Sulfur-containing phosphonic acid or their pharmaceutically acceptable salts or esters and pharmaceutical compositions on their basis

 

(57) Abstract:

Sulfur-containing phosphonic acid of the formula I, where R is the group-RHO3H2or P(O) (OH)R4, R4- alkyl, R1is hydrogen, C1-8alkyl, possibly substituted by phenyl, phenyl or two adjacent carbon atoms, together with R1form a cyclopentane or cyclohexane, R2- C1-8alkyl or phenyl, R2- H or HE, n is an integer from 1 to 6, or their pharmaceutically acceptable salts or esters can be used for the treatment and prevention of disorders of abnormal calcium and phosphate metabolism. 3 c. and 3 C.p. f-crystals, 2 PL.

The present invention relates to new serosoderjaschei phosphonate compounds, including biphosphate, phosphonocrotonate, phosphonocarboxylate and phosphosulfate. The invention relates also to pharmaceutical compositions containing these novel compounds and to a method of treatment or prevention of certain bone diseases, metabolic nature, caused by abnormal calcium and phosphate metabolism, using compounds or pharmaceutical compositions of the present invention. In addition, this invention relates to a method of treatment or prevention of arthritis, obretenie. In particular, this invention relates to a method of treating or preventing osteoporosis and arthritis, especially rheumatoid arthritis and osteoarthritis by using the compounds or pharmaceutical compositions of the present invention.

A number of pathological conditions that cause pain to a warm-blooded animal, includes calcium and phosphate metabolism. Such States can be divided into two main categories.

1. States, which are characterized by anomalous mobilization of calcium and phosphate, leading to General or specific bone disorders such as osteoporosis and Paget's disease; or excessively high levels of calcium and phosphate in the body fluids, such as hypercalcemia malignant condition. Such States are referred to here as strong pathological tissue demineralization.

2. Conditions that are caused by or are the result of abnormal deposits of calcium and phosphate in the body, such as rheumatoid arthritis and osteoarthritis. These States are referred to here as pathological vascular calcification.

The first category includes the most common metabolic bone disease - osteoporosis osteoporosis is a condition in which e is defined as the reduction in the quantity of bone or atrophy of skeletal tissue. Brain and bone space increases, communication fibers are reduced and compact bone becomes fragile. Osteoporosis can be divided into subclasses, such as postmenopausal osteoporosis, senile, caused by a drug (e.g., adrenal cortical occurring steroid treatment) induced disease (arthritic and tumor), and others; however, the symptoms are similar. The most common are two types of osteoporosis: primary and secondary. Secondary osteoporosis is a result of individual identifiable disease or the action of any agent. However, approximately 90% of all cases of osteoporosis are the "primary osteoporosis". Such primary osteoporosis includes postmenopausal osteoporosis, "uncommon" osteoporosis associated with age, osteoporosis (mainly affecting individuals aged 70 to 80 years) and idiopathic osteoporosis, developing the men and women of the middle and younger age.

For some suffering from osteoporosis individuals bone loss are large enough so that the cause mechanics, suffering from postmenopausal osteoporosis. The result can also be kyphosis (abnormal increase in the curvature of the thoracic part of the spine).

It is clear that the mechanism of bone loss in osteoporosis is the imbalance in the process of bone reconstruction. Bone reconstruction occurs throughout life, causing restoration of the skeleton and maintaining the bone fortress. This reconstruction includes erosion and filling of the discrete areas on the surface of the bone with the help of an organized group of cells called the "basic multicellular units" or "OME". OME are originally from osteoclasts, osteoblasts and their cell precursors. In the loop process of reconstruction of bone resorbed "activated" OME, using osteoplast, forming the corresponding cavity. Then the cavity is filled with bone with osteoblasts.

Usually, an adult cycle reconstruction leads to a small loss of bone due to incomplete filling of the cavity resorption. Thus, even in a healthy adult are age-related bone loss. However, in osteoporosis, the number of activated OME increase. This increase aktivirovani age osteoporosis is not entirely clear, we can assume that there are many risk factors associated with osteoporosis. They include low body weight, low calcium intake, lack of exercise and estrogen deficiency.

Modern treatment of osteoporosis is widely used calcium and estrogen.

The second category includes state, manifested in the abnormal deposition of calcium and phosphate, includes progressive mosinee ossification, total calcification and diseases such as arthritis (including, for example, rheumatoid arthritis and osteoarthritis, neuritis, bursitis, tendonitis and other conditions that predispose the affected tissue and the deposition of calcium.

In addition to osteoporosis, bone loss may be a result of rheumatoid arthritis and osteoarthritis. Rheumatoid arthritis is a chronic, General and sustavnoi inflammatory disease characterized by the weakening of the capsules and ligaments, followed by the destruction of cartilage, ligaments, tendons and bones and viscosity reduction and other changes in synovial fluid. The symptoms of rheumatoid arthritis include General weakness, fatigue, localized pain, stiffness and weakness and swelling and deformation of the ligaments. Rheumatoid arthritis nitrite, leading to destruction of the joints, characterized by two stages: 1) exudative phase, including the microcirculation and the presence of synovial cells, which promotes the penetration of plasma proteins and cellular elements in the joints and 2) chronic inflammatory phase that occurs in subsynovial layer and subarashiki part of the bone, characterized by annonym (granulation tissue) formation of joint space, bone erosion and destruction of cartilage. Pannus may lead to the merger and the scar tissue that causes deformity of the joint, characterized for rheumatoid arthritis.

The etiology of rheumatoid arthritis remains unclear. Infectious agents such as bacteria and viruses, are assumed as the reason. Modern hypothesis is that the agent that causes rheumatoid arthritis is a virus Epsteix-Barr (EBV).

Modern treatment of rheumatoid arthritis is mainly symptomatic relief introduction nonsteroidal anti-inflammatory drugs. Non-steroidal anti-inflammatory treatment is mainly effective in the early stages of rheumatoid arthritis; it is unlikely is the weakening of inflammation WM, immunodepressant and corticosteroids.

On the other hand, osteoarthritis is primarily non-inflammatory disorder of movable joints characterized by damage and wear of articular cartilage and formation of new bone on the surface of the joint. As the progression of osteoarthritis, the surface of the articular cartilage is destroyed and the particles of the joint fall into the synovial fluid, which in turn stimulates the phagocytosis of cells macrophages. Thus, the inflammatory response over time induced by osteoarthritis. Common clinical symptoms of osteoarthritis are cartilage and bone growth of finger joints numbness in the revival and pain during movement.

General symptomatic treatment of osteoarthritis includes analgesics, anti-inflammatories, steroids and physical therapy.

For the treatment and prevention of diseases involving abnormal calcium and phosphate metabolism, has been invited to many derivatives of phosphonic acid. For example, numerous references are all United here in reference, disclose compositions containing polyphosphonate, in particular, bipositional, such as ethane-1-hydroxy-1,1-Oia and phosphate in animal tissues: U.S. Patent 3 683 080, issued August 8, 1972, and U.S. Patent 4 230 700, issued October 28, 1980, both belonging to Francis, and U.S. Patent 4 868 164, issued September 19, 1989, Ebetino. Many other references describe heterocyclic substituted diphosphonic acid used for the treatment of osteoporosis and/or arthritis, are combined here by reference: U.S. Patent 4 868 164 Ebetino and others, issued September 19, 1989; U.S. Patent 5 104 863 Benedict and others, issued April 14, 1992; U.S. Patent 4 267 108 Blum and others, issued may 12, 1981; European Patent Application Boehringer Mannhein GmbH N 170 228, published February 5, 1986; European Patent Application N 186 405 Benedict and Perkins, published July 2, 1986; U.S. patent 4 754 993 Bosies and others, issued November 15, 1988, U.S. Patent 4 939 130 Jaeggi and others, issued July 3, 1990; U.S. Patent 4 971 958 Bosies and others , issued November 20, 1990; DE 40 11 777, Jaeggi, K., published on October 18, 1990; WO 90/12017 Dann and others, published October 18, 1990 ; WO 91/10646 Joussefyen, R and others, published July 25, 1991; AU-A-26738/88 Jaeggi, published June 15, 1989, AU-A-45467/89 (intended for Ciba-Geigy), published may 31, 1990, and U.S. Patent 4 208 401 Bauman, published June 17, 1980

In addition, European patent 0 298 533 Ebetino, published on January 11, 1989, describes a thiol-substituted among a huge number of other substituted in cachestore connection increases antiresorptive and antiarthritic activity in a number of other disclosed in the patent deputies.

In addition, some references describe sulfur-containing phosphonic acid, which, as indicated, are useful in the treatment of inflammatory symptoms, see, for example, U.S. Patent 4 746 654 Breliere, etc. designed for Sanofi, published on may 24, 1988, and EPO 100 718 Breliere, etc. designed for Sanofi), published on 15 February 1984

Further, U.S. Patent 4 876 247 Barbiere and other (intended for Sanofi), published October 24, 1989, describes sulfur-containing methylenediphosphonate acid derivative used for the treatment of disorders associated with inflammatory phenomena, particularly for the treatment of arthritic conditions. U.S. patent 5 071 840 Ebetino and other published December 10, 1991, describes serosoderjaschei substituted heterocyclic diphosphonates, in which dephosphatation carbon residue attached to the carbon atom in the nitrogen-containing six-membered ring heterocycle. The compound used in the treatment of conditions involving abnormal calcium and phosphate metabolism, in particular, osteoporosis and arthritis.

None of these references disclose the use of serosoderjaschei biphosphonates connection, in which structuresa chain contains to the CSOs compounds for the prevention and treatment of osteoporosis and rheumatoid arthritis and osteoarthritis. Described here titlestyle include thiol, alkylthiol, thioethers, alkylthiophene, dayevery and alkylthiophene, THIOCARBAMATE, alkyldiethanolamine, dithiocarbamate, alkyldiethanolamine, thiocarbonate, alkylthiocarbamates, dithiocarbonate and dithiocarbonate.

In addition, disclosed herein compounds are characterized by osteotomies activity on the part of joint destruction in arthritic conditions and some additional activity in the treatment of arthritis in addition to the usual withdrawal symptoms of inflammation. Used herein, the term "osteopata activity" means activity in the modification of the disease on the bone and surrounding soft tissue at the site of joint destruction.

It has been unexpectedly found that the compounds of this invention are characterized by a higher antiresorptive activity and greater therapeutic activity in the treatment of osteoporosis and arthritis compared with heterocyclic biphosphate compounds not having titlestyle.

Therefore, the purpose of this invention is to provide new, more effective compounds, which would be highly effective inhibitors of bone resorption, useful in the treatment of osteoporo is the purpose of this invention is to provide pharmaceutical compositions used for the treatment and prevention of abnormal calcium and phosphate metabolism and for the treatment and prevention of arthritis, especially rheumatoid arthritis and osteoarthritis. In addition, the purpose of this invention is to provide a method of treating or preventing diseases characterized by abnormal calcium and phosphate metabolism in humans and other mammals, including osteoporosis and arthritis, especially arthritis and osteoarthrit.

These and other objectives of the present invention become apparent from the detailed description is presented of the invention, below.

This invention relates to new serosoderjaschei phosphate compounds and new tizamidine compounds, including bisphosphonates, phosphonocrotonate, phosphonocarboxylate and phosphosulfate and to their pharmaceutically acceptable salts and esters. This invention also relates to pharmaceutical compositions containing a safe and effective amount of the compounds of this invention and pharmaceutically acceptable excipients. Finally, the invention relates to methods osteotomies treatment and prevention of pathological conditions characterized by abnormal calcium and phosphate rheumatoid arthritis and osteoarthritis. This method comprises the administration to a human or other mammal in need of such treatment, a safe and effective amount of the compounds or compositions of the present invention. These compounds have the following General formula:

< / BR>
in which m and n represent integers from 0 to 10, and m + n is from 0 to 10 and in which

(a) X is O or S;

(b) Z is a covalent bond; monocyclic or polycyclic carbocyclic ring residue; or a monocyclic or polycyclic heterocyclic ring residue containing one or more heteroatoms such as O, S or N;

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

(d) represents COOH, SO3H, PO3H2or P(O)(OH)R4where R4is substituted or unsubstituted C1-C8by alkyl;

(e) Each R1is independently-SR6; -R8SR6; null hydrogen; unsubstituted or substituted C1-C8by alkyl; monocyclic or polycyclic carbocyclic ring residue; unsubstituted or substituted aryl; substituted or unsubstituted thiophene; substituted or unsubstituted oxadiazole; substituted or unsubstituted pyranone; samase-C(O)N(R3)2; -N(R3)C(O)R3; substituted or unsubstituted benzyl; nitro; or combinations thereof;

(f) R2independently-SR6, -R8SR6, -CO2R3; -O2CR3; -C(O)N(R3)2; -N(R)3C(O)R3and nil; hydrogen; unsubstituted or substituted C1-C8by alkyl; unsubstituted or substituted aryl; hydroxy; substituted or unsubstituted benzyl; nitro or their combinations;

(g) each R3is independently hydrogen; substituted or unsubstituted C1-C8the alkyl or R8SR6;

(h) R5is-SR6, R8SR6, hydrogen; hydroxy; amino; halogen; unsubstituted or substituted C1-C8by alkyl;

(i) R6independently is H; -C(O)R7and C(O)NR72; where R7is hydrogen or unsubstituted or substituted C1-C8the alkyl and

(j) R8is substituted or unsubstituted C1-C8the alkyl.

