Derivatives of amides methylenephosphonic acids and methods for their production

 

(57) Abstract:

Usage: in medicine as complexing agents in the regulation of metabolism of the body. The inventive products, the derivatives of amides methylenephosphonic acids of General formula I, where W1- W4- OR1or NR2R3where R1is hydrogen, lower alkyl, R2and R3is hydrogen or C1-8-alkyl, provided that at least one of the groups W1- W4represents hydroxyl, and at least one of the groups W1- W4represents an amino group NR2R3, Q1and Q2independently of one another denote hydrogen or halogen, or their pharmacologically acceptable salts. Reagent 1: methylenephosphonic acid or partial ester. Reagent 2: Amin other2R3. The process is conducted in the medium of organic solvent at room temperature.

. table 1.

The invention relates to new derivatives methylenephosphonic acid, especially to new, halogensubstituted Amida and ether-Amida (ester-Amida) methylenephosphonic acid, methods of producing these new compounds, as well as to pharmaceutical compositions, which contains some complex therefire, but it does contain several references to the corresponding partial esters, partial Amidah and incomplete ether-Amidah.

Obtaining complex tetrapyrrol methylenephosphonic acids disclosed in the following publications: J. Am. Chem. Soc. 78 (1956), 4450; J. Chem. Soc. (1959) 2272; J. Am. Chem. Soc. 84 (1962) 1876; J. Org. Chem. 35 (1970) 3149; J. Org. Chem. 36 (1971) 3843 and Phosphorus. Sulful and Silicon, 42 (1989) 73.

In the European patent 356866 described optionally halogen-substituted esters and amide-esters methylenephosphonic acid, which are inhibiting the biosynthesis of cholesterol activity.

According to the invention, discovered that the new partial amides and incomplete ester-amides methylenephosphonic acids and their salts, in many cases, have more favorable properties than the corresponding bisphosphonic acids and salts due to their better dynamics and availability, their ability to participate as complexing agents in the regulation of metabolism of the body, which will be discussed next.

They are well suitable for the treatment of disorders associated with calcium metabolism and others, especially the divalent metals. They can be used for the treatment of diseases of the skeletal system, especially Costea agcih tissues, such as deposits and vascular calcification and irregularities in osteogenesis.

On the other hand, being analogues of pyrophosphate, new substituted derivatives of methylenephosphonic acids are also suitable for treating disorders (pyro/phosphate body functions, including such functions, where active, but prone to irregularities or malfunctioning organic part connected with (pyro)phosphate or acts as a metal complex, or a combination of the above-mentioned recent cases.

New bisphosphonates regulate directly or indirectly the quality and level of cations and/or pyrophosphate compounds, freely present in body fluids, as well as related, active and released from the tissues. Thus they are able to regulate metabolism, growth and destruction of cells. Therefore, they are suitable for the treatment of, for example, bone cancer and its metastasis, ectopic vascular calcification, urolithiasis, rheumatoid arthritis, bone infections and destruction of bones.

Typical of the new substituted methylenephosphonate is desirable selective and controlling the action providing the best therapeutic index.

The invention relates to the W4independently from each other represent a group OR1or the group NR2R3where R1, R2, R3independently from each other, represent hydrogen or linear or branched, optionally substituted C1-C22-alkyl; optionally substituted, optionally unsaturated C3-C10-cycloalkyl, aryl, aralkyl or silyl SiR3or the group R2and R3together with the adjacent nitrogen atom form a 3-10-membered saturated, partially unsaturated or aromatic heterocyclic ring which, in addition to the nitrogen atom may be one or two heteroatoms from the group comprising N, O and S, provided that in formula I at least one of the groups W1, W2, W3and W4denotes hydroxyl and at least one of the groups W1, W2, W3and W4represents an amino group NR2R3;

Q1and Q2, independently of one another, denote hydrogen, fluorine, chlorine, bromine and iodine;

including stereoisomers such as geometrical and optically active isomers, of the compounds; as well as their pharmacologically compatible salts.

Alkyl, alkenyl and quinil, as a group, R1, R2and R3contain, nez is 4, accordingly, 2-4 C-atoms.

Cycloalkyl or cycloalkenyl, as a group, R1, R2and R3contains 3-10 C-atoms, preferably 5 or 6 C atoms and can be unsubstituted or substituted, for example, lower C1-C4-alkyl. Mainly it refers to cyclopropyl, cyclobutyl, cyclopentyl, tsiklogeksilnogo or cycloheptyl or appropriate cycloalkenyl group.

Aryl or aralkyl, as a group, R1, R2and R3denotes optionally substituted lower alkyl with C1-C4, lowest arcoxia with C1-C4or halogen monocyclic aryl or aralkyl, such as phenyl and benzyl, however, preferably unsubstituted phenyl or benzyl. Halogen represents chlorine, bromine, fluorine or iodine.

In the silyl group SiR3the group R represents a lower alkyl with C1-C4and especially methyl, ethyl, isopropyl, butyl, tert.-butyl, or represents phenyl or R substituted phenyl, as well as various combinations of the lower Akilov and fanilow, such as dimethyl-tert. -butyl, maildisplay, dimetilfenil, diethylphenyl, methyl-tert.-butyl-phenyl, aminobutiramida-/2,6-dimethyl-phenyl/.

When R2and R3

Q1and Q2both preferably denotes chlorine.

Salts of compounds of formula I are particularly preferably represent their salts with pharmaceutically compatible bases, such as metal salts, for example alkali metal salts, especially salts of lithium, sodium and potassium, salts of alkaline earth metals such as calcium salts or 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, and Quaternary ammonium salts such as the halides, sulfates and hydroxides; salts with aminoalcohols, such as ethanol-, diethanol - and triethanolamines, Tris/oximeter/-aminomethan; 1 - and 2-methyl - 1,1-, 1,2 - and 2,2-dimethylamino and Criptana, and heterocyclic ammonium salt, such as salt azetidine, pyrrolidine, piperidine, piperazine, morpholine, pyrrole, imidazole, pyridinium, pyrimidine, chinoline etc.

Examples of preferred compounds of the invention are: P,P,P'-Tris/diethylamid/ /dihlormetilen/bisphosphonates acid; P-mono/diethylamid/ P-monoisopropyl ether /dihlormetilen/bisphosphonates acid; P, P-bis/diethylamid/ /dihlormetilen/-bisphosphonates acid; mono/diethylamid/ /dihlormetilen/bisphosphonates acid; mono/phenyl-N-methyl-amide/ /dihlormetilen/bisphosphonates acid; mono/benzylated/ /dihlormetilen/-bisphosphonates acid; P,P'-bis-/diethylamid/ /dihlormetilen/-bisphosphonates acid.

