JPS61210033A - Pharmacological composition containing gem-diphosphonate - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION Technical Field The present invention relates to pharmaceutical compositions containing compounds that are important in the treatment or prevention of diseases characterized by abnormal calcium and phosphate metabolism, particularly diseases characterized by abnormal bone metabolism.

The present invention further relates to methods for treating or preventing diseases characterized by abnormal calcium and phosphate metabolism using the pharmaceutical compositions of the present invention.

Includes calcium and phosphate metabolism. Such conditions can be divided into two broad categories.

1. Due to abnormal calcium and phosphate mobilization leading to general or specific bone loss or excessively high calcium and phosphate concentrations in body fluids 4! The state of being imaged. Such a condition may be referred to herein as pathological hard tissue demineralization.

2. Conditions that cause or result from abnormal calcium and phosphate deposition in the body. These conditions may be referred to in the present invention as pathological calcification.

The first category is osteoporosis, a condition in which bone hard tissue is lost disproportionately and new hard tissue develops.
teoporosis). The bone marrow and blue spaces become more enlarged, the fibrous connections decrease, and the tight bones become brittle.

Osteoporosis can be subcategorized into menopausal, perimenopausal, drug-induced (e.g., adrenocorticoids, as occurs with steroid therapy), and disease-induced (e.g., arthritis and tumors). , the symptomatology is virtually identical. Another condition in the first category is Beget's disease (osteitis deformans). In this disease, normal bone dissolution occurs, which is then replaced by excessively soft, poorly mineralized tissue that becomes deformed from weight-bearing pressures, especially in the tibia and femur. Hyperparathyroidism, malignant hypercalcemia, and osteolytic bone metastases are also conditions included in the first category.

The second category includes conditions expressed by abnormal calcium and phosphate deposition, such as myositis ossificans progressiva, generalized calcinosis, and arthritis, neuritis, bursitis, phlegmonitis, and other affected diseases. It includes conditions such as inflammatory conditions that predispose tissues to deposit calcium phosphate.

Polyphosphonic acids and their pharmaceutically acceptable salts have been proposed for use in the treatment and prevention of such conditions. Especially ethane-1-human hydroxy-1,1-
Diphosphonic acid (RHDP), propane-3-amino-
! -Hydroxy-1,1-diphosphonic acid (muPD),
and diphosphonates such as dichloromethane diphosphonic acid (C12MDP) have been the subject of considerable research effort in this area. Baget's disease and heterotopic ossification are currently being treated more successfully than 1HDpK. These diphosphonates tend to inhibit bone tissue resorption, which is beneficial for patients suffering from excessive bone loss. However, mDP, muPD, and many other prior art diphosphonates have a tendency to suppress bone mineralization when administered at high dosage rates.

The inhibition of mineralization is mainly due to mass-related physical-chemical effects, whereas the inhibition of absorption is thought to be caused by biological interactions with cells. Therefore, low doses can be administered with little or no mineralization inhibition, and
Thereby, it would be desirable to develop more biologically potent diphosphonate compounds with wider safety margins. Low doses are also desirable to avoid the gastrointestinal discomfort (such as diarrhea) that sometimes accompanies the oral administration of large amounts of diphosphonates.

Accordingly, it is an object of the present invention to provide a high-strength composition for the treatment and prevention of abnormal calcium and phosphate metabolism. It is a further object of the present invention to provide improved methods of treating diseases characterized by abnormal calcium and phosphate metabolism.

BACKGROUND OF THE INVENTION US Pat. No. 3,683,080 discloses compositions comprising polyphosphonates, particularly diphosphonates, and their use in inhibiting abnormal deposition and mobilization of calcium phosphate in animal tissues.

Japanese Patent Publication No. 55-98193 discloses pyridylethanediphosphophone W1. B-(pyridyl)-thiomethane diphosphonic acid and its derivatives with halogen or alkyl group substitution on the pyridyl ring are disclosed.

These compounds have been used as herbicides after expression.

Japanese Patent Publication No. 55-98105 discloses N-(3-pyrrolidyl)-aminoethane diphosphonic acid for herbicidal use, and derivatives obtained by substitution of a halogen or alkyl group on the pyridyl ring.

Each f! N-(pyridyl)-aminomethane diphosphonates are also disclosed in German Patent No. 2.831.578 for herbicidal use.

Yo 0 Tsuba % permission IJi 100.718 No. m
* (Published Feb. 15, 984) discloses various alkyl diphosphonates substituted with a sulfide attached to a 5- or 6-membered nitrogen- or sulfur-containing heterocycle. These compounds are anti-inflammatory and anti-reactive:
-Used as a gusset drug.

British Patent Application No. 2.004.888 (April 1, b979)
(Released on the 1st) is N-(3-methyl-2-
[Picolyl]-aminoethane and related compounds are disclosed.

Blogger et al, Z, A
nOrg.

411g, Ohem, , 389, 119
(b972):l discloses the synthesis of N-(4-pyridyl)-aminoethane diphosphonic acid. The properties or uses of this compound are not disclosed.

SUMMARY OF THE INVENTION The present invention relates to a pharmaceutical composition comprising: (al) a gem-diphosphonic acid compound of about 0.001 mg P to about 600 mg P, or a pharmaceutically acceptable salt or ester thereof; , in which the diphosphonic acid-containing carbon is linked directly or through a chain from 1 to about 5 carbons in length to a 6-membered aromatic ring containing one or more nitrogen atoms, and the Where the moiety contains: the ring is substituted and unsubstituted (saturated or unsaturated)
Alkyl groups having ~6 carbon atoms, substituted and unsubstituted oryl groups, substituted and unsubstituted benzyl, hydroxy, halogen, carbonyl, alkoxy, nitro, amido, amino, substituted amino, carboxylate, and substituted with one or more substituents selected from the group consisting of a combination thereof, or unsubstituted;
- the linking chains are all carbon atoms, nitrogen atoms or nitrogen-containing chains, oxygen atoms or oxygen-containing species, or selenium atoms or selenium-containing chains, which chains independently contain nitrogen atoms and/or
or substituted or unsubstituted on a carbon atom with one or more substituted or unsubstituted (saturated or unsaturated) alkyl having from 1 to about 4 carbon atoms, and the nitrogen atom is also substituted by an acyl group. The diphosphonate-containing carbon may be substituted or unsubstituted (saturated or unsaturated) alkyl, substituted or unsubstituted aryl, substituted or unsubstituted, having 1 to about 6 carbon atoms. benzyl, amino, substituted amino, amido, hydroxy, alkoxy, halogenated or carboxylate, or unsubstituted (provided that the diphosphonate-containing carbon is substituted with a nitrogen, selenium or oxygen atom in the chain). When attached directly, the substituents are substituted or unsubstituted (saturated or unsaturated) alkyl, substituted or unsubstituted alkyl, or substituted or unsubstituted benzyl having from 1 to about 6 carbon atoms. and (b)) a pharmaceutical carrier.

The present invention further features a method of treatment characterized by abnormal calcium and phosphate metabolism, comprising administering a safe and effective amount of the diphosphonic acid-containing composition of the present invention to a human or animal in need of such treatment. It encompasses methods.

DETAILED DESCRIPTION OF THE INVENTION The present invention provides a pharmaceutical carrier and a safe and effective amount of gem-diphosphonic acid compounds or gem-diphosphonic acid compounds in which the diphosphonic acid-containing carbon is linked to a six-membered aromatic ring containing one or more nitrogen atoms. The present invention relates to pharmaceutical compositions, preferably in unit dosage form, comprising pharmaceutically acceptable salts and esters. Preferred rings are pyridine, pyridazine, pyrimidine, and pyrazine. Most preferred is pyrimidine, especially pyridine. These rings include substituted and unsubstituted alkyls (saturated or unsaturated) having from 1 to about 6 carbon atoms.
, substituted and unsubstituted groups (e.g., phenyl and
methyl), substituted and unsubstituted benzyl, hydroxy, halogen, carbonyl (e.g. -01i0 and -00C+H
, ), alkoxy (e.g., methoxy and ethoxy), nitro, amido (e.g., -NHcoon, ), amino-substituted amino (e.g., dimethylamino, methylamino, and diethylamino), carboxylate (e.g., -0000
133, and combinations thereof, or unsubstituted.