In this General formula, Z is a covalent bond, monocyclic or polycyclic, saturated or unsaturated, substituted or unsubstituted carbocyclic ring residue or a monocyclic or polycyclic saturated silt is carried out by integers from 0 to 10, n is preferably from 1 to 5 and m+n is preferably from 1 to 10. Q is a covalent bond or a residue such as oxygen or sulphur; R is COOH, PO3H2or P(O)(OH)R4. Further, in this General formula, each of R1, R2, R3and R5independently selected from a variety of substituents; the preferred values of R1, R2, R3and R5are alkoxy, hydrogen, hydroxy and amino. Most preferred for R4is C1-C8alkyl, and most preferred for R5is hydrogen, halogen, amino or hydroxy. For R6the most preferred values are H, C(O)R7or C(O)R72where R7is hydrogen or C1-C8the alkyl. Finally, in this General formula, when Q represents S or O, Q-containing chain is not attached to Z heterocyclic ring residue at the heteroatom of the heterocyclic ring.

Further, the presented invention relates to new tizamidine compounds, their pharmaceutically acceptable salts and esters and to pharmaceutical compositions containing a safe and effective amount of such new aeginetan and effective amount of such new compounds together with pharmaceutically acceptable excipients. Finally, this invention relates to methods for treating or preventing pathological conditions characterized by calcium and phosphate metabolism in humans and other mammals, in particular for the treatment of arthritis. This method consists in the introduction of a human or other mammal in need of such treatment, a safe and effective amount of the compounds or compositions of the present invention.

New tizamidine the compounds of this invention have the following structure:

< / BR>
where m and n represent integers from 0 to 10 and m+n is from 0 to 10 and where:

(a) Z is a covalent bond; monocyclic or polycyclic carbocyclic ring residue or a monocyclic or polycyclic heterocyclic ring residue containing one or more heteroatoms such as O, S or N;

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

(c) each R1independently represents-SR6; -R8SR6; nil; hydrogen; unsubstituted or substituted C1-C8alkyl; monocyclic or polycyclic carbocyclic to ewenny oxadiazol; substituted or unsubstituted pyranone; substituted or unsubstituted furans; hydroxy; -CO2R3; -O2CR3; -NR32; -OR3; -N(R3)C(O)R3; -C(O)N(R3)2; substituted or unsubstituted benzyl; a nitro, or combinations thereof;

(d) R2independently represents-SR6, -R8SR6; -CO2R3; O2C-NR32; -N(R)3C(O)R3, -OR3; -C(O)N(R3)2; nil; hydrogen; unsubstituted or substituted C1-C8alkyl; unsubstituted or 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;

9f) R5is selected from-SR6; R8SR6; hydrogen; hydroxy; halogen; unsubstituted or substituted C1-C8of alkyl;

(g) R6represents H, -C(O)R7; C(S)R7; C(O)N(R7)2; C(S)N(R7)2C(O)OR7or C(S)OR7; where R7is hydrogen or unsubstituted or substituted C1-C8the alkyl and

(h) R8is substituted or unsubstituted C1-C8by alkyl;

when s="ptx2">

As stated above, it is essential that at least one of R1, R2, R3and R5was SR6or R8SR6; when any one of R1, R2, R3or R5is SR6or R8SR6heterocyclic phosphonate is tizanidine connection. Relevant titlestatus in the compounds of this invention are thiols, alkylthiol, thioethers, alkylthiophene, dayevery, alkyldimethyl, THIOCARBAMATE, alkylthiomethyl, dithiocarbamate, alkalitolerant, thiocarbonate, allylthiourea, dithiocarbonate and alkyldithiophosphate.

Finally, this invention relates to the treatment of arthritis in humans or other mammals in need of such treatment, consisting in the introduction of the named person or other mammal a safe and effective amount tizamidine phosphonate compounds having the following structure:

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

(a) Z is covalent bond, monocyclic or polycyclic carbocyclic ring residue or a monocyclic or polycyclic heterocyclic ring residue containing one who allows a COOH, SO3H, PO3H2or P(O)(OH)R4where R4is substituted or unsubstituted C1-C8by alkyl;

(d) each R1independently represents-SR6; -R8SR6; nil; hydrogen; unsubstituted or substituted C1-C8alkyl; monocyclic or polycyclic carbocyclic ring residue; unsubstituted or substituted aryl; substituted or unsubstituted thiophene; substituted or unsubstituted, oxadiazole; substituted or unsubstituted, pironon; substituted or unsubstituted furan; hydroxy; -CO2R3; -O2CR3; - NR32; -OR3; -N(R3)C(O)R3; -C(O)N(R3)2; substituted or unsubstituted benzyl; a nitro, or combinations thereof;

(e) R2is one or more substituents, such as-SR6, -R8SR6; -CO2R3; -OR3; -O2CR3; -C(O)N(R3)2; -NR32; -N(R)3C(O)R3and zero; hydrogen, substituted or unsubstituted C1-C8alkyl; substituted or unsubstituted aryl; hydroxy; substituted or unsubstituted benzyl; a nitro, or combinations thereof;

(f) each R3independently selected from hydrogen, substituted or unsubstituted C1-CSi; amino, halogen, unsubstituted or substituted C1-C9of alkyl;

(h) R6represents H, -C(O)R7; C(S)R7; C(O)N(R7)2; C(S)N(R7)2; C(O)OR7or C (S)OR7where R7is hydrogen or unsubstituted or substituted C1-C8by alkyl; and

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

These compounds are used in the treatment of arthritis, especially rheumatoid arthritis and osteoarthritis, as they are characterized osteotomies activity in the ruin of the joint; this activity has an additional advantage in addition to the usual relief of symptoms of inflammation.

Definitions and use of terms

There follows a list of definitions of terms used in this work.

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

"Alkyl" is an unsubstituted or substituted, straight chain or branched, saturated or the carbon atoms, preferably, unless otherwise specified, from 1 to 4 carbon atoms; named hydrocarbon chain may be unsaturated, containing from 2 to 8 carbon atoms, preferably, unless otherwise noted, from 2 to 4 carbon atoms. Accordingly, the term "alkyl", as used here, encompasses alkeneamine unsaturated hydrocarbon chain having at least one olefinic double bond, and alkyline unsaturated hydrocarbon chain having at least one triple bond. Preferably, the alkyl groups include, but are not limited to: methyl, ethyl, propyl, isopropyl and butyl.

"Heteroalkyl" represents an unsaturated or saturated chain containing from 3 to 8 members and comprising carbon atoms and one or two heteroatoms.

"Carbocyclic ring" or "Carbocycle" used herein means unsubstituted or substituted, saturated or unsaturated or aromatic hydrocarbon ring, which generally contain from 3 to 8 atoms, preferably from 5 to 7 atoms. Used herein, the term "carbocyclic ring residue" has a monocyclic or polycyclic ring system fused or unfused, n is generally contain from 3 to 8, preferably from 5 to 7 carbon atoms, or they may be polycyclic. Polycyclic carbocyclic ring residues, consisting of two rings usually contain 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 here, means unsubstituted or substituted, saturated, unsaturated or aromatic ring containing from 3 to 8, preferably 5-7 carbon atoms and one or more heteroatoms in the ring. Used herein, the term "heterocyclic ring residue" has a monocyclic or polycyclic system, condensed or unfused, unsaturated or saturated, substituted or unsubstituted. Monocyclic heterocyclic ring residues usually contain from 3 to 8 atoms, preferably from 5 to 7 atoms. Polycyclic heterocyclic ring residue, consisting of two rings, mostly contain from 6 to 16, preferably from 10 to 12 atoms. Polycyclic heterocyclic ring residue, consisting of three rings, usually contain from 13 to 17 atoms,toate only heterocycles or both of heterocycles, and carbocycles. If not specifically mentioned, the heteroatoms in the heterocyclic ring residue may independently represent nitrogen, sulfur and oxygen.

"Aryl" represents an aromatic carbocyclic ring. Preferably, the aryl groups include, but are not limited to phenyl, talila, xilian, kamenolom and naphthyl.

"Heteroaryl" represents an aromatic heterocyclic ring. Preferred heteroaryl groups include, but are not limited to tanila, fullam, pirollo, pyridinyl, pyrazinium, oxazolium, thiazolium, hyalinella, pyrimidinium and tetrazolium.

"Alkoxy" represents an oxygen atom, containing a Deputy of the hydrocarbon chain in which the hydrocarbon chain is an alkyl or alkenyl (for example, O-alkyl or O-alkenyl). Preferably, the alkoxy group includes, but is not limited to methoxy, ethoxy, propoxy and alkoxy.

"Hydroxyalkyl" represents a substituted hydrocarbon chain, which contains the hydroxy substituent (e.g.,- OH), and may have other substituents. Preferably, the hydroxyalkyl group includes, but is not limited to hydroxyethyl, hydroxypropyl which contains carboxyl substituent (for example, -COOH) and may have other substituents. Preferably, carboxyamide group include carboxymethyl, carboxyethyl and other acids and esters.

"Aminoalkyl" represents a hydrocarbon chain (e.g., alkyl), substituted amine residue (for example, alkyl-NH), such as aminomethyl.

"Alkylamino" is an amine residue containing one or two alkyl substituent (for example, -N-alkyl), such as dimethylamine.

"Alkynylamino" is an amine residue containing one or two alkenyl substituent (for example, -N-alkenyl).

"Alkynylamino" is an amine residue containing one or two etkinlik substituent (for example, -N-quinil).

"Alkylamino" is an imine residue containing one or two alkyl substituent (for example, -N-alkyl).

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

"Arylamino represents an amine residue, a substituted aryl group (e.g.,- NH-aryl).

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

"Acyl" or "carbonyl"uppada are but not limited to, - acetyl, propionyl, butanoyl and benzoyl.

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

"Acylamino" represents an amino residue, acyl having a substituent (for example, N-acyl); for example, -NH-(C=O)-alkyl.

"Halo", "halogen" or "halide" is an atomic radicals of chlorine, bromine, fluorine or iodine. The preferred halides are the chloro-, bromo -, fluorescent-group.

Also, as mentioned here, "the lower hydrocarbon residue (e.g., lower alkyl) represents a hydrocarbon chain, comprising, unless otherwise indicated, from 1 to 6, preferably from 1 to 4 carbon atoms.

Used herein, the term "thio-Deputy" is described by the formula SR6or R8SR6where R8represents a C1-C8alkyl. Specific titlestyle include thiol (-SH, where R6=H); thioethers (where R6is COR7); THIOCARBAMATE ( where R6is CONR7); dithiocarbamate (where R6is CSNR72); dayevery (where R6is CSR72); thiocarbonate (where R6is C(O)OR7and ditio or unsubstituted C1-C8the alkyl. It is clear that groups SR6may be preceded by R8(i.e., C1-C8alkyl); this will lead to the formation of alkylthiols, alkylthiophenes, acidification, architekturbuero, alkyldiethanolamine, alkylthiophenes and alkyldithiophosphate.

The terms "biphosphonate" or "bebopalula acid", as used here, refers to such phosphonates or phosphonic acids, which have two phosphate groups attached to the same carbon atom and are used here interchangeably with the terms of diphosphonate and diphosphonic acids. When using these formulas, the remainder R in these compounds is a PO3H2.

"Pharmaceutically acceptable" salt means cationic salt formed any acidic (e.g., carboxyl) group, or an anionic salt formed any basic (e.g., amino) group. Many such salts are known in this area, as described in World Patent Publication 87/05297, Johnston and others, published September 11, 1987, included in the link. Preferred cationic salts are alkali metal salts (such as sodium and potassium), and salts of alkaline earth metals (such as the major salt.

"Biohydrology ester" is an ester phosphonate compounds which do not interfere with the activity of the compounds or are readily converted in the body of man or other animal, giving an active connection. Many of these esters are known in the field as described in World Patent Publication 87/05297 Johnston and others, published September 11, 1987, and incorporated herein by reference. Such esters include lower alkalemia esters, lower aryloxyalkyl esters (such as acetoxymethyl, ecotoxicology, aminocarbonylmethyl, pivaloyloxymethyl and pivaloyloxymethyl esters), lactonase esters (such as Caligraphy and tittilicious esters), lower alkoxyalkanols esters (such as methoxycarbonylmethyl, ethoxycarbonylmethyl and isopropoxycarbonyloxymethyl esters), alkoxyalkyl esters, kalinovye esters and acylaminoalkyl esters (such as acetamidomethyl esters).

As defined above and as employed here, the substituents may themselves be substituted. Such substitution may be performed by one or more substituents. Such substituents include, but are not limited to zamestitelyami listed in the work of C. Hansch and A. Leo, Substituent Constant is ogranichivayutsya them alkyl, alkenyl, alkoxy, hydroxy, oxo, amino, aminoalkyl (for example, aminomethyl and so on), cyano, halogen, carboxy, alkoxyalkyl (for example, carboethoxy and so on ), thio, thiol, aryl, cycloalkyl, heteroaryl, heteroseksualci, (for example, piperidinyl, morpholinyl, piperazinil, pyrrolidinyl and so on), imino, thioxo, hydroxyalkyl, aryloxy, arylalkyl and combinations thereof.

New sulfur-containing phosphonate compounds

New sulfur-containing compounds phosphonic acids of this invention and their pharmaceutically acceptable salts and esters are connected through structureas chain; containing phosphonic acid carbon atom attached to structuresa chain that contains the carbonyl carbon atom. The remainder of Z can represent a covalent bond, carbocyclic ring residue or a heterocyclic ring residue. The connection of the carbon atom containing phosphonic acid with the sulfur atom may be directly through a covalent bond (mostly simple connection) or through a chain length (n), consisting of from 1 to 10 atoms. Carbon atoms in the linking chain in structuresa circuit can independently be unsubstituted or substituted by one or more Deputy shall indicability), hydrogen, alkoxy, hydroxy, methyl, ethyl or propyl.

For compounds in which the oxygen atom attached to the heterocyclic ring residue (Z) this oxygen atom connected to a carbon atom of a ring and is not associated with a ring heteroatom. When Q is a covalent bond, connecting the chain can be attached or to a carbon atom or heteroatom of the ring (Z).

