JPH09202794A - Diphosphonic acid compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new diphosphonic acid compound which us a specific diphosphonic acid derivative useful for treatment and prevention, etc., of diseases such as osteoporosis, Paget disease or calcinosis universalis related to abnormal calcium and phosphate metabolism, especially abnormal bone metabolism.

SOLUTION: This new diphosphonic acid compound (salt or ester) is represented by the formula [Z is ring such as pyridine, pyridazine pyrimidine or pyrazine; R₁ is H, a (substituted) amino, amide, OH, an alkoxy, a halogen, carboxylate, a 1-6C (substituted) hydrocarbon chain, a (substituted) aryl or a (substituted) benzyl; R₂ is H, a 1-4C (substituted) hydrocarbon chain; R₃ is H, a 1-6C (substituted) hydrocarbon chain, a (substituted) aryl, a (substituted) benzyl, OH, a halogen, an alkoxy, etc.; R₄ is H, a 1-4C (substituted) hydrocarbon chain or an acyl] and is effective in treatment, prevention, etc., of diseases related to abnormal calcium and phosphate metabolism. The compound represented by the formula is obtained by reacting an amino group- and nitrogen-containing heterocyclic compound with tetraethyl vinyldiphosphonate, etc.

COPYRIGHT: (C)1997,JPO

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to compounds which are important in the treatment or prevention of diseases characterized by abnormal calcium and phosphate metabolism, especially diseases characterized by abnormal bone metabolism.

[0002]

Numerous pathological conditions can affect background warm-blooded animals invention SUMMARY and ART includes abnormal calcium and phosphate metabolism. Such situations fall into two broad categories.

[0003] 1. A condition characterized by general or special bone loss in body fluids or abnormal calcium and phosphate mobilization leading to excessively high calcium and phosphate concentrations. Such a condition is sometimes referred to in the present invention as pathological hard tissue demineralization.

[0004] 2. A condition that causes or results in the abnormal deposition of calcium and phosphate in the body. These conditions are sometimes referred to in the present invention as pathological calcifications.

The first category includes osteoporosis, a condition in which the hard tissue of bone is disproportionately lost and new hard tissue develops. The bone marrow and bone spaces become more enlarged, fibrous bonds are reduced, and tight bones become brittle. Osteoporosis can be subdivided into menopausal, senile, drug-induced (eg, adrenocorticoids such as occurs in steroid therapy), disease-induced (eg, arthritis and tumor). However, the onset of symptoms is substantially the same. Another condition in the first category is Paget's disease (osteitis deformans). In this condition, normal bone lysis occurs, which in turn becomes deformed from the body-supporting pressures, especially in the tibia and femur, by replacement with poorly mineralized tissue. Hyperparathyroidism, malignant hypercalcemia and osteolytic bone metastasis are also included in the first category.

The second category, which includes conditions expressed by abnormal calcium and phosphate deposition, is progressive ossifying myositis, generalized calcification and arthritis, neuritis, bursitis, tendinitis and other Includes conditions such as inflammatory conditions that facilitate calcium phosphate deposition in the affected tissue.

Polyphosphonic acids and their pharmaceutically acceptable salts have been proposed for use in the treatment and prevention of such conditions. Especially ethane-1-hydroxy-
1,1-diphosphonic acid (EHDP), propane-3-amino-1-hydroxy-1,1-diphosphonic acid (AP
D), and dichloromethane diphosphonic acid (Cl ₂ MD
Diphosphonates such as P) have been the subject of considerable research effort in this area. Paget's disease and ectopic ossification are currently successfully treated with EHDP. These diphosphonates tend to inhibit bone tissue resorption, which is beneficial to patients suffering from excessive bone loss. However, EHDP, APD and many other prior art diphosphonates have the propensity to inhibit bone mineralization when administered at high dose rates.

Inhibition of mineralization is predominantly a mass-related physico-chemical effect, whereas inhibition of absorption appears to result from biological interactions with cells. Therefore, to develop a more biologically potent diphosphonate compound that can be administered at a low dose that causes little or no inhibition of mineralization, thereby obtaining a wider safety margin. Is desirable. Low doses are also desirable to avoid gastrointestinal discomfort (such as diarrhea), which can sometimes be associated with oral administration of large amounts of diphosphonates.

Accordingly, it is an object of the present invention to provide high strength compounds for the treatment and prevention of abnormal calcium and phosphate metabolism.

US Pat. No. 3,683,080 discloses compositions comprising polyphosphonates, especially diphosphonates, and their use in inhibiting the abnormal deposition and mobilization of calcium phosphate in animal tissues.

JP-A-55-98193 discloses pyridylethanediphosphonic acid, S- (pyridyl) -thiomethanediphosphonic acid, and derivatives by substitution of halogen or alkyl groups on the pyridyl ring. These compounds have been used as post-emergent herbicides.

Japanese Unexamined Patent Publication No. 55-98105 discloses N- (3-pyrrolidyl) -aminoethanediphosphonic acid for use as a herbicide, and a derivative obtained by substituting a halogen or alkyl group on the pyridyl ring. . Various N-
(Pyridyl) -aminomethane diphosphonates are also disclosed in West German Patent 2,831,578 for herbicides.

European Patent Application 100,718 (published February 15, 1984) discloses various alkyl diphosphonates substituted by sulfides attached to 5- or 6-membered nitrogen- or sulfur-containing heterocycles. The class is disclosed. These compounds are used as anti-inflammatory and anti-rheumatic drugs.

British Patent Application 2,004,888 (19
(Published April 11, 1979) provides N- (3-) for herbicide compositions.
Disclosed are methyl-2-picolyl) -aminoethane and related compounds.

Progar et al. [W. Prologer et al., Z. Anorg.
Allg. Chem., 389, 119 (1972)] discloses the synthesis of N- (4-pyridyl) -aminoethanediphosphonic acid. No properties or uses of this compound are disclosed.