These rings may be fused with other rings, including fused rings such as benzene and pyridine (eg, quinoline), and cyclohexane and pyridine (CP1%5,6,7.8-tetrahydroquinoline). Other substituents may include substituted or unsubstituted sulfides, □sulfoxides, sulfates, or sulfones.

Attachment from a non-phosphonic acid-containing carbon to the ring may be directly through a single bond or through a chain from 1 to about 5 carbons in length. The chains may be all carbon atoms, nitrogen atoms or nitrogen-containing chains, oxygen atoms or oxygen-containing chains, or selenium atoms or selenium-containing chains. The carbon and nitrogen atoms in these chains are independently one (or one or two in the case of carbon atoms) substituted or unsubstituted alkyl (saturated or unsaturated) having from 1 to about 4 carbon atoms.
(methyl and ethyl are preferred) or unsubstituted. Nitrogen atoms in the chain may also be substituted with acyl groups (eg, -cocn, ). Unsubstituted carbon and nitrogen atoms in the chain are preferred. Also,
Also preferred are chains of one atom in length, namely -OH, -1-trillion, and -0-.

The carbon atom bonded to the phosphonate group may be unsubstituted (e.g. hydrogen atom) or amino, substituted amino, amido, hydroxy, alkoxy, halogen, carboxylate, 1
Optionally substituted with substituted or unsubstituted aryl having up to about 6 carbon atoms, or substituted or unsubstituted benzyl. For compounds in which a phosphonate-containing carbon is linked to a ring via an oxygen, selenium, or nitrogen-containing chain, and the oxygen, selenium, or nitrogen atom is directly bonded to the phosphonate-containing carbon, the substituent on the phosphonate-containing carbon is 1
~Substituted or unsubstituted alkyl having about 6 carbon atoms (
(saturated or unsaturated), substituted or unsubstituted aryl, or substituted or unsubstituted benzyl.

In this context, the phosphonic acid compounds included in the pharmaceutical compositions of the present invention have the following structural formula: [Q is oxygen, -HR,
-, selenium, or a single bond, preferably oxygen, -NR
4-1 or a single bond, m+n is O to about 5, and m+ for Q is oxygen, selenium, or -NR, -
n#O* or 1 is preferred, otherwise m+n#
1 or 2 is preferred, and Z is a ring selected from the group consisting of pyridine, pyridazine, pyrimidine, and pyrazine, with pyrimidine and especially pyridine being preferred: R
8 is hydrogen, substituted or unsubstituted amino, amido, hydroxy, alkoxy, halogen, carboxylate, substituted or unsubstituted alkyl (saturated or unsaturated) having 1 to about 6 carbons, substituted or unsubstituted alkyl; , or substituted or unsubstituted benzyl (provided that nwo and Q are oxygen,
When it is selenium or -HR4-, R1 is hydrogen,
substituted or unsubstituted alkyl (saturated or unsaturated) having 1 to about 6 carbon atoms, fIL-substituted or unsubstituted aryl, or substituted or unsubstituted benzyl), where R is hydrogen, chloro, amino; , methyl or hydroxy are preferred; each R1 is independently hydrogen or 1
~ Substituted or unsubstituted alkyl having about 4 carbon atoms (
saturated or unsaturated], R*k1 is preferably hydrogen: R3 is hydrogen, substituted or unsubstituted alkyl (saturated or unsaturated) having 1 to about 6 carbon atoms, substituted and unsubstituted aryl, Substituted and unsubstituted benzyl, hydroxy, halogen, carbonyl, alkoxy, nitro,
l or more substituents selected from the group consisting of amido, amino, substituted amino, carboxylate and combinations thereof, preferably hydrogen, methyl, amino,
chloro, methoxy, nitro, hydroxy or a combination thereof; R4 is hydrogen, substituted or unsubstituted alkyl (saturated or unsaturated) having from 1 to about 4 carbon atoms, or acyl (i.e., nitrogen amide); hydrogen, methyl or ethyl], and pharmaceutically acceptable salts and esters of these compounds. Finally, for any of the R1, R2, R3, or R4 substituents that are themselves substituted, substitution on these substituents may be of any one or more of the above substituents, and is preferred. are methyl, ethyl, amino, chloro,
Nitro, methoxy, hydroxy, acetamide and acetate.

More specifically, the diphosphonic acid compounds and their pharmaceutically acceptable salts and esters included in the pharmaceutical compositions of the present invention are of the structure: (wherein m + n , Z , R1, R2, R3,
and R4 are as defined above).

Generally preferred diphosphonic acid compounds and their pharmaceutically acceptable salts and esters for inclusion in the pharmaceutical compositions of the present invention are of the following structure.

(m+nml or 2 in the above formula for both structures,
R□ is hydrogen, chloro, amino, or hydroxy; R3 is hydrogen, methyl, amino, or hydroxy; or (n-〇 or 1 in the above four structural formulas; R1 is n
-1, it is hydrogen, chloro, 7mino, or hydroxy; in the case of nwo, R1 is hydrogen; i R
3 is hydrogen, methyl, amino, or a substituent, and R4
is hydrogen, methyl, or ethyl).

Specific examples of compounds that can be utilized in the compositions of the present invention include the following compounds: 2N-(z-pyridyl)-aminomethane diphosphonic acid; N-(2-(5-amino)-pyridyl )-aminomethane diphosphonic acid; N-(2-(5-chloro)-pyridyl)-aminomethane diphosphonic acid; N-(2-(5-nitro)-pyridyl)-aminomethane diphosphonic acid; N- (2-(3,5-dichloro)-pyridyl)-aminomethane diphosphonic acid; N-(4-pyridyl)-N-ethyl-aminomethane diphosphonic acid; N-(2-(3-picolyl)) -aminomethane diphosphonic acid; N-, (2-(4-picolyl))-aminomethane diphosphonic acid; N-(2-(5-picolyl))-aminomethane diphosphonic acid; N-(2-( 6-picolyl))-aminomethane diphosphonic acid; N-(2-(3,4-lutidine)-aminomethane diphosphonic acid; N-(2-(4,6-lutidine)-aminomethane diphosphonic acid; N-(2-pyrimidyl)-aminomethane diphosphonic acid: N-(4-(2,6-dimethyl)-pyrimidyl)-aminomethane diphosphonic acid; N-(2-(4,6-dihydroxy)-pyrimidyl )−
Aminomethane diphosphonic acid; N-(2-(5-methoxy)-pyridyl)-aminomethane diphosphonic acid; N-(2-pyridyl)-2-aminoethane-1゜1-diphosphonic acid; N-(2- (3-picolyl)-2-aminoethane-1
,1-diphosphonic acid; N-(3-pyridi/I/)-2-amino-1-chloroethane-1,1-diphosphonic acid; N-(2-(4-picolyl))-2-amino-1- Hydroxyethane-1,1-diphosphonic acid; (2-pyridyl)-methane diphosphonic acid; (3-pyridyl)-aminomethane diphosphonic acid; (2-pyridiN)-chloromethane diphosphonic acid; (4- pyridyl)-hydroxymethane diphosphonic acid; 2-(2-pyridi/I/)-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-methoxytwopyridyl)-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,
l-diphosphonic acid; 2-(3-pyridyl)-1-hydroxy-ethane-1,
1-diphosphonic acid; 2-(4-pyridyl)-1-hydroxy-ethane-1,
1-diphosphonic acid; 3-(3-pyIJdyl)-1-hydroxy-propane-
1,1-diphosphonic acid; 0-(2-pyridyl)-2-oxa-ethane-1゜l-
Diphosphonic acid; 0-(2-pyridyl)-oxamethanediphosphonic acid; 0-(2-pyrimidyl)-oxamethanediphosphonic acid; 0-(2-(4-amino)-pyridylco-oxamethanediphosphonic acid); 〇-(2-pyrimidyl)-2-oxa-ethane-j, 1
-diphosphonic acid; 0- (2-(3-picolyl))-2-oxa-ethane-1,1-diphosphonic acid: 0- (2-(3-picolyl))-oxamethane-diphosphonic acid; 0-(2 -pyridyl)-1-hydroxy-2-oxa-
Ethane-1,1-diphosphonic acid; 0-(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)-aminomethane diphosphonic acid; N-(2-(5-chloro)-pyridyl)-aminomethane diphosphonic acid: N-(2- (3-picolyl))-aminomethane diphosphonic acid; N-(2-(4-picolyl))-aminomethane diphosphonic acid; N-(2-(5-picolyl))-aminomethane diphosphonic acid; N -(2-(6-picolyl))-aminomethane diphosphonic 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-pyridylconitane-1,1-diphosphonic acid; 2-(3-pyridyl)-ethane-1,1- Diphosphonic acid; 2-(4-pyridyl)-ethane-1,1-diphosphonic acid: 2-(2-pyridylAJ)-1-hydroxy-ethane-1
,1-diphosphonic acid; 2-(3-pyridyl)-1-hydroxy-ethane-1
,]-diphosphonic acid; z-<4-pyridyl)-1-hydroxy-ethane-1,
■-Diphosphonic acid; 0-(2-(3-bicoli/I/)-oxamethane-diphosphonic acid; or (゛ is a pharmaceutically acceptable salt or ester thereof).

