Containing a quaternary nitrogen phosphonates for treating abnormal calcium and phosphate metabolism, and the prevention and treatment of dental plaque and dental stones, pharmaceutical compositions and method of treatment

 

(57) Abstract:

The invention relates to a new containing Quaternary nitrogen compounds of phosphonates and their pharmaceutically acceptable salts and esters having the General structure I. in Addition, the invention also relates to pharmaceutical compositions containing an effective and safe amount of the compounds of the present invention and pharmaceutically acceptable carriers. And finally, it also relates to a method of treatment or prevention of pathological conditions characterized by disturbances of calcium and phosphate metabolism, such as osteoporosis, rheumatoid arthritis and osteoarthritis in humans or other mammals and to methods of treatment or prevention of dental stones, dental plaque and gingivitis. This method includes 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. 5 s and 5 C.p. f-crystals.

The invention relates to a new containing Quaternary nitrogen phosphonate compounds, including bisphosphonates, phosphonocarboxylate, phosphonocarboxylate and phosphosulfate, preferably bisphosphonates and phosphonocarboxylate. Etodo treatment or prevention of certain disorders of bone metabolism, characterized by abnormal calcium and phosphate metabolism, using the compounds or pharmaceutical compositions of the present invention. Specifically, the invention relates to a method of treatment or prevention of osteoporosis and arthritis, in particular rheumatoid arthritis and osteoarthritis using the compounds or pharmaceutical compositions of the present invention. This invention also relates to pharmaceutical compositions containing these novel compounds and to a method of treatment or prevention of dental raids, stones and gingivitis. In particular, this invention relates to a method of treating or preventing the formation of dental plaque and dental stones using the compounds or pharmaceutical compositions of the present invention.

A number of pathological conditions that affect warm-blooded animals include abnormal calcium and phosphate metabolism. Such States can be divided into two broad categories.

1. States, which are characterized by anomalous mobilization of calcium and phosphate, leading to a General or specific loss of bone, such as osteoporosis or Paget's disease, or extremely high sod is Oceania sometimes called pathological demineralization hard tissues.

2. Conditions that cause or are the result of abnormal deposits of calcium and phosphate in the body, such as arthritis, including rheumatoid arthritis and osteoarthritis. Such States are called here the pathological calcification.

The first category includes the most common metabolic bone disorders, osteoporosis; osteoporosis is a condition in which hard tissue bone is lost disproportionately to the development of new bone tissue. Osteoporosis is usually defined as a decrease in the quantity of bone or atrophy of skeletal tissue. Bone and brain space become more fibrous binding is reduced, and a compact bone to become fragile. Osteoporosis can be divided into subclasses, such as postmenopausal, senile, caused by a drug (e.g., adrenocorticoids in steroid therapy); caused by disease (arthritis and swelling), etc. but manifestations of its essentially the same. There are two types of osteoporosis: primary and secondary. Secondary osteoporosis is a result of some pathological process or agent. However, approximately 90% of all cases of osteoporosis are the "primary osteoporosis the majority of older people aged 70 - 80 years), and idiopathic osteoporosis, which affects men and women of the middle and younger age.

Some people suffering from osteoporosis, depression of bone tissue is so great that it causes mechanical damage to the bone structure. Bone fractures often occur in the hip and spine in women suffering from postmenopausal osteoporosis. May develop kyphosis (abnormal increased bending of the thoracic spine).

Consider that the mechanism of bone loss in osteoporosis includes the imbalance in the process of bone reconstruction. Reconstruction of bone occurs throughout life, updating the skeleton and maintaining bone strength. This reconstruction includes erosion and filling of the discrete areas on the surface of the bone by an organized group of cells, called "basic multicellular unit" or "OME". OME mainly consist of osteoclasts, osteoblasts and their cell precursors. In the loop reconstruction bone undergoes resorption in place "activated" OME with osteoclast, forming a resorption cavity. This cavity is then filled with bone with osteoblasts.

Usually in adults cycle is I. Thus, even in healthy adults with age there is a loss of bone tissue. However, in osteoporosis, the number of OME, which are activated, may increase. This increased activation accelerates the reconstruction of the bone and leads to abnormally high bone loss.

Although its etiology is not entirely clear, there are many risk factors that are perceived to be associated with osteoporosis. They include low body weight, low calcium intake, physical inactivity, and lack of estrogen.

A common treatment of osteoporosis is mainly in the introduction of calcium and estrogen.

The second category includes States that are characterized by abnormal deposition of calcium and phosphate, covers progressive myositis, calcification, and diseases such as arthritis, including rheumatoid arthritis and osteoarthritis, neuritis, bursitis, tendonitis and conditions which predispose involved tissue to deposition of their calcium.

In addition to osteoporosis, the bone loss may be a result of rheumatoid arthritis and osteoarthritis. Rheumatoid arthritis is a chronic, systemic and articular inflammatory disorder, x is Lee and bones and reduce the viscosity and other changes in synovial fluid. Symptoms of rheumatoid arthritis include systematic weakness, fatigue, local pain, difficulty of movement and weakness, swelling and deformity of the joints. Rheumatoid arthritis is most common in women from 40 to 60 years.

Pathogenesis of rheumatoid arthritis, leading to destruction of the joints, characterized by two phases: 1) exudative phase, including circulation and synovial cells, which allow you to enter plasma proteins and cellular elements in the joint and 2) the phase of chronic inflammation, which occurs in polinomialnoi and subarashiki bone, characterized by the formation of pannus (granulation tissue) in the articular space, bone erosion and destruction of cartilage. Pannus may form adhesions and granulation tissue, which cause the deformation of joints is characteristic of rheumatoid arthritis.

The etiology of rheumatoid arthritis remains unclear. Require the involvement of infectious agents such as bacteria and viruses. Currently, there is a hypothesis that the cause of rheumatoid arthritis is the virus of Epstein-Barr (EVE).

Modern treatment of rheumatoid arthritis is mainly symptomatic ass is giving effectively mainly in the early stages of rheumatoid arthritis; it is unlikely that this treatment will suppress sustavnoi inflammation, if the illness lasts more than a year. Gold, methotrexate, immunosuppressants and corticosteroids also gave limited results in the treatment.

On the other hand, osteoarthritis is a violation of the non-inflammatory nature in the joints, characterized by damage to and erosion of articular cartilage and formation of new bone on the articular surface. During the progression of osteoarthritis, the surface of the articular cartilage is destroyed, and its particles are transported into the synovial fluid, which in turn stimulates phagocytosis by cells of the macrophage. Thus, over time, osteoarthritis causes an inflammatory response. Common clinical symptoms of osteoarthritis include cartilage and bone increase of finger joints, difficulty movements after sleep and pain during movement.

General symptomatic treatment of osteoarthritis including analgesics, anti-inflammatory drugs, steroids and physical therapy.

Dental plaque and stones

Dental deposits represent a rough sticky plaque on teeth, which is formed from saliva, bacteria and food particles and singing which is tonew for the formation of stones, known as Tartar, solid calcinatory deposits, if they are stuck.

The plaque is formed when mineral salts from saliva, mainly phosphorus and calcium, are embedded in the plaque, forming a solid hard deposits. The stones tend to be deposited in the openings of the salivary channels: on the lingual surfaces of the lower incisors and the distal surfaces of the upper molars. With the development of a Mature stone it becomes visible as white or yellowish education, if not painted or not discolored by any external agent. Besides the fact that the stone is not aesthetic, it is constantly covered with bloom. The toxins in plaque and stone irritate the gums, causing inflammation and recession, which can lead to other complications.

It was suggested many chemical and biological agents to reduce the formation of stones or their removal after formation. Chemical treatment to reduce the formation of stone usually involves the inhibition of crystal growth, which prevents the formation of stones. The chelation of calcium ions destroys the stone by removing calcium, but this is undesirable because it also removes the usual ash fabric. Mechanical has Been invited to many derivatives phosphorylate for use in the treatment and prevention of diseases, caused by abnormal metabolism of calcium and phosphate. For example, many links that are included, the disclosed compositions containing polyphosphonate, in particular diphosphonates, such as ethane-1-hydroxy-1,1-diphosphonate ("EHDP") and their use to reduce anomalous deposition and mobilization of calcium and phosphate in animal tissues: U.S. patent 3683080, issued August 8, 1972, and U.S. patent 4230700, issued October 28, 1980, both Francis and U.S. patent 4868164 Ebetino, issued September 19, 1989, Numerous other works describe heterocyclic substituted phosphorylate, useful in the treatment of osteoporosis and/or arthritis, which is included here as reference. This following sources: U. S. Patent 5, 071, 840, to Ebetino et al., issued December 10, 1991; U. S. Patent 4,858,164, to Ebetino, et al., issued September 19, 1989; U. S. Patent 5,104,863, to Benedict, et al., issued April 14, 1992; U. S. Patent 4,267,108, to Blum et al., issued May 12, 1981; U. S. Patent 4,746,654 to Breliere et al., issued May 24, 1988; U. S. Patent 4,876,247, to Barbier et al. , issued October 24, 1989, and European Patent Application Publication No. 100,718, of Breliere, published February 15, 1984; European Patent Application Publication No. 170,228, of Boehringer Mannheim GmbH, published February 5, 1986; European Patent Application Publication No. 186,405, of Benedict and Perkins, published July 2, 1986; European Patent Application Publication No. 298,553, of Ebetino, published January 11, 1989; U. S. Patent 4,754,993, to Bosies et al., issued November 15, 1998; U. S. Patent 4,939,130, to Jaeggi et al., issued July 3, 1990; U. S. 4,971,958 une 15, 1989; AU-A-45467/89 of Ciba-Geigy, publication date May 31, 1990.

Finally, in U.S. patent 4208401 Bauman, issued June 17, 1980, disclosed substituted Quaternary bisphosphonates ammonium nheterocyclic ring, are useful as protivokashlevyh agents.

Published application DE 4011777 Jaeggi on October 18, 1990 discloses substituted diphosphonic heterocyclic ring in which the specified heterocyclic ring may be substituted by lower alkyl. Specified heterocyclic ring connected bridge connection with a group of phosphorylate through Quaternary Nicolaou the nitrogen atom. DE' 777 discloses that compounds significantly inhibit bone resorption and thus suitable for the treatment of osteoporosis, inflammatory diseases and diseases associated with degeneration of the joints, peridotite and hyperparathyroidism. These patents and applications are included here as reference.

However, none of these links does not reveal the usefulness of heterocyclic phosphonate compounds containing Quaternary nitrogen, in the prevention and treatment of osteoporosis, arthritis, and dental stones, plaque and gingivitis.

Compounds of the present invention have osteo-protective activity in place of razrusheny is on drugs simply alleviate symptoms of inflammation. Used herein, the term "osteo-protective activity" means an activity that modifies the disease process on the bone and surrounding soft tissue in the place of destruction of the joint.

Unexpectedly it was found that heterocyclic phosphonate compounds of the present invention, which contain stereoselectivity nitrogen atom, have a stronger antiresorptive activity and therapeutic utility in the treatment and prevention of osteoporosis, arthritis (including rheumatoid arthritis and osteoarthritis) and dental stones, raids than phosphonate compounds with heterocyclic ring, which does not contain the stereoselectivity of the nitrogen atom. In addition, the compounds of the present invention exhibit unusual properties solubility. Thus, the compounds of the present invention is much easier absorbed when administered orally. The easier it is absorbed connection, the more effective it can be at lower doses. Lower doses are usually more preferred because of reduced unwanted side effects.

Therefore, the aim of the invention to provide new, more potent compounds that is of rcrit) and in the treatment and prevention of dental stones and raids. Another object of the invention is the obtaining of pharmaceutical compositions for the treatment and prevention of osteoporosis and arthritis, especially rheumatoid arthritis and osteoarthritis. In addition, the present invention is a method of treatment or prevention of osteoporosis, rheumatoid arthritis and osteoarthritis, as well as methods of treatment or prevention of dental plaque and stones.

These and other objectives of the present invention will be apparent from the detailed disclosure below.

The present invention relates to containing a Quaternary nitrogen heterocyclic compounds of phosphonates and their pharmaceutically acceptable salts and esters with the General formula

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

a) Q is a covalent bond or karuppa selected from O, S, NR1;

in) Y - N+(R8)2or C(R1)2and if Y - C(R1)2at least one of R2must be N+(R8)3;

C) Z is a saturated or unsaturated, or aromatic, monocyclic or polycyclic carbocycle or a heterocycle containing one or more heteroatoms selected from O, S, or N;

(d) R - COOH; PO3H2; SO3H or P(O)(/SUP> is selected from the group consisting of zero; SR6; R9SR6; hydrogen; hydroxy; substituted or unsubstituted WITH1- C8of alkyl; OR3; -CO2R3; -O2CR3; -NR32; -N/R3/C/O/R3; -C/O/N/R3/2; halogen; -C/O/R3; arylalkyl; nitro; substituted or unsubstituted aryl, and combinations thereof.

(f) each R2represents one or more substituents on Z group is independently selected from the group consisting of N+/R8/3; SR6; R9SR6; hydrogen; substituted or unsubstituted C1- C8of alkyl; OR3, -CO2R3, -O2CR3, -NR32, -N/R3/C/O/R3-C/O/N/R3/2, halogen, hydroxy, -C/O/R3, arylalkyl, nitro, substituted or unsubstituted aryl.

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

(h) R5is selected from the group consisting of hydrogen, halogen, SR6, R9SR6, amino, hydroxy, and substituted or unsubstituted C1- C8the alkyl.

(i) each R6the independent is S/OR7-C/O/OR7in which R7is hydrogen or substituted or unsubstituted C1- C8alkyl.

(j) each R8independently selected from the group consisting of zero, substituted or unsubstituted alkyl having 1 to 35 carbon atoms, substituted or unsubstituted phenyl, benzyl, or R9SR6and

(k) R9substituted or unsubstituted C1- C8alkyl.

