JP2798666B2 - Diphosphonic acid compounds - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [0001] BACKGROUND OF THE INVENTION 1. Field of the Invention
Diseases characterized by phosphate metabolism, especially abnormal bone
Important for treating or preventing diseases characterized by metabolism
Wherein the compound is [0002] [Prior art and problems to be solved]Background of the Invention Many pathological conditions that can affect warm-blooded animals are abnormal calcium
Includes metabolism and phosphate metabolism. There are two such situations
Can be divided into broad categories. [0003] 1. General or special bones in body fluids
Loss or excessively high calcium and phosphate concentrations
Unusual calcium and phosphate mobilization
The condition characterized. Such a condition is a disease in the present invention.
Sometimes called physical hard tissue demineralization. [0004] 2. Abnormal calcium and phosphes in the body
A condition that causes or results in the deposition of a gate. this
These conditions are called pathological calcifications in the present invention.
May be lost. [0005] The first category is the disproportionate loss of hard bone tissue
Osteoporo is a state where new hard tissue develops
Osteoporosis. Bone marrow and bone space
The bones become weaker and tighter and less tight. Oh
Steoporosis may be menopausal, aging, drugs
Induced (eg, as occurs in steroid therapy)
Adrenocorticoids), disease-induced (eg, arthritis and
Tumors), etc., but their manifestations
Are substantially the same. Another one in the first category
The condition is Paget's disease (osteoarthritis). This disease
In normal bone lysis occurs, which then
Especially soft and poorly mineralized tissue
Deform from weight-bearing pressure in the tibia and femur
Become so. Hyperparathyroidism, malignant hypercalcemia
Diseases and osteolytic bone metastases are also included in the first category.
State. Unusual calcium and phosphate precipitation
The second category, which includes conditions expressed by dressing, is progressive ossification
Myositis, generalized calcification and arthritis, neuritis, bursa
Calcium phosphate to remove inflammation, tendinitis and other affected tissues
Includes symptoms such as inflammatory conditions that make it easier for the system to deposit. Use for the treatment and prevention of such conditions
Polyphosphonic acids and their pharmaceutically acceptable
Salt has been proposed. Especially ethane-1-hydroxy-
1,1-diphosphonic acid (EHDP), propane-3-a
Mino-1-hydroxy-1,1-diphosphonic acid (AP
D), and dichloromethane diphosphonic acid (Cl₂MD
Diphosphonates such as P) have considerable
Was the subject of research effort. Paget's disease and ectopic
Ossification is now successfully treated by EHDP. This
These diphosphonates are useful for patients suffering from excessive bone loss
Shows a tendency to suppress beneficial bone tissue resorption. However
While EHDP, APD and many other conventional techniques
Surgical diphosphonates when administered at high dose rates
It has a tendency to suppress mineralization of bone. [0008] Mineralization control is mainly mass-related physics
Is a biological effect, whereas absorption suppression is a biological
It seems to be caused by the interaction. Therefore, almost
Or a low dose that does not cause any mineralization inhibition
To obtain a wider safety margin
A more biologically powerful diphosphonate compound
It is desirable to develop. Lower doses may also
The gastrointestinal tract that sometimes accompanies oral administration of phosphonates
It is also desirable to avoid discomfort (such as diarrhea). [0009] Therefore, the object of the present invention is to provide an abnormal calcium and
Strength for the treatment and prevention of phosphate and phosphate metabolism
Is to provide a compound of the formula: US Pat. No. 3,683,080 describes
Compositions comprising polyphosphonates, especially diphosphonates
Of calcium phosphate in foods and their animal tissues
Discloses applications to control abnormal deposition and mobilization
You. Japanese Patent Application Laid-Open No. 55-98193 discloses
Zirethane diphosphonic acid, S- (pyridyl) -thiometa
Diphosphonic acid and halogen on the pyridyl ring or
A derivative with alkyl group substitution is disclosed. these
The compounds have been used as post-emergent herbicides. Japanese Patent Application Laid-Open No. 55-98105 discloses weed killing.
-(3-Pyrrolidyl) -aminoethane for use as an agent
Diphosphonic acid and halogen or amino on the pyridyl ring
Disclosed are derivatives by alkyl group substitution. Various N-
(Pyridyl) -aminomethane diphosphonates are west again
German Patent 2,831,578 for herbicides
It is shown. [0013] European Patent Application No. 100,718
(Published February 15, 1984) is a 5- or 6-membered ring
Sulfides linked to nitrogen- or sulfur-containing heterocycles
Various alkyl diphosphonates substituted by
Disclose. These compounds are anti-inflammatory and anti-leu
Used as a gusset drug. British Patent Application 2,004,888 (19
(Published April 11, 1979) provides N- (3-) for herbicide compositions.
Methyl-2-picolyl) -aminoethane and related compounds
Disclose things. Progar et al. [W. Prologer et al., Z. Anorg.
 Allg. Chem., 389, 119 (1972)] is N- (4-pyridyl).
Disclosed is the synthesis of l) -aminoethanediphosphonic acid. This
No properties or uses of the compound are disclosed. [0016] [Means for Solving the Problems]Summary of the Invention The present invention relates to a diphosphonic acid compound having the following structure:
RU: [0017] Embedded image Wherein Z is pyridine, pyridazine, pyrimidine and
A ring selected from the group consisting of pyrazines,₁Is water
Unsubstituted or substituted or unsubstituted amino, amide, hydroxy, a
Lucoxy, halogen, carboxylate, 1-6 charcoal
Substituted or unsubstituted, saturated or unsaturated hydrocarbons having sulfur
Strand, substituted or unsubstituted aryl, or substituted or unsubstituted
A substituted benzyl, R₂Is hydrogen or 1 to 4 carbons
Substituted or unsubstituted, saturated or unsaturated hydrocarbon having a number
A strand, R₃Is hydrogen, a unit having 1 to 6 carbon atoms
Substituted and unsubstituted, saturated or unsaturated hydrocarbon chains, substituted and unsubstituted
And unsubstituted aryl, substituted and unsubstituted benzyl, hydr
Roxy, halogen, carbonyl, alkoxy, nitro,
Amides, amino, substituted amino, carboxylate, and
One or more selected from the group consisting of
Or more substituents, R₄Is hydrogen, 1-4 carbon atoms
Substituted or unsubstituted, saturated or unsaturated hydrocarbon having
Chain or acyl], and pharmaceutically acceptable
Salts and esters.Detailed description of the invention The present invention comprises a pharmaceutical carrier and a safe and effective amount of a diphosphonic acid.