The invention relates also to a method for producing compounds of the formula I, according to which:

a) the compound of formula I':

,

in which Q1and Q2have the above significance, and

W1, W2, W3and W4also have the above value with the exception of hydroxyl, at least one ester group OR1and/or amino group NR2R3hydrolized to the free hydroxyl group to obtain a partial amide or incomplete ester-amide of the formula I":

,

which is not necessarily in chloranhydride form, and where Q1and Q2have the above significance; W1W4indicate the group OR1where at least one of the groups R1represents hydrogen, and the remaining groups R1have the above meaning; when the connection I have one hydroxyl group, at least one ester group OR1turn in the amide group, and when the connection I have more than one hydroxyl group, the free hydroxyl group lidiruyut using suitable amine with other2R3and/or ester group is converted into an amide group to a partial amide or a partial ester-amide of the formula I containing at least one hydroxyl group and at least one amino group, or

in) phosphonate of the formula IX:

Y-CQ1Q2 (IX)

enter into interaction with activated phosphate or hydrogen phosphate of the formula X:

,

where Y denotes hydrogen, hydroxyl or halogen or other removable group; Z represents hydrogen, halogen, acyloxy, sulfonyloxy, alkoxy or aryloxy; and W1-W4and Q1and Q2have the above significance, or

BBO is W1-W4and Q1and Q2have the meaning mentioned above, or the corresponding hydrophosphate, are oxidized to compounds of formula I, where Q1and/or Q2denote hydrogen, is converted into a compound of formula I, where Q1and/or Q2denote halogen; and/or the resulting compound of formula I, where Q1and/or Q2denote halogen, mono - or di-dehalogenases to the compounds of formula I, where Q1and/or Q2represent hydrogen; and/or, if desired, the compound obtained of the formula I is converted into another corresponding to the formula I compound by esterification to complex ester, transesterification, amidation or parametervalue and/or, if desired, the obtained partial amide or a partial ester-amide acid is turned into salt or obtained salt is converted into the free acid.

According to one variant of the method, compounds obtained by selective hydrolysis of the ester or amide group of the corresponding Tetra(amide-ester) compounds of the formula I. Thus, as a starting material is used as a compound in which Q1and Q2have the above significance and group W1-W4have the same meaning as in formula I, for IP/SUP>R3and at least one ester or amide group contained in the compound, hydrolyzing to a free hydroxyl group, or at least one of several amide groups leave.

Over the course of the hydrolysis can be monitored, for example, by chromatography or by using31P-NMR spectroscopy. The reaction may be interrupted when the concentration of the desired partial (complex ester)amide reaches its maximum, and the product can be isolated from the reaction mixture or in the form of the free acid or as a salt by precipitation, extraction or chromatography, and the salt form can be converted into the free acid or the free acid can be converted into its salt.

Compounds according to the invention, therefore, can be obtained by selective esterification and amidation bisphosphonic acids. As the source material can be used tetraconata (W1-W4OH), which can be a free acid or salt, such as salt of the metal or ammonium, or an appropriate tetrachlorohydrex bisphosphonates acid, and a suitable amine with other2R3. Similarly, there may be ispolnali their salt or the corresponding acid chloride acid. The ester group can be converted to amide group through galoyanized or directly using known methods.

Partial amides and ester-amides according to the invention, therefore, can be obtained by constructing the P-C-P structure of its parts:

,

where Y denotes hydrogen, hydroxyl, or halogen, or other removable group; Z represents halogen, acyloxy, sulfonyloxy, alkoxy or aryloxy, and W1-W4and Q1and Q2have the above significance. As a basis you can use, for example, sodium hydride, utility or diisopropylamide lithium. The original material is optionally present free acid sites and/or amino-hydrogens (one of the groups R1-R3H) can be neutralized by using a sufficient amount of base to the reaction mixture.

Can also be used in the reaction Michaelis-Arbuzov, and the second reaction component is postit, or reaction Michaelis-Arbuzov, where Z denotes hydrogen.

Amides and ester-amides according to the invention can also be obtained from P-C-P-structures with a low degree of oxidation by oxidation:

,

where W1in equilibrium with hydrophosphate structure. As oxidizing agents suitable all the usual oxidizing agents or their solutions, such as hydrogen peroxide, pergolide connection, nagkalat, permanganate, etc.

Also, the compounds according to the invention can be obtained by halogenation of the corresponding compounds where one or both groups Q1and Q2denote hydrogen, or by sharing halogen(new) to another, or by removing one or both:

.

In formulas W1-W4and Q1and Q2have the above significance. Halogenoalkane carried out as described below.

Partial amides and ester-amides bisphosphonic acids according to the invention can also be obtained from other partial amides or ester-amides through the implementation of intermolecular or intramolecular exchange reaction.

Used as starting materials in the above reaction of Tetra(ester)amides and the corresponding tetracyclic can be obtained in itself known from the literature of ways by constructing P-C-P structure of its parts, for example, using the above reaction Michaelis-Becker, Michaelis-Arbuzov or carbanion reaction.

If you polyrinia into account obtaining desirable incomplete (complex ester)amide. Thus, amide and ester groups W1-W4can be converted directly or via the corresponding acid chloride phosphonic acid or by using other known methods.

The halogen atoms can be introduced instead of hydrogen to carbon located between the phosphorus atoms of bisphosphonates in the form of Tetra(ester)amides by reaction is preferably carried out using hypokalaemia. Also apply the usual reaction of halogenation, such as reaction bisphosphonic of carbanions derived from a strong base, with elements of Halogens, or by halogenoalkane using N-haloamines and other active halides or Prigorodnyi connections.

Halide substituents of carbon can also be entered in bisphosphonate structure in the form of halogenated monophosphate IX, where Q1and/or Q2are halogen-free. Halogen Y carbon structure can also be exchanged for hydrogen, often by nucleophilic dehalogenase, or another halogen, using known reactions. Mixed halide compounds can also be obtained by applying the above reactions halogenic the-amides can better be obtained by using optically active compounds, such as optically active alcohols, upon receipt of the above starting materials, intermediates and target products, or by exchange reactions.

The properties of the compounds according to the invention was tested in the following test systems.

Inhibitory bone resorption stimulated by parathyroid hormone activity of compounds was determined in vitro on the vault of the skull of a mouse (Reynolds and Dingle /Calc Tiss Res 1970; 4:339/).

The table shows the superiority of the relative in vitro activity of the compounds of the invention, especially considering the fact that they are linked only to a limited extent with hydroxyapatite and partially inhibit the growth of crystals. They provide the best therapeutic index, showing fewer side effects.

Partial amides and incomplete ester-amides of substituted bisphosphonic acids of formula I can be used in pharmacy as such or in the form of their farmakologicheskaya salts, such as alkali metal salts or ammonium. Such salts can be obtained by reaction (ester)amides of the acids with the appropriate inorganic or organic bases. Depending on the reaction conditions, also C is x2">

The new compounds I according to the invention can be introduced enterline (inside) or parenteral. Take into account all normal for the introduction of forms, such as tablets, capsules, granules, syrups, solutions, implants and suspensions. Can also be used any auxiliary means for receiving, dissolution or administration of the drug, such as stabilizers, viscosity regulators, dispersing agents, and buffers.

Such excipients include, for example, tartrate and citrate buffers, alcohols, etc and other non-toxic complexing agents, solid and liquid polymers and other sterile substrates, starch, lactose, mannitol, methylcellulose, talc, silicic acid, fatty acids, gelatine, agar-agar, calcium phosphate, magnesium stearate, animal and vegetable fats and, if desirable, flavouring and sweetening agents.

Dosage depends on several factors such as the type of administration, sex, age and individual condition. Daily dose is about 1-1000 mg, typically 10-200 mg per person, and they can be entered as single dose or can be divided into several doses.

The following are examples of typical capsules and tablets:
R>
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 or intramuscularly injecting the injectable preparation can be manufactured, for example, in the form of a concentrate for infusion, which as auxiliary substances can be used, for example, sterile water, phosphate buffer, NaCl, NaOH or HCl or other suitable known pharmaceutical excipients.

