Derivative guanidinate-1,1-bis-phosphonic acid, the retrieval method, the drug and its production method

 

(57) Abstract:

Derivative guanidinate-1,1-bisphosphonate acid in the form of the tautomers of the formulae Ia, IB or IB, where R1, R3, R4, R5, R6and R7is hydrogen, R2is hydrogen, benzimidazole, or a group-P(O)-(OR18)2; R18- C1-5alkyl; X is hydrogen, R8, R9, R10, R11- H, C1-5alkyl; l = 1-4, m = 0 or 1, n = 0-4 and the sum of the numbers l, m, n is 4 or less, except for the connection tetraethyl ester 1-[(amino-iminomethyl)] -methane-1,1-bis-phosphonic acid. The compounds of formula I are effective for the treatment and prevention of osteoporosis with minor side effects. 2 c. and 5 C.p. f-crystals, 1 PL.

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Osteoporosis is a common bone disease. Various forms of osteoporosis lead to severe bone loss, so in the end you lose mechanical stability of the bone. In healthy people the speed with which the formation of osteoclasts and osteoplasty, is developing so that bone formation and bone resorption is in equilibrium. In osteoporosis, the balance is disturbed, which leads to destruction of bones.

1. Maier (Phosphorus and Sulfur, 1981, 11, S. 311-322) describes nametil/-methane-1,1 - bis-phosphonic acid. No use for this intermediate product is not specified.

In the desire to obtain an effective compound for the treatment and prevention of osteoporosis with minor side effects now unexpectedly found that the proposed according to the invention guanidinate-1,1-bis-phosphonic acid reduces bone resorption.

The subject invention are derived guanidinate-1,1 - bis-phosphonic acid in the form of the tautomers of the formula Ia, IB, IC:

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where

R1means hydrogen;

R2means hydrogen or a group:

the benzimidazole;

where

R18- linear or branched C1- C5-alkyl;

R3is hydrogen;

R4is hydrogen;

R5is hydrogen;

X is hydrogen;

R6and R7is hydrogen;

R8, R9, R10, R11the same or different and independently of one another denote hydrogen, linear or branched C1- C5-alkyl;

l = 0 - 4; m = 0 or 1,

n = 0 to 4, and the sum of the numbers l, m, n equal to 4 or less

except for the connection: tetraethyl ester 1-//amino - imino-methyl/-amino/-methane-1,1-bis-phosphonic acid.

Predpochtitel the>, R7represent hydrogen, R8, R9, R10, R11are the same or different and independently of one another denote hydrogen, linear or branched C1-C4alkyl; 1 means 0-4; m is 0 or 1; n indicates 0-4 and the sum of the numbers l, m, n is 4 or less, except for the connection tetraethyl ester 1-//amino - iminomethyl/-amino/-methane-1,1-bis-phosphonic acid.

The most preferred compounds of formula Ia, IB, IB, in which R means a hydrogen atom;

R2means the group:

or benzimidazole;

R18means a linear or branched C1-C4-alkyl;

R3, R4, R5, R6and R7mean hydrogen;

R8, R9, R10, R11are the same or different and independently of one another denote hydrogen, linear or branched C1-C4-alkyl;

l is 0-3;

m denotes 0 or 1;

n means 0-3;

moreover, the sum of l, m, n equal to 4 or less.

Except for the connection tetraethyl ester 1-//amino - iminomethyl/-amino/-methane-1,1-bis-phosphonic acid.

The most interesting are compounds representing: tetraethyl ester 2-the Ino]-ethane-1,1-bis-phosphonic acid;

tetraethyl ester 2-[(benzimidazole-aminoiminomethyl)-amino]- ethane-1,1-bis-phosphonic acid;

2-[(benzimidazolinone)-amino]-ethane-1,1-bis-phosphonic acid,

4-[(aminoiminomethyl)-amino]-butane-1,1-bis-phosphonic acid.

Proposed according to the invention derived guanidinate - 1,1-bis-phosphonic acid in the form of the tautomers of the formula Ia, IB, IB under item 1, where R8and R9- independently from each other represent a linear or branched C1-C5-alkyl, R10and R11is identical or different independently of each other denote hydrogen, a linear or branched C1-C5-alkyl, the sum of the numbers l, m, n is 2, is produced by the interaction of the compounds of formula:

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where the values of R8-R11above, Y represents hydrogen, with a compound of formula IV or IV.

