The use of phosphonates and nonsteroidal anti-inflammatory drugs for arthritis treatment, treatment

 

(57) Abstract:

The invention relates to medicine, in particular to rheumatology, and for the treatment of arthritis. For that purpose a combined introduction of phosphonate and non-steroidal anti-inflammatory medicines are in a certain mode. The method leads to the suppression of intra-articular destruction of bone and cartilage structures, reducing inflammation. 8 C.p. f-crystals, 1 table.

The invention relates to methods of treating arthritis, including rheumatoid arthritis and osteoarthritis. In particular, this invention relates to methods of treatment, which consists in the introduction of phosphonate compounds, active against bone, and nonsteroidal anti-inflammatory drugs (NSPs). Active against bone phosphonates and NSPs operate in conjunction with each other, and their introduction leads to decreased inflammation, and suppresses degradation of bone and hard tissue in the intra-articular region of the joint, which enables the recovery subarashiki bone and hard tissue.

Bone loss or change in metabolism in bone tissue may be due to arthritis or be associated with many forms of arthritis, vklycheniem and disease of the joints, characterized by the weakening of the joint capsules and ligaments with subsequent destruction of the cartilage, ligaments, tendons and bones, and viscosity reduction and other changes of the synovial membrane and fluid. Symptoms of rheumatoid arthritis include General weakness, fatigue, localized pain and stiffness, weakness, swelling and deformity of the joints of the body. Rheumatoid arthritis occurs most frequently in women in the period from the fourth to the sixth decade of life.

Pathogenesis of rheumatoid arthritis, leading to destruction of the joints, characterized by two phases: 1) exudative phase, including the circulation of synovial cavities, which allows penetration of plasma proteins and cellular elements in the joint, and 2) the phase of chronic inflammation occurring in subsynovial and subarashiki bone, characterized by the formation of pannus (granulation tissue) in the cavity of a joint, bone erosion and cartilage destruction. Pannus may form adhesions and scar tissue, which causes deformation of the joints, characteristic of rheumatoid arthritis.

The etiology of rheumatoid arthritis remains unclear. Involved in infective agents such as bacteria and viruses. When revmatoidnom arthritis:

Currently used in the treatment of rheumatoid arthritis is mainly symptomatic relief by introducing non-steroidal anti-inflammatory drugs (NSPs). Treatment NSPs effectively mainly in the early stages of rheumatoid arthritis; it is unlikely that it will cause suppression of inflammation of the joints, if the disease has existed for more than one year. Were tested gold, methotrexate, immunosuppressants and corticosteroids with limited success.

On the other hand, osteoarthritis, by its nature, is non-inflammatory musculoskeletal disease of the joints characterized by damage to and erosion of articular cartilage and formation of bone tumors at the periphery of the joint. As osteoarthritis progresses, the surface of the articular cartilage is destroyed and erased particles are accessed in the synovial fluid, which in turn stimulates phagocytosis by cells of the macrophage. Thus, ultimately called inflammatory response in osteoarthritis. The usual clinical signs and symptoms of osteoarthritis include bone and cartilage growth in the finger joints and stiffness when waking up and the pain when movement is especiallyh funds modifying the disease of anti-arthritis drugs (SPAL, DMARDs s), steroids and physical therapy.

The number of derivatives polyphosphorous acid has been proposed for use in the treatment and prevention of diseases involving abnormal metabolism of calcium and phosphate. For example, numerous references disclose compositions containing polyphosphonate, in particular bisphosphonates, such as 1-hydroxyethylidenediphosphonic acid ("EGDF"), and their application to suppress abnormal deposition and mobilization of calcium and phosphate in animal tissues: U.S. patents 3683080, published on 8 August 1972 and 4230700, published October 28, 1980, both belong Froncis, and U.S. patent 4868164 belonging Ebetin, published on September 19, 1989 In numerous other bibliographic sources describe substituted phosphonic acid, applicable for the treatment of osteoporosis and/or arthritis: U.S. patents 5071840 belonging Ebetino et al., published December 10, 1991, U.S. patent 4868164, Ebetino et al., published on September 19, 1989; U.S. patent 5104863, Benedict et al. published on April 14, 1992; U.S. patent 4267108, Blum et al., published may 12, 1981; European patent application, publication N 170228 Boenhringer Mannheim Cm. H. published 5 Feb the ls, et al., published November 15, 1988; U.S. patent 4939130 Jaeggi, et al., published July 3, 1990; U.S. patent 4971958 Bosils, et al., published November 20, 1990; 0 90/12017 Dunn, et al., published on October 18, 1990; 0 91/10646 Youssefyeh P. et al., published July 25, 1991; A-A-26738/88 Jaeggi, K. A. , date of publication 16 June 1989; A-A-45467/89 Ciba-Geigy, published may 31, 1990.

Suitable for use in this case phosphonate compounds include those compounds which are described in the following bibliographic sources listed here as references: European patent application, publication N 186405, Benedict and Perkins, published July 2, 1986; sulfur-containing phosphonate compounds, described in U.S. patent Breliere, et al. published on may 24, 1988; U.S. patent 4876247 Barbier et al., published on October 24, 1989; European patent application, publication N 100718 Breliere. A. published February 15, 1984; and those containing a Quaternary nitrogen phosphonate compounds, which are described in U.S. patent 4208401 Bauman (representing Colgate - Palmelive Co.), published on June 17, 1980; and E4011777, Jaeggi, K., outdoor 18 October 1990

NSPs was widely used in the treatment of arthritis for several years. The following sources, listed here by reference, describe various NSPs suitable for apny Ciba-Geigy), published in 1971; U.S. patent 3843681 (transferred to American Home Products), published 1974; U.S. patent 3766263 Godfrey (transferred RecKitt and Colman), published 1973; U.S. patent 3845215 Goldfrey (transferred RecKitt and Colman), published 1974; U.S. patent 3600437 Marshall (sent Eli Lilly), published in 1971; U.S. patent 3228831 Nicholson and Adams (transferred to Boots Pure Drug) published in 1966; (U.S. patent 3385886 Nicholson and Adams (transferred to Boots Pure Drug) published in 1968; U.S. patent 3161654 Shen (transferred to MercK and Co. published in 1964; U.S. patent 3904682 Fried and Harrison (transferred Syntex), published in 1975; U.S. patent N 4009197 Fried and Harrison (transferred Syntex), published in 1977; U.S. patent 3591584 Lombardino (transferred to Pfizer), published in 1971; U.S. patent 5068458 Dales et al. (transferred to Beecham Group, PLC.), published on November 26, 1991; U.S. patent 5008283 BlacKburn et al. (transferred to Pfizer, Inc.), published April 16, 1991; U.S. patent 5006547 Loose (transferred to Pfizer, Inc.), published April 9, 1991.

Introduction NSPs and active against bone phosphonates were offered as a way of strengthening the anti-inflammatory activity NSPs. Such treatment using bifosfonatami and NSPs disclosed in the following bibliographic sources, all listed here by reference; U.S. patent 4269828 Flora et al., opublikovala 1981, U.S. patent 4282214 Flora et al., published on August 4, 1981.

The applicant has found that the introduction active against bone phosphonates and NSPs not only reduces inflammation, but also inhibits the destruction of bone and dense tissue in the synovial cavity of the joint, allows recovery Podhradie bone and maintains and/or increases the degree of mobility of the joints. Agent, acting as NSPs, and phosphonate active agent work together. Accordingly, the advantages obtained by the treatment of arthritis, when used in a manner described herein, greater than those observed in the application of any of the two active substances or their amounts if they are used separately. The use of this method reduces the number NSPs that you want to enter a patient with arthritis and, in addition, also provides an opportunity to reduce the dose of phosphonate introduced over time. The methods of this invention are effective treatments of arthritis, including osteoarthritis and rheumatoid arthritis, with reduced side effects compared to known in this field such methods.

The present invention predstavlenie a person or animal, your arthritis and enable recovery Podhradie bones. Two active substances used in these methods of treatment described herein operate with each other together attenuation of inflammation and suppression of intra-articular destruction much more when NSPs and phosphonate are used in the treatment together than the amount of such benefits, when any of the two active agents is introduced separately. Accordingly specified method of treatment of arthritis can significantly reduce therapeutic dose NSPs and thereby reduce or alleviate undesirable side effects associated with therapy NSPs. In addition, this therapy can also significantly reduce the dose active against bone phosphonates, thereby reducing therapeutic dose in time, and at the same time preserves the integrity of the joint. These treatments consist of one or more than sixty (60) day periods of treatment, including the optional injection mode NSPs regime and the introduction of phosphonate, and

(a) the specified optional injection mode NSPs includes the introduction of a specified subject NSPs level from 20% to 80%, prepective introduces provided that specified NSPs is introduced in sufficient quantities and for a sufficient number of days to relieve the symptoms of inflammation, and with

(b) the specified mode is the introduction of phosphonate includes the introduction of a specified subject phosphonate in a dose equivalent to the system number equal to from about 0,0005 mg/kg to about 1.0 mg/kg / day, where the phosphonate is entered; provided that the phosphonate is at least 1 day in each specified sixty (60) day period of treatment.

Definitions and use of terms

Below is a list of definitions of terms used in the description.

"Heteroatom is a nitrogen atom, sulfur or oxygen. Group containing one or more heteroatoms may contain different heteroatoms.

"Alkyl" is unsubstituted or substituted, straight or branched, saturated or unsaturated hydrocarbon chain, and the specified hydrocarbon chain may be saturated, having from 1 to 8 carbon atoms, and preferably, unless otherwise specified, from 1 to 4 carbon atoms; specified hydrocarbon chain may be unsaturated, having from 2 to 8 carbon atoms, and preferably, if not aniline unsaturated hydrocarbon chain, having at least one olefinic double bond, and alkyline unsaturated hydrocarbon chain having at least one triple bond. Preferred alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl and butyl.

"Heteroalkyl is unsubstituted or substituted, saturated chain having from 3 to 8 members and containing carbon atoms and one or two heteroatoms.

"Carbocyclic ring" or "carbocycle" as used here, refers to unsubstituted or substituted, saturated, unsaturated or aromatic hydrocarbon ring, typically containing from 3 to 8 atoms, preferably from 5 to 7 atoms. Carbocyclic ring may be monocyclic, having from 3 to 8, preferably from 5 to 7 carbon atoms, or they may be polycyclic. Polycyclic carbocycle consisting of two rings usually have from 6 to 16, preferably from 10 to 12 atoms. Polycyclic carbocycle consisting of three rings usually contain from 13 to 17, preferably from 14 to 15 atoms.

"Heterocyclic ring" or "heterocycle" as used herein are unsubstituted or substituted, saturated, unsaturated or AIH heteroatoms in the ring. The term "heterocyclic ring", as it is used here, includes monocyclic and polycyclic ring systems, condensed or nscontainerframe, unsaturated, saturated or unsubstituted. Monocyclic heterocyclic ring parts usually contain from 3 to 8 atoms, preferably from 5 to 7 atoms. Polycyclic heterocyclic ring part, consisting of two rings usually contain from 6 to 16, preferably from 10 to 12 atoms. Polycyclic heterocyclic ring part, consisting of three rings usually contain from 13 to 17 atoms, preferably from 14 to 15 atoms. In addition, polycyclic heterocyclic ring part can consist of heterocyclic compounds (one of which must contain a nitrogen atom), or from heterocyclic compounds (one of which must contain a nitrogen atom), and carbocycles. Each heterocyclic ring component must have at least one nitrogen atom. Unless otherwise specified, any additional heteroatom in the heterocyclic ring component can be independently selected from nitrogen, sulfur and oxygen.

"Aryl" is an aromatic carbocyclic ring. Preferred heteroaryl" is an aromatic heterocyclic ring. Preferred heteroaryl groups include, but are not limited to, thienyl, furyl, pyrrolyl, pyridinyl, pyrazinyl, oxazolidinyl, chinoline, pyrimidinyl and tetrazolyl.

"Alkoxy" is a substituent in the hydrocarbon chain, having an oxygen atom, where the hydrocarbon chain is an alkyl or alkenyl (for example, -O-alkyl or-O-alkenyl). Preferred alkoxygroup include, but are not limited to, methoxy, ethoxy, propoxy and alkoxy.

"Hydroxyalkyl" is substituted hydrocarbon chain, which has hydroxy-substituent (e.g.,- OH), and may have other substituents. Preferred hydroxyalkyl groups include, but are not limited to, hydroxyethyl, hydroxypropyl and hydroxyalkyl.

"Carboxylic" is substituted hydrocarbon chain, which has a carboxy-Deputy (e.g.,- COOH) and may have other substituents. Preferred carboxialkilnuyu group include carboxymethyl, carboxyethyl and their acids and esters.

"Aminoalkyl" is a hydrocarbon chain (e.g., alkyl), substituted amine substituent (for example, alkyl - NH-), such as methylamine.

"Alkylamino" is amino

"Alkynylamino" is amino Deputy, having one or two alkenyl substituent (for example, -N-alkenyl).

"Alkynylamino" is amino Deputy, having one or two alkinilovymi substituent (for example, -N-quinil).

"Alkylamino" is aminosubstituted having one or two alkyl substituents (for example, N-alkyl-).

"Arylalkyl" is alkyl Deputy, a substituted aryl group. Preferred arylalkyl groups include benzyl and phenylethyl.

"Arylamino" is amino Deputy, substituted aryl group (e.g.,- NH-aryl).

"Aryloxy" is an oxygen atom, aryl having a substituent (for example, -O-aryl).

"Acyl" or "carbonyl" is a carbon linked to oxygen double bond (e.g., R-C(= O)-O). Preferred alkylsilane groups include, but are not limited to, acetyl, propionyl, butanoyl and benzoyl.

"Acyloxy" is an oxygen atom, acyl having a substituent (for example, -O-acyl); for example, -O-C(=O)-alkyl.

"Acylamino" is aminosubstituted with the acyl substituent (for example, N-acyl); for example, (NH-(C=O)-alkyl;

"Halo", "halogen" Illidari.

And, as mentioned here, "the lower hydrocarbon substituent (for example, "lower alkyl is a hydrocarbon chain containing, unless otherwise specified, from 1 to 6, preferably from 1 to 4, carbon atoms.

In phosphonate compounds, as described in section I. B I. C here, the term "thio-Deputy" is denoted SR6or, R8SR6where R8is C1-C8the alkyl. Separate titlestyle include thiol (-SH, where R6= H); thioethers

< / BR>
where R6is COR7;

THIOCARBAMATE

< / BR>
where R6is CONR7;

dithiocarbamate

< / BR>
where R6is CSNR72;

dayevery

< / BR>
where R6is CSR7;

thiocarbonate

< / BR>
where R6is C(O)OR7;

and dithiocarbonate

< / BR>
where R6is C(S)OR7, R7,

as used here, is hydrogen or substituted or unsubstituted C1-C8-alkyl.

You should also understand that the groups defined above may be preceded by R8(i.e., C1-C8alkyl): it would alkylthiol, alkylthiophene, alkyldimethyl, alkyldiethanolamine, alkylation is a", as used here refer to those phosphonates and phosphonium acids, which have two phosphonate groups associated with the same carbon atom and are used interchangeably with the terms of diphosphonate and diphosphonate acid. When using phosphonate structures of the active components described in parts B and C, in these compounds the substituent R is RO3H2.

"Pharmaceutically acceptable salt" is a cationic salt formed with any acidic (e.g., carboxyl) group, or an anionic salt formed with any basic (e.g., amino) group. Many such salts are known in this area, which are described in International patent publication (World Patent Publication) 87/05297, Johnston et al, published September 11, 1987, included here as a reference. Preferred cationic salts include alkali metal salts (such as sodium and potassium) and alkaline earth metals (such as magnesium and calcium). Preferred anionic salts include halide (such as chloride), acetate and phosphate salts.