Carbon atom which has attached to it phosphonate group may be unsubstituted (i.e., a hydrogen atom or substituted. Carbon atom may be replaced by two phosphonate groups (turning into biphosphonate connection); or one phosphonate group and one phosphinate group (giving phosphonocrotonate connection); phosphonate group and a sulfate group (giving phosphosulfate connection); or phosphonate group and a carboxyl group (giving phosphonocarboxylate connection).

In addition, the carbon atom in the heterocyclic ring (Z) can be unsubstituted or substituted independently by one or more substituents. The heteroatom in the heterocyclic ring can be unsubstituted or substituted.

Thus,the following structure:

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

(a) X is O or S;

(b) Z is a covalent bond; monocyclic or polycyclic carbocyclic ring residue; or a monocyclic or polycyclic heterocyclic ring residue containing one or more heteroatoms such as O, S or n

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

(d) R is COOH, SO3H, PO3H2or P(O)(OH)R4where R4is substituted or unsubstituted C1-C8by alkyl;

(e) each R1independently selected from SR6; -R8S R6; nil; hydrogen; unsubstituted or substituted C1-C8of alkyl; monocyclic or polycyclic carbocyclic ring residue; 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; -OR3; -C(O)N(R3)2; -N(R3)C(O)R3; unsubstituted or substituted benzyl; a nitro, or combinations thereof;

(f) R2the independent is 3)C(O)R3; and zero; hydrogen, unsubstituted or substituted alkyl (C1-C8; unsubstituted or substituted aryl; hydroxy; unsubstituted or substituted benzyl; a nitro, or combinations thereof;

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

(h) R5is selected from-SR6, -R8SR6, hydrogen; hydroxy; amino; halogen; unsubstituted or substituted C1-C8the alkyl and

(i) -R6independently represents H; -C(O)R7and C(O)NR72; where R7is hydrogen or an unsaturated or saturated C1-C8the alkyl and

(j) R8is a saturated or unsaturated C1-C8the alkyl.

In this General formula, Z is a covalent bond; monocyclic or polycyclic, saturated or unsaturated, substituted or unsubstituted carbocyclic ring residue or a monocyclic or polycyclic, saturated or unsaturated, substituted or unsubstituted heterocyclic ring residue. Named heterocyclic ring residue may be a monocyclic ring system (i.e., one carbocyclic rings). Each Z residue may contain one or more heteroatoms, such as oxygen, sulfur or nitrogen.

In this General formula, Q is a covalent bond (preferably a simple link), sulfur or oxygen. Further, m and n and m + n are integers from 0 to 10 with a preferred value for n from 1 to 5 and m + n is from 1 to 10.

Described herein residues R can represent COOH, SO3H, PO3H2or P(O)(OH)R4where R4is C1-C8the alkyl. When R is equal to PO3H2, tizamidine phosphonate compound is biphosphonate; when R is equal to P(O)(OH)R4tizanidine phosphonate compound is phosphonocrotonate, when R is equal to the SO3H, tizamidine phosphonate compound is phosphosulfate; when R is COOH, tizamidine phosphonate compound is phosphonocarboxylates.

The remains of R1are substituents and independently selected from thiol, alkylthiol, thioesters, alkylthiophenes, THIOCARBAMATE, alkyldiethanolamine, hydrogen, halogen, C1-C8the alkyl, unsubstituted or substituted aryl, unsubstituted or substituted benzyl; hydroxy; -C(O)N(R3)2; -OR3; >independently selected from R8SR6, hydrogen or substituted or unsubstituted C1-C8the alkyl, preferably hydrogen or C1-C8the alkyl. When Q is a covalent bond and R1equal to 0, adjacent with R1must be zero; this means unsaturation communication. However, when n = 0, then R5is selected from hydrogen; R8SR6and alkyl containing from 1 to 6 carbon atoms.

The preferred values of R1are hydrogen, chlorine, methyl, ethyl, hydroxy, unsaturated amino, (N-methyl) amino, (N,N-dimethyl)amino, -CO2H and their pharmaceutically acceptable salts, -CO2CH3and-CONH2. The preferred values of R1are hydrogen, methyl, chlorine, amino and hydroxy. The most preferred values are hydrogen, hydroxy or amino.

The remainder Z (when he is a carbocyclic ring residue or a heterocyclic ring residue) in the compounds of this invention may be unsubstituted or substituted at the ring atoms is independently one or more substituents (R2). Group R2can be at one and the same carbon atom or different atoms of the residue z

6; R8SR6; hydrogen; halogen; C1-C8of alkyl; unsubstituted or substituted aryl; unsubstituted or substituted benzyl; -C(O)N(R3)2; -OR3; -CO2R3; -O2CR3; -NR32; -N(R3)C(O)R3; nitro, and combinations thereof, where R3is selected independently from hydrogen or unsubstituted or substituted C1-C8the alkyl, preferably hydrogen.

Preferred R2substituents are independently selected from thio-substituents; (SR6, R8SR6), hydrogen, methyl, ethyl, hydroxy unsubstituted or substituted amino, (N-methyl)amino, (N,N-dimethyl)amino, chloro, methoxy, ethoxy, nitro, -CO2H and their pharmaceutically acceptable salts, -CO2CH3, CONH2and their combinations. More preferred R2substituents are independently hydrogen, methyl, amino, chloro, methoxy, hydroxy and combinations thereof. The most preferred R2substituents are independently amino, hydrogen and methyl.

In the here above General formula, R5denotes hydrogen, halogen, hydroxy, amino, titlestyle, i.e. SR6or R8SR6, unsubstituted or substituted C1-C8

R6denotes Deputy when serosoderjaschei the Deputy, -SR6. R6is hydrogen; -C(O)R7; -C(O)NR72where R7is hydrogen or unsubstituted or substituted C1-C8the alkyl. Preferred for R6are H, C(O)R7C(O)NR7most preferred for R6is hydrogen. Preferred for R7is hydrogen or C1-C8alkyl.

The residue Z of the compounds of the present invention is a covalent bond, carbocyclic ring residue or a heterocyclic ring residue. Named heterocyclic ring residue has one or more heteroatoms selected from O, S or N. the Remainder of Z can be monocyclic carbocyclic or heterocyclic ring residue containing from 3 to 8 atoms, or may be polycyclic carbocyclic or heterocyclic ring residue containing from 6 to 17 atoms. Called polycyclic ring residue may contain two or more number of carbocycles, two or more compounds, or one or more heterocycles with one or more carbocyclic to Lavie residues, are pyrimidine, pyrazin, piperidine and pyridine. Preferred polycyclic Z remains representing a heterocyclic ring residues are quinoline, pyrrolopyridine, cinoxacin and imidazopyridine. Preferred monocyclic remnants of Z, which represents a carbocyclic ring residues are phenyl, cyclopentyl, cyclohexyl and cycloheptyl.

In addition, in the above General formula, when m = 0 and Q is oxygen accession residue Q to a heterocyclic ring residue (Z) is preferably limited as follows. The residue Q is attached to a heterocyclic ring with the carbon atom that is not attached directly to the heteroatom in the heterocyclic ring.

Preferred serosoderzhashchimi phosphonate compounds having a carbonyl carbon in the chain that connects the phosphorus-containing carbon atom, with the remainder of Z are, but not limited to thioethers, Dityatin, thiocarbonate and dithiocarbonate.

Preferred thioethers include compounds having the following General formula:

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< / BR>
The preferred dayaverage are soedineniya, which have the following General formula:

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< / BR>
The preferred dithiocarbonate are compounds that have the following General formula:

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< / BR>
< / BR>
Further, this invention relates to new tizamidine compounds, their pharmaceutically acceptable salts and esters and to pharmaceutical compositions containing a safe and effective amount of such new compounds and pharmaceutically acceptable excipients. In addition, this invention relates to methods for treating or preventing pathological conditions characterized by abnormal calcium and phosphate metabolism in humans and other mammals. This method consists in the introduction of a human or other mammal in need of such treatment, a safe and effective amount of the compounds or compositions of the present invention. These new tizamidine compounds have the following General formula:

< / BR>
where m and n are integers from 0 to 10 and m+n is from 0 to 10 and where:

(a) Z is a covalent bond; monocyclic or polycyclic carbocyclic ring residue or a monocyclic or polycyclic heterocyclic ring residue containing one and the R4: where is C1-C8by alkyl;

(c) Each R1is selected independently from-SR6; -R8SR6; nil; hydrogen; unsubstituted or substituted C1-C8of alkyl; monocyclic or polycyclic carbocyclic ring residue; unsubstituted or substituted aryl; substituted or unsubstituted thiophene; substituted or unsubstituted oxadiazole; substituted or unsubstituted of pyranone; substituted or unsubstituted furan; hydroxy; -CO2R3; -O2CR3; -NR23; -N(R3)C(O)R3; -OR3; -C(O)N(R3)2; substituted or unsubstituted benzyl; nitro, and combinations thereof;

(d) R2is selected independently from-SR6; -R8SR6; -CO2R3; -O2CR3; -NR23; -N(R)3C(O)R3; OR3; -C(O)N(R3)2; nil; hydrogen; unsubstituted or substituted C1-C8of alkyl; unsubstituted or 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; R86is H; -C(O)R7; -C(S)R7; -C(O)NR27; -C(S)NR27; C(O)OR7or C(S)OR7where R7is hydrogen or unsubstituted or substituted C1-C8the alkyl and

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

In this General formula, Z is a covalent bond; a saturated or unsaturated, substituted or unsubstituted carbocyclic ring residue; monocyclic or polycyclic, saturated or unsaturated, substituted or unsubstituted heterocyclic ring residue. Called the Z residue may be monocyclic ring system (i.e., one carbocyclic ring or another heterocyclic ring or may be a polycyclic ring system (i.e., one or more heterocyclic rings, one or more carbocyclic rings and one or more heterocyclic together with one or more carbocyclic rings). Each Z residue may contain one or more heteroatoms, such as oxygen, sulfur or nitrogen.

In these General formulas, m and n are the P> Described herein residues R can represent COOH, SO3H, PO3H2or P(O)(OH)R4where R4is C1-C8the alkyl. When R has a value of PO3H2tizanidine phosphonate compound is biphosphonate; when R is equal to P(O)(OH)R4, tizamidine phosphonate compound is phosphonocrotonate, when R is equal to the SO3H, tizamidine phosphonate compound is phosphosulfate; when R is COOH, tizamidine phosphonate compound is phosphonocarboxylate.

As noted above, it is important that at least one of R1, R2, R3or R5mattered SR6or R8SR6; when any one of R1, R2, R3or R5is SR6or R8SR6, phosphonate compound is tizamidine. Suitable titlestatus for compounds of this invention are thiols, alkylthiol, thioethers, alkylthiophene, dayevery, alkyldimethyl, THIOCARBAMATE, allylthiourea, dithiocarbonate and alkalitolerant.

The remains of R1are substituents and independently selected from thiol, alkylthiol, thioesters, alkylthiophenes, dityatev, thiocarbonates, dithiocarbonates, alkyldithiophosphate, hydrogen, halogen, C1-C8the alkyl, unsubstituted or substituted aryl, unsubstituted or substituted benzyl; hydroxy; -C(O)N(R3)2; -OR3; -CO2R3, -O2CR3; -NR23; -N(R3)C(O)R3; nitro, and combinations thereof, where R3independently selected from R8SR6, hydrogen or substituted or unsubstituted C1-C8the alkyl, preferably tizamidine of Akilov.

However, when n=0, R5is selected from hydrogen, R8SR6; alkyl containing from 1 to 8 carbon atoms; and pharmaceutically acceptable salts and esters of these compounds and their combinations.

The preferred values of R1are thio-substituents, hydrogen, chlorine, methyl, ethyl, hydroxy, unsubstituted amino, (N-methyl)amino (N, N-dimethyl)amino, -CO2H and their pharmaceutically acceptable salts, -CO2CH3and-CONH2. The preferred values of R1are thiol (or tiradera deputies), hydrogen, methyl, chlorine, amino and hydroxy. Most preferred are the thiol hydrogen, hydroxy or amino. In addition, as mentioned above, it is important that the compounds of the present invention poly R8SR6.

When the residue Z is a carbocyclic ring residue or a heterocyclic ring residue, called ring residue may be unsubstituted or substituted with atoms of the ring are independently one or more substituents (R2). Group R2can be located at the same carbon atom or different ring atoms of the residue.

Thus, the group R2are substituents at one or several atoms of the heterocycle are independently zero; SR6; R8SR6; hydrogen, halogen; C1-C8the alkyl, unsubstituted or substituted aryl; unsubstituted or substituted benzyl; -C(O)N(R3)2; -OR3; -CO2R3; -O2CR3; -NR23; -N(R3)C(O)R3; nitro and combinations thereof, where R3is selected independently from hydrogen or unsubstituted or substituted C1-C8the alkyl, preferably titlesong of alkyl.

Preferably, the substituents and R2independently selected from titlestyle (SR6, R8SR6), hydrogen, methyl, ethyl, hydroxy, unsubstituted amino, (n-methyl)amino, (N, N-dimethyl)amino, chlorine, methoxy, taxpreparation values of R2are independently cisternasii substituents, hydrogen, methyl, amino, chloro, methoxy, hydroxy and combinations thereof. The preferred meanings of the substituents R2are independently cisternasii substituents, hydrogen and methyl. In addition, as mentioned above, it is important that the compounds of this invention at least one of R1, R2, R3and R5was diastereomer Deputy, i.e. SR6or R8SR6.