Connection in amide and ester-amide of the acid form according to the invention are liquid or waxy substances, which are usually soluble in organic solvents and in some cases in water. Their salts are solid, crystalline or typical powdery substances, which are usually highly soluble in water, in some cases, in organic solvents, but only some structural types are poorly soluble in all solvents. The connection is very stable in neutral solutions at room temperature.

The structure of the compounds can be easily confirmed by using the1H,13- And31P-NMR spektroskopiya and impurities is very suitable31P-spectrometry. For polar compounds as such can be used ion-exchange and exclusion HPLC, and Tetra(ester)amides and related similarbank derivatives can be used in gas-liquid chromatography or gas chromatography/mass spectrometry. Nitrogen, sodium, and other metals compounds are defined separately, as well as the possible content of crystallization water.

Example 1. P',P'-bis/Diethylamid/ /dihlormetilen/bisphosphonates acid and its disodium salt.

a 3.83 g (0.01 mol) P', P'-bis/diethylamide/ P, P-dimethyl ester /dihlormetilen/bisphosphonates acid dissolved in 20 ml of anhydrous methylene chloride and add to 3.06 g (0.02 mol) of bromotrimethylsilane under stirring, as of 3.00 g (0.02 mol) of sodium iodide and the mixture is stirred for 6 h at room temperature (the reaction is monitored by NMR). The solvent is evaporated in vacuum and the residue is dissolved in anhydrous ether. The mixture is filtered and the filtrate is evaporated under vacuum to constant weight, getting P', P'-bis/diethylamid/ P, P-bis/trimethylsilyl ether/ /dihlormetilen/bisphosphonates acid in quantitative yield as a brown oil. On the s 5 min and evaporated to constant weight under vacuum, receiving P',P'-bis/diethylamid/ /dihlormetilen/bisphosphonates acid as a brown, viscous-fluid oil. It is dissolved in 35 ml of a mixture of methanol with acetone (1:1) and to the solution was added, with stirring and cooling, 3 ml of 5N. NaOH solution. The solution is evaporated under vacuum and to the residue add acetone and the mixture is stirred. The precipitate is filtered and washed with acetone and dried in air. The output is 2.8 g (70% of theory) of colorless, crystalline disodium salt of P', P'-bis/diethylamide/ /dihlormetilen/bisphosphonates acid (31P-NMR /D2O/: 6,60 m DV /P/; 32,16 memorial plaques /P'/,2JPP= 15.6 Hz;3JPH= 9,2 Hz); the concentration of >90%

The following amides and ester-amides bisphosphonates acid, as well as their sodium salts, can be obtained in a similar way:

From P'-ethyl-P-methyl-P,P'-bis/diethylamido/ /dihlormetilen/-bisphonate through P, P'-bis-trimethylsilyl)/-P, P'-bis/diethylamido/ /dihlormetilen/a bisphosphonate: P, P'-bis/diethylamido/ /dihlormetilen/bis-phosphonate (example 6) /31P-NMR /CDCl3/: d, M. D. 15,66/, which can be converted to its disodium salt as described above /31P-NMR /D2O/: d 13,94 M. D./.

From P'-ethyl-P, P-dimethyl-P'-morpholino/dihlormetilen/bisphosphonates (example 4) through P,P,PP>P-NMR/ D2O/: d, M. D. 6,02 /P/; 18,06 /P'/;2JPP=17.6 Hz/ and trinacria Sol /31P-NMR /D2O/: d, M. D. 9,44 /P/; 10,75 /P'/;2JPP= 18,1 Hz/.

Of P, P,P'-trimethyl-P'-dibutylamino/dihlormetilen/-bisphosphonates (example 4) through P,P,P'-Tris/(trimethylsilyl)/-P'/dibutylamino//Diplomatie/a bisphosphonate: P'/dibutylamino/ /dihlormetilen/-bisphosphonate /trinacria salt, 31P-NMR /D2O/: d, M. D. 9,58 /P/; 12,58 /P'/;2JPP= 15.2 Hz/.

From P-methyl-P'-butylamide/dihlormetilen/a bisphosphonate (example 6) [or P,P, P'-trimethyl-P-/butylamide//dihlormetilen/-bisphosphonates] through P, P, P'-Tris/(trimethylsilyl)/-P'/butylamide//dihlormetilen/ a bisphosphonate: P'/butylamide//dihlormetilen/a bisphosphonate/31P-NMR /D2O/: d, M. D. 7,11 /O/; 9,49 /PP/;2JPP= 21,0 Hz/.

Of P-ethyl-P, P'-dimethyl-P'-/dioctylamine//dihlormetilen/bis-phosphonate (example 4) through P,P,P'-Tris/(trimethylsilyl)/-P'/dioctylamine/-/dihlormetilen/-bisphosphonate /31P-NMR /CDCl3/: d, M. D. 7,16 /P'/, 6,28 /P/,2JPP= 27,2 Hz/: P'/dioctylamine//dihlormetilen/a bisphosphonate/31P-NMR /CDCl3/: d, M. D. 9,78 /P/, 15,41 /P'/,2JPP= 23,2 Hz/ and trinacria Sol /31P-NMR/D2O/: d, M. D. 12,23 /P/, TO 18.01 /P'/,2JPP= 22,0 Hz/.

From P'-ethyl-P,P-dimethyl-P'-/dichlormethane/a bisphosphonate: P'/benzylmethylamine/-/dihlormetilen/a bisphosphonate /31P-NMR /D2O/: d, M. D. 10,32 /P/, 15,60 /P'/;2JPP= 14,9 Hz/.

From P'-ethyl-P,P-dimethyl-P'-/benzylmethylamine-//chlormethine/bis-phosphonate (example 10) through P,P,P'-Tris-trimethylsilyl)/-P'/benzylmethylamine//chlormethine/a bisphosphonate: P'/benzylmethylamine//chlormethine/a bisphosphonate.

Of P, P, P'-trimethyl-P'/diethylamido//chlormethine/-bisphosphonates (example 10) through P,P,P'-Tris/(trimethylsilyl)/-P'/diethylamido//chlormethine/a bisphosphonate: P'/diethylamido//chlormethine/bis-phosphonate /trinacria salt, 31P-NMR /D2O/: d, memorial plaques being 9.61 /P/, 17,84 /P'/,2JPP= 2,9 Hz/.

Of P,P-dimethyl P',P'-bis/diethylamido//chlormethine/-bisphosphonates (example 10) through P,P-bis-trimethylsilyl)/-P',P'-bis-/diethyl-amido//chlormethine/-bisphosphonate: P', P'-bis/diethylamido//chlormethine/a bisphosphonate /disodium salt,31P-NMR /D2O/: d, M. D. 7,92 /P/; 34,17 /P'/,2JPP= 3.1 Hz,2JPH= 16,7 Hz/.