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where

Z - amino group;

R1, R2, R3above.

In the process it is preferable to use equimolar amount or up to three-fold excess components, if necessary in an inert solvent like dimethyl sulfoxide (DMSO), dimethylformamide (DMF), toluene, (C1-C4)alkanol, tetrahed is Ino in the presence of a solvent 25oC or corresponds to the boiling temperature of the solvent, in particular 70oC. the reaction Time is onset 6 to 48 hours, preferably 12-24 hours. The end of the reaction can be determined, for example, using thin-layer chromatography.

The invention also relates to drugs, inhibiting the release of calcium from bone tissue in the prevention and treatment of osteoporosis, which contain at least one compound of formulas Ia, IB, IC and/or at least one physiologically compatible salts of the compounds of formulas Ia, IB, IC or tetraethyl ester 1-//aminoiminomethyl/-amino/-methane-1,1-bis-phosphonic acid, together with physiologically acceptable auxiliary substances and carriers, diluents and/or other biologically active substances.

The invention relates further to the use of compounds of formula 1A, 1B or 1C and/or their physiologically compatible salts for the prevention and treatment of osteoporosis.

Proposed according to the invention medicines can be administered intravenously, intramuscularly, administered intraperitoneally, subcutaneously, intra-articular, periartikulyarno, rectally, topically, on the skin, through the nose or mouth.

Receive offer COGSA least one of the compounds of formula 1A, 1B or 1C and/or one of its physiologically acceptable salts together with auxiliary substances and/or receive media suitable for the reception of the form.

For oral forms of introduction can be applied such excipients as starch, for example potato, corn or wheat starch; cellulose, and its derivatives, respectively, in particular microcrystalline cellulose; silica; various sugars as lactose; magnesium carbonate and/or calcium phosphate. It is preferable to oral forms add auxiliary substances, which improve the compatibility of the components. For better compatibility, you can use capsules, insoluble in gastric juice. It may be preferable to add to the finished shape of a component of the combined drug, prolonging tool, if necessary in the form of permeable membranes, such as, for example based on cellulose or polystyrene resin or an ion exchanger.

The applied dosage proposed in the invention of the medicinal product depends on various factors, as a form of introduction, and the condition, weight, and severity of illness of the patient. Daily dose of approximately 5000 mg offer according to their dose, about 10-2500 mg. Introduction daily dose proposed in the invention medicines may be in the form of a unit dose, or as multiple small doses. Preferably the introduction of 3-8 doses per day.

The invention is explained in more examples. Percentage data refer to volume percent, unless nothing else.

Example 1: Getting diethylethanamine

9.6 g (100 mmol) of guanidine hydrochloride is treated with 8 g (200 mmol) of sodium hydroxide which is dissolved in 50 ml of water and 20 ml of ethanol and cooled to 0oC. Add a solution of 13.8 g (100 mmol) of diethylphosphate in 50 ml of carbon tetrachloride and stirred for 24 hours at 25oC. Then add 30 ml of water and extracted with methylene chloride (3 x 30 ml). The combined organic phases dried (K2CO3). After processing on a rotary evaporator to receive the oil which partially crystallizes. The crude product is recrystallized from 100 ml of acetic ether. Receive, after the extraction, the colorless product. Yield: 5.7 g (24% of theory). So pl.: 112-113oC.

Analysis: calculated % C = 30,6, H = 7.2 for N = 21,4

found, % C = 30,2, H = 6,9 N = 21,7

31P-NMR spectroscopy: (D2O) P = 8,54 M. D.

An example is hydroxide sodium, are dissolved in 50 ml of water and 20 ml of ethanol and cooled to 0oC. this was added dropwise over 15 minutes a solution of 16.2 g (834 mmol) isobutylacetate in 50 ml of carbon tetrachloride. Then remove the cooling and stirred for additional 4 hours at 25oC. the Organic phase is separated and obtaining the aqueous phase is extracted a further 2 times 50 ml floriforme. The combined extracts are dried over potassium carbonate. After processing on a rotary evaporator and drying gain of 18.3 g of crude product which is recrystallized from 180 ml of ethyl acetate. Output: 13.3 g (64,7%). So pl. 152-156oC.

