Phosphonocarboxylate compounds for treating abnormal calcium and phosphate metabolism, the pharmaceutical composition

 

(57) Abstract:

The invention relates to the field of medicine. Pharmaceutical composition containing pharmaceutically acceptable carriers and phosphonocarboxylate or its pharmaceutically acceptable salt having a structure according to formula (I)

< / BR>
where A is selected from the group consisting of hydrogen; halogen; SR1; R2SR1; amino; hydroxy, and substituted or unsubstituted C1- C8alkyl; B stands for NH2etc. or A or B are covalently bound to the C*for education monocyclic or bicyclic ring having the structure

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The proposed compositions have strong bone antiresorptive activity and are useful for the treatment of osteoporosis and arthritis. 4 C. and 7 C.p. f-crystals.

The invention relates to new phosphonocarboxylates connections. Then, the present invention relates to pharmaceutical compositions containing phosphonocarboxylate compounds, and to methods of treatment and prevention of diseases of metabolism in bone tissue, characterized by abnormal calcium and phosphate metabolism through the use of the compounds or pharmaceutical compositions of the present invention. In particular, Dunn is rcrit or osteoarthritis, by using the compounds or pharmaceutical compositions of the present invention.

Many pathological conditions that can affect humans or warm-blooded animals include abnormal calcium and phosphate metabolism. Such States can be divided into two broad categories:

(1) state, which are characterized by anomalous mobilization of calcium and phosphate, leading to total or partial loss of bone, such as osteoporosis and disease Paget (Paget), or excessively high levels of calcium and phosphate in the body fluids, such as hypercalcemia tumor origin. Such States are sometimes referred to here as pathological demineralization of hard tissues;

(2) state, which are caused by or are the result of abnormal deposits of calcium in the body and phosphate, such as arthritis, including rheumatoid arthritis and osteoarthritis. These States are sometimes referred to here as the pathological deposition of salts.

The first category includes the most common metabolic disorder in the bone tissue, osteoporosis; osteoporosis is a condition in which the bone hard tissue is lost disproportionately to the development of new solid fuel is Kani skeleton. Bone marrow and bone cavity become more coagulation of the fibers is reduced and dense bone becomes fragile. Osteoporosis can be divided into postmenopausal, senile, caused by medicines (for example, adrenocorticoids that can occur with steroid therapy), caused by a disease (arthritis or a tumor), and so on; but the manifestations of essentially the same.

Mainly, there are two types of osteoporosis; primary and secondary. Secondary osteoporosis is a result of a separate disease processes or agents. However, approximately 30% of all cases of osteoporosis are the "primary osteoporosis". Such primary osteoporosis includes postmenopausal osteoporosis, osteoporosis from inaction associated with age, osteoporosis (affecting most individuals over the age of 70 - 80 years) and idiopathic osteoporosis, affecting men and women of the middle and younger age.

Some of the subjects suffering from osteoporosis, bone loss is significant, what is causing mechanical damage to the bone structure. For example, women suffering from postmenopausal osteoporosis, often there is the spine).

The mechanism of bone loss in osteoporosis is considered to include an imbalance in the process of bone remodeling". Bone remodeling occurs throughout life, updating the skeleton and supporting bone. Remodeling includes erosion and filling of discrete areas of the surface of the bone, an organized group of cells, called basic multicellular units" or "OME", OME mainly contain osteoclasts and osteoblasts and their cell precursors. In the cycle of remodelirovania bone tissue is resorbed in the areas of "activated" OME by osteoclasts, forming a cavity resorption. These cavities are filled then the bone with osteoblasts.

Usually in adults cycle remodulate leads to a small deficit in bone mass caused by incomplete filling of the cavity resorption. Thus, even in a healthy adult is bone loss associated with age. However, in the case of osteoporosis may be an increase in the number OME, which is activated. This increased activation accelerates remodeling of bone tissue, leading to abnormally high loss of bone tissue.

Although the etiology is not fully understood, which is tion, physical inactivity and estrogen deficiency.

Currently, the treatment of osteoporosis includes mainly the introduction of calcium and estrogen.

In addition to osteoporosis bone loss may be the result of arthritis, including rheumatoid arthritis and osteoarthritis. Rheumatoid arthritis is a chronic systemic sustavnoi inflammatory disease involving destruction of cartilage, ligaments, tendons and bone tissue and decreasing the viscosity, and other changes in synovial fluid. Symptoms of rheumatoid arthritis include weakening of the body, fatigue, local pain, stiffness and swelling and deformation of the joints of the body. Rheumatoid arthritis is most common in women in the fourth to sixth decade of life.

Osteoarthritis is a non-inflammatory violation of the joints, characterized by damage to and erosion of articular cartilage and formation of new bone on the surface of the joint. With the development of osteoarthritis, the surface of articular cartilage is torn and worn out particles gain access to the synovial fluid, which when handling stimulates phagocytosis by cells of the macrophage. Thus, it may be called will pospolite the Noah fabric on the finger joints and stiffness when waking from sleep and painful movements.

It was suggested various derivatives of polyphosphoric acid for use in the treatment and prevention of diseases, including abnormal metabolism of calcium and phosphate. For example, different sources, all incorporated herein as references, describe compounds containing polyphosphonate, in particular, bisphosphonates, such as ethane-1-hydroxy-1,1-diphosphorous acid (EGDF"), and their use for the inhibition of abnormal deposits of salts and mobilization and phosphate in the tissue of animals: U.S. patent 3683080, published on August 8, 1972, and U.S. patent 4230700, published October 28, 1980, both Francis and U.S. patent 4868164, Ebetino, published 19 September 1989. Many other sources describe substituted phosphonic acid used for the treatment of osteoporosis and/or arthritis, and is included here as a reference: U.S. patent 5071840, Ebetino et al., published December 10, 1991, U.S. patent 4868164, Ebetino, published on September 19, 1989; U.S. patent 5104863, Benedict et al. published on April 14, 1992; U.S. patent 4267108. Blum et al., published may 12, 1981; U.S. patent 4746654, Breliere et al., published on may 24, 1988; U.S. patent 4876247, Barbier et al., published on October 24, 1989; European patent publication N 100718, Brelier S. A., published February 15, 1984; European patent publication N na July 2, 1986; European patent publication N 289553, Ebetino, published on January 11, 1989; U.S. patent 4754993, Bosies et al., published July 3, 1990; U.S. patent 4971958, Bosies et al., published November 20, 1990; WO 90/12017, Dunn et al. published October 18, 1990; WO 91/10646, Joussefyen, R., et al., published July 25, 1991; AU-A-26738/88, Taeggi, K. A., published June 15, 1989; AU-A-45467/89, Giba-Gligy, published may 31, 1990. A limited number phosphonocarboxylates groups described in the literature, such as the US 4939131, 1990. However none of the sources does not involve the use phosphonocarboxylate compounds of the present invention, useful for the prevention and treatment of bone metabolism.

It was unexpectedly found that the compounds of the present invention, having phosphonocarboxylate group can have a strong bone antiresorptive activity and usefulness for the treatment of osteoporosis and arthritis. Moreover, these compounds have low affinity for bone tissue compared with bisphosphonates. This reduced tool for bone tissue can reduce the side effects associated mainly with high affinity to bone bifosfonatami. These side effects include inhibition of bone formation and inhibition of chastity nitrogen radical. These compounds exhibit unusual properties solubility. Thus, containing a Quaternary nitrogen phosphonocarboxylate compounds of the present invention can more easily absorbed with oral administration. The increase in absorption with oral administration can improve therapeutic effect at lower doses. Lower doses are usually preferred because of reduced unwanted side effects.

Therefore, an object of the present invention is a new and important class of compounds, which are powerful inhibitors of bone resorption, as well as agents useful in the treatment of osteoporosis, and anti-arthritis agents, useful in the treatment of arthritis, especially osteoarthritis and rheumatoid arthritis. Further object of the present invention are pharmaceutical compositions used in the treatment and prevention of abnormal calcium and phosphate metabolism. In addition, an object of the present invention is a method for the treatment and prevention of diseases characterized by abnormal calcium and phosphate metabolism in humans and other mammals.

These and other objects of the invention will become clear from the presented children's songs, contains a safe and effective amount of phosphonocarboxylate or its pharmaceutically acceptable salt having a structure according to formula (I)

< / BR>
where

(A) (1) A is selected from the group consisting of hydrogen; halogen; SR1; R2SR1; amino; hydroxy; substituted or unsubstituted C1- C8alkyl;

(2) B denotes

(a) NH2;

(b) saturated or unsaturated C1- C15alkyl chain substituted by one or more substituents selected from the group consisting of-R3N(R4)2; -R3[-N(R5)3]+; -R3N(R4)C(O)R4; -R3N(R4)C(S)R4; -R3N(R4)C(N)R4and R3C(O)N(R4)2,

(c) substituted or unsubstituted, saturated or unsaturated heteroalkyl chain containing from 2 to 15 atoms in the chain, where one or more of these atoms is nitrogen;

(d) substituted or unsubstituted heteroalkyl chain containing from 2 to 15 atoms in the chain, where one or more of these atoms selected from S and O; and where this heteroalkyl chain substituted by one or more substituents selected from the group consisting of-R3N(R4)2; -R3[-N(R5)3]+; -R3 or

(e) R6-L-, where

(i) L is absent or selected from the group consisting of N; -N(R5)+3; S; O; substituted or unsubstituted, saturated or unsaturated C1- C15the alkyl chain; and substituted or unsubstituted, saturated or unsaturated heteroalkyl chain containing from 2 to 15 atoms in the chain, where one or more of these atoms selected from S and O, and

(ii) R6selected from the group containing saturated monocyclic or polycyclic carbocyclic nucleus; unsaturated monocyclic or polycyclic carbocyclic nucleus; saturated monocyclic or polycyclic heterocyclic nucleus; and unsaturated monocyclic or polycyclic heterocyclic nucleus; R6may be substituted by one or more substituents independently selected from the group consisting of hydrogen; R3SR1; substituted or unsubstituted C1- C8alkyl; R3OR4; -R3CO2R4; -R3O2CR4; -R3N(R4)2; -R3[-N(R5)3] +; -R3N(R4)C(O)R4; -R3N(R4)C(S)R4; -R3N(R4)C(N)R4; -R3C(O)N(R4)2; halogen; -R3C(O)R4; Ari is containing hydrogen, -C(O)R7; -C(S)R7; -C(O)N(R7)2; -C(O)OR7; -C(S)N(R7)2; and-C(S)OR7; where R7is hydrogen or a saturated or unsaturated C1- C8by alkyl;

(b) R2is a saturated or unsaturated C1- C8by alkyl;

(c) R3absent or selected from the group consisting of saturated or unsaturated C1- C8alkyl;

(d) R4independently selected from the group consisting of hydrogen; saturated or unsaturated C1- C8alkyl; and R2SR1;

(f) R5independently selected from the group consisting of saturated or unsaturated C1- C15alkyl; substituted or unsubstituted phenyl; benzyl; and R2SR1;

or (B) A and B are covalently bound to the C*for education monocyclic or bicyclic ring having the following structure:

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where

(1) W denotes a substituted or unsubstituted, saturated or unsaturated carbocyclic ring containing C*X and X', with the specified carbocyclic ring has from 3 to 6 carbon atoms; or substituted or unsubstituted, saturated or unsaturated heterocyclic ring containing C*X and X', with the specified gets the N, O or S;

(2) V is absent or represents substituted or unsubstituted, saturated or unsaturated carbocyclic ring containing X and X', with the specified carbocyclic ring has from 3 to 8 carbon atoms; or substituted or unsubstituted, saturated or unsaturated heterocyclic ring containing X and X', with the specified heterocyclic ring has from 3 to 8 atoms, where one or more of these ring atoms is N, O or S, and

(3) X and X' independently denote N or C; except that neither V nor W are nitrogen-containing heterocycle, when at least one of V or W is substituted by one or more substituents selected from the group consisting of-R3N(R4)2; -R3[-N(R5)3]+; -R3N(R4)C(O)R4; -R3N(R4)C(S)R4;

-R3N(R4)C(N)R4and R3C(O)N(R4)2.

The invention relates further to phosphonocarboxylate compounds and their pharmaceutically acceptable salts. The new compounds of the present invention are further defined in accordance with formula (I) as containing A selected from hydrogen, halogen, SR1, R2SR1, amino, hydroxy or samemanner the holding group or structureas group. When B is other than pericystectomy group, Quaternary nitrogen-containing group or structuresa group A selected from halogen, SR1, R2SR1, amino or hydroxy.

Finally, the present invention relates to methods of treatment and prevention of conditions characterized by abnormal calcium and phosphate metabolism in humans and other mammals. These methods include the introduction of a human or other mammal in need of such treatment a safe and effective amount of the compounds or compositions of the present invention.

Detailed description of the invention.

Pharmaceutical compositions containing phosphonocarboxylate Connection

The compositions of the present invention contain phosphonocarboxylate or its pharmaceutically acceptable salt. The methods of the present invention include the introduction of phosphonocarboxylate or compositions containing phosphonocarboxylate. The compounds used in the compositions and methods of the present invention have a structure according to formula (I)

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where

(A)(1) A is selected from the group consisting of hydrogen; halogen; SR1; R2SR1; amino; hydroxy; and substituted sennou C1- C15alkyl chain substituted by one or more substituents selected from the group consisting of-R3N(R4)2; -R3[-N(R5)3]+; -R3N(R4)C(O)R4; -R3N(R4)C(S)R4; -R3N(R4)C(N)R4and R3C(O)N(R4)2;

(c) substituted or unsubstituted, saturated or unsaturated heteroalkyl chain containing from 2 to 15 atoms in the chain, where one or more of these atoms is nitrogen;

(d) substituted or unsubstituted, saturated or unsaturated heteroalkyl chain containing from 2 to 15 atoms in the chain, where one or more of these atoms selected from S and O, and where specified heteroalkyl chain substituted by one or more substituents selected from the group consisting of-R3N(R4)2; -R3[-N(R5)3]+; -R3N(R4)C(O)R4; -R3N(R4)C(S)R4; -R3N(R4)C(N)R4; and R3C(O)N(R4)2; or

(e) R6-L-, where

(i) L is absent or selected from the group consisting of N; -N(R5)3+; S; O; substituted or unsubstituted, saturated or unsaturated C1- C15the alkyl chain; and substituted or unsubstituted, saturated or nenas is from S and O; and

(ii) R6selected from the group containing saturated monocyclic or polycyclic carbocyclic nucleus; unsaturated monocyclic or polycyclic carbocyclic nucleus; saturated monocyclic or polycyclic heterocyclic nucleus; and unsaturated monocyclic or polycyclic heterocyclic nucleus; R6may be substituted by one or more substituents independently selected from the group consisting of hydrogen; R3SR1; substituted or unsubstituted C1- C8alkyl; R3OR4; -R3CO2R4; -R3O2CR4; -R3N(R4)2; -R3[-N(R5)3]+; -P3N(R4)C(O)R4; -R3N(R4)C(S)R4; -RN(R4)C(N)R4; -R3C(O)N(R4)2; halogen; -R3C(O)R4; arylalkyl; nitro, substituted or unsubstituted aryl; and hydroxy; and

(3)(a) R1independently selected from the group consisting of hydrogen, -C(O)R7; -C(S)R7; -C(O)N(R7)2; -C(O)OR7; -C(S)N(R7)2; and-C(S)OR7; where R7is hydrogen or a saturated or unsaturated C1-C8by alkyl;

(b) R2is a saturated or unsaturated C1-C8-C8alkyl;

(d) R4independently selected from the group consisting of hydrogen; saturated or unsaturated C1-C8alkyl; and R2SR1;

(f) R5independently selected from the group consisting of saturated or unsaturated C1-C15alkyl; substituted or unsubstituted phenyl; benzyl; and R2SR1; or

(B) A and B are covalently bound to the C*for education monocyclic or bicyclic ring having the following structure:

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where

(I) W denotes a substituted or nezlesine, saturated or unsaturated carbocyclic ring containing C*X and X', with the specified carbocyclic ring has from 3 to 6 carbon atoms; or substituted or unsubstituted, saturated or unsaturated heterocyclic ring containing C*X and X', with the specified heterocyclic ring has from 4 to 6 atoms, where one or more of these ring atoms is N, O or S;

(2) V is absent or represents substituted or unsubstituted, saturated or unsaturated carbocyclic ring containing X and X', with the specified carbocyclic ring has from 3 to 8 carbon atoms; or substituted or unsubstituted, nasishennie only from 3 to 8 atoms, where one or more of these ring atoms is N, O or S, and

(3) X and X' independently denote N or C; except that neither V nor W are nitrogen-containing heterocycle, when at least one of V or W is substituted by one or more substituents selected from the group consisting of-R3N(R4)2; -R3[-N(R5)3]+; -R3N(R4)C(O)R4; -R3N(R4)C(S)R4;

-R3N(R4)C(N)R4; and R3C(O)N(R4)2.