In this General structure Z is a monocyclic or polycyclic saturated or unsaturated heterocyclic group, and Y - N+/R8/2or C/R1/2. In addition, m and n and m + n are integers from about 0 to about 10 and Q is a covalent bond or a group selected from the group consisting of oxygen, sulfur or NR1. Later in this General structure, each R1independently selected from a variety of substituents, preferably of R9SR6and hydrogen. Each R2is Deputy on the heterocyclic ring, selected from a variety of substituents, preferably N+C/R8/3C1- C8of alkyl, amino, hydroxy, alkoxy, or R9SR6. When Y - C/R1/2at least one of R24in which R4is a lower alkyl group. R5select from a variety of substituents, preferred are hydrogen, hydroxy, halogen and amino. R6select from a variety of substituents, the preferred H-C/O/R7and-C/S/R7in which R7represents a substituted or unsubstituted C1- C8alkyl. R8is selected from substituted or unsubstituted C1- C35the alkyl, preferably C1- C8of alkyl; substituted or unsubstituted phenyl, benzyl, or R9SR6. R9is substituted or unsubstituted C1- C8the alkyl, preferably C1- C4the alkyl.

The present invention further relates to pharmaceutical compositions containing a safe and effective amount of a compound of the invention and pharmaceutically acceptable carriers or excipients. Finally, the invention concerns methods of treatment or prevention of pathological conditions characterized by abnormal metabolism of calcium and phosphate, such as osteoporosis, rheumatoid arthritis and osteoarthritis in humans or other mammals and to methods of treatment or prevention of dental stones, raids the Institute, safe and effective amount of the compounds or compositions of the present invention.

Below is a list of definitions for terms used in the present invention.

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

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

"Carbocyclic ring or carbocycle" used in the estuaries and lzo. Carbocycle can be monocyclic or polycyclic. Monocyclic rings usually contain from 3 to 8 atoms, preferably from 5 to 7 atoms; polycyclic ring containing two rings and from 6 to 16, from 10 to 12 atoms, and which with three rings - from 13 to 17, preferably from 14 to 15 atoms.

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

"Heterocyclic ring" or "heterocycle" refers to unsubstituted or substituted, saturated, unsaturated or aromatic ring including the carbon atoms and one or more heteroatoms in the ring. Heterocyclic rings may be monocyclic or polycyclic. Monocyclic rings usually contain from 3 to 8 atoms, from 5 to 7 atoms. System polycyclic ring consisting of two rings usually contain from 6 to 16, preferably from 10 to 12 atoms. System polycyclic rings, three rings, usually consist of from 13 to 17 atoms, preferably from 14 to 15 atoms. Half of the heterocyclic ring may consist of or heterocycles heterocycles and carbocycles. Each provincialnye heteroatoms independently selected from nitrogen, sulfur and oxygen.

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

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

"Alkoxy" is an oxygen atom having a carbon chain Vice, where the hydrocarbon chain is an alkyl or alkenylphenol (for example, -O-alkyl, or-O-alkenyl). A preferred group of alkoxy include, but are not limited to methoxy, ethoxy, propoxy, allyloxy.

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

"Carboxylic" - substituted hydrocarbon chain, which has a carboxy substituent (e.g., COOH) and may have other substituents. Preferred carboxialkilnuyu the circuit, the one (i.e. alkyl), substituted amine part (for example, NH-alkyl-), such as manometer.

"Alkylamino" - amino groups having one or two alkyl substituent (for example, -N-alkyl), such as dimethylamino.

"Alkynylamino" - amino group having one or two etkinlik Deputy (i.e.,- N-quinil).

"Alkynylamino" - amino group with 1 or 2 alkenylamine substituents.

"Alkylamino" - aminogroup having one or two alkyl substituent (i.e.,- N-alkyl-).

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

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

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

"Acyl" or "carbonyl" includes the double bond carbon-oxygen, i.e., R-C(=O). Preferred acyl groups include, but are not limited to acetyl, propionyl, butanoyl and benzoyl.

"Acyloxy" is an oxygen atom, with the acyl substituent (i.e.,- O-acyl), for example,- O-C/=O/-alkyl.

"Acylamino" - amino group with the acyl substituent (i.e.,- N-acyl), for example, -NH-/C=O/-alkyl.

"what are chlorine, bromine and fluorine.

Referred to here as the "lower" hydrocarbon part (for example, "lower alkyl) - hydrocarbon chain containing from 1 to 6, preferably from 1 to 4 carbon atoms, unless otherwise specified.

In addition, as used herein, the term "thio-Deputy" (SR6or R9SR6includes thiols [-SH], where R6=N; thioethers [-SC/O/R7], where R6=C/O/R7; dayevery [-SC/S/R7] , where R6= C/S/ R7; THIOCARBAMATE [-SC/O/N/R7/2], where R6= C/O/N/R7/2; dithiocarbamate [-SC/S/N/R7/2], where R6=C/S/N/R7/2; thiocarbonate [= SC/O/OR7] , where R6=C/O/OR7; and dithiocarbonate [-SC/S/OR7], where R6=C/S/OR7. R7is hydrogen or substituted or unsubstituted C1- C8alkyl. Any SR6substituents may themselves be substituted with R9where R9substituted or unsubstituted C1- C8alkyl. Accordingly, additional thio-substituents denoted by R9SR6represent alkylthiol, alkylthiophene, alkyldimethyl, alkyldiethanolamine, alkyldiethanolamine, alkylthiocarbamates and alkyldithiophosphate.

The terms "bisphosphonate" or "bisphosphonate" refers to the FOSFA amazements terms "diphosphonate" and "dephosphorylate". In the structures described here, R is PO3H2.

By "pharmaceutically acceptable salt" refers to a cationic salt formed with any acid group (i.e., carboxyl) or anionic salt obtained from any basic group, (i.e., amino). Many such salts are known in the field of engineering and is described in international patent publication 87/05279, Johnston and others, published on 11 September 1987 and is included here as a reference. Preferred cationic salts include salts of alkali metal (such as sodium and potassium salts), and salts of alkaline-earth metals (such as magnesium and calcium). Preferred anionic salts include halide (such as chloride), salt, acetate and phosphate.

"Biohydrology ester" is an ester containing Quaternary nitrogen heterocyclic phosphonate compounds, which does not affect therapeutic activity of the compounds, or that is readily converted in the body of man or animal. Many of these esters are known and described in international patent publication 87/05297 Johnston and other Such esters include esters of lower alkyl, esters of lower aryloxyalkyl (such as acetoxymethyl, acetoxyethyl, am the Fira of phthalidyl and totalidea), esters of lower alkoxyalkyl (such as esters of methoxycarbonylmethyl, ethoxycarbonylmethyl, and isopropoxycarbonyloxymethyl), esters of alkoxyalkyl, esters of choline and esters of acylaminoalkyl (such as esters of atsetamidometil).

As mentioned above, the group's Deputy may themselves be substituted. Such substitution can be carried out by one or more substituents. Such substituents include, but are not limited to those specified in C. Hansch and A. Leo, Substituent Constants for Correlation Analysic in Chemistry, Biology (1979), included here as a reference. Preferred substituents include, but are not limited to, alkyl, alkenyl, alkoxy, hydroxy, oxo, amino, aminoalkyl (for example, aminomethyl and etc.), cyano, halo, carboxy, alkoxyalkyl (for example, carboethoxy etc), thio, thiol, aryl, cycloalkyl, heteroaryl, heteroseksualci, (piperidinyl, morpholinyl, piperazinil, pyrrolidinyl etc), imino, thioxo, hydroxyalkyl, aryloxy, arylalkyl and combinations thereof.

Quaternary nitrogen-containing heterocyclic compounds

The compounds of the present invention are containing Quaternary nitrogen phosphonate compounds and their pharmaceutically acceptable salts and esters is eskay part of the heterocyclic ring. The relationship of the carbon atom containing phosphorylate, heterocyclic ring part can be osushestvlenie through a covalent bond, preferably a single bond), or by using the chain length of from 1 to 10 atoms. If the communication is performed via a connecting circuit, this circuit may all be composed of carbon atoms, may be a nitrogen atom or nitrogen chain, an oxygen atom or an oxygen-containing chain or sulfur atom or sulfur chain. Atoms of carbon and nitrogen in binding chains can independently be unsubstituted or substituted by one or more substituents selected from methyl, ethyl, propyl, SR6, R9SR6. Preferred unsubstituted carbon atoms and nitrogen in the chain. Preferable chain length of one atom, i.e.,- CH2-, -NH - S - and-O-.

For compounds in which the sulfur atom, nitrogen or oxygen in the junction circuit connected to the heterocyclic ring part, this atom of sulfur, nitrogen or oxygen is connected with the ring carbon atom and is not directly linked to the nitrogen atom of the ring. For compounds in which the carbon in the binder chain is linked to the heterocyclic ring, the carbon may be connected with the ring carbon atom or, directly is be unsubstituted (e.g., a hydrogen atom, or substituted. The carbon phosphorylate may contain two phosphonate group, which gives the connection bisphosphonates, a group of phosphonate and carboxylate group, which gives the connection of phosphonocarboxylate; a phosphonate group and a sulfonate group, which gives the connection phosphosulfate; group phosphinate and a phosphonate group, which gives the connection of phosphonocrotonate. In addition, the carbon atoms may be in the heterocyclic ring unsubstituted or substituted independently by one or more substituents. The nitrogen atom in the heterocyclic ring may be /Y = N+/R8/2/ or may not be /Y = C/R1/2/ quaternity, but hemerocallidaceae connection phosphonate must contain a Quaternary nitrogen atom in at least one of Y or R2the deputies. Accordingly, either Y = N+/R8/2or at least one of R2= N+/R8/3.

Thus containing a Quaternary nitrogen saturated and unsaturated heterocyclic phosphonate compounds of the present invention and their pharmaceutically acceptable salts and esters have the General structure:

< / BR>
In this General structure Z represents a Quaternary ring asotas is or heterocyclic ring group. Specified heterocyclic ring contains one or more additional heteroatoms selected from oxygen, sulfur or nitrogen. The group Z in the compounds of the present invention may be a heterocyclic ring part specified heterocyclic ring part can have one or more heteroatoms selected from O, S, or N; at least one may be a Quaternary nitrogen.

Z part can be monocyclic, heterocyclic or carbocyclic ring part with 3 to 8 atoms, or it may be a polycyclic heterocyclic or carbocyclic ring part 7 - 17 atoms. This polycyclic ring part can contain either two or more heterocycles, two or more carbocycles, one carbonyl and one or more heterocycles, or one heterocycle and one or more carbocyclic rings. Preferably Z heterocyclic ring contains at least one Quaternary nitrogen atom and preferably monocyclic Z part are: pyrimidine, piperidine, pyridine, quinoline, pyrrolopyridine, cinoxacin and imidazopyridine.

In this General structure Y is a member of the cyclic part and can be N+1or sulfur. In addition, m and n and m + n are integers from 0 to 10 and preferably, if m + n = 0 or 1. Q can be a covalent bond, oxygen, sulfur or-NR1; preferably, when Q is a covalent bond; m + n = 0, 1, 2 or 3. R groups described herein may be COOH, SO3H, PO3H2or P/O//OH/R4where R4- C1- C8alkyl; preferably R is PO3H2or P/O//OH/R4.

R1is selected from zero, SR6, R9SR6, hydrogen, halogen, substituted and unsubstituted C1- C8of alkyl, arylalkyl, nitro, substituted and unsubstituted aryl, hydroxy, -OR3, -CO2R3, -O2CR3, -NR32, -N/R3/C/O/R3-C/O/N/R3/2-C/O/R3and combinations thereof, in which R3is hydrogen, alkyl having 1 to 8 carbon atoms and R9SR6where R9- C1- C8alkyl. R6- H, -C/O/R7C/S/R7C/S/NR7-THE C/S/OR7-C/O/NR7-C/O//OR/7in which R7zero, hydrogen or substituted or unsubstituted C1- C8alkyl. Moreover, when containing a Quaternary nitrogen compound phosphonate is a thio-substituted, preferably R6assetstore, R9SR6or alkyl having from 1 to 8 carbon atoms.

Preferably R1choose from SR6, R9SR6, hydrogen, chlorine, methyl, ethyl, hydroxy, unsubstituted amino, N-methyl/-amino, /N,N-dimethyl/amino, -CO2H and their pharmaceutically acceptable salts, -CO2CH3and-CONH2. Preferably R1is selected from SR6, R9SR6, hydrogen, methyl, chlorine, amino and hydroxy. More preferably, from SR6, R9SR6, hydrogen, hydroxy or amino.

Heterocyclic ring portion of the compounds of the present invention can be unsubstituted on the carbon atoms independently by one or more substituents /R2/. Group R2can be on the same carbon atom or on different atoms of the heterocyclic ring part.

Thus, the group R2are substituents on one or more carbon atoms of the heterocyclic ring part, independently selected from N+/R8/3, SR6, R9SR6, hydrogen, hydroxy, halogen, alkyl having 1 to 8 carbon atoms, -OR3, -CO2R3, -O2CR3, -NR32, -N/R3/C/O/R3-C/O/N/R3
is hydrogen, substituted or unsubstituted alkyl, or R9SR6.

Preferred R2substituents independently selected from the N+/R8/3, SR6, R9SR6, hydrogen, methyl, ethyl, hydroxy, unsubstituted amino, N-methyl/n, /N, N-dimethyl/amino, chlorine, methoxy, ethoxy, nitro, -CO2H, -CO2CH3, -CONH2and combinations thereof. More preferred R2substituents independently selected from SR6, R9SR6, hydrogen, methyl, amino, chlorine, methoxy, hydroxy and combinations thereof. Even more preferred substituents R2independently selected from R9SR6, SR6, hydrogen, amino, and methyl.

R5is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted alkyl having from 1 to 8 carbon atoms, R9SR6, hydroxy and amino. If n = 0 and Q is oxygen, sulfur or nitrogen, then R5is selected from the group consisting of hydrogen, substituted or unsubstituted alkyl with 1 to 8 carbon atoms, or R9SR6.