Analysis: calculated % C 43,0 H 8,83 N 16,7

found, % 42,8 8,70 16,5

1H-NMR spectroscopy (CDCl3): 0,93 (D., 7.5 Hz, 12H, aliphatic)

1,90 (m t, 2H, aliphatic); the 3.65 (t, 7.5 Hz, aliphatic).

31P-NMR spectroscopy: (CDCl3): P = 7,87 M. D.

Example 3: Getting tetraethyl ester 2-//O - diisobutyrate//aminoiminomethyl/-amino/-ethano-1,1-bis-phosphonic acid

10 g (40 mmol) Diisobutylphthalate and 12.4 g (41 mmol) of tetraethyl ester vinylphosphonic acid are dissolved in 150 ml of THF. To this solution add 0.5 g of potassium carbonate and boiled for 8 hours. After the distillation and removal on a rotary is likehell. The solvent is acetic ether with 20% ethanol. Yield: 11.4 g (51% of theory).

Analysis: calculated, % 41,3 C H 8,0 N 7,6

found, % 41,1 8,0 7,4

1H-NMR spectroscopy (CDCl3): 0,95 (D., 7.5 Hz, 12 H, aliphatic);

1,34 (MP., 12H, aliphatic); 1,92 (MC., 2H, aliphatic); 3,45 (M. C. , 1H); 3,82 (etc, 2H); 3,74 (M. C., 4H); 4,10-to 4.28 (m, 8H, aliphatic).

31P-NMR-spectroscopy (CDCl3): P1= 9,11; P2= 21,94 M. D.

Example 4: Obtaining 2-phthaloyl-ethane-1-monoethylfumarate-1 - beatificante

30 g (146 mmol) of Phthaloylglycine, and 26.8 g (225 mmol) of thionyl chloride and 1 ml DMF are combined and with vigorous stirring for 4 hours, heated at 50-55oC. after the gas evolution of the excess thionyl chloride is removed under reduced pressure. To the resulting acid chloride acid are then slowly added dropwise to 49.9 g (300 mmol) of triethylphosphite, 41,4 g (296 mmol) of diethylphosphate and 2 g of triethylamine. By adding these components, the reaction temperature reaches 60-70oC. After the addition the reaction temperature is increased slowly to 115oC so that the emission is not interrupted. After reaching 115oC this temperature support the next hour and then flashing part of the LEM with acetic ether as solvent. You get a pure substance in the form of a light yellow oil. Output: 28.4 g (46,1% of theory).

Analysis: calculated % C 46,1 H 5,5 3,7 N

found, % 45,8 5,5 3,3

31P-NMR-spectroscopy (CDCl3): P1= - 0.58; P2=16,63 M. D.

Example 5: Obtain 2-amino-ethane-1-monoethylfumarate-1 - beatificante

8 g (19,1 mmol) 1-Phthaloyl-ethane-1-monoethylfumarate-1 - beatificante dissolved in 50 ml of ethanol and mix at 1.34 g (21,4 mmol) of hydrazine hydrate is added and boiled for hours. After removal of the solvent remains colorless residue. It rubbed at 0oC in 35 ml of 5 n acetic acid and the resulting precipitate was separated. The filtrate at 0oC alkalinized with 2 n sodium hydroxide solution to pH 7 and extracted 3 times with 60 ml of methylene chloride. In the aqueous phase set pH 9 and again extracted with 2 times 50 ml of methylene chloride. The extracts are combined and washed 3 times with 80 ml of 10% aqueous solution of sodium chloride. Then the organic phase is dried over magnesium sulfate, filtered and treated on a rotary evaporator. The crude product is purified on a column of silica gel using ethanol as solvent. You get the product as a pale yellow oil. Yield: 3.4 g (61.8% of theory).