Designation and use of terms.

The following lists identify and use terms used here.

"Heteroatom" means an atom of nitrogen, sulfur or oxygen. Group containing one or more heteroatoms, may contain heteroatoms. "Alkyl" means unsubstituted or substituted, straight or branched, saturated or unsaturated hydrocarbon chain, where the specified hydrocarbon chain may be saturated, having from 1 to 15 carbon atoms, and preferably, unless otherwise stated, from 1 to 4 carbon atoms; where the specified hydrocarbon chain may be unsaturated, having from 2 to 8 carbon atoms, and preferably, unless inog is hydrogen unsaturated chain, having at least one olefinic double bond, and the alkyl unsaturated hydrocarbon chain, having at least one triple bond. Preferred alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl and butyl.

"Heteroalkyl" means unsubstituted or substituted, saturated or unsaturated, straight or branched heteroalkyl chain, where the chain has from 2 to 15, preferably from 2 to 8 members, and contains at least one carbon atom and at least one heteroatom. The term "heteroalkyl", as used here, includes alkeneamine heteroalkyl circuit having at least one olefinic double bond, and alkeneamine heteroalkyl unsaturated chain with at least one triple bond. "Carbocyclic ring" or "carbocycle", as used here, implies unsubstituted or substituted, saturated, unsaturated or aromatic hydrocarbon ring. Carbocycle can be monocyclic or polycyclic. Monocyclic rings usually contain from 3 to 8 atoms, preferably from 5 to 7 (or 8) atoms. Polycyclic ring having two rings contain from 6 to 16, preferably from 10 to 12, ptx2">

"Heterocyclic ring" or "heterocycle", as used here, implies unsubstituted or substituted, saturated, unsaturated or aromatic ring containing 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, preferably from 5 to 7 atoms. Polycyclic ring system having two rings, usually contain from 6 to 16, preferably from 10 to 12 atoms. Polycyclic ring system having three rings usually contain from 13 to 17, preferably from 14 to 15 atoms. If not stated otherwise, the heteroatom may be independently selected from nitrogen, sulfur and oxygen. Unsaturated non-aromatic heterocycles include, but are not limited to, substituted or unsubstituted thiophene, substituted or unsubstituted oxadiazole, substituted or unsubstituted Pirani, and substituted or unsubstituted furans.

"Aryl" means an aromatic carbocyclic ring. Preferred aryl groups include, but are not limited to, phenyl, tolyl, xylyl, isopropylphenyl and naphthyl.

"Heteroaryl" means aromatic heteros is l, pyrrolyl, pyridinyl, pyrazinyl, oxazolyl, thiazolyl, chinoline, pyrimidinyl and tetrazolyl.

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

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

"Aminoalkyl" means a hydrocarbon chain (e.g., alkyl), substituted amino group (for example, NH-alkyl-), such as aminomethylated.

"Alkylamino" means an amino group having one or two alkyl substituents (for example, -N-alkyl), such as dimela (for example, -N-alkenyl).

"Alkylamino" means an amino group having one or two alkyl substituents (for example, -N-quinil).

"Alkylamino" means aminogroup having from one to two alkyl substituents (for example, -N-alkyl).

"Arylalkyl" means alkyl group, substituted aryl group. Preferred arylalkyl groups include benzyl or phenylethyl.

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

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

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

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

"Acylamino" means an amino group, a substituted acyl substituent (for example, N-acyl); for example, -NH-C(=O)-alkyl.

"Halo", "halogen" or "halogen" means chlorine atom, bromine, fluorine or iodine. Chlorine, bromine and fluorine are the emer, "lower alkyl means hydrocarbon chain containing, unless otherwise stated, from 1 to 6, preferably from 1 to 4, carbon atoms.

As defined here, the term "titlesonly" (SR1or R2SR1include thiols [-SH] , where R1=H; thioethers [-SC(O)R7], where R1=C(O)R7; dayevery [-SC(S)R7] , where R1= C(S)R7; THIOCARBAMATE [-SC(O)N(R7)2], where R1=C(O)N(R7)2; dithiocarbamate [-SC(S)N(R7)2] where R1=C(S)N(R7)2; thiocarbonate [-SC(O)OR7], where R1= C(O)OR7and dithiocarbonate [-SC(S)OR7], where R1=C(S)OR7. R7means hydrogen or C1- C8alkyl. Any of the Vice-SR1may be substituted, R2radical, where R2is substituted or unsubstituted C1- C8the alkyl. Accordingly, additional titlestyle denoted by R2SR1are alkylsilane, alkylthiophene, alkyldimethyl, allylcarbamate, alkyldiethanolamine, alkyldithiophosphate, alkyldiethanolamine and alkyldithiophosphate.

The term - phosphonocarboxylate", as defined here, refers to compounds that have the phosphonate group (PC3is CI acceptable salt implies cationic salt, formed at any acidic (e.g., carboxyl) group, or an anionic salt formed at any basic (e.g., amino) group. Many such salts are known in the art, as described in international patent publication 87/05297, Johnston et al., published September 11, 1987, incorporated herein by reference. Preferred cationic salts include alkali metal salts (such as sodium or potassium), and salts of alkaline earth metals (such as magnesium or calcium). Preferred anionic salts include halides (such as chloride), acetate and phosphate salts.

"Biohydrology broadcast" means broadcast phosphonocarboxylate compounds, which does not prevent the manifestation of therapeutic activity of compounds or which easily undergoes metabolism in humans or other mammals. Experts know many such esters, as described in international patent publication 87/05297, Johnston et al., published September 11, 1987, incorporated herein by reference. Such esters include lower alkyl esters, lower aryloxyalkyl esters such as esters of acetoxymethyl, acetoxyethyl, aminocarbonylmethyl, pivaloyloxymethyl and pivaloyloxymethyl), lactonic methoxycarbonylmethylene, ethoxycarbonylmethylene and isopropoxycarbonyloxymethyl esters), alkoxyalkyl esters, esters of choline and acylaminoalkyl esters (such as acetamidomethyl ether).

As indicated above, and is used here, the group of substituents themselves can be substituted. Such substitution may be performed by one or more substituents. These substituents include, but are not limited to, those listed C. Hansch and A. Leo, Substituent constants for Correlation Analysis Chemistry and Biology (1979), incorporated herein by reference. Preferred substituents include, but are not limited to, alkyl, alkenyl, alkoxy, hydroxy, oxo, thioxo (-C(=S)-); amino, aminoalkyl (for example, aminomethyl and etc.), cyano, Quaternary amine, Quaternary aminoalkyl, amidino, medinalis, halogen, carboxy, alkoxyalkyl (for example, carboethoxy and so on ), thio, thiol, aryl, cycloalkyl, heteroaryl, heteroseksualci (for example, piperidinyl, morpholinyl, piperazinil, pyrrolidinyl and so on), imino, thioxo, hydroxyalkyl, aryloxy, arylalkyl, quinil and combinations thereof. Especially preferred substituents include, but are not limited to, amino, aminoalkyl, Quaternary amino, amidino, Quaternary aminoalkyl and medinalis.

In addition, as the COI is defined when using as a Deputy in many positions. As used here, this radical is each time independently selected.

As for the compositions containing the compound of formula (I), where A is A sulfur-containing radical, the preferred radical is SR1where R1preferably hydrogen or acyl. Particularly preferably, when R1is hydrogen. Preferred A radical is amino or hydroxy. Particularly preferably, when A is hydroxy. As noted, and other data the following definitions of A possible preferred types of compounds used in the compositions and methods of the present invention are also preferred implementation of new compounds of the present invention.

When B denotes a saturated or unsaturated C1-C15alkyl, the alkyl chain may be substituted by one or more substituents selected from the group consisting of-R3N(R4)2; -R3[-N(R5)3]+; -R3N(R4)C(O)R4; -R3N(R4)C(S)R4;

-R3N(R4)C(N)R4; and R3C(O)N(R4)2. Preferably the desired Deputy selected from R3N(R4)2; -R3[-N(R5)3preferably, when requested by the Deputy is selected from R3N(R4)2; R3[-N(R5)3]+and R3N(R4)C(O)R4. The alkyl chain may be substituted by one or more substituents selected from the group, not containing or containing-R3SR1; hydrogen; substituted or unsubstituted C1-C8alkyl; R3OR4; -R3CO2R4; -R3O2CR4; halogen; -R3C(O)R4; nitro; hydroxy; substituted or unsubstituted saturated monocyclic or polycyclic carbocyclic rings; substituted or unsubstituted unsaturated monocyclic or polycyclic carbocyclic rings; substituted or unsubstituted saturated monocyclic or polycyclic heterocyclic ring; substituted or unsubstituted unsaturated monocyclic or polycyclic heterocyclic ring. Preferred are C1-C8alkyl chain.

When B denotes a saturated or unsaturated heteroalkyl having from 2 to 15 atoms, where one of these atoms is nitrogen, heteroalkyl the chain may be substituted by one or more substituents selected from the group consisting of-R3SR1; in the 3
O2CR4; -R3N(R4)2; -R3[-N(R5)3] +; -R3N(R4)C(O)R4; -R3N(R4)C(S)R4; -R3N(R4)C(N)R4; -R3C(O)N(R4)2; halogen; -R3C(O)R4; nitro; hydroxy; substituted or unsubstituted saturated monocyclic or polycyclic carbocyclic rings; substituted or unsubstituted unsaturated monocyclic or polycyclic carbocyclic rings; substituted or unsubstituted saturated monocyclic or polycyclic heterocyclic ring; and substituted or unsubstituted unsaturated monocyclic or polycyclic heterocyclic ring. Preferred nitrogen-containing heterocyclic chains have from 2 to 8 atoms in the ring.

When B denotes a saturated or unsaturated heteroalkyl having from 2 to 15 atoms, where one of these atoms is sulfur or oxygen and heteroalkyl chain no nitrogen atom, heteroalkyl the chain may be substituted by one or more substituents selected from the group consisting of-R3N(R4)2; -R3[-N(R5)3]+; -R3N(R4)C(O)R4; -R3N(R4)C(S)R4; -R3N(R4N(R4)2; -R3[-N(R5)3]+; -R3N(R4)C(O)R4; -R3N(R4)C(S)R4or-R3N(R4)C(N)R4. Most preferably, when requested by the Deputy is selected from R3N(R4)2; -R3[-N(R5)3] +; or R3N(R4)C(O)R4. Heteroalkyl chain may also be substituted by one or more substituents selected from the group, not containing or containing-R3SR1; hydrogen; substituted or unsubstituted C1-C8alkyl; R3OR4; -R3CO2R4; -R3O2CR4; halogen; -R3C(O)R4; nitro; hydroxy; substituted or unsubstituted saturated monocyclic or polycyclic carbocyclic rings; substituted or unsubstituted unsaturated monocyclic or polycyclic carbocyclic rings, substituted or unsubstituted saturated monocyclic or unsubstituted unsaturated monocyclic or polycyclic heterocyclic rings are Preferred nitrogen-non-containing heterocyclic chains have from 2 to 8 atoms.

When B is R6- L-, the radical L can be substituted by one or more substituents selected from g>; -R3CO2R4; -R3O2CR4; -R3N(R4)2;

-R3[-N(R5)3]+; -R3N(R4)C(O)R4; -R3N(R4)C(S)R4; -R3N(R4C(N)R4; -R3C(O)N(R4)2; halogen; -R3C(O)R4; nitro; hydroxy; substituted or unsubstituted saturated monocyclic or polycyclic carbocyclic rings; substituted or unsubstituted unsaturated monocyclic or polycyclic carbocyclic rings; substituted or unsubstituted saturated monocyclic or polycyclic heterocyclic ring; and substituted or unsubstituted unsaturated monocyclic or polycyclic heterocyclic ring. The radical L is preferably containing a nitrogen atom (including a Quaternary nitrogen), nitrogen containing heteroalkyl or alkyl. When L is heteroalkyl or alkyl chain, the chain preferably contains from 2 to 3 atoms. The preferred Deputy radical L is hydrogen.

The radical R6may be substituted or unsubstituted saturated monocyclic or polycyclic by carbocycle or heterocycle. When R6is a monocyclic carbocyclic, preferably refers to six-membered nitrogen-containing ring, including pyridine, pyrimidine, piperidine. Such preferred are such six-membered heterocycles, which have a Quaternary nitrogen atom kernel, including pyridine, pyrimidine, piperidine, pyrazole. preferred monocyclic heterocycles also include five-membered nitrogen-containing heterocycles, including imidazole, pyrrole and pyrrolidine. Also preferred are five-membered nitrogen-containing heterocycles having a Quaternary nitrogen atom cores, including imidazoline, pyrrole and pyrrolidine. When R6is political, preferred are heterocyclic compounds having the six-membered ring condensed with another six-membered ring, and having a six-membered ring fused to the five-membered ring. Preferred polycyclic heterocycles also include those which have a Quaternary nitrogen atom. Particularly preferred radicals R6include cycloheptyl or cyclohexyl.

When B is R6-L-, the preferred compounds are those where one or both of R6and L is a nitrogen-containing radical.

The radical R3preferably Atsuta the nitrogen atom, attached to three carbon-containing radicals. The radical R5substituted on carbon atom to other radicals, thus obtained Quaternary nitrogen group. As noted in the General structure of the Quaternary nitrogen group may be a Deputy of any chain or cyclic radicals described above.

B is preferably heteroalkyl circuit having at least one nitrogen atom in the chain, or R6-L-. Especially preferred B radical is R6-L-.

According to the formula (I), A and B can be taken together with the C*X and X' form a cyclic structure. Preferred cyclic structures are such, where V is a heterocycle having at least one nitrogen atom in the ring. Ring nitrogen atom may be secondary, tertiary or Quaternary amine. When neither V nor W are nitrogen-containing heterocycles, then at least one of V and W must be replaced by one or more substituents selected from the group consisting of-R3N(R4)2; -R3[-N(R5)3] +; -R3N(R4)C(O)R4; -R3N(R4)C(S)R4; -R3N(R4)C(N)R4; -R3C(O)N(R4)2.

the diversified group, containing-R3SR1; hydrogen: substituted or unsubstituted C1- C8alkyl; R3OR1; -R3CO2R4; -R3O2CR4; halogen; -R3C(O)R4; hydroxy; substituted or unsubstituted, arylalkyl; nitro and unsubstituted or substituted aryl.