"Biohydrology ether is an ether tizanidine phosphate compounds, which does not interfere with activity of the compounds, or that is easily converted No in this area, as described in International patent publication 87/05297, Fohnston et al, published September 11, 1987, and included here as a reference. Such esters include esters of lower Akilov, esters of lower aryloxyalkyl (such as acetoxymethyl, ecotoxicology, aminocarbonylmethyl, pivaloyloxymethyl and pivaloyloxymethyl esters), lactonase esters (such as Caligraphy and tittilicious esters), lower esters of alkoxyalkanols (such as methoxycarbonylmethyl, ethoxycarbonylmethyl, ethoxycarbonylethyl and isopropoxycarbonyloxymethyl esters), alkoxyalkyl esters, kalinovye esters and acylaminoalkyl esters (such as acetamidomethyl esters).

As defined above and is used here, substituting groups may themselves be substituted. Such substitution may be performed by one or more substituents. Such substituents include, but are not limited to, those listed in C. Hansch and A. Leo, Substituent Constants for Correlation Analysis in Chemistry and Biology (1979), included here as a reference. Preferred substituents include, but are not limited to, alkyl, alkenyl, alkoxy, hydroxy, oxo, amino, aminoalkyl (for example, aminomethyl and so on ), cyano, ha is lcil (for example, piperidinyl, morpholinyl, piperazinil, pyrrolidinyl and so on), that is, thioxo, hydroxyalkyl, aryloxy, arylalkyl and combinations of these groups.

The term "system number", as used here, refers to the dose of phosphate compounds in mg/kg, which is suitable for use in the methods of the present invention. The claimed level doses of phosphonates, equal from 0.0005 mg/kg to 1.0 mg/kg is the dose that should be used in the methods of treatment described herein, when the specified dose is injected systemically, i.e., parenterally. Oral administration of course it is supposed to use here, and for reasons of acceptability and convenience is preferred. Because adsorption of phosphonates, administered orally is from 1% to 5%, the level of oral dosage from about twenty to a hundred times higher than systemic dosage.

This invention is methods of treating human or animal affected by arthritis. Using the above methods is suppressed destruction of the articular bone and joint, substantially reduces or decreases the periarticular inflammation, and possible recovery subarashiki bone at the specified subaverages when these active substances are used in the same therapeutic mode more than the sum of these effects have been observed when one of the substances introduced separately. In addition, if the specified method of treatment of arthritis are significantly reduced dosages of substances active as NSPs, and at the same time preserves the integrity of the articular bone and joints and even drop unwanted side effects associated with chronic therapy NSPs. In addition, these methods can give the possibility of reducing the dosage of phosphonate compounds introduced during the period. The method includes one or more than sixty(60) day periods of treatment, including the optional injection mode NSPs regime and the introduction of phosphonate, and

(a) the specified optional mode introduction NSPs includes the introduction of a specified subject NSPs at a level equal to from 20 to 80%, preferably from 20 to 70%, most preferably from 20 to 50% of commonly prescribed daily dose for each day, which is NSPs; provided that the specified NSPs is introduced in sufficient quantities and in a sufficient number of days to relieve symptoms of inflammation, and with

(b) injection mode specified phosphonate includes the introduction of a specified subject phosphonate dose, which I specified phosphonate; provided that the phosphonate is at least 1 day from each of the specified sixty (60)-day treatment period.

The treatment methods described herein are suitable for use as a long-term maintenance therapy for use in the treatment of patients with arthritis. Long-term maintenance therapy is usually preferably consists of a consecutive sixty (60) day periods of treatment, which should vary according to the dose and/or types NSPs and/or phosphonates, with each period of treatment followed by one after another. As indicated above, the methods of treatment described herein lead to a reduction of inflammation of soft tissues in macroglossinae region, and also inhibits the destruction of bone and dense tissue in the intra-articular region of the joint, thus enabling recovery Podhradie bone.

These methods allow to reduce the number NSPs imposed by the patient with arthritis over a period of two ways:

1) can be reduced equal to from 20 to 80%, preferably from 30 to 80%, most preferably from 50 to 80% of conventional therapeutic doses described patients on the day when the active state of the disease; and

2) may be reducing the quantity arthritis.

The term "generally accepted therapeutic dosage" as used here, refers to a daily dose of a specific NSPs listed in the 46th edition Physician''s DesK Reference (1992). When given multiple levels of dosage, usual therapeutic dose for a specific NSPs is that dose which is provided for the active stages of the disease or to relieve pain. Sometimes it is a higher dose, which should be used for limited periods (such as during a sudden and strong attacks), which is much higher (often 1 1/2 - 2 times higher) than the generally accepted therapeutic dose. The term "period of active sudden flare-up", as it is used here, refers to the period or phase of arthritis, which is characterized by a sudden exacerbation of the disease typically manifested as a rapid swelling of the soft tissues and increased pain, stiffness and inflammation. Accordingly, reducing the number NSPs imposed for the period result as a reduction in the daily dose, and a reduction in the number of days in which the patient is injected dose medications. It is usually assumed that the greatest damage to the bone and dense tissue occurs during periods activitiesmay daily dosage NSPs; the ultimate goal of this therapy must be fully cancel the introduction NSPs and introduction only phosphonate compounds. Because the periods of treatment described herein can be provided by the introduction NSPs for fewer days during the treatment period and decreasing the daily dosage NSPs, will decrease the total number NSPs entered for the period. In addition to a significant reduction of many unwanted side effects associated with chronic therapy NSPs, this method of treatment suppresses the degradation of bone and dense tissue in macroglossinae area affected joints, allowing recovery Podhradie bones. After some time many patients it leads to fewer periods of exacerbation and result in less destruction of bones and joints and lower inflammation and pain.

Specific schemes to be followed during periods of treatment described herein may vary from patient to patient depending on the specific features that appear in a patient in any given period. Accordingly, sixty (60)day periods of treatment may change one after another, based on the status and needs of the patient. The end is very basic introduction) with stabilization or decrease in the same time period frequency of outbreaks activity and limit the frequency and severity of inflammation. Various more specific treatment regimens are described hereafter.

The active substance

1. Active against bone phosphonates:

The methods of this invention include the introduction of some active against bone phosphonates, in particular, the compounds of risedronate and phosphonate compounds containing a Quaternary nitrogen and sulfur-containing (e.g., serotonestvic) phosphonates, which will be described here below.

A. Risedronate active ingredient

The term "risedronate" as it is used here, refers to diphosphonate connection 3-pyridyl-1-hydroxyethylidene-1,1 - biphosphonate acid having the following structure

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Connection risedronate, in addition, are described in the following publications, all included here as a reference EPO patent application 0186405 Benedict et al. , (transferred Procter and Gamble Co.), published July 1, 1986; and "An International Conference, Bisphosphonates: Current Status and Future Prospect, The Royal College of Physcians, London, Enyland, May 21 - 22, 1990, organized by IBC Techniral Services

The term "risedronate active ingredient" includes risedronate, salts and esters of risedronate or any mixture. As an active residronate ingredient in the new the ski acceptable non-toxic salt or ester of residronate. Salt of residronate can be salts of accession acid, in particular, ammonium group, and hydrogen chloride, as well as any pharmaceutically acceptable non-toxic salts with organic and inorganic acids can be used. In addition, there may be used salts formed with the carboxylic group, including, but not limited to, salts of alkali metals (K, Na) and salts of alkaline earth metals (Ca, Mg), preferably salts of Ca and Na.

In particular, other esters of risedronate, which are suitable for use as active ingredient in this invention described herein are alkalemia esters of C1-C18with a straight or branched chain, including, but not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, amyl, hexyl, p, oktilovom, nonlevy, decroly, lauric, ministerului, cetyl and stearyl, alkenilovyh esters of C2-C18with a straight or branched chain, including, but not limited to, vinyl, alkilany, undeniably and linalilovy, C3-C8cycloalkane esters, including, but not limited to, cyclopropylethyl, cyclobutylamine, cyclopentylamine, CI, toluene, Kilroy, nattily, alicyclic ethers, including, but not limited to, metalowy, Arakelova esters, including, but not limited to, benzyl and finitely.

B. Active phosphonate ingredients containing Quaternary nitrogen

In addition, phosphonate compounds suitable for use herein are heterocyclic phosphonate compounds containing Quaternary nitrogen, and their pharmaceutically acceptable salts and esters which have the following structure

< / BR>
where

m and n are integers from 0 to 10; and m + n is from 0 to 10;

(a) Q is a covalent bond or a Deputy chosen by O, S, NR1;

(b) z is a saturated, unsaturated or aromatic monocyclic or a polycyclic heterocycle containing one or more heteroatoms selected from O, S or N, and at least one heteroatom is an atom of the Quaternary nitrogen;

(c) R is COOH; PO3H2; SO3H; or P(O)(OH)R4where R4is substituted or unsubstituted alkyl of 1 to 8 carbon atoms;

(d) each of R1is selected from the group consisting of zero; SR6; R9SR6; hydrogen; hydroxy; substituted-N(R3)C(O)R3; -C(O)N(R3)2; halogen; -C(O)R3; aryl-alkyl; nitro; substituted or unsubstituted aryl, and combinations thereof;

(e) each of R2is one or more substituents in part, independently selected from the group consisting of SR6; R9SR6; hydrogen, substituted or unsubstituted C1- C8of alkyl, -OR3, -CO2R3; -O2CR3; -NR32; -N(R3)C(O)R3; -C(O)N(R3)2; halogen; hydroxy; -C(O)R3; arylalkyl; nitro; substituted or unsubstituted aryl;

(f) each R3independently selected from the group consisting of hydrogen, substituted or unsubstituted alkyl having 1 to 8 carbon atoms, and R9SR6;

(g) R5is selected from the group consisting of hydrogen, halogen, SR6; R9SR6; amino; hydroxy; substituted or unsubstituted C1- C8of alkyl;

(h) each R6independently selected from the group consisting of H; -C(O)R7; -C(S)R7; -C(O)NR72; -C(S)N(R7)2; -C(S)OR7; -C(O)OR7where R7is hydrogen or substituted or unsubstituted C1- C8by alkyl;

(i) each R8independently selected from groupseminole phenyl, the benzyl or R9SR6and

(j) R9is substituted or unsubstituted C1- C8the alkyl.

Preferred diphosphopyridine compounds for use in the methods of this invention can have the following structure

< / BR>
Also preferred for use in the methods described herein, diphosphopyridine connections linking chain has a heteroatom, i.e., O = S, O or NR1(see Fig. 1),

< / BR>
< / BR>
< / BR>
Preferred compounds for use in the methods of the present invention, in which z is a polycyclic heterocycle include compounds having the structure shown in Fig.2.

< / BR>
< / BR>
< / BR>
< / BR>
The compounds of this invention may also have the following General structure

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< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
These compounds are described in more detail in U. S. S. N Ebetino et al., registered on may 29, 1992, included here as a reference.

Other suitable containing Quaternary nitrogen phosphonate compounds suitable for use in the methods described herein are containing bicyclic ring phosphonates and their pharmaceutically acceptable salt of R & d>1;

(b) m and n and m + n are integers from 0 to 5; p and q and p + q are integers from 0 to 3;

(c) each R1independently selected from the group consisting of zero, R9SR6; SR6hydrogen, hydroxy; unsubstituted or substituted C1- C8of alkyl, -OR3; -CO2R3; -O2CR3; NR32, -N(R3)C(O)R3, -C(O)N(R3)2, halogen, -C(O)R3, arylalkyl, nitro, unsubstituted or substituted aryl and combinations thereof;

(d) each R2is selected from the group consisting of substituted or unsubstituted C1- C35of alkyl, substituted or unsubstituted phenyl, benzyl, or R9SR6;

(e) each R3independently selected from the group consisting of hydrogen, substituted or unsubstituted C1- C8the alkyl and R9SR6;

(f) each R6independently selected from the group consisting of H, -C(O)R7; -C(O)OR7; -C(S)OR7, -C(S)OR7; -C(S)R7, -C(O)NR72, -C(S)NR72where R7is hydrogen or substituted or unsubstituted C1- C8by alkyl;

(g) R is-COOH, -SO3H2, -PO3H2or-P(O)(OH)R4where R4is substituted or alkyl.

Particularly preferred bicyclic compounds for use in the method of treatment described herein are substituted or unsubstituted of octahydronaphthalene and its pharmaceutically acceptable salts and esters having the General structure

< / BR>
referred to here as "unsubstituted or substituted, octahydro-5,5-diphosphono-1,1-dialkyl-1-pyridine";

< / BR>
referred to here as "unsubstituted or substituted, octahydro-5,5-diphosphono-2,2-dialkyl-2-pyridinium salts";

< / BR>
referred to here as the "salt of unsubstituted or substituted, octahydro-6,6-diphosphono-1,1-dialkyl - 1-pyridinium";

< / BR>
referred to here as the "salt of unsubstituted or substituted, octahydro-6,6-diphosphono-2,2-dialkyl-2-pyridinium";

< / BR>
referred to here as "salt octahydro-7,7-diphosphono-1,1-dialkyl-1-pyridinium";

< / BR>
referred to here as "salt octahydro-6,6-diphosphono-1-alkyl-1-dialkyl-1-pyridinium";

< / BR>
referred to here as-thio-substituted "octahydro-6,6-diphosphono-1,1-ciacil-1-pyridinium salts; and

< / BR>
referred to here as the "thio-substituted, octahydro-7,7-diphosphono-2,2-dialkyl-2-pyridinium salts".

These compounds are described in more detail in U. S. S. N Ebetino et al. registered on may 29, 1992, vclearance Quaternary nitrogen phosphonate compounds and their pharmaceutically acceptable salts and esters, having the following General structure

< / BR>
where m is an integer from 0 to 10; n is an integer from 0 to 10; and m + n is from 1 to 10;

(a) R1is selected from the group consisting of zero; - SR6; - R9SR6; hydrogen, substituted or unsubstituted C1-C8of alkyl; OR3; - CO2R3; - O2CR3; -NR32; - N(R3)C(O)R3; - C(O)N(R3)2; halogen; - C(O)R3; nitro; hydroxy; substituted or unsubstituted saturated monocyclic or polycyclic heterocyclic rings; substituted or unsubstituted saturated monocyclic or polycyclic carbocyclic rings;

(b) R5is selected from the group consisting of - SR6; - R9SR6; hydrogen; substituted or unsubstituted C1-C8of alkyl; OR3; - CO2R3; - O2CR3; -NR32; - N(R3)C(O)R3; - C(O)N(R3)2; halogen; - C(O)R3; nitro; hydroxy; substituted or unsubstituted saturated monocyclic or polycyclic heterocyclic rings; substituted or unsubstituted saturated monocyclic or polycyclic carbocyclic rings; substituted or unsubstituted unsaturated monocyclic or polycyclic carbocyclic rings, and combinations thereof; 4 (C) each R2is selected from the group consisting of substituted or unsubstituted C1-C35of alkyl; unsubstituted or substituted phenyl; benzyl; or R9SR6;

(d) R3is selected from the group consisting of H; unsubstituted or substituted C1-C8of alkyl; R9-SR6;

(e) R6is selected from the group consisting of-H; - C(O)R7; - C(S)R7; - C(O)N(R7)2; - C(O)OR7; - C(S)N(R7)2; - C(S)OR7; where

R7is hydrogen or unsubstituted or substituted C1-C8by alkyl;

(f) R is selected from the group consisting of-COOH; - SO3H; -PO3H2and - P(O)(OH)R4where

R4is an alkyl group having 1-3 carbon atoms.

(g) R9is substituted or unsubstituted C1-C8by alkyl;

(h) R8is selected from the group consisting of hydrogen, halogen, SR6; R9SR6; amino, hydroxy; substituted and unsubstituted C1-C8of alkyl;

Preferred containing Quaternary nitrogen phosphonates having substituent R1selected from substituents R1described here previously, include

< / BR>
N-(3-hydroxy-3,3-diphosphonates)-N,N-dimethyl-hydroxy-3,3-diphosphonates)-N,N,N-dialkylammonium salt.

Preferred containing Quaternary nitrogen phosphonates having a saturated monocyclic or polycyclic heterocycle as Deputy R1where the atom of the Quaternary nitrogen is associated with carbon phosphonic acid binder chain, include

< / BR>
N-(3-hydroxy-3,3-diphosphonates)-N, N-dimethyl-N- (2-piperidinoethyl)ammonium chloride.

