic acid) (180 mg) and sodium acetate trihydrate (165 mg) in water (2 mQ) at room temperature for 30 minutes Filter. Add ethanol (6m
Add Q), heat and filter off insoluble matter. The filtrate was allowed to stand, and the precipitated crystals were collected by filtration to obtain disodium salt (131 mg) of [(2-pyridinecarboxamide)metelenchobis(phosponic acid) as a white powder.

Melting point: >300℃ IR: 3700-2300 (
br), 1670 cm-'NMR (D20.δ
): 4.64 (1B, t, c20Hz), 7.
64-7.71. (IH, m), 8.04-8.1
4 (2H, +n), 8.66 (1) 1. dJ=5H
2) In the same manner as Example 78, the following (Examples 79 and 80)
) is obtained.

Example 79 Disodium salt of (benzoylaminomethylene)his(phosphonic acid) Melting point: >260°C NMR (D20,8)' 4.66 (I
H,tj=20Hz), ? -20-7,50 (3H,
m), 7.85 (28, d, J=8 Hz) Example 80 Disodium salt of [(4-chlorobenzoylamino)methylene]bis(phosphonic acid) Melting point i >260°C NMR (D20.δ): 4 .65 (LH,tj=
20Hz), 7.55 (2H, dJ=9Hz), 7
．． 83 (2H, d, J = 9 Hz) Example 81 [(2-(1-(tert-butoxycarbonyl)imidazol-4-yl)acetamido]methylene]bis(posponate)te]-raethyl (67 mg) Methylene chloride (
Iodotrimethylsilane (0.12 nQ) was added dropwise to the 1 ml solution while stirring under an ice-water bath in a nitrogen stream. The mixture is stirred under the same conditions for 1 hour and then at room temperature for 2 hours. Water (1 mQ) was added to the reaction mixture while stirring under water cooling, and the mixture was stirred for 15 minutes. Water (4 mQ) and chloroform (41 nQ) were added, the aqueous layer was separated, washed four times with chloroform (5 mQ), and concentrated under reduced pressure to obtain a yellow oil (70 mg). The obtained oil was mixed with water (0.5
U-1 dissolved in mQ) was stirred at room temperature for 3 hours to obtain a white precipitate, which was collected by filtration. The residue was washed with cold water (1 mQ) [(
A white powder of 2-(imidazol-4-yl)acetamido)methylene]bis(phosphonic acid) (20 mg) is obtained.

Melting point: 247-250°C NMR (D20-8)' 3.77 (
2H9s), 4.55 (IHlt.

J=21Hz), 7.24 (11,s), 8.5
1 (IH,s) Example 82 (phenylsulfonylaminomethylene)bis(phosphonic acid)tetraethyl (400mg) in methylene chloride (4m
Q) Add iodotrimethylsilane (Q, 3mQ) dropwise to the solution while stirring in an ice-water bath in a nitrogen stream, and stir at the same temperature for 30 minutes and then at room temperature for 1.5 hours. Water (1 omQ) and chloroform (3 mQ) are added to the reaction mixture under water cooling. The aqueous layer is separated, washed with chlorine, and concentrated under reduced pressure. The resulting residue was washed with ethanol and (phenylsulfonylaminomethylene)bis(phosphonic acid) (
194 mg) of -1,19- white powder is obtained.

Melting point: 215-216°C NMR (D20.δ): 3.95 (IN, t, J
=21H7>, 7.50-7.70 (3H,m>,
7.89 <LH, dd, J=1.8Hz) Example 8
The following compounds (Examples 83 to 86) are obtained in the same manner as in 2.