[0016]

SUMMARY OF THE INVENTION The present invention relates to diphosphonic acid compounds having the structure:

[0017]

Embedded image [In the formula, Z is a ring selected from the group consisting of pyridine, pyridazine, pyrimidine, and pyrazine, and R ₁ is hydrogen, substituted or unsubstituted amino, amide, hydroxy, alkoxy, halogen, carboxylate, 1 to 6 A substituted or unsubstituted hydrocarbon chain having carbon, a saturated or unsaturated hydrocarbon chain, a substituted or unsubstituted aryl, or a substituted or unsubstituted benzyl, R ₂ is hydrogen, or a substituted or unsubstituted having 1 to 4 carbon atoms, A saturated or unsaturated hydrocarbon chain, R ₃ is hydrogen, a substituted or unsubstituted hydrocarbon chain having 1 to 6 carbon atoms, a saturated or unsaturated hydrocarbon chain, a substituted or unsubstituted aryl, a substituted or unsubstituted benzyl, a hydroxy , Halogen, carbonyl, alkoxy, nitro,
One or more substituents selected from the group consisting of amido, amino, substituted amino, carboxylate, and combinations thereof, R ₄ is hydrogen, substituted or unsubstituted having 1 to 4 carbon atoms , Saturated or unsaturated hydrocarbon chains or acyl], and pharmaceutically acceptable salts and esters thereof. DETAILED DESCRIPTION OF THE INVENTION The present invention is directed to a pharmaceutical carrier and a gem-diphosphonic acid compound or a safe and effective amount of a diphosphonic acid-containing carbon linked to a 6-membered aromatic ring containing one or more nitrogen atoms. It relates to compounds, preferably used in pharmaceutical compositions in unit dosage form, comprising pharmaceutically acceptable salts and esters. Preferred rings are pyridine, pyridazine, pyrimidine, and pyrazine. Most preferred are pyrimidines, especially pyridine. These rings are 1 to
Hydrocarbon chains (saturated or unsaturated) such as substituted and unsubstituted alkyl having about 6 carbon atoms, substituted and unsubstituted aryl (eg, phenyl and naphthyl), substituted and unsubstituted benzyl, hydroxy, halogen, carbonyl ( examples, -CHO and -COCH _3), alkoxy (e.g., methoxy and ethoxy), nitro, amido (e.g., -NHCOCH _3), amino, substituted amino (e.g.,
Dimethylamino, methylamino, and diethylamino), carboxylates (eg, —OCOCH ₃ ), and combinations thereof, which are substituted with one or more substituents selected from the group consisting of a combination thereof and unsubstituted. These rings may be fused with other rings such as benzene and pyridine (eg quinoline), and cyclohexane and pyridine (eg 5,6,7,8-tetrahydroquinoline).
And condensed rings. Other substituents include
It can be a substituted or unsubstituted sulfide, sulfoxide, sulfate or sulfone.

The bond from the diphosphonic acid-containing carbon to the ring may be directly via a single bond or by a chain of 1 to about 5 carbons in length. The chains may all be carbon atoms, nitrogen atoms or nitrogen-containing chains, oxygen atoms or oxygen-containing chains. The carbon and nitrogen atoms in these chains are independently one (or one or two in the case of carbon atoms).
C) of a substituted or unsubstituted hydrocarbon chain having 1 to about 4 carbon atoms (saturated or unsaturated) (methyl and ethyl are preferred) or unsubstituted. Nitrogen atoms in the chain may also be acyl groups (eg,
It may be substituted with —COCH ₃ ). Unsubstituted carbon and nitrogen atoms in the chain are preferred. Further, the length 1 atom of the chain i.e. _-CH 2 -, - NH-, and -O- are also preferred.

The carbon atom having a phosphonate group bonded thereto is unsubstituted (eg, hydrogen atom), amino, substituted amino,
It may be substituted with amido, hydroxy, alkoxy, halogen, carboxylate, substituted or unsubstituted aryl having 1 to about 6 carbon atoms, or substituted or unsubstituted benzyl. The phosphonate-containing carbon has oxygen in the ring,
Alternatively, for compounds in which the oxygen or nitrogen atom is directly attached to the phosphonate-containing carbon linked through a nitrogen-containing chain, the substituents on the phosphonate-containing carbon are 1 to
It is a hydrocarbon chain (saturated or unsaturated) such as substituted or unsubstituted alkyl having about 6 carbon atoms, substituted or unsubstituted aryl or substituted or unsubstituted benzyl.

Thus, the phosphonic acid compounds of the present invention have the following structural formula:

[0021]

Embedded image [Q is oxygen, —NR ₄ — or a single bond, preferably oxygen, —NR ₄ — or a single bond, and m + n is 0.
Is about 5 and is preferably m + n = 0 or 1 when Q is oxygen or —NR ₄ —, otherwise m + n.
n = 1 or 2 is preferred, Z is a ring selected from the group consisting of pyridine, pyridazine, pyrimidine, and pyrazine, pyrimidine, and especially pyridine are preferred; R ₁ is hydrogen, substituted or unsubstituted amino, amido, hydroxy , Alkoxy, halogen, carboxylate,
Hydrocarbon chain (saturated or unsaturated) such as substituted or unsubstituted alkyl having 1 to about 6 carbons, substituted or unsubstituted aryl, or substituted or unsubstituted benzyl {where n is
= 0 and Q is oxygen, or R ₁ is hydrogen when —NR ₄ —, a hydrocarbon chain (saturated or unsaturated) such as substituted or unsubstituted alkyl having 1 to about 6 carbon atoms,
Substituted or unsubstituted aryl, or substituted or unsubstituted benzyl}, and R ₁ is preferably hydrogen, chloro, amino, methyl or hydroxy; each R ₂ is independently hydrogen or 1 to about 4 carbons. Hydrocarbon chains such as substituted or unsubstituted alkyl having a number (saturated or unsaturated)
And R ₂ is preferably hydrogen; R ₃ is hydrogen, 1
A hydrocarbon chain (saturated or unsaturated) such as substituted or unsubstituted alkyl having about 6 carbon atoms, substituted and unsubstituted aryl, substituted and unsubstituted benzyl, hydroxy, halogen, carbonyl, alkoxy, nitro, amide, One or more substituents selected from the group consisting of amino, substituted amino, carboxylate and combinations thereof, preferably hydrogen, methyl, amino, chloro, methoxy, nitro, hydroxy or combinations thereof; R ₄ is hydrogen or a hydrocarbon chain (saturated or unsaturated) such as a substituted or unsubstituted alkyl having 1 to about 4 carbon atoms,
Alternatively, it is an acyl (ie amide of nitrogen), preferably hydrogen, methyl or ethyl], and pharmaceutically acceptable salts and esters of these compounds.
Finally, for any R ₁ , R ₂ , R ₃ , or R ₄ substituents which are themselves substituted, the substitutions on these substituents are any one or more of the above substituents. It may be methyl, ethyl, amino, chloro, nitro, methoxy, hydroxy, acetamide and acetate.

More specifically, the diphosphonic acid compounds of the present invention and their pharmaceutically acceptable salts and esters that can be used in pharmaceutical compositions are of the structure:

[0023]

Embedded image (In the formula, m + n, Z, R ₁ , R ₂ , R ₃ , and R ₄ are as defined above).