Furthermore, preferred compounds for use in the methods of this invention include compounds having the following structure:

< / BR>
< / BR>
Preferred compounds for use in the methods of this invention also include containing Quaternary nitrogen tizanidine phosphonates.

< / BR>
< / BR>
< / BR>
< / BR>
These compounds are described in more detail in U. S. S. N Fracis et al, registered on may 29, 1992, included here as a reference.

C. Active sulfur-containing phosphonate ingredients

Containing sulfur (e.g., thio-substituted) phosphonate compounds are also suitable for use as a phosphonate of the active ingredients in the treatment regimens described herein. Especially suitable thio-substituted nitrogen-containing heterocyclic phosphonate compounds which have the following General solcom, containing one or more heteroatoms selected from O, S or N, at least one of which is N:

(b) Q is a covalent bond; O,S,N or NR1;

(c) R is COOH, SO3H, PO3H2or P(O)(OH)R4where R4is substituted or unsubstituted WITH1-C8by alkyl;

(d) each R1is selected independently from - SR6; - R8SR6; nil; hydrogen; unsubstituted or substituted C1-C8of alkyl; unsubstituted or substituted aryl; hydroxy; -CO2R3; -O2CR3; -NR32; -OR3; -C(O)N(R3)2; N(R3)C(O)R3; substituted or unsubstituted benzyl, nitro, or combinations thereof,

(e) R2represents one or more substituents atoms in the portion z and independently selected from SR6and R8SR6; where R6is H; - CO2R3; -O2CR3; -N(R3)C(O)R3; and nil; hydrogen; unsubstituted or substituted C1-C8of alkyl; unsubstituted or substituted aryl; hydroxy; substituted or unsubstituted benzyl; nitro; or combinations thereof;

(f) each R3independently selected from hydrogen; substituted or unsubstituted C1-C81-C8the alkyl and

(h) R6independently selected from H, -C(O)R7C(S)R7, -C(O)NR72, -C(O)(OR7) and C(S)(OR7), where R7is hydrogen or unsubstituted or substituted C1-C8by alkyl;

(i) R8is substituted or unsubstituted C1-C8by alkyl; and at least one of R1, R2, R3or R5must be SR6or R8SR6.

As stated above, it is essential that at least one of R1, R2, R3and R5was SR6or R8SR6; when any of R1, R2, R3or R5is SR6or R8SR6, heterocyclic phosphonate is tizamidine. Suitable thio-substituents in these compounds, preferred for use herein are thiols, alkylthiol, thioethers, alkylthiophene, dayevery, alkyldimethyl, THIOCARBAMATE, alkyldiethanolamine, dithiocarbamate, alkyldiethanolamine, thiocarbonate, allylthiourea, dithiocarbonate and alkyldithiophosphate.

Preferred tizamidine, pyridinediamine connection biphosphonates acid, etc is their structure:

< / BR>
< / BR>
< / BR>
Also preferred tizamidine, pyridinediamine bisphosphonates, in which the binder chain has a heteroatom, i.e., Q = S, O, N, or NR1.

< / BR>
< / BR>
< / BR>
In addition, tizamidine piperidine biphosphonate acids and their pharmaceutically acceptable salts and esters suitable for use in the methods of this invention can alternatively have the following General structure

< / BR>
< / BR>
Other tizamidine connection biphosphonates acids include those compounds where Z is a polycyclic ring consisting of two rings.

< / BR>
< / BR>
< / BR>
< / BR>
Other preferred substituted sulfur-containing heterocycle biphosphonate acids are those compounds in which part of Z is a pyrimidine. These compounds and their pharmaceutically acceptable salts and esters have the General structure

< / BR>
< / BR>
Other suitable tizanidine heterocyclic biphosphonate acids include those compounds in which is semiclean containing a nitrogen heterocycle having the following General structure

< / BR>
Tizanidine heterocyclic biphosphonate acid, where Z is a five-membered heterocycle that is R>< / BR>
< / BR>
< / BR>
These compounds are described in more detail in U. S. S. N Kaas et al., registered on may 29, 1992, included here as a reference.

Other, suitable for use as phosphonate compounds tizanidine bicyclic compounds have the following General structure

< / BR>
where

(a) X and Y are independently selected from zero, O, S and N;

(b) R is COOH, SO3H, PO3H2, P(O)(OH)R4where R4is substituted or unsubstituted C1-C8by alkyl;

(c) m and n are integers from 0 to 5, and m + n is equal to from 0 to 5;

(d) p and q are integers from 0 to 3, and p + q is from 0 to 3;

(e) each R1independently selected from - SR6; R8SR6; zero; hydrogen, substituted or unsubstituted C1-C8of alkyl; unsubstituted or substituted aryl; hydroxy; - CO2R3; - O2CR3; -NR32; ; -OR3; C(O)N(R3)2; -N(R3)C(O)R3; substituted or unsubstituted benzyl; nitro; and combinations thereof;

(f) R2represents one or more substituents X and Y independently is selected from the group consisting of R8SR6; zero, hydrogen, substituted or unsubstituted Cwhat about or unsubstituted benzyl, or their combinations;

(g) R3independently selected from hydrogen, substituted or unsubstituted C1-C8the alkyl, or R8SR6;

(h) R6independently selected from H, C(O)R7, -C(S)R7, -C(O)N(R7)2, -C(S)N(R7)2, -C(O)OR7and-C(S)OR7where R7is hydrogen or substituted or unsubstituted C1-C8by alkyl; and

(i) R8is substituted or unsubstituted C1-C8by alkyl; provided that at least one of R1, R2and R3is SR6or R8SR6.

Preferred compounds for use in the methods of this invention are tizamidine octahydrophenanthrene acids and their farmatsevticheskii salts and esters having the General structure

< / BR>
< / BR>
referred to here as "tizamidine octahydro-1-pyrindine-5,5-diphosphonic acids"

< / BR>
< / BR>
referred to here as "tizamidine octahydro-2-pyrindine-5,5-diphosphonate acid

< / BR>
< / BR>
referred to here as "tizamidine octahydro-1-pyrindine-6,6-diphosphono acid

< / BR>
< / BR>
referred to here as "tizamidine octahydro-2-pyrindine-6,6 - diphosphonic acid

< / BR>
< / BR>
aimie here as tizamidine octahydro-2-pyrindine-7,7 - diphosphonic acids" and

< / BR>
referred to here as "dihydro-1-pyrindine-6,6-diphosphonic acid" and

< / BR>
referred to here as "dihydro-2-pyrindine-6,6-diphosphonic acid".

These and other compounds are described in more detail in U. S. S. N Kaas et al., registered on may 29, 1992, included here as a reference.

Other preferred phosphonate compounds for use in the methods described herein are those sulfur-containing phosphonate compounds, which have the following General structure

< / BR>
where

m and n are integers from 0 to 10, and m + n equals 0 to 10, and where

(a) X represents O or S;

(b) z is a covalent bond; monocyclic or polycyclic carbocyclic ring; or a monocyclic or polycyclic heterocyclic structural part containing one or more heteroatoms selected from O, S or N;

(c) Q is a covalent bond, O, or S;

(d) R is-COOH, -SO3H, -PO3H2or P(O)(OH)R4,

where

R4is substituted or unsubstituted C1-C8by alkyl;

(e) each R1independently selected from-SR6the polycyclic structural part; unsubstituted or substituted aryl, substituted or unsubstituted thiophene, substituted or substituted oxadiazole, substituted or unsubstituted of Paramonov; substituted or unsubstituted furan; hydroxy; -CO2R3; -O2CR3; -NR32; -OR3; -C(O)N(R3)2; -N(R3)C(O)R3; substituted or unsubstituted benzyl; nitro; or combinations thereof;

(f) R2independently selected from-SR6; -R8SR6; -CO2R3; -O2CR3; -C(O)N(R3)2; -N(R3)C(O)R3and zero, hydrogen, unsubstituted or substituted C1-C8of alkyl; unsubstituted or substituted aryl; hydroxy; substituted or unsubstituted benzyl; nitro sludge or combinations;

(g) each R3independently selected from hydrogen, substituted or unsubstituted C1-C8the alkyl, or R8SR6< / BR>
(h) R5is selected from-SR6, R8SR6, hydrogen; hydroxy; amino; halogen; unsubstituted or substituted C1-C8of alkyl;

(i) R6independently selected from H; -C(O)R7; and-C(O)N(R7)2where R7is hydrogen or unsubstituted or substituted C1-C8by alkyl; and

(j) R8yavlyaetsya here have the following General structure

< / BR>
where m and n are integers from 0 to 10, and m + n equals 0 to 10, and where

(a) z is a covalent bond; monocyclic or polycyclic structural part; or a monocyclic or polycyclic heterocyclic structural part containing one or more heteroatoms selected from O, S, or N;

(b) R is COOH; SO3H; PO3H2or P(O)(OH)R4where R4is C1-C8by alkyl;

(c) each R1independently selected from-SR6; -R8SR6, zero, hydrogen, unsubstituted or substituted C1-C8of alkyl, monocyclic or polycyclic carbocyclic structural parts; unsubstituted or substituted aryl, substituted or unsubstituted thiophene, substituted or unsubstituted oxadiazole; substituted or unsubstituted of Paramonov; substituted or unsubstituted furan; hydroxy; -CO2R3, -O2CR3; -NR32; ; -N(R3)C(O)R3; OR3; -C(O)N(R3)2; substituted or unsubstituted benzyl; a nitro, or combinations thereof;

(o) R2independently selected from-SR6; -R8SR6; -CO2R3, -O2CR3. -NR72; -N(R)3C(O)R3; OR3; -C( substituted aryl, hydroxy, substituted or unsubstituted benzyl; a nitro, or combinations thereof;

(e) each R3independently selected from hydrogen, substituted or unsubstituted C1-C8the alkyl or R8SR6.

(f) R5is selected from-SR6; R8SR6; hydrogen, hydroxy, unsubstituted or substituted C1-C8of alkyl, amino; halogen;

(g) R6is H, -C(O)R7, -C(S)R7; -C(O)NR72; ; -C(S)NR72; ; -C(O)OR7or-C(S)OR7where R7is hydrogen or unsubstituted or substituted C1-C8the alkyl,

(i) R8is substituted or unsubstituted C1-C8the alkyl and at least one of R1, R2, R3or R5is SR6or R8SR6.

Other tizamidine phosphonate compounds have the following structure

< / BR>
where m and n are integers from 0 to 10, and m + n equals 0 to 10, where

(a) z is a covalent bond; monocyclic or polycyclic carbocyclic structural part or a monocyclic or polycyclic heterocyclic structural part containing one or more heteroatoms selected from O, S or N;

(b) Q I/SUP> where R4is C1-C8by alkyl;

(d) each R1independently selected from-SR6; -R8SR6, zero, hydrogen, unsubstituted or substituted C1-C8of alkyl; substituted or unsubstituted monocyclic or polycyclic carbocycle, unsubstituted or substituted aryl, unsubstituted or substituted thiophene, substituted or unsubstituted oxadiazole; substituted or unsubstituted of pyranone; substituted or unsubstituted furan; hydroxy, alkoxy, CO2R3; -O2CR6; NR32, -N(R3)C(O)R3, -OR3, -C(O)N(R3)2substituted or unsubstituted benzyl, nitro, or combinations thereof;

(e) R1represents one or more substituents selected from-SR6, -R8SR6, -CO2R3, -O2CR3, -C(O)N(R3)2, NR32N(R3)C(O)R3and zero, hydrogen, substituted or unsubstituted aryl, hydroxy, substituted or unsubstituted benzyl, nitro, or combinations thereof;

(f) each R3independently selected from hydrogen, substituted or unsubstituted C1-C8the alkyl or R8SR6;

(g) R5is selected from-SR6, R8SR6 is H, -C(O)R7, -C(S)R7, -C(O)NR72,-C(S)NR72, -C(O)OR7or-C(S)OR7where R7is hydrogen or unsubstituted or substituted C1-C8the alkyl,

(i) R8is C1-C8substituted or unsubstituted alkyl, and at least one of R1, R2, R3or R5is SR6or R8SR6.

Preferred thioethers, suitable for use in the methods described herein include compounds having the following General structure

< / BR>
< / BR>
< / BR>
Preferred delievery include compounds having the following General structure

< / BR>
Preferred thiocarbonate include compounds which have the following General structure

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
Preferred dithiocarbonate include compounds which have the following General structure

< / BR>
< / BR>
< / BR>
Preferred tizanidine phosphonate compounds suitable for use in the treatment regimens of the present invention include, but are not limited to, compounds having the following basic structure

< / BR>
< / BR>
< / BR>
< / BR>
Especially preferred are the following t is N. Francis et al, registered on may 29, 1992, cited as references.

Specific phosphonate active ingredients

Specific phosphonate compounds which are suitable for use here, and described in parts I, A, B, and C above, include, but are not limited to, the following compounds and their farmatsevticheskii salts and esters:

3-pyridyl-1-hydroxyethylidene-1,1-bisphosphonic acid,

N-(2'-(3'-methyl)-pyridinyl)aminomethanesulfonic acid,

N-(2'-(5'-methyl)-pyridinyl)aminomethanesulfonic acid,

N-(2'-(5'-methyl)-piperidinylidene)aminomethanesulfonic acid,

N-(2-(3-methyl)piperidinylidene)aminomethylphosphonic acid.

2-(2'-pyridinyl)ethane-1-phosphono-1-methylphosphonous acid,

2-(2'-piperidinyl)ethane-1-phosphono-1-methylphosphonous acid,

2-(p-AMINOPHENYL)-1-hydroxyethane-1-phosphono-1-methylphosphonous acid,

2-(m-AMINOPHENYL)-1-hydroxyethane-1-phosphono-1-methylphosphonous acid,

N-(1-(5-amino-2-methyl-1-oxo)-pentyl)aminomethylphosphonic acid.

N-(2'-(3'-methyl)-piperidinylidene)aminomethanesulfonic acid;

S-(2'-pyridinyl)timeandestimation-1-phosphono-1-methylphosphonous acid;

2-(N-imidazolyl)-1-hydroxyethane-1-phosphono-1-methylphosphonous acid.

3-(N-pentyl-N-methylamino)-1-hydroxypropan-1-phosphono-1-methylphosphonous acid;

4-amino-1-hydroxybutane-1-phosphono-1-methylphosphonous acid.

3-(N-pyrrolidino)-1-hydroxypropan-1-phosphono-1-methyl-phosphinic acid;

N-cyclohexenyltrichlorosilane acid.

S-(p-chlorophenyl)timeandestimation acid.

(7-dihydro-1-pyridine)metapopulation acid.

(7-dihydro-1-pyridine)hydroxymethylphosphonate acid.

(6-dihydro-2-pyridine)hydroxymethylphosphonate acid

2-(6-pyrrolopyridine)-1-hydroxyethane-1-phosphono-1-methylphosphonous acid.

1-aminoethane-1,1-biphosphonate acid.

2-aminoethane-1,1-biphosphonate acid.

3-aminopropane-1,1-biphosphonate acid.

3-aminopropan-1-hydroxy-1,1-biphosphonate acid.

3-(dimethylamino)-1-hydroxypropane-1,1-biphosphonate acid.

3,3-dimethyl-3-amino-1-hydroxypropane-1,1-biphosphonate acid, phenylaminopyrimidine acid.

N,N-dimethylaminomethylphenol acid.

N-(2-hydroxy is 5-amino-1-hydroxypentanal-1,1-biphosphonate acid.

6-amino-1-hydroxyhexane-1,1-biphosphonate acid indan-2,2-biphosphonate acid,

hexahedronal-2,2-biphosphonate acid.

2-(2-pyridyl)-1-hydroxyethane-1,1-biphosphonate acid.

N-(2-(5-amino)-pyridyl)-aminomethylphosphonic acid.

N-(2-(5-chloro) pyridyl)-aminomethylphosphonic acid.

N-(2-(3-picolyl))-aminomethylphosphonic acid.

N-(2-(4-picolyl))-aminomethylphosphonic acid.