Six-membered carbohydrate containing one or more nitrogen atoms
Gem-diphosphonic acid compound linked to an aromatic ring or
Contains their pharmaceutically acceptable salts and esters
Preferably used in a pharmaceutical composition in unit dosage form
Related to the compound. Preferred rings are pyridine, pyridazi
, Pyrimidines, and pyrazines. Most preferred
Is a pyrimidine, especially pyridine. These rings are 1 to
Substituted and unsubstituted alkyl having about 6 carbon atoms, etc.
Hydrocarbon chains (saturated or unsaturated), substituted and unsubstituted
Aryl (eg, phenyl and naphthyl), substituted and
Unsubstituted benzyl, hydroxy, halogen, carbonyl
(E.g., -CHO and -COCH₃), Alkoxy
(Eg, methoxy and ethoxy), nitro, amide
(Eg, -NHCOCH₃), Amino, substituted amino (eg,
Dimethylamino, methylamino, and diethylamino
G), carboxylate (eg, -OCOCH)₃), And
Or one selected from the group consisting of
It is substituted or unsubstituted with the above substituents. This
These rings may be fused with other rings, for example with benzene
Pyridine (eg, quinoline), and cyclohexane
Lysine (eg, 5,6,7,8-tetrahydroquinoline)
And condensed rings. Other substituents include
Substituted or unsubstituted sulfide, sulfoxide, sulphate
Or sulfone. The bond from the diphosphonic acid-containing carbon to the ring is a single bond.
A chain of 1 to about 5 carbons in length, directly or through one bond
May be used. The chains are all carbon atoms, nitrogen
Elemental or nitrogen-containing chains, oxygen atoms or oxygen-containing chains
May be. The carbon and nitrogen atoms in these chains are
Independently one (or one or two in the case of carbon atom)
Substituted or unsubstituted having from 1 to about 4 carbon atoms
Hydrocarbon chains such as alkyl (saturated or unsaturated) (methyl
And ethyl are preferred) or substituted
It may be. Nitrogen atoms in the chain may also be acyl groups (eg,
-COCH₃) May be substituted. Unsubstituted in the chain
Carbon and nitrogen atoms are preferred. In addition, the length of one atom
Chain or -CH₂-, -NH-, and -O- are also preferred.
No. Carbon atom having a phosphonate group bonded thereto
Is unsubstituted (eg, hydrogen atom) or amino, substituted amino,
Amide, hydroxy, alkoxy, halogen, carbox
Silates, substituted or unsubstituted having 1 to about 6 carbon atoms
Substituted with substituted aryl or substituted or unsubstituted benzyl
It may be. The phosphonate-containing carbon has oxygen in the ring,
Or linked through a nitrogen-containing chain to
Where the carbon atom is directly bonded to the phosphonate-containing carbon
For the compound, the substituent on the phosphonate-containing carbon is 1-
Substituted or unsubstituted alkyl having about 6 carbon atoms
Hydrocarbon chains (saturated or unsaturated), substituted or unsubstituted
Reel or substituted or unsubstituted benzyl. As described above, the phosphonic acid compound of the present invention is as follows:
Has the structural formula: [0021] Embedded image [Q is oxygen, -NR₄-Or a single bond, preferably
Oxygen, -NR₄-Or a single bond, and m + n is 0
Q is oxygen, or -NR₄For-
m + n = 0 or 1 is preferable, and in other cases, m + n
n = 1 or 2 is preferred, and Z is pyridine, pyridazi
Selected from the group consisting of pyridine, pyrimidine, and pyrazine
Pyrimidines, and especially pyridine
K; R₁Is hydrogen, substituted or unsubstituted amino, amide,
Droxy, alkoxy, halogen, carboxylate,
Substituted or unsubstituted alkyl having 1 to about 6 carbons, etc.
Hydrocarbon chains (saturated or unsaturated), substituted or unsubstituted
Aryl or substituted or unsubstituted benzyl, where n
= 0 and Q are oxygen, or -NR₄If-
R₁Is hydrogen, substituted with 1 to about 6 carbon atoms, or
Hydrocarbon chains (saturated or unsaturated) such as unsubstituted alkyls,
Substituted or unsubstituted aryl, or substituted or unsubstituted aryl
ジ ル, R₁Hydrogen, chloro, a
Mino, methyl or hydroxy is preferred;₂Is German
Hydrogen or substituted or substituted with 1 to about 4 carbon atoms
Is a hydrocarbon chain such as unsubstituted alkyl (saturated or unsaturated)
And R₂Is preferably hydrogen; R₃Is hydrogen, 1
Substituted or unsubstituted alkyl having up to about 6 carbon atoms, etc.
Hydrocarbon chains (saturated or unsaturated), substituted and unsubstituted
Aryl, substituted and unsubstituted benzyl, hydroxy, ha
Logen, carbonyl, alkoxy, nitro, amide, a
Mino, substituted amino, carboxylate and their combination
One or more substituents selected from the group consisting of
And preferably hydrogen, methyl, amino, chloro,
Toxic, nitro, hydroxy or combinations thereof
R;₄Is a substituent having 1 to about 4 carbon atoms of hydrogen or
Hydrocarbon chains (saturated or unsaturated) such as unsubstituted alkyls,
Alternatively, it is an acyl (ie, an amide of a nitrogen), preferably
Hydrogen, methyl or ethyl], and compounds thereof
Pharmaceutically acceptable salts and esters of the compound.