The generally preferred diphosphonic acid compounds of the invention and their pharmaceutically acceptable salts and esters used in pharmaceutical compositions are of the following structures:

[0025]

Embedded image (For both structures, m + n = 1 or 2 in the above formula,
R ₁ is hydrogen, chloro, amino or hydroxy, R ₃ is one or more substituents selected from the group consisting of hydrogen, methyl, amino, chloro, nitro, methoxy, hydroxy and combinations thereof. ), Or

[0026]

[Chemical 6] (In the above four structural formulas, n = 0 or 1; R ₁ is n
= 1 is hydrogen, chloro, amino, or hydroxy, and when n = 0, R ₁ is hydrogen; R ₃ is hydrogen, methyl, amino, chloro, methoxy, nitro, hydroxy, and those. One or more substituents selected from the group consisting of, and R ₄ is hydrogen,
Methyl or ethyl).

Specific examples of compounds of the invention that can be utilized in the pharmaceutical compositions include the following compounds: N- (2-pyridyl) -aminomethanediphosphonic acid; N- (2- (5 -Amino) -pyridyl) -aminomethanediphosphonic acid; N- (2- (5-chloro) -pyridyl) -aminomethanediphosphonic acid; N- (2- (5-nitro) -pyridyl) -aminomethanedi Phosphonic acid; N-
(2- (3,5-Dichloro) -pyridyl) -aminomethanediphosphonic acid; N- (4-pyridyl) -N-ethyl-
Aminomethanediphosphonic acid; N- (2- (3-picolyl))-aminomethanediphosphonic acid; N- (2- (4-
Picolyl))-aminomethanediphosphonic acid; N- (2-
(5-picolyl))-aminomethanediphosphonic acid; N-
(2- (6-picolyl))-aminomethanediphosphonic acid; N- (2- (3,4-lutidine))-aminomethanediphosphonic acid; N- (2- (4,6-lutidine))- Aminomethanediphosphonic acid; N- (2-pyrimidyl) -aminomethanediphosphonic acid; N- (4- (2,6-dimethyl) -pyrimidyl) -aminomethanediphosphonic acid; N-
(2- (4,6-dihydroxy) -pyrimidyl) -aminomethanediphosphonic acid; N- (2- (5-methoxy)-
Pyridyl) -aminomethanediphosphonic acid; N- (2-pyridyl) -2-aminoethane-1,1-diphosphonic acid;
N- (2- (3-picolyl))-2-aminoethane-
1,1-Diphosphonic acid; N- (3-pyridyl) -2-amino-1-chloroethane-1,1-diphosphonic acid; N-
(2- (4-Picolyl))-2-amino-1-hydroxy-ethane-1,1-diphosphonic acid; (2-pyridyl)
-Methanediphosphonic acid; (3-pyridyl) -aminomethanediphosphonic acid; (2-pyridyl) -chloromethanediphosphonic acid; (4-pyridyl) -hydroxymethanediphosphonic acid; 2- (2-pyridyl)- Ethane-1,1-diphosphonic acid; 2- (3-pyridyl) -ethane-1,1-diphosphonic acid; 2- (4-pyridyl) -ethane-1,1-
Diphosphonic acid; 2- (2-pyridyl) -1-amino-ethane-1,1-diphosphonic acid; 2- (2-pyrimidyl)
-1-hydroxy-ethane-1,1-diphosphonic acid; 2
-(2- (3-picolyl))-1-chloro-ethane-
1,1-diphosphonic acid; 2- (2- (4-methoxy)-
Pyridyl) -ethane-1,1-diphosphonic acid; 1- (2
-Pyridyl) -propane-2,2-diphosphonic acid; 2-
(2-Pyridyl) -1-chloro-ethane-1,1-diphosphonic acid; 2- (2-pyridyl) -1-hydroxy-ethane-1,1-diphosphonic acid; 2- (3-pyridyl)-
1-hydroxy-ethane-1,1-diphosphonic acid; 2-
(4-pyridyl) -1-hydroxy-ethane-1,1-
Diphosphonic acid; 3- (3-pyridyl) -1-hydroxy-propane-1,1-diphosphonic acid; O- (2-pyridyl) -2-oxa-ethane-1,1-diphosphonic acid; O
-(2-pyridyl) -oxamethanediphosphonic acid; O-
(2-pyrimidyl) -oxamethanediphosphonic acid; O-
(2- (4-amino) -pyridyl) -oxamethanediphosphonic acid; O- (2- (pyrimidyl) -2-oxa-ethane-1,1-diphosphonic acid; O- (2- (3-picolyl) ) -2-Oxa-ethane-1,1-diphosphonic acid;
O- (2- (3-picolyl))-oxamethane-diphosphonic acid; O- (2- (pyridyl) -1-hydroxy-2
-Oxa-ethane-1,1-diphosphonic acid; O- (4-
Pyridyl) -1-amino-2-oxa-ethane-1,1
-Diphosphonic acid; and pharmaceutically acceptable salts and esters thereof.

Preferred compounds include N- (2- (5
-Amino) -pyridyl) -aminomethanediphosphonic acid;
N- (2- (5-chloro) -pyridyl) -aminomethanediphosphonic acid; N- (2- (3-picolyl))-aminomethanediphosphonic acid; N- (2- (4-picolyl))-
Aminomethanediphosphonic acid; N- (2- (5-picolyl))-aminomethanediphosphonic acid; N- (2- (6-
Picolyl))-aminomethanediphosphonic acid; N- (2-
(3,4-lutidine))-aminomethane diphosphonic acid;
N- (2-pyrimidyl) -aminomethanediphosphonic acid;
N- (2-pyridyl) -2-aminoethane-1,1-diphosphonic acid; 2- (2-pyridyl) -ethane-1,1-
Diphosphonic acid; 2- (3-pyridyl) -ethane-1,1
-Diphosphonic acid; 2- (4-pyridyl) -ethane-1,
1-diphosphonic acid; 2- (2-pyridyl) -1-hydroxy-ethane-1,1-diphosphonic acid; 2- (3-pyridyl) -1-hydroxy-ethane-1,1-diphosphonic acid; 2- ( 4-pyridyl) -1-hydroxy-ethane-
1,1-diphosphonic acid; O- (2- (3-picolyl))
-Oxamethane-diphosphonic acid; or a pharmaceutically acceptable salt or ester thereof.

The diphosphonate compound of the present invention contained in the pharmaceutical composition is described in JP-A-55-98,193,
Japanese Patent Application Laid-Open No. 55-98,105, West German Patent 2,8
31,578 and W.C. Proger, etc.
et al., Z. Anog. Allg. Chem., 389, 119 (1972)], and the disclosures of these can be applied to the present invention. However, aminoethanediphosphonic acid compounds are best prepared as follows. Synthesis of N- (2- (3-picolyl)) aminoethane DP The above compounds are tetraethylvinyldiphosphonate and 2-
Prepared by a typical Michael reaction between amino-3-picoline [H. O. House (HOHouse),
Modern Synthetic Reactoin 2nd Edition, WA Benjamin,
p. See 595-623. The disclosure content of this document is applied mutatis mutandis in the present invention.