P, P-Dimethyl P', P'-bis/diethylamido//dihlormetilen/a bisphosphonate, used above as a starting material, can be obtained in the following way:

Stage 1. In THF-hexane solution GAVE (diisopropylamide lithium), which contains 0.10 mol Gave, under stirring in nitrogen atmosphere and at a temperature of -75 -78oC add anhydride metaphosphates acid and diethylamine) in 20 ml of anhydrous THF. After the addition, the mixture is stirred for 15 minutes, then add 7,22 g (0.05 mol) of dimethyl ether chlorophonias acid in 10 ml of anhydrous THF and stirring is continued for the next 15 min at -75 - -78oC. the Temperature of the mixture increases to a value of about 50oC and the pH is adjusted to 5-6 using 5N. HCl. The mixture is heated to room temperature and the solvent is distilled off in vacuum. The residue is extracted 3 times with 70 ml CHCl3and the combined extracts washed with 10% solution of NaHCO3and water and dried with MgSO4and filtered. The filtrate is evaporated in vacuum, and get about 15.7 g (100% of theory) of P,P-dimethyl P',P'-bis/diethylamido/-methylenephosphonate in the form of a slightly yellowish oil /31P-NMR /CDCl3/: d, M. D. 25,43 /P/, 25,51 /P'/,2JPP= 4.5 Hz), the concentration of which 98%

The following symmetric and asymmetric ester-amides methylenephosphonic acid can be obtained in a similar way.

From methyl/diethylamido/methylphosphonate /31P-NMR /CDCl3/: d3 4,56 memorial plaques/ and dimethylthiophosphate: P, P, P'-trimethyl-P'/diethylamido/methylenephosphonate /31P-NMR /CDCl3/: d, M. D. 23,89 /P/, 25,11 /P'/,2JPP5,4 Hz/.

From methyl-/diethylamido/methylphosphonate and Estepona /31P-NMR /CDCl3/: d, M. D. 26,69 /P/, 26,66 /P'/, 24,78 /24,91 /P/;2JPP= 7,7 /1,9 Hz/.

From isopropyl/diethylamido/methylphosphonate /31P-NMR /CDCl3/: d 27,67 memorial plaques/ and dimethylthiophosphate: P,P-dimethyl-P'-isopropyl-P'/diethylamido/methylenephosphonate/ 31P-NMR /CDCl3/: d, M. D. 22,10 /P/, 24,38 /P'/,2JPP= 5.8 Hz/.

From dimethylphosphate and ethylmethanesulfonate /31P-NMR /CDCl3/: d 14,16 M. D. /: P'-ethyl-P,P-dimethyl-P'-morpholinobutyrophenone /31P-NMR /CDCl3/: d, M. D. 21,43 /P/, 23,39 /P'/2JPP= 3,4 Hz/.

From methyl/dibutylamino/methylphosphonate /31P-NMR /CDCl3/: d 35,94 memorial plaques/ and dimethylthiophosphate: P, P,P'-trimethyl-P'/dibutylamino/methylenephosphonate /31P-NMR /CDCl3/: d, M. D. 24,11 /P/, 25,30 /P'/,2JPP= 6,1 Hz/.

From dimethylphosphate and ethyl/dioctylamine/chlorophosphate /31P-NMR /CDCl3/: d 17,23 M. D. /: P'-ethyl-P,P-dimethyl-P'-/dioctylamine/methylenephosphonate /31P-NMR /CDCl3/: d, M. D. 23,70 /P/, 24,39 /P'/,2JPP= 6,4 Hz/.

From bis/diethylamido/methylphosphonate /31P-NMR /CDCl3/: d, M. D. 34,63 / and ethyl/diethylamido/chlorophosphate /31P-NMR /CDCl3/: d 16,51 M. D./: P-ethyl-P, P, P'-Tris/diethylamido/methylenephosphonate /31P-NMR /CDClChlorophosphate /31P-NMR /CDCl3/: d 17,69 M. D./: P'-ethyl-P,P-dimethyl-P'-/benzylmethylamine/methylenephosphonate /31P-NMR /CDCl3/: d, M. D. 24,19 /P/, 24,29 /P'/,2JPP= 3.0 Hz/.

From diethylmalonate and ethylpiperidine /31P-NMR /CDCl3/. /: P,P,P'-triethyl-P'-piperazineethanesulfonic.

From dimethylmethylphosphonate and methyl/diallylamine/-chlorophosphate /31P-NMR /CDCl3/: d 16,18 M. D./: P,P,P'-trimethyl-P'/diallylamine/methylenephosphonate.

From dimethylmethylphosphonate and ethyl/N-methylpiperazine/chlorophosphate /31P-NMR /CDCl3/: d 14,84 M. D./: P'-ethyl-P,P-dimethyl-P'-/N-methylpiperazine/methylenephosphonate /31P-NMR /CDCl3/: d, M. D. 21,72 /P/, 23,92 /P'/,2JPP= 3,4 Hz.

Stage 2. 15.7 g (0.05 mol) of residue after evaporation P',P'-bis-diethylamide/P, P-dimethyl ester methylenephosphonic acid, obtained in stage 1, dissolved in 200 ml of CCl4and add 200 ml of 10% aqueous solution of NaOCl and 10 g of benzyltriethylammonium. The mixture is stirred for 45 min at room temperature (the reaction is monitored by NMR) and the organic phase is separated and washed with water and dried over Na2SO4and filtered. The filtrate is evaporated under vacuum, thanks Casanovas acid in the form of a slightly yellowish oil /31P-NMR /CDCl3/: d, M. D. 12,91 /P/, 25,31 /P'/,2JPP= 22.7 Hz/, the concentration of which 97%

The following symmetric and asymmetric ester-amides /dihlormetilen/-bisphosphonates acid can be obtained in a similar way.

Of P-ethyl-P'-methyl-P, P'-bis/diethylamido/methylenephosphonate: P-ethyl-P'-methyl-P, P'-bis/diethylamido//dihlormetilen/ a bisphosphonate /31P-NMR /CDCl3/: d, M. D. 16,39/16,48 /P/; 18,60/ 18,36 /P'/;2JPP= 20,5/17,9 Hz/.

Of P-ethyl-P, P', P'-Tris/diethylamido/methylenephosphonate: P-ethyl-P,P', P'-Tris/diethylamido//dihlormetilen/a bisphosphonate /31P-NMR /CDCl3/: d, M. D. 17,66 /P/, 26,54 /P'/,2JPP= 20.7 Hz.

Example 2. Tris/diethylamid/ /dihlormetilen/bisphosphonates acid and its piperidinium salt.

4.4 g (0.01 mol) of P,P',P'-three/diethylamide/ P-ethyl ether /dihlormetilen/bisphosphonates acid (example 1) in 22 ml of piperidine is stirred for 1 h at about 100oC and excess piperidine is evaporated in vacuum. The residue in 15 ml of anhydrous ether is stirred under cooling and the precipitate is filtered off and dried in air. The output is approximately 4.2 g (85% of theory) of colorless, crystalline piperidinium salt of Tris/diethylamide/ /dihlormetilen/bishops which the corresponding acid may be liberated by treatment with acid.

Using processing pyridine get the same way N-ethylpyridinium salt of Tris/diethylamide/ /dihlormetilen/-bisphosphonates acid /31P-NMR /CDCl3/: d, M. D. 10,23 /P/, 29,51 /P'/2JPP= 17,7 Hz/.

Example 3. P'-Ethyl ester P'-morpholino/dihlormetilen/bisphosphonates acid.