Finally, R which is itself substituted₁, R₂, R₃Or some
Iha R₄For any of the substituents,
Is any one or more of the above substituents
And preferably methyl, ethyl, amino,
B, nitro, methoxy, hydroxy, acetamide and
And acetate. More specifically, it can be used in pharmaceutical compositions.
The diphosphonic acid compounds of the present invention and their pharmaceutically acceptable
Acceptable salts and esters are of the following structure: [0023] Embedded image (Where m + n, Z, R₁, R₂, R₃, And R₄Is
Is synonymous with the above). Generally preferred for use in pharmaceutical compositions
Diphosphonic acid compounds of the present invention and their pharmaceutically
Acceptable salts and esters are of the following structure: [0025] Embedded image (For both structures, m + n = 1 or 2 in the above formula,
R₁Is hydrogen, chloro, amino, or hydroxy
R₃Is hydrogen, methyl, amino, chloro, nitro,
The group consisting of toxic, hydroxy and their combinations
Or one or more substituents selected from [0026] Embedded image (Wherein n = 0 or 1 in the above four structural formulas; R₁Is n
= 1, hydrogen, chloro, amino, or hydroxy
And if n = 0, R₁Is hydrogen; R₃Is
Hydrogen, methyl, amino, chloro, methoxy, nitro, ar
Selected from the group consisting of droxy, and combinations thereof.
One or more substituents; and R₄Is hydrogen,
Methyl or ethyl). [0027] It can be used in pharmaceutical compositions.
Specific examples of the compound of the present invention include the following compounds.
Yes: N- (2-pyridyl) -aminomethanediphosphone
Acid; N- (2- (5-amino) -pyridyl) -aminometh
Tandiphosphonic acid; N- (2- (5-chloro) -pyridi
) -Aminomethanediphosphonic acid; N- (2- (5-d
Toro) -pyridyl) -aminomethanediphosphonic acid; N-
(2- (3,5-dichloro) -pyridyl) -aminometh
Diphosphonic acid; N- (4-pyridyl) -N-ethyl-
Aminomethane diphosphonic acid; N- (2- (3-picoline)
))-Aminomethanediphosphonic acid; N- (2- (4-
Picolyl))-aminomethanediphosphonic acid; N- (2-
(5-picolyl))-aminomethanediphosphonic acid; N-
(2- (6-picolyl))-aminomethanediphosphone
Acid; N- (2- (3,4-lutidine))-aminomethane
Diphosphonic acid; N- (2- (4,6-lutidine))-A
Minomethane diphosphonic acid; N- (2-pyrimidyl) -a
Minomethane diphosphonic acid; N- (4- (2,6-dimethyl
Ru) -pyrimidyl) -aminomethanediphosphonic acid; N-
(2- (4,6-dihydroxy) -pyrimidyl) -ami
Nomethanediphosphonic acid; N- (2- (5-methoxy)-
Pyridyl) -aminomethanediphosphonic acid; N- (2-pi
Lysyl) -2-aminoethane-1,1-diphosphonic acid;
N- (2- (3-picolyl))-2-aminoethane-
1,1-diphosphonic acid; N- (3-pyridyl) -2-a
Mino-1-chloroethane-1,1-diphosphonic acid; N-
(2- (4-picolyl))-2-amino-1-hydroxy
Cyethane-1,1-diphosphonic acid; (2-pyridyl)
-Methanediphosphonic acid; (3-pyridyl) -aminometh
Diphosphonic acid; (2-pyridyl) -chloromethanedipho
Sulfonic acid; (4-pyridyl) -hydroxymethanediphos
Honic acid; 2- (2-pyridyl) -ethane-1,1-dipho
Sulfonic acid; 2- (3-pyridyl) -ethane-1,1-di
Phosphonic acid; 2- (4-pyridyl) -ethane-1,1-
Diphosphonic acid; 2- (2-pyridyl) -1-amino-e
Tan-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-diho
Sulfonic acid; 2- (2-pyridyl) -1-hydroxy-e
Tan-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-pyridi
Ru) -2-oxa-ethane-1,1-diphosphonic acid; O
-(2-pyridyl) -oxamethanediphosphonic acid; O-
(2-pyrimidyl) -oxamethanediphosphonic acid; O-
(2- (4-amino) -pyridyl) -oxamethandipho
Sulfonic acid; O- (2- (pyrimidyl) -2-oxa-e
Tan-1,1-diphosphonic acid; O- (2- (3-picoline)
Ru))-2-oxa-ethane-1,1-diphosphonic acid;
O- (2- (3-picolyl))-oxamethane-diphos
Fonic 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 its pharmaceutically acceptable salts and
And esters. Preferred compounds include N- (2- (5
-Amino) -pyridyl) -aminomethanediphosphonic acid;
N- (2- (5-chloro) -pyridyl) -aminomethane
Diphosphonic acid; N- (2- (3-picolyl))-amino
Methanediphosphonic acid; N- (2- (4-picolyl))-
Aminomethane diphosphonic acid; N- (2- (5-picoline)
))-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-di
Phosphonic 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-hydro
Xy-ethane-1,1-diphosphonic acid; 2- (3-pyri
(Jill) -1-hydroxy-ethane-1,1-diphosphone
Acid; 2- (4-pyridyl) -1-hydroxy-ethane-
1,1-diphosphonic acid; O- (2- (3-picolyl))
-Oxamethane-diphosphonic acid; or its pharmaceutically acceptable
Acceptable salts or esters. The diphospho of the present invention contained in a pharmaceutical composition
Nate compounds are disclosed 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)).