R5in the above General formula represents hydrogen, halogen, hydroxy, amino, titlestyle, i.e. SR6or R8SR6, unsubstituted or substituted C1-C8alkyl. The preferred value of R5is hydroxy, amino, hydrogen, halogen, thio; most preferred is hydroxy, amino, and hydrogen.

R6denotes Deputy in serosoderjaschei the Deputy - SR6. R6is hydrogen; -C(O)R7; C(S)R7; -C(O)NR27; -C(S)NR27C(O)OR7, -C(S)OR7where R7represents hydrogen or unsubstituted or substituted C1-C8alkyl. The preferred value of R6is H, C(O)R7C(O)NR7most pre is or C1-C8alkyl.

The residue Z of the present invention is a covalent bond; carbocyclic ring residue or a heterocyclic ring residue having one or more heteroatoms such as O, S or N. the Remainder of Z can be monocyclic carbocyclic ring residue or a heterocyclic ring residue containing from 3 to 8 atoms, or polycyclic carbocyclic ring residue or a heterocyclic ring residue containing from 6 to 17 atoms. Called polycyclic ring residue may contain two or more carbocyclic or two or more compounds, or one or more heterocycles with one or more carbocyclic rings.

Preferred monocyclic residue and Z represents a heterocyclic ring residue, are pyrimidine, pyrazin, piperidine and pyridine. Preferred polycyclic remnants Z represents a heterocyclic ring residues are quinoline, pyrrolopyridine, chynoxaline and imidazopyridine. Preferred monocyclic remnants of Z, which carbocyclic ring residues alleycode m=0, join residue NR1to the heterocyclic ring residue (Z) is preferably limited to the following. The remainder NR1attached to the heterocyclic ring with a carbon atom.

Proposed new tizamidine phosphonate compounds of this invention include, but are not limited to compounds having the following General formula:

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Especially preferred are the following tizanidine aminoalkylphosphonic connection:

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Finally, this invention relates to the treatment of disorders of calcium and phosphate metabolism, in particular, arthritis, especially rheumatoid arthritis and osteoartritis, in humans and other mammals in need of such treatment. Named the method includes the appointment of a named person or other mammal a safe and effective amount tizamidine phosphonate compounds having the following formula:

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where m and n are integers from 1 to 10, and m+n is from 0 to 10 and where:

(a) Z is a covalent bond; monocyclic or polycyclic carbocyclic ring residue, or a monocyclic or polycyclic heterocyclic ring residue, is SUP>1;

(c) R is COOH; SO3H; PO3H2or P(O)(OH)R4; where R4is C1-C8by alkyl;

(d) each R1is selected independently from-SR6; -R8SR6; nil; hydrogen; unsubstituted or substituted C1-C8of alkyl; substituted or unsubstituted monocyclic or polycyclic carbocycle; unsubstituted or substituted aryl; substituted or unsubstituted thiophene; substituted or unsubstituted oxadiazole; substituted or unsubstituted of pyranone; substituted or unsubstituted furan; hydroxy; alkoxy; -CO2R3; -O2CR3; -NR32; -N(R3)C(O)R3; -OR3; -C(O)N(R3)2; substituted and unsubstituted benzyl; a nitro, or combinations of these substituents;

(e) R1is one or more substituents selected from-SR6; R8SR6; -CO2R3; -O2CR3; -C(O)N(R3)2; -NR23; -N(R3)C(O)R3and zero; hydrogen; substituted or unsubstituted C1-C8of alkyl; substituted or unsubstituted benzyl; a nitro, or combinations thereof;

(f) each R3is selected independently from hydrogen; substituted or nezamestnanosti; hydroxy; unsubstituted or substituted C1-C8of alkyl; amino; halogen;

(h) R6is H; -C(O)R7; -C(S)R7; -C(O)NR27; -C(S)NR27; C(O)OR7or C(S)OR7where R7is hydrogen or unsubstituted or substituted C1-C8the alkyl and

(i) R8is substituted or unsubstituted C1-C8by alkyl; and at least one of R1, R2, R3or R5is an R6or R8SR6.

These compounds are used in the treatment of arthritis or other disorders of calcium or phosphate metabolism; these compounds reveal osteotsity activity in the place of destruction of the joint. This activity is activity in changing illness in the place of destruction of the joint, significantly higher than the normal relief of symptoms of inflammation.

In these General formulas, Q is a covalent bond (preferably a simple link) or residues, such as oxygen, sulfur, nitrogen, or-NR1-. Further, m and n and m+n are integers from 0 to 10 with a preferred value of m+n is from 1 to 5.

Described herein residues R can be COOH, SO3H, PO3H2or P(O)(OH)R4where R4is biphosphonate; when R is P(O)(OH)R4, tizamidine phosphonate compound is phosphonocrotonate, when R has a value of SO3H tizanidine phosphonate compound is phosphosulfate; when R is COOH tizanidine phosphonate compound is phosphonocarboxylates.

As stated above, it is important that at least one of R1, R2, R3or R5represented SR6or R8SR6; when any one of R1, R2, R3and R5is SR6or R8SR6, phosphonate compound is tizanidine connection. Suitable titlestyle for compounds of this invention include thiols, alkylthiol, thioethers, alkylthiophene, dayevery, alkyldimethyl, THIOCARBAMATE, alkylthiomethyl, dithiocarbamate, alkalitolerant, thiocarbonate, allylthiourea, dithiocarbonate and alkalitolerant.

The remains of R1represent substituents and independently selected from thiol, alkylthiol, thioesters, alkylthiophenes, dityatev, acidification, THIOCARBAMATE, alkyldiethanolamine, dithiocarbamate, alkyldiethanolamine, thiocarbonates, alkylthiophenes, dithiocarbonates, acidity the or substituted benzyl; hydroxy; -C(O)N(R3)2; -OR3; -CO2R3; -O2CR3; NR23; -N(R3)C(O)R3; nitro, and combinations thereof, where R3independently selected from R8SR6, hydrogen or unsubstituted or substituted C1-C8the alkyl, preferably tizamidine of Akilov. When Q is a covalent bond, and any one of R1is zero, the adjacent R1must be zero; this means unsaturated bond. When Q represents NR1, R1may be null, which means the presence of a double bond of carbon-nitrogen.

However, when n=0 and Q is oxygen, sulfur or nitrogen, R5is selected from hydrogen; R8SR6; alkyl containing from 1 to 8 carbon atoms; and pharmaceutically acceptable salts and esters and combinations thereof.

Preferably R1selected from titlestyle, hydrogen, chlorine, methyl, ethyl, hydroxy, unsubstituted amino, (N-methyl)amino, (N, N-dimethyl)amino, -CO2H and their pharmaceutically acceptable salts, -CO2CH3and-CONH2. The preferred value of R1is a thiol (or cisternasii deputies), hydrogen, methyl, chlorine, amino and hydroxy. The most preferred value of R1th invention at least one of R1, R2, R3and R5was diastereomer Deputy, i.e. SR6or R8SR6.

R5in the above General formula means hydrogen, halogen, hydroxy, amino, titlestyle, i.e. SR6or R8SR6substituted or unsubstituted C1-C8alkyl. Preferably R5represents a hydroxy, amino, hydrogen, halogen, thio; the most preferred value of R5is hydroxy, amino, and hydrogen.

R6denotes Deputy when serosoderjaschei the Deputy, -SR6. R6is hydrogen; -C(O)R7; C(S)R7; -C(O)NR27; -C(S)NR27; -C(O)OR7, -C(S)OR7where R7is hydrogen or unsubstituted or substituted C1-C8the alkyl. Preferably R6represents H, C(O)R7C(O)NR7most preferred for R6value is hydrogen. Preferably R7is hydrogen or C1-C8the alkyl.

In addition, in the above General formula, when m=0 and Q is oxygen, sulfur or nitrogen compound residue Q with the heterocyclic ring is preferably limited to the following: balance Q prisoedinyaetsya include:

[2-[(2,2-dimatia-1-oxopropyl)thio]ethylidene]bis[phosphonic acid];

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

[2-(n-methoxy-benzylthio)ethylidene]bis[phosphonic acid];

[2-(n-amino-benzylthio)ethylidene]bis[phosphonic acid];

[2-(acetylthio)ethylidene]bis[phosphonic acid]; disodium salt;

[2-mercapto-2-(phenyl)ethylidene]bis[phosphonic acid];

[2-mercapto-2-(o-AMINOPHENYL)ethylidene]bis[phosphonic acid];

[2-mercapto-2-(m-AMINOPHENYL)ethylidene]bis[phosphonic acid];

[2-mercapto-2-(n-AMINOPHENYL)ethylidene]bis[phosphonic acid];

[2 Acetylthio-2-(phenyl)ethylidene]bis[phosphonic acid];

[3-mercapto-1-hydroxybutylidene]bis[phosphonic acid];

[3-mercapto-3-methyl-1-hydroxybutylidene]bis[phosphonic acid];

[4-amino-3-mercapto-1-hydroxybutylidene]bis[phosphonic acid];

[4-amino-2-mercapto-1-hydroxybutylidene]bis[phosphonic acid];

[2-amino-1-hydroxy-3-mercapto-3-methylbutyrate]bis[phosphonic acid];

[2-amino-1-hydroxy-3-acetylthio-3-methylbutyrate]bis[phosphonic acid] ;

1-[(Hydroxy)methylphosphinyl]-2-mercaptoethylamine acid;

[2-Mercapto-2-methylpiperidin]bis[phosphonic acid];

[2-(Acetylthio)-2-metals[phosphonic acid];

[1-Hydroxy-2-(3-acetyldigitoxin)ethylidene]bis[phosphonic acid];

[1-Hydroxy-2-(4-acetyldigitoxin)ethylidene]bis[phosphonic acid];

[1-Hydroxy-2-(2-mercaptonicotinic)ethylidene]bis[phosphonic acid];

[1-Hydroxy-2-(3-mercaptoacetic)ethylidene]bis[phosphonic acid];

[1-Hydroxy-2-(4-mercaptonicotinic)ethylidene]bis[phosphonic acid];

[1-Hydroxy-2-(2-(3-mercaptopropyl)cyclohexyl)ethylidene] bis [phosphonic acid];

[1-Hydroxy-2-(3-(2-mercaptoethyl)cyclohexyl)ethylidene] bis [phosphonic acid];

[1-Hydroxy-2-(2-acetylthiophene)ethylidene]bis [phosphonic acid];

[1-Hydroxy-2-(3-acetylthiophene)ethylidene]bis [phosphonic acid];

[1-Hydroxy-2-(2-mercaptonicotinic)ethylidene]bis [phosphonic acid];

[1-Hydroxy-2-(3-mercaptoacetate)ethylidene]bis [phosphonic acid];

[1-Hydroxy-2-(2-(2-mercaptoethyl)cyclopentyl)ethylidene] bis [phosphonic acid];

[1-Hydroxy-2-(2-(3-mercaptopropyl)cyclopentyl)ethylidene] bis [phosphonic acid];

[2-Mercapto-5-phenylindolizine]bis[phosphonic acid];

[2-Mercapto-5-(o-AMINOPHENYL)pentylidene]bis[phosphonic acid];

[2-Mercapto-5-(m-AMINOPHENYL)pentylidene]bis[phosphonic cycle[phosphonic acid];

[2-Mercapto-5-(o-AMINOPHENYL)butylidene]bis[phosphonic acid];

[2-Mercapto-5-(m-AMINOPHENYL)butylidene]bis[phosphonic acid];

[2-Mercapto-5-(n-AMINOPHENYL)butylidene]bis[phosphonic acid];

[2 Acetylthio-5-phenylindolizine]bis[phosphonic acid];

[2 acetylthio-5-(n-AMINOPHENYL)pentylidene]bis[phosphonic acid];

[3-(3-furfuryl)-2-mercaptoethylamine]bis[phosphonic acid];

[3-cyclohexyl-2-mercaptopropionyl]bis[phosphonic acid].

In order to evaluate the pharmacological activity test was carried out on animals diphosphonate compounds using various well-known in this field of analysis. So, bone antiresorptive activity in vivo can usually be demonstrated by analysis, a key test of the ability of these compounds to inhibit bone resorption, while bone resorption is a characteristic of abnormal calcium and phosphate metabolism. Examples of such well-known tests are the Schenk model rats and adjuvant arthritic test. Apply the test in vitro for inhibition of crystal growth of hydroxyapatite. These and other suitable methods for testing the pharmacological activity raskryvayut); Russell and others, Calcijied Jissue Research, 6, PP 183-196 (1970); Muhlbauer and Fleisch, Mineral Electrolyte lletab., 5, pp. 296 - 303 (1981); Nancollas and others , Oral.Biol 15, 731 (1970); U.S. Patent 3 683 0 80 Francis, published on August 8, 1872; U.S. Patent 4 134 969 Schmidt-Dunker, published on 16 January 1979 and EPO Patent application publication N 189 662, published August 6, 1986; open all articles and patent descriptions are fully incorporated herein by reference. Some of these tests are also more detail in the following Examples.

In addition to the use for the treatment or prevention of pathological conditions characterized by abnormal calcium or phosphate metabolism, the compounds of this invention may have other uses. For example, it is assumed that the compounds of this invention are useful as bone scanning agents after they were labeled with technetium 99m. In addition, the compounds of this invention are useful as investing agents for polyvalent metal ions, in particular two (for example, calcium and magnesium) and trehletnij metals (e.g., India). Thus, the compounds of this invention are useful as components in detergents and cleaners, or for processing the La to prevent the formation of deposits (i.e., deposits and/or debris on the teeth. Finally, the compounds of this invention can be used as herbicides that are toxic to animals.

Phosphonate compounds of this invention can be prepared using the methods given here below in Examples A-R.