The diphosphonate compounds contained in the pharmaceutical composition of the present invention are described in Japanese Patent Publication No. 55-98,193, Japanese Patent Application Publication No. 55-98,105, and West German Patent No. 2,831,5.
No. 78 and W. Ploger et al.
tal,, Z, Anog, A11g,
Ohem, , 389, 119 (b97
2)], and the disclosures thereof are solely used in the present invention. However, the aminoethane diphosphonic acid compound is best prepared as follows.

Synthesis of N-(2-(3-picolyl))aminoethane DP The above compound is synthesized by the synthesis of tetraethyl vinyl diphosphonate and 2-
Prepared by the typical Michael reaction between amino-3-picoline [Hoo,)-Us(El, 01H
ouse), Modern 5ynthetic Re
action 2nd edition, W.A., Benjamin Co., Ltd.
See p. 5 No. 5-623. The disclosure content of this document is solely used in the present invention].

1.62 g (b5) of 2-amino-3-picoline in a solution of 4.50 in tetrahydrofuran at 5°C.
g (+5 mmol) of tetraethyl vinyl diphosphonate were 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/l) to give pure tetraethyl N-(2-(3-picolyl))-2-aminoethane diphosphonate.

The p-31 NMR of this pure tetraethyl ester in CDC Yu3 shows a resonance at 22.1 DI)m. This ester was hydrolyzed in 6N HCl by refluxing it overnight. This product has a pH of -1 at D20.
2 showed a P-31 NMR signal of 19.0 ppm.

N-(2-pyridyl)-2-aminoethane DP and N
-(2-(5-picolyl))-]2-aminoethane D was prepared in a similar manner.

Compounds having the following general formula: where n is an integer from 1 to about 5, preferably n-1; and 2% R2 and R3 are as defined above, preferably 2 is pyrimidine and especially pyridine. and preferred R2 is hydrogen and preferred R3 is one or more substituents selected from the group consisting of hydrogen, methyl, amino, chloro, nitro, methoxy, hydroxy, and combinations thereof) It is best prepared as follows: 6. In a three-neck round-bottomed flask equipped with a reflux condenser and magnetic stirring bar.
94 g (0.04 mo/I/) of 2-pyridine acetic acid,
9.84 g (0.14 mo/I/) of phosphoric acid and 150 ml of chlorobenzene were charged. The reaction mixture was heated on a boiling water bath and 16.5 g (0.12 mol) of phosphorus trichloride were added dropwise with stirring. This reaction mixture was mixed with 21/! Heated for an hour, during which time a viscous yellow oil formed. The reaction mixture was then cooled in a water bath and the chlorobenzene solution was decanted from the solidified product. The reaction flask containing this solidified product was charged with 150101 water and heated in a boiling water bath for several hours. The hot solution was then filtered through (!emi15 545R). 300 ml of methanol was added to the warm filtered solution and a precipitate formed. After cooling in water for 1 hour the precipitate was filtered with P
Separated and washed with methanol/water (Vl v/I), methanol, and ether and air dried. This product may be recrystallized from hot water. The yield is approximately 5.9 g (
52%). This sample was divided into P-31 and 0-0-
Characterized by 13N.

"Pharmaceutically acceptable salts and esters" as used in the present invention refer to diphosphonates which have the same general pharmacological properties as the acid form from which they are derived, and which are also acceptable from a toxicological standpoint. Refers to hydrolyzable salts and esters of compounds. Pharmaceutically acceptable materials include alkali metals (sodium and potassium), alkaline earth metals (calcium and magnesium), and non-toxic heavy metals (
tin and indium), and ammonium and low molecular weight substituted ammonium (seven-, di-, and triethanolamino) salts.

Preferred compounds are sodium, potassium and ammonium salts.

As used herein, "pharmaceutical carrier" refers to one or more compatible solid or liquid filled diluents or encapsulating materials. As used herein, "compatibility" refers to the ability of the components of a composition to be mixed together under normal conditions of use without interaction that would substantially reduce the pharmaceutical efficacy 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, etc.; 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 theobroma oil; polyols such as propylene glycol, glycerin, sorbitol, mannitol, yolk polyethylene glycol; agar; alginic acid; pyrogen-free water: isotonic saline; and phosphate buffered solutions, There are also non-toxic compatible materials used in other pharmaceutical formulations. Wetting agents and lubricants such as sodium lauryl sulfate, as well as coloring agents, flavoring agents, lubricants, excipients, tabletting agents,
Stabilizers, antioxidants, preservatives, and the like may also be present. Other compatible pharmaceutical excipients and active substances, such as vitamin D or vitamin D metabolites and mineral supplements, may also be included in the pharmaceutical compositions of the invention.

The choice of pharmaceutical carrier for use in combination with the diphosphonates of the present invention is determined primarily by the manner in which the diphosphonate is administered. When the compound is injected, a preferred pharmaceutical carrier is sterile saline whose pIl is adjusted to about 7.4. However, since the preferred mode of administration for the diphosphonates of the invention is oral, the preferred unit dosage form is therefore from about 0.1 mg F to about 600 mg F.
mg F of the diphosphonic acid compound described in the present invention. Pharmaceutical carriers suitable for preparing unit dosage forms for oral administration are known. Their selection will depend on secondary considerations that are not important for the purposes of the invention, such as taste, cost, storage stability, etc., and can be made without difficulty by those skilled in the art. Pharmaceutical carriers used with the diphosphonates of this invention are used in concentrations sufficient to provide practical administration. Preferably, the pharmaceutical carrier accounts for about 0.01 of the total composition.
~99.99% by weight.

example! Prepare capsules containing the following ingredients in a conventional manner:
min mg/capsule N-(2”(
3-picolyl)) AMDP 100 (mgP
Starch 55.60 Sodium Lauryl Sulfate 2.90 Oral administration of the above capsules twice daily for 6 months substantially reduced bone resorption in a patient weighing approximately 70 kg suffering from osteoporosis. do. In the above capsule, N
Similar results are obtained when the following compound is used in place of -(2-(3-picolyl))-aminomethane diphosphonic acid or its pharmaceutically acceptable salt or ester: N-(2- (5-amino)-pyridyl)-aminomethane diphosphonic acid; N-(2(5-chloro)-pyridyl)-aminomethane diphosphonic acid; N-(2-(4-picolyl))-7minomethanedi Phosphonic acid; u-(z-(s-picolyl))-aminomethane diphosphonic acid; N-(2-(6-picolyl))-aminomethane diphosphonic 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; Z-(S-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 ■ Tablets having the following composition are prepared by a conventional method: N-(2
-pyrimidyl) AMDP 25.00
Lactose 40.00 Starch
2.50 Magnesium Stearate 1.00 Administration of the above tablet orally twice daily for 6 months substantially reduced bone resorption in a patient weighing approximately 70 kg suffering from osteoporosis. Similar results are obtained when using the following compounds: N-(2-(5-amino)-pyridyl)-aminomethane diphosphonic acid; N-(2-(5-chloro)-pyridyl)-amino Methanediphosphonic acid; N-(2-(3-picolyl))-7minomethanediphosphonic acid; N-(2-(4-picolyl))-aminomethanediphosphonic acid; N-(2-(5- picolyl))-aminomethane diphosphonic acid; N-(2-(6-picolyl))-7minomethane diphosphonic acid; N-(2-(3,4-lutidine))-aminomethane diphosphonic acid; H -(2-pyridyl)-2-aminoetha/-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-diphospho2-
(2-pyridyl)-1-hydroxy-ethane-1,1-
Diphosphonic acid: 2-(a-pyridyl)-1-hydroxy-ethane-1,
1-diphosphonic acid; 2-(4-?'lysyl)-1-hydroxy-ethane-1
, 1-diphosphonic acid; 0-(2-(3-picolyl)-oxamethane-diphosphonic acid); or a pharmaceutically acceptable salt or ester thereof.