It can be made using the synthesis methods shown
The contents shown apply mutatis mutandis in the present invention. However,
Noethanediphosphonic acid compounds are prepared as follows:
Is the best.Synthesis of N- (2- (3-picolyl)) aminoethane DP The above compound is tetraethylvinyl diphosphonate and 2-
Typical Michael anti-amino-3-picoline
[H. O. House (H.O.House),
Modern Synthetic Reactoin 2nd edition, W.A.Benjamin,
p. See 595-623. The disclosure of this document is based on the present invention.
Applied mutatis mutandis]. 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) of tetraethylvinyl diphosphonate
Was added. The reaction mixture was stirred at room temperature for 16 hours. Dissolution
The solvent is distilled off and the product is chromatographed on silica gel.
(Acetone / hexane, 4/1)
Ethyl N- (2- (3-picolyl))-2-aminoeta
The diphosphonate was obtained. This pure tetraethyles
Tell CDCl₃P-31 NMR in the medium was 22.1
The resonance is shown in ppm. This ester in 6N HCl
The mixture was refluxed for 24 hours to hydrolyze. This product is D
₂19.0 ppm P-31N at pH = 12 in O
An MR signal was indicated. N- (2-pyridyl) -2-aminoethane
DP and N- (2- (5-picolyl))-2-amino
Ethane DP was prepared similarly. A compound having the following general formula: [0033] Embedded image Wherein n is an integer from 1 to about 5, preferably n = 1
And Z, R₂And R₃Has the same meaning as above,
Preferred Z is pyrimidine and especially pyridine,
New R₂Is hydrogen, and preferred R₃Is hydrogen, methyl,
Amino, chloro, nitro, methoxy, hydroxy, and
Or one selected from the group consisting of
The above substituents) Is best prepared as follows:2- (2-pyridyl) -1-hydroxy monoethane-1,
Synthesis of 1-diphosphonic acid Three-necked round bottom hula with reflux condenser and magnetic stir bar
6.94 g (0.04 mol) of 2-pyridine vinegar
Acid, 9.84 g (0.14 mol) phosphoric acid, and 15
0 ml of chlorobenzene was charged. The reaction mixture is boiled.
16.5 g (0.12 mol) of trisalt
The phosphorus hydride was added dropwise with stirring. The reaction mixture is
/ 2 hours, during which a viscous yellow oil is formed
Was. The reaction mixture was then cooled in an ice bath and chlorobenzene
The solution was decanted from the solidified product. This solidification
Put 150 ml of water into the reaction flask containing the product,
Heated for several hours in a boiling water bath. Hot solution then
Celite 545^RAnd filtered through. 300ml
Methanol was added to the warm filtered solution and a precipitate formed.
Occurred. After cooling for 1 hour in ice, the precipitate was filtered off and
Knol / water (1/1 v / v), methanol, and ethanol
Wash with tel and air dry. This product is recrystallized from hot water
May be. The yield was about 5.9 g (52%).
This sample was characterized by P-31 and C-13 NMR
did. As used in the present invention, "pharmaceutically acceptable
"Salts and esters" refer to the acid form from which they are derived.
Have the same general pharmacological properties and from a toxicity point of view
Hydrolysable diphosphonate compounds that are acceptable
Means salts and esters. With pharmaceutically acceptable salts
Alkali metals (sodium and potassium)
Lucari earth metals (calcium and magnesium), non
Toxic heavy metals (tin and indium), and ammonium
And low molecular weight substituted ammonium (mono-, di-,
And triethanolamine). Like
New compounds are sodium, potassium, and ammonium
Salt. The "drug" which can be used as a compound in the present invention
"Chemical carrier" means one or more compatible solid or liquid fillers
Diluent or encapsulated material. In the present invention
"Compatibility" refers to the conditions under which the components of the composition are used
Substantially reduce the pharmaceutical efficiency of the entire composition under
Can be mixed without any interaction
Means to come. Some of the substances that can serve as pharmaceutical carriers
Some specific examples include lactose, glucose and
Sugars such as sucrose; corn starch and potatoes
Starch such as tart; examples of cellulose and its derivatives
For example, sodium carboxymethyl cellulose, ethyl acetate
Lulose, cellulose acetate, etc .; powdered tragaca
Malt; gelatin, talc; stearic acid; stear
Magnesium phosphate; calcium sulfate; vegetable oils such as pi
-Nut oil, cottonseed oil, sesame oil, olive oil, corn
Oil and theobroma oil; polyols such as propylene
Len glycol, glycerin, sorbitol, mannitol
And polyethylene glycol; agar; algin
Acid; pyrogen-free water; isotonic saline; and phosphate buffered solution
Liquids, as well as non-
There are toxic compatible substances. Wetting agent and sodium lauryl sulfate
Lubricants such as thorium, coloring agents, flavoring agents, lubricants, and shapes
Tablets, tablets, stabilizers, antioxidants and preservatives.
Could exist. Other compatible pharmaceutical excipients
And active substances (eg, vitamin D or vitamin D metabolism)
And mineral supplements) are also pharmaceutical compositions of the present invention.
Can be included in adult products. Used in combination with the diphosphonates of the present invention
The choice of pharmaceutical carrier to be used is basically
Determined by the method provided. Where compounds are injected
If so, the preferred pharmaceutical carrier has its pH adjusted to about 7.4
Sterile saline solution. However, the present invention
The preferred mode of administration of the diphosphonates is oral
Thus, the preferred unit dosage form is therefore from about 0.1 mgP to about
600 mg P of the diphosphonic acid compound described in the present invention
Tablets, capsules and the like. Oral dosage unit
Pharmaceutical carriers suitable for the manufacture of dosage forms are known. It
Their choice is not important for the purposes of the present invention.
Considerations such as taste, cost, storage stability, etc.