Pharmaceutical compositions containing phosphonate compounds

Described here phosphonate compounds can be administered to humans or other mammals using various techniques, including but not limited to such as oral dosage forms and injections (intravenous, intramuscular, intraperitoneal and subcutaneous). Many other dosage forms containing the new tizamidine phosphonate compounds of this invention can be easily prepared by a specialist using suitable pharmaceutical excipients as shown below. To comply with sick mode and scheme of treatment is usually the most preferred are oral dosage forms.

Used herein, the term "pharmaceutical composition" means a combination of a safe and effective amount tizamidine phosphate active ingredient and an effective amount" means an amount of compound or composition sufficiently large in magnitude to significant positive changes in symptoms and/or condition, which must be subjected to treatment, but small enough to avoid serious side effects (at a reasonable ratio of success/risk) on the basis of clear medical research. Safe and effective amount of the active ingredient for use in pharmaceutical compositions in the method of the invention proposed here will vary depending on the specific condition, powerhouses treatment, the age and physical condition of the patient, the severity of the condition, duration of exposure, the nature of concurrent therapy, the specific applied active ingredient, used concrete pharmaceutically acceptable fillers and the like factors within the knowledge and observations of the treating physician.

Used here, the term "pharmaceutically acceptable excipients" means any physiologically inert, pharmacologically inactive substance known to the specialist, which is compatible with the physical and chemical characteristics of the particular active ingredient based on phosphonate compounds selected for use. Pharmaceutically acceptable excipients include, but are not limited to polymers, Smania, the leavening agents, solvents, co-solvents, buffer systems, surfactants, preserving agents, agents which impart sweetness, improves the taste and odor agents, dyes and pigments, pharmaceutical classification and agents that regulate the viscosity.

Used herein, the term "oral dosage form" means any pharmaceutical composition intended for the systematic acceptance of the individual by delivery of the above composition in the gastrointestinal tract of the individual through the mouth. In accordance with the purpose of the present invention form for such delivery may serve as coated or uncoated tablets; solution, suspension, or coated or uncoated capsules.

Used herein, the term "injection" means a pharmaceutical composition intended for the systematic admission of a human or other mammal by delivery of a solution or emulsion containing the active ingredient by injections named individual with the purpose of delivering these solution or emulsion in his circulatory system by any means of injection intravenously, intramuscularly, intraperitoneally or subcutaneously.

Speed Seeley more of the following factors:

(a) the actual active ingredient;

(b) pharmaceutically acceptable excipients; while options have no effect on the activity of the specific active ingredient;

(c) the type of filler and the corresponding desired thickness and permeability (swelling properties) called filler;

(d) conditions time dependence of the filler and/or inside of fillers;

(e) the particle size of the granules of the active ingredient and

(f) the conditions according to the pH of the fillers.

In particular, solubility, acidity and sensitivity to hydrolysis of various tizanidine phosphonate active ingredients, such as acid additive salts, salts formed with carboxyl groups, for example, salts of alkali metals, salts of alkaline earth metals, etc., and ethers, for example, Elgiloy, alkenilovyh, arrowy, Arakelova can be used as the primary criterion for selection. In addition, appropriate pH conditions can be created within the oral pharmaceutical dosage forms by adding to the active ingredient in a suitable buffer in accordance with the desired release rate.

As mentioned above, the pharmaceutical is binding substances, solvents, chemicals, giving a smooth, leavening agents, agents which impart sweetness, improves the taste and odor agents, buffer systems, dyes or pigments pharmaceutical classification and agents, giving the viscosity.

The preferred solvent is water.

Used here improves the taste and odor agents are agents that are similar to those described in Remingten's Pharmacentical Sciences, 18th ed, Mack Publichign Company, 1990, pp. 1288-1300, incorporated herein by reference. Suitable for use here pharmaceutical compositions typically contain from 0 to 2% to improve the taste and reserve additions.

Used here, the dyes or pigments are similar to those described in Handbook of Pharmacentical Expipcents pages 81-90, 1986 American Pharmacentical Association & Tre Pharmacentical Societg of Great Dritain, incorporated herein by reference. Pharmaceutical compositions typically contain from 0 to 2% of dyes or pigments.

The proposed co-solvents include, but are not limited to ethanol, glycerin, propylene glycol, polyethylene glycols. The pharmaceutical compositions of this invention contain from 0 to 50% of cosolvent.

The proposed buffer systems include, but are not limited to okaerinasai, gluconic, glutaric and glutamic acids and their sodium, potassium and ammonium salts. Most preferred are phosphoric, tartaric, citric and acetic acids and their salts. The pharmaceutical compositions of this invention usually contain from 0 to 5% buffer systems.

Preferred surface active agents include, but are not limited to fatty acid esters of polyoxyethylenesorbitan, monoalkylamines esters of polyoxyethylene, monoamine sucrose and lanolin esters and ethers, alkylsulfate salts, sodium, potassium and ammonium salts of fatty acids. The pharmaceutical compositions of this invention contain from 0 to 2% surfactant.

Preferred curing agents include, but are not limited to phenol, alkylamino esters of parahydroxybenzoic acid, o-phenylphenolate acids and their salts, boric acid and its salts, sorbic acid and its salts, chlorbutanol, benzyl alcohol, finalstate acetate and nitrate, nitromersol, benzalconi chloride, pyridinium chloride, methyl paraben and propyl paraben. Most preferred are salts of benzoic acid, pyridinium chloride, methylparaben and impregnated Stateline sweeteners include, but not confined sucrose, glucose, saccharin, sorbitol, mannitol and aspartame. Most preferred are sucrose and saccharin. The pharmaceutical compositions of the present invention contains 0-5% sweeteners.

Preferred agents regulating the viscosity, are, but are not limited to: methyl cellulose, sodium carboxymethyl cellulose, hypromellose, hydroxypropylcellulose, sodium alginate, carbomer, povidone, gum, guar gum, xanthan gum and tragakant. Most preferred are methyl cellulose, carbomer, xanthan gum, guar gum, povidone, sodium carboxymethylcellulose and magnesium-aluminum silicate. The compositions of this invention contain 0-5% agents regulating the viscosity.

Preferred fillers include, but are not limited to: lactose, mannitol, sorbitol, trehosnovnoy calcium phosphate, dibasic calcium phosphate, pressed sugar, starch, calcium sulfate, dextro - and microcrystalline cellulose. The compositions of this invention contain 0-75% fillers.

Preferred lubricants include, but are not limited to: magnesium stearate, Starinov">

The preferred substances, improve slip, include, but are not limited to: talc and colloidal silicon dioxide. The compositions of this invention contain 0-5% substances that improve the slip.

The preferred leavening agents include, but are not limited to: starch, sodium, glycolate starch, crosspovidone, sodium crosscarmellose, and microcrystalline cellulose. The pharmaceutical compositions of this invention include 4-15% of the disintegrator.

Preferred binders include, but are limited to: gum, tragakant, hydroxypropylcellulose, pre gelatinising starch, gelatin, povidone, hydroxypropylcellulose, hypromellose, methylcellulose, the solution of sugars, such as sucrose and sorbitol, and ethylcellulose. The compositions of this invention contain 1-10% of the binder.

The compounds of this invention can comprise from about 0.1% to about 99.9% by weight of the composition of the present invention. Preferably, the compounds of this invention comprise from about 15% to 95% by weight on the composition of the pharmaceutical compositions of the present invention.

Accordingly, the pharmaceutical compositions of this is and compounds; 0-2% improves the taste and odor additives; 0-50% co-solvents; 0-5% buffer system; 0-2% surface-active agents; 0-2% preservatives; 0-5% sweeteners; 0-5% agents regulating the viscosity; 0-75% fillers; 0.5 to 2% lubricants; 1-5% of substances which improve the sliding; 4-15% baking powder and 1-10% of a binder.

The choice of pharmaceutical filler used in combination with tizamidine the phosphonates of these compositions is determined mainly by the way will be the introduction of phosphonate compounds. If the connection is intended for injection, the preferred pharmaceutical carrier is sterile, physiological saline solution, pH of which is brought to 7.4. However, the preferred method of reception of phosphonates of this invention is the oral method and therefore preferred standard dosage form are tablets, capsules, etc., containing from about 0.1 mg P to 600 mg in the above-described compounds diphosphonic acid. Pharmaceutical carriers suitable for the preparation of standard dosage forms intended for oral administration are well known in the industry. Their curves are not necessary for the subject matter of this invention and do not pose difficulties for the expert in this field.

Used herein, the term "mg P" means the weight of phosphorus atoms contained in a certain number of connections diphosphonic acids of the present invention. This unit is used to standardize the number of connections diphosphonic acids of the present invention used in the pharmaceutical compositions and methods of the present invention. For example, 2-(acetylthio)ethylidene bis[phosphonic acid], disodium salt has a molecular weight of 308 g/mol, of which 20% (62 g/mol) are in two phosphorus atom present in the molecule. One milligram of this connection, therefore, should be 0.20 mg P (1 mg x 20,0%). Thus, to obtain pharmaceutical compositions containing 1 mg P this connection, the composition should contain 5 mg compounds and dosages of this compound at 1 mg/kg patient weight of 50 kg should take 250 mg of this substance.

The pharmaceutical carrier employed in conjunction with the phosphonates of this invention is used in a sufficient concentration to ensure the practical value of the measured ratio. Preferably, pharmaceutically acceptable carriers, in General, approximately from 0.1% to 99.9% by weight of the total weight composol from 20% to 80%.

Corresponding pharmaceutical compositions are described in the Examples U-W. To obtain a large number of pharmaceutical compositions for the specialist, there are huge opportunities in the changes described here are examples, not limited to these examples.

The method of treatment or prevention of diseases characterized by abnormal calcium and phosphate metabolism

Another aspect of the present invention consists in methods of treating or preventing diseases characterized by abnormal calcium or phosphate metabolism. Such methods include administration to a human or lower animal in need of such treatment a safe and effective amounts described herein diphosphatase connection.

The preferred method of administration is oral, but also offered other known routes of administration, such as, for example, dermato-mucosal (e.g., dermal, rectal, etc.,) and parenteral (e.g. subcutaneous injection, vnutrishkolnye injection, intraarticular injection, intravenous injection, etc). In way of introduction are also included inhalation. Thus, specific methods of administration include, without limitation, oral, transdermal is the train and a local application.

Used herein, the term "abnormal calcium and phosphate metabolism" means (1) States, which are characterized by anomalous mobilization of calcium and phosphate, leading to General or specific bone loss or excessively high levels of calcium and phosphate in the body fluids and (2) conditions that cause or are the result of abnormal deposits of calcium and phosphate in the body. The first category includes, but is much more than knowledge of them: osteoporosis, Paget's disease, hyperparathyroidism, hypercalcemia malignant tumors, heterotopic ossification, and osteolytic bone metastases. The second category includes, but is not limited to, - misita progressive osteogenetic, calcinosis universalis, and diseases such as arthritis, rheumatoid arthritis, osteoarthritis, neuritis, bursitis, tendonitis and other that predispose affected tissue to deposition of calcium and phosphate.

Used herein, the term "rheumatoid arthritis" refers to a chronic total and sustavnoi inflammatory disease of unknown etiology. It is characterized by destruction of articular cartilage, ligaments, tendons and bones.

Used here, the term "osteoarthritis" means non-communicable dis is Oh bone on the articular surface.

The terms "person at risk" and "the person needing such treatment", as used here, means any person or other mammal, which is experiencing a significant risk of abnormal calcium and phosphate metabolism, if it stops the treatment, and any person or other mammal diagnosed as affected abnormal calcium and phosphate metabolism. For example, women in postmenopausal period; people affected by a particular steroid treatment; people receiving anticonvulsant medications, people diagnosed as having Paget's disease, hyperparasites, hypercalcemia malignant tumor or etericnimi bone metastases; people diagnosed as suffering from one or more different forms of osteoporosis; people who belong to groups known as having a higher chance of developing osteoporosis in comparison with the average value, for example, women in the postmenopausal period, men older than 65 years and those subjected to treatment with drugs known to cause osteoporosis as a side effect; people diagnosed as suffering from myositis ossificans progressiva or calcinosis universalis, and people, p is that predispose the tissue to deposition of calcium and phosphate.

The phrase "safe and effective amount", as used here, means the number of compounds or compositions of the present invention is high enough to cause significant positive change in the condition being treated, but low enough to avoid serious side effects (at a reasonable relation to the success/risk) in terms of a thorough medical examination. Safe and effective amount diphosphonate compounds of the present invention is subject to variation depending on the specific conditions being treated, the age and physical condition of the patient being treated, on the severity of the condition and duration of treatment, the nature of concurrent therapy, the specific applicable phosphonates, from using a particular pharmaceutically acceptable excipients, and other factors within the competence of the knowledge and opinions of the treating physician. However, single dosages can vary in the range from about 0.01 mg P to 3500 mg P or from 0.0002 to 70 mg P/kg body weight (calculated on the weight of 50 kg). The preferred unit dose is a dose from about 1 mg P to 600 mg P or from 0.02 to 12 g of P/kg of body weight (p is the antecedent does not require daily dosage of more than 500 mg/kg, that may cause undesirable side effects. Within this interval, the higher the dosage, of course, required in the case of oral administration due to limited absorption.

The following examples describe and illustrate the proposed implementation in the scope of this invention. Examples are given solely for illustration and may not be construed as limiting the invention, since it is possible there are many varieties of such examples does not violate the essence and scope of the invention.

Example A.

Synthesis of [2-[(2,2-dimethyl-1-oxopropyl)thio]ethylidene]bis [phosphonic acid]

< / BR>
I. Synthesis of [2-[(2,2-dimethyl-1-oxopropyl)thio] -ethylidene] bis[phosphonic acid], tetraethyl ester

Tetraethyl attalides(phosphonate) (3.00 g, 10.0 mmol) [prepared as described by C. R. Degenhardt and D. C. Burdsall, J. Org. Chem, T. 51, page 3488 - 3490 (N 18) 1986] and trimethylhexane acid (1.54 g, 13.0 mmol) are mixed in chloroform (50 ml) at room temperature for 96 hours. The reaction mixture is evaporated under reduced pressure, giving tiefer (Android 4.04 g) as a pale yellow oil with 98% yield.