Example 6: Getting 2-//aminoiminomethyl/-amino-ethane-1,1 - bis-phosphonic acid

1 g (1.8 mmol) of Tetraethyl ester 2-/O-diisobutyrate/- -/aminoiminomethyl/-amino/-etano/-ethane-1,1-bis-phosphonic acid in 20 ml of concentrated hydrochloric acid is refluxed for 5 hours. At the same time ethanol, which is formed, Argonauts. Then remove excess hydrochloric acid. The remaining oil was stirred in 30 ml of acetone with 10% methanol and removed by decantation. After it is boiled with 20 ml of methanol (10% water) and left to stand for 24 hours for crystallization. Colorless crystals are sucked off and dried. Yield: 0.35 g (79.5% of theory). So pl. 230oC (decomposition).

Analysis: calculated % C 14,6 H 4.5 N 17,0

found, % 14,3 4,8 17,4

1H-NMR spectroscopy (D2O): 1,92 (T. T., 1H); 3,54 (etc, 2H).

31P-NMR spectroscopy: (NaOD): P1= 18,88 M. D.

Example 7: Obtain 4-//aminoiminomethyl/amino/butane-1,1 - bis-phosphonic acid

The solution to 0.69 g (2 mmol) tetraethyl ester 4-aminobutane-1,1 - bis-phosphonic acid (according to the patent Germany 3 225 469 AI, 05.01.1984 and 0,402 g (2 mmol) of nitrate 3,5-dimethylpyrazol-1 carboxamidine in 10 ml of DMF is boiled in the tech acetic ether (organic extracts drop) the aqueous phase is distilled in vacuum. Remains dark oil (0,89 g). It to the boil for 8 hours in 15 ml of concentrated hydrochloric acid. Excess hydrochloric acid is distilled off and the residue is mixed with a small amount of water, DMF and acetone. The precipitate is sucked off and dried in vacuum.

Yield: 137 mg So pl. 190-195oC. Mass spectroscopy: m/z = M + H = 274.

Example 8: Getting tetraethyl ester 2-/4-triptorelin/- Penilaian-1,1-bis-phosphonic acid

50 ml of Absolute tetrahydrofuran is cooled to -10oC and slowly added dropwise it 7,42 g (39 mmol) of titanium tetrachloride, this type 2,84 (16.3 mol) of p-triftorbyenzola and 5.63 g (a 19.6 mmol) tetraethyl ester metadatastorage acid and leave the reaction temperature to rise to 0oC. the reaction mixture was added dropwise to 7.75 g (to 76.6 mmol) of triethylamine, and the temperature does not exceed 5oC. the mixture is Then stirred for 3 hours at room temperature and then add 100 ml of ice water. The resulting mixture was extracted with diethyl ether (CH ml). The combined ether extracts washed with water until, until you get a neutral extract. Then the ether phase is washed with a saturated solution of sodium chloride and dried over sulfate NAT (34,7% of theory).

Analysis: calculated % C 45,9 H 5,6

found, % 46,4 5,3

1H-NMR spetroscopy (CDCl3): 1,14 was 1.43 (m, 12H); 3,94-4,32 (m, 8H); to 7.64-to 7.84 (m,4H, aromatic); 8,18-to 8.45 (m, 1H, aliphatic).

Example 9: Getting tetraethyl ester N,N-dibenzylamino-1,1-bis-phosphonic acid

197,3 g (1 mmol) Dibenzylamine and 171,9 g (of 1.16 mol) rotatelog ester of formic acid and 290 g (2.1 mol) of diethylphosphate for 3 hours, heated at 150oC with simultaneous distillation of ethanol. Then flashing part is removed in a high vacuum (approximately 10-3Torr) and the crude product is purified on a column of silica gel with acetic ether as solvent. Get 197 g of crude product. 60 g of purified on a column of silica gel with acetic ether as solvent, and get a pure substance in the form of a light yellow oil. Output: 20,8 g (40,7% of theory).

Analysis: calculated % C 57,1 H 7,3 2,9 N

found, % 57,4 7,4 3,2

Example 10: Getting tetraethyl ester 1-aminomethane-1,1 - bis-phosphonic acid

17.1 g (of 35.4 mmol) Tetraethyl ester N,N-dibenzylamino - 1,1-bis-phosphonic acid are dissolved in 170 ml of ethanol and added 3.4 g of 5% Pd/C. the Hydrogenation is carried out at normal pressure. On the second pressure and room temperature (duration of reaction approximately 16 hours). Then the catalyst is filtered off and sucked off. After removal of the solvent gain of 10.9 g of crude product. Cleaning is carried out through a column of silica gel using ethanol as solvent. The output of 9.9 g (92,5% of theory).