It can be performed without difficulty by those skilled in the art. Of the present invention
Pharmaceutical carriers used with diphosphonates are
Used at a concentration sufficient to give a practical
Can be Preferably, the pharmaceutical carrier comprises about 0.0% of the total composition.
From about 1 to about 99.99% by weight. [0038] 【Example】Example I Prepare capsules containing the following ingredients in the usual manner:Component mg / capsule       N- (2- (3-picolyl)) AMDP 100 (as mgP)       Starch 55.60       Sodium lauryl sulfate 2.90 The above capsule is orally administered twice daily for 6 months
Approximately 70 kg of body weight with osteoporosis
Bone resorption is substantially reduced in these patients. Capse above
N- (2- (3-picolyl))-aminomethyl
Tandiphosphonic acid or its pharmaceutically acceptable salt or
The same applies when the following compound is used in place of the ester
The result is: N- (2- (5-amino) -pyridi
) -Aminomethanediphosphonic acid; N- (2- (5-
(Rolo) -pyridyl) -aminomethanediphosphonic acid; N-
(2- (4-picolyl))-aminomethanediphosphone
Acid; N- (2- (5-picolyl))-aminomethanedipho
Sulfonic acid; N- (2- (6-picolyl))-aminometh
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-pi
Lysyl) -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-pyridi
Ru) -1-Hydroxy-ethane-1,1-diphosphone
Acid; O- (2- (3-picolyl) -oxamethane-dipho
Sulfonic acid; or a pharmaceutically acceptable salt or S thereof
Tell.Example II A tablet having the following composition is prepared in a conventional manner:Component mg / tablet       N- (2-pyrimidyl) AMDP 25.00       Lactose 40.00       Starch 2.50       Magnesium stearate 1.00 The tablet is orally administered twice daily for 6 months
And about 70 kg of body weight with osteoporosis
Bone resorption in the patient is substantially reduced. The above tablets
N- (2-pyrimidyl) AMDP or its pharmaceutical
Use the following compounds in place of the acceptable salts or esters
The same result is obtained when N- (2- (5-
Amino) -pyridyl) -aminomethanediphosphonic acid; N
-(2- (5-chloro) -pyridyl) -aminomethanedi
Phosphonic acid; N- (2- (3-picolyl))-amino
Tandiphosphonic acid; N- (2- (4-picolyl))-a
Minomethane diphosphonic acid; N- (2- (5-picoline)
))-Aminomethanediphosphonic acid; N- (2- (6-
Picolyl))-aminomethanediphosphonic acid; N- (2-
(3,4-lutidine))-aminomethane diphosphonic acid;
N- (2-pyridyl) -2-aminoethane-1,1-di
Phosphonic 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-hydro
Xy-ethane-1,1-diphosphonic acid; 2- (3-pyri
(Jill) -1-hydroxy-ethane-1,1-diphosphone
Acid; 2- (4-pyridyl) -1-hydroxy-ethane-
1,1-diphosphonic acid; o- (2- (3-picolyl)-
Oxamethane-diphosphonic acid; or its pharmaceutically acceptable
Possible salts or esters.Example III 1.0 ml of either saline or aqueous solution and
3.5 mg of 2- (2-pyridyl) -ethane-1,1-
Injectable solution adjusted to pH 7.4 using diphosphonic acid
A liquid is prepared by a conventional method. One injection every day for 4 days gives about 70k
Malignant hypercalcemia in patients with a body weight of g
Is considerably reduced. In the above treatment, 2- (2-pyridi
R) -Ethane-1,1-diphosphonic acid
Similar results are obtained with the compound: N- (2-
(5-amino) -pyridyl) -aminomethanediphosphone
Acid; N- (2- (5-chloro) -pyridyl) -amino
Tandiphosphonic acid; N- (2- (3-picolyl))-a
Minomethane diphosphonic acid; N- (2- (4-picoline)
))-Aminomethanediphosphonic acid; N- (2- (5-
Picolyl))-aminomethanediphosphonic acid; N- (2-
(6-picolyl))-aminomethanediphosphonic acid; N-
(2- (3,4-lutidine))-aminomethane diphospho
Acid; N- (2-pyrimidyl) -aminomethane diphospho
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-diho
Sulfonic acid; 2- (4-pyridyl) -1-hydroxy-e
Tan-1,1-diphosphonic acid; o- (2- (3-picoline)
L) -oxamethane-diphosphonic acid; or its pharmaceutical
Acceptable salts or esters. The composition of the present invention contains abnormal calcium and e.
Useful for the treatment of sulfate metabolism. Other diphospho
Acid and their pharmaceutically acceptable salts are such diseases
Has been proposed for the treatment and prevention of conditions. In particular, d
Tan-1-hydroxy-1,1-diphosphonic acid (EHD
P), propane-3-amino-1-hydroxy-1,1
-Diphosphonic acid (APD) and dichloromethane dipho
Sulfonic acid (Cl₂MDP) has significant research in this area.
It was the subject of ultimate effort. However, the composition of the present invention generally comprises
Bone resorption more than diphosphonates disclosed in the prior art
Biologically more potent in suppression. That is, the present invention
Is based on the diphosphonates disclosed in the prior art.
Provide one or more of the following advantages: (1) bone resorption
(2) Mineralization (ml
neralization) suppression is primarily mass-related physics
Of bone mineralization because it is considered to be a biological effect
(3) generally less potential
A wider safety margin (ie, a minimum effective anti-absorption dose
Broader doses between the lowest dose that results in reduced mineralization
(Dose interval), to allow lower oral doses than (4)
Sometimes associated with higher doses of diphosphonates
Avoid gastrointestinal discomfort (such as diarrhea), and
(5) Have potential for flexibility of administration method
When. Another aspect of the present invention relates to abnormal calcium
And diseases particularly characterized by phosphate metabolism
Disorders characterized by abnormal bone metabolism
Treatment or prevention in at-risk humans
Therefore, humans in need of such treatment can safely and safely use the present invention.