The preferred compounds used in the compositions and methods of the present invention are phosphonocarboxylate and their pharmaceutically acceptable salts, having the General structure according to formula (II)

< / BR>
where

(A)(1) denotes A hydroxy and

(2) B denotes

< / BR>
where

(a) m denotes an integer from 0 to 10; n represents an integer from 0 to 10; and m + n represents an integer from 0 to 10;

(b) R8absent or independently selected from the group consisting of-R3SR4; hydrogen; substituted or unsubstituted C1- C8alkyl; R3OR1; -R3CO2R4; -R3O2CR4; -R3N(R4)2; -R3[-N(R5)3]+; -R3N(R4)C(O)R4; -R3N(R4)C(S)R4;

-R3N(R4)C(N)R4; -R3C(O)N(R4)2; halogen; -R3C(O)R4; nitro; hydroxy; substituted sludge is displaced unsaturated monocyclic or polycyclic carbocyclic rings; substituted or unsubstituted saturated monocyclic or polycyclic heterocyclic ring; and substituted or unsubstituted unsaturated monocyclic or polycyclic heterocyclic ring;

(c) R1independently selected from the group consisting of hydrogen; -C(O)R7; -C(S)R7; -C(O)N(R7)2; -C(O)OR7; -C(S)N(R7)2and-C(S)OR7; where R7is hydrogen or a saturated or unsaturated C1- C8by alkyl;

(d) R3no;

(e) R4independently selected from the group consisting of hydrogen; saturated or unsaturated C1- C8alkyl; and R2SR1;

(f) R5independently selected from the group consisting of saturated or unsaturated C1- C15alkyl; substituted or unsubstituted phenyl; benzyl and R2SR1;

(g) L is absent or selected from the group consisting of-N(R8)-; [-N(R5)2-]+; -S-; -O - and-D-C(= E)-S-, where D is selected from the group consisting of covalent bond, O, or S, and E represents O or S; and where the

(i) when L is-N(R8)- , or when L is [-N(R5)2-]+and m denotes an integer from 1 to 10, R3absent or independently selected from the group consisting of hydrogen; SUP>5)2-]+and m = 0, R9selected from the group consisting of substituted or unsubstituted C1- C35alkyl; R2SR1and R10; or

(iii) when L is absent or is-S-, -O - or-D-C-(=E)-S, R9is R10;

(h) R10is a saturated, unsaturated or aromatic monocyclic or polycyclic by carbocycle or a saturated, unsaturated or aromatic monocycle or political and containing one or more heteroatoms; where the specified carbocycle or heterocycle substituted by one or more substituents R11;

(i) each R11independently selected from the group consisting of-R3SR1; hydrogen; substituted or unsubstituted C1- C8alkyl; R3OR4; -R3CO2R4; -R3O2CR4; -R3N(R4)2; -R3[-N(R5)3]+; -R3N(R4)C(O)R4; -R3N(R4)C(S)R4; -R3N(R4)C(N)R4; -R3C(O)N(R4)2; halogen; -R3C(O)(R4); hydroxy; substituted or unsubstituted, arylalkyl; nitro; unsubstituted or substituted aryl;

or (B) A and B, covalently linked to the C*form a monocyclic or bicyclic ring having with tereasa-O-, -S-, and-NR12-;

(b) Q or absent or selected from the group-NR12- [- N(R13)2]+;

(c) X and X' are independently selected from C or N;

(d) R12absent or independently selected from the group consisting of-R3SR1; hydrogen; substituted or unsubstituted C1-C8alkyl; R3OR4; -R3CO2R4; -R3O2CR4; -R3N(R4)2; -R3[-N(R5)3]+; -R3N(R4)C(O)R4; -R3C(O)N(R4)2;

halogen; R3C(O)R4; hydroxy; unsubstituted or substituted arylalkyl; nitro and unsubstituted or substituted aryl;

(e) R13absent or independently selected from the group consisting of substituted or unsubstituted C1-C15alkyl; substituted or unsubstituted phenyl; benzyl and R2SR1;

(f) when Q is present, k and j and k + j is an integer from 0 to 5;

when Q is absent, k and j and k + j is an integer from 0 to 6;

(q) p and q and p + q are independently an integer from 0 to 3; except that, if Q is missing at least one of R11or R12selected from the group consisting of-R3N(R4)2; -R3[-N(R5)3]+; -R3N(RASS="ptx2">

Preferred phosphonocarboxylate compounds of formulas (I) and (II) nitrogen-containing heterocycle attached to phosphonocarboxylates carbon through the connecting circuit. They include phosphonocarboxylate compounds having the following General structure:

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
where the nitrogen-containing heterocycle is pyridine or pyridinium

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
where the nitrogen-containing heterocycle is a monocycle, other than pyridine or pyridinium;

< / BR>
< / BR>
< / BR>
< / BR>
where the nitrogen-containing heterocycle is political.

Preferred are also phosphonocarboxylate compounds having nitrogen-containing heterocyclic radical attached to the phosphonate containing carbon. Such compounds include compounds having the following structure, where R8and R9are acyclic substituents;

< / BR>
Preferred are also the compounds having the following structure, where R9is cycloheptyl ring;

< / BR>
Preferred are substituted or unsubstituted, octahydrophenanthrene, having the General structure is R>
< / BR>
listed here as "unsubstituted or substituted, octahydro - 5-phosphono-5-carboxyl-2-pyridine";

< / BR>
listed here as "unsubstituted or substituted, octahydro-6-phosphono-6-carboxyl-1-pyridine";

< / BR>
listed here as "unsubstituted or substituted, octahydro-6 - phosphono-6-carboxyl-2-pyridine";

< / BR>
listed here as "octahydro-7-phosphono-7-carboxyl-1 - pyridine";

< / BR>
listed here as "octahydro-7-phosphono-7-carboxyl-2 - pyridine";

Preferred are substituted or unsubstituted, octahydrophenanthrene pyridinium, having the General structure:

< / BR>
listed here as "octahydro-5-phosphono-5-carboxyl - 1-pyridine";

< / BR>
listed here as "octahydro-5-phosphono-5-carboxyl-2 - pyridine";

< / BR>
listed here as "octahydro-6-phosphono-6-carboxyl-1 - pyridine";

< / BR>
listed here as "octahydro-6-phosphono-6-carboxyl-2 - pyridine";

< / BR>
listed here as "octahydro-7-phosphono-7-carboxyl-1 - pyridine";

< / BR>
listed here as "octahydro-7-phosphono-7-carboxyl-2 - pyridine".

Specific examples of the compounds of the present invention are of the formula given in the end of the description, and pharmaceutically pokerpacific compounds, which have the same basic pharmacological properties, as acids from which they are formed, and which are acceptable from the standpoint of toxicity. Pharmaceutically acceptable salts include alkali metal salts (such as sodium or potassium), salts of alkaline earth metals (such as magnesium or calcium), non-toxic heavy metal salts (for example, tin and indium), and ammonium salts or low molecular weight substituted ammonium (such as mono-, di - and triethanolamine). The preferred compounds are sodium, potassium and ammonium salts.

To identify and study of pharmacological activity test phosphonocarboxylate compounds on animals carried out using various known in the art methods. So, antiresorption bone activity in vivo can be demonstrated, using the experience, including the study of the ability of these compounds to inhibit the resorption of bone in which bone resorption is a characteristic abnormal calcium or phosphate metabolism. One of these tests, known to experts, is a model of Schenk (Schenk model). Other used by specialists test is a test for induced Rhodesia tests to study the pharmacological activity described and/or disclosed to reference them in Shinoda et al., Calcified Tissue International, 35, pp 87-99 (1983); Schenk et al. , Calcified Tissue Research, 11, pp 196-214 (1973); Russel et al. , Calcified Tissue Research, 6, pp 183-196 (1970); Muhlbauer and Fleisch, Mineral Electrolyte Metab, 5, pp 296-303 (1981); Nancollas et al., Oral. Biol., 15, 731 (1970); U.S. patent 3683080, Francis published on August 8, 1972; U.S. patent 4134969, Schmidt-Dunker; published January 16, 1979; European patent application N 189662, published on August 6, 1986; descriptions of all these articles and patents is incorporated herein by reference in its entirety. Some of these tests to determine the pharmacological activity is also described in more detail in the examples below.

In addition to their usefulness for the treatment and prevention of pathological conditions characterized by abnormal calcium and phosphate metabolism, compounds of the present invention may have other applications. For example, the compounds of the present invention are believed useful as a bone scan agent after tagging 99m-technetium. In addition, the compounds of the present invention are useful as sequestered agents for polyvalent metal ions, in particular di- (for example, calcium and magnesium) and trivalent (e.g., indium) metal ions. Thus, the compounds of the present invention are useful in Ilizarov compounds. In addition, they can be useful to prevent the formation of stone (e.g., stones) and deposits on the teeth. Finally, the compounds of the present invention can be useful as herbicides, which are non-toxic to animals.

Phosphonocarboxylate compounds of the present invention is obtained from commercially available materials in accordance with non-limiting examples 1-65.

Compositions containing the new phosphonocarboxylate connection.

Phosphonocarboxylate compounds of the present invention can be administered to the human or other mammal in various ways, including, but not limited to, oral dosage forms and injections (intravenous, intramuscular, intraperitoneal and subcutaneous). Various other dosage forms containing the new phosphonocarboxylate compounds of the present invention, can be prepared by specialists using suitable pharmaceutical excipients, as described next. For convenience, patients are usually the most preferred oral form.

The term "pharmaceutical composition", as used here, means a composition comprising a safe and effect is asepticheski acceptable fillers.

The phrase "safe and effective amount", as used here, means such amount of the compound or composition, which is large enough for significant positive changes in symptoms and/or condition being treated, but low enough to avoid serious side effects (at a reasonable ratio of success/risk) in accordance with the concept of common medical sense. Safe and effective amount of the active ingredient for use in the pharmaceutical compositions used according to the method of the present invention, will vary with the specific condition being treated, the age and physical condition of the patient being treated, the severity of the condition, the duration of treatment, the nature of concurrent therapy, the specific applied active ingredient, the pharmaceutically acceptable carrier, and such factors are accounted for in accordance with experience and opinion of the treating physician.

The term "pharmaceutically acceptable carrier", as used here, includes physiologically inert, pharmacologically inactive material known in the art, which is compatible with the physical the data for use. Pharmaceutically acceptable carriers include, but are not limited to, polymers, resins, plasticizers, binders, lubricating, glidant (solitai - ?), leavening agents, solvents, co-solvents, buffer systems, surfactants, conservatives, sweetening agents, flavouring agents, dyes or pigments pharmacological profile and agents that increase the viscosity.

The term "oral dosage form" as used here means any pharmaceutical composition intended for regular use by an individual through the mouth, releasing the connection specified in the gastrointestinal tract of the individual. According to the present invention release form may be in the form of tablets, coated or uncoated; solution; suspension or capsules, coated or uncoated.

The term "injection" as used here means any pharmaceutical composition intended for the regular introduction of a human or other mammal by administration of a solution or emulsion containing the active ingredient, skin puncture specified individual for the introduction of the specified solution or emulsion in the circulatory system is of the present invention can range from about 0.1 to about 99.9% by weight of the pharmaceutical composition of the present invention. Preferably the compounds of the present invention comprise from about 20% to about 80% by weight of the pharmaceutical composition of the present invention.

Accordingly, the pharmaceutical composition of the present invention includes from 15 to 95% active ingredient phosphonocarboxylate compounds or mixtures of these compounds; 0 - 2% flavoring agent; 0 to 50% of co-solvent; 0 to 5% buffer system; 0 - 2% surfactant; 0 to 2% of conservatives; 0 - 5% sweetening agents; 0 to 5% of agents that increase viscosity; 0 - 75% fiber; 0.5 to 2% of a lubricant; 1 - 5% glidants; 4 - 15% baking powder and 1 to 10% binder.

Acceptable pharmaceutical compositions described herein in examples 66 to 68. The specialist can easily change non-limiting examples described herein, to achieve a wide range of pharmaceutical compositions.

The choice of pharmaceutically acceptable carrier for use in combination with the phosphonate compounds of the present invention is mainly determined by way of the introduction of phosphonate compounds. If the connection must be introduced by injection, the preferred pharmaceutical carrier is a sterile saline solution, pH of which ustache, suitable for use in creams, gels, suppositories and the like.

Pharmaceutically acceptable carrier used in connection with phosphonocarboxylate compounds of the present invention is used in a sufficient concentration to ensure the practical value of the appropriate dosage. Pharmaceutically acceptable carriers, in General, can be from 0.1 to 99.9% by weight of the pharmaceutical compositions of the present invention and preferably from 20% to 80%.

The preferred route of administration phosphonocarboxylate compounds of the present invention is oral. Preferred unit dosage forms are tablets, capsules and the like, containing a safe and effective amount of phosphonate compounds of the present invention. Pharmaceutically acceptable carrier, suitable for the preparation of unit dosage forms for oral administration are well known in the art. His choice will depend on secondary circumstances taken into account, such as taste, cost, and stability during storage, which are not critical for the purposes of the present invention, and can be without difficulty preetam by manipulating one or more of the following factors:

(a) an active ingredient;

(b) a pharmaceutically acceptable carrier; to the extent that the variation does not interfere with the activity of the specific active ingredient selected;

(c) the type of media, and accompanying the desired density and permeability (swelling properties) of these fillers;

(d) time-dependent parameters of the media itself and/or within the media;

(e) the particle size of the granulated active ingredient; and

(f) pH - dependent parameters of the media.

In particular, as a guide for proper selection can be used solubility, acidity, sensitivity to hydrolysis of various phosphonocarboxylate active ingredients, such as salts of addition of acids, salts formed with a carboxyl group, for example, salts of alkali metals, salts of alkaline earth metals, etc. and ethers, for example, alkyl, alkeline, aryl, kalkilya. In addition, the oral dosage form can be set to the appropriate pH conditions by adding a suitable buffer to the active ingredient in accordance with the desired model release.

As noted above, pharmaceutically acceptable nosirree, the co-solvents, surfactants, conservatives, sweetening agents, flavouring agents, buffer systems, dyes or pigments pharmaceutical profile and agents that increase the viscosity.

The preferred solvent is water.

Flavouring agents among others, used here include described in Remington's Pharmaceutikal Sciences 18-th Edition, Mack Publisning Company, 1990, PP. 1288-1300, incorporated herein by reference. Pharmaceutical compositions suitable here to use, usually contain from 0 to 2% flavouring agents.

Dyes or pigments among others, used here include are described in Handbook of Pharmaceutical Excipients, PP. 81-90, 1986, by American Pharmaceutical Associasin & the Pharmaceutical Society of Great Britain, incorporated herein by reference. Pharmaceutical compositions usually contain from 0 to 2% of dyes or pigments.

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

Preferred buffer systems include, but are not limited to, acetic, boric, carbonic, fosfamidon acids and their sodium, potassium and ammonium salts. Particularly preferred phosphoric, tartaric, citric and acetic acids and salts. The pharmaceutical compositions of the present invention typically contain from 0 to 5% buffer systems.

Preferred surfactants include, but are not limited to, polyoxyethylene ethers of sorbitan fatty acids, polyoxyethylene monoalkyl ethers, monetary sucrose and lanolin simple and complex esters, salts of alkyl sulphates, sodium, potassium and ammonium salts of fatty acids. The pharmaceutical compositions of the present invention comprise from 0% to 2% surface-active compounds.

Preferred preservatives include, but are not limited to, phenol, alkalemia esters by parahydroxybenzoic acid, o-phenylphenolate acid and its salts, boric acid and its salts, sorbic acid and its salts, chlorbutanol, benzyl alcohol, thimerosal, fenilsalicilat and nitrate, nitromersol, benzalkonium chloride, pyridinium chloride, methylparaben and propylparaben. Particularly preferred salts of benzoic acid, pyridinium chloride, methylparaben and propylparaben. The compositions of the present invention include from 0 to 2% preservatives.

the ol, mannitol and aspartame. Especially preferred sucrose and saccharin. The pharmaceutical compositions of the present invention comprise from 0 to 5% of podslushivala.

Preferred agents that increase the viscosity include, but are not limited to, methylcellulose, sodium carboxymethylcellulose, hypromellose, hydroxypropylcellulose, sodium alginate, carbomer, povidone, gum Arabic, guar gum, xanthan gum and tragakant. Especially preferred methyl cellulose, carbomer, xanthan gum, guar gum, povidone, sodium carboxymethylcellulose and magnesium silicate. The compositions of the present invention comprise from 0 to 5% of agents that increase the viscosity.

Preferred fibers include, but are not limited to, lactose, mannitol, sorbitol, rejonowy calcium phosphate, dibasic calcium phosphate, compressible sugar, starch, calcium sulfate, dextro and microcrystalline cellulose. The compositions of the present invention contain from 0 to 75% of the fibers.

The preferred lubricant include, but are not limited to, magnesium stearate, stearic acid and talc. The pharmaceutical compositions of the present invention include from 0, the first silicon dioxide. The compositions of the present invention include from 1 to 5% of glidants.

Preferred loosening agents include, but are not limited to, starch, sodium starch glycolate, crosspovidone, crosscarmellose sodium and microcrystalline cellulose. The pharmaceutical compositions of the present invention include from 4 to 15% of a lubricant.

Preferred binders include, but are not limited to, gum Arabic, tragakant, hydroxypropylcellulose, pre gelatinizing starch, gelatin, povidone, hypromellose, methylcellulose, solutions of sugar, such as sucrose and sorbitol and ethylcellulose. The compositions of the present invention include from 1 to 10% of the binding.

The term "mg R" listed here, means the weight of the presented phosphorus atom in the amount of phosphonocarboxylate compounds of the present invention. This unit is used to standardize the number phosphonocarboxylate compounds of the present invention for use as pharmaceutical compositions and methods of the present invention. For example, 2-hydroxy-2-phosphono-3-(3-pyridyl)propionic acid has a molecular weight 247 g/mol, 12.5 percent (31 g/mol) heat 0.125 mg R. Thus, for the preparation of pharmaceutical compositions containing 0.125 mg P this connection, the composition will contain 1 mg of the composition; and at a dose of 0.125 mg P/kg of this compound for a patient weighing 50 kg, the patient will receive 50 mg of the compound.

Method for the treatment or prevention of diseases characterized by abnormal calcium and phosphate metabolism.

Another aspect of the present invention are methods of treatment or prevention of diseases characterized by abnormal calcium and phosphate metabolism. Such methods include administration to a human or lower animal in need of such treatment a safe and effective amount phosphonocarboxylate compounds of the present invention.