N-(2-(5-picolyl))-aminomethylphosphonic acid.

N-(2-(6-picolyl))-aminomethylphosphonic acid.

N-(2-(3,4-lutidine))-aminomethylphosphonic acid.

N-(2-pyrimidyl)-aminomethylphosphonic acid.

N-(2-pyridyl)-2-aminoethane-1,1-biphosphonate acid.

2-(2-pyridyl)-ethane-1,1-biphosphonate acid.

2-(3-pyridyl)-ethane-1,1-biphosphonate acid.

2-(4-pyridyl)-ethane-1,1-biphosphonate acid.

2-(2-(3-picolyl))-oxetan-1,1-biphosphonate acid.

2-(3-pyridyl)-1-hydroxyethane-1,1-biphosphonate acid.

2-(N-imidazolyl)-1-hydroxyethane-1,1-biphosphonate acid.

3-(N-pentyl-N-methylamino)-1-hydroxypropane-1,1-biphosphonate acid.

3-(N-pyrrolidino)-1-hydroxyprop the l)timetemperature acid,

(7-dihydro-1-pyrindine)metamethodology acid,

(7-dihydro-1-pyrindine)hydroxymethylphosphonate acid,

(6-dihydro-2-pyrindine)hydroxymethylphosphonate acid,

2-(6-pyrrolopyridine)-1-hydroxyethyl-1,1-biphosphonate acid,

3-amino-1-hydroxypropane-1,1-biphosphonate acid,

6-amino-1-hydroxyhexane-1,1-biphosphonate acid,

2-(3-pyridyl)-1-hydroxyethane-1,1-biphosphonate acid,

2-(N-imidazolyl)-1-hydroxyethane-1,1-biphosphonate acid,

3-(N-pentyl-N-methylamino)-1-hydroxypropane-1,1-biphosphonate acid,

3-(N-pyrrolidino)-1-hydroxypropane-1,1-biphosphonate acid,

N-cycloheptaamylose acid,

(7-dihydro-1-pyrindine)-metamethodology acid,

(7-dihydro-1-pyrindine)hydroxymethylphosphonate acid,

(6-dihydro-2-pyrindine)hydroxymethylphosphonate acid,

2-(6-pyrrolopyridine)-1-hydroxyethane-1,1-biphosphonate acid,

octahydro-1,1-dimethyl-5,5-diphosphono-1-pyrindine salt,

octahydro-2,2-dimethyl-5,5-diphosphono-2-pyrindine salt,

octahydro-1,1-dimethyl-6,6-diphosphono-1-pyrindine salt,

octahydro-2,2-dimethyl-6,6-diphosphono-2-pyrindine salt,

octahydro-1,1-dimethyl-7,7-diphosphono-1-pyrindine salt,

octahydro-ahydro-1,3-diethyl-2,2-dimethyl-5,5-diphosphono-2-pyrindine salt,

octahydro-1,1-dimethyl-6,6-diphosphono-7-hydroxy-1-pyrindine salt,

octahydro-2,2-dimethyl-6,6-diphosphono-4-methoxy-2-pyrindine salt,

octahydro-7,7-diphosphono-1-ethyl-1-methyl-5-vinyl-1-pyrindine salt,

octahydro-2,2-dimethyl-1-(dimethylamino)-7,7-diphosphono-2-pyrindine salt,

octahydro-2-(3,4-dichlorophenyl)-1,1-dimethyl-7,7-diphosphono-1-pyrindine salt,

octahydro-1,1-diethyl-2-(p-dimethylaminophenyl)-7,7-diphosphono-1 - pyrindine salt,

octahydro-4-chloro-1,1-diethyl-6,6-diphosphono-1-pyrindine salt,

octahydro-4-amino-6,6-diphosphono-1-ethyl-1-propyl-1-pyrindine salt,

octahydro-7-carboxy-6,6-diphosphono-1,1-dipropyl-1-pyrindine salt,

octahydro-5-carboxymethyl(ether)-1,1-dimethyl-6,6-diphosphono-1-pyrindine salt,

octahydro-2,2-diethyl-6,6-diphosphono-4-hydroxy-2-pyrindine salt,

octahydro-5,5-diphosphono-2-ethyl-7-(ethylketone)-2-methyl-2-pyrindine salt,

octahydro-1,1-dimethyl-6,6-diphosphono-4-nitro-1-pyrindine salt,

octahydro-1,1-dimethyl-5,5-diphosphono-1-pyrindine salt,

octahydro-2,2-dimethyl-5,5-diphosphono-2-pyrindine salt,

octahydro-1,1-dimethyl-6,6-diphosphono-1-pyrindine salt,

octahydro-2,2-methyl-6,6-diphosphono-2-pyrindine salt,

octahydro-1,1-dimethyl-7,7-diphosphono-1-pyrindine salt,

OK the>/BR>octahydro-4-amino-1,1-dimethyl-6,6-diphosphono-1-pyrindine salt,

2-(2-hydroxy-2,2-diphosphonates)-1,1-dimethylpiperidine iodide,

3-(2-hydroxy-2,2-diphosphonates)-1-methylpyridine iodide,

3-(2-hydroxy-2,2-diphosphonates)-1-methylpyridine hydroxide,

3-(2,2-diphosphonates)-1-ethylpyridine chloride,

3-(2,2-diphosphonates)-1-(2-mercaptoethyl)pyridinium chloride,

2-(2-hydroxy-2,2-diphosphonates)-1-methylpyridine hydroxide,

3-(3-hydroxy-3,3-diphosphonates)-1-methylpyridine hydroxide,

3-(2,2-diphosphono-2-hydroxyethyl)-1,1-dimethylpiperidine iodide salt,

3-(2,2-diphosphonates)-1-heptylamine chloride,

3-(2,2-diphosphonates)-1-methylpyridine chloride,

3-(2,2-phosphoramidothioate)-1-methylpyridine iodide,

3-(2-phosphono-2-sulphoethyl)-1-methylpyridine chloride,

3-(2-carboxy-2-phosphonoethyl)-1-methylpyridine chloride,

2-diphosphonate-1,1-dimethylpiperidine chloride,

3-dipropionate-1,1-dimethylpiperidine chloride,

4-diphosphonate-1,1-dimethylpiperidine chloride,

2-(2,2-diphosphonates)-1,1-dimethylpiperidine chloride,

3-(2,2-diphosphonates)-1,1-dimethylpiperidine chloride,

4-(2,2-diphosphonates)-1,1-dimethylpiperidine chloride,

2-(2,2-diphosphonates)-1-methyl-1(2-mercaptoethyl)-1-methyl-1-(2-mercaptoethyl)piperidine chloride,

2-2,2-diphosphono-1-(2-mercaptoethyl)ethyl-1,1-dimethylpiperidine chloride,

3-2,2-diphosphono-1-(3-mercaptopropyl)ethyl-1,1-dimethyl-piperidine chloride,

4-2,2-diphosphono-1-(2-acetylethyl)ethyl-1,1-dimethylpiperidine chloride,

2-(2,2-diphosphono-2-hydroxyethyl)-1,1-dimethylpiperidine chloride,

3-(2,2-diphosphono-2-hydroxyethyl)-1,1-dimethylpiperidine chloride,

4-(2,2-diphosphono-2-hydroxyethyl)-1,1-dimethylpiperidine chloride,

2-(2,2-diphosphono-2-hydroxyethyl)-1,1,3-trimethylpyridine chloride,

2-(2,2-diphosphono-2-hydroxyethyl)-1,1,5-trimethylpyridine chloride,

2-(2,2-diphosphonates)-1,1,3-trimethylpyridine chloride,

2-2(2-diphosphonate)-1,1,5-trimethylpyridine chloride,

2-(3,3-diphosphonates)-1,1-dimethylpiperidine chloride,

3-(3,3-diphosphonates)-1,1-dimethylpiperidine chloride,

4-(3,3-diphosphonates)-1,1-dimethylpiperidine chloride,

2-(3,3-diphosphono-3-hydroxypropyl)-1,1-dimethylpiperidine chloride,

3-(3,3-diphosphono-3-hydroxypropyl)-1,1-dimethylpiperidine chloride,

4-(3,3-diphosphono-3-hydroxypropyl)-1,1-dimethylpiperidine chloride,

2-(2,2-diphosphonates)-1,1-dimethylpiperidine chloride,

3-(2,2-diphosphonates)-1,1-dimethylpiperidine chloride,

4-(2,2-diphosphonates)-1,1-dimethylpiperidine ipipeline chloride,

4-(2,2-diphosphono-2-amino-ethyl)-1,1-dimethylpiperidine chloride,

2-(2,2-diphosphono-2-amino-ethyl)-1,1,3-trimethylpyridine chloride,

2-(2,2-diphosphono-2-amino-ethyl)-1,1,3-trimethylpyridine chloride,

3-(2,2-diphosphono-2-amino-ethyl)-1,1,5-trimethylpyridine chloride,

2-(2,2-diphosphono-2-(methylamino)ethyl)-1,1-dimethylpiperidine chloride,

2-(4,4-diphosphono-4-hydroxybutyl)-1,1,3-trimethylpyridine chloride,

2-(4,4-diphosphono-4-hydroxybutyl)-1,1-dimethylpiperidine chloride,

2-(2,2-diphosphono-2-hydroxyethyl)-3-carboxy-1,1 - dimethylpiperidine chloride,

2-(2,2-diphosphono-2-hydroxyethyl)-5-carboxy-1,1 - dimethylpiperidine chloride,

2-(2,2-diphosphonates)-1-methylpyrimidine chloride,

4-(2,2-diphosphonates)-1-methylpyrimidine)chloride,

2-(2,2-diphosphono-2-hydroxyethyl)-1-methylpyrimidine chloride,

4-(2,2-diphosphono-2-hydroxyethyl)-1-methylpyrimidine chloride,

2-(3,3-diphosphonates)-1-methylpyrimidine chloride,

4-(3,3-diphosphonates)-1-methylpyrimidine chloride,

2-(3,3-diphosphono-1-hydroxypropyl)-1-methylpyrimidine chloride,

4-(3,3-diphosphono-1-hydroxypropyl)-1-methylpyrimidine chloride,

2-(2,2-diphosphono-2-amino-ethyl)-1-methylpyrimidine chloride,

3-(diphosphonates)oxo-1,1-dimethylpiperidine chloride,

4-(the

4-(2,2-diphosphonates)oxo-1,1-dimethylpiperidine chloride,

3-(diphosphonates)thio-1,1-dimethylpiperidine chloride,

4-(diphosphonates)thio-1,1-dimethylpiperidine chloride,

3-(2-hydroxy-2,2-diphosphonates)-1-methylpyridine iodide,

3-(2-hydroxy-2,2-diphosphonates)-1-methylpyridine hydroxide,

3-(2,2-diphosphonates)-1-(2-mercaptoethyl)pyridinium chloride,

2-(2-hydroxy-2,2-diphosphonates)-1,1-dimethylpiperidine iodide salt,

3-(2,2-diphosphono-2-hydroxyethyl)-1,1-dimethylpiperidine iodide salt,

3-(2,2-diphosphonates)-1-heptylamine chloride,

3-(2,2-diphosphonates)-1-methylpyridine chloride,

2-(2,2-diphosphonates)-1,1-dimethylpiperidine chloride,

3-(2,2-diphosphonates)-1,1-dimethylpiperidine chloride,

4-(2,2-diphosphonates)-1,1-dimethylpiperidine chloride,

2-(2,2-diphosphono-2-hydroxyethyl)-1,1-dimethylpiperidine chloride,

3-(2,2-diphosphono-2-hydroxyethyl)-1,1-dimethylpiperidine chloride,

4-(2,2-diphosphono-2-hydroxyethyl)-1,1-dimethylpiperidine chloride,

2-(2,2-diphosphono-2-hydroxyethyl)-1,1,3-trimethylpyridine chloride,

2-(2,2-diphosphono-2-hydroxyethyl)-1,1-5-trimethylpyridine chloride,

2-2,2-diphosphono-1-(2-mercaptoethyl)ethyl-1,1-dimethylpiperidine chloride,

3 - 2,2-diphosphono-1(3-mercaptopropyl 3-(2,2-diphosphonates)-1-methyl-1-(2-mercaptoethyl)piperidine chloride,

4-(2,2-diphosphonates-1-methyl-1-(2-mercaptoethyl)piperidine chloride,

3-(2-hydroxy-2,2-diphosphonates)-1-methylpyridine iodide,

3-(2-hydroxy-2,2-diphosphonates)-1-methylpyridine hydroxide,

3-(2,2-diphosphonates)-1-(2-mercaptoethyl)pyridinium chloride,

2 - 2,2-diphosphono-1-(2-mercaptoethyl)-ethyl-1,1-dimethylpiperidine chloride,

3 - 2,2-diphosphono-1-(3-mercaptopropyl)-ethyl-1,1 - dimethylpiperidine chloride,

2-(2,2-diphosphonates)-1-methyl-1-(2-mercaptoethyl)piperidine chloride,

3-(2,2-diphosphonates)-1-methyl-1-(2-mercaptoethyl)piperidine chloride,

N-(4-hydroxy-4,4-diphosphonate)-N,N,N-trimethylammonium iodide,

N-(3-hydroxy-3,3-diphosphonates)-N,N-dimethyl-N-pentylamine iodide,

N-(3-hydroxy-3,3-diphosphonates)-N,N,N-trimethylammonium iodide,

N-cycloheptyl-N,N-dimethyl-N-(diphosphonates)ammonium iodide,

N-(2-acetylethyl)-N-(4-hydroxy-4,4-diphosphonate)-N, N - dimethylammonio bromide,

N-(2-acetylethyl)-N-(3-hydroxy-3,3-diphosphonates)-N-methyl - N-pentylamine bromide,

N-(4-hydroxy-4,4-diphosphonate)-N-(3-mercaptopropyl)-N, N - dimethylammonio chloride

N-(4-hydroxy-4,4-diphosphonate)-N-(mercaptomethyl)-N, N - dimethylammonio chloride,

N-(4-hydroxy-4,4-diphosphonate)-N-(4-methoxybutyl)-N,N - dimethylammonio chlorite is-diphosphonate)-N, N, N - trimethylammonium chloride,

N-(3-hydroxy-2-mercapto-3,3-diphosphonates)-N,N-dimethyl-N - pentylamine chloride,

N-(3-hydroxy-2-acetylthio-3,3-diphosphonates)-N, N-dimethyl-N - pentylamine chloride,

N-(3-hydroxy-3,3-diphosphonates)-N-methyl-N-pentyl-N-(2-(3-pyridyl)ethyl)ammonium chloride;

N-cycloheptyl-N-(2-mercaptoethyl)-N-methyl-N-(diphosphonates) ammonium chloride,

N-cycloheptyl-N-(mercaptomethyl)-N-methyl-N-(diphosphonates) ammonium)chloride,

N, N-dimethyl-N-(4,4-diphosphonate)-N-(2-(3-piperidinyl)-ethyl) ammonium chloride,

[2-[(2,2-dimethyl-N-oxopropyl)thio]ethylidene] bebopalula acid],

[2-(benzylthio)ethylidene]bi(phosphonic acid);

[2-(p-methoxybenzylthio)ethylidene]bi(phosphonic acid);

[2-(p-aminobenzoate)ethylidene]bi(phosphonic acid);

