Derivatives methylenephosphonic acid

 

(57) Abstract:

Usage: in medicine as shapers of the complexes in the regulation of metabolism of the body. The inventive products: derivatives metalliferous acid f-ly I

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where R1, R2, R3and R4independently are C1-C22- alkyl or hydrogen, Q1and Q2- chlorine, provided that one of the groups R1-R4is hydrogen and at least one of the groups R1-R4other than hydrogen, including stereoisomers and pharmaceutically acceptable salts. Reagent 1: tetraeder methylenephosphonic acid. Reagent 2: water. Reaction conditions: in the presence of inorganic or organic acids or bases at 20 - 150oC. for 6 h.p. f-crystals, 1 table.

The invention relates to new derivatives methylenephosphonic acid, in particular to new halogensubstituted partial esters methylenephosphonic acid and salts of esters, as well as to methods of producing these new connection, as well as pharmaceutical compositions containing these new compounds.

In several publications disclosed methylenephosphonate acids, their salts or some complex TETRAPOL (incomplete esters). In U.S. patent 4478763 (1984) described a new method for producing asymmetric complex isopropyl esters (mono - and deformation)bisphosphonic acids. As other publications that reveal the fluorine-substituted compounds, may be mentioned the following: J.Org. Chem, 51 (1986), 4788, J. Am. Chem. Soc (1987), 5542 and Bioorg. Chem (1988) III. Thus the properties of the new partial esters (halogenation) bisphosphonic acids and their salts according to the invention, as well as their use as pharmaceuticals, have not been previously investigated.

According to the invention it was found that the new partial esters methylenephosphonic acids and their salts, in many cases, have more favorable properties than the corresponding bisphosphonic acids and their salts due to their better kinetics and lack of scarcity, their ability to participate as shapers of the complexes in the regulation of metabolism of the supported body.

In addition, they are well suitable for treating disorders related to calcium metabolism and others, especially ferrous metals. They can be used to treat diseases in the skeletal system, in particular disorders of bone formation and rascal violation of the terms of deposits and mineralization and bone formation.

New salts and esters bisphosphonic acids regulate, either directly or through intermediate mechanism the level of cations, freely present in body fluids, as well as cations bind to the tissues, active in, and secreted from them. Thus, they are able to regulate cellular metabolism, growth and destruction. Therefore, they are useful for the treatment of, for example, bone cancer and its metastasis, ectopic calificaci, urolithiasis, rheumatoid arthritis, bone infections and destruction of bones.

The invention concerns new derivatives methylenephosphonic acid of General formula I

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in which R1, R2, R3and R4independently of one another denote C1-C22-alkyl, C2-C22alkenyl, C2-C22-quinil, C3-C10-cyclooctyl, C3-C10-cycloalkenyl, aryl, aralkyl, silyl or hydrogen, in formula I at least one of the groups R1, R2, R3and R4denotes hydrogen, and at least one of the groups R1, R2, R3and R4is not a hydrogen atom, Q1denotes hydrogen, fluorine, chlorine, bromine or iodine, and Q2denotes chlorine, bromine or iodine, including stereo is almost acceptable salts of these compounds.

C1-C22-alkyl represents a straight or branched, preferably lower alkyl with 1 to 7 C atoms, preferably 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl or butyl, isobutyl, terbutyl or tertbutyl, or pentyl, hexyl or heptyl, while preferably at least two, but preferably three of the groups R1, R2, R3and R4denote hydrogen, or is it WITH8-C22-alkyl, while preferably at least two, but preferably three of the groups R1, R2, R3and R4denote hydrogen. Long chain preferably is a straight or branched C14-C18-alkyl. C2-C22alkenyl may also be straight or branched and it preferably represents lower alkenyl with 2 to 7 carbon atoms, preferably from 2 to 4 carbon atoms, and a represents a vinyl, 1-methyl-vinyl, 1-propenyl, allyl or butenyl, 2-methyl-2-propenyl or pentenyl, isopentenyl, 3-methyl-2-butenyl, hexenyl or heptenyl, while preferably at least two, but preferably three of the groups R1, R2, R3and R4denote hydrogen, eltri of the groups R1, R2, R3and R4denote hydrogen. Senior alkenyl preferably denotes a straight or branched C14-C18-alkenylphenol group. These alkeneamine groups can have E - or Z-form, or they may represent a paired or unpaired danily, such as 3,7-dimethyl-2,6-octadien, tritely, such as farnesyl, or politely.

C2-C22-quinil may also be straight or branched and it preferably indicates the lowest quinil with 2 to 7 carbon atoms, preferably from 2 to 4 atoms, and represents ethinyl, 1-PROPYNYL, propargyl or butynyl, or pentenyl, hexenyl or heptenyl, while preferably at least two, but preferably three of the groups R1, R2, R3and R4denote hydrogen, or is it also WITH8-C22-quinil, while preferably at least two, but preferably three of the groups R1, R2, R3and R4denote hydrogen. Higher quinil preferably denotes a straight or branched C14-C18-alkylamino group. Also we are talking about paired or unpaired di-, industry polyaniline groups and alkenyl groups.

As possible substitutes, as in CIS-and TRANS-isomers, can be used for example WITH1-C4-alkyl or alkenyl.

Aryl denotes a substituted or unsubstituted carbocyclic aromatic ring, such as phenyl, or poly-, in particular bicyclic, mating or bridge unsaturated or partially saturated ring system such as naphthyl, tenantry, indenyl, indanyl, tetrahydronaphthyl, biphenyl, di - and triphenylmethyl etc.

Aralkyl can be illustrated by the following formula

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in which group And denote independently of each other C1-C4-alkyl, C1-C4-alkoxy, halogen or nitro, and q denotes an integer from 0 to 3, n denotes an integer from 0 to 6, and represents a straight or branched C1-C

In the silyl group (SiR3group R stands for lower alkyl containing from 1 to 4 carbon atoms, and represents in particular methyl, ethyl, isopropyl, butyl, tertbutyl, or denotes phenyl or R-substituted phenyl, in which results can also apply different combinations of lower alkyl and phenyl groups, such as dimethyl-tert-butyl-, methyl di-isopropyl-, dimethyl - and diethyl-phenyl-, methyl tert-butyl phenyl-, di-isopropyl-(-,6-dimethyl phenyl)-, dimethyl(2,4,6-triisopropyl phenyl)silyl.

Salts of compounds of formula I are in particular their salts with pharmaceutically acceptable bases, such as metal salts, for example alkali metal salts, in particular salts of lithium, sodium and potassium, salts of alkaline earth metals such as calcium salts and magnesium salts of copper, aluminum or zinc, as well as ammonium salts with ammonia or with primary, secondary and tertiary, as aliphatic and alicyclic, and aromatic amines as well as Quaternary ammonium salts, such as halide, sulfates and hydroxides, salts with aminoalcohols, such as ethanol-, diethanol - and triethanol-amines, Tris(hydroxymethyl)aminomethane, 1 - and 2-methyl and 1,1-, 1,2 - and 2,2-dimethylaminoethanol, N-mono - and N,N-dialkyl the ical ammonium salts, such as salt azetidine, pyrrolidine, piperidine, piperazine, morpholine, pyrrole, imidazole, pyridinium, pyrimidine, chinoline etc.

Suitable sub-group of compounds of the formula I contains a complex of mono-, di - and treatery formula I, in which Q1=Q2=chlorine, and R1-R4denote lower alkyl, in particular methyl and ethyl. Other suitable subgroup includes the compounds of formula I in which Q1=Q2=chlorine, and one or two of the groups R1-R2denote C14-C18-alkyl or-alkenyl.

Particularly useful compounds according to the invention is a complex monomethyl and monoethylamine (dichloro-, perchlor-, Brahler and dibromoethylene)bisphosphonic acids.

A particularly suitable compound is a complex onomatology and monotropy ether (dihlormetilen)bisphosphonates acid.

The invention also relates to a method for producing compounds of formula I.

According to one method, these connections receive selective hydrolysis of complex tetrapyrrol corresponding to the formula I. Thus, a complex tetraethyl II used as starting material, in which groups R1-R4(not atom is I stepped as shown at the end of the description scheme 1 in ester trehosnovnoy acid III, in an ester of dibasic acid IV and V and in complex monoether VI (reaction takes place in the direction of the upper arrow). If required, a partial ester III VI or its salt can be isolated and purified extraction, fractional crystallization or chromatography, and, if necessary, the free acid can be converted into a salt or a salt into the free acid.

Hydrolysis of esters chetyrehosnuju acid of the formula I can be carried out by treatment of the acids and bases, using thermal decomposition, and in some cases also using water, alcohol, amide or other neutral or non-neutral agents transaminirovania, transsylvania and transalliance. It is advisable to carry out the hydrolysis in the temperature range from 20 to 150oC, usually from about 50oC to the boiling point of the mixture. It is desirable that the acid was a common inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid and a Lewis acid such as athirat boron TRIFLUORIDE, titanium tetrachloride, etc. as well as a number of organic acids, such as oxalic acid, formic acid, acetic acid and other carb is about chlorine and fluorine derivatives of carboxylic and sulfonic acids, such as trichloroacetic acid, triftoratsetata, and their aqueous solutions.

The grounds are mainly hydroxide of alkali metals and ammonium and ammonia and aqueous solutions, as well as a number of amines such as primary, secondary and tertiary amines, such as diethyl -, triethyl, di-isopropyl, and tributylamine, aniline and N - and N,N-alkyl substituted anilines and heterocyclic amines such as pyridine, morpholine, piperidine, piperazine, etc., and hydrazines, such as N,N-dimethylhydrazine.

In addition to this you may use acids and bases associated with a solid substrate, such as Amberlite, or in the presence of an organic solvent or water or mixtures of solvents, or in their absence.

Additionally, in the processing of some alkali metals such as sodium or lithium, or suitable inorganic salts such as sodium iodide, lithium bromide, ammonium chloride and NaBr/PTC, the ether group may be converted to its corresponding salt, such as phosphonates, sodium, ammonium, and lithium.

Thermal decomposition usually takes place at a temperature of from about 100 to 400oC usually, however, when temple salt of Quaternary ammonium, allows to carry out the reaction faster and at lower temperatures. Some active substituents, such as benzyl or allyl, can be removed by catalytic regeneration or electrical means.

To improve solubility and to control the reaction temperature during the reaction as co-solvents can be used organic, inert solvents such as lower alcohols and stable ketones and esters, haloalkyl, such as chloroform or 1,2-dichloroethane, ethers, such as dioxane, dimethoxyethane, diglyme, etc.

When all the complex ester group R1-R4in complex therefore according to the formula II are the same, the hydrolysis is graded according to the scheme I, and it is stopped when the concentration of the desired partial ester is maximum.