1.62 g (15 mmol) of 2-amino-3
4.5 in a solution of picoline in tetrahydrofuran at 5 ° C.
0 g (15 mmol) tetraethyl vinyl diphosphonate was added. The reaction mixture was stirred at room temperature for 16 hours. The solvent was evaporated and the product was chromatographed on silica gel (acetone / hexane, 4/1) to give pure tetraethyl N- (2- (3-picolyl))-2-aminoethanediphosphonate. P-31 NMR of this pure tetraethyl ester in CDCl ₃ gives 22.1
The resonance is shown in ppm. The ester was hydrolyzed in 6N HCl at reflux overnight. This product is D
19.0 ppm P-31N at pH = 12 in ₂ O
An MR signal was indicated.

N- (2-pyridyl) -2-aminoethane DP and N- (2- (5-picolyl))-2-aminoethane DP were similarly prepared.

A compound having the following general formula:

[0033]

Embedded image Where n is an integer from 1 to about 5, preferably n = 1; and Z, R ₂ and R ₃ are as defined above, preferred Z is pyrimidine and especially pyridine, and preferred R ₂ is Hydrogen, preferred R ₃ is hydrogen, methyl,
The one or more substituents selected from the group consisting of amino, chloro, nitro, methoxy, hydroxy, and combinations thereof are best prepared as follows: 2- (2- Pyridyl) -1-hydroxy-ethane-1,
Synthesis of 1-diphosphonic acid 6.94 g (0.04 mol) 2-pyridine acetic acid, 9.84 g (0.14 mol) phosphoric acid in a 3-neck round bottom flask equipped with reflux condenser and magnetic stir bar , And 15
0 ml of chlorobenzene was charged. The reaction mixture was heated on a boiling water bath and 16.5 g (0.12 mol) phosphorus trichloride was added dropwise with stirring. The reaction mixture is
Heated for 2 hours, during which time a viscous yellow oil was formed. The reaction mixture was then cooled in an ice bath and the chlorobenzene solution was decanted from the solidified product. The reaction flask containing the solidified product was charged with 150 ml of water,
Heated for several hours in a boiling water bath. And filtered through Celite 545 ^R is then hot solution. 300 ml
When methanol was added to the warm filtered solution, precipitation occurred. After cooling in ice for 1 hour, the precipitate was filtered off, washed with methanol / water (1/1 v / v), methanol, and ether and air dried. This product may be recrystallized from hot water. The yield was about 5.9 g (52%). The sample was characterized by P-31 and C-13 NMR.

"Pharmaceutically acceptable salts and esters" as used in the present invention have the same general pharmacological properties as the acid form from which they are derived, and are acceptable in terms of toxicity. By hydrolyzable salts and esters of phosphonate compounds. Pharmaceutically acceptable salts include alkali metals (sodium and potassium), alkaline earth metals (calcium and magnesium), non-toxic heavy metals (tin and indium), and ammonium and low molecular weight substituted ammonium (mono-, di-,
And triethanolamine). Preferred compounds are the sodium, potassium, and ammonium salts.

By "pharmaceutical carrier" which may be used as a compound in the present invention is meant one or more compatible solid or liquid filler diluents or encapsulating substances. "Compatible" as used in the present invention means that the components of the composition can be combined under normal conditions of use without any interaction that would substantially reduce the pharmaceutical efficiency of the overall composition. means.

Some specific examples of substances that can serve as pharmaceutical carriers include sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose, cellulose acetate and the like. Powdered tragacanth; malt; gelatin, talc; stearic acid; magnesium stearate; calcium sulfate; vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and theobrom oil; polyols such as propylene glycol, glycerin, sorbitol, mannitol , And polyethylene glycol; agar; alginic acid; pyrogen-free water; isotonic saline; and phosphate buffered solutions, and others Is compatible non-toxic substance used in pharmaceutical formulations. Lubricating agents such as wetting agents and sodium lauryl sulphate, as well as colorants, flavors, lubricants, excipients, tablettings, stabilizers, antioxidants and preservatives and the like can also be present. Other compatible pharmaceutical additives and actives (eg, vitamin D or vitamin D metabolites and mineral supplements) and the like can also be included in the pharmaceutical compositions of the present invention.

The choice of pharmaceutical carrier to be used in combination with the diphosphonate of the present invention is determined essentially by the method by which the diphosphonate is administered. When the compound is injected, the preferred pharmaceutical carrier is sterile saline, the pH of which is adjusted to about 7.4. However, since the preferred mode of administration of the diphosphonates of the present invention is oral, the preferred unit dosage form is therefore a tablet, capsule, etc. comprising from about 0.1 mgP to about 600 mgP of the diphosphonate compound described herein. . Pharmaceutical carriers suitable for the manufacture of unit dosage forms for oral administration are known. Their choice depends on secondary considerations which are not critical for the purposes of the invention, such as taste, cost, storage stability, etc. and can be made by the person skilled in the art without difficulty. The pharmaceutical carrier used with the diphosphonates of the present invention is used at a concentration sufficient to provide a practical method of administration. Preferably, the pharmaceutical carrier comprises about 0.0% of the total composition.
From about 1 to about 99.99% by weight.

[0038]