II. Synthesis of [2-[(2,2-dimethyl-1-oxopropyl)thio]ethylidene] bis [phosphonic KIS is anatoy temperature for 120 hours. The reaction mixture is rapidly cooled by the addition of methanol (40 ml), then concentrated under reduced pressure. The residue is ground in hexane and the product is collected by filtration and dried in vacuum desicator education bisphosphonates acid (2.21 g) in 69% yield.

Example B

Synthesis of [2-(Benzylthio)ethylidene]bis[phosphonic acid]

< / BR>
I. Synthesis of [2-(Benzylthio ethylidene]bisphosphonates acid], tetraethyl ester

To tetraethyl ethylidene(phosphonate) (5.25 g, 17.43 mmol) [obtained as described in C. R. Dagenhardt, and D. C. Burdsall, J. Org. Chem. so 51, page 3488 - 3490 (N 18) 1986] in chloroform (50 ml) is added diamentina acid (2.65 g, 19.17 mmol). The reaction mixture was stirred at room temperature under nitrogen atmosphere for 4 days. Then the reaction mixture was washed with water (2 x 100 ml), then saturated aqueous NaCl (1 × 100 ml). The organic layer is dried over sodium sulfate, filtered and concentrated under reduced pressure, forming thioether in the form of a yellow oil (6.6 g) in 87% yield.

II. Synthesis of [2-(Benzylthio)ethylidene]bisphosphonates acid

Phosphonate esters hydrolyzed in anhydrous conditions action tetraethylpyrophosphate (4.15 g, 9.47 mmol) with 10 equivalents brome mixture was stirred for 30 minutes with water (20 ml) and ethyl acetate (20 ml). The layers are separated and the aqueous layer was treated with charcoal, filtered and concentrated to education bisphosphonates acid (1.3 g) in 43% yield.

Example C

Synthesis of [2-(Acetylthio)ethylidene]bis[phosphonic acid]

Disodium salt

< / BR>
Chetyrehmetrovy attalides(phosphonate) (2.76 g, 10 mmol) [obtained as described in U.S. Patent 3 686 290 R. L. Carroll (1972), and in Canadian Patent 811 736 (1969) R. L. Carroll, and M. M. Crutchfield] and colocasia acid (3.81 g, 50 mmol) dissolved in water (20 ml) and mixed at room temperature in nitrogen atmosphere for 20 hours. Then the reaction mixture is concentrated under reduced pressure and further dried in vacuum over night. The solid product is ground in a heat ethanol, cooled and filtered while washing with diethyl ether, forming pure product as pale yellow solid substance.

Example D

Synthesis of [2-mercapto-2-(phenyl)ethylidene]bis[phosphonic acid]

< / BR>
I. Synthesis of 4,4'-(phenylmethylene)bomarton

Suspension benzene (10 ml) containing 3-pyridinecarboxamide (3.97 g, 37.09 mmol), boron trioxide (4.31 g, 61.94 mmol) and morpholine (7.76 g, 89.02 mmol) is stirred at room temperature for 2 hours. The reaction mixture milf pressure with the formation of bisamine (7.17 g) good purity with a yield of 73%.

II. Synthesis of [2-phenylacetylide]bis[phosphonic acid] tetraethyl ester

To bisamino (5.0 g, 19.1 mmol) in toluene (30 ml) is added triperoxonane acid (4.45 g, 39 mmol). The mixture is heated for 15 minutes at 60oC, is added tetraethylethylenediamine (5.49 g, 19.0 mmol) and the reaction mixture is stirred generally for 22 hours at 60oC. Then, the reaction mixture is cooled and water is added. The layers are separated and the aqueous layer was extracted with methylene chloride (3 x 15 ml). Organic layers combined, dried over sodium sulfate and concentrated under reduced pressure. Bisphosphonate is separated from unreacted methylenediphosphonate and pyridinecarboxamide chromatographytandem through silica gel (97:3 methylene chloride/isopropyl alcohol) with the formation of the vinyl adduct (3.84 g) with 49% yield as pale yellow oil.

III. Synthesis of [2-acetylthio-2-(phenyl)ethylidene]bis[phosphonic acid]tetraethyl ester

[2-fenretinide] bis[phosphonic acid], tetraethyl ester (3.83 g, 10.19 mmol) and colocasia acid (0.85 g 11.21 mmol) are mixed in anhydrous chloroform (100 ml) for 48 hours at room temperature. Then, the reaction mixture of kontsentrirueshsya-2-(phenyl)ethylidene] (1.01 g) in good purity.

IV. Synthesis of [2-mercapto-2-(phenyl)ethylidene]bis[phosphonic acid]

The solution thioacetate (0.50 g, 1.11 mmol) in concentrated hydrochloric acid is heated under reflux during the night. The reaction mixture is evaporated in a vacuum until dry, giving the desired product (0.10 g) with 30% yield.

Example E

Synthesis of [2-Acetylthio-2-(phenyl)ethylidene]bis[phosphonic acid]

< / BR>
I. Synthesis of [3-(2-phenyl)attalides]bis[phosphonic acid]

[2-phenylacetylide]bis[phosphonic acid], tetraethyl ester [obtained as described in Example D above (part II)] (5.25 mmol) is mixed with bromotrimethylsilane (42.00 mmol) in chloroform (175 ml) at 50oC for 12 hours under nitrogen atmosphere. Then the reaction mixture is stirred for 30 minutes with water (50 ml) and ethyl acetate (50 ml). The layers are separated and the aqueous layer was treated with charcoal, filtered through celite and concentrated, forming a bisphosphonic acid as pale yellow solid.

IV. Synthesis of [2-Acetylthio-2-(3-phenyl)ethylidene]bis[phosphonic acid]

To [3-(2-phenyl]attalides]bis[phosphonic acid] (2.50 mmol) in water (10 ml) is added colocasia acid (12.50 mmol). After stirring at whom is with acetone and then dried in a high vacuum, forming a bisphosphonic acid as pale yellow solid.

Example F

Synthesis of [3-Mercapto-1-hydroxybutylidene[bis[phosphonic acid]

< / BR>
I. Synthesis of 3-Acetylthiocholine acid

A solution of crotonic acid (4.30 g, 50 mmol) and teoksessa acid (5.71 g, 57.5 mmol) in anhydrous hexane (12.5 ml) is heated under reflux for 24 hours. Then the reaction mixture was concentrated under reduced pressure to form thioacetate (8.11 g), which can be used without further purification.

II. Synthesis of 3-acetylthiocholine chloride

To a solution of 3-acetylthiocholine acid (8.0 g, 49.3 mmol) in methylene chloride (50 ml) is added a solution of oxalyl chloride (39.5 g, 247 mmol) in methylene chloride (25 ml). The reaction mixture was stirred at room temperature under nitrogen atmosphere for 18 hours. The solvents are removed by distillation, is added methylene chloride and the reaction mixture is then dried by a rotary evaporation under reduced pressure, forming the acid chloride (5.28 g).

II. Synthesis of 3-Acetylthio-1-oxobutanoic acid, dimethyl ester

To the acid chloride (4.28 g, 23.7 mmol) at 0oC slowly added trimethylphosphite (2.94 g of the first mixture is dried in vacuum, forming the desired product (4.0 g) of suitable purity.

IV. Synthesis of [3-Acetylthio-1-hydroxybutylidene] bis[phosphonic acid]tetramethyl ether

To the phosphonate (3.0 g, 18.0 mmol) at 0oC is added dimethylphosphite (2.28 g, 20.6 mmol). Then the reaction mixture is heated to 55-65oC and stirred for 48 hours. The desired product is purified flash chromatographytandem using 10% isopropanol in methylene chloride on silica gel.

V. Synthesis of [3-Mercapto-1-hydroxybutylidene] bis[phosphonic acid]

[3 Acetylthio-1-hydroxybutylidene] bis[phosphonic acid]tetramethyl ester (4.0 g, 1.1 mmol) is heated under reflux in concentrated hydrochloric acid (8 ml) for 7 hours in a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure and obtained the desired product (0.28 g) in 94% yield by further drying in a vacuum dessicator.

Example G

1-[(Hydroxy)methylphosphinyl]-2-mercaptoethyl phosphonic acid

< / BR>
1. Synthesis of (Attalides)phosphonomethylglycine acid, teeterboro ether

Using basically the same techniques that are described in the work of C. R. Degenhardt and D. C. Burdsall, J. Org. Chem. so 51 p. 3400 - 3490 (N 18) 1986, methyl is 5)] becomes (attalides)phosphonomethylglycine tritely ether.

II. Synthesis of 1-[(Hydroxy)methylphosphinyl] -2-(acetylthio) ethylphosphonic acid, teeterboro ether

Solution (attalides)phosphonomethylglycine acid, teeterboro ether (11.62 g, 43.0 mmol) and thioglucose acid (3.27 g, 43.0 mmol) in anhydrous chloroform (116 ml) was stirred at room temperature for 72 hours. The reaction mixture pariveda under reduced pressure, forming the desired product (8.3 g) as a pale yellow oil.

III. Synthesis of 1-[(Hydroxy)methylphosphinyl]-2-mercaptoethanol acid

1-[(Hydroxy)methylphosphinyl] -2-(acetylthio)phosphonic acid tritely ester (8.3 g) is heated under reflux in concentrated hydrochloric acid (130 ml) for 7 hours in a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure, forming 1-[(hydroxy)methylphosphinyl]-2-mercaptoethylamine acid.

Example H

Synthesis of [2-Mercapto-2-methylpiperidin]bis[phosphonic acid]

< / BR>
I. Synthesis of 2-Methylpropylsulfonic acid, dimethyl ester

A solution of 1-bromo-2-methylpropane (100.0 g, 0.73 mol) and trimethylphosphite (135.7 g, 1.09 mmol) is heated at 90oC for 72 hours while maintaining the flow of nitrogen through the reaction semispontaneous of methylene chloride on silica gel. The product can be used in the next reaction without further purification.

II. Synthesis of [2-Methylpiperidin]bis[phosphonic acid], diethyldiphenylurea ether

To a solution of 2-methylpropylsulfonic acid, dimethyl ether (2.20 g, 14.47 mmol) in anhydrous THF (200 ml) is added secondary utility (20.04 ml, 26.05 mmol, 1.3 M in cyclohexane) at 0oC. Then, adding and stirring continued for a further 30 minutes. Then, the solution is slowly added to the solution diethylphosphate (2.50 g, 14.47 mmol) in anhydrous THF (100 ml) at room temperature. After stirring the reaction mixture during the night it cooled rapidly by the addition of saturated aqueous sodium bicarbonate solution and then extracted with methylene chloride. The combined organic extracts dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product is purified flash chromatographytandem when using 30% acetone in hexane on silica gel.

III. Synthesis of [2-Methyl-1-phenylthioureido]bis[phosphonic acid] diethyldiphenylurea ether

To a mixture of 35% KN in mineral oil (0.42 g, 3.68 mmol) in anhydrous toluene (75 ml) at 0oC is added dropwise a solution of [2-methylpropene is warm to room temperature and stirred for additional 60 minutes. To this solution is added dropwise a solution of phenoldisulfonic (0.80 g, 3.68 mmol) in toluene (25 ml). After stirring over night at room temperature the reaction mixture is diluted with water and extracted with diethyl ether. The combined organic layers are dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product is purified using flash chromatography was carried out using 5% isopropanol in methylene chloride on silica gel.

IV. Synthesis of [2-Methyl-1-propenylidene]bis[phosphonic acid] diethyldiphenylurea ether

To a solution of [2-methyl-1-(fenistil)propylidene] bis[propionic acid], diethyldiphenylurea ether (2.31 g, 5.63 mmol) in anhydrous chloroform (65 ml) at 0oC is added dropwise a solution of 3-chloroperoxybenzoic acid (1.07 g, 6.19 mmol) in chloroform (25 ml). After stirring for 2 hours at 0oC is added 10% aqueous solution of sodium sulfate and the mixture is stirred vigorously for an additional 10 minutes. Then, the layers are separated and the aqueous layer was extracted still chloroform. The organic extracts are combined and then washed with saturated aqueous sodium bicarbonate, followed by the camping and concentrated under reduced pressure. The crude residue purified flash chromatographytandem on silica gel using 50% acetone in hexane.

V. Synthesis of [2-Acetylthio-2-methyl-1-propylidene]bis[phosphonic acid], diethyldiphenylurea ether

To a solution of [2-methyl-1-properties]bis[phosphonic acid] diethyldiphenylurea ether (0.55 g, 1.83 mmol) in anhydrous chloroform (50 ml) is added colocasia acid (0.17 g, 2.28 mmol). The reaction mixture was stirred at room temperature under nitrogen atmosphere for 72 hours, then concentrated under reduced pressure. To the crude residue is added to the acetone and the mixture is again evaporated to the dry state. The resulting product can be used in the next step without further purification.

VI. Synthesis of [2-Mercapto-2-methylpiperidin]bis[phosphonic acid], disodium salt

Thioacetate (0.50 g, 1.33 mmol) is heated under reflux in concentrated hydrochloric acid (10 ml) in nitrogen atmosphere for 3 hours. Then, the reaction mixture is concentrated under reduced pressure. The desired product is obtained by recrystallization of the crude solid residue in water and ethanol.