Analysis: calculated % C 35,7 H 7,7 4,6 N

found, % 35,3 8,1 4,5

31P-NMR-spectroscopy (CDCl3): P = 20,48 M. D.

Example 11: Obtain O-diisobutyrate-S-ethyl - estimacion

of 18.5 g (0.1 mol) of Hydrobromide S-utilizationfocused dissolved in 50 ml of water, 20 ml of ethanol and 8 g (0.2 mol) of sodium hydroxide and cooled to 0oC. for 10 minutes was added dropwise a solution of 19.4 g (0.1 mol) of diisobutylamine in 50 ml of carbon tetrachloride. Then remove the cooling and conduct the reaction at room temperature and stirred for further 4 hours. After separation of the organic phase the aqueous phase is again extracted with 2 times 100 ml of chloroform, dried over potassium carbonate, filtered and treated on a rotary evaporator. Receive 0,0-diisobutyrate-S-ethyl-estimacion in the form of an orange oil. Output: 24,9 g (84,1% of theory).

Analysis: calculated:% C 44,5 H 8,5 9,5 N

Found:% 44,8 8,1 9,3

31P-NMR spectroscopy: (CDCl3): P = 4,29 M. D.


4 g (to 13.8 mmol) 2-Amino-ethane-1-monoethylfumarate-1-bis - ethylphosphonate and 4.15 g (14 mmol) of 0,0-diisobutyrate-S-ethyl - estimacion dissolved in 40 ml of DMF and boil. After 6 hours, remove DMF and get the crude mixture is treated further as described in example 3, and enter into interaction next. Output: 1.8V,

31P-NMR spectroscopy: (NaOD): P = 18,9 M. D.

Example 13: Synthesis of tetraethyl ester 4-bis-/1,1 - dimethylethoxysilane/-aminoiminomethyl/-amino/-butane-1,1 - bis-phosphonic acid

The prestage of tetraethyl ester 4-aminobutane-1,1-bis-fosforos acid obtained as described in the patent Germany 3255469 A1, N,N-bis-/1,1-Dimethylethoxysilane/-S-methylisothiazoline receive as described in the literature K. Niwak, Roczniki, Chem. Ber. 43, (1), 23, 1969.

A solution of 1.8 g (6.2 mmol) of N,N-bis-/1,1-dimethylethoxysilane/-S-methylisothiazoline and 4.4 g (12.7 mmol) of tetraethyl ester 4-aminobutane-1,1-bis-phosphonic acid in 50 ml of THF is heated at 40oC for 2 days. Then the organic phase is washed with saturated NaCl solution, dried over magnesium sulfate and the THF removed under reduced pressure. The resulting crude product chromatografic on Florisil (60-100 mesh). The solvent comprises methylene chloride with methanol = 98:2. ): = 3300, 3285 (=C-NH); 1722, 1636 (C=O); 1617 (C=N) cm-1< / BR>
1H-NMR spectroscopy (CDCl3): of 1.34 (t, 12H, OCH2CH3); 1,49 (C., 18H, CH3); 1,8-2,1 (m, 4H, N-CH2CH2CH2CH); 2,33 (TT, P-CH-P); of 3.45 (m, 2H, N-CH2); 4,19 (m, 8H, OCH2CH3).

Example 14. Synthesis of 4-/aminoiminomethyl/amino/-butane-1,1 - bis-phosphonic acid

A solution of 0.92 g (2.56 mmol) of tetraethyl ester 4-/bis-/1,1-dimethylethoxysilane/-aminoiminomethyl/-amino/- butane-1,1-bis-phosphonic acid in 15 ml of concentrated hydrochloric acid is boiled for 12 hours. After concentration the residue is mixed with ethanol. The precipitate is sucked off under reduced pressure and dried under reduced pressure. Recrystallization is carried out from a mixture of ethanol with water. Yield: 115 mg So pl. 260oC.