1.85 g (0,005 mol) P'-ethyl-P, P-dimethyl P'-morpholino-/dihlormetilen/-bisphosphonates acid (example 4) and 1.84 g (0.012 mol) of trimethylsilylpropyne in 30 ml of anhydrous CH2Cl2stirred at the boiling temperature under reflux for 30 min and evaporated under vacuum. The residue is dissolved in 30 ml of anhydrous methanol and stirred for 15 min at room temperature and evaporated under vacuum, thereby gain of about 1.7 g (80% of theory) P'-ethyl ester P' -morpholino/dihlormetilen/bisphosphonates acid /31P-NMR /CDCl3/: d, M. D. 8,29 /P/, 13; 39 /P'/,2JPP= 22,6 Hz/ in the form of a yellow oil with a concentration of >85%

Example 4. /Mono/diethylamid/dihlormetilen/bisphosphonates acid and its trinacria salt.

5.5 g (0.02 mol) of P'-Diethylamide P,P,P'-trimethylboron ether methylenephosphonic acid (example 1) when 0oC with stirring to a mixture containing 26 g NaH room temperature (the reaction course is monitored by NMR). The mixture is filtered and the filtrate is extracted with toluene. The combined toluene extracts are washed with 10% solution of NaHCO3and dried over Na2SO3and filtered. The filtrate is evaporated in vacuum and thereby gain approximately 5.8 g (85% of theory) P'-diethylamide P,P,P'-trimethylboron ether /dihlormetilen/-bisphosphonates acid /31P-NMR /CDCl3/: d, M. D. 12,02 /P/, 17,09 /P'/,2JPP= 1,4 Hz/ in the form of a colourless oil with a concentration of >97%

The residue after evaporation of hydrolyzing to/mono/diethylamide/dihlormetilen/bisphosphonates acid /31P-NMR /CDCl3/: d, memorial plaques 10.00 /P/, 13,90 /P'/,2JPP= 18.5 Hz/ through P'-diethylamid P,P,P'-trimethylsilyl ether /dihlormetilen/-bisphosphonates acid /31P-NMR /CDCl3/: d, M. D. 9,10 /P/, OF 5.29 /P'/,2JPP= 25,7 Hz/ described in example 1 with output of approximately 90%

The product can be converted into the corresponding chinatravel salt by treating an acetone solution of the material using 3 equivalents 5h. NaOH solution. Concentration trinational salt, crystallized from a mixture of water with methanol /31P-NMR /D2O/: d, M. D. 10,23 /P/, 15,72 /P'/,2JPP= 15.2 Hz/ more than 95%

Similarly, the following can be derived si is propyl-P'/diethylamido/-methylene/-bisphosphonates (example 1): P,P-dimethyl-P'-isopropyl-P'/diethylamido/-dihlormetilen/a bisphosphonate /31P-NMR /CDCl3/: d, M. D. 12,13 /P/, 13,50 /P'/,2JPP= 22,8 Hz/.

From P'-ethyl-P,P-dimethyl-P'-morpholinobutyrophenone (example 1): P'-ethyl-P, P-dimethyl-P'-morpholino/dihlormetilen/a bisphosphonate /31P-NMR /CDCl3/: d, M. D. 11,68 /P/, OF 12.26 /P'/;2JPP= 22,4 Hz/.

Of P,P,P'-trimethyl-P'/dibutylamino/methylenephosphonate (example 1): P,P, P'-trimethyl-P-/diethylamido//dihlormetilen-bisphosphonate /31P-NMR /CDCl3: d, M. D. 11,88 /P/, 16.78 IN /P'/,2JPP= 21,3 Hz/.

From P'-ethyl-P,P-dimethyl-P'-/dioctylamine/methylenephosphonate (example 1): P'-ethyl-P, P-dimethyl-P'-dioctylamine/ /dihlormetilen/-bisphosphonate /31P-NMR /CDCl3/: d, M. D. 11,93 /P/, BR15.15 /P'/,2JPP= 22,1 Hz/.

From P'-ethyl-P, P-dimethyl-P'-/benzylmethylamine/-methylene-bisphosphonates (example 1): P'-ethyl-P,P-dimethyl-P'-/benzylmethylamine/ /diethylethylene/-bisphosphonate /31P-NMR /CDCl3/: d, M. D. 11,70 /P/, 15,01 /P'/,2JPP= 23,0 Hz/.

From P'-ethyl-P, P-dimethyl-P'-/methylamide/methylenephosphonate (example 9): P'-ethyl-P, P-dimethyl-P'-/methylamide/-/dihlormetilen/-bisphosphonate /31P-NMR /CDCl3/: d, M. D. 13,26 /P/, 10,75 /P'/,2JPP= 23,0 Hz/.

Of P, P, P'-trimethyl-P'/butylamide/methylenephosphonate: P,P,P'-trimethyl-P'/butylamide//dihlormetilen/bi is metilen/-bisphosphonate.

Of P,P,P'-triethyl-P'/diallylamine/methylenephosphonate (example 1): P,P, P'-triethyl-P, diallylamine-/dihlormetilen/-bisphosphonate.

Example 5. Tetrakis/diethylamid/ /dihlormetilen/bisphosphonates acid.

To 10.0 g (0.04 mol) of tetrachlorinated methylenephosphonic acid (obtained from tetraisopropyldisiloxane and pentachloride phosphorus) in 60 ml of anhydrous toluene at a temperature below the 50oC for about 30 min type of 23.4 g (0.32 mol) of diethylamine in 40 ml of anhydrous toluene, and then the mixture is stirred for 1 h at about 50oC and the mixture is cooled and filtered. The filtrate is evaporated under vacuum and thereby gain about 12,6 g (80% of theory) of tetrakis/diethylamide/methylenephosphonic acid /31P-NMR /CDCl3/: d, M. D. 27,78 /in the form of a slightly yellowish oil with a concentration of more than 85%

The residue after evaporation (8.0 g 0.02 mol) glorious as described in example 1 (mixing 72 h at room temperature thereby gain of about 7.5 g (80% of theory) of tetrakis/diethylamide/ /dihlormetilen/bisphosphonates acid /31P-NMR /CDCl3/: d 26,29 memorial plaques) in the form of a slightly yellowish oil with a concentration of >90%

Similarly from tetrachlorinated my acid: Tetrakis/dioctylamine//dihlormetilen/a bisphosphonate /31P-NMR /CDCl3/: d, M. D. 26,50/ via tetrakis/dioctylamine/methylenephosphonate /31P-NMR /CDCl3/: d 28,00 M. D./.

Example 6. P-methyl ester P'-morpholino-/dihlormetilen/-bisphosphonates acid and its dimorpholino salt.

of 18.5 g (0.05 mol) of P'-ethyl-P, P-dimethyl P'-morpholino-/dihlormetilen/-bisphosphonates acid (example 4) in 70 ml of piperidine is stirred for 20 min at about 100oC and the mixture is evaporated in vacuum. The residue is stirred in anhydrous ether and the precipitate is filtered and washed with ether and dried to constant weight. The output is approximately 20 g (80% of theory) of colorless crystalline dipiperidino salt of P-methyl ester P'-morpholino/dihlormetilen/-bisphosphonates acid /31P-NMR /D2O/: d, M. D. 0,82 /P/, 9,70 /P'/,2JPP= to 15.4 Hz/ s concentration of >97% of which by acid treatment can release the corresponding free bisphosphonic acid /31P-NMR /CDCl3/./.