Each R8group independently selected from the group consisting of zero, substituted or unsubstituted alkyl with 1 to 35 carbon atoms, phenyl, benzyl, or R+/R8/2). Z part, as mentioned above, can be carbocycle or heterocycle and may be either saturated, unsaturated, or aromatic. Whether Z heterocyclic portion is saturated, unsaturated or aromatic, will determine the number R8substituents, which are necessary for the quaternization of the nitrogen heteroatom, when Y = N+/R8/2. When Z represents an unsaturated or aromatic monocyclic or polycyclic heterocyclic ring part, the nitrogen heterocyclic ring quaternized only one R8the Deputy. Thus, when Z part is unsaturated or aromatic, monocyclic or polycyclic heterocyclic ring part, one of R8substituents may be null. When Z part represents a saturated monocyclic or polycyclic heterocyclic ring part, the nitrogen heterocyclic ring quaternized two R8substituents. Therefore, when the Z part is a saturated monocyclic or polycyclic heterocyclic ring part, none of R8cannot be null, to form a Quaternary nitrogen heterocyclics is the accordingly, if Y - C/R1/2at least one of R2must be N+/R8/3.

Introduction R8half of the heteroatom nitrogen leads to the formation of Quaternary nitrogen-containing parts, suitable as R2Deputy or as y

Preferred R8for compounds of the present invention, useful in the treatment or prevention of disorders of calcium and phosphate metabolism, is a substituted or unsubstituted alkyl with 1 to 10 carbons and R9SR6. Preferred R8for compounds of the present invention, are useful for the treatment or prevention of dental stones, plaque and gingivitis, is unsubstituted or substituted alkyl having 10 to 20 carbon atoms.

In addition, in the above General structures, if m = 0 and Q is oxygen, nitrogen or sulfur, communication Q parts with nitrogen heterocyclic Z part preferably limited as follows. Q part is linked to a heterocyclic ring carbon atom and are not directly linked to a nitrogen atom in the heterocyclic ring.

Preferred compounds diphosphopyridine of the present invention may have the following General Streatham, i.e., Q = S, O, or R

< / BR>
< / BR>
< / BR>
Preferred compounds of the present invention, in which Z is a polycyclic heterocycle include compounds with the following structure:

< / BR>
< / BR>
< / BR>
< / BR>
Compounds of the present invention may also have the following General structure:

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
Specific examples of the compounds of the present invention include:

salt of 2-(-2-hydroxy-2,2-diphosphonates)-1,1-dimethylpiperidin iodide;

3-(2-hydroxy-2,2-diphosphonates)-1-methylpyridin iodide; ;

3-(2-hydroxy-2,2-diphosphonates)-1-methylpyridin hydroxide;

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

3-(2,2-diphosphonates)-1-(2-mercaptoethyl)pyridine chloride;

2-(2-hydroxy-2,2-diphosphonates)-1-methylpyridin hydroxide;

3-(3-hydroxy-3,3-diphosphonate)-1-methylpyridin-hydroxide;

salt of 3-(2,2-diphosphono-2-oxyethyl)-1,1-dimethylpiperidin iodide;

3-(2,2-diphosphonates)-1-gatheredin chloride;

3-(2,2-diphosphonates)-1-methylpyridin chloride;

3-(2,2-phosphoramidothioate)-1-methylpyridin iodide;

3-(2-phosphono-2-sulphoethyl)-1-methylpyridin chloride;

3-(2-carboxy-2-phosphonoethyl)-1-methylpyridin chloride;

2-diphosphonate-1,1-dimethylpiperidin chlorine is 2-(2,2-diphosphonates)-1,1-dimethylpiperidin chloride;

3-(2,2-diphosphonates)-1,1-dimethylpiperidin chloride;

4-(2,2-diphosphonates)-1,1-dimethylpiperidin chloride;

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

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

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

2-/2,2-diphosphono-1-(2-mercaptoethyl)ethyl/-1,1-dimethylpiperidin chloride;

3-/2,2-diphosphono-1-(3-mercaptopropyl)ethyl/-1,1-dimethylpiperidin chloride;

4-/2,2-diphosphono-1-(2-acetylethyl)ethyl/-1,1-dimethylpiperidin chloride;

2-(2,2-diphosphono-2-oxyethyl)-1,1-dimethylpiperidin chloride;

3-(2,2-diphosphono-2-oxyethyl)-1,1-dimethylpiperidin chloride;

4-(2,2-diphosphono-2-oxyethyl)-1,1-dimethylpiperidin chloride;

2-(2,2-diphosphono-2-oxyethyl)-1,1,3-trimethylpyridine chloride;

2-(2,2-diphosphono-2-oxyethyl)-1,1,5-trimethylpyridine chloride;

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

2-(2,2-diphosphonates)-1,1,5-trimethylpyridine chloride;

2-(3,3-diphosphonates)-1,1-dimethylpiperidin chloride;

3-(3,3-diphosphonates)-1,1-dimethylpiperidin chloride;

4-(3,3-diphosphonates)-1,1-dimethylpiperidin chloride;

2-(3,3-diphosphono-3-oksipropil)-1,1-dimethylpiperidin chloride;

3-(3,3-diphosphono-3-oksipropil)-1,1-dimethylbutan piperidin chloride;

3-(2,2-diphosphonates)-1,1-dimethylpiperidin chloride;

4-(2,2-diphosphonates)-1,1-dimethylpiperidin chloride;

2-(2,2-diphosphono-2-amino-ethyl)-1,1-dimethylpiperidin chloride;

3-(2,2-diphosphono-2-amino-ethyl)-1,1-dimethylpiperidin chloride;

4-(2,2-diphosphono-2-amino-ethyl)-1,1-dimethylpiperidin chloride;

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

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

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

2-(2,2-diphosphono-2-(methylamino)ethyl)-1,1-dimethylpiperidin chloride;

2-(4,4-diphosphono-4-oxobutyl)-1,1,3-trimethylpyridine chloride;

2-(4,4-diphosphono-4-oxobutyl)-1,1-dimethylpiperidin chloride;

2-(2,2-diphosphono-2-oxyethyl)-3-carboxy-1,1-dimethylpiperidin chloride;

2-(2,2-diphosphono-2-oxyethyl)-5-carboxy-1,1-dimethylpiperidin chloride;

2-(2,2-diphosphonates)-1-methylpiperidin chloride;

4-(2,2-diphosphonates)-1-methylpiperidin chloride;

2-(2,2-diphosphono-2-oxyethyl)-1-methylpiperidin chloride;

4-(2,2-diphosphono-2-oxyethyl)-1-methylpiperidin chloride;

2-(3,3-diphosphonates)-1-methylpiperidin chloride;

4-(3,3-diphosphonates)-1-methylpiperidin chloride;

2-(3,3-diphosphono-1-oksipropil)-1-methylpiperidin chloride;

4-(3,3-diphosphono-1-axiel)oxo/-1,1-dimethylpiperidin chloride;

4-/(diphosphonates)oxo/-1,1-dimethylpiperidin chloride;

3-/(2,2-diphosphonates)oxo/-1,1-dimethylpiperidin chloride;

4-/(2,2-diphosphonates)oxo/-1,1-dimethylpiperidin chloride;

3-/(diphosphonates)thio/-1,1-dimethylpiperidin chloride;

4-/(diphosphonates)thio/-1,1-dimethylpiperidin chloride;

and their pharmaceutically acceptable salts and esters.

Preferred compounds of the present invention include:

3-(2-hydroxy-2,2-diphosphonates)-1-methylpiperidin iodide;

3-(2-hydroxy-2,2-diphosphonates)-1-methylpiperidin hydroxide;

3-(2,2-diphosphonates)-1-(2-mercaptoethyl)pyridine chloride;

salt of 2-(2-hydroxy-2,2-diphosphonates)-1,1-dimethylpiperidin iodide;

salt (2,2-diphosphono-2-oxyethyl)-1,1-dimethylpiperidin iodide;

3-(2,2-diphosphonates)-1-gatheredin chloride;

3-(2,2-diphosphonates)-1-methylpyridin chloride;

2-(2,2-diphosphonates)-1,1-dimethylpiperidin chloride;

3-(2,2-diphosphonates)-1,1-dimethylpiperidin chloride;

4-(2,2-diphosphonates)-1,1-dimethylpiperidin chloride;

2-(2,2-diphosphono-2-oxyethyl)-1,1-dimethylpiperidin chloride;

3-(2,2-diphosphono-2-oxyethyl)-1,1-dimethylpiperidin chloride;

4-(2,2-diphosphono-2-oxyethyl)-1,1-dimethylpiperidin chloride;

2-(2,2-diphosphono-2-oxyethyl)-1,1,3-trimethylpentanediol/-1,1-dimethylpiperidin chloride;

3-/2,2-diphosphono-1-(3-mercaptoethyl)ethyl/-1,1-dimethylpiperidin chloride;

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

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

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

The most preferred compounds of the present invention include:

3-(2-hydroxy-2,2-diphosphonates)-1-methylpyridin iodide;

3-(2-hydroxy-2,2-diphosphonates)-1-methylpyridin hydroxide;

3-(2,2-diphosphonates)-1-(2-mercaptoethyl)pyridine chloride;

2-/2,2-diphosphono-1-(2-mercaptoethyl)ethyl/-1,1-dimethylpiperidin chloride;

3-/2,2-diphosphono-1-(3-mercaptopropyl)ethyl/-1,1-dimethylpiperidin chloride;

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

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

To identify and assess pharmacological activity, a test was conducted phosphonate compounds on animals using a variety of techniques known in the art. So, antiresorptive activity in vivo can be demonstrated using an assay designed to test the ability of these compounds to inhibit bone resorption, which characterizes the metabolism of calcium and phosphate. Titsa test on adjuvant arthritis. In vitro also used the test for inhibition of crystal growth of hydroxyapatite. These and other acceptable tests for pharmacological activity are disclosed and/or referred to in Shinoda and others, Calcified Tissue Intern. 35, pages 87 - 99 (1983); Shenk and others, Calcified Tissue Research, 11, PP 96 - 214 (1973); Russell and others, Calcified Tissue Research 6, pp. 83 - 96 (1970); Muhlbauer and Fleisch, Mineral Electrolyte M. 5, pp. 296 - 303 (1981); Nancollas and other Oral. Biol. 5, 73 (1970); U.S. patent 3683080 Francis, issued August 8, 1972, the U.S. patent 4134969 issued Schmidt-Dunker January 16, 1979; and in the publication of the European patent application 189662 on August 6, 1986; all these sources are fully included here as reference. Some of these tests for pharmacological activity are also described in detail in the examples below.

In addition, these compounds of the present invention are used in the treatment or prevention of pathological conditions characterized by the metabolism of calcium and phosphate, they may have other uses. For example, they can be used in the prevention of stone formation and/or deposits on teeth. Also, consider that they may be useful as agents bone scan after tagging their 99-m technetium. They are also useful as sequestered agents for polyvalent ions of the metal, in the ve binder components in detergents and cleaning agents or water treatment. They are also useful as stabilizers compounds. And finally, they can be used as herbicides, which are non-toxic to animals.

Substituted heterocycle containing Quaternary nitrogen phosphonates entered in the pharmaceutical compositions of the present invention, can be obtained by the following unlimited examples 1 to 16.

Compositions containing the new containing Quaternary nitrogen compounds

New containing Quaternary nitrogen compounds phosphonate of the present invention it is possible to introduce people or other mammals in a variety of ways, including, but not limited by them, oral dosage forms and injections (intravenous, intramuscular, vnutrepenialnye and subcutaneous). Many other dosage forms containing the new containing Quaternary nitrogen compounds phosphonate of the present invention can be easily prepared by a person skilled in the art using suitable pharmaceutical excipients, as described below. Oral dosage forms are the most preferred subject sick mode and regimens.

The term "pharmaceutical composition", as used here, means the combination status is private connection or mixtures thereof and pharmaceutically acceptable excipients.

The phrase "safe and effective amount", as used here, means the amount of compound or composition large enough to significantly and positively modify the symptoms and/or condition of the patient, yet small enough to avoid serious side effects (reasonable value of the benefit/risk) within the error of the medical evaluation. Safe and effective amount of the active ingredient for use in pharmaceutical compositions will vary depending on the specific subject of the treatment status, age and physical condition of the patient, extent of disease, duration of treatment, the nature of concurrent therapy, the specific active ingredient, the pharmaceutically acceptable excipient and other similar factors, based on the knowledge and experience of the treating physician.

The term "pharmaceutically acceptable excipients" includes any physiologically inert, pharmacologically inactive material, which is familiar to specialists, and which is compatible with the physical and chemical characteristics of concerne. Pharmaceutically acceptable excipients include, but are not limited to, polymers, resins, plasticizers, fillers, binders, lubricating agents, galantai, leavening agents, solvents, co-solvents, buffer systems, surfactants, preservatives, flavouring and sweetening agents, dyes and pigments and agents that regulate the viscosity.

The term "oral dosage form" means any pharmaceutical composition intended for the systematic introduction of the individual into the gastrointestinal tract through the mouth. The input form may be in the form of tablets, coated or without a solution, suspension or capsules with coating or without it.

The term "injection" here means the introduction of any of the pharmaceutical compositions systematically for a person or other mammal in the form of a solution or emulsion containing the active ingredient, with an injection through the skin for the delivery of a specified solution or emulsion in the circulatory system of the individual or intravenous, intramuscular, intraperitoneal, or subcutaneous injection.

Dose systematic introduction can control specialist regulation of one or more of which, what if they do not affect the activity of the specific active ingredient;

(C) the type of filler, the thickness and permeability (swelling properties) of these fillers;

d) time-dependent state of the filler itself (or fillers);

e) particle size granulirovannogo active ingredient and

f) the state of fillers depending on pH.