The EXAMPLES Example I an ordinary method to prepare capsules containing the following ingredients: Ingredients mg / capsule N-(2-(3- picolyl)) (as mgP) AMDP 100 Starch 55.60 Sodium lauryl sulfate 2. 90 When the above capsules are administered orally twice daily for 6 months, bone resorption is substantially reduced in patients with about 70 kg body weight suffering from osteoporosis. Similar results are obtained when the following compounds are used in the above capsules instead of N- (2- (3-picolyl))-aminomethanediphosphonic acid or its pharmaceutically acceptable salts or esters: N- (2- (5-amino) -pyridyl) -aminomethanediphosphonic acid; N- (2- (5-chloro) -pyridyl) -aminomethanediphosphonic acid; N-
(2- (4-picolyl))-aminomethanediphosphonic acid; N- (2- (5-picolyl))-aminomethanediphosphonic acid; N- (2- (6-picolyl))-aminomethanediphosphonic acid Acid; N- (2- (3,4-lutidine))-
Aminomethane diphosphonic acid; N- (2-pyrimidyl)-
Aminomethane diphosphonic acid; N- (2-pyridyl) -2
-Aminoethane-1,1-diphosphonic acid; 2- (2-pyridyl) -ethane-1,1-diphosphonic acid; 2- (3-
Pyridyl) -ethane-1,1-diphosphonic acid; 2- (4
-Pyridyl) -ethane-1,1-diphosphonic acid; 2-
(2-pyridyl) -1-hydroxy-ethane-1,1-
Diphosphonic acid; 2- (3-pyridyl) -1-hydroxy-ethane-1,1-diphosphonic acid; 2- (4-pyridyl) -1-hydroxy-ethane-1,1-diphosphonic acid; O- (2- . (3-picolyl) - Okisametan - diphosphonic acid; or a pharmaceutically acceptable salt or ester example II by a conventional method to prepare tablets having the following composition: Ingredient mg / tablet N-(2-pyrimidyl) AMDP 25.00 Lactose 40.00 Starch 2.50 Magnesium stearate 1.00 When the above-mentioned tablet was orally administered twice a day for 6 months, bone resorption in a patient of about 70 kg with osteoporosis was observed. In the above tablets, instead of N- (2-pyrimidyl) AMDP or a pharmaceutically acceptable salt or ester thereof, Similar results are obtained when using an object: N- (2- (5-
Amino) -pyridyl) -aminomethanediphosphonic acid; N
-(2- (5-Chloro) -pyridyl) -aminomethanediphosphonic acid; N- (2- (3-picolyl))-aminomethanediphosphonic acid; N- (2- (4-picolyl))-amino Methanediphosphonic acid; N- (2- (5-picolyl))-aminomethanediphosphonic acid; N- (2- (6-
Picolyl))-aminomethanediphosphonic acid; N- (2-
(3,4-lutidine))-aminomethane diphosphonic acid;
N- (2-pyridyl) -2-aminoethane-1,1-diphosphonic acid; 2- (2-pyridyl) -ethane-1,1-
Diphosphonic acid; 2- (3-pyridyl) -ethane-1,1
-Diphosphonic acid; 2- (4-pyridyl) -ethane-1,
1-diphosphonic acid; 2- (2-pyridyl) -1-hydroxy-ethane-1,1-diphosphonic acid; 2- (3-pyridyl) -1-hydroxy-ethane-1,1-diphosphonic acid; 2- ( 4-pyridyl) -1-hydroxy-ethane-
1,1-diphosphonic acid; o- (2- (3-picolyl)-
Oxamethane-diphosphonic acid; or a pharmaceutically acceptable salt or ester thereof. Example III 1.0 ml of either saline or aqueous solution and 3.5 mg of 2- (2-pyridyl) -ethane-1,1-
An injectable solution adjusted to pH 7.4 with diphosphonic acid is prepared by a conventional method.

One injection every day for 4 days gives about 70k
Malignant hypercalcemia is significantly alleviated in patients with a body weight of g. Similar results were obtained by substituting the following compounds for 2- (2-pyridyl) -ethane-1,1-diphosphonic acid in the above treatments: N- (2-
(5-Amino) -pyridyl) -aminomethanediphosphonic acid; N- (2- (5-chloro) -pyridyl) -aminomethanediphosphonic acid; N- (2- (3-picolyl))-aminomethanedi Phosphonic acid; N- (2- (4-picolyl))-aminomethanediphosphonic acid; N- (2- (5-
Picolyl))-aminomethanediphosphonic acid; N- (2-
(6-picolyl))-aminomethanediphosphonic acid; N-
(2- (3,4-lutidine))-aminomethanediphosphonic acid; N- (2-pyrimidyl) -aminomethanediphosphonic acid; N- (2-pyridyl) -2-aminoethane-1,
1-diphosphonic acid; 2- (3-pyridyl) -ethane-
1,1-Diphosphonic acid; 2- (4-pyridyl) -ethane-1,1-diphosphonic acid; 2- (2-pyridyl) -1-
Hydroxy-ethane-1,1-diphosphonic acid; 2- (3
-Pyridyl) -1-hydroxy-ethane-1,1-diphosphonic acid; 2- (4-pyridyl) -1-hydroxy-ethane-1,1-diphosphonic acid; o- (2- (3-picolyl) -oxamethane -Diphosphonic acid; or a pharmaceutically acceptable salt or ester thereof.

The compositions of the present invention are useful in the treatment of abnormal calcium and phosphate metabolism. Other diphosphonic acids and their pharmaceutically acceptable salts have been proposed for the treatment and prevention of such conditions. In particular, ethane-1-hydroxy-1,1-diphosphonic acid (EHD
P), propane-3-amino-1-hydroxy-1,1
-Diphosphonic acid (APD), and dichloromethane diphosphonic acid (Cl ₂ MDP) have been the subject of considerable research effort in this field.

However, the compositions of the present invention are generally biologically more potent in inhibiting bone resorption than the diphosphonates disclosed in the prior art. Thus, the compositions of the present invention provide one or more of the following advantages over the diphosphonates disclosed in the prior art: (1) more potent in inhibiting bone resorption, (2) mineralized. (Ml
neralization) has less potential for inhibiting bone mineralization because it is believed to be primarily a mass-related physicochemical effect, (3) generally has a wider margin of safety (ie , A wider dose interval between the minimum effective anti-resorptive dose and the lowest dose that results in inhibition of mineralization), (4) sometimes allowing higher oral doses of diphosphonate. Avoid gastrointestinal discomfort (such as diarrhea) associated with the likes, and (5) have the potential for flexibility in administration.

Another aspect of the present invention is a method of treating or preventing diseases characterized by abnormal calcium and phosphate metabolism, particularly diseases characterized by abnormal bone metabolism, in humans at risk of such diseases. And administering a safe and effective amount of the diphosphonic acid-containing composition of the present invention to a human in need of such treatment.

The preferred mode of administration is oral, however, other modes of administration include transdermal, mucosal, sublingual, intramuscular, intravenous, intraperitoneal and subcutaneous administration and topical application. It is not limited to.

The term "abnormal calcium and phosphate metabolism" used in the present invention means (1) general or special bone loss, that is, abnormal calcium and phosphate which leads to abnormally high calcium and phosphate concentrations in body fluids. It refers to pathologies characterized by mobilization, and (2) pathologies that cause or result in abnormal calcium and phosphate deposits in the body. The first category includes, but is not limited to, osteoporosis, Paget's disease, hyperparathyroidism, malignant hypercalcemia and osteolytic bone metastases. The second category is progressive ossifying myositis, generalized calcinosis, and arthritis, neuritis, bursitis, tendinitis, and other inflammatory conditions that facilitate calcium phosphate deposition in other affected tissues. However, the present invention is not limited to these.