Example I

Synthesis of [2-(Acetylthio)-2-methyl is Oh acid] TETRANITRATE salt

To a solution of [2-methyl-1-properties]bis[phosphonic acid] dimethyl ether [prepared as described in Example H above (part IV)] (1.25 g, 4.17 mmol) in anhydrous chloroform (50 ml) is added freshly bromotrimethylsilane (6.38 g, 41.7 mmol). The reaction mixture is heated at 50oC for 5 hours. Added ethyl acetate 910 ml) and water (25 ml) and the reaction mixture is subjected to vigorous stirring for 30 minutes. The layers are separated and the aqueous layer was treated with charcoal, filtered and concentrated under reduced pressure. The crude residue is rubbed with diethyl ether, then dried in vacuum over night. The solid residue is dissolved in water and its pH is brought to 12 by adding IN NaOH. The product is precipitated by adding ethanol and collected by filtration.

II. Synthesis of [2-(Acetylthio)-2-methylpiperidin] bis[phosphonic acid] Dvunatrievogo salt

[2-Methyl-1-properties]bis[phosphonic acid]Terentieva salt (1.10 g, 4.23 mmol) and colocasia acid (1.61 g, 21.15 mmol) dissolved in water (15 ml) and mixed at room temperature in nitrogen atmosphere for 20 hours. Then, the reaction mixture is concentrated under reduced pressure and further dried in a V diethyl ether, forming pure product as pale yellow solid.

Example J

Synthesis of [1-Hydroxy-2-(2-acetyldigitoxin)ethylidene] bis[phosphonic acid]

< / BR>
I. Synthesis of [2-(1-Cyclohex-1-enyl)-1-hydroxy]bis[phosphonic acid]

A solution containing 1-cyclohexasiloxane acid (1.0 mmol), phosphonic acid (2.9 mmol), trichlorethane (2.0 mmol) and diethylphosphate (12 mmol), stirred for 30 minutes at room temperature, then heated at 60oC for 24 hours. Then, the reaction mixture is cooled to room temperature and added concentrated hydrochloric acid (50 ml). The reaction mixture is heated overnight under reflux, then cooled to room temperature, filtered through celite and concentrated in a vacuum until dry. The crude product is pounded in ethanol, collected by filtration and dried in air.

II. Synthesis of [1-Hydroxy-2-(2-acetyldigitoxin)ethylidene] bis[phosphonic acid]

To bisphosphonates acid (0.75 g, 2.62 mmol) in distilled water (50 ml) is added colocasia acid (0.50 g, 6.55 mmol) and the reaction mixture is subjected to photolysis using the fluorescent cuesmes concentrated under reduced pressure and the solid residue is ground in ethanol. It turns out the desired product of suitable purity, which is further dried overnight in vacuum.

Example K

Synthesis of [1-Hydroxy-2-(2-mercaptonicotinic)ethylidene]bis[phosphonic acid]

< / BR>
[1-Hydroxy-2-(2-(acetylthio)cyclohexyl)ethylidene]bis[phosphonic acid] is heated under reflux in concentrated hydrochloric acid for 7 hours. The reaction mixture was concentrated under reduced pressure and the solid residue is ground in ethanol. The product is obtained by recrystallization of the crude solid in ethanol and water.

Example L

Synthesis of [1-Hydroxy-2-(2-acetylthio)cyclopentyl)ethylidene] bis[phosphonic acid]

< / BR>
I. Synthesis of [2-(Cyclopent-1-enyl)-1-hydroxy]bis[phosphonic acid]

Using basically the same methods described in Example J (part I), 1-cyclopent-1-analyssa acid into [2-(cyclopent-1-enyl)-1-hydroxy]bis[phosphonic acid].

II. Synthesis of [1-Hydroxy-2-(2-acetyldigitoxin)ethylidene] bis [phosphonic acid]

Using basically the same methods described in Example J (part II), [2-(1-cyclopentenyl)-1-hydroxy]bis[phosphonic acid is BR>
Synthesis of [1-hydroxy-2-(2-mercaptonicotinic)ethylidene]bis [phosphonic acid]

< / BR>
Using basically the same technique as described in Example K, [1-hydroxy-2-(2-(acetylthio)cyclohexyl)-ethylidene]bis[phosphonic acid], obtained as described in Example L above, becomes [1-hydroxy-2-(2-mercaptonicotinic)-ethylidene]bis[phosphonic acid].

Example N

Synthesis of [2-Mercapto-5-phenylindolizine]bis[phosphonic acid]

< / BR>
I. Synthesis of [5-finalment-1-enylidene]bis[phosphonic acid], diethyldiphenylurea ether

Using basically the same methods described in Example H (part I-IV), 5-phenyl-1-chloropentane becomes [5-finalment-1-enylidene] bis[phosphonic acid], determinately ether.

II. Synthesis of [2-acetylthio-5-phenylindolizine]bis[phosphonic acid], diethylethylene ether

To pentylidene Tetra ether (2.00 mmol) in anhydrous chloroform (75 ml) is added teoksessa acid (2.15 mmol). The reaction mixture was stirred at room temperature for 22 hours under nitrogen atmosphere. Then, the reaction mixture is washed with water, followed by aqueous saturated solution of NaCl. The organic layer is dried over sodium sulfate, filtered and concentrated at the C [2-mercapto-5-phenylindolizine]bis[phosphonic acid]

Thioacetate (1.5 mmol) is heated under reflux in concentrated hydrochloric acid (15 ml) for 5 hours in nitrogen atmosphere. Then, the reaction mixture is cooled to room temperature, treated with charcoal and filtered through celite. The aqueous filtrate is concentrated under reduced pressure and the crude residue is ground in acetone. The resulting solid precrystallization of water and isopropanol, to form [2-mercapto-5-phenylindolizine]bis[phosphonic acid].

Example O

Synthesis of [2-Acetylthio-5-phenylindolizine]bis[phosphonic acid]

< / BR>
Using basically the same technique as described in Example A above (part II) [2-acetylthio-5-phenylindolizine] bis[phosphonic acid], determinately ether [obtained as described in Example N (part II), shown here earlier] , becomes [2-acetylthio-5-phenylindolizine] bis[phosphonic acid].

Example P

Synthesis of [2-Mercapto-5-(3-AMINOPHENYL)pentylidene]bis [phosphonic acid]

< / BR>
I. Synthesis of [2-mercapto-5-(3-nitrophenyl)pentylidene] bis [phosphonic acid], dimethyldithio ether

Using basically the same technique as described in Example H (part I - IV) previously, 5-(3-n the initial broadcast.

II. Synthesis of [2-mercapto-5-(3-nitrophenyl)pentylidene]bis [phosphonic acid]

Using basically the same methods described in Example N here above (part II - III), [5-(3-nitrophenyl)Penta-1 - enylidene]bis[phosphonic acid] , dimethyldithio ether becomes [2-mercapto-5-(3-nitrophenyl)pentylidene]bis[phosphonic acid].

III. Synthesis of [2-mercapto-5-(3-nitrophenyl)pentylidene]bis [phosphonic acid]

[2-Mercapto-5-(3-nitrophenyl)pentylidene] bis[phosphonic acid] (0.25 mmol), distilled water (75 ml) and PtO2(0.20 mg) are placed in a 500 ml-th vessel Parra for hydrogenation. The mixture is subjected to hydrogenation at room temperature (40 psi of 2.81 kg/cm2within 6 hours. The solution is filtered through celite and concentrated under reduced pressure. The resulting solid is ground in acetone and then dried overnight in a vacuum dessicator.

Example Q

Synthesis of [3-(3-furfuryl)-2-mercaptoethylamine]bis[phosphonic acid]

< / BR>
Synthesis of [3-(3-furfuryl)prop-1-enylidene] bis[phosphonic acid], diethyldiphenylurea ether

Using basically the same technique described in Example H here earlier (part I - IV), 3-(3-furfuryl)-1-chloropropane becomes [3-(3-further]bis[phosphonic acid]

Using basically the same technique described previously in Example N (part II - III), [3-(3-furfuryl)prop-1 - enylidene]bis[phosphonic acid] , determinately ether is converted to [3-(3-furfuryl)-2-mercaptoethylamine]bis[phosphonic acid].

Example R

Synthesis of [3-cyclohexyl-2-mercaptopropionyl]bis[phosphonic acid]

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I. Synthesis of [3-(cyclohexyl)prop-1-enylidene]bis[phosphonic acid], deletedialog ether

Using basically the same technique described in Example H (part I - IV), 3-cyclohexyl-1-chloropentane becomes [3-(cyclohexyl)prop-1-enylidene]bis[phosphonic acid], determinately ether.

II. Synthesis of [3-cyclohexyl-2-mercaptopropionyl]bis[phosphonic acid]

Using basically the same technique described in Example N (part II - III), shown here earlier [3-(cyclohexyl)prop-1-enylidene] bis[phosphonic acid] , dimethyldithio ether is converted to [3-cyclohexyl-2-mercaptopropionyl]bis[phosphonic acid].

Example S

Model Schenk

To estimate the effects of compounds in experiments in vivo by inhibition of bone resorption and mineralization was conducted on this well-known animal model system for bone exchange 35, 87-99 (1983) and Schenk and others, Calcif. Tissue Res., 11, 196-214 (1973), the content of which is included in the link.

Materials and methods:

Animals

Pre-weaned 17-day (weighing 30 g) of male rats Sprague, Dawley (Charles River Breeding Laboratories are transported together with their mothers and upon arrival was placed in a plastic cage. Upon reaching the 19-day-old calves receiving Rat Chow and water ad libitum, randomly distributed in the control subjects and groups, each of which consisted of seven animals. On the first day and again on the 7th day all the animals intraperitoneally ("WB") was introduced injection calcein (1% solution in 0.9% saline solution, dosed at 0.2 ml/100 g body weight). On the 4th day all the animals PI were administered an injection of tetracycline hydrochloride 1% solution in 0.9% saline solution; at the dosage of 0.2 ml/100 g body weight). These compounds are known to cause active mineralization of bones and cartilage.

Dosage solutions and method of dosage

All solutions should be prepared for subcutaneous injection in 0.9% normal saline solution and pH is adjusted to 7.4 using NaOH and/or HCl. Calculation of the dosage of the solution is adjusted to the powder mass (calculated on molecular the s at the dosage of 0.2 ml/100 g body weight. Usually all connections are accepted at doses of 0.01, 0.1, 1.0, and 10.0 mg P/kg/day for 7 days. Connection detecting activity at 0.1 mg P/kg/day then tested logarithmically decreasing degree of 0.001 mg P/kg/day. Daily adjustment on change in body weight.

The autopsy, fabric processing and histomorphometry

On the 8th day after the start of dosing, all animals were wordplays the introduction of excessive doses of pentobarbital. Patients bone was cut and placed in 70% ethanol. One bone was degidrirovanii in the ethanol solution and transferred into methyl methacrylate, as described in the work of Schenk, Methods of Calcified Jissue Preparation (G. R. Dickson, Editor; Elsevier Science Publ., The Netherlands; (1984), the contents of which are fully entered in the link. Patient tibia is cut longitudinally through metafisico zone. The samples are marked on one surface silver nitrate and placed on glass slides microscope for evaluation using analyzer Quantimet Image (Cambridge Instuments, Inc.) with the use of light as the incandescent lamp, and ultraviolet light. Metatithemi trabecular bone composition is measured in the area between the fluorescent label and accrued surface and is expressed as about the values of 10 measurements of the cross section.

Statistical evaluation of data was performed using parametric and non-parametric analysis of variance and the total classification Wilcoxons test to determine statistically significant effects in the test animals compared to control animals. The Schenk model and network data in vivo by inhibition of the compounds of bone resorption.

Example T

Adjuvant arthritic model

There are several examples of simulation of arthritis in animals, for example, provoked by the adjuvant arthritis using Microbacterium butyricum. This model applies to mimic rheumatoid arthritis in humans (swelling of the joint is associated with cellular and pannoni invasion of the joint space, bone resorption and release hemotoxicity factors and liposomal components in sustavnoi space) (1, 2). A number of preventive and therapeutic studies indicated the possibility of using anti-inflammatory drugs (3, 4) and diphosphonates in the treatment of arthritis (5, 6).

Links

1. Pearson, C., Wood F. (1959), Studies of polyarthritis and other lesions induced by injection of microbial growth assistive devices 1. The main clinical and pathological., Radziwonik, H., Westwick, J. (1977), Rengenovskiy analysis arthritis in rats caused AIDS. The effect of prednisolone and indomethacin Agents and Actions, 7: 145-151.

3. Winter, C. A., Nuss O. W. (1966), the auxiliary Treatment of arthritis in rats anti-inflammatory drugs, Arth, Rheum. 9:394-404.

4. Winder, C. V., Lembke, L. A. Stephens, M. D. (1969). Comparative biological trials of medicinal products in the treatment of auxiliary-induced arthritis in rats: Flumendosa acid, mefenamovaya acid and phenylbutazone, Arth. Rheum. 12: 472-482.

5. Francis, M. D., Flora, L. King WR (1972) Action Dunadry 1-hydroxy-1-diphosphonate on auxiliary-induced arthritis in rats, Calcif. Tiss. Res. 9:number 109-121.

6. Flora, Z (1979), Comparative anti-inflammatory effect and bone protective effect of two diphosphonates adjuvant arthritis, Arth. Rheum, 22:340-346.

Adjuvant arthritis is a severe cellulite and synovitis induced in male rats (Sprague Dawley or Zewis strain) single subcutaneous (SC) injection Microbacterium butyricum (8 mg/ml) in mineral oil at day 0. Compounds are dosed once a day oral (OP) or parenteral (PE) and can be tested with the use or maintenance (day 0) or the volume of the paws, the body weight loss, the defeat of the bone or reactivated by the formation of new bone compared to the arthritic control group, exposed to injections of saline. The test may be terminated and a response of "exacerbation" (a rapid increase inflammation) is investigated, which reveals the ability of the compounds under study from the point of view of their efficiency.