Example ■ 1.0 ml of either saline or aqueous solution and 3.5 mg of 2-(2-pyridyl)-ethane-
An injectable solution adjusted to pH 7.4 using 1,1-diphosphonic acid is prepared in a conventional manner.

One daily injection for 4 days significantly alleviates malignant hypercalcemia in a patient weighing approximately 70 kg. Similar results are obtained if the following compound is used instead of 2-(2-pyridyl)-ethane-1,1-diphosphonic acid in the above treatment: N-(2-(s-amino)-pyridyl)- 7minomethanediphosphonic acid; N-(2-(5-chloro)-pyridyl)-aminomethane diphosphonic acid; N-(2-(3-picolyl))-aminomethane diphosphonic acid; N-(2- (4-picolyl))-aminomethane diphosphonic acid; N-(2-(5-picolyl))-aminomethane diphosphonic acid; N = (2-(6-picolyl))-aminomethane diphosphonic acid; N -(2-(3,4-lutidine))-7minomethanediphosphonic acid; N-(2-pyrimidyl)-aminomethane diphosphonic 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-hydroxyetha l-1,
1-diphosphonic acid; z-(3-pyridyl)-t-hydroxy-ethane-1,
1-diphosphonic acid; 2-(4-pyridyl)-t-hydroxy-ethane-1,
1-diphosphonic acid; 0-(2-(3-picolyl)-oxamethane-diphosphonic acid); or a pharmaceutically acceptable salt or ester thereof.

Compositions of the invention are useful in treating 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 (EHDP), propane-3-amino-1-hydroxy-1,1-diphosphonic acid (APD), and dichloromethane diphosphonic acid (C12MDP) are used in this field. It has been the subject of considerable research effort.

However, the compositions of the present invention are generally biologically more potent in inhibiting bone resorption than diphosphonates disclosed in the prior art. That is, the compositions of the present invention provide one or more of the following advantages over diphosphonates disclosed in the prior art: C1) more potent at inhibiting bone resorption; (2) mineralization ( m1naral
(3) generally have a wider margin of safety (i.e. (4) sometimes higher doses of diphosphonates by allowing for lower oral doses (4) a wider dose interval between the lowest effective antiresorptive dose and the lowest dose that results in mineralization inhibition); (5) have the potential for flexibility in administration methods;

Another aspect of the invention is a method for treating or preventing diseases characterized by abnormal calcium and phosphate metabolism, particularly diseases characterized by abnormal bone metabolism, in humans at risk for such diseases, the method comprising: The method comprises the step of 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,
Examples include, but are not limited to, intravenous, intraperitoneal, and subcutaneous administration, as well as topical application.

"Abnormal lucicum and phosphate metabolism" as used in the present invention refers to (b) abnormal mobilization of calcium and phosphate leading to general or specific bone loss, i.e. abnormally high calcium and bosphate concentrations in body fluids; mobili-zation
and (2) conditions that cause or result from abnormal calcium and phosphate deposition in the body. The first interstitial layer includes, but is not limited to, osteoporosis, Beget's disease, parathyroid disease, malignant hypercalcemia, and osteolytic bone metastasis. The second layer is myositis ossificans progressiveus, generalized calcinosis, and other inflammations that predispose the affected tissues to calcium phosphate deposits such as arthritis, neuritis, bursitis, olucitis, and others. Examples include, but are not limited to, pathological conditions.

As used herein, a "person at risk" or "person in need of such treatment" refers to any person who is at substantial risk of abnormal calcium and phosphate metabolism if discharged untreated. or lower animals, and any human or lower animal diagnosed as suffering from abnormal calcium and phosphate metabolism. For example, postmenopausal women, people on certain steroid treatments, people taking certain antispasmodics, Beget's disease, parathyroid disease, malignant hypercalcemia or osteolytic disease. Humans diagnosed with bone metastases and suffering from one or more of the various forms of osteoporosis are known to have a significantly higher than average chance of developing osteoporosis. Myositis ossificans progressiveis, such as postmenopausal women, men over 65 years of age, and people treated with drugs known to cause osteoporosis as a side effect; or those diagnosed as suffering from generalized calcinosis and those suffering from arthritis, neuritis, bursitis, phlegmonitis, and other inflammatory conditions that predispose affected tissues to calcium phosphate deposits. , etc.

As used in the present invention, "a person or lower-grade animal suffering from or at risk of osteoporosis" refers to a patient diagnosed with one or more of the various forms of osteoporosis, or an average person who develops osteoporosis. patients who belong to groups known to have a significantly greater chance than those of patients, such as postmenopausal women, men over 65 years of age, and drugs known to cause fosthioboroses as a side effect. (e.g., people treated with adrenocorticoids).

As used herein, a "safe and effective amount" is defined as an amount sufficiently high, within the scope of sound medical judgment, to meaningfully target the condition to be treated, but sufficient to avoid serious side effects. means a sufficiently low (reasonable benefit/risk ratio) value of the compound or composition. The safe and effective diet of diphosphonates depends on the particular disease being treated, the age and physical condition of the patient being treated, the severity of the disease, the duration of treatment, the nature of concurrent treatments, and the particular diphosphonate used. Varies depending on the W1 value of the phosphonate. However, a single dose ranges from about 0.001 mg P to about 3500 mg
P, i.e. o, 111 gP/kg body weight ~ about 500 m
It may be in the range g P /kg body weight. A preferred single dose is 0.1 mg P to about 600 mg P, or about 0
．． O1 to about 50 mg P/kg body weight. Single doses up to 4 times per day can be administered.6 Daily doses larger than approximately 2000 mg P/kg are not required to obtain the desired effect and may cause undesirable side effects. be. Of course, for oral administration, doses higher than this range are required due to limited absorption.

The 8chenk model compound was evaluated for its inhibition of bone resorption and mineralization in vivo in an animal model system known as the 8chenk model in the field of bone metabolism. The general principle of this model system is explained by Kunoda et al.
l,, Ca1cif %Ti5sue mt,, 3
5.

87-99 (b983)) and Shie/Ri et al. (8c
b+snk @ta11Calcif%Ttaaus
Res, 11, 196-214 (b9]3)]
These disclosures are solely used in the present invention.

Materials and Methods Animals 17 day old (3o g) male sprags before weaning
ueDst'wls7 rat (Charlea Rlv
er Broiling Labo-ratoris
a) was transported with the mother and placed in a plastic cage with the mother upon arrival. Rat pups receiving rat food and water ad libitum at postnatal day 1 were randomly assigned to treatment groups of 5 animals in each group, while control animals received saline and consisted of 10 rats per group. Ca1 as a 1% solution in 0.9% NaCl solution to label the skeleton in all animals at 06 and again at 18.
A subcutaneous injection of cein (81 gma) was given.

Dosing Solutions and Dosing Procedures All solutions were prepared as subcutaneous injection solutions in Q, 9% normal saline and adjusted to pH 7.4 using NaOH and/or HCI. Dosage solution calculation is mgP/k
This was done taking into account the amount of active substance powder (based on molecular weight, hydrated) in mg/kg (body weight) corresponding to H. Concentrations were based on a dose of 0.2 ml 7100 g body weight.