Example 83 (Tosylaminomethylene]bis(phosphonic acid) Melting point:
232-233'''C NMR (D20.8): 3.98 (IH, t, J
=21Hz), 7.78 and 7.41 (4H,A
Bq, J4. IHz) Fire [(4-chlorophenyl)sulfonylaminomethylene]
Bis(bosphonic acid) Melting point: 255-256°C (decomposition) NMR (D2CLδ): 3.94 (LH, t, J
=22Hz>, 7.60(2)1. d, J=8Hz),
7.88 (2H, d, J=8Hz) In the same manner as in Example 78, [(4-chlorophenyl)sulfonylaminomethylene]his(phosphonic acid) and sodium acetate trihydrate were prepared from [(4-chlorophenyl) The disodium salt of sulfonylaminomethylene]bis(bosphonic acid) is obtained.

Melting point: >260°C NMR (D20.l; )' 3.80 (1,)I
, t, J-20Hz), 7.59 (2H', d, J=8
Hz>, 7.88 (2H, d, J=8Hz>Example 85 [(S,a-dichlorophenyl)sulfonylaminomedelencobis(phosphonic acid) Melting point: >250°C IR (Sdisil); 3100. 1345.
1270. 1230°1050 cm-” NMR ([)20.δ): 3.74 (IH,t,
J=20Hz>, 7.70(IH, d,, T-9Hz
), 7.80 (IH, d, J=9Hz>, 8.0
9(LH,s) Example 86 [(2-chenyl)sulfonylaminomethylene]bis(
Phosphonic acid) Melting point: 231°C (decomposition) IR (Fuji 1-l): 3540. 1325.
1165 cm' NMR (D20.8):
3.98 (IH, t, J=21Hz>, 7.1-
7.2(], H, m>, 7.73 (IH, d, J
=3.5Hz>, 7.79 (11°dJ=5Hz
) Example 87 In the same manner as in Example 84, the disodium salt of [(8-quinolyl)sulfonylaminomethylene]bis(phosphonic acid) is obtained.

Melting point: >260°C NMR (D20.8)' 3.65 (IHlt,
J=19Hz>, 7.61 (LH, J d, J=3.7
H7), 7.65 (IH, t, J=7Hz).

8.11 (IJ(,d,J=7Hz), 8.40
(IH, d, J=7Hz).

8.44 (IH, d, J=7Hz), 8.96 (
1B, d,, C3Hz) Meeting

Claims (9)