Similarly, you can obtain the following symmetric ether-amides /dihlormetilen/bisphosphonates acid:

Of P,P,P'-trimethyl-P'/diethylamido//dihlormetilen/-bisphosphonates (example 4): P-methyl-P'/diethylamido//dihlormetilen/-bisphosphonate (disorganizational//dihlormetilen/-bisphosphonates (example 4): P-methyl-P'/dibutylamino//dihlormetilen/-bisphosphonate (disodium salt,31P-NMR /D2O/: d, M. D. 11,16 /P/, 12,88 /P'/, 2JPP= 16.2 Hz/.

Of P,P,P'-trimethyl-P'-piperidino/dihlormetilen/-bisphosphonates (example 4): P-methyl-P'-piperidino/dihlormetilen/a bisphosphonate (piperidinium salt,31P-NMR /D2O/: d, M. D. 10,90 /P/, 10,41 /P'/,2JPP= 15.3 Hz/.

Of P,P,P'-triethyl-P'/diallylamine//dihlormetilen/-bisphosphonates (example 4): P-ethyl-P'/diallyl//dihlormetilen/-bisphosphonate (disodium salt,31P-NMR /D2O/: d, M. D. 9,98 /P/, 12,48 /P'/,2JPP= 15.6 Hz).

Of P, P, P'-trimethyl-P'/phenylamino//dihlormetilen/-bisphosphonates: P-methyl-P'/phenylamino/-/dihlormetilen/-bisphosphonate) denisonia salt,31P-NMR /D2O/: d, memorial plaques of 10.25 /P/, 6,60 /P'/,2JPP= 17.3 Hz).

Of P,P,P'-trimethyl-P'/phenylisopropylamine//dihlormetilen-bisphosphonates: P-methyl-P'/phenylisopropylamine//dihlormetilen/a bisphosphonate (bis-/N-isopropylaniline Sol/31P-NMR /D2O/: d, M. D. 10,38 /P/, 6,74 /P'/,2JPP= 17.3 Hz).

From P'-ethyl-P,P-dimethyl-P'-/benzylmethylamine//dihlormetilen/-bisphosphonates (example 4): P-methyl-P'/benzylmethylamine/-dihlormetilen/a bisphosphonate (piperidinium salt,31P-NMR /D2O/: d, M. D. 10,86 /P/, 12,20 /P'/,2JPP= to 15.4 Hz).

Of P, P, P'-trimethyl-B>2
O/: d, M. D. 8,15 /P/, OF 9.30 /P'/,2JPP= 20.2 Hz).

From P'-ethyl-P-methyl-P, P'-bis-/diethylamido//dihlormetilen/-bisphosphonates (example 1): P,P'-bis-/diethylamido//dihlormetilen/-bisphosphonate (disodium salt,31P-NMR /D2O/: d 13,94 memorial plaques). (alternate: example 1).

Example 7. P'-Diethylamid P'-isopropyl ether /dihlormetilen/-bisphosphonates acid and its disodium salt.

of 7.4 g (0.02 mol) of P'-Diethylamide P'-isopropyl-P,P-dimethyl ester /dihlormetilen/bisphosphonates acid (example 4) is dissolved in 120 ml of anhydrous CH3CN and under stirring and cooling add 5.6 ml (0.04 mol) of anhydrous triethylamine, as well as of 20.3 ml (0.16 mol) of chlorotrimethylsilane. The mixture is stirred at the boiling point under reflux for 5 h and evaporated in a vacuum and thereby gain approximately 9.7 g, (100% of theory) of almost colorless oil P'-diethylamide P'-isopropyl-P, P-bis-trimethylsilyl)/ether /dihlormetilen/bisphosphonates acid /31P-NMR /CDCl3/: d, M. D. 8,92 /P/, 14,51 /P'/,2JPP= 23,7 Hz/.

The residue after evaporation within 15 min stirred in 100 ml of anhydrous methanol and the mixture is evaporated in vacuum. The output is about 6.1 g (90% of theory) almost bestv the P-NMR /CDCl3/: d, memorial plaques of 8.37 /P/,15,42 /P'/;2JPP= 23,0 Hz/ s concentration of >97%, and which by treatment with sodium hydroxide can be converted to the corresponding disodium salt (31P-NMR/D2O/: d, M. D. 7,93 /P/; 12,89 /P'/,2JPP= 15.7 Hz).

Similarly can be obtained following a single ether-amide (dihlormetilen)-bisphosphonate acid.

From P'-ethyl-P, P-dimethyl-P'-/benzylmethylamine//dihlormetilen-bisphosphate through P'-ethyl-P, P-bis/(trimethylsilyl)/-P'/benzylmethylamine//dihlormetilen/- bisphosphonate: P'-ethyl-P'/benzylmethylamine//dihlormetilen/a bisphosphonate, which then can be converted to the corresponding disodium salt (31P-NMR /D2O/: d, M. D. 7,63 /P/, 23,86 /P'/,2JPP= 15.3 Hz).

Example 8. P, P-Bis(diethylamido)-P'-methyl-(dihlormetilen)-bisphosphonic acid and its tributylammonium salt.

7,66 g (0.02 mol) of P,P-bis(diethylamido)-P',P'-dimethyl(dihlormetilen)-bisphosphonates (example 1) and 3,71 g (0.02 mol) of anhydrous tributylamine dissolved in 20 ml of anhydrous chloroform. The solution is stirred at the boiling point under reflux for 4 h and the solvent is evaporated under vacuum and thereby gain approximately 11.1 g (98% of theory) methods pale yellow oil (31P-NMR /CDCl3/: d, memorial plaques to 27.88 (P), 6,17 (P'),2JPP= 17,2 Hz;3JPP= 10,2 Hz;3JPH= 9,0 Hz) with a concentration of 95%, and from which by treatment with acid may be released corresponding acid.

Example 9. P'-Benzylmethylamine P'-ethyl-P-methyl ester (dihlormetilen)bisphosphonates acid and its tributylammonium salt.

and 4.40 g (0.01 mol) of P'-Benzylmethylamine P'-ethyl-P,P-dimethyl ester (dihlormetilen)bisphosphonates acid (example 4) was dissolved in 20 ml of anhydrous chloroform, add 1.85 g (0.01 mol) of tributylamine and stirred at the boiling point under reflux for 4 hours (over the course of the reaction is monitored by NMR) and evaporated under vacuum. The output is approximately 5.8 g (100% of theory) tributylammonium salt P'-benzylmethylamine P'-ethyl-P-methyl ester (dihlormetilen)bisphosphonates acid in the form of oil (31P-NMR /CDCl3/: d, M. D. 4,94 (P), 18,77 (P'), 2JPP= 17,9 Hz) with a concentration of >97%, and which by the acid treatment can be converted to the corresponding acid.

Similarly can be obtained following a single ether-amide (dihlormetilen)bisphosphonates acid.

From P'-isopropyl-P,P-dimethyl-P'-(diety(dihlormetilen)bisphosphonates (free acid31P-NMR /CDCl3/: d, M. D. 8,53 (P), 15,18 (P'),2JPP= 21.1 Hz).

Example 10. (Mono)methylamide (dihlormetilen)bisphosphonates acid and its trinacria salt.