With the purpose of obtaining special patterns of incomplete complex ester is advisable to use a complex tetraethyl formula II, in which groups of ester unequal (mixed complex tetraeder), and contain groups that behave in a different way with respect to hydrolysis. It was, for example, found that the rate of hydrolysis of alkyl and silyl esters savii step process of hydrolysis by the size and shape of alkyl and silyl substituent, as well as using electronic factors. In some cases it may be appropriate to use partial complex ether, which from the point of view of thermodynamics is more favorable, for example, because of the formation of chelate compounds. Often it is expedient to carry out the esterification with the purpose of changing or improving the speed of hydrolysis of various parts of ester. In particular the methyl ester can be converted into the corresponding acid through a complex silloway ether.

Pure partial esters thus can be preferably obtained by carrying out selective hydrolysis, if necessary, graded mixed complex tetraeder formula II, which was prepared using a complex ester groups, which are suitable from the viewpoint of hydrolysis, or relevant legalitarian compounds, with gorodilova can be carried out after hydrolysis.

Can also be used in the reaction of selective hydrolysis, known in particular from the chemistry of phosphate and monophosphates.

Over the course of the hydrolysis can be monitored, for example, by chromatography or by using31P-I the th, and it can be isolated from the reaction mixture or in the form of the free acid or salt by precipitation, extraction or chromatographic means, and the salt form can be converted into the free acid or the free acid in its salt.

Compounds according to the invention can be prepared by selective esterification bisphosphonic acids in accordance with the above reaction scheme I (the reaction takes place in the direction of the lower arrow).

As source material used (halogenation)bisphosphonic acid according to the formula VII or legalizirovala bisphosphonic acid, which does not necessarily represent salt such as a salt of the metal or ammonium, or it is advisable to use appropriate tetrachlorohydrex phosphonic acid, and depending on the desired end result, from 1 to 4 equivalents of the desired aliphatic or aromatic alcohol, or the corresponding activated reagents alkylation, sililirovanie and arilirovaniya, such as ortho-, imido and vinylether, catenateall and other suitable reagents migration alkyl, silyl, and aryl groups, such as diazocompounds, active complex floor when anhydrous conditions, preferably in a temperature range from 0 to 150oC, or by using an inert co-solvent, at the boiling point.

Esters II-IV can also be obtained during the reaction of nucleophilic substitution between the anion bisphosphonates, part of the ammonium salt bisphosphonates acid and an organic halide compound, or a sulfonate, or during the reaction of another reagent, such as amidate, such as halogenated, as well as during the condensation reaction between the group of phosphonic acid and alcohols or phenols corresponding to the desired radicals R1-R4using reagent removal of water, such as carbodiimide and carbonyl - and sulfanilate, alkyl - or arylsulfonate, such as TPS, or oxidative esterification, such as phosphine + ester of azodicarboxylic acid.

Clean complex partial esters and mixed esters may thus be obtained preferably by selective esterification, optionally stepwise, halogenated bisphosphonic acids of formula VIII, or relevant legalitarian acids, with gorodilova may be carried out after the esterification.

Over the course of the esterification reactions can be monitored, for example, by chromatography or by using31P-NMR, and the reaction is interrupted when the content of the required bulk of ester is the maximum, and it stands out from the mixture by precipitation, extraction or chromatographic means, and if necessary, the resulting salt into the free acid or the free acid is transformed into its salt.

Partial esters bisphosphonates acid according to the invention can also be obtained by construction of structure P-C-P of its parts

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where Y denotes the formula hydrogen or halogen or another leaving group, Z represents halogen, aryloxy, sulfonyloxy or alkoxy, and R1-R4and Q1, Q2have the specified values, and Q2can also have the meaning of hydrogen. The Foundation represents, for example, NaH, BuLi or LDA. When Q2denotes hydrogen, gorodilova carried out after cooking patterns. The original material is not necessarily present the plots of the free acid (R1, R2, R3or R4=H), which must be neutralized by using a sufficient number of bases before the reaction societyvolume existing anionic site at carbon.

Can also be used reactions Michaelis-Arbuzov, whereby the compound of formula X is replaced by the corresponding postitem, or reaction Michaelis-Becker, in which Z denotes hydrogen.

Partial esters bisphosphonic acids according to the invention can also be obtained by oxidation of compounds P-C-P with a lower level of oxidation (for example PIII> PV).

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in the formulas, R1-R4and Q1, Q2have the above values, resulting in fosforitnaya structure can be in equilibrium with acidic phosphonate structure.

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All the usual oxidation agents or their solutions, such as hydrogen peroxide, pergolide connection, nagkalat, permanganate, etc. can be used.

Partial esters bisphosphonates acid according to the invention can also be obtained by gorodilova relevant legalitarian partial esters, stepped, or halogen(s) may be replaced by other, or one of the two can be deleted.

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In these formulas, R1-R4and Q1, Q2have the above values, while d is E. When one or more of the radicals R1-R4are hydrogen must be added to the base in a quantity sufficient to neutralize the plots of the free acid, as described above.

Partial esters bisphosphonic acids according to the invention can be obtained also graded using the above processes, previously known from the chemistry of phosphate and monophosphates.

They may also use other selective reactions, previously known from the chemistry of phosphate and monophosphates.

Partial esters I bisphosphonates acid according to the invention can also be obtained from other partial esters VIII by reaction of intra - and intermolecular exchange.

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in this formula VIII, R1-R4and Q1, Q2have the above values.

The above reactions can be monitored, for example, using chromatography or31P-NMR, and can be interrupted when the content of the desired product is maximum, and the product isolated from the reaction mixture in the form of the free acid or in the form of its salts by precipitation, extraction or chromatographic means, and when neomenia terrafire II and the corresponding tetracyclic IV, used as starting materials in the above reaction, can be obtained using methods known in themselves, such as the lattice P-C-P of its parts. Regardless of the final bulk of ester will often be reasonable to obtain a complex tetraethyl formula II, using the structures of esters, which are useful in relation to obtaining the required bulk of ester. In some cases when cooking grates ether bisphosphonates acid can be formed by partial esters, in particular salts of symmetrical esters, due to immediate incomplete hydrolysis occurring at the reaction conditions.

Lattice ether bisphosphonates acid can be obtained, for example, using the following known reactions.

a) Reaction Michaelis-Becker

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In these formulas, R1-R4and Q1, Q2have the above values, while also Q2may denote hydrogen, and Y is halogen, acyloxy or sulfonyloxy. The base represents Na, NaH, Bu-Li, LDA or KO-tert-Bu/PTC.

b) Reaction of the Michaelis-Arbuzov

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In these formulas, R1-R4and Q

in) Karanina reaction

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In these formulas, R1-R4and Q1, Q2have the same meaning as in formula II, Q2can also denote hydrogen, Y' denotes hydrogen or halogen, Z represents halogen, alkoxy, acyloxy or sulfonyloxy. The base is a BuLi, LDA, AlkMgHal or Alk2CuLi.

Considering obtaining the required bulk of ester, videolocity complex terrafire II can be converted into other suitable complex terrafire using the exchange reactions. In the group OR1-OR4can exchange directly or through the appropriate phosphonoformic or by other methods previously known from the chemistry of phosphate and monophosphates.

The halogen atoms can be substituted for hydrogen atoms on the carbon between the phosphorus atoms in the ether bisphosphonates acid, mainly in the form of complex tetraeder II, it is reasonable reaction to exercise using hypohalite. Can also be used other conventional reaction haloiding, such as reakcija of haloiding N-haloaluminate and other active halides or Prigorodnyi connections. It must, however, be noted that, contrary to what is stated in the publication J. General. Chem. 39 (1969) 845-8, chlorination of the intermediate carbon with phosphorus pentachloride did not give a positive result (see for example, J. Chem. Soc (1966) 757; see also example 14). In the first mentioned publication specifically stated that the processing tetratziklinovogo ether methylenephosphonic acid with phosphorus pentachloride yields a symmetric dicyclohexylurea ether (dihlormetilen)bisphosphonates acid. However, it seems that this is the wrong conclusion based on a unclean structure.

Halogen substituents of the carbon can also be introduced into the structure of the ether disphosphonate acid in the form of a halogenated ether monophosphate acid IX and Q1and/or Q2denote halogen. This halogen on the carbon in the lattice can also be substituted with hydrogen, usually by nucleophilic dehalogenase, or other halogen, using known reactions. Mixed halogen compounds I can also be obtained by stepwise application of the above reactions haloiding or exchange (see. Phoaphorus and Sulfur 37 (1988) 1).

Optically active partial esters of l can be obtained n the alcohols, when receiving the above-mentioned starting materials, intermediates and final products, or during exchange reactions.

Bisphosphonates inhibit osteoclastic resorption of bone. They are characterized by neytralizuet communication P-C-P, which directs these compounds on bone. They inhibit both the formation and dissolution of bone material (Fleisch H. B. Peck WA, ed. Bone and Mineral Research, Amsterdam: Ekcerpta Medica 1983:319 (Annual 1)). However, compounds that are good inhibitors of crystallization of calcium phosphate may cause as a side effect of the inhibition of mineralization.

In addition to its physico-chemical interaction with crystals calciufetta bisphosphonates also affect cellular metabolism (H. Shinoda et al. Calcif Tissue Jnt 1983; 35:87). The exact mechanism of inhibition of bone resorption has not yet been clarified. In addition, the effects seem to vary from one bisphosphonates to another.

Bisphosphonates are absorbed, stored and excreted in unchanged form. Intestinal absorption is usually below 5% of the oral dose. A significant portion of the absorbed bisphosphonates localizes in bone, while the remainder is rapidly excreted in the urine. The half-life of circulating bisphos is Rania in the skeleton has a greater long-term.

The aim of the invention is the introduction of new derivatives of bisphosphonates, which have low affinity to the bone, in order to eliminate side effects without loss of activity to inhibition of bone resorption. Simultaneously, the increase of their absorption after oral administration could bring to getting better therapeutic substances for the treatment of bone diseases.

Measured biological activity of the compounds according to the invention for the prevention of bone resorption in vivo and in vitro, as well as the interaction of compounds with the mineral substance of the bone and their relative bioavailability after oral administration. It was found that they showed a lower affinity for bones than the reference compound clodronate. Despite this they regained their biological activity, as indicated in the course of experience resorption in vitro and in vivo. In addition, these compounds are better absorbed after oral administration than clodronate.

The relative toxicity of the inventive compounds as low as for clodronate. For example, the value of LD50for dichloroisoproterenol acid, distrimination ester salt monopeptide totallitarian methylene-bisphosphonic acids can also be used as pharmaceutical agents as such or in the form of their pharmaceutically acceptable salts, such as alkali metal salts or ammonium salts. Such salts can be obtained by introducing in the reaction of partial esters of the acid with the appropriate inorganic or organic bases. Depending on the reaction conditions, salts of esters is obtained directly during the above reaction, when the reaction conditions employed to produce compounds of formula I.