[Claims] (1) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R^1-A- is the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, ▲ Numerical formulas, chemical formulas,
▼ or R^1-SO_2-NH- (wherein R^1 is a substitution selected from the group consisting of lower alkyl, lower alkoxy, lower alkylthio, halo(lower) alkyl, acyl, acylamino, and halogen) an aryl group or a heterocyclic group which may be substituted with a group, or a lower alkyl group which may be substituted with a heterocyclic group which may have an acyl group, X means O or S, respectively) R^2 means hydrogen or a lower alkyl group, respectively, and when R^1 is an unsubstituted lower alkyl group, R^1-A
- is a formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ or R^1-SO
A diphosphonic acid compound and a salt thereof, which is a group represented by _2-NH- (wherein R^1 and (2) R^1 is substituted with a substituent selected from the group consisting of lower alkyl, lower alkoxy, lower alkylthio, halo(lower) alkyl, lower alkoxycarbonyl, lower alkanoylamino, lower alkylsulfonylamino, and halogen; a phenyl group, naphthyl group, pyridyl group, imidazolyl group, thienyl group, quinolyl group, benzothienyl group or benzothiazolyl group, or a lower alkyl group optionally substituted with imidazolyl optionally having lower alkoxycarbonyl; A compound according to claim 1. (3) R^1-A- is the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. , mono- or dihalophenyl group,
Halo (lower) alkylphenyl group, lower alkanoylaminophenyl group, lower alkylsulfonylaminophenyl group, phenyl group substituted with halogen and halo (lower) alkyl, phenyl group substituted with lower alkoxy and halo (lower) alkyl, Pyridyl group, benzo[b
]thienyl group or lower alkyl group, X is O or S
3. The compound according to claim 2, wherein R^2 is hydrogen. (4) The compound according to claim 3, wherein R^1 is a phenyl group, a monohalophenyl group, a mono[halo(lower)alkyl]phenyl group, or a mono(lower)alkylsulfonylaminophenyl group. (5) [N-(phenyl)thiocarbamoylmethylene]
5. The compound according to claim 4, which is a disodium salt of bis(phosphonic acid). (6) R^1-A- is the formula ▲There are mathematical formulas, chemical formulas, tables, etc. The groups indicated by ▼ The compound according to claim 2, which is (7) R^1-A- is the formula Group represented by R^1-SO_2-NH- The compound according to claim 2, which is (8) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R^1-A- is the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, ▲ Numerical formulas, chemical formulas,
▼ or R^1-SO_2-NH- (wherein R^1 is a substitution selected from the group consisting of lower alkyl, lower alkoxy, lower alkylthio, halo(lower) alkyl, acyl, acylamino, and halogen) an aryl group or a heterocyclic group which may be substituted with a group, or a lower alkyl group which may be substituted with a heterocyclic group which may have an acyl group, X means O or S, respectively) R^2 means hydrogen or a lower alkyl group, respectively, and when R^1 is an unsubstituted lower alkyl group, R^1-A
- is a formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ or R^1-SO
_2-NH- (In the formula, R^1 and etc. ▼ [In the formula, R^2 means hydrogen or a lower alkyl group] A compound or its salt represented by the formula R^1-NCX [In the formula, R^1 is lower alkyl, lower alkoxy, lower an aryl group or a heterocyclic group optionally substituted with a substituent selected from the group consisting of alkylthio, halo (lower) alkyl, acyl, acylamino and halogen;
or a lower alkyl group optionally substituted with a heterocyclic group optionally having acyl, X means O or S respectively] or an equivalent thereof or a salt thereof is reacted to form a compound of the formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, R^1, R^2 and There are chemical formulas, tables, etc. ▼ [In the formula, R^2 has the same meaning as before] The compound represented by or its reactive derivative at the amino group, or their salt has the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [Formula [In the formula, R^1 and Each R^2 has the same meaning as before]
Obtain the diphosphonic acid compound or its salt represented by (c) Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R^2 has the same meaning as before] Reaction in the compound represented by the formula or its amino group A compound represented by the formula R^1-SO_-OH [wherein R^1 has the same meaning as above] or a reactive derivative at its sulfo group or a salt thereof is reacted with the reactive derivative or a salt thereof to obtain the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R^1 and R^2 each have the same meaning as before]
Obtain a diphosphonic acid compound or a salt thereof, or (d) formula ▲ There is a mathematical formula, chemical formula, table, etc. ▼ [In the formula, R^1-A- is the formula ▲ There is a mathematical formula, chemical formula, table, etc. ▼ or ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R^1 and X each have the same meaning as before), R^3, R^4, R^5 and R^6 are each protected. R^2 means a hydroxy group, and R^2 has the same meaning as before] The compound represented by or its salt is subjected to the elimination reaction of the hydroxy protecting group to form the formula ▲ mathematical formula, chemical formula, table, etc. ▼ [Formula wherein R^1-A- and R^2 each have the same meaning as above.] A method for producing a diphosphonic acid compound or a salt thereof, which is characterized in that a diphosphonic acid compound or a salt thereof is obtained. (9) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R^1-A- is the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, ▲ Numerical formulas, chemical formulas,
▼ or R^1-SO_2-NH- (wherein R^1 is a substitution selected from the group consisting of lower alkyl, lower alkoxy, lower alkylthio, halo(lower) alkyl, acyl, acylamino, and halogen) an aryl group or a heterocyclic group which may be substituted with a group, or a lower alkyl group which may be substituted with a heterocyclic group which may have an acyl group, X means O or S, respectively) R^2 means hydrogen or a lower alkyl group, respectively, and when R^1 is an unsubstituted lower alkyl group, R^1-A
- is a formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ or R^1-SO
A bone metabolism improving agent containing a diphosphonic acid compound or a salt thereof as an active ingredient.