Analysis: calculated,%: C 21,8 H 5,5 N 15,3 22,4

found,% 22,0 5,6 14,9 22,5

1H-NMR spectroscopy (D2O) NaOD): 1,60 (t, 1H, P-CH-P); to 1.79 (m, 4H, CH2CH2); the 3.11 (m, 2H, N-CH2).

Mass spectroscopy: m/z = M + H++= 276

Example 15. Synthesis of tetraethyl ester 2-//benzimidazolinone/-amino-ethane-1,1-bis-phosphonic acid

2.0 g (11,4 mmol) Svejeprigotovlennogo benzimidazolidinone together with 3.4 g of tetraethyl ester utilize the m supplements diethyl ether to the resulting oil is obtained target product in the form of colorless powder. Output: 4,9, So pl. 143oC.

Analysis: calculated% C got 45.47 H 6,57 N 3,10

found,% 45,1 5,9 3,2

1H-NMR spectroscopy: (CDCl3) TMS: 1,11-of 1.29 (m, 12H, OCH2CH3); 3.75 to 3,93 (TT, 1H, Metin-H); 3,96-4,11 (m, 8H, OCH2CH3); 4,50-br4.61 (m, 2H, -CH2-); 7,00-7,11 (2H, aromatic H); 7.18 in-7,29 (m, 1H, aromatic H); of 7.36-the 7.43 (m, 1H, aromatic H).

31P-NMR-spectroscopy (CDCl3): 21,43 M. D.

Example 16: Synthesis of 2-//benzimidazolinone/-amino-ethane - 1,1-bis-phosphonic acid

1 g (2.1 mmol) of product from example 15 in the course of 4.5 hours is refluxed with 20 ml of concentrated hydrochloric acid. After removal of excess hydrochloric acid in vacuo, the obtained viscous oil is recrystallized from water. Get the target compound in the form of colorless powder. Yield: 250 mg So pl. above 230oC.

Analysis: calculated% C 33,07 H 4,16 N 19,28

found,% 32,8 19,5 3,9

1H-NMR spectroscopy: (D2O) NaOD = 2,63-2,83 (TT, 1H, Metin-H); 4,43-4,63 (m , 2H, -CH2-); 7,00-to 7.09 (2H, aromatic H); 7,33-7,47 (m, 1H, aromatic H); EUR 7.57-of 7.70 (1H, aromatic H).

31H-NMR spectroscopy (D2O/NaOD): 18,55 M. D.

The activity proposed in the invention compounds detected in Viti embryonic rats, who are the age of 20 days. Bones mark the fact that pregnant rats inyeccion 200 Kiu/kg45CaCl2for 2 days before the opening of the cranial membranes of the fruit.

1. Cultivation bones

Cranial shell of the fruit is divided into two halves. One half of the skull shell serves as a control, the other half is incubated with proposed according to the invention compounds.

Each half of the skull is cultivated in a sterile plastic Cup. Media for cultivation (BGJb-medium, Gibco) containing 1 ml of 10% fetal calf serum, penicillin-streptomycin (10000 u/l, Gibco) and ascorbic acid (50 mg/l). Half skull incubated at 37oC, in a gas atmosphere of 5% CO2and 95% oxygen. After 48 hours the medium for cultivation replace fresh, add proposed in the invention compounds and parathroid hormone (10-7M) and incubated for 48 hours. Control add parathyroid hormone (10-7M, Sigma). At the end of the experiment is determined by the activity45Ca in culture medium and in the bones. The results tables show the inhibition highlight 45Ca in the culture medium in percent. The results represent the average of 3-5 former is 200 g starch are thoroughly mixed and moistened with a solution of 5 g sodium dodecyl sulfate and 10 g polyvinylpyrrolidone approximately 200 ml of water. The wet mixture is sieved, dried, and sift again. Add 100 g microcrystalline cellulose and 15 g hydrogenated vegetable oil. All mixed and pressed into tablets, receiving 10,000 tablets each containing 10 mg of active ingredient.

Example 18: Preparation of capsules

20 g of the active ingredient, 6 g of lauryl sodium, 56 g of starch, 56 g of lactose, 0.8 g of silicon dioxide, and 1.2 g of magnesium stearate are mixed with each other. The mixture then fill 1000 suitable hard gelatin capsules, each containing 20 mg of active ingredient.