The new compounds I according to the invention can be introduced interline or parenteral. All the usual forms of administration, such as tablets, capsules, granules, syrups, solutions and suspensions, can also be used. In the same way all the additives for the manufacture, ensure solubility and drug administration as well as stabilizers, viscosity regulators and dispersion and buffers can also be used.

Such additives tartrate and citrate buffers, alcohols, EDTA and other non-toxic complexing substances, solid and liquid polymers and other sterile substrates, starch, lactose, mannitol, methylcellulose, talc, silicic acid, fatty acid, gelatin, agar-agar, calcium phosphate, magnesium stearate, animal and vegetable fats and optionally flavoring and sweetening substances the individual state. The daily dose is from 1 to 1000 mg, typically from 10 to 200 mg per person, and they can be administered in a single dose or can be divided into several doses.

Below are examples of typical capsules and tablets.

Capsule mg/capsule

The active ingredient 100,0

Starch 20,0

Magnesium stearate 1,0

Tablet mg/tablet

The active ingredient 400,0

Microcrystalline cellulose 20,0

Lactose 67,0

Starch 10,0

Talc 4,0

Magnesium stearate 1,0

For medical use may also be made of parenteral the injectable preparation, for example a concentrate for infusion or injection. In concentrate for infusion, for example, can be used sterile water, phosphate buffer, NaCl, NaOH or HCl or other known pharmaceutical supplements and injections are also suitable pharmaceutical preservatives.

You can also make a topical formulation, administered in a suitable carrier.

Connections in the form of ester-acids are liquid or waxy substance, usually soluble in organic solvents and in some cases in water. Salts of esters are solid, crystalline or usually p is ritesh and only a few patterns in this poorly soluble in all solvents. These compounds are very stand, in neutral solutions at room temperature.

The structure of these compounds can easily be checked using the1H,13C and31P-NMR and FAB-mass spectrometry, or siciliani, using E1-mass spectrometry. To determine the concentration of impurities is very suitable31P-NMR-spectroscopy. For polar compounds, as such, can be used ion-exchange and gel permeation high-performance liquid chromatography, and for complex tetrapyrrol and similarbank derivatives of esters of acids -0 GC or GC/MS. For compounds were determined separately sodium and other metals, as well as the possible content of water of crystallization. The salts of amines was determined by nitrogen.

Example 1. Trihexy(dihlormetilen)bisphosphonate and monosodium salt.

of 29.1 g (0.05 mole) tetradecyl (dihlormetilen) bisphosphonates (31P-NMR (CDCl3): cent to 8.85) and 290 ml of pyridine is refluxed for about 1 h (reaction monitored using31P-NMR), and the mixture is evaporated in vacuum. The remainder (N-hexylpyridine salt trihexy(dihlormetilen)-bisphosphonates) are dissolved in 300 ml of toluene and the solution was washed with 2 x is from evaporation is dissolved with 100 ml of CH3OH and the solution is treated with activated charcoal and filtered. The filtrate is evaporated to constant weight under vacuum, the result is approximately 21 g (80% of theoretical) of the monosodium salt of complex tridecylamine (dihlormetilen)bisphosphonates acid (31P-NMR (D2O): d 13,06 (P), 5,18 (P'),2IPP= 18,0 Hz), with a concentration of 05% of which trihexy (dihlormetilen)-bicarbonate can be separated by treatment with acid.

Similarly can be obtained nigelegashie complex truefire methylenephosphonic acid and the corresponding sodium salt:

from tetrabutyl(dihlormetilen) bisphosphonates:

tributyl (dihlormetilen) a bisphosphonate,

from tetraphenyl (dihlormetilen) bisphosphonates:

triphenyl (dihlormetilen) a bisphosphonate,

from tetrahedral (dihlormetilen) bisphosphonates:

trileptal (dihlormetilen) a bisphosphonate,

from tetrapropyl (dihlormetilen) bisphosphonates:

tripropyl (dihlormetilen) a bisphosphonate,

from tetraisopropyl (dihlormetilen) bisphosphonates:

triisopropyl (dihlormetilen) a bisphosphonate,

(odnonatrieva salt) (31P-NMR (D2O): d 11.87 per (P), 5,19 (P')2IPP=17.3 Hz),

from tetraethyl (dihlormetilen) bisphosphine (31P-NMR (D2O): d 12,47 (P) OF 1.30 (P'),2IPP= 17.5 Hz),

triethyl (dihlormetilen) bisphosphonate (odnonatrieva salt) (31P-NMR (D2O): d 13,47 (P), 5,58 (P'),2IPP=17,0 Hz),

from tetrakis(1-methylbutyl) (dihlormetilen) bisphosphonates:

Tris(1-methylbutyl) (dihlormetilen)a bisphosphonate,

of tetrakis (1-ethylpropyl) (dihlormetilen) bisphosphonates:

Tris(1-ethylpropyl) (dihlormetilen) a bisphosphonate,

from tetracyclines (dihlormetilen) bisphosphonates:

thrillometer (dihlormetilen) a bisphosphonate,

from tetraalkyl (dihlormetilen) bisphosphonates:

triallyl (dihlormetilen) a bisphosphonate,

from tetraphenyl (dihlormetilen) bisphosphonates:

triphenyl (dihlormetilen) a bisphosphonate,

from tetrabenzyl (dihlormetilen) bisphosphonates: tribunil (dihlormetilen) a bisphosphonate,

of tetramethyl (dihlormetilen) bisphosphonates;

trimethyl (dihlormetilen) bisphosphonate (31P-NMR (CDCl3): d 16,46 (P), 3,42 (P'),2IPP= 19.6 Hz), (monosodium salt) (31P-NMR (CDCl3): d 15,74 (P), TO 6.58 (P'),2IPP= 17,0 Hz), (tributylammonium salt) (31P-NMR (CDCl3): d 15,50 (P), 4,25 (P'), and 16.6 Hz),

of Tetra-(Z)-3-hexenyl (dihlormetilen)bisphosphonates:

three-(Z)-3-hexenyl (dichlormethane

of P,P-diethyl-P',P'-aminobutiramida (dihlormetilen)bisphosphonates:

P,P-aminobutiramida P'-ethyl (dihlormetilen) bisphosphonate (N-ethyl-pyridinium salt) (31P-NMR (CDCl3): d 11,81 (P) 5,95 (P'),2IPP=16.6 Hz),

of R,R-aminobutiramida P',P'-dimethyl (dihlormetilen)bisphosphonates:

P,P-aminobutiramida P'-methyl (dihlormetilen) bisphosphonate (tributylammonium salt (31P-NMR (CDCl3): d 11,12 (P) 4,85 (P'), and 17.3 Hz),

of R,R-aminobutiramida P',P'-dihexyl (dihlormetilen) bisphosphonates;

P, P-aminobutiramida P'-hexyl (dihlormetilen) bisphosphonate (N-hexyl pyridinium salt) (31P-NMR (CDCl3): d 8,67 (P), 6,57 (P'),2IPP=20,9 Hz),

from Tetra(3-chlorophenyl) (dihlormetilen) bisphosphonates:

three(3-chlorophenyl) (dihlormetilen) a bisphosphonate,

from Tetra(3-phenyl 2-propenyl) (dihlormetilen) bisphosphonates:

three(3-phenyl 2-propenyl) (dihlormetilen) a bisphosphonate,

of Tetra(2-butynyl) (dihlormetilen) bisphosphonates:

three(2-butynyl) (dihlormetilen) a bisphosphonate,

from tetradecyl (dibromomethyl) bisphosphonates:

trihexy (dibromomethyl) a bisphosphonate,

from tetraisopropyl (dibromomethyl) bisphosphonates:

triisopropyl (dibromomethyl) a bisphosphonate,

from tetrcycline (dibromomethyl) R> triethyl (monobromomethane) a bisphosphonate,

from tetradecyl (monobromomethane) bisphosphonates:

trihexy (monobromomethane) a bisphosphonate,

from tetraisopropyl (monobromomethane) bisphosphonates:

triisopropyl (monobromomethane) a bisphosphonate,

from tetracyclines (monobromomethane) bisphosphonates:

thrillometer (monobromomethane) a bisphosphonate,

from tetraisopropyl (diiodomethyl) bisphosphonates:

triisopropyl (Diocletian) a bisphosphonate,

from tetraphenyl (Diocletian) bisphosphonates;

triphenyl (Diocletian) a bisphosphonate,

from tetraisopropyl (monodomain) bisphosphonates:

triisopropyl (monodomain) a bisphosphonate,

from tetraisopropyl (monochloramine) bisphosphonates:

triisopropyl (monochloramine) a bisphosphonate,

from tetracyclines (monochloramine) bisphosphonates:

thrillometer (monochloramine) a bisphosphonate,

from tetraethyl (monochloramine) bisphosphonates:

triethyl (monochloramine) a bisphosphonate,

from tetradecyl (monochloramine) bisphosphonates:

trihexy (monochloramine) a bisphosphonate,

from tetracyclics (monochloramine) bisphosphonates:

tricyclohexyl (monochloramine) a bisphosphonate,

Aunts were obtained as follows.

to 17.6 g (0.1 mole) methylenephosphonic acid and 253 g (0,8 mol) trihexy-ortogonalnogo ether is refluxed for 3 h and then distil under vacuum until reaching an internal temperature of about 170oC/1 mm RT.article As the distillation residue receive approximately 51 g (100% of theoretical) tetradecyl methylenephosphonate (31P-NMR (CDCl3): d 20,04) as a colourless oil, the concentration of which is 90%

Type of 25.6 g (0.05 mole) tetradecyl methylene bisphosphonates with stirring to 250 ml of 10% aqueous solution of NaOCl at 0oC for about 30 minutes, after which stirring is continued for 1 h at 0oC and 2 h at room temperature. The mixture is extracted with 2 x 100 ml of toluene, and collected together the extracts are washed with 50 ml of 1N NaOH and 2 x 50 ml water and dried (MgSO4) and filtered. The filtrate is evaporated under vacuum, resulting in a gain of approximately 25 g (85% of theoretical) tetradecyl (dihlormetilen) bisphosphonates (31P-NMR (CDCl3): d, cent to 8.85) having a concentration of 95%