The preferred route of administration oral, but other known methods of introduction also refers to, for example, through the skin and mucous membranes (for example, skin, rectal, and the like) and parenteral (e.g. subcutaneous injection, intramuscular injection, intra-articular injection, intravenous injection and the like). Inhalation is also included. Thus, specific methods of administration include, without limitation, Perera is a great introduction, as well as external use.

The term "abnormal calcium and phosphate metabolism", as used here, implies (1) States, which are characterized by abnormal metabolism of calcium and phosphate, leading to total or partial loss of bone tissue, or particularly high levels of calcium and phosphate in the body fluids; and (2) state, which is caused by or resulting from abnormal deposits of calcium and phosphate in the body. The first category includes, but is not limited to, osteoporosis, disease Paget, hyperparathyroidism, hyperkalemia tumor origin, abnormal ossification and bone destroying metastases. The second category includes, but is not limited to, the development mizinova ossification, total deposition of salts and diseases such as arthritis, osteoarthritis, nephritis, inflammation of the Bursa, inflammation of the tendons and other inflammatory conditions, which require the inclusion of tissue deposition of calcium phosphates.

The term "rheumatoid arthritis" as used here, implies a chronic systemic and sustavnoi disease of unknown etiology. It is characterized by destruction of articular cartilage, ligaments, tendons and bone tissue 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 "subject at risk" and "subject in need of treatment", as used herein, mean any person or lower animal which suffers from significant risk of abnormal calcium and phosphate metabolism, if not subjected to treatment, and any person or lower animal that is diagnosed as affected abnormal calcium and phosphate metabolism. For example, women in postmenopausal period; persons who were subjected to some treatment with steroids; host to some of anticonvulsive drugs; installed disease Paget, hyperparathyroidism, high content of calcium in the blood of malignant origin or osteolytic metastases in the bone tissue; suffering from one or more of various forms of osteoporosis, persons originating from a group known as having a significantly higher than average, the chance of developing osteoporosis, for example, women in postmenopausal women and men over 65 years of age and persons being treated with drugs that have known side effect is salt; and people living with arthritis, osteoarthritis, neuritis, inflammation of the bags, inflammation of the tendons and other inflammatory conditions, which require the inclusion of tissue deposition of calcium phosphates.

The phrase "safe and effective amount", as used here, means such amount of the compound or composition, which is large enough for significant positive changes in symptoms and/or condition being treated, but low enough to avoid serious side effects (at a reasonable ratio of success/risk) in accordance with the concept of common medical sense. Safe and effective amount of the active ingredient for use in the pharmaceutical compositions used according to the method of the present invention, will vary with the specific condition being treated, the age and physical condition of the patient being treated, the severity of the condition, the duration of treatment, the nature of concurrent therapy, the specific applied active ingredient, the pharmaceutically acceptable carrier, and such factors are accounted for in accordance with experience and opinion of the attending physician. body 50 kg). Preferably the unit dose of from 1 mg P to 600 mg P, or from 0.02 to 12 mg P/kg of body weight (based on body weight 50 kg). Can be assigned up to four single doses per day. Daily dose of more than 500 mg P/kg not required to obtain the desired effect and may cause unwanted side effects. In the case of oral administration, of course, require a higher dose levels due to limited absorption.

The following examples describe and illustrate the preferred embodiment in the scope of the present invention. Examples are given only for the purpose of illustration and are not intended to limit the present invention, since variations without deviating from its meaning and scope.

Example 1. Synthesis of 4-(N,N-dimethylamino)-2-hydroxy-2 - phosphonobutane acid

< / BR>
I. Synthesis of ethyl-2-oxo-3-butenoate

A solution of 41 g (0.30 mol) of acrocallosal in 500 ml of anhydrous diethyl ether is stirred in an atmosphere of nitrogen in a bath at -78o. To it is added dropwise within 1 to 2 hours, 100 ml ( 0.10 mol) of a solution of vinylmania of 1.0 molar in tetrahydrofuran). The reaction mixture is stirred for 30 minutes at -78oand then allow to warm to 0oin t is of delocalised. The residue is again suspended in ether and the mixture is stirred in an ice bath. To it is slowly added a solution of 2 g (0.01 mol) of triethylamine in 10 ml of ethanol. Mixture was allowed to warm to room temperature and filtered. The cake on the filter, well washed with ether. The filtrate is evaporated and the residue partitioned between 200 ml of ether and 200 ml of water. The aqueous layer was extracted with 10 ml of ether. The combined ether layers are washed twice with 100 ml of 1 N. aqueous acetic acid, twice with 100 ml of 1 N. aqueous NaHCO3and once with 100 ml saturated NaCl solution. The organic layer is dried over NaSO4and evaporated to dryness on a rotary evaporator to obtain the crude product. Its clean flash chromatography on silica gel to obtain ethyl-2-oxo-3-butenoate in the form of butter.

II. Synthesis of ethyl-4-(N,N-dimethylamino)-2-oxobutanoate

To a stirred solution of 12.8 g (0.10 mol) of ethyl-2-oxo-3-butenoate in 200 ml of anhydrous ether under nitrogen atmosphere (in an ice bath) is added over 1 hour to a cold solution of 4.5 g (0.10 mol) of dimethylamine in 200 ml of anhydrous ether. The reaction was stirred at 0owithin a few hours and then at 20 - 25owithin one day. The solvent is removed and the resulting crude product was then purified the Proc. of ethyl 2-diethoxyphosphoryl-4-(N,N-dimethylamino)- 2-hydroxybutanoic

Mix with 8.05 g (0.05 mol) of ethyl 4-(N,N-dimethylamino)-2-oxobutanoate in 31 g (0,225 mol) of diethylphosphate stirred at 20 - 30owithin 3 to 5 days. Excess diethylphosphate removed on a rotary evaporator under high vacuum at a bath at a temperature of 50 - 70oto obtain the crude product as a viscous oil.

IV. Synthesis of 4-(N,N-dimethylamino)-2-hydroxy-2-phosphono - butane acid

Hydrolysis of the above teeterboro ester (3.2 g) is carried out by boiling under reflux in 6 BC HCl for 18 hours. Aqueous HCl is removed in vacuo and the resulting residue is dissolved in water, treated with activated charcoal and filtered. The filtrate is concentrated to a few ml and add ethanol to the planting of the product. It is collected by filtration and dried in a desiccator to obtain 4-(N,N-dimethylamino)-2-hydroxy-2-phosphonobutane.

Example 2. Synthesis of N-(3-carboxy-3-hydroxy-3-phosphonopropyl)- N,N,N-ammonium iodide

< / BR>
A solution of 2.27 g (0.01 mol) of 4-(N,N-dimethylamino)-2-hydroxy-2 - phosphonobutane acid (obtained as described in example 1) in 20 ml of water and 30 ml of ethanol is brought to pH 7.0 by adding 1 N. aqueous NaOH. Added to 7.1 g (0.05 mol) of methyliodide and the reaction stirred at 30 - 50ofor one the new water and treated with cation exchange resin in the H+-form. The resin is filtered off, the aqueous solution concentrated to a few ml and added dropwise acetone for planting of the product. Its clear by recrystallization from water/acetone to obtain N-(3-carboxy-3-hydroxy-3-phosphonopropionic)- N,N,N-ammonium iodide.

Example 3. Synthesis of N-(3-carboxy-3-hydroxy-3-phosphonopropyl)- N,N-dimethyl-N-ethylammonium iodide

< / BR>
A solution of 2.27 g (0.01 mol) of 4-(N,N-dimethylamino)-2-hydroxy-2 - phosphonobutane acid (obtained as described in example 1) in 20 ml of water and 40 ml of ethanol is brought to pH 7.0 by adding 1 N. aqueous NaOH. To it add 6,24 g (0.04 mol) of ethyliodide and the reaction stirred at 30 - 50owithin one day. The reaction mixture is evaporated to dryness under reduced pressure. The resulting residue is dissolved in distilled water and treated with cation exchange resin in the H+-form. The resin is filtered off, the aqueous solution concentrated to a few ml and added dropwise acetone for planting of the product. Its clear by recrystallization from water/acetone to obtain N-(3-carboxy-3-hydroxy-3 - phosphonopropionic)-N,N-dimethyl-N-ethylammonium iodide.

Example 4. Synthesis of N-(3-carboxy-3-hydroxy-3-phosphonopropyl)- N,N-dimethyl-N-(phenylmethyl)ammonium Brunoy, as described in example 1) in 10 ml of water and 40 ml of ethanol is brought to pH 7.0 by adding 1 N. aqueous NaOH. To it add 5,13 g (0.03 mol) of benzyl bromide and the reaction heated at about 50owithin one day. The reaction mixture is evaporated to dryness under reduced pressure. The resulting residue is suspended in water and the mixture extracted several times CHCl3. The aqueous solution evaporated to small volume to remove traces of chloroform and treated with cation exchange resin in the H+-form. The resin is filtered off, the aqueous solution concentrated to a few ml and added dropwise ethanol for planting of the product. Its clear by recrystallization from water/acetone to obtain N-(3-carboxy-3-hydroxy-3-phosphonopropionic)- N, N-dimethyl-N-(phenylmethyl)ammonium bromide.

Example 5.

Synthesis of N-(2-(acetylthio)ethyl)-N-(3-carboxy-3-hydroxy-3 - phosphonopropyl)-N,N-dimethylammonium bromide.

< / BR>
A solution of 2.27 g (0.01 mol) of 4-(N,N-dimethylamino)-2-hydroxy-2 - phosphonobutane acid (obtained as described in example 1) in 20 ml of water and 40 ml of ethanol is brought to pH 7.0 by adding 1 N. aqueous NaOH. To it add 9,16 g (0.05 mol) of S-acetyl-2-brometalia and the reaction heated at about 40 - 80owithin a few hours. Rea is one (acetone extracts drop). The remaining residue dissolved in distilled water and treated with cation exchange resin in the H+-form. The resin is filtered off, the aqueous solution concentrated to a few ml and added dropwise acetone for planting of the product. Its clear by recrystallization from water/acetone to obtain N-(2-(acetylthio)ethyl)-N-(3-carboxy-3-hydroxy-3-phosphonopropyl)- N,N-dimethylammonium bromide.

Example 6

Synthesis of N-(3-carboxy-3-hydroxy-3-phosphonopropyl)- N, N-dimethyl-N-(2-(thioethyl)ammonium chloride

< / BR>
A solution of 1 g of N-(2-(acetylthio)ethyl-N-(3-carboxy-3-hydroxy-3 - phosphonopropyl)-N, N-dimethylammonium bromide in 50 ml of water is treated with anion exchange resin in the chloride form. The solution is concentrated to 20 ml and add 20 ml 12 N. HCl. The solution is heated to boiling under reflux in nitrogen atmosphere for 12 hours and then evaporated to dryness. The residue is dissolved in 50 ml of fresh 6 N. hydrochloric acid and again evaporated to dryness. Treated with few ml of water and periostat ethanol to obtain N-(3-carboxy-3-hydroxy-3-phosphonopropyl)- N,N-dimethyl-N-(2-(thioethyl)ammonium chloride.

All these operations are carried out in an atmosphere of N2 using deoxygenating solvents to minimize formation dial
I. Synthesis of ethyl 4-((N-methyl-N-pentyl)amino)-2-oxobutanoate

A solution of 10.1 g (0.10 mol) of N-methyl-N-pentylamine and 12.8 g (0.10 mol) of ethyl-2-oxo-3-butenoate (obtained according to example 1) in 50 ml of toluene in a nitrogen atmosphere is stirred at 30 - 50owithin a few hours. The solvent is removed and the resulting crude product was then purified flash chromatography on silica gel.

II. Synthesis of ethyl 2-diethoxyphosphoryl-2-hydroxy-4-((N-methyl-N-pentyl)amino)butanoate

A mixture of 10.9 g (0.05 mol) of ethyl 4-((N-methyl-N-pentyl)-amino)-2-oxobutanoate in 31 g (0,225 mol) of diethylphosphate stirred at 20-30owithin 5 days. Excess diethylphosphate removed on a rotary evaporator under high vacuum at a bath at a temperature of 50-70oto obtain the crude product as a viscous oil. Its clear by chromatography on silica gel using chloroform/methanol as eluent.

III. Synthesis of 2-hydroxy-4-((N-methyl-N-pentyl)amino)-2-phosphonobutane acid

Hydrolysis of the above teeterboro ether (3.3 grams) carried out by boiling under reflux in 6 BC HCl for 18 hours. Aqueous HCl is removed in vacuo and the resulting residue is dissolved in water, treated with activated charcoal and filtered. The filtrate is concentrated until the bore is the group of 2-hydroxy-4-(N-methyl-N-pentylamine)-2-phosphonobutane.

Example 8

Synthesis of N-(3-carboxy-3-hydroxy-3-phosphonopropyl)-N, N - dimethyl-N-pentylammonium iodide

< / BR>
This connection receive according to the method of example 2 from 2-hydroxy-4-(N-methyl-N-pentylamine)-2-phosphonobutane acid.

Example 9. Synthesis of N-(3-carboxy-3-hydroxy-3-phosphonopropyl)-N-ethyl-N-methyl-N-pentylammonium iodide

< / BR>
This connection receive according to the method of example 3 from 2-hydroxy-4-(N-methyl-N-pentylamine)-2-phosphonobutane acid.

Example 10. Synthesis of N-(3-carboxy-3-hydroxy-3-phosphonopropyl)- N-methyl-N-pentyl-N-(phenylmethyl)ammonium bromide

< / BR>
This connection receive according to the method of example 4 from 2-hydroxy-4-(N-methyl-N-pentylamine)-2-phosphonobutane acid.

Example 11. Synthesis of N-(2-acetylethyl)-N-(3-carboxy-3-hydroxy-3-phosphonopropyl)-N - methyl-N-pentylammonium bromide

< / BR>
This connection receive according to the method of example 5 from 2-hydroxy-4-(N-methyl-N-pentylamine)-2-phosphonobutane acid.

Example 12. Synthesis of N-(3-carboxy-3-hydroxy-3-phosphonopropyl)-N-methyl-N-pentyl-N- (2-thioethyl)ammonium chloride

< / BR>
This connection receive according to the method of example 6 based on N-(2-(acetylthio)ethyl)-N-(3-carboxy-3-hydroxy-3-phosphonopropyl)-N - methyl-N>BR>
I. Synthesis of ethyl 4-(1-imidazolyl)-2-oxobutanoate

A solution of 6.8 g (0.10 mol) of imidazole and 12.8 g (0.10 mol) of ethyl 2-oxo-3-butenoate (obtained according to example 1) in 50 ml of tetrahydrofuran in a nitrogen atmosphere is stirred at 50 - 80owithin a few hours. The solvent is removed and the resulting crude product was then purified flash chromatography on silica gel.

II. Synthesis of ethyl 2-diethoxyphosphoryl-2-hydroxy-4-(1-imidazolyl)butanoate

The mixture 9.81 g (0.05 mol) of ethyl 4-(1-imidazolyl)-2-oxobutanoate in 31 g (0,225 mol) of diethylphosphate stirred at 20 - 30owithin about 4 days. Excess diethylphosphate removed on a rotary evaporator under high vacuum at a bath at a temperature of 50 -70 oobtaining a crude product. Its clear by chromatography on silica gel using chloroform/methanol as eluent.

III. Synthesis of 2-hydroxy-4-(1-imidazolyl)-2-phosphonobutane acid

Hydrolysis of the above teeterboro ether (5 g) is carried out by boiling under reflux in 100 ml of 6 N. HCl for 18 hours. Aqueous HCl is removed in vacuo and the resulting residue is dissolved in water, treated with activated charcoal and filtered. The filtrate is concentrated to a few ml and add acetone to VisiFault, which is dried in a desiccator to obtain 2-hydroxy-4-(1-imidazolyl)-2-phosphonobutane acid.

Example 14. Synthesis of 2-hydroxy-2-phosphono-4-(1-pyrrolidinyl)-butane acid

< / BR>
I. Synthesis of ethyl 2-oxo-4-(1-pyrrolidinyl)propanoate

A solution of 7.1 g (0.10 mol) of pyrrolidine and 12.8 g (0.10 mol) of ethyl 2-oxo-3-butenoate (obtained according to example 1) in 50 ml of toluene in a nitrogen atmosphere is stirred at 50 - 80owithin a few hours. The solvent is removed and the resulting crude product was then purified flash chromatography on silica gel.