The dosage depends on various factors, for example, the form of the introduction of money, status, weight, and severity of illness of the patient. For people weighing 70 kg, the preferred daily dose of about 10-2500 mg

1. Derivative guanidinate-1,1-bisphosphonate acid formulas in the form of tautomers 1A, 1B or 1C:

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where R1is hydrogen;

R2is hydrogen or the group:

the benzimidazole, where R18means a linear or branched C1- C5-alkyl;

R3is hydrogen;

R4is hydrogen;

R5is hydrogen;

X is hydrogen;

R61- C5-alkyl;

l = 0 - 4;

m = 0 or 1;

n = 0 - 4,

moreover, the sum of the numbers l, m, n is 4 or less, except for the connection: tetraethyl ester 1-//amino-iminomethyl/-amino/-methane-1,1-bisphosphonate acid.

2. Connection on p. 1 of formula 1A, 1B or 1C, in which R1, R2, R3, R4, R5, R6and R7represent hydrogen, R8, R9, R10, R11are the same or different and independently of one another denote hydrogen, linear or branched C1- C4-alkyl; l = 0 - 4;

m = 0 or 1;

n = 0 - 4,

moreover, the sum of the numbers l, m, n is 4 or less, except for the connection: tetraethyl ester 1-[(amino-iminomethyl)-amino]-methane-1,1-bisphosphonate acid.

3. Connection on p. 1 of formula 1A, 1B, 1C, in which R1means a hydrogen atom; R2mean group

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or benzimidazole; R18means a linear or branched C1- C4-alkyl; R3, R4, R5, R6and R7mean hydrogen; R8, R9, R10, R11are the same or different and independently of one another denote hydrogen, linear or branched C1- C4

4. Connection on p. 1, representing tetraethyl ester 2-[0,0-diisobutyrate)-(aminoiminomethyl)-amino] - ethane-1,1-bisphosphonate acid; 2- [(aminoiminomethyl)-amino] - ethane-1,1-bisphosphonic acid, tetraethyl ester 2-[(benzimidazole-aminoiminomethyl)-amino] -ethane-1,1-bisphosphonate acid; 2-[(benzimidazolinone)-amino]-ethane-1,1-bisphosphonic acid, 4-[(aminoiminomethyl)-amino] - butane-1,1-bisphosphonic acid,

5. The method of obtaining derivatives guanidin-alkyl-1,1-bisphosphonate acid in the form of the tautomers of the formula 1A, 1B, 1C under item 1, where R8and R9independently of one another represent linear or branched C1- C5alkyl; R10, R11the same or different and independently of one another denote hydrogen, linear or branched C1- C5-alkyl, the sum of the numbers l, m, n equal to 2, characterized in that the compound of the formula:

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where the values of R8- R11above, Y represents hydrogen, is subjected to the interaction with the compound of the formula IVa or IV:

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where z is an amino group;

R1, R2, R3listed in paragraph 1.

6. Drug, inhibiting the release of calcium from bone tissue in the prevention and treatment of EMule 1A, 1B or 1B PP.1 - 4 or tetraethyl ester 1-[(amino-iminomethyl)-amino] -methane-1,1-bisphosphonate acid together with physiologically acceptable auxiliary substances and carriers.

7. The method of obtaining drugs under item 6, characterized in that at least one compound of formula 1A, 1B or 1C add physiologically acceptable excipients and carriers, if necessary, other additives and/or biologically active substances.

Priority points and features:

12.12.91 on PP.1 - 7, in addition to R2-benzimidazole;

09.04.92 on PP. 1 to 7, where R2the benzimidazole.

 

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

The invention relates to a derivative of guanidine-1,1-bis phosphonic acid, method for their production and to their use
The invention relates to the field of chemistry of organophosphorus compounds, in particular, to methods for producing uranyl trinational the salt postemergency acid, used in medicine and cosmetics as an anti-virus drug

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 containing these new compounds

The invention relates to new nitrogen-containing chemical compounds which possess valuable biological properties, in particular to new derivatives of amidine, which may constitute the active principle of the pharmaceutical composition having an antagonistic action on leukotriene4
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