By their own choice can be varied, in particular, solubility, acidity and ability to hydrolysis of various active ingredients containing Quaternary nitrogen phosphonates, such as salts of acid accession, salts formed with the carboxylic group, for example salts of alkali metal, alkaline earth metal, etc. and esters, for example alkalemia, arrouye, Arakelova. In addition, can be created suitable pH conditions within the oral dosage forms by adding a suitable buffer to the active ingredient in accordance with the desired rate of release of the active ingredient.

The most acceptable form for administration of the compositions acting on Tartar and raids, are: cleaning of teeth (including toothpastes and powders, elixirs, liquid is of funds for brushing your teeth. Components of toothpastes usually include a cleaning agent (from 10 to 50%), a surfactant (from 0.5 to 10%), thickening agent (from 0.1% to 5%), humectant (10 - 55%), perfume (from 0.04 to 2%), sweetening agent (0.1 to 3%), dye (0.01 to 0.5%) and water (20 - 45%). Means for brushing your teeth can also include a safe and effective amount of a source of fluoride ion, which is usually present in the form of a water-soluble fluoride. This water-soluble compound of fluorine is included in the composition of the invention in a quantity sufficient to give a fluoride concentration 0.005 to 2.0% by weight. The preferred source of fluoride is sodium fluoride, acidulated forfattere, monitoroff sodium. U.S. patent 3678154, issued June 18, 1972, Widder, etc. disclose such salts, as well as others and is included here as a reference.

Other preferred compositions of the invention are rinse for the mouth and sprays. Components of such mouthwashes and sprays include water (from 45% to 95%), ethanol (from 0% to 25%), a humectant (from 0% to 50%), a surfactant (from 0.01% to 7%), perfume (from 0.04 to 2%), sweetener (from 0.1 to 3%), dye (from 0.001 to 0.5%). Such mouthwashes or sprays may also include one or more agents (from 0.15 to 3%), acting on the stones and on raids (from 0.1 to 5%).

Other precaut water (90 to 99%), preservative (0,01 - 0,5%), thickening agent (from 0 to 5%), flavoring (0.04 to 2%), sweetener (0,1 - 3%) and surfactant (from 0 to 50%).

Gel composition for oral assignments typically contain water (0 - 99%), a humectant, such as glycerin (from 0 to 99%), thickener (0,1 - 5%), flavoring (0.04 to 2%) and sweetener (0,01 - 0,5%).

The chewing gum composition include one or more of the grounds for gum (from 50 to 90%), perfume (0.04 to 2%), sweetener (0.01 to 20%).

As mentioned earlier, pharmaceutically acceptable excipients include, but are not limited to resins, fillers, binders, lubricants, solvents, glidants, leavening agents, co-solvents, substances, surfactants, preservatives, politicala, perfumes, buffer systems, pharmaceutical dyes or pigments and agents, giving the viscosity.

The preferred solvent is water.

Odorants used here include those described in Remington's Pharmaceutical Sciences, 18th edition, Mack Publish. Company, 1990, pp. 1288 - 1300, included here as reference. Pharmaceutical compositions suitable for use, usually contain from 0 to 2% fragrance.

It is especially good to use as flavoring substances are also useful in the treatment or butter onion. Odorants are typically included in the composition to remove stones and deposits in the amount of from 0 to 3%, and preferably from 0.04 to 2% by weight.

Dyes or pigments that are used here include those described in the Handbook of pharmaceutical excipients, pp. 81 - 90, 1986, the American pharmacists Association and the pharmaceutical society of great Britain, which is included here by reference. Here, the pharmaceutical compositions typically contain from 0 to 2% of pigments.

Preferred co-solvents include, but are not limited to, ethanol, glycerin, propylene glycol, polyethylene glycol. The pharmaceutical compositions of the present invention comprise from 0 to 50% of cosolvent.

Preferred buffer systems include, but are not limited to acetic, boric, carbonic, phosphoric, succinic, malic, tartaric, citric, benzoic, lactic, glyceric, glutinosae and glutamic acid and their sodium, potassium and ammonium salts. The preferred phosphoric, tartaric, citric and acetic acids and their salts. The pharmaceutical composition of the present invention typically contains from 0 to 5% buffer systems.

Preferred surfactants include, but are not limited to, polio the esters of lanolin, salts of alkyl sulfate, salts of sodium, potassium and ammonium fatty acids. The pharmaceutical compositions of the present invention include 0 - 2% surfactant. Preferred surfactants for compounds of the present invention, useful in the treatment or prevention of dental stones or deposits include those surfactants that are stable enough to form the foam in a wide pH range, including nemaline anionic, nonionic, zwitterionic and amphoteric organic synthetic detergents. Many suitable surfactants are disclosed in U.S. patents 4051234, issued September 27, 1977, Gieske, etc. and 3959458, issued may 25, 1976, Agricola, Briner, Granger, both are included here as reference. Such surfactants are typically present in the compositions of the invention from 0 to 10%, better from 0.2 to 5%.

They can also be used as agents which impart solubility in order to help to preserve components in solution, for example, odorants, surfactants suitable for this purpose include Polysorbate and poloxamer.

Preferred preservatives include, but are not limited to phenol, alkyl esters, parahydroxybenzoic acid, o-phenylphenolate acid and their salts, boric acid and its salts, sorbic acid and its salts, chlorbutanol, benzyl sleep the Dean, methyl paraben and propyl-paraben. The most preferred salt of benzoic acid, chloride cetylpyridinium, methyl paraben and propyl paraben. Compositions of the present invention typically include from 0 to 2% preservatives.

Preferred sweeteners include, but are not limited to, sucrose, glucose, saccharin, sorbitol, mannitol and aspartame. The most preferred sucrose and saccharin. Compositions of the present invention comprise 0 to 5% sweeteners.

Agents that regulate the viscosity include, but are not limited to, methylcellulose, carboxymethylcellulose sodium, hypromellose, hydroxypropylcellulose of alginate sodium carbomer, povidone, Arabian, xantanovu gum and other and tragakant. The most preferred methyl cellulose, carbomer, xanthan gum, povidone, carboxymethylcellulose sodium, and silicate of alumina magnesium. Compositions of the present invention comprise 0 to 5% of agents regulating the viscosity.

Preferred fillers include, but are not limited to, lactose, mannitol, sorbitol, trehosnovnoy calcium phosphate, dibasic calcium phosphate, compressible sugar, starch, calcium sulfate, dextro and microcrystalline cellulose. esta include, but are not limited to magnesium stearate, stearic acid and talc. They are included in the composition in the amount of 0.5 - 2%.

Glidant include, but are not limited to talc and colloidal silicon dioxide. Compositions of the present invention include 1 - 5% of such substances.

Leavening agents include, but are not limited to starch, starch glycolate, sodium, crosspovidone, croscarmellose sodium and microcrystalline cellulose. These substances included in the composition of from 4 to 15%.

Binders include, but are not limited to gums, tragakant, hydroxypropylcellulose, gelatinising starch, gelatin, povidone, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, solution of sugar, such as sucrose and sorbitol, and ethyl cellulose. Compositions of the present invention include 1 - 10% of binders.

In the preparation of oral compositions used in the treatment and prevention of dental stones and raids, it is desirable for the toothpaste to add a binder and/or thickening agents. Such agents include, for example, carboxyvinyl polymers, polysaccharide gums, such as xantanova, carrageenan, hydroxyethyl cellulose and water soluble salts EF is about to use natural gums, such as karaya, gum Arabic and tragakant. To improve the structure as part of a thickener, you can use colloidal silicate of alumina, magnesium or finely powdered silicon. These thickeners and binders are usually present in amounts of 6%, preferably from 0.1% to 5 wt.%.

Another optional component in the preparation of oral compositions - humidifier. The humectant serves to keep toothpaste in the wetted state and not allow them to harden upon contact with air. Certain humectants can also impart a pleasant fragrance compositions rinse for mouth and tooth pastes. The humidifier is usually 0 to 70%, better from 2 to 55% by weight of the composition. Suitable humectants include edible polyhydric alcohols such as glycerin, sorbitol, xylitol, polyethylene glycol and propylene glycol, better sorbitol and glycerin.

Can also be used additive in toothpastes to make them opaque. Suitable additives include titanium dioxide and some abrasive substances, for example, silicate of alumina magnesium.

Preferred grinding teeth substances used in the preparation of tools for cleaning teeth, include, nab, who LCIA, tricalcium phosphate, polymetaphosphate calcium, insoluble polymetaphosphate calcium, hydroclimate and resinous abrasive materials such as from melannie condensation products of urea and formaldehyde, and other materials, such as those disclosed in U.S. patent 3070510, Gooley, etc. issued December 25, 1962, included here by reference. You can use a mixture of abrasive tools.

Grinding means for the teeth of the silica of various types provide exceptional cleaning action and grinding of the teeth without damaging the enamel or dentin. It is therefore desirable use them.

The average particle size of the abrasive grinding material is from 0.1 to 30 μm, preferably from 5 to 15 μm. Abrasive material can be precipitated silica or silica gels, such as silicagel described in U.S. patent 3538230, issued March 2, 1970, Pader, etc. and 3862307, dated June 21, 1975, DiGiulio, they are included here as reference. Predpochitayut ilikecereal under trademarks naimenovanie SyloidRcompany W. R. Grace and Co., Davidson Chemical Division. Predpochtitelnye material of precipitated silica include materials Huber Corporation under the trade name LeodentR119. These kremnezemov abrasives described in the patent With the Number of abrasive or grinding material in the compositions, described here varies from 6 to about 70%, preferably from 15 to 50%, if this toothpaste. A higher content of up to 90%, can be used in tooth powder.

Compounds of the present invention can comprise from 0.1 to 99.9% by weight of the pharmaceutical compositions of the present invention. Preferably the compounds of the present invention comprise from 20% to about 80 wt.% pharmaceutical compositions useful in the treatment or prevention of osteoporosis and arthritis, including rheumatoid arthritis and osteoarthritis.

Accordingly, the pharmaceutical compositions of the present invention, useful in the treatment or prevention of osteoporosis and arthritis, including rheumatoid arthritis and osteoarthritis, contain from 15 to 95% active ingredient containing Quaternary nitrogen compounds phosphonate, or mixtures thereof; 0 to 2% fragrance; 0 - 50% co-solvents; 0 - 5% buffer systems; 0 - 2% surfactant; 0 to 2% preservatives; 0 - 5% sweeteners; 0 to 5% of agents viscosity; 0 - 75% fillers; 0.5 to 2% lubricants; 1 - 5% glidants; 4 - 15% baking powder and 1 to 10% binder.

Compositions of the present invention, intended for the treatment or prevention of dental plaque and stones, preferably consist of aqueous solutions with the about 5% by weight, and preferably from 0.5 to 3 wt.% compounds of the present invention. In preparation for rinsing the teeth with the most preferred concentration of the compound of the invention is about 1 to 20% by weight.

Suitable pharmaceutical compositions are described herein in the examples 19 to 21. Dental compositions described in examples 22 to 23. The person skilled in the art can use the examples described here to achieve a wider range of pharmaceutical compositions.

The choice of pharmaceutical filler used together with containing a Quaternary nitrogen compounds, phosphonate in these compositions, determined mainly by way of its introduction. If the connection is intended for injection, the preferred pharmaceutical carrier is a sterile saline solution, the pH is increased to 7.4. However, the best way of introducing phosphonates - oral and the best dosage form is a tablet, capsule or other form, containing from 0.1 mg P to 600 mg P compounds phosphorylate described here. Pharmaceutical carriers suitable for the preparation forms for oral destination, well known in this field. Their choice will depend on secondary considerations, such as what rudnany specialists in this field.

The term "mg R", used herein, means the weight of phosphorus atoms present in the number of connections phosphorylate of the present invention. This unit is used to standardize the number of connections phosphorylate of the present invention used in the pharmaceutical compositions and methods of treatment and prevention. For example, 3-(2,2-diphosphonates)-1-(2-mercaptoethyl)pyridine chloride has a molecular weight of 363,7 g/mol, 17% of which 963 g/mol) is the weight of the two phosphorus atoms present in the molecule. Therefore, it is calculated that one milligrams which this connection is 0.17 mg R. so, in order to obtain a pharmaceutical composition containing 0.17 mg P this connection, the composition should contain 1 mg of the compound; and to introduce a dose of 0.17 mg P this compound to a patient weighing 50 kg, the patient should enter 50 instant connection.

Pharmaceutically acceptable filler, used in conjunction with phosphonates of the invention is used in a sufficient concentration to unit dosage had a reasonable size. Carriers typically comprise from 0.1 to 99.9% by weight of the total composition, and more often from 30 to 80%.

Method for the treatment or prevention of diseases associated with impaired obmolotili diseases, associated with abnormal metabolism of calcium and phosphate. In addition, the invention relates to a method of treating and preventing the formation of dental plaque and dental stone. Such methods include administration to a human or other mammal in need of such treatment, a safe and effective amount of phosphonate compounds of the present invention.

The preferred method of administration is oral, but other known methods of administration are also used, for example, dermatomyositis (skin, rectal and other applications) and parenteral (subcutaneous, intramuscular, intravenous, intra-articular injection, etc.). Inhalation is also included in the method of administration. Thus, specific methods of administration include, without limitation, oral, transdermal, mucosal, sublingual, intramuscular, intravenous, nutritionally and subcutaneous methods, as well as local use.

The term "abnormal metabolism of calcium and phosphate" means (1) States, which are characterized by anomalous mobilization of calcium and phosphate, leading to General or specific to the rarefaction of bone tissue or excessively high content of calcium and phosphate in the body fluids; and (2)I category includes, but not limited to osteoporosis, Paget's disease, hyperparathyroidism, hypercalcemia malignant origin of heterotopic ossification and metastases asterita bones. The second category includes, but is not limited to progressive myopathy with bone formation, calcification General and diseases such as arthritis (including rheumatoid arthritis and osteoarthritis, neuritis, bursitis, tendant and other inflammatory condition that causes the affected tissue to deposition of calcium and phosphate.