II. Synthesis of ethyl 2-diethoxyphosphoryl-2-hydroxy-4-(1-pyrrolidinyl)butanoate

The mixture 9,96 g (0.05 mol) of ethyl 2-oxo-4-(1-pyrrolidinyl)-butanoate in 31 g (0,225 mol) of diethylphosphate stirred at 20 - 30ofor about 3-6 days. Excess diethylphosphate removed on a rotary evaporator under high vacuum at a bath at a temperature of 50 - 70oto obtain the crude product as a viscous oil. Its clear by chromatography on silica gel using chloroform/methanol as eluent.

III. Synthesis of 2-hydroxy-2-phosphono-(1-pyrrolidinyl)-butane acid

Hydrolysis of the above teeterboro ester (3.2 g) is carried out by boiling under reflux in 6 BC HCl in the charcoal and filtered. The filtrate is concentrated to a few ml and add ethanol to the planting of the product. It is collected by filtration and dried in a desiccator to obtain 2-hydroxy-2-phosphono-(1-pyrrolidinyl)butane acid.

Example 15. Synthesis of N-(3-carboxy-3-hydroxy-3-phosphonopropyl)-N-methylpyrrolidinium iodide

< / BR>
This connection receive according to the method of example 6 from 2-hydroxy-2-phosphono-4-(1-pyrrolidinyl)butane acid.

Example 16. Synthesis of N-(3-carboxy-3-hydroxy-3-phosphonopropyl)-N-ethylpyrrolidin iodide

< / BR>
This connection receive according to the method of example 3 from 2-hydroxy-2-phosphono-4-(1-pyrrolidinyl)butane acid.

Example 17. Synthesis of N-(3-carboxy-3-hydroxy-3-phosphonopropyl)-N-(phenylmethyl)pyrrolidine bromide

< / BR>
This connection receive according to the method of example 4 from 2-hydroxy-2-phosphono-4-(1-pyrrolidinyl)butane acid.

Example 18. Synthesis of N-(2-(acetylthio)ethyl)-N-(3-carboxy-3-hydroxy-3-phosphonopropyl) pyrrolidine bromide

< / BR>
This connection receive according to the method of example 5 from 2-hydroxy-2-phosphono-4-(1-pyrrolidinyl)butane acid.

Example 19. Synthesis of N-(3-carboxy-3-hydroxy-3-phosphonopropyl)-N-(2-thioethyl)pyrrolidine chloride

Example 20. Synthesis of N-amino-2-hydroxy-2-phosphonobutane acid

< / BR>
Method 1.

I. Synthesis of ethyl-2-oxo-4-phthalimidobutyl

To a solution of 12.8 g (0.10 mol) of ethyl 2-oxo-3-butane acid (obtained according to example 1) in 75 ml of anhydrous ethanol is added phthalimide (14,7 g, 0.10 mol) and phthalimide potassium (0,92 g of 0.005 mol). The mixture is heated at 50 - 80ofor about one day. Cooled in an ice bath and quenched with 20 ml of 0.5 N. HCl. THF is removed in vacuo and the residue partitioned between water and CH2Cl2. The aqueous layer was extracted with CH2Cl2and the combined extracts washed with aqueous 5% solution of NaHCO3and dried over MgSO4. The crude product obtained after removal of solvent, chromatographic on silica gel to give the desired ether.

II. Synthesis of ethyl-2-diethoxyphosphoryl-2-hydroxy-4-phthalimidobutyl

The mixture 13,76 g (0.05 mol) of ethyl 2-oxo-4-phthalimidobutyl in 31 g (0,225 mol) of diethylphosphate stirred at 20 - 30oin a few days. Excess diethylphosphate removed on a rotary evaporator under vacuum at a bath at a temperature of 50 - 70oobtaining a crude product. Its clear by chromatography on silica gel using chloroform/methanol as eluent.

Example 21. Synthesis of 5-amino-2-hydroxy-2-phosphonopentanoate acid

< / BR>
Method 1.

I. Synthesis of ethyl 2-diethoxyphosphoryloxy

To a solution of 2.36 g (0.10 mol) of ethyl 2-diethoxypropionate (J. Ord, Chem. , 43, 1259 (1978)) in 150 ml of methylene chloride was added 50 ml of 0.5 N. aqueous solution of NaHCO3. The mixture was rapidly stirred at room temperature under slow addition of meta-chloroperbenzoic acid (0.01 mol). After stirring for about 6 hours methylenchloride layer is separated and washed with 0.5 N. NaOH solution and then with water. Dried over Na2SO4and evaporated to dryness to obtain ethyl 2-diethoxyphosphoryl is R> In a nitrogen atmosphere in a dry glass container is stirred solution of 4.1 g (0.10 mol) of acetonitrile in about 30 ml of anhydrous tetrahydrofuran at -78oin a bath of dry ice/acetone. To him slowly added by syringe to a cold solution of 0.10 mole of lithium diisopropylamide in tetrahydrofuran. The reaction mixture is stirred for 30 to 60 minutes at - 78oand then quickly add 2,52 g (0.10 mol) of ethyl 2-diethoxyphosphoryloxy. The reaction mixture was stirred at -78ofor 30 minutes and then quenched by the addition of 0.1 N. ethanolic HCl. The mixture is heated to room temperature and the solvent is removed in vacuum. The resulting residue partitioned between water and CH2Cl2and the aqueous layer was then extracted with CH2Cl2. The combined layers washed with a solution of NaHCO3then water, dried (MgSO4) and the solvent is removed to obtain cyano-triavir in the form of oil, which was purified flash chromatography on silica gel.

III. Synthesis of 4-cyano-2-hydroxy-2-phosphonobutane acid

The solution 2,77 g (0.01 mol) of ethyl 4-cyano-2-diethoxyphosphoryl-2-hydroxybutanoic in 30 ml of CHCl3process of 10.7 g (0.07 mol) of trimethylsilylpropyne. The solution was stirred at 50owithin one day. Odny layer is washed several times CHCl3. The aqueous layer was evaporated to dryness in vacuo and the residue is treated with acetone to convert it into a solid product (filtered for his collection), which is 4-cyano-2-hydroxy-2-phosphonobutane acid.

IV. Synthesis of 5-amino-2-hydroxy-2-phosphonopentanoate acid

Hydrogenation of 4-cyano-2-hydroxy-2-phosphonobutane acid is carried out with the use of technology hydrogenation Freifelder (J. Am. Chem. Soc., 82, 2386 (1960)). Cenocoeliinae (of 2.09 g, 0.01 mol) are placed in 20 ml of 10% methanolic ammonia. Add the catalyst (0.5 g), rhodium on aluminum (5%) and the mixture hydronaut at 40 psi in a Parr apparatus for several hours (until complete absorption of hydrogen). The catalyst is filtered off and the filtrate evaporated to dryness. The residue is treated with cation exchange resin in the H+form for conversion of the product in an acidic form. Containing the solution evaporated to dryness in a vacuum. The product was then purified by dissolving the residue in water, the addition of ethanol to obtain a precipitate and collecting the solid product by filtration. Further purification carried out again by recrystallization from water/ethanol.

Method 2.

1. Synthesis of ethyl 4-cyano-2-oxobutanoate

To a solution of 12.8 g (0.10 mol) of ethyl 2-oxo-3-butane acid (obtained is UP> within one hour, during which slowly added dropwise a solution of 6.0 g (0.10 mol) of acetic acid in 20 ml of ethanol. After completion of addition, the mixture is cooled to room temperature and the solvent is removed in vacuum. The residue is partitioned between water and CH2Cl2the layers are separated and the aqueous extracted with CH2Cl2. The combined organic layers are dried (Na2SO4) and the solvent is removed to obtain the crude product. Its clean flash chromatography on silica gel to obtain ethyl 4-cyano-2-oxobutanoate in the form of butter.

II. Synthesis of ethyl-2-diethoxyphosphoryl-4-cyano-2-hydroxybutanoic

A mixture of 7.75 g (0.05 mol) of ethyl 4-cyano-2-oxo-4-butanoate in 31 g (0,225 mol) of diethylphosphate stirred at 20-30owithin 3-4 days. Excess diethylphosphate removed on a rotary evaporator under high vacuum at a bath at a temperature of 50 - 70oobtaining a crude product in the form of oil. Its clear by chromatography on silica gel.

III. Synthesis of 4-cyano-2-hydroxy-2-phosphonobutane acid

The solution 2,77 g (0.01 mol) of ethyl 4-cyano-2-diethoxyphosphoryl-2-hydroxybutanoic in 30 ml of CHCl3process of 10.7 g (0.07 mol) of trimethylsilylpropyne. The solution was stirred at 50ofor the AOI are separated and the aqueous layer was washed several times CHCl3. The aqueous layer was evaporated to dryness in vacuo and the residue is treated with acetone to convert it into a solid product (filtered for his collection), which is 4-cyano-2-hydroxy-2-phosphonobutane acid.

IV. Synthesis of 5-amino-2-hydroxy-2-phosphonopentanoate acid

Hydrogenation of 4-cyano-2-hydroxy-2-phosphonobutane acid is carried out with the use of technology hydrogenation Freifelder (J. Am. Chem. Soc., 82, 2386 (1960)). Cenocoeliinae (of 2.09 g, 0.01 mol) are placed in 20 ml of 10% methanolic ammonia. Add the catalyst (0.5 g), rhodium on aluminum (5%) and the mixture hydronaut at 40 psi in a Parr apparatus for several hours (until complete absorption of hydrogen). The catalyst is filtered off and the filtrate evaporated to dryness. The residue is treated with cation exchange resin in the H+form for conversion of the product in an acidic form. Containing the solution evaporated to dryness in a vacuum. The product was then purified by dissolving the residue in water, the addition of ethanol to obtain a precipitate and collecting the solid product by filtration. Further purification carried out again by recrystallization from water/ethanol.

Example 22. Synthesis of 2-hydroxy-3-(1-imidazolyl)-2-phosphonopropionic acid

< / BR>
I. Synthesis of ethyl 2-oxo-3-(1-imidazolyl)propanoate
4) to obtain the crude product. Its clean flash chromatography on silica gel using as eluent a mixture of methylene chloride/ethanol.

II. Synthesis of triethyl-2-hydroxy-3-(1-imidazolyl)-2-phosphonopentanoate

Suspension 14,62 g (0.10 mol) of ethyl 2-oxo-3-(1-imidazolyl)propanoate 62 g (0.45 mol) of diethylphosphate stirred at 20 - 30owithin 3-7 days. Excess diethylphosphate removed on a rotary evaporator under high vacuum at a bath at a temperature of 50 - 70o. The obtained viscous residue is purified by chromatography on silica gel using chloroform/methanol as eluent.

III. Synthesis of 2-hydroxy-3-(1-imidazolyl)-2-phosphonopropionic acid

The above tritely ester (0.02 mol) hydrolyzing by boiling under reflux in 6 BC HCl (100 ml) for 18 hours. The reaction mixture is evaporated in vacuum to dryness. The resulting residue is treated with activated carbon, filtered and the filtrate is evaporated almost to dryness. The addition of ethanol causes the precipitation of the product, the I. Synthesis of methyl 2-dimethoxyphosphinyl-3-(3-pyridyl)-propanoate

The solution And get the slow addition of 2.00 g (0,050 mol) of NaH (60% in mineral oil) to a solution of 8.09 ml (0,050 mol) of trimethylphosphate in 50 ml of anhydrous dimethyl sulfoxide (DMSO) with minimal foaming. The reaction mixture is bright yellow solution. (All the above done in a dry glass container at room temperature in a nitrogen atmosphere).

To the mixture to 8.20 g (0,050 mol) of the hydrochloride of 3-picolylamine in 50 ml of anhydrous DMSO under nitrogen atmosphere is added slowly (over 5 minutes to minimize foaming) 2.0 g (0,050 mol) of NaH (60% in mineral oil). The reaction mixture is stirred for 75 minutes. This mixture is then added dropwise within 40 minutes the solution A. the resulting solution was stirred at room temperature for 18 hours. The solvent is removed in vacuum to obtain a sticky reddish-brown residue. It is placed in 100 ml of a saturated aqueous solution of NH4Cl and extracted with 3100 ml of CH2Cl2. The combined extracts dried with MgSO4and evaporated in vacuum to obtain 11.3 g of oil. From it extracted mineral oil with hexane 3100 ml, remains 9.6 g of red-brown substances is 2-phosphono-3-(3-pyridyl)-propanoate.

II. Synthesis of 2-phosphono-3-(3-pyridyl)propanoic acid

Triavir hydrolized by boiling it (2 g) under reflux in 50 ml of 6 N. HCl for 3-6 hours. Water and HCl is removed in vacuum. The resulting residue is again dissolved in water and evaporated again to dryness to remove HCl. Again dissolved in a few ml of H2O and slowly add the ethanol, which causes the precipitation of the desired product.

Example 24. Synthesis of 3-(2-carboxy-2-phosphonoethyl)-1-methylpyridinium chloride

< / BR>
A solution of 2.5 (0,009 mol) of methyl 2-dimethoxyphosphinyl-3-(3-pyridyl)propanoate (obtained according to example 23) and 2.25 ml (at 0.020 mol) of methyliodide in 5 ml of anhydrous tetrahydrofuran is stirred at room temperature for 18 hours. During this time, the formed resin. The solvent is drained and the resin washed twice with portions of ether and 10 ml.

The ether group is hydrolyzed by dissolving the resin in 25 ml of 6 N. HCl and boiling under reflux the resulting solution for 3 hours. The solution is cooled and extracted several times with chloroform to remove 12. The aqueous layer was evaporated in vacuum to obtain a brownish resin. It was dissolved in 20 - 25 ml of hot absolute ethanol. The solution is cooled and add 10 - 15 ml shohat filtration and washed with acetone and then ether to obtain 2.0 g of a pale yellowish solid product. It then purified by stirring in 10 ml of anhydrous ethanol for 2-3 hours, then filtered and washed with a few ml of ethanol, then with acetone and finally with ether. Get 1,82 g (71% yield) of 3-(2-carboxy-2-phosphonoethyl)-1-methylpyridinium chloride.

Example 25. Synthesis of 3-(2-carboxy-2-phosphonoethyl)-1-ethylpyridinium chloride

< / BR>
A solution of 2.5 g (0,009 mol) of methyl 2-dimethoxyphosphinyl-3-(3-pyridyl)propanoate (obtained according to example 23) and 3.12 g (at 0.020 mol) of ethyliodide in 5 ml of anhydrous tetrahydrofuran is stirred at room temperature for 18 hours. During this time, the formed resin. The solvent is drained and the resin washed twice with portions of ether and 10 ml.

The ether group is hydrolyzed by dissolving the resin in 25 ml of 6 N. HCl and boiling under reflux the resulting solution for 3 hours. The solution is cooled and extracted several times with chloroform to remove 12. The aqueous layer was evaporated in vacuum to obtain resin. It is dissolved in 20-25 ml of hot absolute ethanol, treated with activated charcoal and filtered. The filtrate is cooled and add 10 - 15 ml of dry acetone. While stirring this solution for several hours, a solid product. It collected the filter is of idini chloride.

Example 26. Synthesis of 3-(2-carboxy-2-phosphonoethyl)-1-(2-thioethyl)-pyridine chloride

< / BR>
A solution of 2.5 g (0,009 mol) of methyl 2-dimethoxyphosphinyl-3-(3-pyridyl)propanoate (obtained according to example 23) and 3,66 g (at 0.020 mol) of S-acetyl-2-bromacetyl in 5 ml of anhydrous tetrahydrofuran is stirred at room temperature for 2 to 3 hours. During this time, the formed resin. The solvent is drained and the resin washed twice with portions of ether and 10 ml.

Broadcasting group hydrolized by dissolving the resin in 50 ml of 6 N. HCl and boiling under reflux the resulting solution for 24 hours in nitrogen atmosphere. The solution is cooled and extracted several times with chloroform. The aqueous layer was evaporated in vacuum and the obtained residue was dissolved in 20 - 25 ml of hot absolute ethanol, treated with activated charcoal and filtered. The filtrate is concentrated and add a few ml of dry acetone. While stirring this solution for several hours, a solid product. It is collected by filtration and recrystallized once from water/ethanol/acetone to obtain 3-(2-carboxy-2-phosphonoethyl)-1-(2-thioethyl)pyridine chloride.

Example 27. Synthesis of 2-hydroxy-2-phosphono-3-(3-pyridyl)propanoic acid

o
within 3 days. Excess dimethylphosphite removed on a rotary evaporator under high vacuum at a bath at a temperature of approximately 55oto obtain 21.1 g of a viscous orange oil. Its clean flash chromatography on silica gel using chloroform/methanol (20/1) as eluent. Get about 6 to 8 g of pure product.