Initially, all compounds were tested at 0.1.1.0 and 1 for 7 days.
G, Omg P 7kg administered on 7 days. 0.1m8
Compounds showing activity at P/kg 7 days were then 0.0
Log reductions to 0.01 mg P/kg/day were tested. All animals were sacrificed by CO□ asphyxiation 88 days after the start of dosing to adjust the dose based on changes in body IIK. The tibia was incised and placed in 70% ethyl alcohol.
One tibia was dehydrated by placing it in graded concentrations of ethanol and dehydrating it as described by Boyce et al. (Lab.

mveattg, 48, 683-689 (b9
83) - whose disclosure is solely used in the present invention]. This tibia was sectioned longitudinally through the distal line area (bai15 Thor Microdome 15
0μ). One side of the specimen was stained with nitric acid, mounted on a microscope slide, and stained with Quantimet Image Ana.
lyzer (Cambridge
Menta, mc, ) was evaluated using both incandescent and ultraviolet illumination. The trabecular bone inclusion of bone gIA#j was measured in the area between the fluorescent label and the growth plate.
The growth plate width at the epicenter, expressed as - of bone + bone marrow, was obtained as the average of 10 equally spaced measurements across the section. Statistical evaluation of data was compared to control animals. Parametric and non-parametric analyzes of variation were performed to determine statistically significant effects, and the WilCOZOn8 rank sum test was used.

This dienk model provided data on inhibition of bone resorption in vivo by compounds. The lowest effective (anti-absorptive) doses (rLEDJ') for representative compounds tested as determined by the Sienck model are listed in Table I.

Tablet Minimum effective (anti-absorption) dosage chenk Diphosphonate compound LED (mg P/k
g) RHDP
1. OC12MDP
1.0APD
O,IN-(2-pyridyl)AMDP” 0.0IN
-(2-(5-chloro)-pyridyl)AMDP”
0.0IN-(2-(3-picolyl))AMDP
O,001N-(2-(4-picolyl)
) AMDP” 0,001N-(2-
(5-picolyl)) AMDP“ 0,00
1N-(2-(6-picolyl))AMDP”
0.001N-(2-pyrimidyl)AMDP"
0.001N-(4-pyridyl)-
N-ethyl AMDP" 0.12-(2-pyridyl) PDP" 0
．． 012-(3-pyridyl) ICDPl
0.011-(2-pyridyl) propyl DP" 10.EHDP = ethyl/-1-hydroxy-1.1-DPC1 MDP = dichloromethane DP APD: 3-aminopropane-1-hydroxy-
1,1-DP AMDP = aminoethane diphosphonic acid in which II is bonded to amino = compound EDP included in the pharmaceutical composition of the present invention
= ethane-1,1 whose ring is bonded to the 2-position of ethane
-Propyl diphosphonate DP = propane-2,2-diphosphonic acid Diphosphonate compounds that have an inhibitory effect on bone mineralization cause spread of the distal growth plate since matrix formation continues, but mineralization is hindered. The spread of the terminal growth plates seen in the Shefuku model is therefore indicative of the anti-nocturnalization efficacy of the diphosphonate compounds tested.

The lowest tested doses resulting in statistically significant bone m growth plate widening for the compounds tested are shown in Table ■.

Table ■ EHDP
10APD
1GC! 12MDP
- N-(2-pyridyl)AMDP”
0. IN-(4-pyridyl)-N-ethyl AMDP"
-1 1) (z-(3-picolyl))A
MDP" --1) N-(2-(4-picolyl))AMDP" 0. IN-(2-(5
-Picolyl))AMDP” 0.1t(2
-(6-picolyl))AMDP"N-(2-pyrimidyl)AMDP" 1.0N-(2-
(5-chloro)-pyridyl)human MDP"--1)
2-(3-pyridyl)PDP"2-(2-pyridyl)gDp" -10- = No plate spread was observed at the highest tested doseC Unless otherwise specified, the highest tested dose was 10 mgP
/kg 7 days) 1) = Highest dose evaluated, amount is 1 mgP/kg/day (compound is 10 mgP/kg
BHDP = ethane-1-hydroxy-1.1-DP
APD=3-aminopropane-1-hydroxy-1,1
-DP C12MDP = dichloromethane DP AMDP = aminomethane diphosphonic acid in which the ring is bonded to amino EDP = ethane-1,1 in which ll is bonded to the 2-position of ethane
-diphosphonic acid* = Compound contained in the pharmaceutical composition of the present invention Thyroid parathyroidectomy (TPTX) rat model Compounds were evaluated in an animal model system known as the thyroid parathyroidectomy (TPTX) rat model. viv
The strength of inhibiting bone resorption of the sample o was evaluated.

The general principle of this model system is explained by Russell et al.
et am,, Calcif, Ti5sue Re
5earch, 6, 183-196 (b970
) 3, and Muhrbauer and Fleisch [
Muhlbauer and Fleiach, Mi.
neralElectrolyte Metab,,
5, 296-303 (b981)], and the contents of these disclosures apply mutatis mutandis to the present invention. The basic biochemical concept of the TPTX system is the parathyroid gland (PTH).
) - induced increase in serum and ionized calcium concentrations by the respective preactivated polyphosphonates.

Materials and Methods: Materials A low calcium and low phosphorus diet containing approximately 0.1 gram of calcium and 0.22% phosphorus in pellet form.
kladRTest Die15 (Har4an m
industries, Magick, Wisconsin, 53
711.0rder TD 821 No. 5). This diet contained all the essential vitamins and minerals needed by rats except calcium and phosphorus. Calcium and phosphorus concentrations in pellets were confirmed analytically (Proctel & Gamble O
o, , Miami VhllyLaborator
les, Cincinnati, Ohio).

PTH was obtained from powdered bovine extract (81gma Chemical Co., Ltd.) with an activity of 138υ8P units.
P, 0. BO3C14508, St. Louis, Missouri, Orderna P-0892, Loft φ72
F-9650). PTH has a final concentration of Zoo U, 8. P,/ml in 0.9% saline. All solutions are 44 Whatm
Filter through an 2F paper, 0,45, lalMe
Re-passed through a tricel filter.

Administration Solutions and Methods of Administration All compound solutions for testing bone resorption inhibitory potency were
．． Prepared for subcutaneous injection in 90% normal saline and containing Na
Use OH and/or HCI to pH 7.4! Ia
It was torn. Dosing solution calculations were carried out taking into account the mass of the powder of the active substance (molecular weight basis, aqueous phase) in mg y kg (body weight), which corresponds to mg P / kH. concentration is 0
．． Based on a dosage of 2 ml/Zoo g body weight.

Todoroki first, all compounds were administered at 0.01.0,1, and 1, Omg P/kg for 4 days, and 7 days. Animals were dosed with 0.3 LKI) in order to repeat the test if necessary, thereby refining the measurement of LBt). Dosage preparation based on changes in body weight was adapted daily.

Animals In this study, male Wigtar rats weighing approximately 150-160 g were bred (Charles Rlv
er Bras-dlng Laboratories
) The thyroid parathyroid gland was surgically removed. All rats were double housed in suspended cages upon arrival and Pu
RTNA Laboratories Low Phosphorus (0,18
%70.22%) diet (Teklad) and given 2% (W/,/) calcium gluconate supplemented deionized water via water bottle.

Method Ketag all rats on day 4 of low calcium diet.
etR (ketamine hydrochloride, 100mg/
ml, Br1atol Myera) is 0.10
Anesthetized with 7100 g of body weight, bled from the posterior orbital vein of the measuring diameter, and subjected to flame atom adsorption (FAA).
) was used for serum total calcium analysis. 180g
All rats weighing less than 50% were excluded from the study. Animals were then statistically randomized such that the mean total serum calcium in each group was the same. Only rats that were considered hypocalcemic (total serum calcium (8,0 mg 7 dl)) were placed in study groups of 6 animals/group.

Treatment with various experimental compounds began on day 6 and continued until day 9 of the study (1:00 P, M, daily).

The dosing solution was prepared to be applied subcutaneously to the abdominal skin flap where the hind legs meet the trunk at a constant rate of 0.2 ml/Zoo g body weight. All rats received daily body N
was determined and administered. Drugs were administered using a 25-gauge 578-inch needle, and the site of administration was alternated daily. On day 8, animals were changed to ionoexchanged distilled water via water bottle. On day 9 all rats were fasted at approximately 4:00 PoM. No treatments were given on day 1O0 of the study. In the morning, a sample of 600 μm whole blood was collected from each rat in a Microtainer for serum total lucicum.
B-DΦao60) Serum separator tube (
FAA,). Two 125 μm samples of heparinized whole blood were also collected for use in ionized calcium analysis. Immediately after blood collection, all rats were weighed and injected with bovine parathyroid hormone at a rate of 75υ8p (filtered) 7100 g body weight. Total and ionized calcium pool blood sampling was repeated 3 hours after the PTH injection.