1.68 g (0,005 mol) P'-benzylmethylamine P'-ethyl-P,P-dimethyl ester methylenephosphonic acid (example 1) are dissolved in 16 ml of acetic acid and added 340 mg of 10% palladium-on-charcoal grill. The mixture hydronaut at room temperature for 2.5 h and the catalyst was removed by filtration. To the filtrate add fresh catalyst and the hydrogenation continued for 3 hours Add an additional 340 mg of fresh catalyst and 5 drops of water and hydronaut for 18 hours the Mixture is filtered and the filtrate is evaporated under vacuum and thereby gain of about 0.75 g (60% of theory) P'-methylamide P'-ethyl-P, P-dimethyl ester methylenephosphonic acid (31P-NMR /CDCl3/: d, M. D. 24,73 (P, 2,99 (P'),2JPP= 5,5 Hz) with a concentration of >90% was Obtained after evaporation the residue glorious to obtain P'-(mono)methylamide P'-ethyl-P,P-dimethyl ester (dihlormetilen)bisphosphonates acid (31P-NMR /CDCl3/: d, M. D. 10,75 (P), 13,26 (P'),2JPP= 23,0 Hz), according to the method of step 2 of example 1, then P,P,P'-ester groups hydrolyzing the education (mono)methylamide (dihlormetilen)bisphosphonates acid, according to the method of example 1. By treating an acetone solution of the product using three equivalents 5h. NaOH receive appropriate chinatravel salt in the form of a colorless crystalline product.

Example 11 (initial connection).

P'-Benzylmethylamine P'-ethyl-P, P-dimethyl ester (chlormethine)-bisphosphonate acid.

2.0 g (0,005 mol) P'-Benzylmethylamine P'-ethyl-P,P'-dimethyl ester dichlorodibenzofuran acid (example 4) in 20 ml of ethanol at 0oC, was added dropwise to a solution containing 2.4 g Na2SO3in 40 ml of water. After the addition the mixture is stirred for 40 minutes (over the course of the reaction is monitored by NMR). Upon termination of the reaction mixture is extracted with chloroform and the extract washed with water, dried over Na2SO4and filtered. The filtrate is evaporated in vacuum and thereby gain about 1.5 g (80% of theory) P'-benzylmethylamine P'-ethyl-P, P-dimethyl ester (chlormethine)bisphosphonates acid (31P-NMR /CDCl3/: d, M. D. 17,51/17,20 (P), OF 19.91/19,52 (P'), 2JPP= 6,7/10,5 Hz, a pair of diastereoisomers) in the form of almost colorless oil with a concentration of >90%

Similarly, the following can be derived, symmetric and nasimre)-bisphosphonates (example 4): P,P,P'-trimethyl-P'-(diethylamido)-(chlormethine)a bisphosphonate.

Of P,P-dimethyl P',P'-bis(diethylamido)(dihlormetilen)bisphosphonates (example 1): P,P-dimethyl P',P'-bis(diethylamido)-(chlormethine)a bisphosphonate.

Example 12. P,P'-bis(tert.-butyldiphenylsilyl)-P'-dibutylamino (dihlormetilen)-bisphosphonate acid.

1.85 g (0,005 mol) P'-Dibutylamino P-methyl ester (dihlormetilen)bisphosphonates acid (example 6) and 4.12 g (0.015 mol) of tert. -butyldiphenylsilyl in 30 ml of anhydrous CH3CN is stirred for 3 hours at the boiling temperature under reflux and the solvent is evaporated in vacuum. The output is about 4.0 g (100% of theory) P'-dibutylamino P, P'-bis(tert.-butyldiphenylsilyl)-P-methyl ester (dihlormetilen)bisphosphonates acid (31P-NMR /CDCl3/: d, M. D. 2,34/2,29 (P), 5,20/BR4.61 (P'),2JPP= 36,8/27.9 Hz, a pair of diastereomers) with a concentration of >85%

1.64 g (0.002 mol) of P'-Dibutylamino P,P'-bis(tert.-butyldiphenylsilyl)-P-methyl ester (dihlormetilen)bisphosphonates acid are dissolved in 15 ml of anhydrous CH3CN and added 240 mg (0,0029 mol) of chlorotrimethylsilane and 330 mg (0,0022 mol) of sodium iodide and the mixture is stirred for 1 h at room temperature and filtered. The filtrate is evaporated in vacuum and thereby gain of about 1.7 g (95% of theory) P'-d is(31P-NMR /CDCl3/: d, M. D. 7,17/7,73 (P), 7,46/7,44 (P'),2JPP= 28,9/31,3 Hz) in the form of a brownish-yellow solid residue with a concentration of >80%

The residue after evaporation is stirred for 15 min in 10 ml of anhydrous methanol and the solution is evaporated under vacuum. The residue is stirred in 20 ml of anhydrous ether and the mixture filtered. The filtrate is evaporated under vacuum and thereby gain about 1.2 g (95% of theory) of P,P'-bis(tert.-butyldiphenylsilyl)-P'-dibutylamine (dihlormetilen)bisphosphonates acid (31P-NMR /CDCl3/: d, M. D. 0,27/2,13 (P), 8,45/7,37 (P'),2JPP= 23,7/32,3 Hz, a pair of diastereoisomers) as a pale yellow solid residue with a concentration of >88%

Example 13 (receipt of the parent compounds).

P', P'-Tris(diethylamide) P-ethyl ester (dibromomethyl)bisphosphonates acid,

P, P', P'-Tris(diethylamide) P-ethyl ester (bromethalin)bisphosphonates acid and

P, P', P'-Tris(diethylamide) P-ethyl ester (bromchlormethane)-bisphosphonate acid.

In the sodium hypobromite solution, which was obtained by the addition of 8.4 g of bromine to 4,6 NaOH in 50 ml water, add to 7.4 g (0.02 mol) of P,P',P'-Tris(diethylamide) P-ethyl ester methylenephosphonic acid, to which was added 50 ml of toluene and 5.0 g betalghat within 24 hours at temperatures above 40oC. the Mixture is extracted with methylene chloride and the extract washed with water and dried over Na2SO4and filtered. The filtrate is evaporated under vacuum and thereby gain approximately 5.8 g (55% of theory) of P,P',P'-Tris(diethylamide)P-ethyl ester (dibromomethyl)-bisphosphonate acid (31P-NMR /CDCl3/: d, M. D. 16,95 (P), 25,01 (P'),2JPP= 16.6 Hz) with a concentration of >90%

Accordingly from P'-ethyl-P,P-dimethyl-P'-(benzylmethylamine)methylenephosphonate can be obtained P'-ethyl-P,P-dimethyl-P'-(benzylmethylamine)(dibromomethyl)bisphosphonate (31P-NMR /CDCl3/: d, M. D. 11,95 (P), 14,54 (P'),2JPP= 18,1 Hz).

To 4.9 g (0.01 mol) of P'-benzylmethylamine P'-ethyl-P,P-dimethyl ester (dibromomethyl)bisphosphonates acid see above) in 70 ml of absolute ethanol, with stirring and at 0oC, add 2.5 g ZnCl2H2O in 100 ml of water, after which stirring is continued for 15 min and the mixture is extracted with chloroform. The extract is dried over Na2SO4and filtered and the filtrate is evaporated in vacuum and thereby gain of about 2.9 g (70% of theory) P'-benzylmethyl-amide P'-ethyl-P, P-dimethyl ester (bromethalin)bisphosphonates acid (31P-NMR /CDCl3/: d, M. D. 17,29/17,21 (P), 19,76/19,21 (the C(diethylamido)(dibromomethyl)bisphosphonates can be obtained P-ethyl-P, P', P'-Tris(diethylamido) (bromethalin)bisphosphonate (31P-NMR /CDCl3/: d, M. D. 22,79/21,87 (P), 25,37/24,71 (P'), 2JPP= 2,7/a 10.1 Hz, a pair of diastereomers).