[2-(acetylthio)ethylidene]bi(phosphonic acid disodium salt),

[2-mercapto-2-(phenyl)ethylidene]bi(phosphonic acid),

[2-mercapto-2-(o-AMINOPHENYL)ethylidene]bi(phosphonic acid),

[2-mercapto-2-(m-AMINOPHENYL)ethylidene]bi(phosphonic acid),

[2-mercapto-2-(p-AMINOPHENYL)ethylidene]bi(phosphonic acid),

[2 acetylthio-2-(phenyl)ethylidene]bi(phosphonic acid),

[3-mercapto-1-hydroxybutylidene]bi(phosphonic acid),

[2-MANOVA acid),

[4-amino-2-mercapto-1-hydroxybutylidene]bi(phosphonic acid),

[2-amino-1-hydroxy-3-mercapto-3-methylbutyrate]bi(phosphonic acid),

[2-amino-1-hydroxy-3-acetylthio-3-methylbutyrate]bi(phosphonic acid),

1-[(hydroxy)methylphosphinyl]-2-mercaptoethylamine acid,

[2-mercapto-2-methylpiperidin]bi(phosphonic acid),

[2-(acetylthio)-2-methylpiperidin)bi(phosphonic acid)disodium salt,

[1-hydroxy-2-(2-acetyldigitoxin)ethylidene]bi(phosphonic acid),

[1-hydroxy-2-(3-acetyldigitoxin)ethylidene]bi (phosphonic acid),

[1-hydroxy-2-(4-acetyldigitoxin)ethylidene]bi (phosphonic acid),

[1-hydroxy-2-(2-mercaptonicotinic)ethylidene]bi(phosphonic acid),

[1-hydroxy-2-(3-mercaptoacetic)ethylidene]bi (phosphonic acid),

[1-hydroxy-2-(4-mercaptonicotinic)ethylidene]bi (phosphonic acid),

[1-hydroxy-2-(2-(3-mercaptopropyl)cyclohexyl)ethylidene] bi (phosphonic acid),

[1-hydroxy-2-(3-(2-mercaptoethyl)cyclohexyl)ethylidene] bi(phosphonic acid),

[1-hydroxy-2-(2-acetylthiophene)ethylidene]bi (phosphonic acid),

[1-hydroxy-2-(3-acetylthiophene)ethylidene]bi (phosphonic acid),

[1-hydroxy-2-(2 is Ospanova acid),

[1-hydroxy-2-(2-(2-mercaptoethyl)cyclopentyl)ethylidene] bi(phosphonic acid),

[1-hydroxy-2-(2-(3-mercaptopropyl)cyclopentyl)ethylidene] bi(phosphonic acid),

[2-mercapto-5-phenylindolizine]bi(phosphonic acid),

[2-mercapto-5-(o-AMINOPHENYL)pentylidene]bi(phosphonic acid),

[2-mercapto-5-(m-AMINOPHENYL)pentylidene]bi(phosphonic acid),

[2-mercapto-5-(p-AMINOPHENYL)pentylidene]bi(phosphonic acid),

[2-mercapto-5-phenylbutyrate]bi(phosphonic acid),

[2-mercapto-5-(o-AMINOPHENYL)butylidene]bi(phosphonic acid),

[2-mercapto-5-(m-AMINOPHENYL)butylidene]bi(phosphonic acid),

[2-mercapto-5-(p-AMINOPHENYL)butylidene]b)phosphonic acid),

[2 acetylthio-5-phenylindolizine]bi(phosphonic acid),

[2 acetylthio-5-(p-AMINOPHENYL)pentylidene]bi(phosphonic acid),

[3-(3-furfuryl)-2-mercaptoethylamine]bi(phosphonic acid),

[3-cyclohexyl-2-mercaptopropionyl]bi(phosphonic acid),

octahydro-2-mercapto-1-pyrindine-5,5-bebopalula acid,

octahydro-3-mercapto-1-pyrindine-5,5-bebopalula acid,

octahydro-4-mercapto-1-pyrindine-5,5-bebopalula acid,

octahydro-3-thiomethyl-1-pyrindine-5,5-bebopalula acid,

octahydro-3-thioethyl-1 kagero-2-mercapto-1-pyrindine-6,6-bebopalula acid,

octahydro-3-thiopropyl-1-pyrindine-5,5-bebopalula acid,

octahydro-3-dibutyl-1-pyrindine-5,5-bebopalula acid,

octahydro-2-thioethyl-1-pyrindine-5,5-bebopalula acid,

octahydro-4-dipropyl-1-pyrindine-5,5-bebopalula acid,

octahydro-2-methoxy-4-dibutyl-1-pyrindine-5,5-bebopalula acid,

octahydro-3-mercapto-1-pyrindine-6,6-bebopalula acid,

octahydro-4-mercapto-1-pyrindine-6,6-bebopalula acid,

octahydro-3-thiomethyl-1-pyrindine-6,6-bebopalula acid,

octahydro-3-thioethyl-1-pyrindine-6,6-bebopalula acid,

octahydro-3-thiopropyl-1-pyrindine-6,6-bebopalula acid,

octahydro-3-dibutyl-1-pyrindine-6,6-bebopalula acid,

octahydro-2-thioethyl-1-pyrindine-6,6-bebopalula acid,

octahydro-4-dipropyl-1-pyrindine-6,6-bebopalula acid,

octahydro-2-methoxy-4-dibutyl-1-pyrindine-6,6-bebopalula acid,

octahydro-2-mercapto-1-pyrindine-7,7-bebopalula acid,

octahydro-3-mercapto-1-pyrindine-7,7-bebopalula acid,

octahydro-4-mercapto-1-pyrindine-7,7-bebopalula acid,

octahydro-3-thiomethyl-1-pyrindine-7,7-bebopalula acid,

octahydro-3-thioethyl-1-pyrindine-7,7-bebopalula acid,

oktay is and,

octahydro-2-thioethyl-1-pyrindine-7,7-bebopalula acid,

octahydro-4-dipropyl-1-pyrindine-7,7-bebopalula acid,

octahydro-2-methoxy-4-dibutyl-1-pyrindine-7,7-bebopalula acid,

octahydro-1-mercapto-2-pyrindine-5,5-bebopalula acid,

octahydro-3-mercapto-2-pyrindine-5,5-bebopalula acid,

octahydro-4-mercapto-2-pyridine-5,5-bebopalula acid,

octahydro-4-thiomethyl-2-pyrindine-5,5-bebopalula acid,

octahydro-4-thioethyl-2-pyrindine-5,5-bebopalula acid,

octahydro-4-dipropyl-2-pyrindine-5,5-bebopalula acid,

octahydro-4-dibutyl-2-pyrindine-5,5-bebopalula acid,

octahydro-3-thioethyl-2-pyrindine-5,5-bebopalula acid,

octahydro-1-thiopropyl-2-pyrindine-5,5-bebopalula acid,

octahydro-1-methoxy-4-dibutyl-2-pyrindine-5,5-bebopalula acid,

octahydro-4-amino-1-dibutyl-2-pyrindine-5,5-bebopalula acid,

octahydro-4-hydroxy-4-dibutyl-2-pyrindine-5,5-bebopalula acid,

octahydro-1-mercapto-2-pyrindine-6,6-bebopalula acid,

octahydro-3-mercapto-2-pyrindine-6,6-bebopalula acid,

octahydro-4-mercapto-2-pyrindine-6,6-bebopalula acid,

octahydro-4-thiomethyl-2-pyrindine-6,6-bebopalula acid is spanova acid,

octahydro-4-dibutyl-2-pyrindine-6,6-bebopalula acid,

octahydro-3-thioethyl-2-pyrindine-6,6-bebopalula acid,

octahydro-1-thiopropyl-2-pyrindine-6,6-bebopalula acid,

octahydro-1-methoxy-4-dibutyl-2-pyrindine-6,6-bebopalula acid,

octahydro-4-amino-1-dibutyl-2-pyrindine-6,6-bebopalula acid,

octahydro-4-hydroxy-4-dibutyl-2-pyrindine-6,6-bebopalula acid,

octahydro-1-mercapto-2-pyrindine-7,7-bebopalula acid,

octahydro-3-mercapto-2-pyrindine-7,7-bebopalula acid,

octahydro-4-mercapto-2-pyrindine-7,7-bebopalula acid,

octahydro-4-thiomethyl-2-pyrindine-7,7-bebopalula acid,

octahydro-4-dioctahedral-3-amino-5-(1-mercapto-1-methyl)ethyl-1 - pyrindine-octahydro-7-mercapto-1-pyrindine-6,6-bebopalula acid,

octahydro-5-(2-thioethyl)-1-pyrindine-6,6-bebopalula acid,

octahydro-7-thiomethyl-1-pyrindine-6,6-bebopalula acid,

octahydro-7-dibutyl-1-pyrindine-6,6-bebopalula acid,

octahydro-3-amino-7-mercapto-1-pyrindine-6,6-bebopalula acid,

octahydro-3-amino-5-dipropyl-1-pyrindine-6,6-bebopalula acid,

octahydro-3-methoxy-7-(1-mercapto-1-methyl)ethyl-1-pyrindine-6,6 - bebopalula acid,

octahydro-3-Aminova acid,

octahydro-4-dibutyl-2-pyrindine-7,7-bebopalula acid,

octahydro-3-thioethyl-2-pyrindine-7,7-bebopalula acid,

octahydro-1-thiopropyl-2-pyrindine-7,7-bebopalula acid,

octahydro-1-methoxy-4-dibutyl-2-pyrindine-7,7-bebopalula acid,

octahydro-4-amino-1-dibutyl-2-pyrindine-7,7-bebopalula acid,

octahydro-4-hydroxy-4-dibutyl-2-pyrindine-7,7-bebopalula acid,

octahydro-7-(1-mercapto-1-methyl)ethyl-1-pyrindine-5,5 - bebopalula acid,

octahydro-3-hydroxy-7-dibutyl-1-pyrindine-5,5-bebopalula acid,

octahydro-3-dimethylamino-6-thiomethyl-1-pyrindine-5,5-bebopalula acid,

octahydro-7-thioethyl-1-pyrindine-5,5-bebopalula acid,

octahydro-6-hydroxy-7-dipropyl-1-pyrindine-5,5-bebopalula acid,

octahydro-6-(1-mercapto-1-methyl)ethyl-1-pyrindine-5,5-bebopalula acid,

dihydro-2-mercapto-1-pyrindine-6,6-bebopalula acid,

dihydro-3-mercapto-1-pyrindine-6,6-bebopalula acid,

dihydro-4-mercapto-1-pyrindine-6,6-bebopalula acid,

dihydro-3-thiomethyl-1-pyrindine-6,6-bebopalula acid,

dihydro-3-thioethyl-1-pyrindine-6,6-bebopalula acid,

dihydro-3-thiopropyl-1-pyrindine-6,6-bebopalula acid,

dihydro-3-is ihydro-4-dipropyl-1-pyrindine-6,6-bebopalula acid,

dihydro-2-methoxy-4-dibutyl-1-pyrindine-6,6-bebopalula acid,

dihydro-1-mercapto-2-pyrindine-6,6-bebopalula acid,

dihydro-3-mercapto-2-pyrindine-6,6-bebopalula acid,

dihydro-4-mercapto-2-pyrindine-6,6-bebopalula acid,

dihydro-4-thiomethyl-2-pyrindine-6,6-bebopalula acid,

dihydro-4-thioethyl-2-pyrindine-6,6-bebopalula acid,

dihydro-4-dipropyl-2-pyrindine-6,6-bebopalula acid,

dihydro-4-dibutyl-2-pyrindine-6,6-bebopalula acid,

dihydro-3-thioethyl-2-pyrindine-6,6-bebopalula acid,

dihydro-1-thiopropyl-2-pyrindine-6,6-bebopalula acid,

dihydro-1-methoxy-4-dibutyl-2-pyrindine-6,6-bebopalula acid,

dihydro-4-amino-1-dibutyl-2-pyrindine-6,6-bebopalula acid,

dihydro-4-hydroxy-4-dibutyl-2-pyrindine-6,6-bebopalula acid,

dihydro-7-mercapto-1-pyrindine-6,6-bebopalula acid,

dihydro-5-mercapto-1-pyrindine-6,6-bebopalula acid,

dihydro-7-thiomethyl-1-pyrindine-6,6-bebopalula acid,

dihydro-7-dibutyl-1-pyrindine-6,6-bebopalula acid,

dihydro-3-amino-7-mercapto-1-pyrindine-6,6-bebopalula acid,

dihydro-3-amino-5-dipropyl-1-pyrindine-6,6-bebopalula acid,

dihydro-3-marks the th acid,

dihydro-3-mercapto-2-pyrindine-7,7-bebopalula acid,

dihydro-4-mercapto-2-pyrindine-7,7-bebopalula acid,

dihydro-4-thiomethyl-2-pyrindine-7,7-bebopalula acid,

dihydro-4-thioethyl-2-pyrindine-7,7-bebopalula acid,

dihydro-4-dipropyl-2-pyrindine-7,7-bebopalula acid,

dihydro-4-dibutyl-3-pyrindine-7,7-bebopalula acid,

dihydro-3-thioethyl-2-pyrindine-7,7-bebopalula acid,

dihydro-1-thiopropyl-2-pyrindine-7,7-bebopalula acid,

dihydro-1-methoxy-4-dibutyl-2-pyrindine-7,7-bebopalula acid,

dihydro-4-amino-1-dibutyl-2-pyrindine-7,7-bebopalula acid,

dihydro-4-hydroxy-4-dibutyl-2-pyrindine-7,7-bebopalula acid,

dihydro-2-mercapto-1-pyrindine-7,7-bebopalula acid,

dihydro-3-mercapto-1-pyrindine-7,7-bebopalula acid,

dihydro-4-mercapto-1-pyrindine-7,7-bebopalula acid,

dihydro-3-thiomethyl-1-pyrindine-7,7-biophosphonate acid,

dihydro-3-thioethyl-1-pyrindine-7,7-bebopalula acid,

dihydro-3-thiopropyl-1-pyrindine-7,7-bebopalula acid,

dihydro-3-dibutyl-1-pyrindine-7,7-bebopalula acid,

dihydro-2-thioethyl-1-pyrindine-7,7-biophosphonate acid,

dihydro-4-dipropyl-1-pyrindine-7,7-biposto-1-methyl)ethyl-1-pyrindine-5,5-bebopalula acid,

dihydro-3-hydroxy-7-dibutyl-1-pyrindine-5,5-bebopalula acid,

dihydro-3-dimethylamino-6-thiomethyl-1-pyrindine-5,5-bebopalula acid,

dihydro-7-thioethyl-1-pyrindine-5,5-bebopalula acid,

dihydro-6-hydroxy-7-dipropyl-1-pyrindine-5,5-bebopalula acid,

dihydro-6-(1-mercapto-1-methyl)ethyl-1-pyridil-5,5-bebopalula acid,

dihydro-1-mercapto-2-pyrindine-5,5-bebopalula acid,

dihydro-3-mercapto-2-pyrindine-5,5-bebopalula acid,

dihydro-4-mercapto-2-pyrindine-5,5-bebopalula acid,

dihydro-4-thiomethyl-2-pyrindine-5,5-bebopalula acid,

dihydro-4-thioethyl-2-pyrindine-5,5-bebopalula acid,

dihydro-4-dipropyl-2-pyrindine-5,5-bebopalula acid,

dihydro-4-dibutyl-2-pyrindine-5,5-biophosphonate acid,

dihydro-3-thioethyl-2-pyrindine-5,5-bebopalula acid,

dihydro-1-thiopropyl-2-pyrindine-5,5-bebopalula acid,

dihydro-1-methoxy-4-dibutyl-2-pyrindine-5,5-bebopalula acid,

dihydro-4-amino-1-dibutyl-2-pyrindine-5,5-bebopalula acid,

dihydro-4-hydroxy-4-dibutyl-2-pyrindine-5,5-bebopalula acid,

dihydro-2-mercapto-1-pyrindine-5,5-bebopalula acid,

dihydro-3-mercapto-1-pyrindine-5,5-bebopalula kalfopoulou acid,

dihydro-3-thioethyl-1-pyrindine-5,5-biphosphonate acid,

dihydro-3-thiopropyl-1-pyrindine-5,5-biphosphonate acid,

dihydro-3-dibutyl-1-pyrindine-5,5-biphosphonate acid,

dihydro-2-thioethyl-1-pyrindine-5,5-biphosphonate acid,

dihydro-4-dipropyl-1-pyrindine-5,5-biphosphonate acid,

dihydro-2-methoxy-4-dibutyl-1-pyrindine-5,5-biphosphonate acid.

[(5-[mercaptomethyl]-2-piperidinyl)methylene]bi[phosphonic acid].