Similarly, the following can be derived complex terrafire (dihlormetilen) bisphosphonates acid:

from tetrabutyl methylenephosphonate (31P-NMR (C is Teal methylene bisphosphonates (31P-NMR (CDCl3): d grade of 20.06:

tetraphenyl (dihlormetilen) bisphosphonate (31P-NMR (CDCl3): d cent to 8.85,

from tetrahedral methylenephosphonate (31P-NMR (CDCl3): d 20,07:

tetrahedral (dihlormetilen) bisphosphonate (31P-NMR (CDCl3): d 8,86,

from tetrapropyl methylenephosphonate:

tetrapropyl (dihlormetilen) a bisphosphonate,

from tetraisopropyl methylenephosphonate (31P-NMR (CDCl3): d 17,92):

tetraisopropyl (dihlormetilen) bisphosphonates (31P-NMR (CDCl3): d 7,21),

from tetramethyl methylenephosphonate (31P-NMR (DCl3): d 23,27):

tetramethyl (dihlormetilen) bisphosphonate (31P-NMR (CDCl3): d 10,88),

from tetraethyl methylenephosphonate (31P-NMR (CDCl3): d 19,92):

tetraethyl (dihlormetilen) bisphosphonate (31P-NMR (CDCl3): d 8,92,

from tetrax(1-methylbutyl) methylenephosphonate (31P-NMR (CDCl3): d 18,10 (m)):

tetrakis(1-methylbutyl) (dihlormetilen) bisphosphonate (31P-NMR (CDl3): d 7,69,

of tetrakis(1-ethylpropyl) methylenephosphonate (31P-NMR (CDCl3): d 18,37):

tetrakis (1-ethylpropyl) (dihlormetilen) bisphosphonate (31P-NMR (CDCl3): d 7,89),

from tetracycline methylene bisphosphonates (31>from tetraethyl methylenephosphonate (31P-NMR (CDCl3): d 20,60):

tetraalkyl (dihlormetilen) bisphosphonate (31P-NMR (CDCl3): d of 9.21),

from Tetra(Z)-3-hexenyl methylenephosphonate (31P-NMR (CDCl3): d 20,12):

Tetra-(Z)-3-hexenyl (dihlormetilen) bisphosphonate (31P-NMR (CDCl3): d 8,72 (m)),

of tetrakis(2-methyl-2-propenyl) methylenechloride (31P-NMR (CDCl3): d 20,31):

tetrakis(2-methyl-2-propenyl) (dihlormetilen)bestnet (31P-NMR (CDCl3): d 9,06),

from tetraphenyl methylenephosphonate:

tetraphenyl (dihlormetilen) a bisphosphonate,

from tetrabenzyl methylenephosphonate (31P-NMR (CDCl3): d 20,66):

tetrabenzyl (dihlormetilen) a bisphosphonate.

Tetradecyl (dibromomethyl) a bisphosphonate, used as starting material may be obtained as follows.

In the solution of the hydrobromide of sodium, which was obtained by the introduction of 8.4 g of bromine in 4.6 g of NaOH in 50 ml water is added dropwise with stirring, 10.2 g (0,02 mol) tetradecyl methylenephosphonate for about 10 minutes at a temperature of from 0 to 5oC. the Mixture was stirred for 1 h while cooling and 1 h at room temperature and was extracted with methylene chloride is then received an estimated 10.5 g (80% of theoretical) tetradecyl (dibromomethyl) bisphosphonates (31P-NMR (CDCl3): d 8.98 parts per 1 million) as a colourless oil, with a concentration of 97%

Similarly can be obtained, inter alia, the following complex terrafire (dibromomethyl) bisphosphonates acid:

tetramethyl (dibromomethyl) a bisphosphonate,

tetraethyl (dibromomethyl) a bisphosphonate,

tetraisopropyl (dibromomethyl) a bisphosphonate,

tetracyclines (dibromomethyl) bisphosphonate (31P-NMR (CDCl3): d 7,26,

tetrabutyl (dibromomethyl) a bisphosphonate,

tetraphenyl (dibromomethyl) a bisphosphonate.

Tetradecyl (monobromomethane) a bisphosphonate, suitable as starting material may be obtained as follows.

In a solution containing 6,7 (0,01 mol) tetradecyl (dibromomethyl) bisphosphonates in 70 ml of absolute ethanol, add 2.5 g of SnCl2x 2H2O in 100 ml of water under stirring at 0oC. After the addition the mixture is stirred for 15 min and extracted with chloroform and the extract is dried (MgSO4) and filtered. The filtrate is evaporated under vacuum, resulting in a gain of approximately 4.1 g (70% of theoretical) tetradecyl (monobromomethane) bisphosphonates (31P-NMR (CDCl3): d 13,83 parts per 1 million) in the form of colorless Mac is ry (monobromomethane) bisphosphonates acid:

tetramethyl (monobromomethane) bisphosphonate),

tetraethyl (monobromomethane) a bisphosphonate,

tetraisopropyl (monobromomethane) a bisphosphonate,

tetracyclines (monobromomethane) a bisphosphonate.

Tetraisopropyl (monodomain) a bisphosphonate, used as starting material may be obtained as follows.

It is 17.2 g (0.05 mol) tetraisopropyl methylenephosphonate in 300 ml of 10% aqueous solution of K2CO3added dropwise while stirring for about 20 min a solution which contains 6,35 g I2and 20 KI in 50 ml of water. After the addition the mixture is stirred for 2 h and the solution extracted with x 150 ml of CH2Cl2. The extracts are collected together and washed with saturated NaCl solution and dried (MgSO4) and filtered. The filtrate is evaporated under vacuum, resulting in a gain balance resp evaporation of about 20 g in the form of almost colorless oil. As a result, the NMR with31P product contains 44% tetraisopropyl (monodomain) bisphosphonates (31P-NMR (CDCl3): d 14,17) and 56% of the source material.

Tetraisopropyl (monochloramine) a bisphosphonate, used as starting material may be obtained as follows.

In rija and 250 ml of water, add with stirring for 15 minutes at a temperature of from 10 to 15oC, then the mixture is stirred for 1 h, the Mixture is extracted with chloroform and the extract is dried (MgSO4) and filtered. The filtrate is evaporated under vacuum, resulting in a gain of approximately 7.6 g (100% of theoretical) tetraisopropyl (monochloramine) bisphosphonates (31P-NMR (CDCl3): d 12,04 parts per 1 million) as a colourless oil, with a concentration of 98%

Likewise, among others, the following can be derived complex terrafire (monochloramine) bisphosphonates acid:

tetramethyl (monochloramine) a bisphosphonate,

tetraethyl (monochloramine) a bisphosphonate,

tetracyclines (monochloramine) a bisphosphonate,

tetracyclics (monochloramine) a bisphosphonate.

Example 2. Bis (N-hexylpyridine) and the disodium salt of P,P'-dihexyl (dihlormetilen) bisphosphonates.

of 29.1 g (0.05 mole) tetradecyl (dihlormetilen) bisphosphonates and 290 ml of pyridine is refluxed for 1 day and the mixture is evaporated under vacuum, resulting in a gain of bis (N-hexylpyridine) salt complex of P,P'-vexillifera (dihlormetilen) bisphosphonates acid. It is dissolved in 180 ml of toluene and repromat acetone and ethyl acetate and dried in a vacuum dryer, resulting receive approximately 11.5 g (50% of theoretical) disodium salt complex of P, P'-vexillifera (dihlormetilen) bisphosphonates acid (31P-NMR (D2O): d 8,97), with a concentration of 96% P,P'-dihexyl (dihlormetilen) a bisphosphonate may be isolated from their salts by treatment with acid. Instead of pyridine may also be used other amines, such as heterocyclic amines (morpholine, see the other 7), piperidine, piperazine, and so on) or aliphatic, primary, secondary or tertiary amines (di-Isopropylamine, triethylamine, aniline, and so on).

Similarly, inter alia, the following can be derived symmetric complex diesters(dihlormetilen) bisphosphonates acid and diamino and the disodium salt:

of tetramethyl (dihlormetilen) bisphosphonates:

P, P'-dimethyl (dihlormetilen) a bisphosphonate, (disodium salt) (31P-NMR (D2O): d 10,00), piperidinium salt (31P-NMR (D2O): d 9,70),

from tetraethyl (dihlormetilen) bisphosphonates:

P,P'-diethyl (dihlormetilen) bisphosphonate (31P-NMR (D2O): which 9.22) (disodium salt), 8,86 (piperidinium salt),? 7.04 baby mortality (bis (N-ethylpyridinium salt),

from tetrapropyl (dihlormetilen) bisphosphonates:

P,P'-dipropyl (dichloromethyl ifastnet (31P-NMR (D2O): d 7,93 (acid) compared to 8.26 (disodium salt), 7,83 (demoniaca salt), 8,23 (delitala salt),

from tetrabutyl (dihlormetilen) bisphosphonates:

P,P'-dibutil (dihlormetilen) a bisphosphonate,

from tetraphenyl (dihlormetilen) bisphosphonates:

P,P'-dipentyl (dihlormetilen) a bisphosphonate,

from tetrahedral (dihlormetilen) bisphosphonates:

P,P'-diheptyl (dihlormetilen) a bisphosphonate,

from tetracyclines (dihlormetilen) bisphosphonates:

P,P'-dicyclopentyl (dihlormetilen) a bisphosphonate,

from tetraalkyl (dihlormetilen) bisphosphonates:

P,P'-diallyl (dihlormetilen) a bisphosphonate,

of tetrakis (2-methyl-2-propenyl) (dihlormetilen)bisphosphonates:

P,P'-bis(2-methyl-2-propenyl) (dihlormetilen) bisphosphonate (31P-NMR (D2O): d 8,60 (piperidinium salt),

from tetracyclics (dihlormetilen) bisphosphonates:

P,P'-DICYCLOHEXYL (dihlormetilen) a bisphosphonate,

from tetraphenyl (dihlormetilen) bisphosphonates;

P,P'-diphenyl (dihlormetilen) a bisphosphonate,

from tetrabenzyl (dihlormetilen) bisphosphonates:

P,P'-dibenzyl (dihlormetilen) a bisphosphonate,

of P,P'-dimethyl P,P'-diethyl (dihlormetilen)bisphosphonates:

P-methyl, P'-ethyl (dihlormetilen) bisphosphonate (31P NMR (CD is l (dihlormetilen) bisphosphonates and its disodium salt.