II. Synthesis of 2-hydroxy-2-phosphono-3-(3-pyridyl)propanoic acid

About 6 g of the above ester was dissolved in 50 ml of 12 N. HCl and the solution heated under reflux for 5 hours. The solution is concentrated on a rotary evaporator to obtain a viscous oil. It is dissolved in approximately 5 ml of water and the flask RUB a glass rod to cause formation of solid product. The solid product is collected by filtration and washed with several milliliters of water. After drying at 76ounder high vacuum over night get pure 2-hydroxy-2-phosphono-3-(3-pyridyl)propanoic acid as a white solid product.

Example 28. Synthesis of 3-(2-carboxy-2-hydroxy-2-phosphonoethyl)-1-methylpyridinium chloride

< / BR>
This connection get soglasno 29. Synthesis of 3-(2-carboxy-2-hydroxy-2-phosphonoethyl)-1-ethylpyridinium chloride

< / BR>
This connection receive according to the method given in example 25, from 2-dimethoxyphosphinyl-2-hydroxy-3-(3-pyridyl)propanoate.

Example 30. Synthesis of 3-(2-carboxy-2-hydroxy-2-phosphonoethyl)-1-(2-thioethyl)pyridine chloride

< / BR>
This connection receive according to the method given in example 26, from 2-dimethoxyphosphinyl-2-hydroxy-3-(3-pyridyl)propanoate.

Example 31. Synthesis of dihydro-6-phosphono-1-pyridine-6-carboxylic acid

< / BR>
To 70 ml of anhydrous dimethyl sulfoxide (DMSO), stir in a nitrogen atmosphere in an ice bath, add 1.6 g of 60% NaH in mineral oil (0.04 mol). When it dissolves, add dropwise a solution of (still stirring at 0o) triethylphosphate (4,48 g, 0.02 mol) in DMSO. The reaction mixture was stirred at room temperature for one hour. To this mixture, then add a solution of 3.48 g (0.02 mol) of 2,3-bis(chloromethyl)pyridine (see D. Tsuda, et fl., Chem. Pharm. Bull. 1, 142 (1953)) in 15 ml DMSO. The mixture is stirred at room temperature for one hour and then at 80owithin 1 to 3 hours. DMSO is removed in vacuo and the residue purified flash chromatography on silica gel with ispolzovaniem under reflux in 6 B.C. HCl for 20 hours. When the concentration of the reaction solution and cooled on ice residue. It is recrystallized from water to obtain dihydro-6-phosphono-1-pyridine-6-carboxylic acid.

Example 32. Synthesis of dihydro-6-carboxy-1-methyl-6-phosphono-1 pyridine iodide

< / BR>
This connection receive according to the method of example 2 according dihydro-6-phosphono-1-pyridine-6-carboxylic acid.

Example 33. Synthesis of dihydro-6-carboxy-1-ethyl-6-phosphono-1 pyridine iodide

< / BR>
This connection receive according to the method of example 3 from dihydro-6-phosphono-1-pyridine-6-carboxylic acid.

Example 34. Synthesis of dihydro-6-carboxy-1-phenylmethyl-6-phosphono-1 pyridine bromide

< / BR>
This connection receive according to the method of example 4 from dihydro-6-phosphono-1-pyridine-6-carboxylic acid.

Example 35. Synthesis of dihydro-1-(2-(acetylthio)ethyl)-6-carboxy-6-phosphono-1 pyridine bromide

< / BR>
This connection receive by way of example of 5 based on dihydro-6-phosphono-1-pyridine-6-carboxylic acid.

Example 36. Synthesis of dihydro-6-carboxy-6-phosphono-1-(2-thioethyl)-1-pyridine chloride

< / BR>
A solution of 3.0 g dihydro-1-(2-acetylethyl)-6-carboxy-6-phosphono-1 pyridine bromide (pronzitelno 10 ml and add an equal volume of 12 N. HCl. The solution is placed in a nitrogen atmosphere and heated under reflux for 12 hours. The solution is concentrated to dryness and the residue is recrystallized from water/ethanol (minimizing the flow of air in a nitrogen atmosphere) to give the dihydro-6-carboxy-6-phosphono-1-(2-thioethyl)-1-pyridine chloride.

Example 37. Synthesis of octahydro-6-phosphono-1-pyridine-6-carboxylic acid

< / BR>
1.0 g of the Hydrochloride dihydro-6-phosphono-1-pyridine-6-carboxylic acid (example 31) in 50 ml of H2O with 0.5 g PtO2hydronaut in a Parr apparatus at 40 psi and 50owithin 3 days. The catalyst is filtered off and the filtrate evaporated to dryness. The obtained solid product is treated with a minimum amount of water and planted with ethanol to obtain octahydro-6-phosphono-1-pyridine-6-carboxylic acid.

Example 38. Synthesis of octahydro-1-methyl-6-phosphono-1-pyridine-6-carboxylic acid

< / BR>
A suspension of 2.0 g dihydro-6-carboxy-1-methyl-6-phosphono-1 pyridine iodide (example 32) and 1.0 g PtO2in 50 ml of water hydronaut at 40 psi and 50ofor 2 days in a Parr apparatus. After removal of catalyst by filtration, the filtrate is evaporated to dryness. The residue is recrystallized from water/acetone to obtain octahydro-1-methyl-6-phosphono-1-Piri is IDA

< / BR>
This connection receive according to the method of example 2 from octahydro-6-phosphono-1-pyridine-6-carboxylic acid.

Example 40. Synthesis of octahydro-6-carboxy-1-methyl-6-phosphono-1-phenylmethyl-1 pyridine bromide

< / BR>
This connection receive according to the method of example 4 from octahydro-1-methyl-6-phosphono-1-pyridine-6-carboxylic acid.

Example 41. Synthesis octahydro-1-(2-(acetylthio)ethyl)-6-carboxy-1 - methyl-6-phosphono-1 pyridine bromide

< / BR>
This connection receive according to the method of example 5 from octahydro-1-methyl-6-phosphono-1-pyridine-6-carboxylic acid.

Example 42. Synthesis octahydro-6-carboxy-1-methyl-6-phosphono-1-(2-thioethyl)pyridine chloride

< / BR>
This connection receive by way of example 36 from octahydro-(2-(acetylthio)ethyl)-6-carboxy-1-methyl-6-phosphono-1 pyridine bromide

Example 43. Synthesis of 2-phosphono-2-(2-pyridylthio)acetic acid

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I. Synthesis of ethyl 2-(diethoxyphosphoryl)-2-(2-pyridylthio)acetate

A suspension of 0.24 g (0.01 mol) of sodium hydride in 50 ml of anhydrous toluene is stirred in an ice bath in an atmosphere of dry nitrogen. To it is added dropwise 2.24 g (0.01 mol) of trimethylphosphate for more than 15 minutes. The reaction mixture was removed from ice bath and n is 2'-piperidinedione (2.20 g, 0.01 mol) in 30 ml of toluene. The reaction was stirred at 0oin for 1 hour and then add the second portion of NaH 2.24 g (0.01 mol). The reaction mixture is allowed to warm to room temperature and stirred for further 18 hours. Filtered and the filtrate evaporated in vacuum to obtain an oil, which was purified flash chromatography on silica gel with getting Trevira.

II. Synthesis of 2-phosphono-2-(2-pyridylthio)acetic acid

The above triavir (2.0 g) in 25 ml of 6 N. HCl is refluxed for 12 hours. The solution is evaporated in vacuum to dryness on a rotary evaporator. The residue is again dissolved in water and again evaporated to dryness in vacuo to remove HCl. The residue is treated with water and planted by the slow addition of ethanol to obtain 2-phosphono-2-(2-pyridylthio)acetic acid.

Example 44. Synthesis of 2-hydroxy-2-phosphono-4-(2-pyridylamino)butane acid

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I. Synthesis of ethyl-2-oxo-4-(2-pyridylamino)butanoate

A solution of 9.4 g (0.10 mol) of 2-aminopyridine and 12.8 g (0.10 mol) of ethyl 2-oxo-3-butenoate (example 1) in 50 ml of anhydrous tetrahydrofuran was stirred at 30 - 60owithin one day. The solvent is removed in vacuo and the resulting crude product was then purified flash chromatography on silica compound is l) ethyl 2-oxo-4-(2-pyridylamino)butanoate 6.9 g (0.05 mol) of diethylphosphate stirred at 20 - 30owithin 4 days. Excess diethylphosphate removed on a rotary evaporator under vacuum and the crude product is purified by chromatography on silica gel using chloroform/ethanol as eluent.

III. Synthesis of 2-hydroxy-2-phosphono-4-(2-pyridylamino)butane acid

The above tritely ester hydrolyzing boiling under reflux in 6 BC HCl in one day. Aqueous HCl is removed in vacuum and the residue is dissolved in water treated with activated carbon and filtered. The filtrate is again evaporated to dryness. The precipitate is dissolved in a few millimeters of water and add ethanol to the planting of the product. It is then recrystallized from water/ethanol to obtain hydroxy-2-phosphono-4-(2-pyridylamino)butane acid.

Example 45. Synthesis of 2-hydroxy-2-phosphono-4-((2-piperidinylidene)-amino)butane acid

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A mixture of 2-hydroxy-2-phosphono-4-(2-pyridinylamino)butane acid (1.5 g), 100 ml of distilled water and 0.5 g of a catalyst of palladium on coal hydronaut at 40 psi in a Parr apparatus for 2 days. The catalyst was removed by filtration and the filtrate evaporated to dryness in a vacuum. The resulting crude product was then purified, recrystallized from water/ethanol to obtain 2-hydroxy-2-palamino)butane acid

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I. Synthesis of ethyl 2-oxo-4-(3-pyridylamino)butanoate

A solution of 9.4 g (0.10 mol) of 3-aminopyridine and 12.8 g (0.10 mol) of ethyl 2-oxo-3-butenoate (example 1) in 50 ml of anhydrous tetrahydrofuran was stirred at 30 - 60owithin one day. The solvent is removed in vacuo and the resulting crude product was then purified flash chromatography on silica gel.

II. Synthesis of ethyl 2-diethoxyphosphoryl-2-hydroxy-4-(3-pyridylamino)butanoate

The mixture 3,36 g (0.01 mol) of ethyl 2-oxo-4-(3-pyridylamino)butanoate 6.9 g (0.05 mol) of diethylphosphate stirred at 20 - 30owithin 4 days. Excess diethylphosphate removed on a rotary evaporator under vacuum and the crude product is purified by chromatography on silica gel using chloroform/ethanol as eluent.

III. Synthesis of 2-hydroxy-2-phosphono-4-(3-pyridylamino)butane acid

The above tritely ester hydrolyzing boiling under reflux in 6 BC HCl in one day. Aqueous HCl is removed in vacuum and the residue is dissolved in water, treated with activated charcoal and filtered. The filtrate is again evaporated to dryness. The precipitate is again dissolved in a few milliliters of water and add ethanol to the planting of the product. It is then recrystallized from water/ESI-2-phosphono-3-(3-piperidylamine)butane acid

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A mixture of 1 g of 2-hydroxy-2-phosphono-4-(3-pyridylamino)butane acid and 0.5 g of the catalyst 10% Pd/C in 50 ml of distilled H2O is subjected to hydrogenation in a Parr apparatus at 40 psi for 2 days. The catalyst was removed by filtration and the filtrate is concentrated to a few milliliters. For the implementation of the planting of the product is slowly added ethanol and the product was then purified further by recrystallization from water/ethanol.

Example 48. Synthesis of 4-(2-(N,N-dimethylamino)ethylamino)-2-hydroxy-2-phosphonobutane acid

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I. Synthesis of ethyl 4-(2-(N,N-dimethylamino)ethylamino)-2-oxo-butanoate

A solution of 8.8 g (0.10 mol) of 2-(N,N-dimethylamino)ethylamine and 12.8 g (0.10 mol) of ethyl 2-oxo-3-butenoate (example 1) in 50 ml of anhydrous tetrahydrofuran is stirred at room temperature for one day. The solvent is removed in vacuo and the resulting crude product was then purified flash chromatography on silica gel.

II. Synthesis of ethyl 2-diethoxyphosphoryl-4-(2-(N,N-dimethylamino)ethylamino)-2-hydroxybutanoic

A mixture of 2.15 g (0.01 mol) of ethyl 4-(2-(N,N-dimethylamino)ethylamino)-2-oxobutanoate 6.9 g (0.05 mol) of diethylphosphate stirred at 20 - 30owithin 4 days. Excess diethylphosphate removed on a rotary evaporator under vacuum and S="ptx2">

III. Synthesis of 4-(2-(N, N-dimethylamino)ethylamino)-2-hydroxy-2-phosphonobutane acid

The above tritely ester hydrolyzing boiling under reflux in 6 BC HCl in one day. Aqueous HCl is removed in vacuum and the residue is dissolved in water, treated with activated charcoal and filtered. The filtrate is again evaporated to dryness. The precipitate is again dissolved in a few milliliters of water and add ethanol to the planting of the product. It is then recrystallized from water/ethanol to obtain 4-(2-(N,N-dimethylamino)ethylamino)-2-hydroxy-2-phosphonobutane acid.

Example 49. Synthesis of 4-(2-(N,N-dimethylamino)ethylamino)-2-hydroxy-2-phosphonobutane acid

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I. Synthesis of ethyl 4-(2-(N,N-dimethylamino)ethylthio)-2-oxo-butanoate

A solution of 10.5 g (0.10 mol) of 2-(N,N-dimethylamino)ethyl mercaptan and 12.8 g (0.10 mol) of ethyl 2-oxo-3-butenoate (see example 1) in 50 ml of anhydrous tetrahydrofuran is stirred at room temperature for one day. The solvent is removed in vacuo and the resulting crude product was then purified flash chromatography on silica gel.

II. Synthesis of ethyl 2-diethoxyphosphoryl-4-(2-(N,N-dimethylamino)ethylthio)-2-hydroxybutanoic

A mixture of 2.33 g (0.01 mol) of ethyl 4-(2-(N,N-dimethylamino)ethylthio)-2-exabout on a rotary evaporator under vacuum and the crude product is purified by chromatography on silica gel using chloroform/ethanol as eluent.

III. Synthesis of 4-(2-(N, N-dimethylamino)ethylthio)-2-hydroxy-2-phosphonobutane acid

The above tritely ester hydrolyzing boiling under reflux in 6 BC HCl in one day. Aqueous HCl is removed in vacuum and the residue is dissolved in water, treated with activated charcoal and filtered. The filtrate is again evaporated to dryness. The precipitate is again dissolved in a few mellitah water and add ethanol to the planting of the product. It is then recrystallized from water/ethanol to obtain 4-(2-(N, N-dimethylamino)ethylthio)-2-hydroxy-2-phosphonobutane acid.

Example 50. Synthesis of 2-hydroxy-3-(imidazo[1,2-a] pyridine-3-yl)-2-phosphonopropionic acid

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I. Synthesis of 3-(imidazo[1,2-a]pyridine)carboxaldehyde

A solution of 1.75 g (0.01 mol) of 3-(N,N-dimethylaminomethyl)-imidazo[1,2-a]pyridine (obtained as Lombardino, J. Org. Chem., 30,2403 (1965)) and 1.40 g (0.01 mol) of hexamethylenetetramine in 15 ml of 66% propanoic acid added for more than 2-3 hours to boiling under reflux a solution of 1.4 g of hexamethylenetetramine in 10 ml of 66% propanoic acid. The reaction mixture is heated under reflux for another 2 hours and then cooled to room temperature. Add water, resulting in the planting of 3-(imidazo[1,2-a] is requested, cooled ice suspension of 3.6 g (0.15 mol) of NaH in about 100 ml of anhydrous ether is added the mixture is 12.85 g (0,088 mol) 3-(imidazo[1,2-a] pyridine)carboxaldehyde and 23.4 g (0,178 mol) of N,N-dimethylglycinamide ester in 50 ml of ether. The addition of lead for more than one hour. The reaction mixture is stirred for about 18 hours, the time it warmed to room temperature. Then cool on ice and add about 50 ml of saturated aqueous NH4Cl. The layers are separated and the aqueous layer was extracted with ether. The combined organic layers dried and distilled in high vacuum to obtain 2-(N,N-dimethylamino)-3-(imidazo[1,2-a] pyridine)propanoate. It is treated with a mixture of ether (20 ml) and 1 N. HCl (20 ml) and rapidly stirred. Add conc. HCl to establish a pH of 1 or less. The water then extracted with ether to empty the ether extracts. Water is brought to pH 7 solid NaHCO3. The solid residue, which is collected by filtration, washed with water and dried to obtain ethyl 2-oxo-3-(imidazo[1,2-a] pyridine-3-yl)propanoate.