[(5-mercaptomethyl-3-piperidinylmethyl]bi[phosphonic acid].

[(5-mercapto-2-piperidinyl)methylene]bis[phosphonic acid],

[(5-4-mercaptomethyl-2-piperidinyl methylene]bi[phosphonic acid].

[(5-mercapto-3-piperidinyl]methylene]bi[phosphonic acid],

[(5-5-mercaptomethyl-3-piperidinyl]methylene]bi[phosphonic acid].

[(5-2-mercaptoethyl-4-piperidinyl]methylene-biphosphonate acid,

[(5-mercapto-4-piperidinyl)methylene]-bi[phosphonic acid],

[2-[(5-mercapto-2-piperidinyl)ethylidene]bi[phosphonic acid],

[2-[5-3-mercaptopropyl-2-piperidinyl)ethylidene]bi[phosphonic acid],

[2-(5-mercapto-3-piperidinyl)ethylidene]bi[phosphonic acid],

[2-(5-mercapto-4-piperidinyl)ethylidene]bi[phosphonic acid],

the ilidene]bi[phosphonic acid],

[(2-5-mercapto-2-piperidinyl-1-hydroxy)ethylidene]bi[phosphonic acid],

[(2-5-(3-mercaptopropyl)-2-piperidinyl-1-hydroxy)ethylidene]bi [phosphonic acid],

[(2-5-mercapto-3-piperidinyl]-1-hydroxy)ethylidene]bi[phosphonic acid] ,

[(2-[5-(2-mercaptoethyl)-3-piperidinyl-1-hydroxy)ethylidene]-bi [phosphonic acid],

[2-[5-mercapto-4-piperidinyl-1-hydroxy)ethylidene]bi[phosphonic acid],

[2-[5-mercaptomethyl-4-piperidinyl] -1-hydroxy)ethylidene] bis[phosphonic acid].

[(2-5-mercaptomethyl-3-methyl-2-piperidinyl-1-hydroxy)-ethylidene] bi [phosphonic acid],

[(2-5-mercapto-3-methyl-2-piperidinyl-1-hydroxy)-ethylidene]bi [phosphonic acid],

[(2-3-mercaptomethyl-5-methyl-2-piperidinyl-1-hydroxy)-ethylidene] bi [phosphonic acid],

[2-(5-mercaptomethyl-3-methyl-2-piperidinyl)-ethylidene]bi [phosphonic acid]; [2-(3-mercaptomethyl-5-methyl-2-piperidinyl)ethylidene]bi[phosphonic acid],

[3-[5-(mercaptomethyl)-2-piperidinyl]propylidene]bi[phosphonic acid],

[3-[5-(mercaptomethyl)-3-piperidinyl]propylidene]bi[phosphonic acid],

[3-[5-(mercaptomethyl)-4-piperidinyl]propylidene]bi[phosphonic acid],

[3-[5-(mercaptomethyl)-2-piperidinyl]-1-hydroxypropylamino]bi [phosphonic acid],
[2-(3-mercaptomethyl-5-methyl-2-pyridinyl)ethylidene]-bi[phosphonic acid; [2-(5-/3-mercaptopropyl-2-methyl-2-piperidinyl)ethylidene]bi [phosphonic acid],

[(2-[5-(2-mercaptopropyl)-2-piperidinyl]-1-amino)ethylidene]bi [phosphonic acid],

[(2-[5-(3-mercaptopropyl)-3-piperidinyl]-1-amino)ethylidene][bi [phosphonic acid],

[2-(5-[3-mercaptopropyl] -4-piperidinyl)-1-aminoacridine] bi [phosphonic acid],

[(2-[3-methyl-5-(3-mercaptopropyl)-2-piperidinyl] -1-hydroxy) ethylidene] bi[phosphonic acid],

[(2-[3-amino-5-(3-mercaptopropyl)-2-piperidinyl] -1-hydroxy) ethylidene] bi[phosphonic acid],

[2-[5-mercapto-2-(1,4-diazines)ethylidene]bi[phosphonic acid],

[2-[5-(3-mercaptopropyl)-2-(1,4-diazines)]-ethylidene]bi [phosphonic acid],

[2-[5-(3-mercaptopropyl)-2-(1,4-diazines)]-1-hydroxyethylidene] bi[phosphonic acid],

[2-[5-mercapto-2-(1,4-diazines)]-1-hydroxyethylidene]-bi [phosphonic acid],

[2-[5-mercapto-2-(1,3-diazines)]ethylidene]bi[phosphonic acid],

[2-[5-(3-mercaptopropyl)-2-(1,3-diazines)] ethylidene] bi [phosphonic acid],

[2-[5-(3-mercaptopropyl)-2-(1,3-diazines)] -1-hydroxyethylidene] bis[phosphonic acid],

[2-[5-mercapto-2-(1,3-diazines)]-1-hydroxyethylidene]bi [phosphonic acid],

[(5-[3-Mer is]bi[phosphonic acid],

[(5-3-mercaptopropyl-3-piperidinyl)iminomethylene]bi[phosphonic acid],

[(5-mercapto-3-piperidinyl)iminomethylene]bi[phosphonic acid],

[(5-mercapto-4-piperidinyl)iminomethylene]bi[phosphonic acid],

[(5-[3-mercaptopropyl] -4-piperidinyl)aminomethyl] -bi [phosphonic acid],

[(5-mercapto-3-methyl-2-piperidinylidene)iminomethylene] bi [phosphonic acid],

[(5-[3-mercaptopropyl] -3-methyl-2-piperidinylidene)-aminomethyl] bi[phosphonic acid],

[2-(5-mercapto-3-methyl-2-piperidinylidene)aminoethyl]bi [phosphonic acid],

[2-(5-3-mercaptopropyl-3-methyl-2-piperidinylidene)aminomethyl] - bi[phosphonic acid],

[(5-mercapto-2-piperidinylidene)iminomethylene]bi[phosphonic acid],

[(5-[3-mercaptopropyl] -2-piperidinylidene)iminomethylene] bi [phosphonic acid],

[2-(5-mercapto-2-piperidinylidene)aminoethyl]-bi[phosphonic acid],

[(5-[3-mercaptopropyl] -2-piperidinylidene)-aminomethyl] bi [phosphonic acid],

[(5-[3-mercaptopropyl] -2-1,4-diazonamide)iminomethylene] bi [phosphonic acid].

[(5-[3-mercaptopropyl] -2-1,3-diaziridine)aminomethyl]-bi- (phosphonic acid);

[(4-[3-mercaptopropyl]-2-1,3,5-triazinone)aminomethyl]- bi(phosphonic acid), and
< means (NSPs)

Nonsteroidal anti-inflammatory agents suitable for use in the treatment of arthritis, described herein, include all non-steroidal anti-inflammatory drugs (NSPs), used to treat unwanted inflammation of body tissues. Suitable NSPs for use in the regimens described herein, include, but are not limited to, anti-inflammatory agents on the basis of indole (including, among others, indomethacin, indexa and the like); anti-inflammatory agents on the basis of salicylates (including, among others, aspirin, etc); anti-inflammatory agents on the basis of phenylacetic acid (including, among others, fenoprofen, Ketoprofen, MK-830, etc); anti-inflammatory agents on the basis of pyrazolidine (including, among others, phenylbutazone, oxyphenbutazone and so on); and anti-inflammatory drugs on the basis of p-(isobutylphenyl)acetic acid (including, among others, buprofen, ibufenac and so on).

The above anti-inflammatory compounds and their use for the treatment of diseases of the joints known; see, for example (based compounds indole)

Thompson M. et al., "Further experience with indomethacin in the treatment of rhe umatic disorders", 1(1966), pp. 80-83; British Medical Jurnal, vol. Ktrials", Clinical Pharmacological Therapentics, Vol. 9 (1968), pp. 94-107; (salicylates connections) REPORT ON RHEUMATIC DISEASES, No. N 33, London, The Arthritis and Rheumatism councie 1968; Hart, F. D., "Control of Pain in rheumatic disorders", British Medical Journal, Vol. III (1968) pp. 635-640; Hart, F. D., "Antiinflammatorg drugs in the treatment of rheumatic discases", Practitioner, Vol. 205 (1970), pp. 597-603; (compounds based on n-(isobutylphenyl)-acetic acid) Boardman et al., "Ibuprofen in the treatment of rhenmatoid arthritis and osteoarthritis", Ann. Rheum. Dis., Vol. 26 (1967) pp. 560-561; Jasani et al. , "Ibuprofen in Rheumatoid Arthritis; Clinical study of analgesic and anti. inflammatory activity", Ann. Rheum. Dis. Vol. 27 (1968) pp. 457-462; Chalmers et al "Clinical experience with Ibuprofen in the treatment of rheumatoid arthritis", Ann. Rheum. Dis., Vol. 28(5) (1969) pp. 513-517.

NSPs, preferred for use in the methods of treatment described herein include, but are not limited to, salicylates, indomethacin, flurbiprofen, diclofenac, naproxen, piroxicam, tebufelone and ibuprofen. Other NSPs suitable for use here include, but are not limited to, etodolac, nabumetone, tenidap, alkoven, antipyrine, aminopyrine, dipyrone, aminopyrine, phenylbutazone, kliesen, oxyphenbutazone, prexaton, Amazon, benzylamine, bukola, cinchophen, clonixin, tetrazol, epirizole, fenoprofen, floctafenine, flufenamic acid, glutenin, indoprofen, Ketoprofen, meclofenamic acid, mefenamico and niflumova acid, fenac the s NSPs also include any non-steroidal compounds, used to treat unwanted inflammation of body tissues. Inflammation or inflammatory response is the result of a complex of interrelated physiological effects, including increased vascular permeability, fluid accumulation and migration changes of population of inflammatory cells into the area of inflammation. Clinical manifestations of inflammation include swelling (edema), increased local temperature, erythema and pain. The inflammatory reaction can be caused by any number of causal factors, including certain bacteria, irradiation, hypersensitivity to chemicals, arthritis and condition like arthritis. The inflammatory reaction is usually considered the primary defense mechanism of the body, but uncontrolled, it can become excessive and may lead to functional failure. In fact, as stated above, it is considered that the greatest destruction of bones and joints, which occurs when the conditions of arthritis, occurs at times of outbreaks, when inflammation is particularly severe.

As stated above, there are numerous side effects associated with taking NSPs for extended periods and/or excessive Aya ulceration of the stomach and intestines, bleeding and perforation; renal diseases, liver disease, impaired vision, physiological and psychological effects on the Central nervous system. As stated here above, when the daily dosage SPVs used in the regimens described herein, conventional therapeutic daily dose specific NSPs reduced by 20-80%, preferably 30-80%, most preferably 50-80%, of the proposed dose, appropriate for use here, therefore, include from 20% to 80%, preferably from 20 to 70%, most preferably from 20 to 50% of conventional therapeutic doses. Accordingly, table 1 presents suitable for this method of treatment described herein, the dosage of some preferred NSPs. To facilitate comparison the usual therapeutic dose (hereafter SEP) is provided for each preferred NSPs and presents one which is contained in Physician''s Desk Reference, 46th product, 1992 (hereafter PDR), doses are listed for each preferred NSPs. When PDR is given higher doses given for "restricted periods" (OP) or during active exacerbations (AO), these doses are given in a separate column. Dosage NSPs appropriate, equal to from 20% to 80% of the DEPARTMENT presented this specific NSPs.

Treatment

This invention is methods of treating arthritis in humans or animals affected by arthritis, especially rheumatoid arthritis or osteoarthritis, comprising one or more than sixty (60) day periods, consisting of arbitrary injection mode NSPs and the introduction of phosphonate, and

(a) the specified arbitrary injection mode NSPs includes the introduction of a specified subject NSPs level from 20% to 80%, preferably from 20% to 70%, most preferably from 20% to 50% of the commonly prescribed daily doses for each day in which the specified NSPs is entered; provided that the specified NSPs is introduced in sufficient quantities and in a sufficient number of days to relieve symptoms of inflammation, and with

(b) the specified mode is the introduction of phosphonate includes the introduction of a specified subject phosphonate at the system level, approximately from 0.0005 mg/kg to about 1.0 mg/kg per day, when the phosphonate is entered; provided that the phosphonate is at least 1 day from each of the specified sixty(60)day period of treatment.

The methods of this invention include l is now. Specific compounds and compositions to be used in these processes must be, respectively, pharmaceutically acceptable. As used here, such a "pharmaceutically acceptable" component is one that is suitable for use in humans and/or animals without undue adverse side effects (such as toxicity, irritation and allergic response) commensurate with a reasonable relation to the benefit/risk. In addition, as used here, the term "safe and effective amount" means the quantity of a component which is sufficient to obtain the desired therapeutic effect without undue adverse side effects (such as toxicity, irritation or allergic response), commensurate with a reasonable relation to the benefit/risk when used this way, as in this invention. The specific "safe and effective amount" will, obviously, vary with such factors as the particular condition that must be treated, the physical condition of the patient, duration of treatment, the nature of concurrent therapy (if present), and specific applicable dosage forms.

Most of the through pain, swelling, fever and inflammation of the affected joints, and periods when usually present pain and inflammation, but to a much lesser extent. These periods vary in duration and usually actually unpredictable. Often, especially in osteoarthritis, the patient suffers from significant pain, discomfort and reduced range of motion over an extended period of time to visit. First visit to the doctor is often the result of active manifestations of the disease, which is so painful that the individual eventually seek medical treatment.

Modern therapy of arthritis usually consists of initial therapy NSPs to relieve pain and inflammation. In many cases, the initially prescribed dose is increased because the symptoms are not reduced as much as is desirable. In many cases, specific NSPs input shown in higher dose, has a weak effect or no effect on pain and inflammation. At the same time, often the doctor then prescribes another NSPs, repeating the same schema increasing the dose as before. Usually even after satisfactory NSPs (with safe and effect NSPs. Side effects of chronic therapy NSPs include toxicity to the gastrointestinal tract (gastrointestinal tract) (bleeding, ulceration, and perforation), kidney toxicity (papillary necrosis, decreased renal blood flow), the effect on the eye (deposits in the cornea and abnormalities in the retina) and the physiological and psychological effects in the Central nervous system.

Sixty(60)day treatment NSPs described herein above, may vary and/or be repeated again and again, following one after the other directly or with intermediate periods of no treatment or other therapy. There is an essential goal in the treatment of each patient is assigned NSPs to dosage NSPs (daily dose) and/or the number of days during which introduces NSPs (date of receipt of the dose), decreased. NSPs should only be imposed in the case of subsequent exacerbation, preferably at the first sign of deterioration, such as increased inflammation and/or pain. Phosphonate compound is given to suppress the destruction of bone and dense tissue in the intra-articular region of the joint, which then allows you to recover Podhradie bones. Over time it should be TSA periods, when does the greatest damage and destruction, it ultimately should reduce the damage. As an active tool NSPs and active phosphonate means acting together synergistically, dosage NSPs (and possible dosage phosphonate) steadily and continuously reduced, so that maintenance therapy eventually turns into periods of successful treatment, consisting only of phosphonate therapy; therefore, should be most preferably NSPs were completely eliminated by dosing the phosphonate only one time during the sixty(60)day period of treatment. For most patients, the final elimination NSPs should be achieved after successful treatment, in which the introduction (the number of days and/or daily dose) constantly and consistently declined.

Accordingly, sixty(60)day period of treatment includes separate introduction for each of the active substance, i.e. one for NSPs, which is arbitrary, and one for phosphonate compounds. NSPs arbitrarily introduced during the sixty(60)day period of treatment in order to maintain physiological effect NSPs the subject, which should be treated. In other words, NSPs Atsa every day from the specified sixty(60)day period of treatment, or every other day or every third day, or every fourth day, every fifth day, or every sixth day within the specified sixty(60)day period of treatment. It may be more desirable to give NSPs during the first week in one dose, change your other dose during the second, third and/or fourth week. It may be desirable to introduce one and the same and/or different NSPs in different doses on different days of the treatment period. The only limitation for an arbitrary injection mode NSPs is that NSPs should be given when it is necessary to reduce inflammation, swelling and pain and to prevent and/or alleviate periods of active inflammation. The required daily dose NSPs, as stated here, is from 20 to 80%, preferably 30 to 80%, most preferably 50 to 80% of the normal therapeutic dose.