4.5 g (0.01 mol) of P,P',P'-Tris(diethylamide) P-ethyl ester (bromethalin)bisphosphonates acid mixed with 50 ml of toluene, to which was added 3 g of benzyltriethylammonium. The mixture is heated to 40-50oC and add 70 ml of 10% aqueous solution of NaOCl. The mixture is intensively stirred for 24 h at 40-50oC, after which the organic phase is separated and the aqueous phase is extracted with 2 times 50 ml of toluene. The combined toluene phases are washed with 2 times 10 ml saturated NaCl solution, dried over sodium sulfate and filtered. The filtrate is evaporated under vacuum and thereby gain of about 3.4 g (70% of theory) of P,P',P'-Tris(diethylamide) P-ethyl ester (bromchlormethane)bisphosphonates acid (31P-NMR /CDCl3/: d, M. D. 17,00/17,23 (P), 25,72/25,32 (P'),2JPP= 19,2/18,1 Hz, a pair of diastereomers).

1. Derivatives of amides methylenephosphonic acids of General formula

< / BR>
where W1, W2, W3and W4group OR1or the group NR2R3where R1hydrogen or C1- C8-alkyl, R2and R3hydrogen or C1- Sleep group W1W4the amino group NR2R3;

Q1and Q2independently from each other hydrogen or halogen,

or their pharmacologically acceptable salts.

2. Connection on p. 1 of formula I, representing R,R, R1-Tris(diethylamide) dichlorodibenzofuran acid, P-mono(diethylamide) R'-monoisopropyl ether dichlorodibenzofuran acid, P, P1bis(diethylamide) dichlorodibenzofuran acid, P,R1bis(diethylamide) dichlorodibenzofuran acid, mono(diethylamide) dichlorodibenzofuran acid.

3. The method of obtaining compounds of formula I on p. 1, characterized in that the compound of General formula I'

< / BR>
where Q1and Q2have the values listed in paragraph 1;

W1W4have the values listed in paragraph 1, with the exception of hydroxyl,

hydrolyzing at least one ester group OR1and/or aminogroup NR2R3to free hydroxyl groups.

4. The method of obtaining compounds of formula I on p. 1, characterized in that methylenephosphonic acid or its partial ester, which may be in chloranhydride form, the General formula I"

< / BR>
where Q1and Q2have snored, and the rest of the group R1have the values listed in paragraph 1,

at least one ester group OR' turn in the amide group, when the connection I have one hydroxyl group, in that case, if the connection I have more than one hydroxyl group, the free hydroxyl group lidiruyut using amine other2R3and/or ester group is transformed into an amide group with an incomplete amide or incomplete apyramid formula I having at least one hydroxyl and at least one amide group.

 

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-chloroethyl)vinylphosphonate" target="_blank">

The invention relates to the chemistry of organophosphorus compounds, specifically to methods for di-(-chloroethyl)vinylphosphonate (Vinnitsa) by dehydrochlorination di(-chloroethyl)--chloroethylphosphonic (isomerate) in the presence of a nucleophilic reagent by heating

The invention relates to 2-sharonlee - 4,5,6,7 - tetrahydro-2-sharinaletisha-phosphonates and-Phosphinates, inhibiting enzymatic activity; to compositions containing these compounds, their use and the treatment of disruptive disorders, and to methods for their preparation

The invention relates to new derivatives methylenephosphonic acid of General formula I

< / BR>
in which R1, R2, R3and R4independently are C1-C10the alkyl straight or branched chain, optionally unsaturated, C3-C10-cycloalkyl, optionally unsaturated, aryl, aralkyl, silicom SiR3or hydrogen, in formula I, at least one of the groups R1, R2, R3and R4is hydrogen and at least one of the groups R1, R2, R3and R4different from hydrogen

The invention relates to a technology for obtaining esters vinylphosphonic acid, which finds wide use as a reactive flame retardants and plasticizers in the production of various polymer materials

The invention relates to the chemistry of phosphorus - organic compounds, and in particular to a new method of obtaining S-triphenylcarbinol esters of dealkylation and tetrathiofulvalene acids of General formula (I)

(RX)SGePh3where R is lower alkyl; X Is 0, S

The invention relates to compounds of General formula (I):

,

where A is -(CH2)ngroup, and n includes the interval between 1 and 10, R is an acyl residue of a known anti-inflammatory compounds belonging to the class of salicylic, akriluksusnoy, arylpropionate, Anthranilic, 4,5-dihydroxy - or 4,5,8-trihydroxy-9,10-dihydro-9,10-dioxo-2-intracisternally and nicotinic acid

The invention relates to new derivatives methylenephosphonic acid of General formula I

< / BR>
in which R1, R2, R3and R4independently are C1-C10the alkyl straight or branched chain, optionally unsaturated, C3-C10-cycloalkyl, optionally unsaturated, aryl, aralkyl, silicom SiR3or hydrogen, in formula I, at least one of the groups R1, R2, R3and R4is hydrogen and at least one of the groups R1, R2, R3and R4different from hydrogen

The invention relates to a method for oksietilidendifosfonovaya acid formula

< / BR>
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

FIELD: organophosphorus compounds, medicine.

SUBSTANCE: invention relates to new biologically active phosphonate compounds. Invention describes phosphonate compound of the formula:

wherein R1 and R'1 represent independently hydrogen atom (-H) substituted possibly with -O-(C1-C24)-alkyl, -O-(C1-C24)-alkenyl, -O-(C1-C24)-acyl, -S-(C1-C24)-alkyl, -S-(C1-C24)-alkenyl or -S-(C1-C24)-acyl wherein at least one among R and R'1 doesn't represent -H and wherein indicated alkenyl or acyl comprise from 1 to 6 double bonds; R2 and R'2 represent independently -H substituted possibly with -O-(C1-C7)-alkyl, -O-(C1-C7)-alkenyl, -S-(C1-C7)-alkyl, -S-(C1-C7)-alkenyl, -O-(C1-C7)-acyl, -S-(C1-C7)-acyl, -N-(C1-C7)-acyl, -NH-(C1-C7)-alkyl, -N-((C1-C7)alkyl)2, oxo-group, halogen atom, -NH2, -OH or -SH; R3 represents phosphonate derivative of nucleoside or biphosphonate; X represents compound of the formula:

L represents a valence bond or a bifunctional binding molecule of the formula: -J-(CR2)t-G- wherein t is a whole number from 1 to 24; J and G represent independently -O-, -S-, -C(O)O- or -NH-; R represents -H, unsubstituted or substituted alkyl or alkenyl; m means a whole number from 0 to 6; n = 0 or 1. Also, invention describes pharmaceutical compositions comprising phosphonate compounds, method for treatment of osteoporosis in mammal, method for increasing mineral osseous density, method for prophylaxis of apoptosis of osteoblasts and osteocytes in mammal, method for treatment of viral infection in mammal, method for treatment of growing neoplasm in mammal and method for proliferation of cells. Invention provides preparing new compounds eliciting useful biological properties.

EFFECT: valuable medicinal properties of phosphonate compounds.

17 cl, 2 dwg, 7 tbl, 21 ex

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