5.0 g (0,01 mol) of P,P-dihexyl P',P'-aminobutiramida (dihlormetilen) bisphosphonates are dissolved in 100 ml of toluene and to this solution was added 6.7 g (of 0.07 mole) of methanesulfonate, and the solution is stirred under heating, and the progress of the hydrolysis is monitored by NMR31P. When the reaction reaches the desired stage, the mixture is cooled to room temperature and the lower phase is separated. Phase toluene is washed with 10 ml water and dried (MgSO4) and evaporated to constant weight under vacuum, resulting in a gain about 3.3 g (80% of theoretical ) of P, P-dihexyl (dihlormetilen) bisphosphonates (31P-NMR (CDCl3: d (P) 11,89 parts per 1 million P') 5,27 parts per 1 million2IPP=21,0 Hz), with a concentration of 95%

2,07 g (0,005 mol) of the above bisphosphonates acid is mixed with 25 ml of water, and the pH of the mixture to regulate 9 10 using NaOH 1H. The mixture is evaporated to dryness under vacuum and the evaporation is repeated after adding isopropanol. The residue is mixed with acetone-isopropanol (1:1), and the precipitate is filtered and dried. The output is approximately 1.8 g (80% of theoretical) disodium salt complex of P,P-vexillifera (dihlormetilen) bisphosphonates acid, with a concentration of 97%

Similarly receive, among others, the following nesim the P-dibutil P',P'-aminobutiramida (dihlormetilen) bisphosphonates (31P-NMR (CDCl3): d 9,02 (P), 7,17 (P'),2IPP=23,0 Hz):

P,P-dibutil (dihlormetilen) a bisphosphonate,

of P,P-dipentyl, P',P'-aminobutiramida (dihlormetilen) bisphosphonates:

P,P-dipentyl (dihlormetilen) a bisphosphonate,

of P,P-diheptyl P',P'-aminobutiramida (dihlormetilen) bisphosphonates:

P,P-diheptyl (dihlormetilen) a bisphosphonate,

of P,P-diethyl-P',P'-ditretbutyl (dichlorethylene) bisphosphonates:

P,P-diethyl (dihlormetilen) a bisphosphonate,

of P,P-di-4-were P',P'-ditretbutyl (dihlormetilen) bisphosphonates:

P,P-di-4-were (dihlormetilen) a bisphosphonate,

from R-decyl P-propyl P',P'-litreture (dihlormetilen) bisphosphonates:

P-decyl P-propyl (dihlormetilen) a bisphosphonate.

Through the use of an aqueous acid solution, the same image can be obtained the following compounds:

of P,P-diethyl-P',P'-isopropyl (dihlormetilen)bisphosphonates:

P, P-diethyl-P'-isopropyl (dihlormetilen) bisphosphonate (31P-NMR (CDCl3): d 13,86 (P), 5,12 (P'),2IPP=17,0 Hz),

of P,P-aminobutiramida P',P'-dihexyl (dihlormetilen) bisphosphonates:

P, P-dihexyl P'-isopropyl (dihlormetilen) bisphosphonate (31P-NMR (CDCl3): d 10,41 (P), 5,71 (P'),2IPP=21,0 Hz).

P, P-Dihexyl P',P'-diet obtained as follows.

To a tetrahydrofuran-hexane to a solution of LDA (sitedisability), which contains approximately 0,073 mole LDA, with stirring (atmosphere N2) at -78oC 9.0 g (0,034 mole) dihexylphthalate in 10 ml of anhydrous TMF, after which the stirring is continued for 15 minutes To the mixture under stirring at -78oC 7.2 g (being 0.036 mole) of diisopropylfluorophosphate in 10 ml of anhydrous TMF, after which stirring is continued for 15 min at -78oC, and the mixture allowed to warm to -50oC. To the mixture is added 5N HCl at pH 5 to 6, after which the mixture is evaporated under vacuum. The residue is extracted with 3 x 50 ml CHCl3and when put together the extracts washed with 10% solution of NaHCO3and water, dried (MgSO4) and evaporated. The residue is stirred in a simple ether and filtered. The filtrate is evaporated to dryness in vacuo, resulting in a gain of approximately 13 g (90% of theoretical P,P-dihexyl P',P ' aminobutiramida methylenephosphonate (31P-NMR (CDCl3): d 20,13 (P), 17,84 (P'),2IPP= 7,6 Hz), with a concentration of 90% the same product is obtained with a yield of about 80% in the above mentioned manner, but the replacement dihexylfluorene 8.5 g (0,034 mole) of acid dihexylfluorene and diisopropylfluorophosphate of 7.7 g (0.036 mod is l, added under vigorous stirring at 0oC 10.7 g (0,025 mol) of P,P-dihexyl P',P'-aminobutiramida methylene bisphosphonates within 15 minutes After the addition the mixture is stirred for 2 h at 0oC and 2 h at room temperature and extracted with 2 x 100 ml of toluene. Taken together, the extracts washed with 2 x 75 ml of water and dried (MgSO4) and filtered. The filtrate is evaporated under vacuum, resulting in a gain of approximately 10 g (80% of theoretical) of P, P-dihexyl P', P'-aminobutiramida (dihlormetilen) bisphosphonates (31P-NMR (CDCl3): d 8,98 (P), 4,72 (P'),2IPP=22.9 Hz) as a colourless oil with a concentration of 90%

An alternative way of obtaining unbalanced source complex therefire, P, P-diethyl-P',P'-aminobutiramida methylene bisphosphonates, are presented below.

Step 1. To 134 g (0.5 mole) methylene iodine was added with stirring at 160oC (atmosphere N2) 66 g (0,31 mole) of triisopropylphosphine for 30 min, at the same time she released modesty isopropyl. After the addition stirring for 40 min at 160 165oC and the mixture fractionary under vacuum. The output is about 62 g (65% of theoretical) aminobutiramida (iodomethyl)phosphonate, t-RA Kip. from 100 to l) phosphonate gradually added under stirring at 185 205oC (atmosphere N2) 83 g (0.5 mole) of triethylphosphite, while released modesty ethyl Argonauts. After the addition stirring is continued for 10 min 210oC and the mixture is cooled and fractionary under vacuum. The output is approximately 12.5 g (40% of theoretical) of P,P-diethyl-P',P'-aminobutiramida methylene bisphosphonates, so boiling 140 150oC/2 mm (31P-NMR (CDCl3): d 17,77 (P), 20,20 (P'),2IPP=7,4 Hz), at a concentration of 95%

Similarly can be obtained, among others, the following asymmetric complex P,P,P',P'-terrafire (dihlormetilen) bisphosphonates acid:

of P, P-dimethyl P', P'-diethyl methylene bisphosphonates (31P-NMR (CDCl3): d 22,65 (P), 19,55 (P'), 2IPP=6,00 Hz):

P,P-dimethyl P',P'-diethyl (dihlormetilen) bisphosphonate (31P-NMR (CDCl3): d 11,17 (P), 8,45 (P'),2IPP=23.1 Hz),

of P,P-dimethyl P',P'-aminobutiramida methylene bisphosphonates (31P-NMR (CDCl3): d 23,00 (P), 17,43 (P'),2IPP=7,1 Hz):

P, P-dimethyl P', P'-aminobutiramida (dihlormetilen) bisphosphonate (31P-NMR (CDCl3): to 11.56 d (P), 6,79 (P')2IPP=22,8 Hz),

of P,P-diethyl-P',P'-aminobutiramida methylene bisphosphonates (31P-NMR (CDCl3): d 20,20 (P), 17,77 (P'),2IPP=7,4 Hz):

P, P-diethyl-P', P'-dir,P-diethyl-P',P'-ditretbutyl methylene bisphosphonates (31P-NMR (CDCl3): to 20.88 d (P), IS 10.68 (P'), 2IPP=13.3 Hz):

P, P-diethyl-P', P'-ditretbutyl (dihlormetilen) bisphosphonate (31P-NMR (CDCl3): d 10,38 (P) -0,37 (P'),2IPP=19,0 Hz),

of P, P-diphenyl P',P'-dibenzyl methylene bisphosphonates (31P-NMR (CDCl3): d 12,77 (P), 19,27 (P'),2IPP=9,0 Hz):

P,P-diphenyl P',P'-dibenzyl (dihlormetilen) bisphosphonate (31P-NMR (CDCl3): d 0,43 (P), 8,87 (P'),2IPP=22.9 Hz),

of P,P-dibutil P',P'-aminobutiramida methylene bisphosphonates (31P-NMR (DCl3): d 20,22 (P), 17,90 (P'),2IPP=7.9 Hz):

P, P-dibutil P', P'-aminobutiramida (dihlormetilen) bisphosphonate (31P-NMR (CDCl3): d 9,02 (P), 7,17 (P'),2IPP=23,0 Hz),

of R,R-dipentyl P',P'-aminobutiramida methylenephosphonate:

P,P-dipentyl P',P'-aminobutiramida (dihlormetilen) a bisphosphonate,

of R,R-diheptyl, P',P'-aminobutiramida methylene bisphosphonates:

P,P-diheptyl P',P'-aminobutiramida (dihlormetilen) a bisphosphonate,

of P,P,P'-trimethyl P'-isopropyl methylenephosphonate (31P-AMOR (CDCl3): d 22,82 (P), 17,64 (P'),2IPP=6.3 Hz):

P, P, P'-trimethyl P'-isopropyl (dihlormetilen) bisphosphonate (31P-NMR (CDCl3): d 11,24 (P),8,91 (P'), and 23.1 Hz),

of P,P,P'-trimethyl P'-hexyl methylenephosphonate:

P,P,P'-trimethyl P'-GE'-octadecyl (dihlormetilen) a bisphosphonate,

of P, P-aminobutiramida P'-octadecyl P'-tertbutyl methylenephosphonate (31P-NMR (CDCl3): d 15,76 (R), 18,35 (P')2IPP=9,2 Hz):

P,P-vicoprofen P'-octadecyl P'-tertbutyl (dihlormetilen) a bisphosphonate,

of P, P-dimethyl P', P'-diphenyl methylenechloride (31P-NMR (CDCl3): d 20,95 (P), 12,84 (P'),2IPP=7.9 Hz):

P, P-dimethyl P',P'-diphenyl (dihlormetilen) bisphosphonate (31P-NMR (CDCl3): d 10,37 (P) TO 0.17 (P'),2IPP=23,3 Hz).

Example 4. Monohexyl (dihlormetilen) bisphosphonate and its trinacria salt.

4.7 g (0,01 mol) P-hexyl P-tertbutyl P',P'-aminobutiramida (dihlormetilen) bisphosphonates (obtained by chlorination according to example 1 P-hexyl P-tertbutyl P', P'-aminobutiramida methylenephosphonate obtained from hexyl to tertbutyl of chlorophosphate and aminobutiramida methylphosphonate according to example 3) is stirred with 30 ml of hydrochloric acid, 2 N for 1 to 2 hours at about 80oC (over the course of the hydrolysis is monitored by NMR31P). After the reaction mixture is evaporated to constant weight under vacuum, resulting in a gain monohexyl (dihlormetilen) bisphosphonate in the form of an oily residue. The residue from evaporation is dissolved in water and add 5.0 ml 2H NaOH solution and evaporated to constant ve the g (90% of theoretical) traintravel salt monohexyl of ester (dihlormetilen)bisphosphonates acid (31P-NMR (D2O): d 11,50 (P), 9,36 (P'),2IPP=15.7 Hz), with a concentration of 98%

The group, which should be removed, may be instead of tributyl, isopropyl, etc. group and methyl group, which can then be selectively subjected to hydrolysis, for example, over complicated sillavan ether (see example 10).