III. Synthesis of ethyl 2-diethoxyphosphoryl-2-hydroxy-3-(imidazo[1,2-a]pyridine-3 - yl)propanoate

A suspension of ethyl 2-oxo-3-(imidazo[1,2-a]pyridine-3-yl)-propanoate of 2.33 g (0.01 mol) of 5.5 g (0.05 mol) of dimethylphosphite stirred at CME with a bath temperature of about 55oobtaining a crude product. Its clean flash chromatography on silica gel to obtain 2-diethoxyphosphoryl-2-hydroxy-3-(imidazo[1,2-a]pyridine-3-yl)propanoate.

IV. Synthesis of 2-hydroxy-3-(imidazo[1,2-a]pyridine-3-yl)-2-phosphonopropionic acid

The above ester (1.5 g) hydrolyzing dissolved in 20 ml of 12 N. HCl and heating the solution under reflux for 6 hours. The solution is evaporated to dryness on a rotary evaporator. Add distilled water (20 ml) and the solution again evaporated to dryness. The residue is recrystallized from the minimum required quantity of hot water, obtaining 2-hydroxy-3-(imidazo[1,2-a]pyridine-3-yl)-2-phosphonopropionic acid.

Example 51. Synthesis of 2-hydroxy-2-phosphono-3-(2-pyridinyl)propanoic acid

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I. Synthesis of ethyl 2-diethoxyphosphoryl-2-hydroxy-3-(2-pyridyl)propanoate

Suspension 11,64 g (to 0.060 mol) of ethyl 2-oxo-3-(2-pyridinyl)propanoate (synthesized from pyridine 2-carboxaldehyde by analogy obtain the pyridine 3-carboxaldehyde in Liebig''s Annalen der Chemie, 703, 37-43 (1967)) in 30,13 g (0,274 mol) of dimethylphosphite stirred at 20 - 30owithin 3 days. Excess dimethylphosphite removed on a rotary evaporator under high vacuum at a bath temperature of about 55osince p is a (20/1) as eluent.

II. Synthesis of 2-hydroxy-2-phosphono-3-(2-pyridinyl)propanoic acid

About 6 g of the above ester was dissolved in 50 ml of 12 N. HCl and the solution heated under reflux for 5 hours. The solution is concentrated on a rotary evaporator to obtain a viscous oil. It is dissolved in approximately 5 ml of water and the flask RUB a glass rod for planting solid product. The solid product is collected by filtration and washed with several milliliters of water. It is dried in a desiccator to obtain 2-hydroxy-2-phosphono-3-(2-pyridinyl)propanoic acid.

Example 52. Synthesis of 2-(2-carboxy-2-hydroxy-2-phosphonoethyl)-1-methylpyridinium chloride

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This connection will get in the manner given in example 24, from ethyl 2-diethoxyphosphoryl-2-hydroxy-3-(2-pyridyl)propanoate (example 51).

Example 53. Synthesis of 2-(2-carboxy-2-hydroxy-2-phosphonoethyl)-1-ethylpyridinium chloride

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This connection receive according to the method given in example 25, from ethyl 2-dimethoxyphosphinyl-2-hydroxy-3-(2-pyridyl)propanoate (example 51).

Example 54. Synthesis of 2-(2-carboxy-2-hydroxy-2-phosphonoethyl)-1-(2-thioethyl)pyridine chloride

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This connection receive according to the method given in example 26, Ishigaki-3-(1-methyl-2-piperidinyl)-2-phosphonopropionic acid

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A mixture of 1 g of 1-methyl-2-(2-carboxy-2-hydroxy-2-phosphonoethyl)pyridine iodide and 0.5 g of a catalyst of palladium on coal in 50 ml of distilled water hydronaut at 40 psi in a Parr apparatus for 2 days. The catalyst was removed by filtration and the filtrate evaporated to dryness. The residue is treated with ethanol to obtain a solid product, which is collected by filtration. It recrystallization gives 2-hydroxy-3-(1-methyl-2-piperidinyl)-2-phosphonopropionic acid.

Example 56. Synthesis of N, N-dimethyl-2-(2-carboxy-2-hydroxy-2-phosphonoethyl)piperidine iodide

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This connection receive according to the method of example 2 based on hydroxy-3-(1-methyl-2-piperidinyl)-2-phosphonopropionic acid.

Example 57. Synthesis of N-ethyl-N-methyl-2-(2-carboxy-2-hydroxy-2-phosphonoethyl)piperidine iodide

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This connection receive according to the method of example 3 based on hydroxy-3-(1-methyl-2-piperidinyl)-2-phosphonopropionic acid.

Example 58. Synthesis of N-[2-(acetylthio)ethyl] -N-methyl-2-(2-carboxy-2-hydroxy-2-phosphonoethyl)piperidine bromide

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This connection receive by way of example of 5 based on hydroxy-3-(1-methyl-2-piperidinyl)-2-phosphonopropionic acid

Example 59. Synthesis of N-methyl-N-(2-thioethyl)-2-(2-carboxy-2-g is N-[2-(acetylthio)ethyl]-N-methyl-2-(2-carboxy-2-hydroxy-2 - phosphonoethyl)piperidine bromide

Example 60. Synthesis of 2-hydroxy-3-(2-piperidinyl)-2-phosphonopropionic acid

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A mixture of 1 g of 2-hydroxy-2-phosphono-3-(2-pyridinyl)propanoic acid and 0.5 g of a catalyst of palladium on coal in 50 ml of distilled water hydronaut at 40 psi in a Parr apparatus for 2 days. The catalyst was removed by filtration and the filtrate is concentrated to a few milliliters. Slowly add ethanol for planting solid product, which is collected, recrystallized from water/ethanol to obtain 2-hydroxy-3-(2-piperidinyl)-2-phosphonopropionic acid.

Example 61. Synthesis of 2-hydroxy-3-(3-piperidinyl)-2-phosphonopropionic acid

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This connection receive by way of example 60 from 2-hydroxy-2-phosphono-3-(3-piperidinyl)propanoic acid.

Example 62. Synthesis of 2-hydroxy-3-(1-methyl-3-piperidinyl)-2-phosphonopropionic acid

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This connection receive by way of example 55 from 3-(2-carboxy-2-hydroxy-2-phosphonoethyl)-1-methylpyridinium chloride.

Example 63. Synthesis of N, N-dimethyl-3-(2-carboxy-2-hydroxy-2-phosphonoethyl)piperidine iodide

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This connection receive according to the method of example 2 from 2-hydroxy-3-(1-methyl-3-piperidinyl)-2-phosphonopropionic kisloid

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This connection receive by way of example of 5 based on hydroxy-3-(1-methyl-3-piperidinyl)-2-phosphonopropionic acid.

Example 65. Synthesis of N-methyl-N-(2-thioethyl)-3-(2-carboxy-2-hydroxy-2-phosphonoethyl)piperidine chloride.

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This connection receive according to the method of example 6 from N-[2-(acetylthio)ethyl]-N-methyl-3-(2-carboxy-2-hydroxy-2 - phosphonoethyl)piperidine bromide.

Example 66. Prepare capsules having the following composition:

Active ingredient - ml capsule

2-Hydroxy-2-phosphono-3-(pyridyl)propanoic acid - 350,0

Fillers

Lactose - 90,0

Microcrystalline cellulose - 60,0

Magnesium stearate - 1,0

Capsules having the above composition, get the regular ways, as described below.

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

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

The mixture is again placed in a mixer with a rotating casing with lactose and then stirred for approximately fifteen (15) minutes.

Then add the magnesium stearate and mix on the Sabbath.

Any compound obtained according to examples 1 to 65, can be used as the active ingredient in the above capsule.

Example 67. Prepare tablets having the following composition:

The active ingredient mg per tablet

3-(2-carboxy-2-hydroxy-2-phosphonoethyl)-1-(2-thioethyl)pyridine chloride - 700,00

Fillers

Lactose (spray dried) - 200,0

Starch (1500) - 100,0

Magnesium stearate - 25,0

Tablets having the above composition, get the regular ways, as described below.

The active ingredient melyat in a ball mill for about 30 minutes. Ground active ingredient is then mixed in dahejia mixer with spray dried lactose approximately 20 minutes.

To add starch mixture and then the mixture is additionally stirred for approximately fifteen (15) minutes. The mixture is pressed into tablets on a standard tablet press.

Any compound obtained according to examples 1 to 65, can be used as the active ingredient in the above tablet.

Example 68. Injectable solutions are prepared by conventional means using 10.0 ml of physiological solution and 7.0 m the structure of hypercalcemia patient weighing approximately 70 kilograms.

Any compound obtained according to examples 1 to 65, can be used as the active ingredient in the above injection.

Example 69. Male Caucasian, weighing approximately 92 kg, 72 years old, suffering from medium strength and strong pain and occasional swelling in the right knee joint. After approximately one year of ever-increasing discomfort, he visited a doctor who was diagnosed with osteoarthritis in the right knee joint, that was confirmed by x-ray.

After a period of facilitating the treatment of various NSAIDs, including aspirin, naproxen and Ketoprofen, the symptoms continued to worsen and the condition to worsen. He again turned to his doctor, who prescribed the tablets obtained as described in example 67, twice a day for two hours before and after meals for three months. Its clinical symptoms are pain and swelling, especially at the long walk, significantly improved after three months of therapy. Upon completion of three months dose 2 tablets a day treatment lasted at half the dose from the prescribed initially (i.e. 1 tablet per day).

Example 70. Black woman, weighing approximately 65 pounds, 55 years old, complains of ouhsaine and x-ray examinations and a variety of appropriate clinical experiences, approved by the American Association of rheumatologists (ARA), was diagnosed with rheumatoid arthritis.

After unsuccessful analgesic and anti-inflammatory therapy your doctor has prescribed the tablets obtained in example 67, twice a day for two hours before and after a meal for four months. After a month of therapy symptoms swelling of the joints significantly improved and the degree of mobility of the fingers has increased significantly; she continued the treatment until the completion of four months, after which the doctor continued the prescription dose by an additional two months.

Example 71. Girl of Spanish origin, eleven years old, weighs approximately 37 pounds, complains to the doctor for idiopathic juvenile rheumatoid arthritis. Its symptoms include inflammation of many joints, accompanied by fever and pain and observed a fast and pathological change in the function of the joints.

The doctor sent a girl to the rheumatologist, who immediately ordered to active therapy by intravenous solution, obtained as described in example 68, within three days, with an intensity of 1 injection per day, administered within two hours. After intravenous course doctor has prescribed tussinee in improving mobility and reducing pain. In the next two months, the doctor reduced the dose to 3/4 of the original oral dose of the prescribed 3 tablets for 2 days, one 2-day tablet is replaced by 1-day tablet. Upon completion of this course, the dose was again reduced to 1/4 of the original dose, giving her 1 tablet, obtained as described in example 67, every day for four months.

Example 72. 60-year-old female Caucasian, weighing 62 kg, was experiencing severe back pain. Her doctor with the help of a radiologist diagnosed her destruction at crushing L1 vertebrae due to osteoporotic bone loss. The patient is prescribed a three-month course for one day 700 milligrammes tablet obtained according to the method described in example 67. 700 milligrammes take a pill two hours before or two hours after any given meal. After three months the dosage was reduced to 350 milligrammes capsules, obtained as described in example 66, taken every second day for three months. The doctor then ordered to be on the mode maintenance dose when it takes 100 kg capsule every day for six months. After six months course maintenance dose, the patient did not experience any more spinal was baradla from a hip fracture after a fall. She was hospitalized and she was diagnosed with osteoporosis. The course of treatment prescribed calcitonin injections. Calcitonin injections painful for the patient, and she was unable to complete the course. The doctor eased the treatment, appointing oral course of phosphonate. It took 700 milligramme tablets obtained according to the method described in example 67, twice a day for months. At the end of this one month she took one 700 milligrammes pill a day for two months. Upon completion of this two-month period it took 100 milligrammes capsule, obtained according to the method described in example 66, every day for three months. The subsequent visit to the doctor found no decrease in mineral density in the hip, as established by photoabsorption.

Example 74. 85-year-old native American, weighing 65 kg, complains to the doctor for severe back pain. X-ray set multiple minor crushing of the vertebrae, resulting in significant loss of bone caused by osteoporosis. The patient is prescribed a two-month course 700 milligrammes tablets and 350 milligrammes capsules taken in one day, separately, through the on mode, the dosage was reduced to 350 milligrammes pills a day for two months. X-rays showed no new razdavlivanii. Then the patient was on maintenance dose, 100 milligrammes capsule, obtained according to the method described in example 66, every day for six months. After six months there has been a visible manifestations of lowered bone density.

1. Pharmaceutical composition for treating conditions caused by abnormal calcium or phosphate metabolism, containing phosphonocarboxylate derivative as an active substance and a pharmaceutically acceptable carrier, characterized in that it contains as specified derivative compound of formula I

< / BR>
where (A) (1) And is selected from the group consisting of hydrogen, halogen, SR1, R2SR1, amino, hydroxy and substituted or unsubstituted WITH1- C8-alkyl;

(2) means (a) NH2(b) saturated or unsaturated WITH1- C15is an alkyl chain substituted by one or more substituents selected from the group consisting of-R3N(R4)2, -R3[-N(R5)3]+, -R3N(R4)C(O)R4, -R3N(R4)C (S)R4, -R3N(R4)C(N)R4and R3C(O)N(R4)2,

(C) substituted or nezam is it of these atoms is nitrogen, (d) substituted or unsubstituted, saturated or unsaturated heteroalkyl chain containing from 2 to 15 atoms in the chain, where one or more of these atoms selected from S and O, and where specified heteroalkyl chain substituted by one or more substituents selected from the group consisting of-R3N(R4)2, -R3[-N(R5)3]+, -R3N(R4)C(O)R4, -R3N(R4)C(S)R4,

-R3N(R4)C(N)R4and R3C(O)N(R4)2or (e) R6- L-, where (i) L is absent or selected from the group consisting of N, -N(R5)3+, S, O, substituted or unsubstituted, saturated or unsaturated WITH1- C15is an alkyl chain and substituted or unsubstituted, saturated or unsaturated heteroalkyl chain containing from 2 to 15 atoms in the chain, where one or more of these atoms selected from N, S and O, and (ii) R6selected from the group containing saturated monocyclic or polycyclic carbocyclic ring, unsaturated monocyclic or polycyclic carbocyclic ring, saturated monocyclic or polycyclic heterocyclic ring and an unsaturated monocyclic or polycyclic heterocyclic rings, where R6What SUP>SR1substituted or unsubstituted WITH1- C8-alkyl, -R3O R4, -R3CO2R4, -R3O2CR4, -R3N(R4)2, -R3[-N(R5)3]+, -R3N(R4)C(O)R4, -R3N(R4)C(S)R4,

-R3N(R4)C(N)R4, -R3C(O)N(R4)2, halogen, -R3C(O)R4arylalkyl, nitro, substituted or unsubstituted aryl and hydroxy, and (3) (a) R1independently selected from the group consisting of hydrogen, -C(O)R7, -C(S)R7, -C(O)N(R7)2, -C(S)N(R7)2, -C(O)OR7and-C(S)OR7where R7is hydrogen or substituted or unsubstituted WITH1- C8-alkyl, (b) R2is substituted or unsubstituted WITH1- C8-alkyl, (C) R3absent or selected from the group consisting of substituted or unsubstituted WITH1- C8-alkyl, (d) R4 is independently selected from the group consisting of hydrogen, substituted or unsubstituted WITH1- C8-alkyl and R2S R1and (f) R5independently selected from the group consisting of substituted or unsubstituted WITH1- C15-alkyl, substituted or unsubstituted phenyl, benzyl and R2SR1or (C) a and b are covalently bound with*what denotes a substituted or unsubstituted, saturated or unsaturated carbocyclic ring containing*X and X', with the specified carbocyclic ring has from 3 to 6 carbon atoms, or a substituted or unsubstituted, saturated or unsaturated heterocyclic ring containing FROM*X and X', with the specified heterocyclic ring has from 4 to 6 atoms, where one or more of these ring atoms is N, O or S, (2) V is absent or represents substituted or unsubstituted, saturated or unsaturated carbocyclic ring containing X and X', with the specified carbocyclic ring has from 3 to 8 carbon atoms, or a substituted or unsubstituted, saturated or unsaturated heterocyclic ring containing X and X', with the specified heterocyclic ring has from 3 to 8 atoms, where one or more of these ring atoms is N, O or S, and (3) X and X' independently denote N or C, except that if neither V nor W are nitrogen-containing heterocycle, then at least one of V or W is substituted by one or more substituents selected from the group consisting of-R3N(R4)2, -R3[-N(R5)3]+, -R3N(R4)C(O)R4, -R3

2. The composition according to p. 1, characterized in that it contains a compound of the formula (I), where a denotes hydroxy and denotes a substituted or unsubstituted, saturated or unsaturated heteroalkyl chain containing from 2 to 15 atoms in the chain, where one or more of these atoms is nitrogen, or represents R6-L-, where L denotes N, -N(R5)+3WITH1- C15is an alkyl chain or a nitrogen-containing heteroalkyl containing from 2 to 15 atoms in the chain, and where R6is a monocyclic or a polycyclic heterocycle or carbocycle.