As used in the present invention, "human at risk" or "human in need of such treatment" is any substance that has a considerable risk of abnormal calcium and phosphate metabolism when left untreated. And any human or lower animal diagnosed as suffering from abnormal calcium and phosphate metabolism. For example, post-menopausal women, people receiving some steroid treatments, people taking some antispasmodics, Paget's disease, hyperparathyroidism, malignant hypercalcemia or osteolysis. Humans diagnosed with sexual bone metastases, one diagnosed with one or more different forms of osteoporosis, known to have a significantly higher than average chance of developing osteoporosis In a population that is being treated, such as post-menopausal women, men over the age of 65, and those treated with drugs known to cause osteoporosis as a side effect, progressive gastritis myositis. Or in people diagnosed with generalized calcinosis, and in inflammatory conditions that tend to cause calcium phosphate deposition in arthritis, neuritis, bursitis, tendinitis, and other affected tissues. Patients to have people, and the like.

As used in the present invention, “a person suffering from or at risk of osteoporosis or a lower animal” means a patient diagnosed as suffering from one or more of various forms of osteoporosis or osteoporosis developed. Patients belonging to the group known to have a significantly greater chance than the average chance of having, for example a postmenopausal woman,
It includes men over the age of 65 and humans treated with drugs known to cause osteoporosis as a side effect (eg adrenocorticoids).

"Safe and effective amount" used in the present invention
Is high enough to meaningfully and positively alter the condition to be treated within the scope of sound medical judgment,
However, it means a sufficiently low (reasonable benefit / risk ratio) amount of the compound or composition to avoid serious side effects.
A safe and effective amount of diphosphonates will depend on the particular condition being treated, the age and physical condition of the patient being treated, the severity of the condition, the duration of treatment, the nature of the co-treatments and the particular diphosphonate used. It depends on the type. However, a single dose is about 0.001 mg P to about 3500 mg
P, ie, in the range of 0.1 μg P / kg body weight to about 500 mg P / kg body weight. A preferred single dose is 0.1
mgP to about 600 mgP, ie, about 0.01 to about 50 mg
P / kg body weight. Up to four single doses can be administered per day. Daily doses greater than about 2000 mg P / kg are not required to achieve the desired effect and can have undesirable side effects. Of course,
Dosages higher than this range are required for oral administration due to limited absorption.

Schenk Model compounds were evaluated for in vivo inhibition of bone resorption and mineralization in an animal model system known as the Schenk model in the field of bone metabolism. The general principle of this model system is Shinoda et al. [Shinoda et al., Calcif,
Tissue Int., 35, 87-99 (1983)] and Schenk et al. [Sc
henk et al., Calcif, Tissue Res. 11, 196-214 (197
3)], and the contents of these disclosures apply mutatis mutandis to the present invention.

Materials and Methods Animals Pre-weaning 17-day-old (30 g) male Sprague Dawley.
Rats (Charles River Breeding Laboratories) were shipped with their mothers and placed in plastic cages with their mothers upon arrival. On the 21st day after birth, rat pups that received food and water ad libitum were randomly assigned to a treatment group consisting of 5 animals, and the control animals received salt water 1 per group.
It consisted of 0 rats. 0.9% Na to label all animals on day 0 and again on day 1
Subcutaneous injection of Calcein (Sigma) as a 1% solution in Cl solution was given.

Dosing Solutions and Dosing Procedures All solutions were prepared as subcutaneous injections in 0.9% normal saline and adjusted to pH 7.4 with NaOH and / or HCl. Dosing solution calculation is mgP / k
The amount of powder of the active substance in mg / kg (body weight) corresponding to g (molecular weight basis, hydration) was taken into consideration. The concentration was based on a dose of 0.2 ml / 100 g body weight. Initially,
All compounds were 0.1, 1.0 and 10.0 for 7 days.
Administered at mgP / kg / day. Compounds showing activity at 0.1 mgP / kg / day were then added at 0.001 mgP / kg
Tested with log reduction to kg / day. Dose adjustments based on changes in body weight were made daily.

Necropsy, tissue processing and histomorphometry All animals were killed by CO ₂ asphyxiation on the 8th day after the start of administration. The tibia was dissected and placed in 70% ethyl alcohol. A single tibia was dehydrated in graded ethanol and used in Boyce et al., Lab. Investig., 48, 683.
-689 (1983)-This disclosure applies mutatis mutandis to the present invention.)
Embedded in methylmethacrylate using the rapid procedure described by. The tibia was sliced longitudinally through the unlined bone (Leitz ^R Saw Microtome 150
μ). One side of the specimen was stained with silver nitrate and mounted on a microscope slide, and the Quantimet Image Analyzer (Cambridge Instru
ments, Inc.) using both incandescent and ultraviolet illumination. Epiphyseal trabecular bone content was measured in the area between the fluorescent label and the growth plate and expressed as% of total area (bone + bone marrow). Epiphyseal growth plate width was obtained as the average of 10 equally spaced measurements across the section.

Statistical evaluation of the data was performed using a parametric and non-parametric analysis of variability and Wilcoxons rank sum tests to determine statistically significant effects relative to control animals.

This Schenk model is based on in vivo
Data for inhibition of bone resorption of o were given. The minimum effective (anti-absorption) dose ("LED") for the tested representative compounds determined by the Schenk model is listed in Table I.

Table I Minimum Effective (Anti-Absorption) Dose Schenk Diphosphonate Compound LED (mg P / kg) EHDP 1.0 Cl ₂ MDP 1.0 APD 0.1 N- (2-Pyridyl) AMDP ^* 0.01 N- (2- (5-chloro) -pyridyl) AMDP ^* 0.01 N- (2- (3-picolyl)) AMDP ^* 0.001 N- (2- (4-picolyl)) AMDP ^* 0.001 N- (2- (5-picolyl)) AMDP ^* 0.001 N- (2- (6-picolyl)) AMDP ^* 0.001 N- (2-pyrimidyl) AMDP ^* 0.001 N- (4-pyridyl ) -N-Ethyl AMDP ^* 0.1 2- (2-pyridyl) EDP ^* 0.01 2- (3-pyridyl) EDP ^* 0.01 1- (2-pyridyl) propyl DP ^* 10 EHDP = ethane-1 -Hydroxy-1,1-DP l ₂ MDP = aminoethane dichloromethane DP APD = 3- amino-1-hydroxy -1,1-DP AMDP = ring is attached to the amine diphosphonic acid * = compound contained in the pharmaceutical compositions of the present invention EDP = ethane-1,1-diphosphonic acid with ring attached to the 2-position of ethane propyl DP = propane-2,2-diphosphonic acid Matrix formation continues, but mineralization is impeded, thus bone mineral The diphosphonate compound having an anti-metastatic effect causes the epiphyseal growth plate to spread. The extension of the epiphyseal growth plate seen in the Schenk model is therefore a measure of the mineralization inhibitory effect of the diphosphonate compounds tested.