Similarly, additional area can be obtained with the following difficult monetary and the corresponding sodium salt (dihlormetilen) bisphosphonates acid (similarly also were obtained corresponding complex terrafire as source material, see examples 1 and 3):

from P-propyl P-tertbutyl P',P'-aminobutiramida (dihlormetilen) bisphosphonates:

monopril (dihlormetilen) a bisphosphonate,

from P-butyl P-tertbutyl P',P'-aminobutiramida (dihlormetilen) bisphosphonates:

monobutyl (dihlormetilen) a bisphosphonate,

from R-pentyl P-tertbutyl P',P'-aminobutiramida (dihlormetilen) bisphosphonates:

monepantel (dihlormetilen) a bisphosphonate,

of P-heptyl P-tertbutyl P',P'-aminobutiramida (dihlormetilen) bisphosphonates:

monogamy (dihlormetilen) a bisphosphonate,

from R-decyl P-tertbutyl P',P'-aminobutiramida (dihlormetilen) bisphosphonates:

monodecyl (dichloro the Il (dihlormetilen) a bisphosphonate,

from the P-octadecyl P-tertbutyl P',P'-aminobutiramida (dihlormetilen) bisphosphonates:

monooctyltin (dihlormetilen) a bisphosphonate,

of the P-allyl P-tertbutyl P',P'-aminobutiramida (dihlormetilen) bisphosphonates:

monoallyl (dihlormetilen) a bisphosphonate,

of P-phenyl P-tertbutyl P',P'-vicoprofen (dihlormetilen) bisphosphonates:

monophenyl (dihlormetilen) a bisphosphonate,

of P-benzyl P-tertbutyl P',P'-aminobutiramida (dichlorethylene) bisphosphonates:

monobenzyl (dihlormetilen) a bisphosphonate,

of P-cyclohexyl P-tertbutyl P',P'-aminobutiramida (dihlormetilen) bisphosphonates:

monocyclohexyl (dihlormetilen) a bisphosphonate,

of P-phenyl-P-tertbutyl P',P'-aminobutiramida (monochloramine) bisphosphonates:

monophenyl (monochloramine) a bisphosphonate,

from R-4-bromophenyl P-tertbutyl P',P'-aminobutiramida (dihlormetilen) bisphosphonates:

4-bromophenyl (dihlormetilen) a bisphosphonate.

Example 5. Three-isopropyl (dihlormetilen) bisphosphonate and monosodium salt.

413 g (1 mol) tetraisopropyl (dihlormetilen) bisphosphonates mixed with a 4.1 liter of water, and the mixture is stirred at the boil under reflux for 1.5 h and evaporated to a volume of about 750 ml of the alkaline Solution of doing while cooling with 50% n is OSU 315 ml of methanol and stirred for 16 h at room temperature. The mixture is filtered and the filtrate is evaporated to about 140 ml and left for 5 days at room temperature temperature. The precipitate is filtered and washed with 3 x 25 ml of methanol and dried to constant weight at 50oC. the Yield is about 44 g (11% ) odnonatrieva salt complex triisopropylsilyl ether (dihlormetilen) bisphosphonates acid (31P-NMR (CDCl3): d 11.87 per (P), 5,19 (P'),2IPP=17.3 Hz) FAB-MS: mole/mass 393/395/397 (M+H)), with a concentration of 90% in the treatment with acid it can be turned into triisopropyl (dihlormetilen) a bisphosphonate.

Example 6. P,P'-Aminobutiramida (dihlormetilen) a bisphosphonate, monosodium and disodium salt (stage 1). Monoisopropyl (dihlormetilen) bisphosphonate and trinacria salt (step 2).

Step 1. 413 g (1 mol) tetraisopropyl (dihlormetilen) bisphosphonates mixed with 4.1 liters of water and the mixture is stirred at the boil under reflux for 4 h and evaporated to a volume of approximately 870 ml of the alkaline Solution of doing while cooling with 30% aqueous NaOH solution and allowed to stand at room temperature for about 3 days and filtered (the filtrate is collected, see step 2). The precipitate is stirred for 2 h with 190 ml of 5N NaOH solution and the mixture is filtered. Sediment prom is raybaut with 70 ml of absolute ethanol and dried to constant weight at 100oC. the Yield is about 115 g (31% of theoretical) of the disodium salt of P, P'-diisopropyl ester (dihlormetilen) bisphosphonates acid (31P-NMR (D2O): d compared to 8.26) FAB-MS: mol. wt. 373/375/377 (M+H), with the concentration of 99.5% which by treatment with acid may be converted to P,P'-aminobutiramida (dihlormetilen) a bisphosphonate, which can be collected monosodium salt by adding 1 equivalent of NaOH to aqueous acid solution.

Step 2. The filtrate obtained in the first filter in the preceding stage, is evaporated to a volume of about 410 ml and left to stand at room temperature for about 16 hours the Precipitate is filtered off and regulate the pH of the filtrate 8.5 with concentrated hydrochloric acid,and add a solution containing 95 ml of methanol and 63 ml of water, and the mixture is stirred for 3 days at room temperature. The mixture is filtered and dried to constant weight at 100oC. the Yield is about 38 g (11% of theoretical) trinational salt complex monopropylene ether (dihlormetilen) bisphosphonates acid (31P-NMR (D2O): d 10,95 (R), 9,54 (P'), 2IPP=16.6 Hz) FAB-MS: mol. weight 353/355/357 (M+H) at a concentration of 97% which can be turned into monoisopropyl is n) a bisphosphonate and dimorpholino salt.

12.4 g (0,03 mole) tetraisopropyl (dihlormetilen) bisphosphonates, 120 ml of the research and 60 ml of chloroform is stirred at the boil under reflux for 3 h and left to stand at about 4oC for 1 day. The mixture is filtered and the precipitate washed with 60 ml of chloroform and dried. The output is approximately 12.5 g (83% of theoretical) dimorpholino salt complex diisopropyl ether (dihlormetilen) bisphosphonates acid (31P-NMR (D2O): d 7,86, with a concentration of 94% of which upon treatment with acid may be selected P,P'-aminobutiramida (dihlormetilen) a bisphosphonate. When instead the research using other secondary amines such as piperidine, dibutylamine etc. receive appropriate diamino salt, for example, salt bipiperidine and dibutylamine P, P'-diisopropyl ester (dihlormetilen) bisphosphonates acid. (see example 2). The reaction can also be carried out in the absence of co-solvent.

Similarly can be obtained, among others, the following symmetric dimorpholino salt complex diapir (dihlormetilen) bisphosphonates acid:

from tetraethyl (dihlormetilen) bisphosphonates:

P,P'-diethyl (dihlormetilen) bisphosphonate (31P-NMR (D2O): d 8,88,

from the2O): d 7,86),

from tetracyclines (dihlormetilen) bisphosphonates:

P,P'-dicyclopentyl (dihlormetilen) bisphosphonate (31P-NMR (D2O): d scored 8.38),

of tetrakis(1-methylbutyl) (dihlormetilen) bisphosphonates:

P, P'-bis(1-methylbutyl) (dihlormetilen) bisphosphonate (31P-NMR (D2O): d 8,24),

of tetrakis(1-ethylpropyl) (dihlormetilen) bisphosphonates:

P,P'-bis(1-ethylpropyl) (dihlormetilen) a bisphosphonate,

of P,P-aminobutiramida P',P'-dimethyl (dihlormetilen) bisphosphonates:

P-isopropyl P'-methyl (dihlormetilen) a bisphosphonate,

of Tetra-(Z)-3-hexenyl (dihlormetilen) bisphosphonates:

P,P'-di-(Z)-3-hexenyl (dihlormetilen) a bisphosphonate,

of P,P-derril P',P'-dibenzyl (dihlormetilen) bisphosphonates:

P-phenyl P'-benzyl (dihlormetilen) a bisphosphonate,

of R,R-aminobutiramida P',P'-diethyl (dihlormetilen) bisphosphonates:

P-isopropyl P-ethyl (dihlormetilen) a bisphosphonate,

of R,R-aminobutiramida P',P'-dibutil (dihlormetilen) bisphosphonates:

P-isopropyl P'-butyl (dihlormetilen) a bisphosphonate,

of R,R-aminobutiramida, P',P'-dihexyl (dihlormetilen) bisphosphonates:

P-isopropyl P'-hexyl (dihlormetilen) bisphosphonate (31P-NMR (CDCl3): d 6,87 (P), TO 7.67 (P'),2IPP=20.4 Hz),

of P,P,P'-triethyl P'-bizi,

of P,P,P'-triethyl P'-propargyl (dihlormetilen) bisphosphonates;

P-propargyl P'-ethyl (dihlormetilen) a bisphosphonate,

of P,P,P'-triethyl P'-4-methoxyphenyl (dihlormetilen) bisphosphonates;

P-4-methoxyphenyl P'-ethyl (dihlormetilen) a bisphosphonate,

of P,P-diethyl-P'-P'-dimethyl (monochloramine) bisphosphonates:

P-ethyl P'-methyl (monochloramine) bisphosphonate (piperidinium salt)31P-NMR (D2O): d 12,05 (R), Of 13.05 (P'), 2.7 GHz,

from tetraalkyl (monochloramine) bisphosphonates:

P,P'-diallyl (monochloramine) a bisphosphonate,

from tetraalkyl (dibromomethyl) bisphosphonates:

P,P'-diallyl (dibromomethyl) a bisphosphonate,

from tetradecyl (dibromomethyl) bisphosphonates:

P,P'-dihexyl (dibromomethyl) a bisphosphonate, (31P-NMR (D2O): d 11,92,

from tetradecyl (monobromomethane) bisphosphonates:

P,P'-dihexyl (monobromomethane) bisphosphonate (31P-NMR (D2O): d 8,44,

from tetracyclines (monobromomethane) bisphosphonates:

P, P'-dicyclopentyl (monobromomethane) bisphosphonate (piperidinium salt) (31P-NMR (D2O): d of 8.47,

from tetraethyl (dibromomethyl) bisphosphonates:

P,P'-diethyl (dibromomethyl) a bisphosphonate,

from tetrabutyl (dibromomethyl) bisphosphonates:

P,P'-dibutil ilen) a bisphosphonate,

from tetracyclines (dibromomethyl) bisphosphonates: (31P-NMR (D2O): d 7,26),

P,P'-dicyclopentyl (dibromomethyl) a bisphosphonate.

Used complex terrafire (halogenation) bisphosphonates acid (mixed) were obtained according to the method disclosed in examples 1 and 3.