In addition, phosphonate should be given at least one day out of each sixty(60)day period. For example, phosphonate may be given every day from the specified sixty(60)day period of treatment, or every other day in the specified sixty(60)day period of treatment, or every third day, or every fourth day, every fifth day, every sixth day, or every tenth what Can be more desirable to give phosphonate in the first week in one dose, then move on to other doses during the second, third and/or fourth weeks. It may be desirable to introduce one type of phosphonate in some days of treatment and another type on the other days of the treatment. Can also be desirable to introduce the same or different phosphonates on different days of the treatment period. The only restriction is that the phosphonate should be given in a dose that provides system level of 0.0005 mg/kg to 1.0 mg/kg / day, administered at least one day from the specified sixty(60)day period of treatment. Because phosphonate is given at the system level of 0.0005 mg/kg - 1.0 mg/kg per day, he may be given in various doses in the range of 0.0005 mg/kg to 1.0 mg/kg on different days, provided that it is given in some doses in this range for at least one day from the specified sixty(60)day period of treatment.

As stated above, the absorption of oral input phosphonate compounds is only from about 1% to about 5% of the administered dose. Accordingly, to achieve the oral dosage level equivalent system, equal of 0.0005 to 1.0 mg/kg, oral dose should be increased in 20 - to 100-fold.

These sixty(60)day periods Leino calculated taking into account changes of the conditions and needs of the patient. The preferred end-point is the achievement of dose reduction NSPs, while the frequency of exacerbations was reduced, and the inflammation and pain are limited. Illustrative, but not limiting, examples of possible treatment cycles, corresponding to the methods of this invention are described here:

1) Indomethacin is introduced in an amount of about 40 mg per day every day of the specified sixty(60)day period of treatment: through day of the specified sixty(60)day period of treatment (days 1, 3, 5, 7 and so on) is entered risedronate in the system number, equal to about 0,0005 mg/kg per day.

2) Risedronate is administered orally at a dose approximately equal to 0.12 mg/kg per day for twenty(20) days; on the sixth day (the 6th) is introduced piroxicam dose of 10 mg per day within fifteen (15) days; on the twenty-first (21st) day again entered risedronate, but oral dose 0,006 mg/kg within twenty(20) days, and on the twenty-sixth (26th) day appointed ibuprofen, 100 mg per day within fifteen (15) days. The first twenty(20)day period continues to apply piroxicam (before completing a full cycle) in 60 days).

3) Risedronate is entered in the system about 0,002 mg/kg per day each day, and then, on day 41, the introduction of naproxen is interrupted, and is given risedronate through the day number, and is given risedronate in a day in amounts of 0.003 mg/kg, for example, in the days 41, 43, 45,..., 59, prior to the completion of sixty(60)day period.

4) Piroxicam is entered within thirty (30) days in an amount of about 15 mg per day and in days 31 - 60 NSPs not given; on the fifth (5th) day shall be put risedronate, orally, at a dose of about 0.12 mg/kg / day, for thirty days, every fifth (5th) day, i.e. on days 35, 40, 45, 50, 55 and 60.

5) Ibuprofen is injected daily for six(60) days at 100 mg per day; in every second day risedronate is administered orally at a dose of 0.12 mg/kg / day.

6) Indomethacin is introduced at the level of about 100 mg per day for twenty-eight days (28); and in every seventh (7th) day shall be put risedronate, orally, at a dose of 0.2 mg/kg per day; after 28 days NSPs not be entered unless the period of exacerbation.

7) Risedronate is administered orally at a dose of about 0,10 mg/kg per day for thirty (30) days, and piroxicam is given at 15 mg per day in the same thirty days; on the thirty-first (31st) day of ibuprofen is inserted through the day in the amount of 100 mg/kg per day in tea, during the remaining period of treatment.

8) Risedronate is inserted through the day orally in a dose of about 0.02 mg/kg / day for seven (7) days, and each day is entered naproxen at a dose of about 500 mg per day up to 30 days, starting on the 30th day of risedronate is injected every four days oral dose of about 0.1 mg/kg per day; and naproxen is administered orally at a dose of 300 mg/kg / day every other day.

9) Piroxicam is administered orally at a dose of about 15 mg per day for thirty (30) days; risedronate is administered orally at a dose of about 0.1 mg/kg per day, and piroxicam is given every day at the dose of 5 mg per day, starting with 31 days.

The term "low efficiency, medium efficiency and high efficiency" is used to describe the ability antiresorptive action on bone tissue at the phosphonates. For example, inefficient phosphonates has LED, equal to 1.0 and 0.5; average effective phosphonates have LED 0.5 - 0,03, and highly effective phosphonates have LED more 0,03 - 0,0001.

The effectiveness of a particular phosphonate can be expressed by the values of their "LED" or "lowest effective dose", which is the minimum dose of phosphonate, expressed in mg/kg, which is effective in itself, and on their chemical structure and mode of their introduction (so E. oral or parenteral). The lower LED, the higher antiresorptive activity of phosphonate, and it is often desirable to introduce highly active phosphonate in lower doses and fewer days in the specified sixty(60)day cycle of treatment. Similarly, the higher the light, the less antiresorptive action of phosphonate, and it is often desirable to introduce low-phosphonates in higher doses and in a greater number of days during the specified sixty(60)day period of treatment. However, some phosphonates, especially sulfur-containing phosphonates exhibit outstanding efficacy in the treatment of arthritis, even in low doses, given the relatively small number of days, despite the fact that their LED (connected with antiresorptive activity) show that they should be given in higher doses and a greater number of days.

In particular, LED to active against bone phosphonates can be determined using any of several recognized in this field models in vivo. One such model is the model on thyroparathyroidectomy (TPTE") rats. In this model, compounds are evaluated for the efficiency of suppression of bone resorption in vivo by assessing their sleep deleted parasitaemia cancer. This model is described by Russell et al., b Calcifred Tissul Research 183 (1970); Muhlbauer et al. , 5 Mineral Electrolits Metabolism 296 (1981); U.S. patent 4761406, Flora et al. published August 2, 1988; European Patent Publication 298553, Ebetina, published on January 11, 1989; all of which are incorporated herein by reference.

Another model is "a model of Schenk", which assesses the impact active against bone phosphonates on bone growth in young rats. This model is described by Schenk et al., 11 Calcif. Tissul Bes. 196 (1973 Shinoda et al., 35 Calcif. Tissul Int. 87 (1983); U.S. patent 4761406. Flora et al., published August 2, 1988; and European Patent Publication 298553. Ehetino, published on January 11, 1989; which is incorporated here as a reference.

Another model is the model for "ovariectomised" or "OVH" rats, which evaluates the ability is active against bone phosphonates to prevent bone loss associated with estrogen deficiency, in female rats, caused by the removal of the ovaries. This model is described by WronsKi et al., 125, Endocrinology 810 1989), cited here as reference.

Another model is the "disease model" which is called the arthritis in Lewis rats using Mycobacterium butyrcum. This model is the number of features mimics rheumatoid arthritis in humans and thus there is swelling is their chemotactic factors and lysosomal components in the space of the joints. This model is described in more detail in Pearson et al. b Arth. Bhem., Vol. 2, pp. 440-459 (1959) and BlecKman et al., in Agents and Actions, Vol. 7, pp. 145-151 (1977). Antartica efficiency can be evaluated by reducing the volume of the paws, body weight loss, loss of bone tissue response to the new bone tissue formation compared to the controls. The treatment can be stopped and studied the reaction of acute (rapid amplification of inflammation), which shows the ability of a substance to maintain efficiency for significant periods of time without additional treatment.

LED system for dispensing pre-active against bone phosphonates used here are: 0,0003 mg/kg for 2-(3-pyridinyl-1-hydroxyethylidenediphosphonic acid; 0,01 mg/kg for 3-(2,2-diphosphate)-1-(2-mercaptoethyl)pyridine chloride; 0,01 mg/kg for 3-(2,2-diphosphonates)-1-methylpyridinium chloride and 0.001 mg/kg for 3-(2-hydroxy-2,2-diphosphonates)-1-methylpyridine-iodide disodium salt.

LED for oral dosing should be higher depending on the system suction phosphonate. Usually the absorption by oral administration is from about 1% to about 5%. Thus, oral LED is usually about twenty to one hundred and RA is the Creator of matter, expressed in mg of phosphorus substance per kg weight of a subject, which should be treated. As phosphonates differ in molecular weight, and the expression amount in mg/kg normalizes the comparison of phosphonates with different activity. To determine the number of mg/kg, administered to the patient in accordance with the methods of this invention use the following conventional formula

< / BR>
For example, 2-(3-pyridinyl)-1-hydroxyethylidene-1,1-biphosphonate has a molecular weight equal to 350. Two phosphorus atoms have a molecular weight equal to 62. Thus, if the patient is systemically administered dose of a substance at the level of 0.01 mg/kg, is injected 0,002 mg/kg

NSPs usually dosed in mg/kg or mg and total daily dose is usually reported.

The methods of this invention include the treatment of arthritis at all stages of the disease. Because arthritis is a long and evolving process of destruction of the bone and joint and inflammatory reactions, and not the disease, with defined start and end, and "treatment", as used here, includes any method that stops, inhibits, suppresses or modifies a reverse process of the destruction of the bone and joint and/or relieves the symptoms of inflammation, which S="ptx2">

Preferred methods of this invention include the treatment of patients with arthritis before appeared significant damage to joints and bones. Ideally, that at the first sign of pain in the joint, inflammation or reduce the amplitude of movement and before you receive significant damage to the joints or bones or signs of exacerbation, patients with arthritis need to start treatment with phosphonate. Phosphonate therapy, if it is started early enough in the disease process of arthritis, should significantly reduce (or even stop) the extent of damage inside the joint, which was priterpelis if the progression of the disease; it is possible that the patient, which treatment phosphonates started early enough in the disease process, will never suffer from severe acute exacerbations. This unique type ideally should be determined using serum or genetic marker; however, ideally, as a rule, phosphonate therapy begins when the first pain in the bones of the fingers or of the organs of locomotion and/or joint pain, swelling, stiffness, or decreased range of motion in the joint. This initial phosphonate therapy should include the period of saturation, when, in the IDA of trenteseau, depending on the status of a particular patient.

However, most often will occur when the patient does not seek treatment by a physician as long as the symptoms of pain and inflammation will not be present during some extended periods of time and/or develop one or more severe outbreaks. These patients may suffer damage to bones significantly and will need in the introduction of phosphonate compounds in relatively high doses, which are described here, for some period of time, to suppress the destruction inside the joint or bone and allow recovery subarashiki bones. If this patient at this time there is inflammation and/or edema, can also be desirable to introduce NSPs in normal therapeutic doses to relieve inflammation and swelling. If the inflammation and/or swelling is already stable, then therapeutic schemes described herein may be installed at doses of phosphonate compounds from higher doses of therapeutic interval, and NSPs on maintenance levels described here, but at doses high enough to facilitate periods of exacerbation and keep inflammation and swelling affordable possible doses may NSPs, when the periods of acute supported the patient as much as possible, it may depend on a number of factors. Such factors include, for example, the specific active substance, the amount of active substances, the age and gender of the subject, the specific violation that should be treated, used concomitant therapy (if present), General physical health of the patient (including the presence of other diseases), the degree of damage to the bones and joints of the individual and the eating habits of the individual.

The mode of therapeutic treatment using the methods of this invention preferably continued for about twelve months, and mostly it is preferable that maintenance therapy was continued throughout the life of the patient. It is preferable mode of treatment that minimizes dose NSPs, reduced dose of phosphonate and still maintained the integrity of the intra-articular region is limited to pain, inflammation, swelling and/or alleviated or prevented exacerbation. Of course, therapeutic regime can continue unlimited in accordance with sound medical practice.

When methods for the active substance, used in this invention are delivered to the patient who needs treatment, thus, to be effective in restoring bone. The active substance may be introduced by any number of known techniques, for example, orally, through the skin and mucous membranes (for example, through the skin, sublingual, vnutripuzarno and rectal), systematic (i.e., parenteral, for example, by subcutaneous injection, intramuscular injection, intra-arterial injection) and through inhalation. Thus, specific methods of introduction include, but are not limited to, for example, orally, through the skin, through the mucous membranes, sublingual, intramuscular, intravenous, intraperitoneal, subcutaneous administration and local application. No matter what route of administration is used for active phosphonate funds, which must be administered in a dose equivalent to the system level of 0.0005 mg/kg to 1.0 mg/kg as the absorption is only from 1% to 5%, when the phosphonate is administered orally, the oral dose to achieve the desired system-level must be increased by twenty to hundred times the desired system-level.

There are other therapeutic tools in more shall undepressed and modifying disease, used for arthritis means (here the data MSAS), including gold, methotrexate, azathioprine, cyclosporine, penicillamine, and cyclophosphamide. Because most patients who consult their doctor prescribed NSPs primarily due to unwanted side effects and inconveniences of the above therapy, many patients will be transferred to the treatment regimen, consisting, for example, from NSPs and periodic injections of cortisone or NSPs and gold or injections methotrexate. Since then, the needs of the individual patient should be determined by a physician, consider that many patients who need one or more therapeutic tools described above, in addition to therapy NSPs, can be improved using the introduction of phosphonate compounds to such an extent that in the end will not require treatment with corticosteroids, immunosuppressants and MSAS. It is believed that when a patient is entered NSPs and phosphonates during the cycle and stabilization is achieved, it will not be necessary in therapy with the use of these additional funds. After the inflammation and pain is alleviated and the patient's condition is stable, you can begin reducing sutochnogo or filmed dosage NSPs until while inflammation is not reduced, and the aggravation will not be prevented. I believe that it is during periods of exacerbation, when the inflammation of the greatest and strongest pain, intra-articular bone and dense tissue are at greatest damage; reducing inflammation and eliminating the recurrence of exacerbations are of paramount importance.

Practically a method of treatment of arthritis includes initial diagnostic stage to determine the presence of the disease. Thus, the preferred method of this invention includes the execution stage diagnosis in humans to determine arthritis, and after receiving a positive result for a given diagnosis, the introduction of active substances in accordance with the methods of this invention. Such methods of diagnosis of arthritis is well known in this field of medicine and include clinical evaluation and/or research swelling and deformity of the joints, x-rays, determination of erythrocyte sedimentation rate, radiograms, determination of rheumatoid factor levels C1 antibody glycosylation 1C, levels of soluble receptors 11 - 2, magnetic resonance picture (MRI) and levels of synovial neopterin concentrations.

D. in any of a variety of pharmaceutically acceptable compositions. Such compositions may include the active ingredient and pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients include solid or liquid filler diluents or encapsulating substances or mixtures thereof, which are suitable for administration to a human or other animal. The term "compatible", as used here, means that the components of the pharmaceutical composition is able to be mixed with the active substances and with each other so that there is no interaction which would significantly impair the pharmacological efficacy of the pharmaceutical composition under normal conditions of use. Pharmaceutically acceptable excipients should, of course, have a sufficiently high purity and sufficiently low toxicity to render them suitable for administration to a human or other animal, which should be treated.

Some examples of substances which can serve as pharmaceutical excipients, it is a sugar, such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethylcellulose, acetylcellulose; powder tragakant; malt (sprouted, cottonseed oil, sesame oil, olive oil, corn oil, and cocoa butter; polyols such as propylene glycol, glycerin, sorbitol, mannitol and polyethylene glycol; agar; alginic acid; pyrogen-free water; isotonic saline; phosphate buffer solutions; moisturizers and lubricants such as sodium lauryl sulfate; tinted funds; giving a taste of funds and preservatives. Other compatible pharmaceutical additives and active substances can be included in the pharmaceutically acceptable excipients for use in the compositions of this invention.