3. The composition according to p. 2, characterized in that it contains a compound of the formula I, where In denotes the R6-L - and L denotes the N1- C15is an alkyl chain substituted by one or more substituents selected from the group consisting of-R3SR1hydrogen, substituted or unsubstituted WITH1- C8-alkyl, -R3OR4and R3CO2R4or heteroalkyl chain containing from 2 to 15 atoms in the chain, substituted by one or more substituents selected from the group consisting of-R3SR1hydrogen, -R3N(R4)2, -R3[-N(R5)3]+and R3N(R4)C(O)R4.

4th or unsubstituted six-membered monocyclic heterocycle, selected from the group consisting of pyridine, pyrimidine, piperidine, pyridine, pyrimidine and piperidine, substituted or unsubstituted five-membered monocyclic heterocycle selected from the group consisting of imidazole, pyrrole, pyrrolidine, imidazole, pyrrole and pyrrolidine, substituted or unsubstituted monocyclic carbocycle selected from the group consisting of cycloheptyl or cyclohexyl, substituted or unsubstituted polycyclic heterocycle having the six-membered ring condensed with a five-membered ring selected from the group consisting of indole, indole, Prindin, imidazole-(1,2-a)pyridine, imidazole-(1,2-a)pyridine and pyridine, or substituted or unsubstituted polycyclic heterocycle having the six-membered ring fused with a six-membered ring selected from the group consisting of quinoline, isoquinoline, tetrahydroquinoline, octagenarian, chinoline, skinline, tetrahydroindole and octahydrophenanthrene.

5. The composition according to p. 4, characterized in that it contains a compound of the formula I, where R6substituted by one or more substituents selected from the group consisting of-R3SR1hydrogen, -R3N(R4)2, -R3[-N(R5)3]+and R3N (gorodom, R3absent and R4is hydrogen.

6. The composition according to p. 2, characterized in that it contains a compound of the formula I, where a denotes a substituted or unsubstituted, saturated or unsaturated heteroalkyl chain containing from 2 to 15 atoms in the chain, where one or more of these atoms is nitrogen and where specified heteroalkyl chain substituted by one or more substituents selected from the group consisting of-R3SR1hydrogen, substituted or unsubstituted WITH1- C8-alkyl, -R3OR4, -R3CO2R4, -R3N(R4)2, -R3[-N(R5)3]+and R3N(R4)C(O)R4. 7. The composition according to p. 1, characterized in that it contains a compound of the formula I, where a and b together with*form a bicyclic ring, where W represents a five-membered carbocyclic ring, and where V denotes a five-membered heterocyclic ring containing at least one nitrogen atom in the ring, or preferably six-membered heterocyclic ring containing at least one nitrogen atom in the ring.

8. The composition according to p. 7, characterized in that it contains a compound of the formula I, where the specified bicyclic ring semashev>8-alkyl, -R3OR4, -R3O2R4, -R3N(R4)C(S)R4, -R3N(R4)C(N)R4, -R3C(O)N(R4)2,

-R3SR1hydrogen, -R3CO2R4, -R3-N(R4)2R3[-N(R5)3]+and R3N(R4)C(O)R4, R3no, R4is-R3SR1or hydrogen and R1is-C(O)R7, -C(S)R7C(O)N(R7)2or preferably hydrogen.

9. Pharmaceutical composition for treating conditions caused by abnormal calcium or phosphate metabolism, containing phosphonocarboxylate derivative as an active substance and a pharmaceutically acceptable carrier, characterized in that it contains as specified derivative compound of formula II

< / BR>
where (A) (1) And denotes hydroxy and (2) means

< / BR>
where (a) m denotes an integer from 0 to 10, n represents an integer from 0 to 10 and m+n represents an integer from 0 to 10, (b) R8absent or independently selected from the group consisting of-R3SR1hydrogen, substituted or unsubstituted WITH1- C8alkyl, -R3OR4, -R3CO2R4, -R3O2CRUP>N(R4)C(S)R4, -R3N(R4)C(N)R4, -R3C(O)N (R4)2, halogen, -R3C(O)R4, nitro, hydroxy, substituted or unsubstituted saturated monocyclic or polycyclic carbocyclic rings, substituted or unsubstituted unsaturated monocyclic or polycyclic carbocyclic rings, substituted or unsubstituted saturated monocyclic or polycyclic heterocyclic rings and substituted or unsubstituted unsaturated monocyclic or polycyclic heterocyclic rings, (C) R1independently selected from the group consisting of hydrogen, -C(O)R7, -C(S)R7, -C(O)N(R7)2, -C(O)OR7, -C(S)N(R7)2and-C(S)OR7where R7is hydrogen or substituted or unsubstituted WITH1- C8-alkyl, (d) R3absent or selected from the group consisting of substituted or unsubstituted WITH1- C8-alkyl, (e) R4independently selected from the group consisting of hydrogen, substituted or unsubstituted WITH1- C8-alkyl and R2SR1and (f), R5independently selected from the group consisting of substituted or unsubstituted WITH1- C15-alkyl, substituted or unsubstituted phenyl, benzyl and R28)- , or when L is [-N(R5)2-]+and m denotes an integer from 1 to 10, R9absent or independently selected from the group consisting of hydrogen, substituted or unsubstituted WITH1- C35-alkyl, R2SR1and R10(ii) when is [-N(R5)2-]+and n=0, R9selected from the group consisting of substituted or unsubstituted WITH1- C35-alkyl, R2S R1and R10or (iii) when L is absent or is-S-, -O - or-D-C-(=E)-S, R9is R10, (h) R10is a saturated, unsaturated or aromatic monocyclic or polycyclic by carbocycle or a saturated, unsaturated or aromatic monocyclic or a polycyclic heterocycle containing one or more heteroatoms, where the specified carbocycle or heterocycle substituted by one or more substituents R11and (i) each R11independently selected from the group consisting of-R3SR1hydrogen, substituted or unsubstituted WITH1- C8-alkyl, -R3OR4, -R3CO2R4, -R3O2CR4, -R3N(R4)2UP>4
)C(N)R4, -R3C(O)N(R4)2, halogen, -R3C(O) R4, hydroxy, substituted or unsubstituted arylalkyl, nitro and unsubstituted or substituted aryl, or (C) a and b, covalently associated with*form a monocyclic or bicyclic ring having the following structure;

< / BR>
where (a) a and b is either absent or are independently selected from the group of-O-, -S, - NR12-, (b) Q is absent or selected from the group consisting of-NR12- [- N(R13)2-]+(c) X and X' are independently selected from C or N; (d) R12absent or independently selected from the group consisting of-R3SR1hydrogen, substituted or unsubstituted WITH1- C8-alkyl, -R3OR4, -R3CO2R4, -R3O2CR4,

-R3N(R4)2, -R3[-N(R5)3]+, -R3N(R4)C(O)R4, -R3C(O)N (R4)2, halogen, -R3C(O)R4, hydroxy, substituted or unsubstituted arylalkyl, nitro and unsubstituted or substituted aryl, (e) R13absent or independently selected from the group consisting of substituted or unsubstituted WITH1- C35-alkyl, substituted or unsubstituted phenyl, benzyl and R2SR1(f) when Q is constituted the q and p+q are independently an integer from 0 to 3, except that when Q is absent, at least one of RNor R12selected from the group consisting of-R3N(R4)2, -R3[-N(R5)3]+,

-R3N(R4)C(O)R4, -R3N(R4)C(S)R4, -R3N(R4)C(N)R4and R3C(O)N(R4)2. 10. Phosphonocarboxylate and its pharmaceutically acceptable salt having the structure according to the formula I

< / BR>
(A) (1) refers to (a) -NH2, (C) saturated or unsaturated WITH1- C15is an alkyl chain substituted by one or more substituents selected from the group consisting of-R3N (R4)2, -R3[-N(R5)3]+, -R3N(R4)C(O)R4, -R3N(R4)C(S)R4, -R3N (R4)C(N)R4and R3C(O)N(R4)2(c) substituted or unsubstituted, saturated or unsaturated heteroalkyl chain containing from 2 to 15 atoms in the chain, where one or more of these atoms is a nitrogen, (d) substituted or unsubstituted, saturated or unsaturated heteroalkyl chain containing from 2 to 15 atoms in the chain, where one or more of these atoms selected from S and O, and where specified heteroalkyl chain substituted by one or more substituents(R4)C(O)R4, -R3N(R4)C(S)R4, -R3N (R4)C(N)R4and R3C(O)N(R4)2or (e) R6-L-, where (i) L is absent or selected from the group consisting of N, -N(R5)+3; S, O, substituted or unsubstituted WITH1- C15is an alkyl chain and substituted or unsubstituted, saturated or unsaturated heteroalkyl chain containing from 2 to 15 atoms in the chain, where one or more of these atoms selected from N, S or O, and (ii) R6selected from the group containing saturated monocyclic or polycyclic carbocyclic ring, not saturated monocyclic or polycyclic carbocyclic ring, saturated monocyclic or polycyclic heterocyclic ring and an unsaturated monocyclic or polycyclic heterocyclic rings, where R6may be substituted by one or more substituents independently selected from the group consisting of hydrogen, -R5SR1substituted or unsubstituted WITH1- C8-alkyl, R3OR4, -R3CO2R4, -R3O2CR4, -R3N(R4)2, -R3[-N(R5)3]+, -R3N(R4)C(O)R4, -R3N(R4)C(S)R4, -R3N(R4)Stonemany aryl and hydroxy, and (2) (a) when is piridilsoderzhashchimi radical, a radical containing a Quaternary nitrogen, or sulfur-containing moiety And selected from the group consisting of hydrogen, halogen, SR1, R2SR1, amino, hydroxy and substituted or unsubstituted WITH1- C8alkyl, or (b) when different from paradiseparadise radical, a radical containing a Quaternary nitrogen, or serosoderjaschei radical And selected from the group consisting of halogen, SR1, R2SR1, amino and hydroxy, and (3) (a) R1independently selected from the group consisting of hydrogen, -C(O)R7, -C(S)R7, -C(O)N(R7)2, -C(O)OR7, -C(S)N(R7)2and-C(S)OR7where R7is hydrogen or a saturated or unsaturated WITH1- C8-alkyl, (b) R2is substituted or unsubstituted WITH1- C8-alkyl, (C) R3absent or selected from the group consisting of substituted or unsubstituted WITH1- C8-alkyl, (d) R4independently selected from the group consisting of hydrogen, substituted or unsubstituted WITH1- C8-alkyl and R2S R1and (e) R5independently selected from the group consisting of substituted or unsubstituted WITH1- C15-alkyl, substituted or unsubstituted, or a bicyclic ring, having the following structure:

< / BR>
where (1) W denotes a substituted or unsubstituted, saturated or unsaturated carbocyclic ring containing*X and X', with the specified carbocyclic ring has from 3 to 6 carbon atoms, or a substituted or unsubstituted, saturated or unsaturated heterocyclic ring containing FROM*X and X', with the specified heterocyclic ring has from 4 to 6 atoms, where one or more of these ring atoms is N, O or S, (2) V is absent or represents substituted or unsubstituted, saturated or unsaturated carbocyclic ring containing X and X', with the specified carbocyclic ring has from 3 to 8 carbon atoms or a substituted or unsubstituted saturated or unsaturated heterocyclic ring containing X and X', with the specified heterocyclic ring has from 3 to 8 atoms, where one or more of these ring atoms is N, O or S, and (3) X and X' independently denote N or C, except that if V is different from the nitrogen-containing heterocycle, then at least one of V or W is substituted by one or more substituents selected from the group consisting of-R3N (R4)<3N (R4)C(N)R4and R3C(O)N(R4)2.

11. Phosphonocarboxylate and their pharmaceutically acceptable salts, having the General structural according to the formula II

< / BR>
where (A) (1) And denotes hydroxy and (2) means

< / BR>
where (a) m denotes an integer from 0 to 10, n represents an integer from 0 to 10 and n+m represents an integer from 0 to 10, (b) R8absent or independently selected from the group consisting of-R3SR1hydrogen, substituted or unsubstituted WITH1- C8-alkyl, -R3OR4, -R3CO2R4, -R3O2CR4, -R3N(R4)2, -R3[-N(R5)3[+, -R3N(R4)C(O)R4, -R3N(R4)C(S)R4, -R3N(R4)C(N)R4, -R3C(O)N(R4)2, halogen, -R3C(O)R4, nitro, hydroxy, substituted or unsubstituted saturated monocyclic or polycyclic carbocyclic rings, substituted or unsubstituted unsaturated monocyclic or polycyclic carbocyclic rings, substituted or unsubstituted saturated monocyclic or polycyclic heterocyclic rings and substituted or unsubstituted unsaturated monocyclic or SUP>, -C(O)N(R7)2, -C(O)OR7, -C(S)N(R7)2and-C (S)OR7where R7is hydrogen or a saturated or unsaturated WITH1- C8-alkyl, (d) R3missing or represents substituted or unsubstituted WITH1- C8-alkyl, (e) R4independently selected from the group consisting of hydrogen, substituted or unsubstituted WITH1- C8-alkyl, and R2SR1and (f), R5independently selected from the group consisting of substituted or unsubstituted WITH1- C15-alkyl, substituted or unsubstituted phenyl, benzyl and R2SR1(g) L is absent or selected from the group consisting of-N(R8)-, [-N(R5)2]+, -S-, -O-, -D-C(=E)-S-, where D is selected from the group consisting of covalent bond, O or S, and E represents O or S, and where (i) when L is-N(R8)- , or when L is [-N(R5)2]+and m denotes an integer from 1 to 10, R9absent or independently selected from the group consisting of hydrogen, substituted or unsubstituted WITH1- C15-alkyl, R2SR1and R10(ii) when L is [-N(R5)2]+and m = 0, R9selected from the group consisting of substituted or unsubstituted WITH1- C35-alkyl, R2SR1and R10or authorized, unsaturated or aromatic monocyclic or polycyclic by carbocycle or a saturated, unsaturated or aromatic monocyclic or a polycyclic heterocycle including T and containing one or more heteroatoms, where the specified carbocycle or heterocycle substituted by one or more substituent R11and (i) each R11independently selected from the group consisting of-R3SR1hydrogen, substituted or unsubstituted WITH1- C8-alkyl, R3OR4, -R3CO2R4,

-R3O2CR4, -R3N(R4)2, -R3[-N(R5)3]+, -R3N(R4)C(O)R4, -R3N(R4)C(S)R4,

-R3N(R4)C(N)R4, -R3C(O)N(R4)2, halogen, -R3C(O)R4, hydroxy, substituted or unsubstituted arylalkyl, nitro and unsubstituted or substituted aryl, or (C) a and b, covalently associated with*form a monocyclic or bicyclic ring having the following structure:

< / BR>
where (a) a and b are absent or are independently selected from the group consisting of-O-, -S - and-NR12-, (b) Q is absent or selected from the group consisting of-NR12- [-N(R13)2]+, (C) X and X' are independent the location, substituted or unsubstituted WITH1- C8-alkyl, -R3OR4, -R3CO2R4, -R3O2CR4,

-R3N(R4)2, -R3[-N(R5)3]+, -R3N(R4)C(O)R4, -R3C(O)N(R4)2, halogen, -R3C(O)R4, hydroxy, substituted or unsubstituted arylalkyl, nitro and unsubstituted aryl, (e) R13absent or selected from the group consisting of substituted or unsubstituted WITH1- C15-alkyl, substituted or unsubstituted phenyl, benzyl, and R2SR1(f) when Q is present, k and j and k+j is an integer from 0 to 5, and when Q is absent, k and j and k+j is an integer from 0 to 6, (g) p and q and p+q are independently an integer from 0 to 3, except that, if Q is absent, at least one of R11or R12selected from the group consisting of-R3N (R4)2, -R3[-N(R5)3]+, -R3N(R4)C(O)R4, -R3N(R4)C(S)R4, -R3N(R4)C(N)R4and R3C(O)N(R4)2.

 

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< / BR>
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FIELD: medicine, ophthalmology.

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2 cl, 7 dwg, 2 ex

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