The term "rheumatoid arthritis" here refers to a chronic systemic inflammatory violation of the joints of unclear etiology. It is characterized by destruction of articular cartilage, ligaments, tendons and bones.

The term "osteoarthritis" here means non-inflammatory violation of motion of the joints. It is characterized by the destruction and erosion of articular cartilage and formation of new bone on the surface of the joint.

The terms "person at risk" and "person in need of such treatment", here, means any person or mammal, which is exposed to a significant risk of abnormal metabolism of calcium or phosphate if it is not treated any person or the other is a mini-period, persons undergoing steroid therapy; persons treated some anticonvulsant drugs; patients suffering from disease Paget's disease, hyperparathyroidism, hypercalcemia malignant origin or metastatic bone destroying, persons suffering from one or more forms of osteoporosis; persons belonging to the population group with an increased risk of developing osteoporosis, for example, postmenopausal women age, men over 65 years, and those taking medications that cause osteoporosis as a side effect, persons suffering from progressive myositis with ossification or General calcaratum; and persons suffering from arthritis, osteoarthritis, revmatoidnym arthritis, neuritis, the bursitis, tendonitis and other conditions that predispose to the deposition in the tissues of calcium and phosphate.

"Safe and effective amount" means an amount of compound or composition of the invention is large enough to significantly positively modify the condition of the patient, but low enough to avoid serious side effects (at a reasonable ratio benefit/risk) within the error of the medical evaluation. Safe and effective coletania patient, the severity of the condition, the duration of treatment, the nature of concurrent therapy, the specific phosphonate and other factors, based on the knowledge and experience of the attending physician. Single dose in the treatment of disorders of calcium and phosphate may range from 0.01 mg P to 3500 mg P, or from 0.002 to 70 mg P/kg of body weight (weight 50 kg). Preferred single dosage range from 1 mg, R 60 mg P, or from 0.02 to 12 g of P/kg of body weight (weight 50 kg). On the day appointed for up to 4 single doses. Doses over 500 mg P/kg (daily) can cause unwanted side effects. Higher doses in this range are of course required in the case of oral destination due to limited absorption.

Dosage forms of the compounds of the present invention, used in the treatment or prevention of dental plaque and stones, include means for cleaning the teeth, such as tooth pastes and tooth powders containing 0.05 - 10 weight. % of compounds of the present invention, and solutions, such as mouthwash containing 0.05 - 5 wt.% compounds of the present invention. The following examples describe and then demonstrate the preferred options in the scope of the present invention. Examples are given only for purposes of illustration, and does not track the volume of invention.

Example 1

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

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I. Synthesis of 2-/(3-pyridinylamino)bis(phosphorylate)tetraethyl ester.

To a mixture of 60% sodium hydride in mineral oil (4,00 g, 0.10 mm) in DMSO (155 ml) is added tetraethylethylenediamine (30 g, 0.10 mm) in DMSO (20 ml) at 0oC. the Reaction mixture was stirred for 30 minutes at 0oC, and then 30 minutes at room temperature. Then this mixture is delivered dropwise through the funnel to 3-picolylamine (0,11 mm) in DMSO (100 ml) at room temperature. The reaction mixture was stirred 12 hours at room temperature, then the reaction is extinguished by addition of saturated aqueous ammonium chloride. Mentioned reaction mixture is extracted with methylene chloride and the organic extracts combined, dried over sodium sulfate, filtered and concentrated under reduced pressure. The product is purified instant chromatography with 5% methylene chloride on silica gel.

II. Synthesis of tetraethyl-3-(2,2-diphosphonates)-1-ethyl pyridine.

To a solution of tetraethyl-2-(3-pyridinyl)ethylidene-1,1-bisphosphonate-tetraethyl ester (1,96 g of 5.17 mm) in acetone (10 ml) is added Iodate (a 4.03 g, 25,86 mm). The reaction mixture is heated with reverse halterstyle with hexane and then titilation. Thus in the form of a hygroscopic solid orange (2.28 g) obtained product fitting N-ethylpyridine with 83% yield.

III. Synthesis of tetraethyl-3-(2,2-diphosphonates)-1-ethylpyridine chloride

Esters of phosphonate hydrolyzed by boiling under reflux (2,18 g, 4,08 mm) in 6N HCl (30 ml) for 12 hours under nitrogen atmosphere. The reaction mixture is cooled and then concentrated under reduced pressure. Pure product is obtained by rubbing with diethyl ether.

Example 2

Synthesis of 3-(2,2-diphosphonates)-1-(2-mercaptoethyl) pyridine chloride

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I. Synthesis of tetraethyl-3-(2,2-diphosphonates)-1-(2-acetylethyl)pyridine bromide.

To a solution of tetraethyl 2-/3-pyridinyl ethylidene/-1,1-bis/phosphorylate/tetraethyl ester, obtained as described in Example 1 (part 1) above (and 3.16 g, 8,35 mm) in acetone (20 ml) was added S-acetyl-2-bromoethanol (3,82 g to 20.88 mm). The reaction mixture is heated under reflux for 24 hours under nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure and the crude residue is rubbed with hexane and then with diethyl ether. Next, the residue is purified instant chromatography on silica gel with 20% methanol in methylthio the Proc. of 3-(2,2-diphosphonates)-1-(2-mercaptoethyl)pyridine chloride.

Esters of phosphonate hydrolyzed by boiling under reflux (1.45 g, 5,10 mm) in 6N HCl (35 ml) for 20 hours under nitrogen atmosphere. The reaction mixture is cooled to them concentrated. The product is obtained in pure form by rubbing with diethyl ether.

Example 3

Synthesis of 3-(2-hydroxy-2,2'-diphosphonate)-1-methyl-pyridine iodide disodium

< / BR>
I. Synthesis /1-hydroxy-2-(3-pyridinyl)ethylidene/bis(phosphorylate).

In a 250 ml 3-neck flask with a round bottom, equipped with a reflux condenser and addition funnel, is added hydrochloride 3-pyridyloxy acid (1,74 g, 10 mm), phosphorous acid (2,46 g, 30 mm) and 50 ml of chlorobenzene. The flask is placed in a boiling water bath it dropwise from a dropping funnel to the reaction mixture is added to trichloride phosphorus (4.0 g, 30 mm). All this mixed up 3 hours at 100oC and the input of this reaction is a yellow viscous oil. After 3 hours the reaction mixture is cooled in an ice bath and the excess chlorobenzene decanted. The oil is hydrolyzed in 100 ml of 1N HCl overnight, cooled and virasa crystals are filtered and washed with ethanol. The filtrate is evaporated to an oil and dissolved oil is added a small amount of water. To initiate CR the second batch of crystals to obtain 2.1 g of the product of recrystallization from hot water.

II. The synthesis of the salt of 3-(2-hydroxy-2,2-diphosphonates)-1-methyl pyridine iodide.

To a solution of 1-hydroxy-2-(3-pyridinyl)ethylidene/bis(postnatally) (0.5 g, 1.77 in mm) 4.4 ml of 1N NaOH is added 14 ml of distilled water. To the mixture is added methyl iodide in ethanol (12 ml) (1,215 g, 8,83 mm). the pH of the reaction mixture of 6.0. The mixture is heated overnight at 80oC. the Solvents are evaporated and the residue is rubbed with acetone. Product precrystallizer of water and ethanol to obtain 3-(2-hydroxy-2,2-diphosphonates)-1-methyl pyridine iodide, disodium salt.

Example 4

Synthesis of 3-(2-hydroxy-2,2-diphosphonates)-1-methyl-pyridine hydroxide, inner salt

< / BR>
Salt of 3-(2-hydroxy-2,2-diphosphonates)-1-methyl pyridine iodide disodium, obtained as described in example 3 above, (0,42 g, 0.89mm) in 6N HCl (40 ml) is heated under reflux for 12 hours. The reaction mixture is cooled and then washed with chloroform (5 40 ml) to remove iodine. The aqueous layer was concentrated under reduced pressure. The crude residue is rubbed with acetone to obtain a desired inner salt (255 mg) as a pale yellow solid with a yield of 85%.

Example 5

2-(2-hydroxy-2,2-diphosphonates)-1-methylpyridin hydroxide, inner salt, Monona is rlvuu flask with a round bottom, equipped with reflux condenser, addition funnel, is added hydrochloride 2-pyridyloxy acid (1,74 g, 10 mm), phosphorous acid (2,46 g, 30 mm) and 50 ml of chlorobenzene. The flask is placed in a boiling water bath and added dropwise from a dropping funnel to the reaction mixture is added to trichloride phosphorus (4,08 g, 30 mm). All this stirred 3 hours at 100oC and in the course of the reaction is a yellow viscous oil. After 3 hours the reaction mixture is cooled in an ice bath and the excess chlorobenzene decanted. To the oil is added to 100 ml of water and this mixture is heated under reflux during the night. After phlegmasia the mixture cools and begins to precipitate the product. This precipitate is filtered and washed with ethanol to obtain the first output of the crystals. To obtain the second output of the crystals, the filtrate is evaporated to an oil and the oil is added a small amount of water up until it is dissolved. To induce crystallization is added to the ethanol. The second output of the crystals filtered and washed with ethanol and connected with the first output to produce an overall output of 1.87 g after recrystallization from hot water.

II. Synthesis of 2-(2-hydroxy-2,2-diphosphonates)-1-methyl pyridine hydroxide) dissolved 8.8 ml of 1N sodium hydroxide solution and 8.8 ml of distilled water. To this is added iodomethane (17,67 mm, 1.1 ml) in 18 ml of ethanol. This reaction mixture is heated at 80oC to complete the reaction. The solvent is concentrated in vacuo and the residue precrystallizer from ethanol and water to get to 0.92 g of 2-(2-hydroxy-2,2-diphosphonates)-1-methyl pyridine hydroxide, inner salt, salt monolatry.

Example 6

3-(3-hydroxy-3,3-diphosphonates)-1-methylpyridin hydroxide, inner salt

< / BR>
I. Synthesis of 3-(3-pyridinyl)propanoic acid.

-(3-pyridyl)-akeldema acid (10 g) was placed in a hydrogenation vessel Parra with 150 ml of glacial acetic acid, 100 ml of absolute ethanol and a large amount of catalyst is palladium-on-carbon. The solution is shaken at 50 f/d2(3,51 kg/cm2) hydrogen and subjected to the second pressure until, until there is no further absorption of hydrogen (approximately 3 hours). The solution is filtered through celite, washed with ethanol and the solvent evaporated in vacuum and azeotropically toluene to obtain the desired product as white crystals.

II. Synthesis of /-1-hydroxy-3-(3-pyridyl)propylidene/bis(phosphorylate).

In a 250 ml 3-neck flask with a round bottom equipped with a reverse holodil mm) and 50 ml of chlorobenzene. The flask is placed in the 100oC bath and the reaction mixture is added dropwise to trichloride phosphorus (to 20.88 ml, 239 mm). The reaction mixture was stirred for 3 hours, the formed resinous oil, and chlorobenzene decanted and added 100 ml of 1N HCl and the mixture is heated under reflux during the night, when 100oC. the Solution is cooled and the white precipitate that forms is filtered and washed with ethanol and ether to obtain of 16.9 g of the desired product.

III. Synthesis of 3-/3-hydroxy-3,3-diphosphorous/-1-methyl pyridine hydroxide, inner salt.

/1-Oh-3-(3-pyridinyl)propylidene/bis(phosphorylate) (3.37 mm, 1.0 g) is dissolved 8.4 ml of 1N NaOH solution with 29 ml of distilled water. Itmean (equal to 16.83 mm 1,05 ml) is added to 19 ml of ethanol. This reaction mixture is heated at 80oC during the night. The solvent is evaporated in vacuum and the residue is rubbed with acetone, then precrystallizer from ethanol and water to obtain 0.5 g of 3-(3-hydroxy-3,3-diphosphonates)-1-methyl pyridine hydroxide, inner salt.

Example 7

Synthesis of 3-(2,2-diphosphonates)-1-gatheredin chloride

< / BR>
The above-mentioned connection receive and synthesize, as described below.

I. Synthesis of retreat Treaty ester (4.0 g, 10.5 mm) are obtained as described in Example I (part I) below, and 1-Edgerton (7,14 g, 31,6 mm) in dry acetone (25 ml) is heated under reflux for 72 hours in nitrogen. The reaction mixture is evaporated in vacuo to dryness. The residue is ground 2 times in diethyl ether, filtered and dried in a vacuum dryer, to obtain a product of the merger of N-heptyl (6,37 g).

II. Synthesis of 3-(2,J2-diphosphonate)-1-gatheredin chloride.

Product fitting N-heptyl (6.20 g, 10,2 mm) is heated under reflux in 6N hydrochloric acid (62 ml) for 48 hours. The reaction mixture is evaporated in vacuo to dryness, acetone is added to it, the mixture is evaporated in vacuum a second time. The residue is ground in ethanol to obtain a solid yellow color, which is collected by filtration, washed with diethyl ether and dried in a vacuum dryer to obtain 29% (for two steps) of N-heptyl pyridine of bisphosphonate (1.19 g).

Example 8

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

< / BR>
The above-mentioned connection receive and synthesize, as described below.

I. Synthesis of tetraethyl-3-(2,2-diphosphonates)-1-methylpyridin iodide.

The solution containing tetraethyl EF the Tang (the ceiling of 5.60 g, 39,5 mm) and dry acetonitrile (32 ml), heated under reflux for 72 hours. The reaction mixture is evaporated in vacuo to dryness, acetone is added and the mixture is evaporated to dryness second time. The crude product is rubbed in a mixture of hexane/diethyl ether, collected by filtration in a nitrogen atmosphere and dried in a vacuum dryer to obtain 5.0 g of the product of the joining of N-methyl pyridine.