Administering one effective amount of the diphosphonic acid-containing composition.
It is a method to take. The preferred mode of administration is oral, but
However, other modes of administration include transdermal, mucosal, and tongue
Subcutaneous, intramuscular, intravenous, intraperitoneal and subcutaneous and topical
Application, but not limited to
No. The "abnormal calsium" used in the present invention
And phosphate metabolism "means (1) general or
Special bone loss, i.e. abnormally high calci in body fluids
Calcium and phosphate, leading to calcium and phosphate concentrations
Specially due to abnormal mobilization of phosphate
The pathophysiology that is marked, and (2) abnormal calcium in the body
Cause and / or deposits of phosphate and phosphate
Means the resulting pathology. The first category is osteoporosis
Disease, Paget's disease, hyperparathyroidism, malignant high calcium
And osteolytic bone metastases.
It is not limited to these. The second category is progressive ossification
Myositis, generalized calcification, and arthritis, neuritis, bursa
Inflammation, tendinitis, and other affected tissues
And other inflammatory conditions that can make it easier to deposit
However, the present invention is not limited to these. As used in the present invention, "dangerous
"Human" or "Human in need of such treatment"
If left untreated, abnormal calcium and phosphate
Any human or lower level with substantial risk of metabolism
For animals, and abnormal calcium and phosphate metabolism
Any human or lower animal diagnosed as affected
means. For example, postmenopausal women, certain steroids
Human being treated, taking certain antispasmodics
Human, Paget's disease, hyperparathyroidism, malignant hypercalcium
Diagnosed as having shimemia or osteolytic bone metastasis
Human, one or more different forms of osteoporosis
Osteoporosis develops when diagnosed as suffering
Have significantly higher opportunities than the average
People belonging to known population groups, such as post-menopausal women
Sex, men over 65, and osteoporosis
Treated with drugs known to cause side effects
People suffering from progressive gastrifying myositis or generalized calcosis
People diagnosed with, and arthritis, neuritis, bursa
Deposits of calcium phosphate on inflammation, tendinitis and other affected tissues
People suffering from inflammatory conditions that make them easier to wear
Is mentioned. The "osteoporosis" used in the present invention
People or low-grade animals affected or at risk of
Is one or more of the various forms of osteoporosis
Patients diagnosed as having trouble or developing osteoporosis
Have significantly greater opportunities than the average opportunity
Patients belonging to a group of known, for example, postmenopausal women,
Side effects for men over 65 and osteoporosis
Drugs known to cause (eg, adreno
Corticoid) and the like. "Safe and effective amount" used in the present invention
Is treated within the scope of sound medical judgment
High enough to significantly and positively alter the condition
However, it is low enough to avoid serious side effects (reasonable benefits).
(Benefit / risk ratio) means the amount of the compound or composition.
The safe and effective amount of diphosphonates is
Condition, age and physical condition of the patient being treated,
Weight, duration of treatment, nature of concurrent treatment, and used
Depends on the particular type of diphosphonate. But
Thus, a single dose may range from about 0.001 mgP to about 3500 mg
P, ie 0.1 μgP / kg body weight to about 500 mgP / body
Weight can be in the range of kg. 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 per day
Can be administered. More than about 2000mgP / kg
A high daily dose is required to achieve the desired effect
And may have undesirable side effects. Of course,
In the case of oral administration, this range may be due to limited absorption.
Higher doses are required. [0048]Schenk Model Evaluation of compounds in the field of bone metabolism
Vivo bone resorption in known animal model systems
The yield control and the mineralization control were performed. This model
The general principle of the 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 these disclosures are
It applies mutatis mutandis in the invention. [0049]Materials and methods animal Male Sprague Dawley 17 days old (30 g) before weaning
Rat (Charles River Breeding Laboratories) with mother
With the mother at the time of arrival.
I put it in a basket. On day 21 of birth, rats were fed and watered.
Freely receive rat pups randomly consisting of 5 animals
Although assigned to treatment groups, control animals received saline and received 1 per group
It consisted of 0 rats. On day 0 and again on day 1
0.9% Na to label the skeleton on all animals
Subcutaneous injection of Calcein (Sigma) as a 1% solution in Cl solution
Gave. [0050]Dosing solution and dosing procedure All solutions are injected subcutaneously in 0.9% normal saline
Prepared as a liquid, using NaOH and / or HCl
PH was adjusted to 7.4. Dosing solution calculation is mgP / k
Active substance powder in mg / kg (body weight) corresponding to g
The amount was determined in consideration of the amount of the powder (molecular weight basis, hydration). The concentration is
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. 0.1mgP / kg / day
At 0.001 mg P /
Tested with log reduction to kg / day. Change in weight
Adjustment of the dose based on conversion was performed daily. [0051]Necropsy, tissue processing and histomorphometry On day 8 after the start of administration, all animals were₂Killed by suffocation
Was. Dissect the tibia and place in 70% ethyl alcohol
Was. Dehydrate one tibia in graded ethanol
Boyce et al., Lab.Investig., 48, 683
-689 (1983)-This disclosure applies mutatis mutandis to the present invention.)
Methyl methacrylate using the rapid procedure described by
Embedded in the This tibia extends longitudinally through the bone unlined area
(Leitz^RSaw microtome 150
μ). One side of the specimen is stained with silver nitrate and placed on a microscope slide.