Example 8. Tetramethyl (dihlormetilen) bisphosphonate and trimethyl (dihlormetilen) a bisphosphonate.

to 1.2 g (0.05 mole) of anhydrous finely chopped (dihlormetilen) bisphosphonates acid is stirred in 100 ml of anhydrous chloroform, and to this mixture is added dropwise under stirring at 15 to 20oC 53 ml of 2% ether solution diazomethane. After the addition stirring is continued for 30 min at room temperature and the mixture is evaporated to constant weight under vacuum. The output is approximately 1.5 g (100% of theoretical) tetramethyl (dihlormetilen) bisphosphonates (31P-NMR (CDCl3): d 10,88, with a concentration of 98%

When mixing tetramethyl (dihlormetilen) bisphosphonates in water simple ether for 3 h at boiling under reflux, get pure trimethyl (dihlormetilen) a bisphosphonate with output above 90% (31P-NMR (CDCl3): d 16,46 (P), 3,42 (P'),2IPP=19.6 Hz).

oC/1 mm) dissolved in 30 ml of anhydrous toluene and to this solution is added dropwise with stirring at 0 to 5oC 1,02 g (0,01 mol) of 1-hexanol in 10 ml of anhydrous toluene. After the addition stirring is continued for 30 min at t-re from 0 to 5oC and 1 h at about 25oC and added dropwise 10 ml of water, and the mixture is vigorously stirred for 1 h at the t-re from 30 to 40oC. the Solution is cooled to room temperature and regulate pH to 10 to 11 with 2H NaOH and evaporated to constant weight under vacuum. The residue contains about 60% trinational salt complex monohexyl ether (dihlormetilen) bisphosphonates acid, which can be purified by fractional crystallization from water-methanol. The output is approximately 1.8 g (45% of theoretical) and the concentration of >90% (31P-NMR (D2O): d 11,50 (P), 9,36 (P'),2IPP=15.7 Hz).

Example 10. P,P-aminobutiramida (dihlormetilen) bisphosphonate and the disodium salt.

of 7.4 g (0,02 mol) of P,P-aminobutiramida P',P'-dimethyl (dihlormetilen) bisphosphonates are dissolved in 75 ml of anhydrous acetonitrile and added to 6.0 g of iodine sodium, as well as of 22.4 g of chlorotrimethylsilane. The mixture is stirred for 15 minutes at the boil with a reflux is shoshanat (31P-NMR (CDCl3: d 7,50 (P), -9,61 (P'),2IPP=24.3 Hz). It hydrolyzing by adding 25 ml of water with a temperature of about 50oC, then the solution make alkaline with 10% NaOH solution and evaporated to constant weight under vacuum. The solid residue is mixed with 50 ml of acetone and left to stand in ice water for 4 hours the Precipitate is filtered and washed with acetone and dried to constant weight at 70oC. the Yield is about 6.8 g (88% of theoretical) disodium salt complex of P,P-diisopropyl ether (dihlormetilen) bisphosphonates acid (31P-NMR (D2O): d 14,52 (P), 7,20 (P'), 2IPP= 16.0 Hz), with a concentration of 98% which can be converted into the corresponding acid by treatment with acid.

Similar methods can be obtained from the following Silovye and partial esters (dihlormetilen) bisphosphonates acid:

of P,P-dimethyl P',P'-diethyl (dihlormetilen) bisphosphonates:

P, P-bis(trimethylsilyl) P', P'-diethyl (dihlormetilen) a bisphosphonate, from which P',P'-diethyl (dihlormetilen) bisphosphonate (31P-NMR (CDCl3): d 16,67 (P), 7,20 (P'),2IPP=15,5 (sodium salt),

of P,P,P'-trimethyl P'-hexyl (dihlormetilen)bisphosphonates:

P, P, P'-Tris(trimethylsilyl) PUB>O): d 11,50 (P), 9,36 (P'),2IPP=15,74 Hz (trinacria salt),

of P,P,P'-triisopropyl P'-methyl (dihlormetilen)bisphosphonates:

P, P, P'-triisopropyl P'-trimethylsilyl (dihlormetilen) a bisphosphonate, which

P, P, P'-triisopropyl (dihlormetilen) bisphosphonate (31P-NMR (CDCl3): d 11.87 per (P), 5,19 (P'),2IPP=17,2 Hz (odnonatrieva salt),

of P,P,P'-trimethyl P-isopropyl (dihlormetilen) bisphosphonates:

P, P, P'-Tris(trimethylsilyl) P-isopropyl (dihlormetilen) bisphosphonate (31P-NMR (CDCl3): d -1,18 (P), -9,71 (P'),2IPP=27,1 Hz)

monoisopropyl (dihlormetilen) a bisphosphonate,

of R,R-aminobutiramida P',P'-dimethyl (dihlormetilen) bisphosphonates:

P, P-aminobutiramida P'-methyl P'-trimethylsilyl (dihlormetilen) bisphosphonate (31P-NMR (CDCl3): d 7,81 (P) OF 1.12 (P'),2IPP=23,3 Hz)

P,P-aminobutiramida P methyl (dihlormetilen) a bisphosphonate,

of P,P,P'-trimethyl P'-octadecyl (dihlormetilen)bisphosphonates:

P, P,P'-Tris(trimethylsilyl) P'-octadecyl (dihlormetilen) a bisphosphonate, from which octadecyl (dihlormetilen) bisphosphonate and trinacria salt,

of P,P-dimethyl P',P'-diphenyl (dihlormetilen)bisphosphonates:

P, P-bis(trimethylsilyl) P', P'-diphenyl (dihlormetilen) bisphosphonate is shoshanat (31P-NMR (D2O): d 6,48 (P), BR11.01 (P'),2IPP=14,7 Hz (disodium salt),

of P, P, P'-trimethyl P'-(3-methyl-2-cyclohexenyl) (dihlormetilen) bisphosphonates;

P, P,P'-Tris(trimethylsilyl) P'-(3-methyl-2-cyclohexenyl) (dihlormetilen) a bisphosphonate, from which (3-methyl-2-cyclohexenyl) (dihlormetilen) bisphosphonate (31P-NMR (D2O): d 9,25, 8,812IPP=17.6 Hz (trinacria salt)),

of P,P'-diphenyl P,P'-dimethyl (dihlormetilen)bisphosphonates:

P, P'-bis (trimethylsilyl) P,P'-triphenyl (dihlormetilen) a bisphosphonate, from which P,P'-diphenyl (dihlormetilen( a bisphosphonate,

of P,P,P'-trimethyl P'-farnesyl (dihlormetilen)bisphosphonates:

P, P, P'-Tris(trimethylsilyl) P'-farnesyl (dihlormetilen)a bisphosphonate, which

monoparesis (dihlormetilen) a bisphosphonate,

of P,P,P'-trimethyl P'-1-tetrahydronaphthyl (dihlormetilen) bisphosphonates:

P, P,P'-Tris(trimethylsilyl) P-1-tetrahydronaphthyl (dihlormetilen) a bisphosphonate, from which 1-tetrahydronaphthyl (dihlormetilen) a bisphosphonate,

of P,P-diethyl-P',P'-dimethyl (monochloramine)bisphosphonates:

P, P-diethyl-P', P'-bis(trimethylsilyl) (monochloramine) a bisphosphonate, which

P,P-diethyl (monochloramine) a bisphosphonate,

of P,P,P'-trimethyl P'-1-octadecyl (dibromomethyl (dibromomethyl) a bisphosphonate.

Similarly can be obtained the following compounds:

of P,P-diethyl-P',P'-dimethyl (dihlormetilen)bisphosphonates:

P, P-diethyl-P',P'-bis(butyldimethylsilyl) (dihlormetilen) a bisphosphonate, from which P, P-diethyl-P'-tributylammonium (dihlormetilen) bisphosphonate (31P-NMR (CDCl3): d 9,70 (P), -1,06 (P')2IPP=23,7 Hz),

from tetraethyl (dihlormetilen) bisphosphonates:

P,P'-diethyl-P,P'-bis(tributylammonium) (dihlormetilen) a bisphosphonate, which

P,P'-diethyl-P-tributylammonium (dihlormetilen) bisphosphonate (31P-NMR (CDCl3): d 7,05 (P) OF 0.68 (P'),2IPP=23,4 Hz),

of tetramethyl (dihlormetilen) bisphosphonates:

P-methyl, P, P,P'-Tris(tertbutylphenyl) (dihlormetilen) bisphosphonate (31P-NMR (CDCl3): d 1,18 12,08 (P,P'),35,9 Hz).

Example 11. Monocultivar, mobereola, mono-and dikalova, mono - and delitala and mono - and demoniaca salt of P,P'-di-isopropyl (dihlormetilen) bisphosphonates acid.

3,29 g (0,01 mol) of P,P'-aminobutiramida (dihlormetilen) bisphosphonates acid are dissolved in 22 ml of water and added with stirring 3,15 g (0,01 mol) of Ba(OH)2x 8H2O, and stirring is continued for 2 hours the Mixture is filtered and the filtrate is evaporated to postojannaja P,P'-aminobutiramida (dihlormetilen) bisphosphonates acid with a concentration of >98%

Similarly got monocalcium salt, mono - and Pikalevo salt, mono - and deliciious salt, as well as mono - and diammonium salt (yield >95% concentration of >98%).

Example 12. P,P'-aminobutiramida (monochloramine) bisphosphonate and dimorpholino salt.

of 8.2 g (0,02 mol) tetraisopropyl (dihlormetilen) bisphosphonates (obtained as described in example 1) in 80 ml of the research was stirred at the boil under reflux for 24 h and the solution is cooled. The formed precipitate was separated and recrystallized from simple ether. The output is about 8.5 g (90% of theoretical) (monochloramine)bisphosphonates (31P-NMR (D2O): d 11,31 parts per 1 million (dimorpholino salt) with a concentration of about 85% (the product contains about 15% of the relevant dichloroethylene), which can be freed from the corresponding acid by treatment with an aqueous solution of the product of two equivalents of hydrochloric acid.

Similarly we have received the following complex diesters (monochloramine) bisphosphonates acid:

P,P'-diethyl (monochloramine) bisphosphonate (31P-NMR (D2O): d 12,40 parts per 1 million (dipiperidino salt)), P,P'-dicyclopentyl (monochlorotoluenes (dihlormetilen) bisphosphonate and trinacria salt.

5.0 g (of 0.014 mole) of tetraethyl (dihlormetilen) bisphosphonates and 6.7 g (0,045 mol), NaI dissolved in 50 ml anhydrous CH3CN and with stirring 12.2 g (0,112 mole) of tributyltinchloride. After the addition stirring is continued at room temperature, protected from moisture, for about 4 days and evaporated under vacuum. To the resulting mixture in the form of residue (containing as the main component monoethyl Tris(trimethylsilyl) (dihlormetilen) bisphosphonate) add 10 ml of water and the mixture is alkalinized with 10% NaOH solution. The mixture is diluted with 50 ml of CH3OH and leave to stand at 4oC for 2 h, then filtered (sediment represents a sodium salt (dihlormetilen) bisphosphonates acid). To the filtrate add 25 ml of ethanol and left to stand for 1 day at 4oC, then filtered. The filtrate is evaporated under vacuum and the residue is washed with acetone and filtered. The residue is dried to constant weight, resulting in a gain of approximately 2.0 g (50% of theoretical) of colourless crystalline trinational salt complex monoethylene ether (dihlormetilen) bisphosphonates acid (31P-NMR (D2O): d up 11,86 (P) 9,40 (P'),2IPP=to 15.4 Hz) with a concentration of > 90% of which can provide monomethyl (dihlormetilen) bisphosphonate and its chinatravel salt (31P-NMR (D2O): d of 10.58 (P), 8,58 (P'),2IPP=16,7 Hz) of tetramethyl (dihlormetilen) bisphosphonates; (dinitroaminobenzene salt) (31P-NMR (D2O): d 12,97 (P), 9,17 (P'), and 15.1 Hz).