All pre-post-PTH total and ionized calcium are 5
Statistical significance analysis was performed using tuden15 t-tests, analysis of dispersion, and their non-parameters as compared to PTH alone (control). Post-minus preliminary changes and rates of change were also determined for calcium concentration and pre-drug vs. post-drug body weight.The physiological effect of counteracting PTH is an increase in serum calcium concentration, with peak activity seen at 3.5-3. Ta. + in TPTX model! The observed increase in serum calcium concentration is likely the result of resorption of bone material since hormonal and dietary control of calcium metabolism is minimized. Because polyphosphonates tend to inhibit the resorption of bone material, animals pretreated with polyphosphonates showed less of an increase in serum calcium concentration after PTH challenge than that seen in saline-treated control animals. Ta. The lowest dose at which polyphosphonates can inhibit bone resorption is PTH
A measure of the antiresorptive potency of polyphosphonates, as evidenced by the reduced rise in counteractive serum calcium. The LED values of the bone resorption inhibitory strength of each compound determined by the TPTX rat model are shown in Table 3.

Table ■ PTX diphosphonate compound IJD (mg p /
kg)EHDP
1. OC12MDP
1.0APD
O,IN-(2-pyridyl)A
MDP" 0.0tN-(2-(5-amino)-pyridyl)AMDP
0.01 tatami N-(2-(5-chloro)-pyridyl)AMDP
0.01÷ N-(2-(5-nitro)-pyridyl)AMDP
O,IN-(2-(5-carboxy)-pyridyl)
AMDP NN-(2-(3,5-dichloro)-
pyridyl) AMDP 1.0N-(4-pyridyl)
-, H-x chill AMDP” 0.1N
-(2-(3-picolyl)) AMDP"
0°002N-(2-(4-picolyl))
AMDP+ 0.001N-(
2-(5-picolyl)) AMDP"
0,001N-(2-(6-picolyl)) A
MDP“ 0,01N-(2-(3
,4-Af-β)) AMDP“ 0,01N
-(2-(4,6-/l gin))AMDP“ 0
,01 '2N-(2-pyrimidyl)person MDP'
0.01N-(4-(2,6-dimethyl)-pyrimidi→AMDP" 1.0N-(2-
(4,6-dihydroxy)-pyrimidyl)AMDP
o,ol')to(2-pyridyl) AID! D
P” 0.0IN-(2-(3-pyryl)) Agnp” 102-(
2-Biri Ufure) mDp”
0.012-(3-biri υshi)
PDP“
0.012-(4-bili%) TLDP”
0.
1l-(2-biliu υushi)-Prohipre DP”
1,02-(2-pyridyl)-1
-Chloroethane DP" 0.1O-(2
-Pyridyl)-Ocamethane DP” 1.0
o-(z-(a-picolyl))-oknameta/DP”
0. IN: No activity at any dosage concentration tested EHDP = Ethane-1-hydroxy-1.1-DP
C12MDP = dichloromethane DP APD = 3-aminopropane-1-hydroxy-1,1
-DP AMDP = aminoethane diphosphonic acid bound to mkaami/ ARDP = 2-aminoethane-1,1-diphosphonic acid in which Wi is bound to the amino EDP = ethane bound to the 2-position of the ring canitan -1,
1-diphosphonate propyl DP = propane-2,2-diphosphonate/acid
=Compound 1) contained in the pharmaceutical composition of the present invention =Activity level questionable due to lack of administration responseExample ■A patient weighing approximately To kg clinically diagnosed as suffering from malignant hypercalcemia 0.7 mg F2 in
-(2-Pyridyl)-ethane-1+1-diphosphonic acid or its pharmaceutically acceptable salt or ester daily.
It is administered by intravenous infusion every 21/2 hours for 4 days. This treatment results in significant relief of malignant hypercalcemia.

In the above treatment, 2-(2-pyridyl)-ethane-1
, 1-diphosphonic acid, similar results are obtained if the following compound is used: N-(2-(5-7ξ))-
pyridyl)-aminomethane diphosphonic acid; N-(2-(5-chloro)-pyridyl)-aminomethane diphosphonic acid; N-(2-(3-picolyl))-aminomethane diphosphonic acid; N-( 2-(4-picolyl))-aminomethane diphosphonic acid; N-(2-(5-picolyl))-aminomethane diphosphonic acid; N-(2-(6-picolyl))-aminomethane diphosphonic 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-(3-pyridyl)-ethane-1,1-diphosphonic acid: 2-(4-pyridyl)-ethane-1,1-diphosphonic acid; in 2-(z-pyridyl)-1-hydro Ceetan-1.
1-Dibosphonic acid; 2-(3-pyridyl)-1-hydroxy-ethane-1,
1-diphosphonic acid; 2- (<-pyridyl)=1-hydrocyethane-1
，! - dinail sulfonic acid; 0-(2-(3-picolyl)-oxamethane-diphosphonic acid); or a pharmaceutically acceptable salt or ester thereof.

Claims (1)