Quantimet Image Analyzer (Cambridge Instru
ments, Inc.) using both incandescent and ultraviolet lighting
did. Trabecular bone content of epiphyseal line between fluorescent label and growth plate
Measured in area and expressed as% of total area (bone + bone marrow)
I was told. Epiphyseal growth plate width is 10 equals across section
Obtained as the average of interval measurements. The statistical evaluation of the data was
Of variation to determine statistically significant effects
Parameter and nonparametric analysis, and Wilcoxons
The test was performed using a total sum test. This Schenk model is based on in vivo
o Data were given for bone resorption inhibition. Schenkmode
For the representative compound tested as determined by the
Low effective (anti-absorption) doses ("LEDs") are listed in Table I
You. [0054]Table I Lowest effective (anti-absorption) dosage                                                         Schenk         Diphosphonate compounds LED (mg P / kg)     EHDP 1.0     Cl₂MDP 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     Cl₂MDP = dichloromethane DP     APD = 3-aminopropane-1-hydroxy-1,1-DP     AMDP = aminoethanediphosphonic acid with ring attached to amine     * = Compound included in the pharmaceutical composition of the present invention     EDP = ethane-1,1-diphosphonic acid having a ring bonded to position 2 of ethane     Propyl DP = propane-2,2-diphosphonic acid Matrix formation continues, but mineralization is impeded
Diphosphone which is harmful and has a bone mineralization inhibitory effect
The compound causes the epiphyseal growth plate to spread. Schenkmode
The spread of the epiphyseal growth plate seen in the
Of the effect of diphosphonate compounds on mineralization
It is cheap. Statistical significance for tested compounds
Table II shows the minimum test dose that results in the spread of the epiphyseal growth plate
Shown in [0056]Table II Mineralization control (Schenk model)                                                 Statistically significant epiphyses                                                 Brings the spread of the long plate         Diphosphonate compounds Minimum test dose (mgP / kg)     EHDP 10     APD 10     Cl₂MDP-     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⁾     -= No plate spreading observed at highest test dose (unless otherwise noted)         The highest test dose is 10 mgP / kg / day)     1) = The highest dose evaluated is 1 mg P / kg / day (10 mg compound         It is fatally toxic at P / kg / day)     EHDP = ethane-1-hydroxy-1,1-DP     APD = 3-aminopropane-1-hydroxy-1,1-DP     Cl₂MDP = dichloromethane DP     AMDP = Aminomethanediphosphonic acid with ring bound to amine     EDP = ethane-1,1-diphosphonic acid having a ring bonded to the 2-position of ethane     * = Compound included in the pharmaceutical composition of the present inventionThyroid parathyroidectomy (TPTX) rat model Evaluation of Compounds in Thyroid Parathyroidectomy (TPTX) Rats
In vivo with animal model systems known as models
Was evaluated for bone resorption inhibition strength. One of this model system
The general principle is that of Russell et al. (Russell et al., Calcif.
 Research, 6,183-196 (1970)], and Murbauba
And Fleisch (Muhlbauer and Fleisch, Mineral
 Electrolyte Metab., 5, 296-303 (1981)]
These disclosures are applied mutatis mutandis in the present invention.
You. The basic biochemical concept of the TPTX system is parathyroid (PT
H) suppression -Serum with each bone-active polyphosphonate and
Induced increase in ionized calcium concentration. [0057]Materials and methods: material A low calcium and low phosphorus diet with about 0.1% calcium
Telk in the form of pellets of
ad^RTest Diets (Harlan Industries, Wisconsin
Prepared by Madison State, 53711, Order # TD 82195)
did. This diet is for rats except calcium and phosphorus
Contains all necessary essential vitamins and minerals
Was. The calcium and phosphorus concentrations of the pellet are analytically determined.
(Procted & Gamble Co., Miami Vally Laborato
ries, Ohio, Cincinnati). PTH has an activity of 138 USP units per mg
Powdered bovine extract (Sigma Chemical Co., P.O.B.
ox 14508, St. Louis, MO, Order #P
-0892, lot # 72F-9650). PTH is
0.9% salt to a final concentration of 100 U.S.P./ml
Prepared in water. All solutions are # 4 Whatman filter paper
0.45 μm Metricel^RFilter
Refiltered through. [0059]Dosing solution and dosing method All compound solutions for testing bone resorption inhibition strength
Prepared for subcutaneous injection in 0.9% normal saline,
adjusted to pH 7.4 with aOH and / or HCl
did. Dosing solution calculation is mg / k corresponding to mgP / kg
mass of active substance powder in g (body weight) (molecular weight group)
Quasi-hydration). 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. Repeat the test as needed, thereby
In order to make the measurement of LED accurate, 0.5 LED
Was administered. Dosage adjustments should be made daily based on changes in body weight.
Was. [0060]animal In this study, a male Wi weighing about 150-160 g
Breeding star rats (Charles River Breeding Laborat
thyroid gland parathyroidectomy. All of
Rats are placed in double cabins in the hanging basket upon arrival, and Purina
 LaboratoriesRodent Chow^RAnd gave tap water.
After acclimation to the laboratory environment for 3-5 days, the rats are
Low-phosphorus (0.18% / 0.22%) diet (Tekla
d^R) And 2% (w / v) calcium via water bottle
Um gluconate supplemented ion-exchanged water was provided. [0061]Method Ketaset all rats on day 4 of low calcium diet^R
(Ketamine hydrochloride, 100 mg / ml, Br
Istol Myers) with anesthesia at 0.10ml / 100g body weight
Bleed from the retro-orbital venous plexus after weighing,
Analysis of serum total calcium using atomic adsorption (FAA)
Was. All rats weighing less than 180 g were excluded from the study.
Removed. The animals were then equal in the mean total serum calcium of each group.
Statistically randomized to be one. Low calcium
Considered as blood serum (total serum calcium <8.0 mg / dl)
Only rats that were removed were placed in a study group consisting of 6 rats / group. Treatment with various experimental compounds started on day 6
And continued until day 9 of the study (1:00 p.d.
M.). Dosing solution is applied to the abdominal skin where the hind legs meet the torso
Subcutaneously applied to the valve at a constant rate of 0.2 ml / 100 g body weight
It was prepared as follows. All rats are weighed daily
Was given and administered. Using a 25 gauge 5/8 inch needle
The drug was administered, and the administration site was changed every day. Moved on the 8th day
The material is converted into deionized distilled water through a water bottle
Was. On day 9, all rats were fasted to approximately 4:00 PM.