Materials and methods.

A. Animals

Used animals are male Lewis rats (L). At the beginning of the test rats are randomly selected by the computer, generating a random set of numbers, and placed in individual wire suspended cells. Food and water are taken ad libitum throughout the study. Regular care and maintenance of animals were conducted in accordance with State and Federal regulations. Each rat is identified by the number placed on the front part of the cell and on the tail of a rat.

C. the experiment

In day 1 for all the rats were conducted measuring the body weight (W) and volume of the hind legs (HE) [registered according to the method of mixing mercury with the use of a pressure sensor connected to the computer]. Day 0 is induced is the key and get a single PC injection MFA at the base of the tail under aseptic conditions.

Since that time are measured volumes of the legs and the weight of the body on different days, usually twice a week. For preclinical studies in rats at random divided into groups of 8-10 individuals and study day begins with 0 and continues daily until the end. For therapeutic studies of rats selected at random in the study group of 8-10 individuals in accordance with their OL on the 10th day. The introduction of drug dose begins on day 10 and continuing daily until the end. For both studies, animals are placed on day 10 or earlier in shoeboxes with deeply located bedding.

Dosing solutions

The drugs weighed on calibrated scales and then mixed with deoxygenating water in a volumetric flask. The original solution is filtered through a 0.45 μm sterile filter in sellnow storage capacity. In the case when the original solution is not used, it is kept chilled.

In accordance with the daily norm of the initial solution is taken a certain amount of solution is placed in a small chemical beaker and pH content is brought to 7.4 in accordance with the preliminary calculation. If necessary, can be conducted Yes the Batwa are made on the basis of molecular weight, purity of the compounds, quantity, based on mg/kg (body weight) and the required final concentration in mg P/kg Dosed volume in the rat is 0.1 ml/100 g body weight subcutaneously, administered as an injection in the groin crease animal, changing every day, party or 1 ál/200 g body weight, administered orally using a curved dosing tube from stainless steel. Weekly made amendments to the change of body weight.

Radiography, opening and processing of tissue

After the end of the experiment each rat wordplays 1 ml Socombinjected intraperitoneally (IP). Immediately remove total radiogram whole body using x-ray equipment Torrax 120D when MA = 5, ISUP=50 time 60 seconds on medical unshielded film Kodak. From each rat were separated hind legs, and placed in 10% superyoung formalin together with part of the liver, kidney, spleen and thymus. Tibia cartilage joints are calcinato in 4% EDTA (ethylenediaminetetraacetic acid), pH 7.4 and placed usually in paraffin blocks and dye H+E. Organic parts are also processed in paraffin and stained with H + E.

Histological sections are evaluated qualitatively from the point tranoi resorption (CR) 6 anatomical trabecular bone areas on each hind leg in the 4 directions on each front leg on a scale of 0-3, giving arbitrary points total 0-60 for all four legs. From the point of view of new bone formations (ANO) x-rays are measured at the hard scale of 0-3 for lateral and medical surfaces of the tibia, and then on a scale of 0-2 for all the other above-mentioned surfaces, giving an arbitrary number of points 0-44.

D. Statistical analysis

Data analysis the volume of the paw, bone resorption and active new bone formation was carried out using t-test t-test and non-multiple analysis Tukeys (SAS) (12). The difference is significant at p= 0.05 or less.

This model provides in vivo data on the effectiveness of anti-arthritis of the joints, reducing swelling of the legs, bone loss and active new bone formation compared with arthritic animals that were exposed to saline.

Example U

Using standard methods of preparing capsules containing the ingredients:

Active ingredient - Mg capsule

[2-amino-1-hydroxy-3-mercapto-3-methylbutyrate] bis[phosphonic acid] - 350.0

Fillers

Lactose - 90,0

Microcrystallization standard methods, similar described below.

The active ingredient is mixed with microcrystalline cellulose in a rotating drum mixer for approximately ten (10) minutes.

The resulting mixture is passed through a hammer mill with a sieve 80 mesh.

The mixture is placed back in double-drum mixer with lactose and then stirred for fifteen (15) minutes.

The following is added magnesium stearate and implemented additional stirring for five (5) minutes. Then the resulting mixture is compressed by the piston filler capsules.

The above capsules taken orally twice a day for 6 months, reduce bone resorption in a patient weighing approximately 70 kg, suffering from osteoporosis. Similar results were obtained when placed in the above-described capsule [2-amino-1-hydroxy-3-mercapto-3-methylbutyrate] bis[fosforos acid] or its pharmaceutically acceptable salt or ester, synthesized as described in Examples A-R, shown here above, or a pharmaceutically acceptable salt or ester of these phosphonic compounds.

Example V

Tablets get standirtyteen] bis[fossanova acid] - 700.00

Fillers

Lactose (aerial spraying - 200.0

Starch (1500) - 100,0

The stearate - 25,0

Tablets having the above composition, are prepared using standard methods similar to those described below.

The active ingredient is ground in a ball mill for approximately thirty (30) minutes. Then powdered active ingredient is mixed in a two-blade mixer with lactose, dried by spraying for approximately twenty (20) minutes.

To the mixture is added to the starch and produced additional mixing within fifteen (15) minutes. The mixture is compressed into tablets on a standard tablet press.

The above tablet taken orally twice a day for 6 months, significantly reduce bone resorption in a patient weighing approximately 70 kg, suffering from Paget's disease. Similar results are obtained when in the above-described tablets [2-mercapto-2-methylpiperidin] bis[phosphonic acid] is replaced by any of the compounds or their pharmaceutically acceptable salt or ester synthesized in Examples A-R here, or pharmaceutically acceptable salt IOUT standard methods using 10.0 ml of physiological salt solution and 7.0 mg P compounds [2-amino-1-hydroxy-3-mercapto-3-methylbutyrate] bis[phosphonic acid] with bringing the pH of the solution to 7.4.

One injection once a day for 4 days results in a measurable relief of hypercalcemia malignant tumor of a patient weighing approximately 70 kg.

Example X

Caucasian male weighing approximately 92 pounds at the age of seventy-two years of pain from moderate to strong and periodic swelling of the right knee. After about a year continuously increasing discomfort he visits the doctor, who puts him clinical diagnosis of osteoarthritis of the right knee, which was then confirmed by x-ray studies.

After holding for a period of facilitating the treatment of various NSAYD; including aspirin, naproxen and Ketoprofen, the symptoms of his illness continued to worsen and his condition worsened. He returned to his doctor who then prescribes him the capsules obtained as described in Example U, twice a day for two hours before or after meals for three months. 3 months after the start of treatment, the clinical symptoms of pain and swelling, especially when walking has improved significantly. After three months of treatment the dose of 2 capsules per day, the treatment continues indefinitely in nae is and weighs approximately 65 pounds fifty years, suffering from swelling and deformation of the joints of the fingers of both hands with partial loss of strength and/or mobility of her fingers and hands. After visual and x-ray surveys and various relevant clinical trials confirmed the American rheumatology Association (ARA) she was diagnosed with rheumatoid arthritis.

After unsuccessful treatment with analgesics and anti-inflammatory medications her doctor prescribed her the capsules prepared according to the recipe of Example U, twice a day for two hours before meal or after meal for four months. After a month of treatment, her symptoms swelling of the finger joints was significantly improved and the range of motion of the fingers has increased markedly; she continues treatment to the remaining four months, after which her doctor prolongs signed the dose for an additional two months.

Example Z

Girl of Spanish origin twelve years old, weighs approximately 37 pounds go to the doctor with idiopathic juvenile rheumatoid arthritis. Its symptoms include inflammation of many joints, accompanied by fever and pain, which indicates a quick and pathological degeneration of the functions of the joints.

Her doctor recommends that she rheumatologist, who immediately prescribes her vigorously the Oia in the day, take two hours. After the IV regime doctor prescribes capsules, obtained as described in Example U, for two months, during which she revealed marked improvement with increasing mobility and reducing pain. Over the next two months, the doctor lowers her dose to 3/4 of the original oral dose, 3 capsules during the period of time in two days. After completing this mode, the dosage again reduced to 1/4 of the initial dose; get it in pill form, obtained as described in Example V, 1 tablet each day for a further four months.

Physical and biological characteristics of some of the compounds presented in the table.

1. Sulfur-containing phosphonic acids of General formula I

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where R represents a group-RHO3H2or P(O)(OH)R4;

R4represents C1-C8-alkyl;

R1identical or different, represent hydrogen, C1-C8-alkyl which can be substituted by phenyl, phenyl or two adjacent carbon atoms with substituents R1form a cyclopentane or cyclohexane;

R2represents a normal or near;

n represents an integer from 1 to 6,

or their pharmaceutically acceptable salts or esters used for the treatment and prevention of disorders of abnormal calcium and phosphate metabolism.

2. The pharmaceutical composition used for treatment and prevention of disorders of abnormal calcium and phosphate metabolism, characterized in that it contains 15 to 95 wt.% connection on p. 1 and pharmaceutically acceptable excipients.

3. The pharmaceutical composition according to p. 2, characterized in that the fillers are selected from the group consisting of improving the taste and smell of additives and co-solvents, buffer systems, surfactants, preservatives, sweetening substances, agents regulating the viscosity, fillers, lubricants, chemicals, improve slip, baking powder and binder.

4. The pharmaceutical composition according to p. 3, characterized in that it contains not more than 2% improves the taste and scent additives, no more than 50% of alcohol, not more than 5% of a buffer system, not more than 2% of surface-active substances, not more than 2% preservatives, no more than 5% of the sweetening matter, not more than 5% of agents regulating the viscosity of no more than 75% na.

5. Connection on p. 1, useful for the production of a medicinal product for the treatment or prevention of disorders associated with abnormal calcium and phosphate metabolism in humans or other mammals, which is administered to a human or other mammal in a safe and effective amount.

6. Sulfur-containing phosphonic acids of General formula II

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where R represents a group-RHO3H2or-P(O)(OH)R4;

R4represents C1-C8-alkyl,

R1identical or different, represent hydrogen, C1-C8-alkyl or-SH group;

R2represents hydrogen, C1-C8-alkyl group,- SH, -(CH2)pSH, -NH2or NO2;

p represents an integer from 1 to 6;

R5represents hydrogen, hydroxy or C1-C8-alkyl;

Z is a covalent bond;

WITH5-C6-cycloalkyl, phenylene or furfuryl;

n is an integer from 1 to 6,

or their pharmaceutically acceptable salts, are useful for the production of a medicinal product for the treatment and prevention of disorders associated with abnormal calcium and phosphate metabolism in people

 

Same patents:
The invention relates to organic chemistry, specifically to methods of producing phosphoric esters of thiamine, which (namely fosfotiamina and cocarboxylase hydrochloride) is used in medicine as drugs

The invention relates to organic chemistry, to the class of heterocyclic compounds - drive dihydrofuran with one carbonyl group in the cycle and the phosphorus-containing fragment in the side chain, namely to a new way to obtain previously unknown connections - 5-aryl-2-hydroxy-2-(triphenylphosphonio)methoxycarbonylmethyl-2,3-dihydr-3-formulaHBrwhich can find application in medicine as drugs with antimicrobial action

The invention relates to the chemistry of organophosphorus compounds, namely to a new method of obtaining S-dialkyl-, alkylphenyl and diphenylarsinic esters of 4-methoxyphenylacetone acids of General formula I

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where

Ar = 4-MeOC6H4;

R is lower alkyl, phenyl;

R' and R ' = lower alkyl, phenyl

The invention relates to new tizamidine pyridinylmethyl acids f-ly R2-Z-Q-(CR1R1)n-CH[P(O)(OH)2]2(I) where R1-H, -SH, -(CH2)mSH or-S-C(O)-R3, R3- C1-C8-alkyl, m = 1 - 6, n = 0 to 6, Q is a covalent bond or-NH-, Z - pyridinyl, R2- H, -SH, -(CH2)mSH, -(CH2)mS-C(O)R3or-NH-C(O)-R4-SH, where R3and m have the above meaning, R4- C1-C8-alkylen, or their pharmaceutically acceptable salts or esters

The invention relates to a derivative of guanidine-1,1-bis phosphonic acid, method for their production and to their use

The invention relates to organic chemistry, particularly to a technology for higher esters alkylphosphonic acids of General formula

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where

R is alkyl (C1-C2halogenated;

R', R" are alkyl (C4-C8

The invention relates to the production of insecticides, namely, to obtain granulated chlorophos

The invention relates to a method for inhibiting deposits of mineral salts by the interaction of derivatives of ammonia, including ammonium chloride or waste production polyethylenepolyamines, with formaldehyde and phosphorous acid as such or a product of hydrolysis of phosphorus trichloride in an environment of diluted hydrochloric acid at elevated temperature, followed by neutralization of the resulting solution with sodium hydroxide to pH 6.51,0, and the process is conducted at a molar ratio of the initial reagents ammonia: formaldehyde: phosphoric acid 1,0:2,35-2,65:2,2-2,4

The invention relates to a method for producing a solid disodium salt of nitrilotriethanol acid (NTF) by neutralizing the solution NTF - acid with sodium hydroxide to pH 2.5 and 3.4

The invention relates to a method of removing phosphorus-containing wastes generated upon receipt of salts of omega-amino-(C2-C6)alkylidene-1-hydroxy-1,1-bisphosphonic acids, which includes the stages of: a) contacting the aqueous medium after separation of the salts of omega-amino-(C2-C6)alkylidene-1-hydroxy-1,1-bis-phosphonic acid with a compound of chloride of calcium, taken in an amount of 2-10 wt

The invention relates to a new containing Quaternary nitrogen compounds of phosphonates and their pharmaceutically acceptable salts and esters having the General structure I
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