II. Synthesis of 3-(2,2-diphosphonates)-1-methylpyridin chloride.

Esters of phosphonate hydrolyzed by heating under reflux of N-methylated product join (5.0 g, 13.1 mm) in 6N hydrochloric acid (54 ml) for 48 hours. The reaction mixture is evaporated in vacuo to dryness, acetone is added and the mixture evaporated in vacuo to dryness in the 2nd time. The residue is ground in ethanol to obtain a solid, which is collected by filtration. The crude product is ground in a minimum amount of water and treated with charcoal, then filtered through celite. The filtrate is poured into ethanol to precipitate the product, which is collected by filtration and dried in a vacuum drying to obtain N-methylated bisphosphonate (1,05 g, 25% yield for two staminate connection receive and synthesize as opisane below.

I. Synthesis of 2-(3-pyridinylamino)phosphonomethyl phosphorylate, teeterboro ether.

Using virtually the same technique as described in example 1 (part I), supra, tritely ether methylene of phosphonomethylglycine obtained as described Henning, G. H. and Petzold, G. Z. Chem. so 5, page 419 (1965), is converted to tritely ester 2-(3-pyridinylamino)-phosphoramidothioate.

II. Synthesis of triethyl-3-(2-phosphono-2-methylphosphonate)-1-methylpyridin iodide.

Tritely ester 2-(3-pyridinyl)ethylidene phosphonomethyl phosphorylate (2,32 g, 6,64 mm) and iodomethane (9,42 g, 6,44 mm) is heated under reflux for 24 hours in dry acetone (23 ml) under nitrogen atmosphere. The reaction mixture is evaporated in vacuo to dryness, acetone is added and the mixture evaporated in vacuo to dryness second time, to obtain the N-methylated product fitting (2,60 g).

III. Synthesis of 3-(2-phosphono-2-methylphosphonate)-1-methylpyridin iodide.

Product fitting N-methyl pyridine (2,60 g, 6,20 mm) is heated under reflux in 6N hydrochloric acid for 18 hours. The reaction mixture is evaporated in vacuo to dryness, added methanol and the mixture is evaporated to dryness second time. The crude product is dissolved in minicity 0.5 g (for two steps yield 25%) N-methyl pyridine phosphonomethylglycine acid.

Example 10

Synthesis of 3-(2-phosphono-2-sulphoethyl)-1-methylpyridin chloride

1 Above connection receive and synthesize, as described below.

I. Synthesis of triethyl-2-(3-pyridinyl)ethylidene-1-falstone-1-sulfonate.

To a mixture of NaH (1,10 mm) 40% in oil and toluene (10 ml) is added ethyl ether diethoxyphosphoryl methane sulfonic acids (1 mm), obtained as described Carretero and other Tetrahedron, T. 43, page 5125 - 5134 (N 21) 1987, at 0oC in nitrogen atmosphere. After mixing for 30 minutes the reaction mixture is added dropwise through the funnel to 3-picolyl chloride (1.00 mm) in toluene (50 ml) at room temperature. Stirring is continued for 12 hours, the reaction mixture is poured into water and the layers separated. The aqueous layer was extracted with diethyl twice, and the combined organic layers are washed with saturated aqueous sodium chloride. The product is separated from unreacted starting materials instant chromatography on silica gel, 10% isopropyl alcohol in methylene chloride. This gives the output phosphosulfate in the form of a pale yellow oil.

II. Synthesis of triethyl-3-(2-phosphono-2-sulphoethyl)-1-methylpyridin iodide.

The solution containing triethyl-2-(3-pyridinyl)ethylidene-1-phosphono-1-sulfonate (5,camping evaporated in vacuo to dryness, added acetone and the mixture is evaporated to dryness again. The crude product is rubbed in a mixture of hexane/diethyl ether, collected by filtration in a nitrogen atmosphere and dried in a vacuum drying to obtain the product of the joining of N-methyl pyridine.

III. Synthesis of 3-(2-phosphono-2-sulfoethyl)-1-methylpyridin chloride.

Salt-N-methylpyridine (0.3 mm) is hydrolyzed in boiling under reflux 6N hydrochloric acid (10 ml) for 12 hours, the Reaction mixture was evaporated in vacuo to dryness. The crude product is dissolved in a minimum amount of water and treated with charcoal, then filtered through celite. The filtrate is filtered and dried in a vacuum drying to obtain 3-(2-phosphono-2-sulfoethyl)-1-methylpyridin chloride.

Example 11

Synthesis of 2-(2-hydroxy-2,2-diphosphonates)-1,1-dimethyl piperidine iodide

< / BR>
I. Synthesis /1-hydroxy-2-(2-piperidinyl)ethylidene/bis(phosphorylate), monosodium salt.

/1-hydroxy-2-/2-pyridinyl)ethylidene/bis(phosphorylate), obtained as described in example 5, part I, above (2.5 g, 0,0088 mm) is added to 50 ml of water and the pH is brought to 6.0 with 50% NaOH. This solution is placed in a 500 ml hydrogenation vessel Parra and added about 1 g of 10% f/d2(3,164 kg/cm2). After 4 hours add the catalyst and the pressure is again brought to 45 f/d2and the reaction proceeds during the night. The solution is filtered through the zeolite is washed with water and evaporated to pure oil. To the oil is added ethanol (30 ml) and the mixture gently heated under reflux for 48 hours to turn the oil into the powdery white precipitate. It is filtered and washed with ethanol.

II. Synthesis of salts of 2-(2-hydroxy-2,2-diphosphonates)-1,1-dimethylpiperidin iodide.

Salt /1-hydroxy-2-(2-pyridinyl)ethylidene/bis(phosphorylate) monolatry (3.5 mm) is dissolved in a mixture of DMSO (10 ml) and water (50 ml). To this is added methyl iodide (35,0 mm) and the solution was heated under reflux in nitrogen atmosphere for 3 days. The reaction mixture was concentrated under reduced pressure and the Quaternary product is purified of water and isopropanol.

Example 12

Synthesis of 3-(2,2-diphosphono-2-hydroxyethyl)-1,1-dimethyl piperidine iodide

< / BR>
I. Synthesis /1-hydroxy-2-(3-piperidinyl)ethylidene bis(phosphorylate), monosodium salt.

1-hydroxy-2-(3-pyridinyl)ethylidene bis(phosphorylate), obtained as described in example 3, part I, above (2.0 g, 0,0071 mm) is added to 50 ml of water and pH devoter Pd/C. The vessel Parra is placed in hydrogenator Parra and under pressure of H245 lbs/inch2. After 4 hours add the catalyst and the pressure is again brought to 45 f/d2and the reaction proceeds during the night. The solution is filtered through celite, washed with water and evaporated to pure oil. The oil adds ethanol (30 ml) and the mixture is subjected to soft phlegmasia 1 hour for converting oil powdery white precipitate. It is filtered and washed with ethanol.

II. Synthesis of 3-(2,2-diphosphono-2-hydroxyethyl)-1,1-dimethyl piperidine iodide.

Using virtually the same technique described in Example II, part II, above, salt monolatry /1-hydroxy-2-(3-piperidinyl)ethylidene/bis(phosphorylate) turn 3-(2,2-diphosphono-2-hydroxyethyl)-1,1-dimethylpiperidin iodide.

Example 13

Synthesis of 3-(2-carboxy-2-phosphonate)-1-methylpyridin chloride

< / BR>
The above compound is prepared and synthesized as described here below.

I. Synthesis of trimethyl-2-phosphono-3-(3-pyridyl)propanoate.

A solution is prepared by adding 2.00 g (0,050 M) NaH (60% in mineral oil) slowly to a solution of 8.09 ml (0,050 M) of trimethyl phosphonoacetate in 50 ml of anhydrous DMSO to minimize minimarathon environment in the glass, kiln dried in nitrogen atmosphere).

To a mixture of to 8.20 g (50 M) 3-picolyl chloride hydrochloride in 50 ml of anhydrous dimethyl sulfoxide in a nitrogen atmosphere slowly added (over 5 minutes, to reduce foaming) 2.0 g (50 M) NaH (60% in mineral oil). The reaction mixture was stirred for 75 minutes. During the 40 minute period to this reaction mixture is added to the Solution A. the resulting solution was stirred at ambient temperature for 18 hours. The solvent is removed in vacuo to obtain a viscous red-brown material. This material is extracted in 100 ml of a saturated water solution of NH4Cl and extracted 3 100 ml of methylene chloride. The extracts are combined, dried MgSO4and evaporated to dryness in vacuo to obtain 11.3 g of oil. Mineral oil is extracted from this 3 100 ml of hexane and obtained 9.6 g of red-brown material. He cleared podgotovilos HPLC using acetone as eluent to silikagelevye column. Regenerated 2.5 g of the desired product.

II. Synthesis of 3-(2-carboxy-2-phosphonoethyl)-1-methylpyridin chloride.

A solution of 2.5 g (0,009 M) trimethyl 2-phosphono-3-(3-pyridyl) propanoate and 2.25 ml (.020 M) of methyl iodide in 5 ml of dry tetrahydrofuran is poured and the resin washed with 2 10 ml dry ether.

Ester groups hydrolyzed by dissolving the resin in 25 ml of 6N HCl and phlegmasia the resulting solution for 3 hours. The solution is cooled and extracted 3 8 ml CHCl3who removed part I2. The aqueous layer was evaporated in vacuum to obtain a brown resin. It dissolves in 20 to 25 ml of hot absolute ethanol. The solution is cooled and added 10 - 15 ml of dry acetone. After a 14 hour mixing at ambient temperature, a solid substance. It is filtered and washed with acetone and then ether to obtain 2.0 g solid pale yellow color, which is further purified by mixing with 10 ml of anhydrous ethanol for 2.5 hours, then filtered and washed with 3 ml of ethanol, and then 10 ml of acetone and ether. So get 1,82 g (71% yield) of 3-(2-carboxy-2-phosphonoethyl)-1-methylpyridin chloride.

Example 14

Synthesis of salts of 3-(3,3-diphosphonates)-1-hexadecylpyridinium disodium salt

< / BR>
I. Synthesis of tetraethyl ester /3-2-pyridinyl/propylidene/bis(phosphorylate).

Finality (79 ml, 1.96 M in ether, 0,155 M) in 200 ml of dry benzene is cooled to 0oC and added dropwise in 50 ml of benzene is added 2-picoline (12.3 g, 0,132 M). The reaction is stirred 3 hours at room temperature and stirred over night. Cooling is added 1N HCl (132 ml) and the layers separated. the pH of the aqueous phase is brought to 10 and made several extraction with ethyl acetate. The United extracts are dried over sodium sulfate, then filtered and evaporated to obtain to 47.2 g of tetraethyl ester /3-2-pyridinyl/propylidene/bis(phosphorylate). This crude product is purified by parts to use instant chromatography with 7% MeOH/CHCl3. For example, to 13.2 g of the product chromatographically two parts to obtain 8.2 g of the pure product.

II. Synthesis of 3-(3,3-diphosphonates)-1-hexadecylpyridinium iodide, tetraethyl ester.

Tetraethyl bis(phosphonate), obtained as described in part I, (8,2 g, 20,9 mm) palometa in 50 ml of acetonitrile. Added iodohexane (22 g, 62.5 mm) and the mixture heated under reflux for 3 days. The solvent is evaporated and the residue is placed on a dry 10-inch layer of silica gel, which is then eluted with 5% MeOH/CHCl3. The excess of iodohexane eluted in the first three fractions. The product is collected in several fractions. The first three fractions are connected to get 5.3 g of the product, and the following 8 factions unite to get to 7.8 g of the product that the overall gain of 13.1 g

III. Synthesis of 3-(3,3-d is with reflux in 75 ml of 6N HCl for 2 days. The reaction mixture is cooled and extracted with ethyl acetate. The aqueous phase is evaporated, methanol is added and the solution again evaporated to obtain 5.4 g of the product. Added 1N sodium hydroxide 917 ml) and the pH is brought to 7. The solution is dried by freezing and obtain 5.6 g of 3-(3,3-diphosphonates)-1-hexadecylpyridinium disodium salt (79%).

Example 15

Synthesis of (7-diphosphohydrolase)-2-methyl-2-pyridine iodide

< / BR>
I. Synthesis of N-(2,2-diatexite)-N-/(3-methoxyphenyl)methyl/-4-methylbenzenesulfonamide.

m-anisaldehyde (112 g, 0,82 M) and aminoacetaldehyde diethyl acetal (115 g 0,86 mm) in benzene (2.6 liters) are heated under reflux in nitrogen atmosphere for 3 hours. Then concentration under reduced pressure removed approximately 1.8 liters of benzene. The remaining solution is placed in a hydrogenation reactor Parra and hydrogenperoxide at room temperature until, until the capture of theoretical amount of hydrogen (56 lb). Then the solution is filtered through celite and the filtrate concentrated under reduced pressure. The oil obtained is dissolved in pyridine (1 l), and thereto is added dropwise p-methoxybenzoyl sulfonyl chloride (172 g, 0.90 M) in pyridine (600 ml). The reaction mixture was premesis edanww water and stirred at 0oC for 1 hour. The aqueous mixture is extracted with diethyl ether (6 500 ml). The combined organic extracts are washed with saturated aqueous NaCl, dried over magnesium sulfate, filtered and concentrated under reduced pressure to obtain the product (312 g) as a yellow oil (yield 93%).

II. Synthesis of 7-methoxyethylamine

In a two-liter flask with a round bottom, equipped with a magnetic stirrer, condenser and inlet for nitrogen is added (75 g, 0,184 M) N-(2,2-diatexite)-N-/(3-methoxyphenyl)methyl/-4-methyl benzosulfimide, 1.0 l of dioxane and 200 ml of 6N HCl. This suspension is stirred and heated under reflux in nitrogen for 18 hours. Then the reaction solution is slowly poured into 1 l of H2O and stirred for another 30 minutes, then extracted with ether (2 500 ml). the pH of the aqueous layer is brought to 8 with ammonium hydroxide. The product is extracted with dichloromethane. The combined organic extracts are dried over MgSO4, filtered and evaporated to obtain 30 g of oil. The crude product is purified by chromatography with 12.0% acetone in dichloromethane to obtain the product (19.7 g) with a yield of 67%.