[Claims] 1. A pharmaceutical composition comprising the following ingredients: (a) about 0.001 mgP to about 600 mgP of gem-
A diphosphonic acid compound, or a pharmaceutically acceptable salt or ester thereof, in which the diphosphonic acid-containing carbon is directly attached to a 6-membered aromatic ring containing one or more nitrogen atoms, or The moieties of the compound are linked through a long chain of carbon atoms and include: - the ring is a substituted and unsubstituted, saturated or unsaturated ring having from 1 to about 6 carbon atoms; Alkyl groups, substituted and unsubstituted aryl groups, substituted and unsubstituted benzyl, hydroxy, halogen, carbonyl, alkoxy, nitro,
may be substituted or unsubstituted with one or more substituents selected from the group consisting of amido, amino, substituted amino, carboxylate, and combinations thereof, - the linking chain is all carbon atoms, nitrogen an atom or a nitrogen-containing chain, an oxygen atom or an oxygen-containing chain, or a selenium atom or a selenium-containing chain, the chain having one or more carbon atoms having from 1 to about 4 carbon atoms independently on the nitrogen atom and/or the carbon atom; substituted or unsubstituted, saturated or unsaturated alkyl, the nitrogen atom may also be substituted with an acyl group, - the diphosphonate-containing carbon has 1 to about 6 Substituted or unsubstituted, saturated or unsaturated alkyl, substituted or unsubstituted aryl, substituted or unsubstituted benzyl, amino, substituted amino, amido, hydroxy, having carbon atoms;
It may be substituted with alkoxy, halogen, or carboxylate, or it may be unsubstituted (provided that if the diphosphonate-containing carbon is directly bonded to a nitrogen, selenium, or oxygen atom in the linking chain, the substituents may be (a substituted or unsubstituted, saturated or unsaturated alkyl, substituted or unsubstituted aryl or substituted or unsubstituted benzyl having about 6 carbon atoms), and (b) a pharmaceutical carrier. 2. The pharmaceutical composition according to claim 1, comprising the following ingredients: (a) about 0.001 mgP to about 600 mgP having the following structure:
Gem-diphosphonic acid compound of mgP or its pharmaceutically acceptable salt or ester: ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, Z is a ring selected from the group consisting of pyridine, pyridazine, pyrimidine and pyrazine. , Q is oxygen, -
NR_4- or a single bond, m+n is 0 to about 5
R_1 is hydrogen, substituted or unsubstituted amino, amido, hydroxy, alkoxy, halogen, carboxylate, substituted or unsubstituted, saturated or unsaturated alkyl having 1 to about 6 carbon atoms, substituted or unsubstituted alkyl; Substituted aryl, or substituted or unsubstituted benzyl (where n=
When 0 and Q are oxygen or nitrogen, R_1 is hydrogen, substituted or unsubstituted, saturated or unsaturated alkyl having 1 to about 6 carbon atoms, substituted or unsubstituted aryl, or substituted or unsubstituted benzyl. ), R_2 is hydrogen, or a substituted or unsubstituted saturated or unsaturated alkyl having 1 to about 4 carbon atoms, and R_3 is hydrogen 1 to about 6
Substituted and unsubstituted, saturated or unsaturated alkyl, substituted and unsubstituted aryl, substituted and unsubstituted benzyl, hydroxy, halogen, carbonyl, having a carbon number of
one or more substituents selected from the group consisting of alkoxy, nitro, amido, amino, substituted amino, carboxylate, and combinations thereof, and R_4 is hydrogen, a substituent having from 1 to about 4 carbon atoms; or unsubstituted, saturated or unsaturated alkyl, or acyl], and (b) a pharmaceutical carrier. 3. The pharmaceutical composition according to claim 2, comprising the following components: (a) about 0.001 mgP to about 600 mgP having the following structure:
Gem-diphosphonic acid compound of mgP or its pharmaceutically acceptable salt or ester: ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, Z is a ring selected from the group consisting of pyridine, pyridazine, pyrimidine and pyrazine. , m+n is 0~
is an integer of about 5, and R_1 is hydrogen, substituted or unsubstituted amino, amido, hydroxy, alkoxy, halogen, carboxylate, substituted or unsubstituted, saturated or unsaturated alkyl having 1 to about 6 carbon atoms, substituted or unsubstituted aryl, or substituted or unsubstituted benzyl,
R_2 is oxygen or a substituted or unsubstituted saturated or unsaturated alkyl having from 1 to about 4 carbon atoms, and R_3 is hydrogen, substituted and unsubstituted having from 1 to about 6 carbon atoms;
Saturated or unsaturated alkyl, substituted and unsubstituted aryl, substituted and unsubstituted benzyl, hydroxy, halogen,
one or more substituents selected from the group consisting of carbonyl, alkoxy, nitro, amido, amino, substituted amino, carboxylate, and combinations thereof; (b) a pharmaceutical carrier. 4. The pharmaceutical composition according to claim 2, comprising the following ingredients: (a) about 0.001 mgP to about 600 mgP having the following structure:
Gem-diphosphonic acid compound of mgP or its pharmaceutically acceptable salt or ester: ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, Z is a ring selected from the group consisting of pyridine, pyridazine, pyrimidine and pyrazine. , m+n is 0~
is an integer of about 5, and R_1 is hydrogen, substituted or unsubstituted amino, amido, hydroxy, alkoxy, halogen, carboxylate, substituted or unsubstituted, saturated or unsaturated alkyl having 1 to about 6 carbon atoms, substituted or unsubstituted aryl, or substituted or unsubstituted benzyl (however,
When n=0, R_1 is hydrogen, substituted or unsubstituted, saturated or unsaturated alkyl having 1 to about 6 carbon atoms,
(substituted or unsubstituted aryl or substituted or unsubstituted benzyl), R_2 is hydrogen, or substituted or unsubstituted saturated or unsaturated alkyl having 1 to about 4 carbon atoms; R_3 is hydrogen, 1 to about 6 carbon atoms; Substituted and unsubstituted, saturated or unsaturated alkyl, substituted and unsubstituted aryl, substituted and unsubstituted benzyl, hydroxy, halogen, carbonyl, alkoxy, nitro, amido, amino, substituted amino, carboxylate, and the like, having a carbon number of one or more substituents selected from the group consisting of a combination of R_4 is hydrogen, substituted or unsubstituted, saturated or unsaturated alkyl having 1 to about 4 carbon atoms,
or acyl], and (b) a pharmaceutical carrier. 5. The pharmaceutical composition according to claim 2, comprising the following ingredients: (a) about 0.001 mgP to about 600 mgP having the following structure:
Gem-diphosphonic acid compound of mgP or its pharmaceutically acceptable salt or ester: ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, Z is a ring selected from the group consisting of pyridine, pyridazine, pyrimidine and pyrazine. , m+n is an integer from 0 to about 5, and R_1 is hydrogen, substituted or unsubstituted amino, amido, hydroxy, alkoxy, halogen, carboxylate, substituted or unsubstituted, saturated or unsaturated alkyl,
Substituted or unsubstituted aryl, or substituted or unsubstituted benzyl (however, when n=0, R_1 is hydrogen, 1
substituted or unsubstituted, saturated or unsaturated alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted benzyl having from about 6 carbon atoms, and R_2 is hydrogen or about 1 to about 4 carbon atoms. R_3 is hydrogen, substituted and unsubstituted, saturated or unsaturated alkyl having from 1 to about 6 carbon atoms, substituted and unsubstituted aryl, substituted and unsubstituted benzyl, Hydroxy, halogen, carbonyl,
and (b) a pharmaceutical carrier. 6. The pharmaceutical composition according to claim 3, wherein Z is pyridine. 7. The pharmaceutical composition according to claim 3, wherein Z is pyridine. 8. The pharmaceutical composition according to claim 4, wherein Z is pyridine. 9. The pharmaceutical composition according to claim 4, wherein Z is pyrimidine. 10. The pharmaceutical composition according to claim 5, wherein Z is pyridine. 11. The pharmaceutical composition according to claim 5, wherein Z is pyrimidine. 12. The pharmaceutical composition according to claim 3, wherein m+n=1. 13. The pharmaceutical composition according to claim 3, wherein m+n=2. 14. The pharmaceutical composition according to claim 4, wherein m+n=0. 15. The pharmaceutical composition according to claim 4, wherein m+n=1. 16. The pharmaceutical composition according to claim 5, wherein m+n=0. 17. The pharmaceutical composition according to claim 5, wherein m+n=1. 18. The pharmaceutical composition according to claim 6, wherein m+n=1. 19. The pharmaceutical composition according to claim 8, wherein m+n=0. 20. The pharmaceutical composition according to claim 9, wherein m+n=0. 21. The pharmaceutical composition of claim 3, comprising: (a) about 0.001 mgP to about 600 mgP having the following structure:
mgP gem-diphosphonic acid compound or its pharmaceutically acceptable salt or ester ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, m + n = 1 or 2, R_1 is hydrogen, chloro, amino, or hydroxy and (b) a pharmaceutical carrier. 22. The pharmaceutical composition of claim 3, comprising: (a) about 0.001 mgP to about 600 mgP having the following structure:
mgP gem-diphosphonic acid compound or its pharmaceutically acceptable salt or ester: ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, m + n = 1 or 2, R_1 is hydrogen, chloro, amino, or hydroxy, and R_3 is 1 selected from the group consisting of hydrogen, methyl, amino, chloro, methoxy, hydroxy, nitro, and combinations thereof.
or more substituents), and (b) a pharmaceutical carrier. 23. The pharmaceutical composition of claim 4, comprising: (a) about 0.001 mgP to about 600 mgP having the following structure:
mgP gem-diphosphonic acid compound or its pharmaceutically acceptable salt or ester: ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (In the formula, n = 0 or 1, R_1 is hydrogen when n = 1, chloro, amino or hydroxy, and when n=0, R_1 is hydrogen and R_3 is hydrogen, methyl, amino, chloro, methoxy, nitro, hydroxy,
and (b) a pharmaceutical carrier. 24. The pharmaceutical composition of claim 4, comprising: (a) about 0.001 mgP to about 600 mgP having the following structure:
mgP gem-diphosphonic acid compound or its pharmaceutically acceptable salt or ester: ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (In the formula, n = 0 or 1, and when n = 1, R_1 is hydrogen, Chloro, amino or hydroxy, n=0