The minimum test dose that results in a statistically significant epiphyseal plate extension for the compounds tested is set forth in Table II.
Shown in

Table II Inhibition of mineralization (Schenk model) Minimum tested dose of diphosphonate compound (mgP / kg) that results in statistically significant spread of epiphyseal growth plate EHDP 10 APD 10 Cl ₂ MDP --N- (2-Pyridyl) AMDP ^* 0.1 N- (4-pyridyl) -N-ethyl AMDP ^{* -1)} N- (2- (3-picolyl)) AMDP ^{* -1)} N- (2- ( 4-picolyl)) AMDP ^* 0.1 N- (2- (5-picolyl)) AMDP ^* 0.1 N- (2- (6-picolyl)) AMDP ^* --N- (2-pyrimidyl) AMDP ^* 1.0 N- (2- (5- chloro) - ^{pyridyl) AMDP * - 1) 2- (} 3- pyridyl) EDP ^* - 2- (2- pyridyl) EDP ^* - ¹⁾ - = best No spread of the plate was observed at the test dose (maximum test dose is 10 m unless otherwise specified). P / kg / day) 1) = highest dose evaluated is 1 mg P / kg / day (compound is deadly toxic at 10 mg P / kg / day) EHDP = ethane-1-hydroxy -1,1-DP APD = 3-aminopropane-1-hydroxy-1,1-DP Cl ₂ MDP = dichloromethane DP AMDP = aminomethanediphosphonic acid with ring attached to amine EDP = ring in position 2 of ethane Bound ethane-1,1-diphosphonic acid * = compound included in pharmaceutical composition of the invention Thyroid parathyroidectomy (TPTX) rat model Evaluation of compound known as thyroid parathyroidectomy (TPTX) rat model In vivo with live animal model systems
Was evaluated for bone resorption inhibition strength. The general principle of this model system is Russell et al. [Russell et al., Calcif.
Research, 6,183-196 (1970)], and Muhlbauer and Fleisch, Mineral.
Electrolyte Metab., 5, 296-303 (1981)], the disclosures of which are applied mutatis mutandis in the present invention. The basic biochemical concept of the TPTX system is parathyroid (PT
H) inhibition-the induced increase in serum and ionized calcium concentrations by the respective bone-active polyphosphonates.

Materials and Methods: Materials Tekl low calcium and low phosphorus diet in pellet form of approximately 0.1% calcium and 0.22% phosphorus.
Ad ^R Test Diets (Harlan Industries, Madison, Wisconsin 53711, Order # TD 82195). This diet contained all the essential vitamins and minerals needed for rats, apart from calcium and phosphorus. The calcium and phosphorus concentrations of the pellets were confirmed analytically (Procted & Gamble Co., Miami Vally Laborato
ries, Ohio, Cincinnati).

PTH was powdered bovine extract (Sigma Chemical Co., PO B as an activity of 138 USP units per mg).
ox 14508, St. Louis, MO, Order #P
-0892, lot # 72F-9650). PTH was prepared in 0.9% saline to a final concentration of 100 U.SP / ml. All solutions were filtered through a # 4Whatman filter paper, and re-filtered through 0.45MyumMetricel ^R filter.

Dosing Solution and Method of Administration All compound solutions for testing bone resorption inhibitory strength were prepared for subcutaneous injection in 0.9% normal saline.
The pH was adjusted to 7.4 with aOH and / or HCl. Dosing solution calculation is mg / k corresponding to mgP / kg
The weight of the active substance powder in g (body weight) (based on molecular weight, hydration) was taken into consideration. The concentration is 0.2ml / 10
Based on a 0 g body weight dose. Initially, all compounds were 4
0.01, 0.1, and 1.0 mg P / kg / day
Dosing on day. If necessary, repeat the test so that the animal has 0.5 LED to make the LED measurement precise.
Was administered. Preparation of the dose based on changes in body weight was performed daily.

Animals In this study male Wis weighing approximately 150-160 g.
Breeding star rats (Charles River Breeding Laborat
thyroid gland parathyroidectomy. Upon arrival, all rats were placed in a double shed in a suspended cage, Purina
Laboratories Rodent Chow ^R and tap water were provided.
After acclimation to the laboratory environment for 3-5 days, rats were fed a low calcium, low phosphorus (0.18% / 0.22%) diet (Tekla.
Place d ^R), to give 2% through water bottle (w / v) calcium gluconate supplemented deionized water.

[0061] Ketaset all rats on the fourth day of the way low-calcium diet ^R
(Ketamine hydrochloride, 100 mg / ml, Br
Anesthetized with 0.10 ml / 100 g body weight with istol Myers), the body weight was measured, and the blood was then bleeding from the retro-orbital venous plexus, and serum total calcium analysis was performed using flame atom adsorption (FAA). All rats weighing less than 180 g were excluded from the study. Animals were then statistically randomized so that the average total serum calcium in each group was identical. Only rats considered hypocalcemic (total serum calcium <8.0 mg / dl) were placed in a study group of 6 / group.

Treatment with various experimental compounds started on day 6 and continued until day 9 of the study (daily 1:00 p.m.
M.). The dosing solution was prepared to be given subcutaneously to the skin flap on the abdomen where the hindpaw meets the torso at a constant rate of 0.2 ml / 100 g body weight. All rats were weighed and administered daily. The drug was administered using a 25 gauge 5/8 inch needle and the site of administration was changed daily. On day 8, the animals were changed to deionized distilled water via a water bottle. On day 9, all rats were fasted at approximately 4:00 PM. No treatment was given on day 10 of the study. A 600 μl sample of whole blood was collected from each rat in a Microtainer (B-D # 5060) serum separator tube (FAA) for serum total calcium from each rat. Two 125 μl samples of heparinized whole blood were also collected for use in ionized calcium analysis. Immediately after blood collection, all rats were weighed to 75 USP (filtration) / 10
Bovine parathyroid hormone was injected at a rate of 0 g body weight. Blood sampling for total and ionized calcium was repeated 3 and a half hours after PTH injection.

All pre-post-PTH total and ionized calcium were statistically significant relative to PTH alone (control) using the Student's t-test, analysis of variability and their non-parametric equivalents. Analysis was performed. Postminus pre-change and rate of change were also determined for calcium concentration and pre-drug vs. post-drug weight.