III. Synthesis of 7-hydroxyisoquinoline.

In a two-liter three-neck flask with a round bottom, equipped with a mage is Tana. This solution is stirred and cooled to -75oC dry bath of ice/acetone, and maintaining the temperature of -75oC is added dropwise 628 ml (0,628 M) 1,0 M tribromide boron in dichloromethane. After that, the suspension is stirred 18 hours with a slow increase in temperature to room. The reaction suspension is poured into 1 l of ice water and stirred for 1 hour. The layers are separated and then the aqueous layer was brought to acidic to neutral (pH 7) by 1N NaOH. In the sediment fall yellow crystals, they hotelreviews, dried by air and obtain 14.5 g of a yellow solid with a yield of 81%.

IV. Synthesis of 7-hydroxy-8-nitroisoquinoline.

300 l flask with a round bottom is added 14.5 g (0.1 M) 7-hydroxyisoquinoline and 100 ml of heated tetramethylsilane. The brown suspension is stirred and parts added to 18.6 g (0,14 M) tetrafluoroborate Nitron when cooled (ice bath). The reaction mixture was stirred for 3 hours. Then the reaction is extinguished 100 ml of methanol, evaporated to dryness and double pounded in ether to precipitate the substance of dark color (19,0 g, 100%).

V. Synthesis of hydrochloric salt of 8-amino-7-hydroxyisoquinoline.

The hydrogenation reactor I is I as long while stops the capture of hydrogen (40 lb/in2/2.8 kg/cm2). Next, the reaction mixture is filtered through celite and the filtrate concentrated under reduced pressure. The residue is dissolved in methanol. Adding essential-CHI brings the product in the form of a hydrochloric salt (19 g) with a yield of 65%.

VI. Synthesis of 7-hydroxy-8-ethanolinduced chloride.

To the HCl salt of 8-amino-7-hydroxyisoquinoline (4.94 g, 0.025 M) in ethanolic HCl at 0oC is added dropwise a solution of tert-butylnitrite 917,46 ml), ethanol (790 ml) and water (58 ml). After complete addition the solution is stirred for another 2 hours at 0oC. the Product precipitates from the reaction mixture by the addition of datingwho ether (2 l). The product is collected by filtration and washed with diethyl ether to obtain the desired product (2.6 mg) with a yield of 50%.

VII. Synthesis of 2-pyridine-7-carboxylic acid, methyl ester.

7-hydroxy-8-ethanolinduced chloride (0.50 g, 2.4 mm) and sodium bicarbonate (302 mg, 3.6 mm) in anhydrous methanol (650 ml) irradiated by the lamp sunlight 275 watts at 0oC 3 hours. The crude residue is dissolved in water and the product extracted with methylene chloride. The combined organic extracts are dried over magnesium sulfate, filter, the color (210 mg) with a yield of 50%.

VIII. Synthesis of dihydro-2-pyridine-7-carboxylic acid, methyl ester.

A vessel for hydrogenization loaded methyl ether 2-pyridine-7-carboxylic acid (0.8 g, 4,57 mm), 5% Pd on carbon (2.0 g, wet) and methanol (125 ml). Suspension hydrogenesised (40 lb/in2/2.8 kg/cm2as long as you do not stop the absorption of hydrogen. The reaction mixture is filtered through celite and then evaporated to dryness to obtain the product (430 mg) with a yield of 53%.

IX. Synthesis of dihydro-2-pyridine-7-carboxylic acid, HCl salt.

Methyl ester of dihydro-2-pyridine-7-carboxylic acid (0,53 g, 3.0 M) is heated at 58oC in 1N NaOH (3.1 ml) and methanol (30 ml) for 2.5 hours. The solution is evaporated to dryness in vacuum and the obtained residue was stirred in ethanolic HCl to precipitate the product. The desired product is collected by filtration.

X. Synthesis /1-hydroxy(dihydro-2-pyridin-7-yl-methylene/ bis(phosphorylate).

To trichloride phosphorus (1.19 g, 8,63 mm) is added to a suspension of dihydro-2-pyridine-7-carboxylic acid, HCl salt (0.54 g, 2,88 mm), phosphorous acid (708 mg, 8,63 mm) and chlorobenzene (10 ml). The reaction mixture was stirred and heated at 105oC 4 hours. The mixture is then cooled to room temperain refrigerator. Then the reaction mixture is concentrated under reduced pressure and pounded in acetone to obtain the desired product (107 mg) with good purity.

XI. Synthesis of (7-diphosphohydrolase)-2-methyl-2-pyridine iodide.

Using virtually the same technique as described in Example 3, part II, above, /1-hydroxy(dihydro-2-pyridin-7-yl)methylene/bis(phosphorylate) is converted to /7-diphosphohydrolase/-2-methyl-2-pyridine iodide.

Example 16

Synthesis of 3-(2,2-diphosphonates)-N, N, N-trimethyl-benzolamide hydroxide, inner salt

< / BR>
3-(2,2-diphosphonates)-phenyl-trimethyl-ammonium salt is synthesized as described below.

I. Synthesis of tetraethyl ester 2-(3-nitrophenylamino)bis(phosphorylate).

In a flame dried flask with a round bottom with a volume of 50 ml under nitrogen atmosphere was added 1.12 g of potassium hydride (35% in oil, 10,59 mm), which were first rinsed with pentane. Added dry toluene (10 ml) and the suspension cooled to 0oC. is added dropwise tetraethyl methylene of diphosphonate (of 3.31 g, 9,63 mm), and when the addition is completed, the mixture was stirred at room temperature for 1 hour. 3-nitrobenzyl bromide (2,09 g, 9,63 mm) dissolved in 10 ml of toluene in a 100 ml flask and dobavilsya through celite and then concentrated under reduced pressure. The crude residue is purified preparatory liquid chromatography to obtain the tetraethyl ester of 2-(3-nitrophenylamino)bis(phosphorylate).

II. Synthesis of 2-(3-aminophenylacetate)bis(phosphorylate).

Tetraethyl ester 2-(3-nitrophenylamino)bis(phosphorylate) was dissolved in ethanol (50 ml) and to this is added 10% palladium on carbon (0.50 g). The reaction mixture is shaken under pressure (40 f/d2in the hydrogenation vessel Parra 2 hours until complete absorption of hydrogen. The reaction mixture is filtered through celite. Celite is washed with fresh ethanol and then water wash filtrate and ethanol are combined and concentrated under reduced pressure. The residue is dissolved in chloroform and then the product of the joining of amino isolated as HCl salt extraction in 6N HCl. The aqueous layer containing the amino product in the form of tetraethyl ester is heated under reflux for 12 hours under nitrogen atmosphere. The reaction mixture is cooled, treated with charcoal and then filtered through celite. The filtrate is concentrated under reduced pressure to obtain b phosphorylate.

III. Synthesis of salts of 3-(2,2-diphosphonates)-phenyl-trimethyl ammonium.

2-/3-aminophen the'étang and the reaction mixture is heated under reflux in nitrogen atmosphere for 48 hours. The reaction mixture is cooled and concentrated under reduced pressure and the crude residue precrystallizer from ethanol / water to get the salt benzoylamino in a solid white color.

Example 17

Model Schenk

Compounds were evaluated for inhibition of bone resorption and inhibition of mineralization in vivo model system in animals, known in the field of bone metabolism as a Model of Schenk. The General principles of this model are disclosed in Shinoda and other Calcif. Tissue Int. 35, 87 - 99 (1983); and Shenk and other Calcif. Tussue Res. 11, 196 - 214 (1973), included here as a reference.

Materials and methods:

Animals.

Males-suckling rats 17 days of age (30 g) Sprague Dawley (Charles River Breeding Laboratories) were transported with their mothers and placed in a plastic cells with their mothers upon arrival. At the age of 19 days, the rats receiving without limitation, food and water are statistically divided into control group and groups for treatment, containing seven animals per group. In the first and again on the seventh day all the animals were made intraperitoneal injection ("1P") calcein (1% solution in 0.9% saline; with a dosage of 0.2 ml/100 g body weight). On the fourth day all the animals were made WB injection guy who ciruit mineralization of bone and cartilage.

Dose solutions and methods of dispensing.

All solutions for subcutaneous injections are prepared in 0.9% normal saline solution and brought to a pH of 7.4 using NAOH and/or HCl. The calculation of the dosing solution is the conversion of the mass of powder (based on molecular weight, hydration) of the active material in mg/ml body in mg P/kg Concentration is based on the dosage of 0.2 ml/100 g body weight. All connections injected with a dosage of 0.01, 0.1, 1.0, and 10.0 mg P/day for 7 days. Connection demonstrous activity at 0.01 mg P/kg/day was then tested in a logarithmic decrease to 0.001 mg P/kg/day. Dose adjustment depending on changes of body weight were made daily.

The autopsy, fabric processing and histomorphometry

On the 8th day after the start of dosing, all animals were euthanized WB overdose pentobarbital. The tibia was separated and placed in 70% ethyl alcohol. One tibia was degidrirovanii in purified solutions of ethanol and immersed in methyl methacrylate, as described by Schenk, Methods of Calcified Tissue Preparation/G. R. Dickson, Editor, Elsevier Science Publ., The NetherLands, 1984, the disclosure of which is incorporated here by reference in full. The tibial bone was divided longitudinally by megafish. Samples met Image/Cambridge Instruments, Inc./ using both light and ultraviolet light. Content metaphyses trabecular bone were measured in the area between the label fluorescence and plate growth was expressed as a percentage of the total area (bone + marrow). The width of the epiphyseal plate growth was obtained as the average value of 10 measurements at the same distance across the slice.

Statistical evaluation of data was done using parametric and nonparametric analysis of variance and the sum Wilcoxon test to determine statistically significant effect in comparison with the control animals. The Schenk model gives the data for inhibition of bone resorption in vivo by using these compounds.

Example 18

Model-driven arthritis

There are many models of arthritis in animals, among them arthritis, caused by the stimulator using Mycobacterium butyricum. This model is in many ways mimics rheumatoid arthritis in humans (swelling associated with the penetration of cells and pannus in sustavnoi space, bone resorption and release of hemotoxicity factors and liposomal components in sustavnoi space) /1,2/. A number of preventive and therapeutic IP arthritis /5, 6/.

1. Pearson, C., Wood F. (1959), Studies of Polyarthritis and Other Lesions Induced by Injection of Mycobacterial Adjuvant. 1. General Clinical and Pathological Characteristics and Some Modifying Factors, Arth. Rheum., 2 : 440 - 459.

2. Blackman, A., Burns, J. W., Framer, J. B., Radziwonik, H., Westwick, J. (1977), An X-ray Analysis of Adjuvant Arthritis in the Rat/ The Effect of Prednisolone and Indomethacin, Agents and Actions, 7 : 145 - 151.

3. Winter, C. A., Nuss, G. W. (1966), Treatment of Adjuvant Arthritis in Rats with Anti-inflammatory Drugs, Arth. Rheum., 9 : 394 - 404.

4. Winder, C. V., Lembke, L. A., Stephens, M. D. (1969), Comparative Bioassay of Drugs in Adjuvant-Induced Arthritis in Rats: Flufenamic Acid, Mefenamic Acid, and Phenylbutazone, Arth. Rheum., 12 : 472 - 482.

5. Francis, M. D., Flora, L. King, W. R. (1972), The Effects of Disodium Ethane-1-Hydroxy-1-Diphosphonate on Adjuvant Induced Arthritis in Rats, Calcif. Tiss. Res., 9 : 109 - 121.

6. Flora, L. (1979), Comparative Antiinflammatory and Bone Protective Effects of Two Diphosphonates in Adjuvant Arthritis, Arth. Rheum, 22 : 340 - 346.

Stimulated arthritis is a severe cellulite and synovitis caused by Samatov rats (or Vila Sprague Dawley or Lewis/ disposable hypodermic injection (PC) Mycobacterium butyricum (8 mg/ml) in mineral oil at 0 day. Compounds were desirability once daily or oral (peros), or parenteral (PC) and were tested either preventive (0 days) or therapeutic Protocol (9th or 10th or 14th day). Anti-arthritis efficiency was measured by the reduction of the volume of the paws, loss of body weight, divided into what was aCasa only saline. Treatment can be discontinued and to study the reaction of "flash" (rapid amplification of inflammation), which indicates the ability of a joint to ensure the effectiveness.

Materials and methods

A. Animals.

Used animals were male Lewis rats (LEW). Upon arrival, rats are randomly mixed with the help of the random number generator they were placed in a wire suspended cells. Food and water were given without restrictions throughout the study. Care of animals and their contents were in accordance with state and Federal regulations. Each rat was identified by number on the front side of the cell and on the tail of the animal.

B. the Plan of the experiment.

On the first day, all rats were measured body weight (W) and the volume of the hind legs, using the movement of mercury using a pressure sensor associated with the computer. 0 day arthritis was induced using MFA (Mycobacterium butyricum) (MB) 4.4 mg/kg in oil as follows: rats were anesthesiologis and received once injection MFA subcutaneously at the base of the tail under aseptic conditions.

From this moment on different days, usually twice a week was measured body weight and the volume of the paws. the I and continued daily until the end. For therapeutic Protocol rats were randomly divided into groups of 8 to 10 rats in accordance with their PV on day 10. Dosage started with 10 days and continued daily in the cells of Shoe boxes with soft bedding for up to 10 days.

Solutions for dosing

A. For drugs that are not susceptible to oxidation.

Drugs were weighed on calibrated scales and then mixed with distilled water in a volumetric flask. Then the solution was brought to a pH of 7.4 with 0.1 N NaOH. Then the solution was filtered through a sterile filter of 0.45 mm sterile container for storage. When not used, the solution was stored in the refrigerator.