The choice of a pharmaceutically acceptable filler to be used in combination with an active substance is determined, which must be entered active substance. If the active substance shall be given by injection, the preferred pharmaceutical filler is sterile water, saline solution, or mixtures thereof, the pH of such parenteral compositions is preferably brought to approximately 7.4. Suitable pharmaceutically acceptable excipients for topical application include those which are known in this field, used in creams, gels, layer is Amy filler, used in combination with the active substances used in concentrations sufficient to provide a practical size in relation to dosing. Pharmaceutically acceptable excipients generally can range from about 0.1% to about 99.9% by weight of the pharmaceutical compositions for use in the methods of the present invention, preferably, from about 5% to about 80%, and most preferably, from about 10% to about 50%.

The preferred method of introduction of phosphonates and NSPs is oral in pink dosage form (i.e., dosage form containing an amount of active substance corresponding to the introduction of a single dose according to sound medical practice). Preferred single dosage forms for phosphonates include tablets, capsules, suspensions and solutions containing a safe and effective amount of the active substance. Pharmaceutical excipients suitable for the preparation of single dosage forms for oral administration are well known in this area. Their choice will depend on secondary considerations like taste, cost, storage stability, which are not necessary for the purposes of this invention, and may be the AI bone phosphonates contain equivalent, approximately from 0.0005 mg/kg systemic daily dose to systemic daily dose of phosphonate equal to about 1.0 mg/kg As described here above, to achieve the desired system-level, the number of phosphonates that are required for oral dosing, higher systemic doses and depends on the systemic absorption of the phosphonate. Usually oral dose of approximately twenty to one hundred times higher systemic doses to achieve a particular desired system level.

Preferably, a single oral form NSPs contain 20% to 80%, more preferably 20 to 70%, most preferably 20 to 50% of the normal therapeutic dosage of specific NSPs. Dosage varies for specific NSPs and are usually reported in doses for oral administration in mg/day or mg/kg/day.

Sets:

This invention also represents sets for convenient and effective implementation of the methods of this invention. Such kits include one or more single doses active against bone phosphonates, one or more doses NSPs and means for facilitating the application of the methods of this invention. These kits provide a convenient and effective means for ensuring that the entity that needs lakepromenade these kits include any funds to facilitate the introduction of active substances according to the method of this invention. These tools include instructions, packaging and the tools and their combinations. Examples of packaging and means of application are well known in this area, including those described in U.S. patents 4761406, Flra et al., published August 2, 1988; U.S. patent 4812311, Ucht man., released March 14, 1989 and U.S. patent 4833125, Meer et al. published on may 23, 1989, all included here as a reference.

The following non-limiting examples illustrate the compositions, methods, and applications of this invention.

An example of A

Male Caucasian, weighing about 92 pounds, seventy-two years of age suffer from moderate to severe pain, recurrent swelling of the right knee. After approximately one year of ever-increasing discomfort he turns to the doctor, who puts a clinical diagnosis of osteoarthritis of the right knee, which is then confirmed by radiographic diagnosis.

After a period of facilitating the treatment of various NSPs, including aspirin, naprosyn and Ketoprofen, the symptoms he continues to deteriorate, and his condition seemed to be getting worse. His right knee heavily vespolino and swollen and the pain persons shall be (30) days. At the end of the 30-day period, the inflammation and swelling slept. The doctor then prescribes the following therapeutic mode for sixty (60) days; 15 mg piroxicam per day and 60 mg per day of risedronate orally every day, to receive oral dose equal to 0.13 mg/kg Clinical symptoms of pain and swelling in him, especially during prolonged walking, decreased significantly after two months of therapy. In conclusion, these two months, the doctor has prescribed the following mode for six months; 50 mg of ibuprofen once a day and risedronate orally once per week at a dose of 30 mg per day.

Example B

The colored woman, weighing about 65 pounds at the age of 55 years, she developed swelling and deformity of the joints of the fingers on both hands with a partial loss of strength and/or dexterity of the fingers and hands. Visual inspection and x-ray study, and various clinical tests, approved by the American Rneumatologiral Associotion (ARA), she is diagnosed with rheumatoid arthritis.

After unsuccessful analgesic and anti-inflammatory therapy, her doctor prescribes oral risedronate at a dose of 35 mg per day and indomethacin in a dose of 50 mg per day for a period of four months. After a month of therapy symptoms of swelling sustevol therapy over the remaining term of up to four months. Then her doctor reduces the dose of indomethacin 30 mg per day, and risedronate to 15 mg per day orally for two months. After a two-month period there are no significant deterioration, so her doctor prescribed maintenance therapy for a period of six months, consisting of risedronate, oral dose of 15 mg per day, taken once a week, and ibuprofen 100 mg per day.

Example C

Woman of Spanish origin twelve years of age, weighs about 37 pounds, is a doctor with idiopathic juvenile rheumatoid arthritis. Her symptoms include inflammation of many joints, complicated by fever and pain and rapid manifestation and pathological degeneration of joints function. Her doctor is sent to a rheumatologist, who immediately prescribes active therapy by intravenous introduction of a solution containing 7 mg of risedronate daily for the period of six days at the rate of 1 injection per day, administered within two hours. Upon completion mode on/in the doctor prescribes risedronate in a daily dose of 16 mg/day, oral and naproxen daily dose is 400 mg per day for sixty(60)day period, during which not is in the doctor lowers her dose risedronate to 3/4 of the original oral dose and the dose of naproxen 200 mg/day.

In conclusion, this regime daily dosage risedronate again reduced to 1/4 of the original oral dose, taking naproxen she stops and her doctor prescribes ibuprofen 50 mg per day.

Example 1

The sick woman weighing 70 kg, with a sudden and rapidly developing rheumatoid arthritis, breathtaking knee joints, can be treated using this invention as follows:

1) oral capsule indomethacin 50 mg 2 times a day for 2 weeks, then the dose is reduced to 25 mg 2 times a day for 4 weeks, and in the end - to 10 mg 2 times a day for an additional 2 weeks to bring the inflammation of soft tissues and discomfort to a minimum. Then the administration of indomethacin terminated so long, until you are again exacerbation during which this mode repeats

2) Risedronate is administered orally once daily at a dose of 0.1 mg/kg for 70 days (10 weeks), starting therapy at the same time as initial therapy NSPs. After that, all treatment should be stopped until not happening exacerbation of inflammation, during which the injection mode of risedronate repeats. If the exacerbation does not occur after 3 months of absence of any treatment, the treatment of R is of Riem night capsules with a dosage of 0.05 mg/kg for 60 days. After receiving doses may be terminated for an indefinite period, if you do not receive an exacerbation of inflammation.

Example E

Sick woman with established rheumatoid arthritis of the hand and wrist, but asymptomatic (no deterioration) is treated according to this invention as follows:

1) Oral tablets of naproxen at a dose of 300 mg 1 time a day for 4 weeks, then treatment should be stopped. Treatment naproxen is interrupted for an indefinite period, until the exacerbation, during which treatment naproxen will be resumed at a dose of 200 mg 2 times a day for 4 weeks and then stopped.

2) Treat the patient daily pill 3-(2,2-diphosphonates)-1-methylpyridine chloride at a dose of 0.1 mg/kg per day is unlimited.

Example F

The sick man of the East India weighing 60 mg, dened exacerbations of arthritis of the hip in anamnesia, but currently in a state of almost complete remission, treated according to this invention as follows:

1) the Patient will not receive ncpus

2) the Patient will receive 2-mercaptoethane-1,1-diphosphonate (HSEDP) for 3 months to block the start of the exacerbation, and then stop the treatment. EU introduction HSEDP must be renewed after 3 months and when the above mode. If after 4 cycles, the above (2 years), the exacerbation does not appear, the treatment of the phosphonate should be stopped indefinitely, until the aggravation. When this appears, the patient is assigned NSPs (voltaren) simultaneously with HSEDP at doses of 50 mg voltaren 3 times a day and 300 mg HSEDP 1 time per day orally up until the exacerbation does not subside, then the introduction of voltaren stops and continues treatment HSEDP within just 3 months.

Example G

An elderly man, a former athlete with severe osteoarthritis of the knees treated according to this invention as follows.

1) the Patient takes a dose of 1000 mg motrin capsules for 14 days and then the dose is reduced to 500 mg for 2 weeks, then 500 mg every other day for 4 weeks and then stops. Further introduction NSPs not needed if you do not receive damage or spontaneous swelling, which again is assigned motrin dose of 500 mg 2 times a day for 14 days, and then drug therapy is stopped. In addition, if the patient has no swelling, and there is only pain, dosage motrin level is 50 mg/day for 3 weeks, and then the introduction is terminated. In case of a sudden is treated by oral administration of a dose of 30 mg/day of 3-(2,2-diphosphonates/-1-methylpyridine chloride for 4 weeks from starting treatment at the same time, as NSPs, and then the dose is reduced to 20 mg/day orally for an additional 6 weeks.

Example H

The patient is African American with osteoarthritis of the left hip, which is manifested by severe pain at night and lack of movement and pain during the day, be treated in accordance with the invention as follows:

1) Initial mode begins with the introduction of 15 mg of feldene and maintained for 4 weeks. At this time, the dosage during therapy feldene reduced to 5 mg 2 times a day for an additional four weeks, and then the treatment is stopped. Further therapy NSPs not needed, unless there is acute because of the injury, and then the above-mentioned mode is resumed.

2) the Patient begin to heal 2-mercaptoethane-1,1-diphosphonate (HSEDP) at a dose of 500 mg/day for 60 days and then the treatment is discontinued for 30 days, resume the dose of 500 mg/day for 1 month. Then the introduction is discontinued for 30 days, and then the patient is supported on HSEDP for 1 year at a dose of 600 mg 1 time a week. In case of aggravation and/or thigh pain associated with the random damage, the above-described mode is resumed.

1. A method of treating human and animal affected by arthritis, including entered the treatment period includes the introduction of NSPs dose, component of from 20 to 80% of commonly prescribed daily dose for each day, and in a sufficient number of days to relieve symptoms of inflammation, includes the introduction of phosphonate or its pharmaceutically acceptable salt or ester at a dose equivalent to the system level of from about 0.0005 to about 1.0 mg/kg per day, provided that the phosphonate is administered at least 1 day during the specified period of treatment.

2. The method according to p. 1, characterized in that the injection mode NSPs includes an introduction NSPs dose comprising from 20 to 70% of commonly prescribed daily doses for each day in which the specified NSPs is entered.

3. The method according to p. 1, characterized in that the specified active against bone phosphonate is biphosphonates acid or its pharmaceutically acceptable salt or ester.

4. The method according to p. 1, characterized in that the phosphonate selected from the group consisting of 3-pyridyl-1-hydroxyethylidene-1,1-bisphosphonate acid, 3-(2,2-diphosphonates)-1-ethylpyridine chloride, 3-(2,2-diphosphonates)-1-(2-mercaptoethyl)pyridinium chloride, 3-(2-hydroxy-2,2-diphosphonates)-1-methylpyridinium disodium salt, 3-(2-hydroxy-2,2-diphosphonates)-1-methylpyridine of hydroxyphenoxy, 2-(2-hydroxy-2,2-diphosphonates)-1,1-dimethylpiperidine iodide, 3-[2,2-diphosphono-2-hydroxyethyl] -1,1-dimethylpiperidine iodide, 3-(2-carboxy-2-phosphonoethyl)-1-methylpyridine chloride, 3-(3,3-diphosphonates)-1-hexadecylpyridinium, 7-(diphosphohydrolase)-2-methyl-2-pyridinium iodide, octahydro-6,6-diphosphono-1,1-dimethyl-1-pyrindine iodide, octahydro-6,6-diphosphono-2,2-dimethyl-2-pyrindine iodide, octahydro-7,7-diphosphono-1,1-dimethyl-1-pyrindine iodide, dihydro-6,6-diphosphono-1-methyl-1-pyrindine, dihydro-6,6-diphosphono-2-methyl-2-pyridine, tetrahydro-8,8-diphosphono-1-methylinosine iodide, octahydro-8,8-diphosphono-1,1-dimethylaniline iodide, dihydro-1-methyl-6-phosphono-6-sulfone-1-pyrindine chloride, octahydro-6,6-diphosphono-1-(2-mercaptoethyl)-1-methyl-1-pyrindine chloride, octahydro-6,6-diphosphono-1,1-dimethyl-3-(2-mercaptoethyl)-1-pyrindine iodide, 1,3-dihydro-4-(2-mercaptoethyl)-2,2-diphosphono-2H-pyrrolo[3,2-b] pyridinium chloride, [(5-(3-mercaptopropyl)-2-pyridinyl)aminomethyl] bis (phosphonic acid), [(5-(3-acetamiprid)-2-pyridinyl)-aminomethyl] bis(phosphonic acid), [(5-mercapto-2-pyridinyl)aminomethyl] bis(phosphonic acid), [(4-(4-mercaptoethyl)-2-pyridinyl)aminomethyl] bis(phosphonic acid), [(4-(4-acetyltributyl)-2-pyridinyl)aminomethyl] bis(F. the thio-2-(3-pyridinyl)ethylidene] bis(phosphonic acid), [2-mercapto-2-(3-pyridinyl)ethylidene] bis(phosphonic acid), [5-mercapto-2-(3-pyrimidyl)pentylidene] bis(phosphonic acid), dihydro-7-mercapto-1-pirinen-6,6-bisphosphonates acid, octahydro-7-mercapto-1-pirinen-6,6-bisphosphonates acid, dighiero-7-(2-mercaptoethyl)-1-pirinen-6,6-bisphosphonates acid, octahydro-7-(2-mercaptoethyl)-1-pyrindine-6,6-bisphosphonates acid, octahydro-3-mercapto-1-pyrindine-6,6-bisphosphonates acid, dihydro-4-mercapto-2-pyrindine-6,6-bisphosphonates acid, octahydro-4-mercapto-2-pyrindine-6,6-bisphosphonates acid, dihydro-3-(4-mercaptomethyl)-1-pyrindine-6,6-bisphosphonates acid, octahydro-3-(4-mercaptomethyl)-1-pyrindine-6,6-bisphosphonates acid, dihydro-4-(4-mercaptomethyl)-2-pyrindine-6,6-bisphosphonates acid, octahydro-4-(4-mercaptomethyl)-2-pyrindine-6,6-bisphosphonates acid, [1-hydroxy-(dihydro-7-mercapto-2-piring-7-yl)methylene] bis(phosphonic acid), [octahydro-4-(2-mercaptoethyl)-pyrrolo[3,2-b] pyridine-2-yl] bis(phosphonic acid), preferably 3-pyridyl-1-hydroxyethylidene-1,1-bisphosphonate acid, 3-(2,2-diphosphonates)-1-(2-mercaptoethyl)-pyridinium chloride, 3-(2,2-diphosphonates)-1-methylpyridine chloride, 3-(2-hydroxy-2,2-diphosphonates)-1-methylpyridine or their pharmaceutically acceptable salts and esters.

6. The method according to p. 1, characterized in that the specified NSPs selected from the group consisting of salicylates, indomethacin, flurbiprofen, diclofenac, naproxen, piroxicam, tebufelone, ibuprofen, etodolac, nabumetone, tenidap, alkofanka, antipyrine, aminopyrine, dipyrone, aminopyrine, phenylbutazone, clopton, oxyphenbutazone, prexaton, Upasana, benzydamine, bucolome, cinchophen, clonixin, tetrazole, epirizole, fenoprofen, floctafenine, flufenamic acid, glafenine, indoprofen, Ketoprofen, meclofenamic acid, mefenamovoy acid, niflumova acid, fenatsetina, salicylamide, sulindaka, suprofen and tolmetin, preferably salicylates, indomethacin, flurbiprofen, diclofenac, naproxen, pyroxene, tubiflora and ibuprofen.

7. The method according to p. 1, characterized in that the specified NSPs enter each day of the specified period of sixty days of treatment, the day of the specified period of sixty days of treatment, after two days of the specified sixty days of the treatment period, or 15 day 30 day 45 day 60 day of the specified period of sixty days of treatment, preferably 15 day 30 day 45 day 60 day of the specified period of sixty days of treatment.

9. The method according to p. 1, wherein said phosphonate is administered every seventh day of the specified period of sixty days of treatment.

 

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