I let you. No treatment given on day 10 of study
Was. In the morning, a sample of 600 μl whole blood was
Microtainer (B-D # 5060) Serum for Lucium
Collected in a Pareta tube (FAA). Heparinized
Two 125 μl samples of the isolated whole blood were also
Collected for use in calcium analysis. Immediately after blood collection
All rats were weighed and 75 USP (filtered) / 10
Bovine parathyroid hormone was injected at a rate of 0 g body weight. all
And blood sampling for ionized calcium
Repeated three and a half hours after PTH injection. All pre-post-PTH total and ionized
Lucium is a t-test of Students, analysis of variability and
PTH alone (vs.
) Was analyzed statistically. After
Preliminary change and rate of change are also
Before-drug versus after-drug body weights were also determined. The physiological effect of countering PTH was
And the peak activity in three and a half hours
Sex was seen. In the TPTX model, calcium
Xie hormones and dietary controls are minimized
The observed increase in serum calcium concentration
Probably the result of bone material resorption. Polyho
Sulfonates tend to inhibit bone material resorption,
Animals pretreated with phosphonate are treated with saline.
PTH vs. less than those found in control animals
It showed an increase in serum calcium concentration after anti-anti. Poly
Minimum dose that phosphonate can suppress bone resorption
The amount was reduced in serum calcium when challenged with PTH
As demonstrated by the rise, polyphosphonate inhibits bone resorption.
It is a measure of the control strength. Determined by TPTX rat model
Table III shows the LED values of the bone resorption inhibitory strength of each compound.
Show. [0065]Table III Lowest effective (anti-absorption) dosage                                                           TPTX         Diphosphonate compounds LED (mg P / kg)     EHDP 1.0     Cl₂MDP 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)) AMDP^*                0.01     N- (2- (3,4-lutidine)) AMDP^*            0.01     N- (2- (4,6-lutidine)) AMDP^*            0.01¹⁾     N- (2-pyrimidyl) AMDP^*                      0.01     N- (4- (2,6-dimethyl) -pyrimidi 1.0       Le) AMDP^*     N- (2- (4,6-dihydroxy) -pyri 0.01¹⁾       Midil) AMDP^*     N- (2-pyridyl) AEDP^*                        0.01     N- (2- (3-picolyl)) AEDP^*              10     2- (2-pyridyl) EDP^*                          0.01     2- (3-pyridyl) EDP^*                          0.01     2- (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     Cl₂MDP = dichloromethane DP     APD = 3-aminopropane-1-hydroxy-1,1-DP     AMDP = aminoethanediphosphonic acid with ring attached to amine     AEDP = 2-aminoethane-1,1-diphospho with ring attached to amine               Acid     EDP = ethane-1,1-diphosphonic acid having a ring bonded to position 2 of ethane     Propyl DP = propane-2,2-diphosphonic acid     * = Compound included in the pharmaceutical composition of the present invention     1) = Activity level questioned due to lack of dosing responseExample IV Clinically diagnosed as suffering from malignant hypercalcemia
0.7 mgP of 2- (2
-Pyridyl) -ethane-1,1-diphosphonic acid or its equivalent
Pharmaceutically acceptable salts or esters once a day
Dosing by intravenous infusion for 2 hours for 4 days. The conclusion of this treatment
As a result, considerable relief of malignant hypercalcemia is obtained.
You. In the above treatment, 2- (2-pyridyl)
-Instead of ethane-1,1-diphosphonic acid
Similar results are obtained when used: N- (2- (5
-Amino) -pyridyl) -aminomethanediphosphonic acid;
N- (2- (5-chloro) -pyridyl) -aminomethane
Diphosphonic acid; N- (2- (3-picolyl))-amino
Methanediphosphonic acid; N- (2- (4-picolyl))-
Aminomethane diphosphonic acid; N- (2- (5-picoline)
))-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-di
Phosphonic acid; 2- (3-pyridyl) -ethane-1,1-
Diphosphonic acid; 2- (4-pyridyl) -ethane-1,1
-Diphosphonic acid; 2- (2-pyridyl) -1-hydroxy
C-ethane-1,1-diphosphonic acid; 2- (3-pyridi
Ru) -1-Hydroxy-ethane-1,1-diphosphone
Acid; 2- (4-pyridyl) -1-hydroxy-ethane-
1,1-diphosphonic acid; O- (2- (3-picolyl)-
Oxamethane-diphosphonic acid; or its pharmaceutically acceptable
Effective salt or ester.

──────────────────────────────────────────────────続 き Continuation of the front page (73) Patent holder 592043805 ONE PROCTER & GANB LE PLAZA, CINCINNAT I, OHIO, UNITED STATS ES OF AMERICA (72) Inventor Christopher, Mark, Perkins Cincinnati, River, Ohio, USA Road, 6410 (58) Field surveyed (Int. Cl. ⁶ , DB name) C07F 9/58 C07F 9/6509 C07F 9/6512 CA (STN) REGISTRY (STN)

Claims (1)

(57) [Claims] A diphosphonic acid compound having the following structure: [Wherein, 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, saturated or unsaturated hydrocarbon chain having carbon, a substituted or unsubstituted aryl, or a substituted or unsubstituted benzyl, and 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 saturated or unsaturated hydrocarbon chain having 1 to 6 carbon atoms, a substituted or unsubstituted aryl, a substituted or unsubstituted benzyl, , Halogen, carbonyl, alkoxy, nitro,
One or more substituents selected from the group consisting of amide, amino, substituted amino, carboxylate, and combinations thereof, wherein R ₄ is hydrogen, substituted or unsubstituted having 1 to 4 carbon atoms; Or a saturated or unsaturated hydrocarbon chain or acyl], or a pharmaceutically acceptable salt or ester thereof.