where R_1 is hydrogen, R_3 is one or more substituents selected from the group consisting of hydrogen, methyl, amino, chloro, methoxy, nitro, hydroxy and combinations thereof, and R_4 is hydrogen, methyl, or ethyl), and (b) a pharmaceutical carrier. 25. The pharmaceutical composition of claim 5, comprising: (a) about 0.001 mgP to about 600 mgP having the structure:
mgP gem-diphosphonic acid compound or its pharmaceutically acceptable salt or ester: ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, n = 0 or 1, and when n = 1, R_1 is hydrogen, chloro , amino, or hydroxy, when n=0, R_1 is hydrogen, and R_3 is one or more substituents selected from the group consisting of hydrogen, methyl, amino, chloro, methoxy, nitro, hydroxy, and combinations thereof. ), and (b) a pharmaceutical carrier. 26. The pharmaceutical composition of claim 5, comprising: (a) about 0.001 mgP to about 600 mgP having the structure:
mgP gem-diphosphonic acid compound or its pharmaceutically acceptable salt or ester: ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (In the formula, n = 0 or 1, and when n = 1, R_1 is hydrogen, chloro, amino, or hydroxy, n=
In the case of 0, R_1 is hydrogen, R_3 is hydrogen, methyl,
and (b) a pharmaceutical carrier. 27. The pharmaceutical composition according to claim 2, comprising the following ingredients: (a) about 0.001 selected from the group consisting of the following compounds:
mgP to about 600 mgP gem-diphosphonic acid compounds or pharmaceutically acceptable salts or esters thereof: N-(2-(5-amino)-pyridyl)-aminomethalinphosphonic acid, N-(2-(5-chloro )-pyridyl)-aminomethane phosphonic acid, N-(2-(3-picolyl))-aminomethane diphosphonic acid, N-(2-(4-picolyl))-aminomethane diphosphonic acid, N-(2 -(5-picolyl))-aminomethane diphosphonic acid, N-(2-((6-picolyl))-aminomethane diphosphonic acid, N-(2-(3,4-lutidine))-aminomethane diphosphonic acid Phosphonic 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, 0-(2-(3-picolyl))-oxamethane- diphosphonic acid, and (b) a pharmaceutical carrier. 28. The pharmaceutical composition of claim 2, comprising: (a) about 0.001 mgP to about 600 mgP of N-(2
-(3-picolyl))-aminoethane diphosphonic acid or a pharmaceutically acceptable salt or ester thereof, and (b) a pharmaceutical carrier. 29. The pharmaceutical composition of claim 2 comprising: (a) about 0.001 mgP to about 600 mgP of 2-(2
-pyridyl)-ethane-1,1-diphosphonic acid, or a pharmaceutically acceptable salt or ester thereof, and (b) a pharmaceutical carrier. 30. A method for treating diseases characterized by abnormal calcium and phosphate metabolism, in which a safe and effective amount for humans in need of such treatment is provided in claim 1.
A method comprising administering a composition according to paragraph 1. 31. A method for treating diseases characterized by abnormal calcium and phosphate metabolism, in which a safe and effective amount for humans in need of such treatment is provided in claim 2.
A method comprising administering a composition according to paragraph 1. 32. A method for treating diseases characterized by abnormal calcium and phosphate metabolism, in which a safe and effective amount for humans in need of such treatment is provided in claim 3.
A method comprising administering a composition according to paragraph 1. 33. A method for treating diseases characterized by abnormal calcium and phosphate metabolism, in which a safe and effective amount for humans in need of such treatment is provided in claim 4.
A method comprising administering a composition according to paragraph 1. 34. A method for treating diseases characterized by abnormal calcium and phosphate metabolism, in which a safe and effective amount for humans in need of such treatment is provided in claim 5.
A method comprising administering a composition according to paragraph 1. 35. A method for treating diseases characterized by abnormal calcium and phosphate metabolism, in which a safe and effective amount for humans in need of such treatment is provided in claim 2.
A method comprising administering the composition according to item 1. 36. A method for treating diseases characterized by abnormal calcium and phosphate metabolism, in which a safe and effective amount for humans in need of such treatment is provided in claim 2.
A method comprising administering the composition according to item 2. 37. A method for treating diseases characterized by abnormal calcium and phosphate metabolism, in which a safe and effective amount for humans in need of such treatment is provided in claim 2.
A method comprising administering the composition according to item 3. 38. A method for treating diseases characterized by abnormal calcium and phosphate metabolism, in which a safe and effective amount for humans in need of such treatment is provided in claim 2.
5. A method comprising administering the composition according to item 4. 39. A method for treating diseases characterized by abnormal calcium and phosphate metabolism, in which a safe and effective amount for humans in need of such treatment is provided in claim 2.
A method comprising administering the composition according to item 5. 40. A method for treating diseases characterized by abnormal calcium and phosphate metabolism, in which a safe and effective amount for humans in need of such treatment is provided in claim 2.
A method comprising administering the composition according to item 6. 41. A method for treating diseases characterized by abnormal calcium and phosphate metabolism, in which a safe and effective amount for humans in need of such treatment is provided in claim 2.
8. A method comprising administering the composition according to item 7. 42. A method for treating diseases characterized by abnormal calcium and phosphate metabolism, in which a safe and effective amount for humans in need of such treatment is provided in claim 2.
A method comprising administering the composition according to item 8. 43. A method for treating diseases characterized by abnormal calcium and phosphate metabolism, in which a safe and effective amount for humans in need of such treatment is provided in claim 2.
10. A method comprising administering the composition according to item 9. 44. Osteoporosis in humans and lower animals, characterized by administering a safe and effective amount of the compound according to claim 21 to humans or lower animals suffering from or at risk of osteoporosis. methods of treatment or prevention. 45. Osteoporosis in humans and lower animals, characterized by administering a safe and effective amount of the compound according to claim 22 to humans or lower animals suffering from or at risk of osteoporosis. methods of treatment or prevention. 46. Osteoporosis in humans and lower animals, characterized by administering a safe and effective amount of the compound according to claim 23 to humans or lower animals suffering from or at risk of osteoporosis. methods of treatment or prevention. 47. Osteoporosis in humans and lower animals, characterized by administering a safe and effective amount of the compound according to claim 24 to humans or lower animals suffering from or at risk of osteoporosis. methods of treatment or prevention. 48. Osteoporosis in humans and lower animals, characterized by administering a safe and effective amount of the compound according to claim 25 to humans or lower animals suffering from or at risk of osteoporosis. methods of treatment or prevention. 49. Osteoporosis in humans and lower animals, characterized by administering a safe and effective amount of the compound according to claim 26 to humans or lower animals suffering from or at risk of osteoporosis. methods of treatment or prevention. 50. Osteoporosis in humans and lower animals, characterized by administering a safe and effective amount of the compound according to claim 27 to humans or lower animals suffering from or at risk of osteoporosis. methods of treatment or prevention. 51. Osteoporosis in humans and lower animals, characterized by administering a safe and effective amount of the compound according to claim 28 to humans or lower animals suffering from or at risk of osteoporosis. methods of treatment or prevention. 52. Osteoporosis in humans and lower animals, characterized by administering a safe and effective amount of the compound according to claim 29 to humans or lower animals suffering from or at risk of osteoporosis. methods of treatment or prevention. 53, diphosphonic acid compound having the following structure: ▲ Formula,
Chemical formulas, tables, etc. are available▼ [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 ,
substituted or unsubstituted, saturated or unsaturated alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted benzyl having 1 to about 6 carbons, and R_2 is hydrogen or substituted with 1 to about 4 carbons; or unsubstituted saturated or unsaturated alkyl, R_3 is hydrogen, substituted and unsubstituted, saturated or unsaturated alkyl having 1 to about 6 carbon atoms, substituted and unsubstituted aryl, substituted and unsubstituted benzyl, hydroxy, one or more substituents selected from the group consisting of halogen, carbonyl, alkoxy, nitro, amido, amino, substituted amino, carboxylate, and combinations thereof; R_4 is hydrogen;
substituted or unsubstituted, saturated or unsaturated alkyl or acyl having from 1 to about 4 carbon atoms], and pharmaceutically acceptable salts and esters thereof. 54, diphosphonic acid compound having the following structure: ▲ Formula,
Chemical formulas, tables, etc. are available▼ [In the formula, Z is a ring selected from the group consisting of pyridine, pyridazine, pyrimidine, and pyrazine, n is an integer from 1 to about 5, and R_2 is hydrogen, or substituted or unsubstituted, saturated or unsaturated alkyl having 4 carbon atoms, and R_3 is hydrogen, substituted and unsubstituted saturated or unsaturated alkyl having 1 to about 6 carbon atoms;
with one or more substituents selected from the group consisting of substituted and unsubstituted aryl, substituted and unsubstituted benzyl, hydroxy, halogen, carbonyl, alkoxy, nitro, amido, amino, substituted amino, carboxylate, and combinations thereof. ), and pharmaceutically acceptable salts and esters thereof. 55. The diphosphonic acid compound according to claim 54, wherein n=1. 56. The diphosphonic acid compound according to claim 55, wherein 56,2 is pyridine.