Example 14. Processing tetraisopropyl (methylene) bisphosphonates with phosphorus pentachloride.

3,44 g (0,01 mol) tetraisopropyl (methylene) bisphosphonates were treated, under stirring, in portions with the help of 4.16 g (0.02 mol) PCl5resulting mixture was heated to approximately the 50oC. After the addition the stirring was continued for 2 h and light solution evaporated under vacuum.

To the residue was added upon cooling, 20 ml of water and after completion of the exothermic reaction the mixture is stirred at the boil under reflux for 30 min and evaporated under vacuum. Obtained in the form of balance of light oil was analyzed using NMR31P and1H, and was discovered the following composition:

Connection31P-NMR (NaOD); mol.

Methylenephosphonate 17,17; 21,5

Monoisopropyl (methylene) bisphosphonate 19,94, 14,74,2IPP=8,2 Hz; 41

P,P'-diisopropylaminoethanol 17,24; 20

Phosphate 3,33; 15

Monoisopropylamine 3,62; 2,5

No signs that the atoms of moderatormailer) bisphosphonate and P,P'-dicyclopentyl (bromchlormethane) bisphosphonate and its piperidinium salt.

4.8 g (0,01 mol) tetracyclines (monochloramine) bisphosphonates (31P-NMR (CDCl3): to 12.44 parts per 1 million2IPP=17,7 Hz) was dissolved in 20 ml of carbon tetrachloride and added 0.55 g of the chloride of benzyltriethylammonium and 20 ml of 10% aqueous sodium hypobromite solution while cooling and stirring at about 10oC. the Mixture is vigorously stirred for 30 min at about 10oC and the organic phase is separated, washed with water, dried (Na2SO4) and filtered. The filtrate is evaporated in vacuo, resulting in a gain of approximately 5.0 g (90% of theoretical) tetracyclines (bromchlormethane) bisphosphonates (31P-NMR (CDCl3): d 7.68 parts per 1 million) in the form of a colourless oil with a concentration of > 80%

2.8 g (0,005 mol) obtained above tetracyclines (bromchlormethane) bisphosphonates are dissolved in 6 ml of anhydrous piperidine and the mixture is stirred for 1 h at an oil bath with a temperature of approximately 110oC and evaporated in vacuum. The solid residue is mixed with 10 ml of simple ether and the precipitate is filtered and dried. The output is approximately 1.8 g (60% of theoretical) of colourless crystalline dipyridinium salt of P, P'-DICYCLOHEXYL (bromchlormethane) bisphosphonates (31P-NMR (D2O): d of 8.47 otoy.

Example 16. Trimethyl (monobromomethane) bisphosphonate and its lithium salt.

1.04 g (2.5 mmol) tributyltin trimethyl ammonium salt methylenephosphonate (obtained as described in example 1 of tetramethyl methylenephosphonate and tributylamine (31P-NMR (CDCl3): d 30,51 parts per 1 million (R), 9,54 ppm (P'),2IPP=6,9 Hz) dissolved in 40 ml of anhydrous tetrahydrofuran and the mixture is cooled to -70oC and with stirring, add 4.0 ml (5.0 mmol) of a solution of 2.5 BuLi in hexane at about -70oC and stirring is continued for another 10 minutes To the mixture with stirring at about -60oC 0,80 g (5 mmol) of bromine in 20 ml of anhydrous tetrahydrofuran over 10 minutes, after which stirring is continued for 15 minutes at about -60oC, and the mixture is heated to room temperature. The mixture is filtered and the filtrate is evaporated in vacuo, resulting in a gain of approximately 0.6 g (80% of theoretical) of trimethyl (monobromomethane) bisphosphonates, lithium salt (31P-NMR (CDCl3): d 25,03 parts per 1 million (P), 11,59 (P'),2IPP=to 15.4 Hz), which as a result of processing the acid may be converted to the corresponding acid.

Measurement of biological activity tested the possible interaction of compounds with bone material, from the ability to prevent bone resorption in vitro and in vivo and their relative bioavailability after oral administration, below. The results obtained for the four new compounds listed in the table. They have a lower affinity for bones than the compounds for comparison, clodronate and etidronate. Despite this, they retain their biological activity, as shown in experiments on resorbtive in vitro and in vivo. In addition, the compounds are better absorbed after oral administration than clodronate.

Example 17. Binding to hydroxyapatite crystals in vitro.

Hydroxyapatite crystals (Bio-Rad lab. Bio-Gel STP, 0.05 mg/ml, dissolved and equilibrated in 0.01 M barbiturate buffer pH 7.4/ and 14C-disodium clodronate tetrahydrate (5 μm) incubated at room temperature for 2 h in the absence (total) or in the presence of the test compounds at concentrations between 0.6 and 50 μm. After centrifugation measure the radioactivity of supernatant and subtracted from the blank value determined in the absence of crystals.

Specific binding is defined as the excess as compared with nonspecific binding determined with 500 μm clodronate and presented as SUB>), where C=5 ám andD=1,23 μm). The dissociation constant KDand the maximum number of binding sites (Bmax) were determined using analysis of Scatchard in experiments with saturation 14C-clodronate in concentrations between 1 and 10 microns.

Example 18. Inhibition of resorbtive bone in vitro.

Experienced bone resorption in the experience of resorbtive on the cranial vault of the mouse by measuring the allocation of 45 Ca from labeled bones /Keynolds et al. 1979, Lerner et al. 1987, Lerner, 1987/. The pieces of the cranial vault are cultivated in the presence of parathyroid hormone (PTH, 10 nmol/l) and bisphosphonates in concentrations of 100 µmol/l within 72 hours the Results are calculated as a percentage of control values (PTN-stimulated bone without bisphosphonates).

Example 19. Inhibition of resorbtive retinoid-induced bone in vitro.

The inhibitory activity of the test compounds was evaluated on the model of resorbtive retinoid-induced bone on thyroparathyroidectomy rats (SPPH) /Trechsef et al. 1987, Stutzer et al. 1988) with slight modification. Retinoid induces an increase in resorbtive bones and some vertebrates subperiosteally osteoclasts. This model uses a plasma Ca for monitoring changes in resorbtive to the X. Four days after TRUTH retro-orbital draw samples of blood. Counting only the animals with the level of Ca in plasma below 2.2 mmol/l for successful TRUTH. Substitute thyroxine in a dose of 1.0 µg subcutaneously (s.c.) three times a week since TRTH.

Enter retinoid ethyl-n-[(E)-2-/5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl/-1-propenyl] benzoate /Ro 13-6298/ dose of 25 ug/rat s.c. for three consecutive days (days 0, 1, 2). Take blood for measurement of Ca before the first and after 24 h after the last injection retinoid (day 0 and 3).

Compound was administered intravenously at day 0, and then did the first injection retinoid (s.c.). Changes in the level of ca in plasma without (positive control) and with the test compound to TRUTH-rats is a difference of level of Ca in plasma (mmol/l) on the third day after administration of the retinoid and the level of CA in plasma prior to injection retinoid (day 0). A number of definitions for each of the test compounds is 4, and calculating the mean and standard error for the average.

Example 20. Relative bioavailability.

Relative bioavailability partial alilovic esters of clodronate were determined according to urine output in rats. Ratio (F) total quantity. . infusion is a measure of the absorption of drugs:

F=(Xu)orali.v/[Xu]i.v.Doral< / BR>
where (Xu) is the cumulative number of drugs allocated unchanged in the urine and D dose /Gibaldi et al. 1983).

Compounds were injected into male rats (Sprach-daily) orally at dose levels of 100 and 300 µmol/kg and intravenously at the dose level of 100 µmol/kg was Used in three animals at each dose level and route of administration. Urine is collected in metabolicheskikh cells at 0 1 h 1 3 h 3 6 h 6 12 h, 12 to 24 hours, 24 to 48 h and 48 to 72 h after dosing. Measure the volume of urine and analyze compounds by gas chromatography using nitrogen-phosphorus-sensitive detector and a capillary column.

The results show that partial esters according to the invention have a lower affinity for bones than the connection of comparison, even with residual biological activity in experiments both in vivo and in vitro by inhibition of resorbtive. They also have improved bioavailability after oral administration than the corresponding acid, clodronate.

Circuit 1

1. Derivatives methylenephosphonic acid of General formula

< / BR>
where R1R4Ney hydrogen and at least one non-hydrogen;

Q1and Q2chlorine,

including stereoisomers of the compounds and their pharmaceutically acceptable salts.

2. Compounds of General formula under item 1, characterized in that at least one of the groups R1R4is not hydrogen, and the other is hydrogen.

3. Compounds of General formula under item 1, characterized in that one of the groups R1R4hydrogen, one lower alkyl, and the others hydrogen or lower alkyl, preferably methyl or ethyl.

4. Compounds of General formula under item 3, characterized in that one or two of the groups R1R4lower alkyl, preferably methyl or ethyl.

5. Compounds of General formula 4, characterized in that represent onomatology or monotropy ether dihlormetilen-bisphosphonates acid.

6. Compounds of General formula under item 1, characterized in that one or two of the groups R1R4C14C18-alkyl, and the other is hydrogen.

7. Compounds of General formula under item 1, with the ability to participate as shapers of the complexes in the regulation of metabolism of the body.

 

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a highly effective combined and used in power, oil, fragrance, textile, household, medicine, production of mineral fertilizers
The invention relates to chemical technology for reagent collector on the basis of oxyalkylation acids intended for the enrichment of phosphate ores and oxidized ores of non-ferrous metals

The invention relates to new phosphorylated to Surinam General formula

R-- OCH2-COOH,

(I) where R is a saturated or unsaturated aliphatic hydrocarbon residue with a straight or branched chain, containing 6-30 carbon atoms which may be substituted with halogen, -OR, - SR1or-NR1R2group, where R1and R2lowest alkali

The invention relates to a technology for sodium salts of nitrilotriethanol acid (NTF), used as components of detergents, inhibitors and other industries

The invention relates to a new method of obtaining methylenephosphonic acids of the formula I,

where Q1and Q2independently from each other are hydrogen or halogen, by hydrolysis of the corresponding complex tetraeder methylenephosphonic acid of the formula II

where R represents a branched or unbranched alkyl group containing 1-4 carbon atoms, and Q1and Q2have these values

The invention relates to new biologically active compound, specifically to the dichloride 2-[5-(2-methylpyridyl]ethyl, bis{2-[5-(2 - methylpyridine)] ethyl}of phosphoryla (I) of the formula I

MeCCHMeCH2CHP=0

possessing antibacterial activity
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