The physiological effect of PTH challenge was an increase in serum calcium concentration with peak activity seen at 3.5 hours. Since the hormones of calcium metabolism and dietary controls are minimized in the TPTX model, the observed increase in serum calcium concentration is likely a result of bone substance absorption. Since polyphosphonates tend to inhibit the resorption of bone matter, animals pretreated with polyphosphonates show less elevation in serum calcium levels after PTH challenge than that seen in saline treated control animals. It was The lowest dose at which polyphosphonates can inhibit bone resorption is a measure of the bone resorption inhibitory potency of polyphosphonates, as evidenced by the decreased elevation in serum calcium during PTH challenge. Table III shows the LED value of the bone resorption inhibition strength of each compound determined by the TPTX rat model.

Table III Minimum Effective (Anti-Absorption) Dose TPTX Diphosphonate Compound LED (mg P / kg) EHDP 1.0 Cl ₂ MDP 1.0 APD 0.1 N- (2-pyridyl) AMDP ^* 0.01 N- (2- (5-amino) -pyridyl) AMDP ^* 0.01 N- (2- (5-chloro) -pyridyl) AMDP ^* 0.01 N- (2- (5-nitro) -pyridyl) AMDP ^* 0.1 N- (2- (5-carboxy) -pyridyl) AMDP N N- (2- (3,5-dichloro) -pyridyl) AMDP ^* 1.0 N- (4-pyridyl) -N-ethyl AMDP ^* 0.1 N- (2- (3-picolyl)) AMDP ^* 0.002 N- (2- (4-picolyl)) AMDP ^* 0.001 N- (2- (5-picolyl)) AMDP ^* 0.001 N- (2- (6-picolyl)) MDP ^* 0.01 N- (2- (3,4- ^{lutidine)) AMDP * 0.01 N- (2-} (4,6- ^{lutidine)) AMDP * 0.01 1) N-} (2- pyrimidyl) AMDP ^* 0.01 N- (4- (2,6-dimethyl) -pyrimidi 1.0-l) AMDP ^* N- (2- (4,6-dihydroxy) -pyri 0.01 ¹ ) midyl) AMDP ^* N -(2-Pyridyl) AEDP ^* 0.01 N- (2- (3-picolyl)) AEDP ^* 10 2- (2-pyridyl) EDP ^* 0.01 2- (3-pyridyl) EDP ^* 0.012 -(4-Pyridyl) EDP ^* 0.1 1- (2-pyridyl) -propyl DP ^* 1.0 2- (2-pyridyl) -1-chloroethane DP ^* 0.1 O- (2-pyridyl) -oxamethane DP ^* 1.0 O- (2- (3-picolyl))-oxamethane DP ^* 0.1 N = no activity at any dose concentration tested EHDP = ethane-1-hydroxy-1,1-DP Cl ₂ MDP = dichloromethane DP APD = 3-aminopropane-1-hydroxy-1,1- DP AMDP = Aminoethanediphosphonic acid with ring bound to amine AEDP = 2-Aminoethane-1,1-diphosphonic acid with ring bound to amine EDP = Ring is attached to position 2 of ethane Ethane-1,1-diphosphonic acid Propyl DP = Propane-2,2-diphosphonic acid * = Compound contained in the pharmaceutical composition of the present invention 1) = Questionable activity level due to lack of dose response Example IV Clinically For a patient weighing approximately 70 kg who is diagnosed as suffering from malignant hypercalcemia, 0.7 mg P of 2- (2
-Pyridyl) -ethane-1,1-diphosphonic acid or its pharmaceutically acceptable salt or ester once daily
Dosing by intravenous infusion for 2 hours for 4 days. This treatment results in significant alleviation of malignant hypercalcemia.

In the above treatment, 2- (2-pyridyl)
Similar results are obtained when the following compounds are used instead of -ethane-1,1-diphosphonic acid: N- (2- (5
-Amino) -pyridyl) -aminomethanediphosphonic acid;
N- (2- (5-chloro) -pyridyl) -aminomethanediphosphonic acid; N- (2- (3-picolyl))-aminomethanediphosphonic acid; N- (2- (4-picolyl))-
Aminomethanediphosphonic acid; N- (2- (5-picolyl))-aminomethanediphosphonic acid; N- (2- (6-
Picolyl))-aminomethanediphosphonic acid; N- (2-
(3,4-lutidine))-aminomethane diphosphonic acid;
N- (2-pyrimidyl) -aminomethanediphosphonic acid;
N- (2-pyridyl) -2-aminoethane-1,1-diphosphonic acid; 2- (3-pyridyl) -ethane-1,1-
Diphosphonic acid; 2- (4-pyridyl) -ethane-1,1
-Diphosphonic acid; 2- (2-pyridyl) -1-hydroxy-ethane-1,1-diphosphonic acid; 2- (3-pyridyl) -1-hydroxy-ethane-1,1-diphosphonic acid; 2- (4 -Pyridyl) -1-hydroxy-ethane-
1,1-diphosphonic acid; O- (2- (3-picolyl)-
Oxamethane-diphosphonic acid; or a pharmaceutically acceptable salt or ester thereof.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁶ Identification number Internal reference number FI Technical display location A61K 31/675 ADD A61K 31/675 ADD (71) Applicant 592043805 ONE PROCTER & GANBLE E PLAZA, CINCINNATI, OHIO, UNITED STATES OF AMERICA (72) Inventor Christopher, Mark, Perkins, Cincinnati, River, Road, Ohio, USA 6410

Claims (1)

[Claims] 1. A diphosphonic acid compound having the following structure: [In the formula, Z is a ring selected from the group consisting of pyridine, pyridazine, pyrimidine, and pyrazine, and R ₁ is hydrogen, substituted or unsubstituted amino, amide, hydroxy, alkoxy, halogen, carboxylate, 1 to 6 A substituted or unsubstituted hydrocarbon chain having carbon, a saturated or unsaturated hydrocarbon chain, a substituted or unsubstituted aryl, or a substituted or unsubstituted benzyl, R ₂ is hydrogen, or a substituted or unsubstituted having 1 to 4 carbon atoms, A saturated or unsaturated hydrocarbon chain, R ₃ is hydrogen, a substituted or unsubstituted hydrocarbon chain having 1 to 6 carbon atoms, a saturated or unsaturated hydrocarbon chain, a substituted or unsubstituted aryl, a substituted or unsubstituted benzyl, a hydroxy , Halogen, carbonyl, alkoxy, nitro,
One or more substituents selected from the group consisting of amido, amino, substituted amino, carboxylate, and combinations thereof, R ₄ is hydrogen, substituted or unsubstituted having 1 to 4 carbon atoms , Saturated or unsaturated hydrocarbon chains or acyl], and pharmaceutically acceptable salts and esters thereof.