B. For drugs amenable to oxidation.

Drugs were weighed on kalibrovannix balance and then mixed with deoxygenating water in a volumetric flask. The resulting solution is filtered through a sterile filter of 0.45 mm sterile container. If not using the mother liquor is stored in the refrigerator. Every day a certain amount of solution is taken from the mother liquor in a small dosing Cup and then the pH is brought to 7.4 in accordance with a pre-made calculations. If necessary, you can further dilute mastocytoma connection number based on mg/kg body weight and guzheng final concentration in mg P/kg Dosing volume for the rat was 0.1 mg/100 g body weight subcutaneously under the skin in the groin crease of the animal. Changing sides every other day or 1 ml/200 g BW orally using curved steel metering tube. Adjustment due to change in body weight was done on a daily basis.

C. Radiography, the autopsy and the selection of cloth

After each rat was wordplays 1 ml SocombRvnutribruchinno (WB). Immediately made an x-ray of the whole body using x-ray unit Torrox 120D MA = 5, ISUP = 50 time = 60 sec. On unshielded medical film Kodak. The rear leg of each rat were removed and immersed in 10% buffered formalin together with a piece of liver, kidney, spleen and thymus. Tibia-tarsal joints were decalcifications 4% add, pH 7.4 and standard way was poured into paraffin blocks and stained H + that is part of the organs were subjected to similar processing.

Histological sections were evaluated qualitatively to defeat soft and bone tissue using svetoterapii. Done x-rays for bone resorption (CR) 6 anatomical areas treadle all 4 legs. On reactivated the formation of new bone (RNA) x-rays are graded 0 to 3 days lateral and medial surfaces of the tibia and then 0 - 2 for all the other areas mentioned above with an arbitrary 0 - 44.

D. Statistical analysis

Data analysis the volume of the paw, bone resorption and reactivated the formation of new bone produced using the T-test t-test and one-way analysis of variance Tukeys (SAS) /12/. Differences are considered significant at pH = 0.05 or less.

This model provides in vivo data on the effectiveness of anti-arthritis compounds from the viewpoint of reducing the rarefaction of bone tissue on the feet and reactivated the formation of new bone compared with animals that received saline.

Example 19

Capsules are prepared with the following composition:

Active ingredient:

3-(2,2-diphosphonates)-1-(2-mercaptoethyl) pyridine chloride - 350,0

Fillers:

Lactose - 90,0

Microcrystalline cellulose - 60,0

Magnesium stearate - 1,0

Capsules with the above composition is prepared using traditional methods, as described below.

The active ingredient is mixed with microcrystal otcbuy crusher with screen 80 mesh. The mixture is then again transferred to the mixer with double case with lactose and mixed for another 15 minutes. The resulting mixture is pressed on the piston capsule filling machine.

Any of the compounds prepared according to examples 1 to 13 and example 15, can be entered instead of the active ingredient in the capsule, prepared above.

Example 20

preparation of tablets with the following composition:

Active ingredient: - mg tablet

Salt of 3-(2-hydroxy-2,2-diphosphonates/-1-methylpyridin iodide disodium - 700,00

Fillers:

Lactose (spray dried) - 200,0

Starch (1500) - 100,0

Magnesium stearate - 25,0

Tablets with the specified composition are prepared by traditional methods.

The active ingredient is ground in a ball mill for about 30 minutes. Then powdered active ingredient is mixed in the mixer with dual blade with dried lactose approximately 20 minutes. To the mixture is added to the starch and mixing occurs for another 15 minutes. The mixture is compressed into tablets on a standard tabletirujut press. The active ingredient in vyshepredstavlennyh tablets can be replaced by any of the compounds in examples 1 to 13 and 15.

Example 21

A daily injection for 4 days results in a significant reduction of malignant hypercalcemia in patients with a body weight of approximately 70 kg

Any of the compounds obtained in examples 1 to 16, you can replace the active ingredient in the injection solution prepared above.

Example 22

The following is a suggested composition for toothpaste.

Component wt.%

3-(3,3-diphosphonates)-1-hexadecylpyridinium, salt, disodium - 2,0

Sorbitol - 33,0

Saccharin - 0,46

Silica - 22

NaF - 0,243

Glycerin - 9

NaOH (50% solution) - 0,2

The carbopol - 0,2

Central - 0,6

TiO2- 0,2

Alkyl sulfate sodium - 4

PEG 6 - 3

FDuC Blue#I (1% solution) 0.05 to

Odorant - 1,1

Water

First mechanically mixed TiO2, silica, carbopol and X-resin (Central). This is all solid. In the second stage is dissolved active ingredient (2% pyridine in diphosphonate) in water and the pH is brought to 7. Then dissolve NaF, sorbitol, saccharin, glycerin, PEG 6 and FDuC Blue#I (1% solution) in water mixture. Then add the alkyl sodium sulfate (28% solution), NaOH and finally flavoring to the water mixture. Then added to the solid mixture is thoroughly kneaded pasta (temperature should not prdii and, if necessary, brought to 7.0. This operation is carried out by stirring suspension of 1 : 4 means in the water and check the pH of the pop-up layer.

Example 23

Below is the composition for rinsing the mouth.

Component weight%

3-(3,3-diphosphonates)-1-hexadecylpyridinium, salt, disodium - 0,1

EtOH (200%) - 16,25

Surfactant (Tween 80) - 0,12

Glycerin - 10

Saccharin - 0,06

Odorant - 0,041

FuDC Blue#I (1% solution) - 0,022

FuDC Yellow#5 (1% solution) - 0,018

Benzoic acid - 0,0045

Sodium benzoate - 0,054

Water

First dissolve the active ingredient (for example, from 0.5%) in water and adjusted pH to 7 with NaOH if necessary. Then add EtOH, glycerin, saccharin FuDC Blue#I, FuDC Yell.#5, benzoic acid and Na benzoate. Dissolve the odorant in surfactants and add the resin to the above ingredients. Check the pH and if necessary adjust it.

Example 24

Male Caucasian nationality with a weight of approximately 92 kg at the age of 72 years, occasionally severe pain and swelling in his right knee. After approximately one year of continually increasing discomfort he visits the doctor, who puts a clinical diagnosis of osteoarthritis of the right knee, which is then confirmed by x-ray examination.

The disease continued to worsen and his condition had deteriorated. He returned to her doctor who prescribes pills, prepared as in example 20, twice a day before or after meals for 3 months. After three months of treatment, clinical symptoms of pain and swelling, especially at the long walk, have improved significantly. After 3 months course with dosage is 2 tablets daily treatment was continued with half of the initially prescribed dosage (i.e., one tablet per day) for an indefinite period.

Example 25

A Negro woman with a weight of about 65 kg at the age of 55 years came with complaints of swelling and deformity of finger joints of both hands, there was observed a partial loss of strength and mobility in the fingers and hands. After visual and x-ray examinations and clinical tests, approved by the American Association of rheumatologists (ARA) was diagnosed with rheumatoid arthritis.

After unsuccessful treatment analgesic and anti-inflammatory therapy, her doctor prescribes tablets prepared according to example 20 twice a day for two hours before or after meals for 4 months. After one month of treatment the symptoms of swollen joints decreased significantly and dexterity HC is e for 2 months.

Example 26

A little Spanish girl at the age of 12 years, weighing 37 kg came to the doctor with idiopathic juvenile rheumatoid arthritis. Its symptoms include inflammation of many joints, complicated temperature and pain, indicating rapid and pathological dysfunction of the joints.

Her doctor sends her to the rheumatologist, who immediately prescribes aggressive therapy IV purpose solution, prepared as described in Example 21, within 3 days after a single injection per day via IV 2 hours. After the IV regime physician prescribes tablets of Example 20 for 2 months, during which there is a clear improvement with reduction in pain and improvement in motor abilities. In the next two months the doctor reduces the dose to 3/4 of the original oral dose, prescribing 3 tablets for two days, i.e., one day, 2 tablets, and the second is 1 tablet, and so alternately. At the end of this mode, the dosage again reduced to 1/4 of the initial dose and the purpose of the capsules of Example 19, 1 capsule every day for 4 more months.

Example 27

17-year-old Caucasian boy for the first time in 5 years comes to the dentist for routine inspection. the surfaces of the lower incisors and on the distal surface of the upper molars. When conventional mechanical cleaning could not remove the plaque and stones. The doctor suggested that the patient rinse mouth 15 ml of 0.1% oral solution of 3-(3,3-diphosphonates)-1-hexadecylpyridinium, disodium salt prepared as described in Example 23, within one minute. Plaque and stones easily and painlessly retired mechanical means. After that, the dentist prescribes preventive treatment consisting in cleaning the teeth by means containing 3(3,3-diphosphonates)-1-hexadecylpyridinium, disodium salt prepared according to Example 22. This preventive treatment is daily brushing for 3 minutes this tool for cleaning teeth within 3 months. At the end of this period the problems of education raids and stones from the patient were resolved. The patient is recommended to regularly clean the teeth with normal toothpaste and daily mouth rinsing fluid against the formation of stones and deposits on the teeth, which represents a 0.1% solution of 3-(3,3-diphosphonates)-1-hexadecylpyridinium, disodium salt.

Example 28

60-year-old Negro woman, who suffers from a painful gingivitis, for the first time in 10 years of visiting the dentist. Visual examination reveals a strong education raids and rinse your mouth three times, one minute each time 10 ml of 0.1% solution of 3-(3,3-diphosphonates)-1-hexadecylpyridinium, disodium salt. After the raids and the stones were easily removed effortlessly by mechanical means. After that, the dentist prescribed treatment, consisting in cleaning the teeth twice within one minute daily medium containing 2.0% by weight 3-(3,3-diphosphonates)-1-hexadecylpyridinium, disodium salt. This treatment lasted for 6 months. The doctor then confirmed that the problems of the stones and touches under control and gingivitis improved. The doctor prescribes a daily rinse mouth with 10 ml of 0.1% solution of 3-(3,3-lipospheres)-1-hexadecylpyridinium, disodium salt, and daily cleaning of the teeth with toothpaste containing 2% by weight disodium salt 3-(3,3-lipospheres)-1-hexadecylpyridinium.

Example 29

60-year-old female Caucasian nationality weighing 62 kg experiencing a sharp pain in the back. Her doctor with the help of a radiologist diagnoses crushing vertebrae L1 due to bone loss due to osteoporosis. The patient is prescribed within 3 months of treatment, consisting in the daily dosage of 700 mg tablets prepared according to the procedure described in Example 20. Capsule with 700 mg taken two hours before a meal sludge is which was adopted through day three months. Following 6 months, the doctor prescribes another mode of treatment, a daily intake of 100 mg capsules of Example 19. After that the patient is no longer experiencing back pain. X-rays do not reveal any additional crushing.

Example 30

After the fall of the 75-year-old Oriental woman weighing 53 kg detected hip fracture. She was hospitalized and diagnosed with osteoporosis. Prescribed treatment injections of calcitonin. These injections are very painful and the patient refuses them. The doctor puts her on oral therapy phosphonates. Her twice a day during the month are given pills to 700 mg, prepared according to example 20. Then another two months she daily takes on a tablet, and then another three months, it is assigned 100 mg capsule of Example 19 daily. A subsequent visit to the doctor does not detect a significant decrease in mineral density in the bones of hands, as determined by photoabsorption.

Example 31

85-year-old American, white, weight 65 kg complained to the doctor for severe back pain. An x-ray revealed multiple deficiency of bone tissue in the bodies of the vertebrae due to osteoporosis. The patient is prescribed a two-month treatment regimen is about the methods of Examples 20 and 19 respectively. After two months of this treatment, the dose was reduced to capsules once a day for another 2 months. After x-ray was discovered additional crushing. Another 6 months, the patient received a daily capsule 100 mg At the end of this period a significant reduction in bone density was observed.

1. Containing a Quaternary nitrogen phosphonates of General formula

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

Q is a covalent bond;

Y - N+(R8)2or C(R1)2and, if Y is C(R1)2at least one of R2must be N+(R8)3;

Z - unsaturated, or aromatic monocyclic carbocycle or monocyclic or polycyclic heterocycle containing a heteroatom such as nitrogen;

R is COOH, SO3H, PO3H2or P(O)(OH)R4where R4represents C1- C8-alkyl;

R1represents hydrogen or absent;

R2each represents one or more substituents on Z part, independently selected from the group consisting of hydrogen or N+(R8)3;

R5is selected from the group consisting the Xia group, consisting of substituted or unsubstituted C1- C35-alkyl, or R9SR6or missing;

R9substituted or unsubstituted C1- C8-alkyl,

and their pharmaceutically acceptable salts, useful in the treatment and prevention of abnormal metabolism of calcium and phosphate.

2. Connection on p. 1, characterized in that Z represents a monocyclic heterocycle containing a nitrogen atom, and Y - N+(R8)2.

3. Connection under item 1 or 2, characterized in that Z represents a six-membered heterocyclic ring, preferably pyridine.

4. Connection on p. 1, characterized in that Z is a polycyclic heterocycle containing a nitrogen atom, preferably six-membered ring condensed with a five-membered ring.

5. Connection on p. 1, wherein Z is a monocyclic carbocycle, Y - C(R1)2and at least one of R2- N+(R8)3.

6. Connection on p. 1, in which R8represents an unsubstituted or substituted alkyl having 10 to 20 carbon atoms.

7. Pharmaceutical composition for treating abnormal metabolism of calcium and phosphate, including ramie Quaternary nitrogen phosphonates under item 1 in an effective amount.

8. Method for the treatment or prevention of diseases associated with abnormal metabolism of calcium and phosphate with the help of medicines, characterized in that as a drug is injected containing Quaternary nitrogen phosphonates under item 1.

9. Oral composition against the formation of plaque and calculus on the teeth, and also against gingivitis, including the active agent and a filler, characterized in that as the current tools it contains contains a Quaternary nitrogen phosphonates under item 6 in an effective amount.

10. A method of treating or preventing the formation of plaque and calculus on the teeth, and also gingivitis through medicines, characterized in that as a drug is injected containing Quaternary nitrogen phosphonates under item 6.

Priority points:

29.05.92 on p. 2;

30.04.93 on PP.1, 3 - 8.

 

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